Coagulopatias Hereditárias em Odotonlogia

UNIVERSIDADE FEDERAL DE PELOTAS
Faculdade de Odontologia
Programa de Pós-Graduação em Odontologia
Tese
Coagulopatias Hereditárias em Odontologia:

Uma análise da evidência científica e geração de conhecimento para
aplicação na prática clínica
Mateus de Azevedo Kinalski
Pelotas, 2021

Uma análise da evidência científica e geração de conhecimento para aplicação na
prática clínica
Tese apresentada ao Programa de Pós-

Graduação em Odontologia da Universidade
Federal de Pelotas, como requisito parcial à
obtenção do título de Doutor em Odontologia,
área de concentração Clinica Odontológica
(Prótese dentária)
Orientador: Prof. Dr. Mateus Bertolini Fernandes dos Santos
Pelotas, 2021

Uma análise da evidência científica e geração de conhecimento para aplicação na
prática clínica
Tese aprovada, como requisito parcial, para obtenção do grau de Doutor em

Odontologia, Programa de Pós-Graduação em Odontologia, Universidade Federal
de Pelotas.
Data da Defesa: 24/09/2021
Banca examinadora:
Prof. Dr. Mateus Bertolini Fernandes dos Santos (Orientador)

Doutor em Clínica Odontológica (Prótese Dentária) pela Universidade Estadual de
Campinas
Prof. Dr. Rafael Ratto de Moraes (Titular interno)

Doutor em Materiais Dentários pela Universidade Estadual de Campinas
Prof. Dr. Gabriel Kalil Rocha Pereira (Titular externo)

Doutor em Prótese Dentária pela Universidade Federal de Santa Maria
Prof. Dr. Andre Webber Rosa (Titular externo)

Doutor em Implantodontia pela São Leopoldo Mandic
Prof. Dr. Lucas Pradebon Brondani (Suplente externo)

Doutor em Clínica Odontológica (Prótese Dentária) pela Universidade Federal de
Pelotas
Prof. Dr. Cesar Dalmolin Bergoli (Suplente interno)

Doutor em Odontologia (Odontologia Restauradora) pela Universidade Estadual
Paulista Júlio de Mesquita Filho
Dedico este trabalho aos meus pais
pelo incentivo, amor e carinho.
Agradecimentos
À Universidade Federal de Pelotas, em nome da Excelentissima Prof. Dra. Isabela
Fernandes Andrade.
À Faculdade de Odontologia, em nome da direção e de seus funcionários,
instituição que me acolheu por cerca de 10 anos e possibilitou minha formação integral.
Instuição a qual vesti a camiseta e sentirei orgulho de me considerar egresso durante
toda a minha trajetória de vida.
Ao Programa de Pós-Graduação em Odontologia, aos coordenadores Prof. Dr.
Rafael Ratto de Moraes, Profa. Dra. Tatiana Pereira Cenci e Prof. Dra. Giana Silveira
Lima.
Ao Hemocentro Regional de Pelotas, em nome de sua equipe, pelo suporte
oferecido e por acreditar no nosso projeto, visando as melhorias das condições de saúde
bucal de todos os seus pacientes.
Ao meu orientador, Mateus Bertolini Fernandes dos Santos. De um encontro na
SBPqO há alguns anos que, antes mesmo de se tornar orientador, se tornou amigo.
Algumas linhas não seriam suficientes para descrever tudo o que aprendi nesses anos
de convivência. Meu mentor, minha inspiração, meu conselheiro e o irmão que eu jamais
tive. Agradeço imensamente ter tido a possibilidade de dividir contigo (bons e maus)
momentos. Dos almoços frios na sala 502, aos churrascos, finais de semana na praia,
discussões acaloradas e infinitas risadas. Que a tua integridade, a tua verdade e o teu
caratér sejam sempre fruto de inspiração para as pessoas que estão ao teu redor. Muito
obrigado por tudo!

Aos meus pais, pelos ensinamentos de valores, princípios e educação,
imprescindíveis nesta caminhada. Agradeço-lhes por demonstrar que é sempre possível
e, que por mais difícil que seja a jornada, sempre valerá a pena seguir adiante. A vocês,
meu eterno amor e gratidão. A minha irmã, minha primeira amiga e maior conexão que
possuo nesse universo. A minha familia, por acreditarem e compreenderem a ausência
por todos esses anos. A minha namorada Laura, pelo carinho, companheirismo e todo
amor depositado em mim.
Aos meus mestres, agradeço por toda a dedicação ao ensinar e confiança
depositada em mim. Um bom aluno é sempre fruto de um bom educador.
Aos meus amigos, que estiveram ao meu lado compartilhando alegrias, tristezas,
vitorias e derrotas, estimulando a buscar sempre algo a mais, ensinando-me que a vida
não é, apenas, formalidade.

“Strive not to be a success,
but rather to be of value.”
Albert Einstein
Notas Preliminares
A presente dissertação foi redigida segundo o Manual de Normas para

Dissertações, Teses e Trabalhos Científicos da Universidade Federal de Pelotas de
2013, adotando o Nível de Descrição 4 – estrutura em Artigos, descrita no Apêndice D
do referido manual. <http://sisbi.ufpel.edu.br/?p=documentos&i=7> Acesso em:
11/08/2021.
O projeto de pesquisa contido foi apresentado através de sua qualificação
realizada em 11 de Março de 2020 e aprovado pela Banca Examinadora composta pelos
Professores Doutores Mateus Bertolini Fernandes dos Santos (orientador), Prof. Dr.
Marcos Antônio Torriani e Prof. Dra. Ana Paula Neutzling Gomes.
Resumo
KINALSKI, Mateus de Azevedo. Coagulopatias Hereditárias em Odontologia: Uma

análise da evidência científica e geração de conhecimento para aplicação na
prática clínica. 2021. 198f. Tese (Doutorado em Odontologia). Programa de Pós
Graduação em Odontologia. Universidade Federal de Pelotas, Pelotas, 2021.
O objetivo dessa tese foi avaliar a evidência científica em pacientes com Coagulopatias
Hereditárias e sua relação com a Odontologia. As coagulopatias hereditárias são um
conjunto de condições que podem ser causadas por deficiência quantitativa e/ou
qualitativa de fatores de coagulação, sendo as principais a Hemofilia A, Hemofilia B e
doença de von Willebrand. No entanto, há uma lacuna quanto as condições orais,
tratamentos e particularidades em relação aos individuos com coagulopatias hereditárias
em Odontologia. Assim, essa tese apresenta relatos de caso clínico, um estudo clínico
sobre o uso de implantes dentários, revisões de escopo sobre endodontia e cirurgia oral
e uma meta-analise sobre a experiência de cárie comparando individuos com
coagulopatias hereditárias e indivíduos saudáveis. Com isso, a meta dessa tese foi gerar
conhecimento e contribuir para a evidência científica sobre essa temática, a fim de
reduzir as possíveis complicações pós-operatórias apos procedimentos odontológicos
em pacientes com coagulopatias hereditárias.
Palavras-chave: Coagulopatias hereditárias; Hemofilia A; Hemofilia B; Doença de von

Willebrand; Odontologia
Abstract
KINALSKI, Mateus de Azevedo. Inherited bleeding disorders: An analysis of the

scientific evidence and knowledge for the clinical application. 2021. 198p. Ph.D.
project (Ph.D. in Dentistry). Graduate Program in Dentistry. Federal University of Pelotas,
Pelotas, 2021.
This Ph.D. thesis aimed to analyze the scientific evidence considering patients with
Inherited Bleeding Disorders and dental procedures. Inherited bleeding disorders (IBDs)
are a heterogeneous group of genetic conditions in which missing or defective clotting
factors prevent normal blood clotting from occurring, been Hemophilia A, Hemophilia B,
and von Willebrand´s disease the most prevalent. However, the literature is still scarce
about the oral health conditions, type of treatment, and particularities regarding these
subjects and dentistry. This study presents case reports, one clinical study about the use
of dental implants, two scoping reviews (endodontics and oral surgery), and a meta-
analysis comparing the caries experience between IBDs and healthy subjects. Thus, the
goal of this Ph.D. thesis was to generate evidence, contributing to the scientific field,
aiming to reduce postoperative complications after dental procedures in patients with
inherited bleeding disorders.
Key-words: Inherited bleeding disorders; Hemophilia A; Hemophilia B; von Willebrand´s

disease; Dentistry
Sumário
Introdução............................................................................................................................... 13
Objetivos ................................................................................................................................. 22
Hipótese .................................................................................................................................. 22
Projeto de pesquisa .............................................................................................................. 23
Relatório do trabalho de campo ............................................................................................ 1
Artigo 1 – Is there a difference in the oral health status of healthy patients and those
with inherited bleeding disorders? A systematic review and meta-analysis of case-
control studies .......................................................................................................................... 3
Artigo 2 - Inherited bleeding disorders in oral procedures. Assessment of prophylactic
and therapeutic protocols: a scoping review ....................................................................... 3
Artigo 3 - Endodontic therapy in patients with inherited bleeding disorders: a scoping
review ...................................................................................................................................... 44
Artigo 4 - Are dental implants a feasible technique to replace tooth loss in patients with
inherited bleeding disorders? A clinical comparative study with 1-year of follow-up . 61
Artigo 5 - Dental implant therapy on a patient with von Willebrand’s disease: A case
report of 2-years of follow-up............................................................................................... 86
Artigo 6 - Delayed bleeding in a hemophilic patient after sinus floor elevation and
multiple implant placements: A case report .................................................................... 101
Artigo 7 - One-year follow-up of endodontic retreatment in a patient with severe
Hemophilia A: a case report .............................................................................................. 118
Considerações Finais ......................................................................................................... 133
Referências .......................................................................................................................... 137
Introdução
Definição das Coagulopatias Hereditárias

A coagulação sanguínea constitui uma importante defesa do organismo contra o
sangramento. O processo da coagulação corresponde a uma regulada cascata que visa
a formação de um coágulo sanguíneo. A enzima chave relacionada ao processo de
coagulação é denominada trombina, tendo entre suas ações principais a ativação
plaquetária, a conversão de fibrinogênio na rede de fibrina e a ampliação da resposta a
coagulação (Dahlbäck 2000). A atuação dessa enzima se dá após a lesão tecidual que
ocasiona a ativação de sua precursora, protrombina, iniciando a primeira etapa da
formação do coágulo (Krishnaswamy 2013).
As coagulopatias hereditárias são um conjunto de condições que podem ser
causadas por deficiência quantitativa e/ou qualitativa de fatores de coagulação (Antunes,
Thomas et al. 2005). Considerando as hemofilias, os homens são o sexo mais afetado,
ocorrendo devido mutações causais localizadas no cromossomo X, resultado de padrão
hereditário recessivo (Berntorp and Shapiro 2012). Entre as principais coagulopatias
hereditárias, as hemofilias A e B e a doença de von Willebrand correspondem por 95 a
97% dos casos de coagulopatias hereditárias (Mannucci, Duga et al. 2004). Ademais,
condições conhecidas como coagulopatias raras hereditárias correspondem ao restante,
tendo sua incidência associada a 1 a cada 2 milhões de habitantes (MS 2015).
O principal sintoma relacionado as coagulopatias hereditárias é a ocorrência de
sangramento excessivo podendo afetar as articulações, além de hematomas diversos.
Durante a trajetória de vida, essas complicações tendem a variar de acordo com a
severidade da desordem, sendo comuns os sangramentos de articulações, musculares,
subcutâneos, gastrointestinais, entre outros (Chai-Adisaksopha, Hillis et al. 2015). Além
disso, esses indivíduos apresentam maiores chances de sangramentos durante
procedimentos invasivos como cirurgias e extrações dentárias (Mannucci, Duga et al.
2004).
A expectativa de vida dos pacientes com coagulopatias hereditárias têm
aumentado exponencialmente desde a introdução dos fatores de coagulação. Segundo
estudo, indivíduos com hemofilia com severidade leve ou moderada possuem taxa de
mortalidade similar ao de indivíduos sem a presença desta condição (Darby, Kan et al.
2007). No entanto, a falta de conhecimento e de divulgação sobre estas condições ainda
fazem com que os indivíduos com tais condições fiquem em situação de vulnerabilidade.
A World Federation of Hemophilia (WFH) não recomenda nenhum tratamento específico
ou produto para o tratamento dessas condições devido a variabilidade existente entre
cada indivíduo (Srivastava, Santagostino et al. 2020). No entanto, recomenda que haja
um tratamento específico para que cada condição seja corretamente manejada. Entre as
principais terapias utilizadas estão a administração de concentrados de fatores de
coagulação (CFC) e uso de antifibrinolíticos sistêmicos. Segundo avaliação ecônomica
realizada no Sistema Único de Saúde (SUS), os custos diretos com o tratamento de
indivíduos apresentando hemofilia severa são da ordem de mais de R$57.000 anuais
(Ferreira, Brum et al. 2020). Importância deve ser dada ao fato de que quase totalidade
desse valor está associado ao concentrados de fatores de coagulação para a redução
dos episódios de sangramento.
Entre as prioridades dos cuidados e tratamento dos pacientes com hemofilia deve-
se priorizar a prevenção dos sangramentos e danos as articulações, administração da
dor, prevenção e administração de inibidores, redução de comorbidades, qualidade de
vida e a saúde bucal. Segundo a WFH, a manutenção de uma boa saúde oral tem como
objetivo prevenir condições cáries dentárias e doenças periodontais (responsáveis por
sangramentos que podem ser danosos aos pacientes com hemofilia moderada ou
severa) (Srivastava, Santagostino et al. 2020). Com isso, torna-se importante reduzir a
necessidade de extrações dentárias, uma vez que essas podem aumentar o risco de
sangramento desses indivíduos, além da necessidade do uso de medicamentos e
concentrados de fatores de coagulação (Kalsi, Nanayakkara et al. 2012).
A WFH recomenda que os individuos sejam atendidos por pessoas capacitadas
com protocolos baseados em evidência após a recomendação de um hematologista. Por
outro lado, um estudo observacional realizado em pacientes com desordens hereditárias
de sangramento identificou que mais de 20% relatou ter tido um tratamento odontológico
negado devido a sua condição (Kalsi, Nanayakkara et al. 2012). Com isso, na busca para
se aprimorar o conhecimento sobre estas condições e a sua relação a Odontologia, se
faz necessário definir as características das principais coagulopatias hereditárias:
Hemofilia A e B
As hemofilias A e B são desordens hereditárias do cromossomo X causadas pela
deficiência ou ausência de fatores de coagulação VIII ou IX, respectivamente. Devido ao
seu padrão hereditário recessivo, os homens são os mais acometidos por essas
desordens (WFH 2017).
As hemofilias podem ser graduadas de acordo com os níveis de fatores de coagulação
encontradas nos indivíduos. A severidade é dividida em: leve (nível de fator acima de
5%), moderada (nível de fator de 1 a 5%) ou severa (nível de fator abaixo de 1%) (WFH
2017).
De acordo com a Federação Mundial de Hemofilia (WFH), cerca de 184 mil indivíduos
possuem hemofilia A ou B. Estima-se que a Hemofilia A seja quatro vezes mais comum
do que a hemofilia B, correspondendo à cerca de 81% (WFH 2017). Segundo último
censo da WFH, o Brasil possuía cerca de 12.119 indivíduos reportados com hemofilias.
Considerando a severidade da Hemofilia A, 35% dos indivíduos são afetados de maneira
severa, 55% de maneira leve e 15% de maneira moderada (Berntorp and Shapiro 2012).
Doença de von Willebrand

A doença de von Willebrand está intimamente associada a problemas de
hemostasia. Indivíduos portadores dessa condição apresentam sintomas de
sangramento exponencialmente aumentados em relação aos indivíduos normais. A
doença de von Willebrand é a coagulopatia hereditária mais comum. Essa condição é
ocasionada pela alteração no fator de von Willebrand. Esse fator constitui-se de uma
glicoproteína com duas funções principais: proteína carreadora do fator de coagulação
VIII e servindo como uma proteína adesiva envolvida na interação vaso parede-
plaquetária (Laffan, Brown et al. 2004). Os defeitos dessa proteína podem ocasionar
sangramento pela incapacidade de adesão plaquetária ou formação do coágulo de
fibrina.
De acordo com o censo da WFH, (WFH 2017) 76.144 casos foram identificados
com doença de von Willebrand, sendo que 11,2% dos casos foram registrados no Brasil.
Entre os principais problemas encontradas por pacientes com essa condição, têm-se os
sangramentos mucocutâneos, sangramentos gastrointestinais e, principalmente,
sangramento após extrações dentárias, sendo a complicação e manifestação mais
comum desses indivíduos (Castaman and Linari 2017).
Coagulopatias Hereditárias e aspectos relacionados aos pacientes
Saúde mental
As condições de saúde mental dos pacientes com coagulopatias hereditárias são
amplamente descritas na literatura. Sabe-se que a qualidade de vida dos indivíduos com
essas condições é reduzida, uma vez que apresentam dores crônicas, problemas
articulares, perda de mobilidade, além de outras comorbidades (HIV, e hepatites) (Pinto,
Paredes et al. 2018).
A ansiedade e a depressão também são condições frequentemente reportadas
pelos indivíduos. Embora diferentes ferramentas tenham sido utilizadas para avaliar as
condições de saúde mental desses indivíduos, a presença de condições mentais é
altamente prevalente (Ghanizadeh and Baligh-Jahromi 2009). Em estudo realizado nos
Estados Unidos, a prevalência de depressão foi de 37%, onde 20% dos pacientes
relataram possuir sintomas de depressão de moderados à severos (Iannone, Pennick et
al. 2012). No Brasil, aproximadamente 48% dos pacientes com coagulopatias
hereditárias reportaram ansiedade ou depressão moderada à extrema. No entanto,
considerando o tratamento para essas condições, apenas 18% reportou ter realizado ou
estar em tratamento para desordens mentais (Lorenzato, Santos et al. 2019).
Considerando que a saúde mental possui impacto negativo na saúde oral (Kisely,
Sawyer et al. 2016) dos indivíduos associado ao fato de que as coagulopatias
hereditárias também possuem impacto na sua saúde mental, os pacientes com essas
desordens podem apresentar qualidade de saúde oral reduzida.
Condições de saúde orais

A prevalência de cáries dentárias varia de acordo com a literatura. Estudos de
caso-controle têm relatado que crianças com disturbios hereditários de sangramento
apresentam maior incidência de cárie e menor incidência de dentes tratados (Kumar, Pai
et al. 2018, Salem, Seyyedkhamesi et al. 2018). Há também o receio em profissionais
em atender os pacientes com disturbios hemorrágicos de sangramento. Um estudo
observacional relatou que aproximadamente 90% dos cirurgiões-dentistas destacaram
que se sentiriam mais seguros e aptos a realizar os tratamentos odontológicos através
de um consentimento ou supervisão de um hematologista (Kalsi, Nanayakkara et al.
2012). Entre os principais problemas relatados para pacientes com coagulopatias
hereditárias, ressaltam-se a chance de ocorrência de sangramento após extrações cinco
vezes maior, dez vezes maior chance de sangramento cirúrgico e aproximadamente 18
vezes maior chance de sangramento após feridas menores (Tosetto, Rodeghiero et al.
2006).
Para o controle da hemostasia nesses indivíduos, as terapias mais comummente
utilizadas são a prescrição de ácido tranexâmico, desmopressina ou concentrados
contendo alta pureza de fator de von Willebrand, entre outros (Laffan, Lester et al. 2014).
Segundo revisão sistemática recente, o uso de antifibrinolíticos contribui para a redução
do risco de eventos adversos quando comparados ao placebo após a realização de
cirurgias orais menores (van Galen, Engelen et al. 2019).
Terapia com Implantes dentários

Diversos fatores têm sido estudados na implantodontia desde que os conceitos de
osseointegração foram fundamentados por Branemark (Branemark, Hansson et al. 1977)
na tentativa de melhor entender e aprimorar cada vez mais a relação existente entre o
tecido ósseo e os implantes dentários. Um exemplo clássico de evolução dos implantes
é o seu tratamento de superfície, que através do aumento significativo de reatividade do
biomaterial e da área de contato entre a base óssea e o implante propicia um melhor
leito para que a célula osteoblástica consiga aderência ao biomaterial (Shah et al., 2016).
As pesquisas na área de implantodontia vêm reduzindo cada vez mais o tempo de espera
entre a primeira fase cirúrgica (que constitui a instalação do implante) e a segunda
(quando o implante é reaberto para a realização dos procedimentos protéticos).
Inicialmente, foi proposto que para que a osseointegração possa ocorrer seria necessário
um período de 4 a 6 meses. No entanto, ao longo de décadas de pesquisas a instalação
do implante dentário tem se mostrado uma técnica que reduz a morbidade cirúrgica para
o paciente e apresenta taxas de perda óssea marginal similar ou até menor, comparada
aos implantes instalados com carregamento tardio (Mello et al., 2016; Jokstad et al.,
2014; Tealdo et al., 2014; Ter Gune et al., 2016).
Juntamente com fatores relacionados aos implantes, muita evolução ocorreu no
que diz respeito às características específicas dos pacientes. No que se refere à hábitos
ou medicações, o hábito de fumar têm sido associados a redução na taxa de
sobrevivência de implantes dentários. Segundo meta-análise, os indivíduos fumantes
apresentam razão de risco duas vezes maior de falha de implantes dentários do que
indivíduos não fumantes, além de apresentarem complicações como infecções pós-
operatórias e perda óssea marginal aumentadas (Chrcanovic, Albrektsson et al. 2015).
Além disso, indivíduos que fazem uso da terapia com bifosfonatos podem apresentar
aumento na taxa de falha de implantes, uma vez que essa medicação está associada ao
desenvolvimento de osteonecrose dos maxilares, prejudicando o processo de
osseointegração dos implantes dentários (de-Freitas, Lima et al. 2016).
Com relação à aspectos de saúde geral, o diabetes tem sido alvo de diversos
estudos e acompanhamentos longitudinais e, recentemente, uma revisão sistemática da
literatura sugeriu que não há efeito do diabetes na taxa de sobrevivência de implantes;
no entanto, um efeito negativo da doença pode ser observado na perda óssea marginal
ao longo do tempo (Souto-Maior, Pellizzer et al. 2019). Neste contexto, Neves et al.
avaliaram possíveis fatores de risco para falha do implante e peri-implantite em uma
população de pacientes comprometidos sistemicamente (Neves, de Araujo Nobre et al.
2018). Foi observado que distúrbios reumatológicos e cardiovasculares são associados
a um maior número de falhas de implantes, enquanto a hepatite C foi associada à um
maior risco de patologia peri-implantar. Ainda, outros estudos realizaram avaliações da
aplicabilidade de implantes dentários em pacientes soropositivos (Vidal, Vidal et al. 2017)
e transplantados (Radzewski and Osmola 2016, Radzewski and Osmola 2019),
sugerindo que pacientes HIV+ controlados podem ser submetidos à implantes dentários,
desde que a carga viral plasmática do vírus e a contagem de linfócitos T CD4 + estejam
dentro dos parâmetros que indicam estabilidade imunológica, bem como é possível
oferecer tratamento com implantes dentários para pacientes transplantados apesar do
impacto negativo das drogas imunossupressoras no processo de cicatrização óssea.
Apesar da literatura sugerir a possibilidade de indicação de implantes dentários
para pacientes com os comprometimentos sistêmicos citados acima, existe ainda na
literatura uma área escura no que se refere a possibilidade de indicação de implantes
dentários para pacientes que possuam coagulopatias hereditárias. Como se sabe, os
pacientes com coagulopatias hereditárias, dentre elas a hemofilia A, Hemofilia B e a
doença de von Willebrand, são considerados uma população vulnerável, pois,
profissionais de diversas áreas da saúde, por vezes, recusam atendimento ou evitam
indicar alguns tipos de procedimentos pela falta de treinamento apropriado e/ou pela
escassez de evidência científica sobre o tema (Kalsi, Nanayakkara et al. 2012).
Neste contexto cabe salientar que as coagulopatias hereditárias podem afetar o
tratamento com implantes dentários em diferentes momentos, sendo eles: (1) ato
cirúrgico da instalação do(s) implante(s), onde o profissional realiza uma sequência de
procedimentos cirúrgicos, incluindo incisão de tecido mole, fresagem de tecido ósseo,
instalação propriamente dita do implante e sutura da região, onde o principal objetivo
relacionado à coagulopatias hereditárias seria a hemostasia e coagulação da ferida
cirúrgica; (2) o processo de osseointegração que se inicia logo após a instalação do
implante dentário, o contato inicial do sangue com a superfície do implante cria um estado
dinâmico de atividade celular, começando com a ativação de plaquetas e leucócitos no
hematoma peri-implantar e a ligação de proteínas estruturais transitórias, como a fibrina,
à superfície do implante, (Davies, Schupbach et al. 2008) que passa pela formação de
calo ósseo, compactação lamelar, remodelação da interface e maturação compacta que
se dura um período de cerca de 54 semanas (Misch 2014).
Não se sabe ao certo os protocolos medicamentosos específicos para a realização
de procedimentos com implantes dentários e também não se sabe se algum dos estágios
da osseointegração podem ser afetados por coagulopatias hereditárias e, dessa
maneira, ressalta-se a importância da realização de estudos clínicos criteriosos e
controlados com o intuito de gerar resultados confiáveis e garantir a extrapolação dos
resultados para esta parcela desassistida da população. Embora estudos clínicos de
acompanhamento demandem maior tempo e custo para sua realização, o seu alto rigor
científico os coloca no topo da pirâmide da evidência científica (Friedman, Furberg et al.
2010), o que reforça à possibilidade de impactar positivamente a ciência relacionada à
área.
As cirurgias de colocação de implantes dentários são, geralmente, consideradas
procedimentos cirúrgicos menores. Segundo estudo (Solimeno, Escobar et al. 2018), as
cirurgias orais de extração de dentes em pacientes com coagulopatias hereditárias
devem ser planejadas de acordo com o número de dentes ou com a complexidade do
procedimento, como extrações de sisos, no entanto, não há menção na literatura sobre
protocolos medicamentosos para a instalação de implantes dentários. Em uma busca
sobre o tema, foi encontrado apenas o relato de um caso clínico reportando colocação
de implantes dentários em um indivíduo apresentando hemofilia com fator VIII entre 3 a
4% que reportou sucesso cirúrgico e protético do indivíduo. Os autores relatam que é
notória a ausência de protocolos para estes tipos de procedimentos (Gornitsky,
Hammouda et al. 2005).
O principal fator de sucesso após a instalação de um implante dentário é
denominado osseointegração. Esse processo de osseointegração dos implantes
dentários é resultado de uma controlada reação de corpo estranho ao biomaterial
(Albrektsson, Chrcanovic et al. 2017). Dessa maneira, há de se considerar que o
processo de reparo ósseo relacionado à osseointegração pode ser afetado por
coagulopatias hereditárias.
De acordo com meta-análise, adultos com hemofilia severa apresentaram
associação com menor densidade óssea mineral na região lombar do que pessoas sem
hemofilia (Iorio, Fabbriciani et al. 2010). Embora a menor densidade mineral seja
associada a sobrevivência de implantes, uma revisão sistemática recente demonstra que
não há diferenças na sobrevivência de implantes quando comparados indivíduos com
perda de densidade óssea mineral e saudáveis (de Medeiros, Kudo et al. 2018). No
entanto, o possível papel dessa perda óssea mineral em indivíduos com coagulopatias
hereditárias e sua associação com a sobrevivência de implantes dentários ainda não
está elucidada.
Considerando pacientes com hemofilias (A ou B), o guideline da WFH recomenda
reposição de fator para todos os indivíduos com essas condições (Srivastava, Brewer et
al. 2013). A recomendação de infusão de concentrados de fatores como alternativa para
pacientes cirúrgicos apresenta-se como alternativa viável, tanto para hemofilias A e B,
quanto para a doença de von Willebrand (Auerswald, Bade et al. 2013). Em indivíduos
com Doença de von Willebrand, o uso de desmopressina (1-desamino-8-D-arginine-
vasopressin) têm sido recomendado quando há a necessidade de realização de cirurgias
menores ou procedimentos dentários (Miesbach and Berntorp 2017). Além disso, o uso
de ácido tranexâmico são frequentemente utilizados após os procedimentos com objetivo
de reduzir a necessidade de terapia de reposição dos fatores de coagulação.
Um consenso realizado por um grupo de cirurgiões-dentistas da Austrália definiu
alguns parâmetros importantes para o tratamento de indivíduos com desordens de
coagulação, não especificamente trata de cirurgias de implantes dentários (Hewson, Daly
et al. 2011). Além disso, o guideline de administração de indivíduos com coagulopatias
hereditárias, embora tenha indicado o uso de medicações e administração de pacientes
submetidos a cirurgias orais menores (Srivastava, Brewer et al. 2013), ainda não
especifica as particularidades necessárias para o tratamento de indivíduos submetidos
a cirurgias de instalação de implantes dentários.
Objetivos
Objetivo geral
Gerar e divulgar conhecimento sobre o tratamento de pacientes portadores de
hemofilias A e B e doença de von Willebrand na área da Odontologia.
Objetivos específicos
- Avaliar as necessidades odontológicas de pacientes com coagulopatias
hereditárias atendidos no Hemocentro Regional de Pelotas;
- Avaliar a literatura científica quanto aos procedimentos cirúrgico em pacientes
com coagulopatias hereditárias
- Avaliar a taxa de sobrevivência de implantes e próteses sobre implantes
instaladas em pacientes com coagulopatias hereditárias atendidos no Hemocentro
Regional de Pelotas;
- Avaliar as alterações no osso peri-implantar de pacientes com coagulopatias
hereditárias por meio de acompanhamento radiográfico anual;
- Avaliar a literatura científica quanto aos procedimentos não-invasivos em
pacientes com coagulopatias hereditárias
Hipótese
A hipótese nula do estudo é a de que os pacientes com coagulopatias hereditárias
terão taxas de sucesso e sobrevivência similares à pacientes sem distúrbios de
coagulação.
Projeto de pesquisa
UNIVERSIDADE FEDERAL DE PELOTAS

Faculdade de Odontologia
Programa de Pós-Graduação em Odontologia
PROJETO DE PESQUISA
Avaliação do nível de conhecimento de estudantes e profissionais da

Odontologia e dos aspectos psicológicos, necessidades odontológicas e
tratamento e acompanhamento de implantes dentários em pacientes com
coagulopatias hereditárias
Proponentes:
Cirurgião-dentista
Prof. Mateus Bertolini Fernandes dos Santos
Cirurgião-dentista – Protesista
Equipe:
Cecília Fernandes Lorea
Hematologista, oncologista e pediatra
Aline Machado Feijó
Enfermeira
Jalusa de Oliveira Michel
Farmacêutica
Gisele Ortiz Heidrich Pinto
Assistente Social
Pelotas, 2019
Resumo
A reabilitação protética sobre implantes dentários tem se demonstrado uma alternativa
viável para substituição de dentes perdidos. Diversos estudos já avaliaram a viabilidade
da instalação de implantes dentários em indivíduos que apresentem condições
sistêmicas no que se refere ao sucesso desta modalidade terapêutica. O hábito de fumar,
diabetes, osteoporose, entre outros, já foram associados à menores taxas de
sobrevivência de implantes dentários. Embora essas condições sejam amplamente
estudadas, a literatura sobre a colocação de implantes em indivíduos com coagulopatias
hereditárias é escassa. As coagulopatias hereditárias são um conjunto de condições
causadas por deficiência quantitativa e/ou qualitativa de fatores de coagulação. Entre as
principais, destaca-se a Hemofilia A, Hemofilia B e a Doença de von Willebrand,
correspondendo a mais de 95% dos casos de coagulopatias. Com o aumento
exponencial da expectativa de vida dos indivíduos com essas condições, a necessidade
de reabilitação de dentes perdidos torna-se imprescindível. Existe ainda certo tabu com
relação ao atendimento odontológico de pacientes com tais condições, bem como a
inexistência de literatura científica em determinadas especialidades odontológicas. Além
da ausência de dados sobre as taxas de sucesso dos implantes dentários, a literatura
ressente-se, ainda, de dados relacionados ao protocolo medicamentoso necessário para
cirurgias de instalação de implantes dentários bem como a condição oral desses
pacientes. Dessa maneira, o presente projeto de pesquisa se propõe a gerar e divulgar
conhecimento sobre o tratamento de pacientes com coagulopatias hereditárias
(hemofilias A e B e doença de von Willebrand) com implantes dentários através do
atendimento e acompanhamento de pacientes atendidos durante os anos de 2019-2023
na Faculdade de Odontologia da Universidade Federal de Pelotas, submetidos a
inserção de implantes dentários e a confecção de próteses dentárias sobre implante.
Palavras-chave: Coagulopatias Hereditárias, Fator VIII, Fator IX, Hemofilia A, Hemofilia

B, Doença de von Willebrand, Implantes dentários.
1. Introdução
1.1 Identificação da proposta
Diversos fatores têm sido estudados na implantodontia desde que os conceitos de
osseointegração foram fundamentados por Branemark (Branemark et al., 1977) na
tentativa de melhor entender e aprimorar cada vez mais a relação existente entre o tecido
ósseo e os implantes dentários. Um exemplo clássico de evolução dos implantes é o seu
tratamento de superfície, que através do aumento significativo de reatividade do
biomaterial e da área de contato entre a base óssea e o implante propicia um melhor
leito para que a célula osteoblástica consiga aderência ao biomaterial (Shah et al., 2016).
As pesquisas na área de implantodontia vêm reduzindo cada vez mais o tempo de espera
entre a primeira fase cirúrgica (que constitui a instalação do implante) e a segunda
(quando o implante é reaberto para a realização dos procedimentos protéticos).
Inicialmente, foi proposto que para que a osseointegração possa ocorrer seria necessário
um período de 4 a 6 meses. No entanto, ao longo de décadas de pesquisas a instalação
do implante dentário tem se mostrado uma técnica que reduz a morbidade cirúrgica para
o paciente e apresenta taxas de perda óssea marginal similar ou até menor, comparada
aos implantes instalados com carregamento tardio (Mello et al., 2016; Jokstad et al.,
2014; Tealdo et al., 2014; Ter Gune et al., 2016).
Juntamente com fatores relacionados aos implantes, muita evolução ocorreu no
que diz respeito às características específicas dos pacientes. No que se refere à hábitos
ou medicações, o hábito de fumar têm sido associados a redução na taxa de
sobrevivência de implantes dentários. Segundo meta-análise, os indivíduos fumantes
apresentam razão de risco duas vezes maior de falha de implantes dentários do que
indivíduos não fumantes, além de apresentarem complicações como infecções pós-
operatórias e perda óssea marginal aumentadas (Chrcanovic et al., 2015). Além disso,
indivíduos que fazem uso da terapia com bifosfonatos podem apresentar aumento na
taxa de falha de implantes, uma vez que essa medicação está associada ao
desenvolvimento de osteonecrose dos maxilares, prejudicando o processo de
osseointegração dos implantes dentários (De-Freitas et al., 2016).
Com relação à aspectos de saúde geral, o diabetes tem sido alvo de diversos
estudos e acompanhamentos longitudinais e, recentemente, uma revisão sistemática da
literatura sugeriu que não há efeito do diabetes na taxa de sobrevivência de implantes;
no entanto, um efeito negativo da doença pode ser observado na perda óssea marginal
ao longo do tempo (Souto-Maior et al., 2019). Neste contexto, Neves et al. avaliaram
possíveis fatores de risco para falha do implante e peri-implantite em uma população de
pacientes comprometidos sistemicamente (Neves et al., 2018). Foi observado que
distúrbios reumatológicos e cardiovasculares são associados a um maior número de
falhas de implantes, enquanto a hepatite C foi associada à um maior risco de patologia
peri-implantar. Ainda, outros estudos realizaram avaliações da aplicabilidade de
implantes dentários em pacientes soropositivos (Vidal et al., 2017) e transplantados
(Radzewski e Osmola, 2016; Radzewski e Osmola, 2019), sugerindo que pacientes HIV+
controlados podem ser submetidos à implantes dentários, desde que a carga viral
plasmática do vírus e a contagem de linfócitos T CD4 + estejam dentro dos parâmetros
que indicam estabilidade imunológica, bem como é possível oferecer tratamento com
implantes dentários para pacientes transplantados apesar do impacto negativo das
drogas imunossupressoras no processo de cicatrização óssea.
Apesar da literatura sugerir a possibilidade de indicação de implantes dentários
para pacientes com os comprometimentos sistêmicos citados acima, existe ainda na
literatura uma área escura no que se refere a possibilidade de indicação de implantes
dentários para pacientes que possuam coagulopatias hereditárias. Como se sabe, os
pacientes com coagulopatias hereditárias, dentre elas a hemofilia A, Hemofilia B e a
doença de von Willebrand, são considerados uma população vulnerável, pois,
profissionais de diversas áreas da saúde, por vezes, recusam atendimento ou evitam
indicar alguns tipos de procedimentos pela falta de treinamento apropriado e/ou pela
escassez de evidência científica sobre o tema.
Neste contexto cabe salientar que as coagulopatias hereditárias podem afetar o
tratamento com implantes dentários em diferentes momentos, sendo eles: (1) ato
cirúrgico da instalação do(s) implante(s), onde o profissional realiza uma sequência de
procedimentos cirúrgicos, incluindo incisão de tecido mole, fresagem de tecido ósseo,
instalação propriamente dita do implante e sutura da região, onde o principal objetivo
relacionado à coagulopatias hereditárias seria a hemostasia e coagulação da ferida
cirúrgica e (2) o processo de osseointegração que se inicia logo após a instalação do
implante dentário, o contato inicial do sangue com a superfície do implante cria um estado
dinâmico de atividade celular, começando com a ativação de plaquetas e leucócitos no
hematoma peri-implantar e a ligação de proteínas estruturais transitórias, como a fibrina,
à superfície do implante, (Davies et al., 2008) que passa pela formação de calo ósseo,
compactação lamelar, remodelação da interface e maturação compacta que se dura um
período de cerca de 54 semanas (Misch, 2014).
Não se sabe ao certo os protocolos medicamentosos específicos para a realização
de procedimentos com implantes dentários e também não se sabe se algum dos estágios
da osseointegração podem ser afetados por coagulopatias hereditárias e, dessa
maneira, ressalta-se a importância da realização de estudos clínicos criteriosos e
controlados com o intuito de gerar resultados confiáveis e garantir a extrapolação dos
resultados para esta parcela desassistida da população. Embora estudos clínicos de
acompanhamento demandem maior tempo e custo para sua realização, o seu alto rigor
científico os coloca no topo da pirâmide da evidência científica (Friedman et al., 2010), o
que reforça à possibilidade de impactar positivamente a ciência relacionada à área.
1.2 Definição das Coagulopatias Hereditárias

A coagulação sanguínea constitui uma importante defesa do organismo contra o
sangramento. O processo da coagulação corresponde a uma regulada cascata que visa
a formação de um coágulo sanguíneo. A enzima chave relacionada ao processo de
coagulação é denominada trombina, tendo entre suas ações principais a ativação
plaquetária, a conversão de fibrinogênio na rede de fibrina e a ampliação da resposta a
coagulação (Dahlbäck, 2000). A atuação dessa enzima se dá após a lesão tecidual que
ocasiona a ativação de sua precursora, protrombina, iniciando a primeira etapa da
formação do coágulo (Krishnaswamy, 2013).
causadas por deficiência quantitativa e/ou qualitativa de fatores de coagulação (Antunes
et al., 2005). Considerando as hemofilias, os homens são o sexo mais afetado, ocorrendo
devido mutações causais localizadas no cromossomo X, resultado de padrão hereditário
recessivo (Berntorp e Shapiro, 2012). Entre as principais coagulopatias hereditárias, as
hemofilias A e B e a doença de von Willebrand correspondem por 95 a 97% dos casos
de coagulopatias hereditárias (Mannucci et al., 2004). Ademais, condições conhecidas
como coagulopatias raras hereditárias correspondem ao restante, tendo sua incidência
associada a 1 a cada 2 milhões de habitantes (Ms, 2015).
O principal sintoma relacionado as coagulopatias hereditárias é a ocorrência de
sangramento excessivo podendo afetar as articulações, além de hematomas diversos;
os indivíduos que apresentam essas condições também possuem maior chances de
sangramentos durante procedimentos invasivos como cirurgias e extrações dentárias
(Mannucci et al., 2004). Além disso, esses indivíduos apresentam ao longo da trajetória
de vida complicações que podem variar de acordo com a severidade da desordem,
sendo comuns os sangramentos de articulações, musculares, subcutâneos,
gastrointestinais, entre outros (Chai-Adisaksopha et al., 2015).
A expectativa de vida dos pacientes com coagulopatias hereditárias têm
aumentado exponencialmente desde a introdução dos fatores de coagulação. Segundo
estudo, indivíduos com hemofilia com severidade leve ou moderada possuem taxa de
mortalidade similar ao de indivíduos sem a presença desta condição (Darby et al., 2007).
No entanto, a falta de conhecimento e de divulgação sobre estas condições ainda fazem
com que os indivíduos com tais condições fiquem em situação de vulnerabilidade.
Na busca para se aprimorar o conhecimento sobre estas condições e a sua
relação com implantes dentários, se faz necessário definir as características das
principais coagulopatias hereditárias:
1.2.1 Hemofilia A e B
As hemofilias A e B são desordens hereditárias do cromossomo X causadas pela
deficiência ou ausência de fatores de coagulação VIII ou IX, respectivamente. Devido ao
seu padrão hereditário recessivo, os homens são os mais acometidos por essas
desordens (Wfh, 2017).
As hemofilias podem ser graduadas de acordo com os níveis de fatores de
coagulação encontradas nos indivíduos. A severidade é dividida em: leve (nível de fator
acima de 5%), moderada (nível de fator de 1 a 5%) ou severa (nível de fator abaixo de
1%) (Wfh, 2017).
De acordo com a Federação Mundial de Hemofilia (WFH), cerca de 184 mil
indivíduos possuem hemofilia A ou B. Estima-se que a Hemofilia A seja quatro vezes
mais comum do que a hemofilia B, correspondendo à cerca de 81% (Wfh, 2017).
Segundo último censo da WFH, o Brasil possuía cerca de 12.119 indivíduos reportados
com hemofilias. Considerando a severidade da Hemofilia A, 35% dos indivíduos são
afetados de maneira severa, 55% de maneira leve e 15% de maneira moderada
(Berntorp e Shapiro, 2012). O quadro 1 apresenta a comparação entre as hemofilias A e
B.
Semelhanças Diferenças
Aumento no tempo de tromboplastina Farmacocinética dos fatores de
parcial ativada coagulação
Tipo dos eventos de sangramento, Frequência de ocorrência (Hemofilia A >
incluindo hemartrose Hemofilia B)
Associação de morbidades, incluindo Proporção de pacientes em cada nível de
artropatia severidade
Mutações que causam a desordem (mais
Desenvolvimento de inibidores
pontos de mutação na hemofilia B do que
(anticorpos antifatores)
na A)
Risco de problemas associados com o
desenvolvimento inibitório (reações
Gene está no cromossomo X
anafiláticas e nefrose encontrada na B e
sendo incomum na A)
Quadro 1 – Comparação entre as condições observadas em Hemofilia A e B. Adaptado
do estudo de (Berntorp e Shapiro, 2012)
1.2.1 Doença de von Willebrand

A doença de von Willebrand está intimamente associada a problemas de
hemostasia. Indivíduos portadores dessa condição apresentam sintomas de
sangramento exponencialmente aumentados em relação aos indivíduos normais. A
doença de von Willebrand é a coagulopatia hereditária mais comum. Essa condição é
ocasionada pela alteração no fator de von Willebrand. Esse fator constitui-se de uma
glicoproteína com duas funções principais: proteína carreadora do fator de coagulação
VIII e servindo como uma proteína adesiva envolvida na interação vaso parede-
plaquetária (Laffan et al., 2004). Os defeitos dessa proteína podem ocasionar
sangramento pela incapacidade de adesão plaquetária ou formação do coágulo de
fibrina.
De acordo com o censo da WFH, (Wfh, 2017) 76.144 casos foram identificados
com doença de von Willebrand, sendo que 11,2% dos casos foram registrados no Brasil.
Entre os principais problemas encontradas por pacientes com essa condição, têm-se os
sangramentos mucocutâneos, sangramentos gastrointestinais e, principalmente,
sangramento após extrações dentárias, sendo a complicação e manifestação mais
comum desses indivíduos (Castaman e Linari, 2017).
1.3 Coagulopatias Hereditárias e aspectos relacionados aos pacientes

1.3.1 Saúde mental
As condições de saúde mental dos pacientes com coagulopatias hereditárias são
amplamente descritas na literatura. Sabe-se que a qualidade de vida dos indivíduos com
essas condições é reduzida, uma vez que apresentam dores crônicas, problemas
articulares, perda de mobilidade, além de outras comorbidades (HIV, e hepatites) (Pinto
et al., 2018).
A ansiedade e a depressão também são condições frequentemente reportadas
pelos indivíduos. Embora diferentes ferramentas tenham sido utilizadas para avaliar as
condições de saúde mental desses indivíduos, a presença de condições mentais é
altamente prevalente (Ghanizadeh e Baligh-Jahromi, 2009). Em estudo realizado nos
Estados Unidos, a prevalência de depressão foi de 37%, onde 20% dos pacientes
relataram possuir sintomas de depressão de moderados à severos (Iannone et al., 2012).
No Brasil, aproximadamente 48% dos pacientes com coagulopatias hereditárias
reportaram ansiedade ou depressão moderada à extrema. No entanto, considerando o
tratamento para essas condições, apenas 18% reportou ter realizado ou estar em
tratamento para desordens mentais (Lorenzato et al., 2019).
Considerando que a saúde mental possui impacto negativo na saúde oral (Kisely
et al., 2016) dos indivíduos associado ao fato de que as coagulopatias hereditárias
também possuem impacto na sua saúde mental, os pacientes com essas desordens
podem apresentar qualidade de saúde oral reduzida.
1.3.2 Condições orais

Entre os principais problemas relatados para pacientes com coagulopatias
hereditárias, ressaltam-se a chance de ocorrência de sangramento após extrações cinco
vezes maior, dez vezes maior chance de sangramento cirúrgico e aproximadamente 18
vezes maior chance de sangramento após feridas menores (Tosetto et al., 2006).
Para o controle da hemostasia nesses indivíduos, as terapias mais comummente
utilizadas são a prescrição de ácido tranexâmico, desmopressina ou concentrados
contendo alta pureza de fator de von Willebrand, entre outros (Laffan et al., 2014).
Segundo revisão sistemática recente, o uso de antifibrinolíticos contribui para a redução
do risco de eventos adversos quando comparados ao placebo após a realização de
cirurgias orais menores (Van Galen et al., 2019).
1.3.3 Implantes dentários

As cirurgias de colocação de implantes dentários são, geralmente, consideradas
procedimentos cirúrgicos menores. Segundo estudo (Solimeno et al., 2018), as cirurgias
orais de extração de dentes em pacientes com coagulopatias hereditárias devem ser
planejadas de acordo com o número de dentes ou com a complexidade do procedimento,
como extrações de sisos, no entanto, não há menção na literatura sobre protocolos
medicamentosos para a instalação de implantes dentários. Em uma busca sobre o tema,
foi encontrado apenas o relato de um caso clínico reportando colocação de implantes
dentários em um indivíduo apresentando hemofilia com fator VIII entre 3 a 4% que
reportou sucesso cirúrgico e protético do indivíduo. Os autores relatam que é notória a
ausência de protocolos para estes tipos de procedimentos (Gornitsky et al., 2005).
O principal fator de sucesso após a instalação de um implante dentário é
denominado osseointegração. Esse processo de osseointegração dos implantes
dentários é resultado de uma controlada reação de corpo estranho ao biomaterial
(Albrektsson et al., 2017). Dessa maneira, há de se considerar que o processo de reparo
ósseo relacionado à osseointegração pode ser afetado por coagulopatias hereditárias.
De acordo com meta-análise, adultos com hemofilia severa apresentaram
associação com menor densidade óssea mineral na região lombar do que pessoas sem
hemofilia (Iorio et al., 2010). Embora a menor densidade mineral seja associada a
sobrevivência de implantes, uma revisão sistemática recente demonstra que não há
diferenças na sobrevivência de implantes quando comparados indivíduos com perda de
densidade óssea mineral e saudáveis (De Medeiros et al., 2018). No entanto, o possível
papel dessa perda óssea mineral em indivíduos com coagulopatias hereditárias e sua
associação com a sobrevivência de implantes dentários ainda não está elucidada.
Considerando pacientes com hemofilias (A ou B), o guideline da WFH recomenda
reposição de fator para todos os indivíduos com essas condições (Srivastava et al.,
2013). A recomendação de infusão contínua de fatores como alternativa para pacientes
cirúrgicos apresenta-se como alternativa viável, tanto para hemofilias A e B, quanto para
a doença de von Willebrand (Auerswald et al., 2013). Em indivíduos com Doença de von
Willebrand, o uso de desmopressina (1-desamino-8-D-arginine-vasopressin) têm sido
recomendado quando há a necessidade de realização de cirurgias menores ou
procedimentos dentários (Miesbach e Berntorp, 2017). Além disso, o uso de ácido
tranexâmico e o ácido aminocapróico são frequentemente utilizados após os
procedimentos com objetivo de reduzir a necessidade de terapia de reposição dos
fatores de coagulação.
Um consenso realizado em 2011 por um grupo de cirurgiões-dentistas da Austrália
definiu alguns parâmetros importantes para o tratamento de indivíduos com desordens
de coagulação, não especificamente trata de cirurgias de implantes dentários (Hewson
et al., 2011). Além disso, o guideline de administração de indivíduos com coagulopatias
hereditárias, embora tenha indicado o uso de medicações e administração de pacientes
submetidos a cirurgias orais menores (Srivastava et al., 2013), ainda não especifica as
particularidades necessárias para o tratamento de indivíduos submetidos a cirurgias de
instalação de implantes dentários.
2. Objetivos
2.1 Objetivo geral
Gerar e divulgar conhecimento sobre o tratamento de pacientes portadores de
hemofilias A e B e doença de von Willebrand com implantes dentários.
2.2 Objetivos específicos

- Avaliar o nível de conhecimento de estudantes e profissionais da Odontologia
acerca do tratamento de pacientes com coagulopatias hereditárias;
- Avaliar as necessidades odontológicas de pacientes com coagulopatias
hereditárias atendidos no Hemocentro Regional de Pelotas;
- Avaliar o perfil psicológico, a ansiedade, a qualidade de vida relacionada com a
saúde oral, o bruxismo e a desordens temporomandibulares (DTMs) autorelatados, e a
satisfação com o tratamento por meio da aplicação de questionários específicos;
- Avaliar o relato dos pacientes relacionados as experiências e ao fardo de ter
hemofilia, através do questionário específico The Patient Reported Outcomes, Burdens
and Experiences (PROBE) e demais questionários relacionados ao tema.
- Desenvolver protocolo de atendimento de implantodontia para pacientes com
coagulopatias hereditárias;
- Avaliar a taxa de sobrevivência de implantes e próteses sobre implantes
instaladas em pacientes com coagulopatias hereditárias atendidos no Hemocentro
Regional de Pelotas;
- Avaliar as alterações no osso peri-implantar de pacientes com coagulopatias
hereditárias por meio de acompanhamento radiográfico anual;
- Divulgar conhecimento sobre o tratamento odontológico de maneira geral e
específico sobre implantodontia abordando as especificidades de cada desordem de
coagulação sanguínea por meio da realização de palestras, criação de conteúdo
impresso e para meios eletrônicos.
3. Hipótese
A hipótese nula do estudo é a de que os pacientes com coagulopatias hereditárias
terão taxas de sucesso e sobrevivência similares à pacientes sem distúrbios de
coagulação.
4. Metodologia
4.1 Desenho do estudo
Para avaliação dos desfechos será realizado um estudo clínico prospectivo
longitudinal não randomizado.
4.2 Amostra e recrutamento

4.2.1 Pacientes
A amostra será composta por pacientes com coagulopatias hereditárias atendidos no
Hemocentro Regional de Pelotas. A amostra será composta por pacientes atendidos
durante os anos de 2020 a 2023, com a inclusão iniciando a partir da aprovação do
projeto pelo comitê de ética em pesquisa.
O recrutamento da amostra se dará por intermédio do Hemocentro Regional de
Pelotas, que fornecerá aos pacientes com coagulopatias hereditárias atendidos na
referida unidade a possibilidade de participação na pesquisa.
4.2.2 Estudantes e profissionais

Levando-se em conta que a cada semestre letivo ingressam 45 alunos no curso
de Odontologia da FO-UFPel e que do 5º ao 10º semestre (6 semestres) os alunos
frequentam disciplinas clínicas, para o cálculo amostral a população de alunos que
frequentam disciplinas clínicas foi estimada em 270 alunos e estimando-se um erro
estimado de 5% e nível de confiança de 95% o número total de alunos necessários deve
ser de 159 estudantes.
Além disso, profissionais da área da Odontologia serão convidados a participar
através do preenchimento de questionário online que será divulgado pelos
pesquisadores e serão também enviados a entidades de classe com a solicitação de
divulgação do mesmo. Para estes a amostragem será realizada por conveniência e sem
cálculo amostral, pois, não se poderá estimar o número de profissionais alcançados
através de mídias eletrônicas. Dessa maneira, busca-se a obtenção de um tamanho de
amostra semelhante ao calculado para os alunos de modo que se possa realizar uma
comparação entre as respostas dos questionários e o grau de formação.
4.3 Critérios de Elegibilidade

4.3.1 Pacientes
Para ser incluído na amostra os pacientes precisarão apresentar alguma das
seguintes características:
- Ter mais de 18 anos;
- Ter hemofilia A;
- Ter hemofilia B;
- Ter Doença de von Willebrand.
- Possuir disponibilidade financeira para arcar com os custos dos materiais.
Critérios de Exclusão
Não poderão fazer parte da amostra os pacientes com alguma das características
abaixo:
- Paciente com alguma doença sistêmica que impeça a realização da cirurgia para
instalação de implante dentário;
- Pacientes que não possuam disponibilidade de horário para atendimento na
instituição de ensino.
Ressaltamos que os pacientes que não aceitarem fazer parte do estudo serão atendidos
igualmente, sem nenhum tipo de prejuízo ao seu tratamento.
4.3.2 Estudantes e profissionais

4.3.2.1 Estudantes
Critérios de inclusão
Para ser incluído na amostra os estudantes precisarão apresentar as seguintes
características:
- Cursar disciplinas clínicas na Faculdade de Odontologia;
- Aceitar participar da pesquisa
- Alunos que não estejam cursando disciplina onde o coordenador e equipe desta
pesquisa façam parte.
Critérios de exclusão
Não poderão fazer parte da amostra estudantes que:
- Não tenham cursado todas as disciplinas básicas do curso de Odontologia;
- Não aceitem participar da pesquisa.
Ressaltamos aos estudantes que a participação na pesquisa será voluntária e,

caso não desejem participar ou que não aceitem responder a determinado questionário,
não haverá prejuízos.
4.3.2.2 Profissionais
Critérios de inclusão
Para ser incluído na amostra os profissionais precisarão apresentar as seguintes
características:
- Possuir graduação e estar atuando na área da Odontologia;
- Aceitar participar da pesquisa
Critérios de exclusão
Não poderão fazer parte da amostra profissionais que:
- Não aceitem participar da pesquisa.
Ressaltamos aos profissionais que a participação na pesquisa será voluntária e,

caso não desejem participar ou que não aceitem responder a determinado questionário,
não haverá prejuízos.
4.4 Procedimentos clínicos

Saúde Geral dos pacientes
Os pacientes com coagulopatias hereditárias incluídos nesta pesquisa são
periodicamente atendidos no Hemocentro Regional de Pelotas por equipe
multiprofissional.
Exames odontológicos iniciais

Todos os pacientes elegíveis receberão inicialmente exame clínico completo,
preenchimento de questionário sociodemográfico e aplicação de questionário centrados
no paciente (Harding et al., 1980; Pintado et al., 1997; Fioravanti-Bastos et al., 2011;
Lovgren et al., 2016; Skinner et al., 2018).
Todas as necessidades odontológicas apresentadas pelos pacientes serão
tratadas por esta equipe ou encaminhadas para tratamento especializado dentro da
Faculdade de Odontologia da UFPel. Os pacientes com necessidade de instalação de
implantes dentários serão contra referenciados ao Hemocentro para avaliação de saúde
geral, liberação médica para o procedimento e prescrição de profilaxia de acordo com o
tipo e gravidade da desordem de coagulação sanguínea.
Infusão profilática de fatores coagulantes

A profilaxia será prescrita pela hematologista do Hemocentro Regional de Pelotas,
de acordo com a especificidade de cada paciente. Dentro das possibilidades de profilaxia
estão a indicação de uso de antifibrinolíticos e concentrados de fator de coagulação.
Procedimentos de implantodontia
Para todos os pacientes serão solicitados exames de imagem prévios à instalação
dos implantes. Os exames dependerão de cada situação, podendo ser radiografias
periapicais e/ou panorâmicas e/ou tomografias computadorizadas. Cabe salientar que os
exames do tipo radiografias serão realizados de maneira gratuita na própria instituição
de ensino tanto para os momentos de planejamento quanto para todas as reavaliações
longitudinais do caso. Os exames de tomografia computadorizada, que serão realizados
apenas no momento do planejamento do implante, terão seus custos pagos pelos
pacientes. Para isso serão apresentadas aos mesmos três possibilidades de locais para
realização do exame, para que o próprio paciente escolha o local que lhe convir.
Os implantes dentários utilizados no estudo serão da marca Neodent (Curitiba, PR,
Brasil). O diâmetro, tamanho e design da plataforma do implante serão escolhidos pelo
pesquisador, com base na especificidade de cada caso a ser realizado. A instalação dos
implantes será feita utilizando os instrumentais específicos do fabricante, sempre
seguindo as recomendações preconizadas pelo mesmo. A instalação será realizada por
um profissional especialista na área, auxiliado por um aluno de graduação ou pós-
graduação. Haverá, também, uma pessoa responsável pela tabulação dos dados
referentes aos procedimentos.
Imediatamente após a inserção dos implantes serão instalados parafusos de
cobertura ou cicatrizadores, ou ainda provisórios imediatos, respeitando a especificidade
de cada caso clínico. Após a sutura, será obtida radiografia periapical para controle
imediato. Diversas informações relacionadas a cirurgia serão anotadas em prontuário
próprio, e esse momento será considerado o “baseline” para avaliação dos aspectos
cirúrgicos envolvidos na longevidade dos implantes.
Medicações pós-operatórias serão prescritas quando necessárias, dependendo de cada
caso e respeitando as restrições de mediações de acordo com cada condição de saúde
diagnosticada. Uma semana após a cirurgia, os pacientes serão rechamados para
controle e remoção da sutura. Nesse caso, haverá novamente a necessidade de infusão
profilática para a remoção.
Os procedimentos de reabertura dos implantes dentários ocorrerão de dois a seis
meses após o dia da instalação do implante, sob infusão profilática, dependendo da
região de instalação e tipo de implante utilizado. Nesse momento será feita uma pequena
incisão e afastamento do tecido mole localizado sobre o implante, remoção do parafuso
de cobertura e inserção do cicatrizador, cuja altura dependerá da quantidade de tecido
existente sobre o implante. Nesse dia será realizada nova radiografia periapical, para
controle do sucesso da osseointegração e verificação da distância óssea existente entre
a crista óssea e a plataforma do implante.
Procedimentos de Prótese Dentária

A partir da segunda semana após a instalação do cicatrizador será feita a seleção
do pilar protético. Após a instalação dos mesmos, serão realizadas moldagens com
silicone polimerizado por reação de adição (Express XT, Saint Paul, MN, USA) e a
técnica utilizada (moldeira aberta ou fechada) dependerá da escolha do pesquisador. O
tipo de pilar a ser utilizado para confecção da prótese também dependerá das
características individuais de cada caso, sempre seguindo as recomendações e
especificações fornecidas pelo fabricante. Será realizada na mesma sessão clínica a
seleção de cor da prótese dentária baseado na escala VITA e realização de registro
oclusal do paciente para posterior montagem em articulador que serão enviados ao
laboratório de prótese dentária. Reforçamos que sempre será fornecido aos pacientes
duas opções de laboratório, com diferentes faixas de preço, ficando a escolha à cargo
do paciente.
As próteses finalizadas serão avaliadas quanto à adaptação da peça ao
implante/pilar, contato proximal e contatos oclusais. Possíveis ajustes na cerâmica de
cobertura serão realizados utilizando pontas diamantadas e pontas de acabamento de
cerâmicas acopladas a peça reta em baixa rotação. Após os ajustes, as próteses serão
instaladas aplicando-se o valor de torque recomendado pelo fabricante em casos de
próteses parafusadas ou cimentadas com cimento resinoso de polimerização dual. Não
haverá padronização do cimento utilizado, e a manipulação dos mesmos sempre
respeitará recomendações fornecidas pelos fabricantes. Os excessos de cimento serão
removidos com sondas exploradoras e fio dental e a fotoativação será feita com
aparelhos de LED com intensidade mínima de 700 mW/cm 2.
Após a instalação das próteses, todos os pacientes receberão instrução de higiene
oral e será realizada nova radiografia periapical para registro documental e também para
futuras avaliações.
Todas as informações relativas à confecção das próteses serão anotadas em
prontuário odontológico e poderão ser utilizados para posterior acompanhamento e
possível análise da relação de diferentes fatores com as taxas de longevidade.
4.5 Aplicação de questionários centrados no paciente

Esses questionários serão aplicados previamente aos procedimentos clínicos e
terão participação voluntária, onde será esclarecido ao paciente o conteúdo das
ferramentas e, caso não o paciente não queira participar, os procedimentos irão ocorrer
sem nenhum prejuízo ao mesmo, sendo que as ferramentas abaixo não serão aplicadas.
Desordens mentais comuns (DMC)
As desordens mentais comuns são um braço das desordens mentais descritas
como condições não-psicóticas. Essas desordens são comumente representadas pelas
duas principais condições de depressão e ansiedade, irritabilidade e sintomas somáticos
(Goldberg, 1994). Segundo revisão sistemática recente, as desordens mentais comuns
são altamente prevalentes em adultos, sendo incapacitantes ou ocasionando
consideráveis prejuízos sociais (Ormel et al., 1994; Steel et al., 2014).
Para a avaliação das desordens mentais comuns, o questionário Self-Reported
Questionnaire-20 (SRQ-20) (Harding et al., 1980) será utilizada como ferramenta de
rastreio dessas condições.
Traços de Ansiedade
O traço de ansiedade refere-se a relativa disposição estável de responder ao
estresse com ansiedade ou uma tendência a perceber um maior número de situações
como ameaçadora (Spielberger, 2010). Para avaliação dessa condição, o questionário
de traço de ansiedade (STAIT-T) proposto por Spielberger têm sido amplamente
utilizado.
Mais recentemente, a versão reduzida do STAI-T possuindo seis questões tem sido
utilizada em diferentes países (Marteau e Bekker, 1992), tendo sua validação realizada
em português (Fioravanti-Bastos et al., 2011).
Qualidade de vida relacionada com a saúde oral

A qualidade de vida relacionada com a saúde oral é definida como a ausência de
impactos negativos na vida social e senso de autoconfiança positivo relacionado a saúde
oral. Para avaliação desse domínio, diferentes ferramentas têm sido aplicadas. A
ferramenta mais amplamente utilizada tem sido o Oral Health Impact Profile em sua
versão reduzida (OHIP-14) (Slade, 1997). O OHIP-14 possui domínios que se referem a
limitação funcional, dor física, desconforto psicológico, incapacidades físicas e
psicológicas, além de prejuízos funcionais.
Bruxismo
O bruxismo é uma desordem muscular comum caracterizada por apertamento ou
rangimento que pode ocorrer durante a vigília ou durante o sono, sendo considerado
multifatorial com potencial influência do sistema nervoso central (Lobbezoo et al., 2013).
Segundo último consenso, o bruxismo pode ser avaliado de forma possível
através de questionários, embora o diagnóstico definitivo seja realizado através de
polissonografia (Lobbezoo et al., 2018). Para a avaliação do possível bruxismo, o
questionário de Pintado e colaboradores (1997) tem sido amplamente utilizado (Pintado
et al., 1997).
Desordens temporomandibulares (DTM)

As desordens temporomandibulares são um conjunto de condições associadas a
dores na articulação temporomandibular e seus músculos, sons e travamento da
mandíbula, entre outros (Okeson, 2014).
O diagnóstico padrão-ouro para essas desordens consiste no Diagnostic Criteria
(Vilanova et al., 2015), embora seja específico e necessite maior tempo de aplicação.
Por outro lado, o questionário 3Q-TMD tem sido utilizado para avaliar essa condição em
relação ao padrão-ouro DC/TMD (Lovgren et al., 2016). Esse questionário consiste de
três questões que apresentam validade para o rastreio dessas condições (Lovgren et al.,
2018).
Satisfação com o tratamento

Um mês após a instalação das próteses todos os pacientes serão rechamados
para consulta de acompanhamento onde será verificada a situação clínica das próteses
e será aplicado um questionário de satisfação. Esse questionário consistirá em uma
escala visual analógica (EVA) cobrindo aspectos relacionados à estética, fonética,
mastigação e conforto (Baracat et al., 2011; De Lima et al., 2012).
Relato dos pacientes sobre as experiências com a hemofilia (PROBE study)

O questionário PROBE (The Patient Reported Outcomes, Burdens and
Experiences) (Skinner et al., 2018) foi desenvolvido recentemente com o intuito de
avaliar, sob o ponto de vista do paciente, aspectos psicológicos de pacientes com
hemofilia (Chai-Adisaksopha et al., 2018; Chai-Adisaksopha, Skinner, Curtis, Frick,
Nichol e Noone, 2019; Chai-Adisaksopha, Skinner, Curtis, Frick, Nichol, Noone, et al.,
2019).
Qualidade de vida Short Form-36

Para a avaliação de indivíduos com doença de von Willebrand, o questionário
Short Form-36 será aplicado. Essa ferramenta é utilizada para avaliação de saúde
mental, percepções de saúde geral, assim como limitações físicas, sociais e/ou
emocionais (Busija et al., 2011).
4.6 Avaliação do nível de conhecimento de estudantes e profissionais

O conhecimento de profissionais e estudantes de Odontologia sobre as
coagulopatias hereditárias ainda permanece incerto. Dessa forma, é de fundamental
importância que o conhecimento sobre essas condições seja avaliado para que, se
necessário, intervenções sejam feitas com objetivo de disseminar e aprimorar o
background dessa área. Para isso, questionários aplicados centrados em profissionais
(cirurgiões-dentistas) e alunos de graduação em Odontologia têm sido descritos na
literatura.
Conhecimento sobre a doença de von Willebrand
O questionário utilizado em pesquisa prévia para a avaliação do conhecimento
dos profissionais e dos alunos sobre essa condição será utilizado (Ribeiro et al., 2017).
Esse questionário possui domínios sobre o conhecimento geral sobre a doença, os testes
utilizados para o diagnóstico, os principais sinais e sintomas, procedimentos que
necessitam cuidados nesses pacientes, e as medicações que devem ser
contraindicadas.
Conhecimento sobre as hemofilias hereditárias
O questionário utilizado em pesquisa prévia para a avaliação do conhecimento
dos profissionais e dos alunos sobre essa condição será utilizado (Silva et al., 2016).
Esse questionário consiste em três domínios: bloco sociodemográfico, bloco de
conhecimento sobre as disfunções hematológicas e sua interferência na odontologia e
bloco de transmissão da informação (onde foi obtido o conhecimento).
4.7 Treinamento dos executores
Os profissionais que realizarão os procedimentos odontológicos receberão
treinamento sobre as especificidades do atendimento de pacientes com coagulopatias
hereditárias. Todos os procedimentos de implantodontia a serem executados seguirão
as recomendações dos fabricantes dos respectivos materiais.
4.8 Reavaliações anuais

Após a finalização dos casos os pacientes serão rechamados anualmente ao
centro de pesquisa para a realização de consultas de acompanhamento. Nessas
consultas serão avaliadas as condições de saúde oral do paciente e os implantes e
próteses objetos do estudo. Todas as necessidades odontológicas que o paciente
apresentar serão atendidas pelos pesquisadores, não se restringindo apenas aquelas
relacionadas aos objetos do estudo.
4.9 Avaliação dos desfechos dos estudos

Todas as avaliações clínicas serão realizadas por profissionais treinados quanto
às características dos implantes e próteses a serem avaliadas. Além disso, os
avaliadores sempre estarão sob supervisão dos pesquisadores responsáveis. Em todas
as consultas de acompanhamento serão realizadas avaliações clínicas e radiográficas,
avaliando-se desfechos primários e secundários relacionados aos implantes e próteses
sobre implante. Cabe salientar que tanto os exames clínicos e radiográficos realizados
em todas as consultas de reavaliação não acarretarão custos aos pacientes.
Desfechos primários - Implantes

O desfecho primário a ser avaliado será a sobrevivência do implante, que se refere
ao mesmo se encontrar na sua posição de instalação, no momento da consulta,
independentemente da condição dos demais componentes/tecidos a ele relacionados
(Albrektsson et al., 1986).
Desfechos secundários - Implantes
Os desfechos secundários dizem respeito ao sucesso do implante, e ao fato de
que todos os tecidos ao seu redor apresentam condição satisfatória (Misch et al., 2008)
(Tabela 1). Para esse estudo os desfechos avaliados serão profundidade de sondagem,
sangramento gengival, retração gengival, perda óssea ao redor do implante, condição
dos tecidos moles peri-implantares e satisfação do paciente.
Tabela 1. Escala de saúde para implantes dentários. Adaptada do artigo de (Misch et al., 2008)
Escala de Qualidade de Implante
Sucesso a) Sem dor ou sensibilidade durante atividade
b) Ausência mobilidade
c) <2 mm perda óssea radiográfica a partir da cirurgia de
instalação
d) Sem história de exsudatos
Sobrevivência Satisfatória a) Sem dor em função
b) Ausência mobilidade
c) 2 – 4 mm de perda óssea radiográfica
d) Sem história de exsudatos
Sobrevivência Comprometida a) Pode apresentar sensibilidade durante função
b) Sem mobilidade
c) Perda de osso radiográfico >4 mm (menor que 1/2 de
corpo de implante)
d) Profundidade da sondagem >7 mm
e) Pode ter história de exsudatos
Falha (Falha clínica ou absoluta) Qualquer dos seguintes parâmetros:
a) Dor durante função
b) Mobilidade
c) Perda de osso radiográfico >1/2 extensão do implante
d) Exsudatos não-controlados
e) Não estar mais em boca
4.10 Equipe
A equipe de atendimento hematológico será composta pelos profissionais do
Hemocentro Regional de Pelotas:
Cecília Fernandes Lorea - Hematologista, oncologista e pediatra
Aline Machado Feijó - Enfermeira
Jalusa de Oliveira Michel - Farmacêutica
Gisele Ortiz Heidrich Pinto - Assistente Social
A equipe de atendimento odontológico será composta por profissionais treinados
na área. A parte protética será efetuada por alunos de graduação e pós-graduação, sob
supervisão constante de professores. As reavaliações serão realizadas apenas por
docentes e alunos de pós-graduação pertencentes a pesquisa, previamente treinados e
calibrados.
4.11 Análise dos Dados

A análise estatística será realizada com o software SigmaStat (version 3.5; Systat,
Richmond, CA, USA). Análises descritivas serão usadas para caracterizar os implantes
e próteses confeccionados e as razões para as falhas. Curvas de sobrevivências serão
criadas usando o teste de Kaplan-Meier e o teste de Log-rank será usado para examinar
as diferenças entre os grupos de acordo com as variáveis (α=0.05).
4.12 Considerações Éticas

Esse projeto será submetido ao comitê de ética e pesquisa da FO-UFPel, e está
de acordo com a resolução nº. 196, de 10 de outubro de 1996, do Conselho Nacional de
Ética em Pesquisa. Todos os pacientes elegíveis serão informados dos objetivos do
estudo, riscos e benefícios associados aos procedimentos experimentais e os que
aceitarem participar assinarão um termo de consentimento livre e esclarecido (Anexo 1).
Aos que não aceitarem participar não será gerado nenhum prejuízo, com o tratamento
seguindo normalmente.
Em casos de insucesso/complicações, o protocolo será de atendimentos dos pacientes
pelos pesquisadores nos mesmos dias e local onde já ocorrem os tratamentos com
próteses sobre implantes e, quando houver necessidade, encaminhamento para
tratamento específico dentro da própria instituição.
5. Cronograma de atividades
2020
Período Jan Fev Mar Abr Mai Jun Jul Ago Set Out Nov Dez
Atividade
Seleção dos pacientes X X X X X X X X X X X
Procedimentos clínicos X X X X X X X X X
2021
Atividade
Seleção pacientes X X X X X X X X X X X X
Procedimento Clínicos X X X X X X X X X X X X
Rechamadas/Reavaliações X X X X X X X
Análise parcial dos dados e divulgação através de X X X X X X X
eventos e artigos científicos
2022
Atividade
Seleção pacientes X X X X X X X X X X X X
Procedimentos clínicos X X X X X X X X X X X X
Rechamadas/Reavaliações X X X X X X X X X X X X
2023
Atividade
Seleção de pacientes X X X X X X X X X X X X
Rechamadas/Reavaliações X X X X X X X X X X X X
Procedimentos clínicos X X X X X X X X X X X X
Análise dos dados e divulgação através de eventos X X X X X X X X X X X X
e artigos científicos
6. Orçamento detalhado
MATERIAL Qtd VALOR VALOR
INDIVIDUAL TOTAL (R$)
(R$)
Folhas de papel A4 para impressão (pacote com 500 folhas) 2 18,00 36,00
Anestésico local (caixa com 50 unidades) 4 60,00 240,00
Lâmina de bisturi nº 15C (caixa com 100 unidades) 1 50,00 50,00
Seringa Luer de 20 mL 50 1,00 50,00
Fio de sutura de nylon 4.0 (caixa com 24 unidades) 2 40,00 80,00
Sugador Cirúrgico 1 20,00 20,00
Agulha gengival (caixa com 100 unidades) 1 30,00 30,00
Soro Fisiológico 0,9% 10 ml 100 1,00 100,00
Compressa de gaze estéril 100 2,00 200,00
Solução de PVPI 1l 2 20,00 40,00
Silicone de condensação 1 150,00 450,00
Kit cirúrgico/protético Neodent 1 3.000,00 3.000,00
Total 4.246,00
O valor referente a aquisição dos implantes e componentes protéticos

serão pagos pelos pacientes diretamente aos fabricantes. Os valores referentes
a confecção das próteses também serão pagos diretamente pelos pacientes
para o laboratório de escolha. Para essas compras sempre serão apresentados
três orçamentos e o paciente escolherá o mais conveniente.
Os demais materiais de consumo necessários para a execução do projeto
serão bancados pelos pesquisadores.
7. Responsabilidades do Pesquisador e da Instituição
7.1. Responsabilidades dos Pesquisadores
Desenvolvimento de uma pesquisa criteriosa, visando o bem do paciente
e da comunidade e o desenvolvimento científico;
Cumprimento das metas de trabalho propostas no plano de trabalho.
Uso adequado dos equipamentos e da infraestrutura do local;
Divulgação dos resultados obtidos e do nome da Faculdade por meio da
apresentação deste trabalho em Congressos nacionais e, se possível,
internacionais, de maneira a mostrar a boa qualidade dos trabalhos
desenvolvidos na Faculdade de Odontologia da UFPel.
7.2. Responsabilidades da Instituição

Fornecer condições básicas para o desenvolvimento da pesquisa, tais
como: local adequado para trabalho, instalações elétricas e hidráulicas
adequadas, saídas de gases, fornecimento de materiais básicos;
Disponibilizar recursos humanos auxiliares (técnicos) para realizar
procedimentos de rotina, tais como a autoclavagem;
Facilitar a participação em Congressos e/ou Conferências para divulgação
dos resultados.
8. Critérios para suspender a pesquisa

Durante a realização de análise interina dos dados o pesquisador
responsável será obrigado a suspender a pesquisa imediatamente quando: (1)
Constatar algum risco ou danos à saúde do participante da pesquisa; (2)
Constatar superioridade de um método em estudo quando comparado ao outro,
onde o tratamento com melhor resultado será oferecido a todos os participantes
da pesquisa.
9. Local da Pesquisa
A pesquisa será desenvolvida na Clínica Oeste do 1º Andar da Faculdade
de Odontologia da UFPel, Pelotas/RS.
10. Infraestrutura
Clínica Oeste do 1º Andar da Faculdade de Odontologia da UFPel,
Pelotas/RS.
11. Propriedade das Informações

Após a realização da pesquisa, seus resultados serão tornados públicos
por meio de divulgação em revistas para fins acadêmicos e científicos, além de
congressos.
12. Características da População

Participarão deste estudo pacientes adultos hemofílicos, exemplo
Hemofilia A, Hemofilia B e Doença de von Willebrand atendidos no Hemocentro
Regional de Pelotas que possuam indicação para instalação de implantes
dentários e posterior confecção de prótese sobre implantes.
13. Descrição de métodos que afetem os participantes da pesquisa

Em nenhum momento será revelada a identidade destes pacientes.
Nenhum dos procedimentos a serem realizados trará qualquer prejuízo aos
voluntários e à sua integridade, e também não afetarão a saúde bucal dos
mesmos.
14. Fontes de material da pesquisa

Para cada paciente serão anotados dados pessoais, história médica,
história dentária, exames intra e extra-orais, história de antibioticoterapia prévia
ou outra medicação e exames de imagem, bem como questionários centrados
nos pacientes, visando um melhor entendimento de aspectos subjetivos dos
mesmos.
Os dados obtidos dos registros dos aspectos clínicos serão usados
unicamente para os propósitos da pesquisa.
15. Medidas para proteção de riscos e a confiabilidade

Serão observados os seguintes princípios: todos os passos serão
desenvolvidos em ambiente asséptico e com materiais estéreis. Os dados
obtidos serão usados unicamente para os propósitos da pesquisa. Em nenhum
momento será revelada a identidade do paciente.
Com relação aos questionários, em ocasião de possível desconforto ao
responder alguma questão dos questionários. Será disponibilizada ao
participante a opção “prefiro não responder”.
16. Previsão de ressarcimento de gastos

Caberá ao paciente arcar com custos referentes à compra dos implantes
dentários e da confecção da prótese fixa, conforme padrão adotado pela
Faculdade de Odontologia da UFPel.
A escolha da participação do projeto de pesquisa e dos procedimentos
clínicos é uma decisão compartilhada entre o pesquisador do estudo e o
participante de pesquisa. Em caso de danos decorrentes do estudo, o
participante de pesquisa tem direito à indenização de acordo com a Resolução
CNS N° 466 de 2012.
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18. Anexos
18.1 Termo de Consentimento Livre e Esclarecido - PACIENTES
Por meio deste termo você está sendo convidado a participar do projeto de pesquisa “Avaliação do nível de conhecimento de
estudantes e profissionais da Odontologia e dos aspectos psicológicos, necessidades odontológicas e tratamento e
acompanhamento de implantes dentários em pacientes com coagulopatias hereditárias”. Este trabalho tem por objetivo gerar
e divulgar conhecimento sobre o tratamento de pacientes com desordens da coagulação sanguínea com implantes dentários.
Informações: Os pacientes selecionados receberão implantes dentários e a confecção de próteses sobre implantes. O tipo do
implante e da prótese serão realizados de acordo com a especificidade de cada caso, seguindo as recomendações do fabricante e
os conhecimentos do pesquisador. Todos os procedimentos cirúrgicos (instalação de implantes e reabertura) e protéticos (moldagem,
confecção de provisórios) seguirão as recomendações dos fabricantes, desde o início até a conclusão do caso. Após o final do
tratamento o paciente será chamado todo ano para realização de consultas odontológicas a fim de acompanhar as condições de
saúde bucal. Caso o paciente apresente algum problema antes dessa consulta, ele também poderá buscar atendimento. Os custos
materiais do tratamento (implante dentários e parte laboratorial da prótese sobre implante) serão custeados pelo paciente. Caso o
paciente não queira participar da pesquisa (questionários de avaliações multidisciplinares), o tratamento não sofrerá nenhum
impedimento, sendo realizado seguindo os mesmos princípios supracitados.
Riscos: Na cirurgia de instalação de implantes o paciente estará sujeito aos seguintes riscos: (1) implante atingir algum nervo, com
possível perda de sensibilidade da região; (2) fratura de alguma parte da maxila ou mandíbula; (3) perfuração da membrana do seio
maxilar; (4) inchaço ou hematomas após a cirurgia; (5) perda do implante e necessidade de repetição da cirurgia. Com relação à
confecção das próteses, o paciente estará sujeito à riscos como: (1) reação alérgica aos materiais de moldagem, cimentação ou
látex das luvas; (2) desgaste de estruturas dentais para ajuste oclusal. Cabe salientar que os riscos citados são inerentes ao
tratamento, e não à participação na pesquisa. Caso algum destes imprevistos ocorra, os pacientes serão atendidos pelos
pesquisadores e/ou encaminhados para tratamento específico dentro da própria instituição; possíveis custos para nova colocação
de implantes serão arcados pelo próprio paciente. Os procedimentos de implantodontia são considerados cirurgias menores e,
portanto, possuem invasibilidade. Devido a particularidade dos indivíduos com coagulopatias hereditárias, os pacientes podem
apresentar algum sangramento prolongado; nesse caso, o procedimento será suspenso e esses indivíduos serão imediatamente
encaminhados para o serviço de referência (hemocentro ou hospital) para os devidos procedimentos visando a coagulação.
Benefícios: (1) O paciente receberá acompanhamento odontológico de profissionais qualificados antes, durante e após a conclusão
da prótese dentária; (2) ao final do tratamento o paciente apresentará melhora da sua capacidade mastigatória, estética e fonética;
(3) a confecção de próteses sobre implantes, em áreas edêntulas, evita o desgaste de estruturas dentais sadias para a reabilitação
dessas áreas, sendo assim uma estratégia mais conservadora. Os questionários multidisciplinares irão auxiliar no rastreio e/ou
diagnóstico de condições psicológicas, odontológicas ou médicas, contribuindo para o sistema de referência do Hemocentro Regional
de Pelotas. Esse projeto de pesquisa tem como objetivo gerar evidência médica e odontológica sobre o tratamento de indivíduos
com desordens hereditárias de sangramento, e sua participação contribuirá para os diferentes desfechos supracitados.
A escolha da participação do projeto de pesquisa e dos procedimentos clínicos é uma decisão compartilhada entre o pesquisador
do estudo e o participante de pesquisa. Em caso de danos decorrentes do estudo, o participante de pesquisa tem direito à
indenização de acordo com a Resolução CNS N° 466 de 2012.
Ao aceitar participar do estudo o(a) senhor(a) autoriza a execução dos procedimentos, autoriza o uso dos dados sobre suas
características e condições e o uso de imagens (Raio X e fotografias) quando essas forem necessárias. Os pesquisadores se
comprometem em manter sigilo e anonimato sobre os dados de cada paciente, sendo esses dados confidenciais, apenas acessíveis
para os pesquisadores e o próprio paciente.
O material com os dados e imagens (Raio X e fotografias) de cada paciente ficará sob os cuidados do professor responsável,
armazenados em arquivo na sala do mesmo, localizada no 5º andar do prédio da Faculdade de Odontologia da UFPel.
Lembramos que o(a) senhor(a) tem total autonomia em participar ou não da pesquisa, podendo, inclusive, desistir do estudo em
qualquer momento. A decisão de desistir não interferirá no tratamento inicialmente previsto.
Por esse termo, eu ___________________________________, RG n o __________________________ aceito participar do projeto

supracitado e autorizo a realização dos procedimentos descritos acima e a utilização de dados e imagens referentes à minha pessoa
pelos pesquisadores envolvidos no estudo.
Pelotas, ____/____/______ ________________________________________

Assinatura do paciente
_____________________________ ______________________________
Nome do pesquisador Assinatura do pesquisador
Qualquer dúvida o(a) senhor(a) pode entrar em contato com alguns dos pesquisadores responsáveis pelo estudo: Mateus Kinalski
(53 99990-4838) Mateus Bertolini (53 99934-9134). Cômite de Ética: R. Gonçalves Chaves 457, Centro, Pelotas, RS-Brasil; website:
https://wp.ufpel.edu.br/odontologia/; telefone: 3260-2821
1ª Via – Paciente 2ª Via - Pesquisador
18.2 Termo de Consentimento Livre e Esclarecido – ESTUDANTES E PROFISSIONAIS
Por meio deste termo você está sendo convidado a participar do projeto de pesquisa “Avaliação do
nível de conhecimento de estudantes e profissionais da Odontologia e dos aspectos
psicológicos, necessidades odontológicas e tratamento e acompanhamento de implantes
dentários em pacientes com coagulopatias hereditárias”. Este trabalho tem por objetivo gerar e
divulgar conhecimento sobre o tratamento de pacientes com desordens da coagulação sanguínea com
implantes dentários.
Informações: O conhecimento de profissionais e estudantes de Odontologia sobre as coagulopatias
hereditárias ainda permanece incerto. Dessa forma, é de fundamental importância que o conhecimento
sobre essas condições seja avaliado para que, se necessário, intervenções sejam feitas com objetivo
de disseminar e aprimorar o conhecimento sobre essa área. Essa pesquisa possui questionários
multidisciplinares que englobam aspectos relacionados ao conhecimento sobre a área de
coagulopatias hereditárias em Odontologia. Importante ressaltar que essa pesquisa é de caratér
voluntário e, caso o profissional/estudante não queira participar, não haverão prejuízos. Esse
questinário leva em média 5 minutos para ser respondido.
Riscos: Durante a participação no projeto não se caracterizará nenhum tipo de risco aos participantes
da pesquisa. Os questionários possuem respostas objetivas e, caso houver constrangimento, a
participação pode ser suspensa. Para a redução dos riscos, a pesquisa será aplicada de forma
independente.
Benefícios: Avaliar o nível de conhecimento de estudantes e profissionais da Odontologia acerca do
tratamento de pacientes com coagulopatias hereditárias de modo que se possa planejar estratégias
para gerar e divulgar conhecimento sobre o tratamento de pacientes portadores de hemofilias A e B e
doença de von Willebrand. Devido a particularidade do tema, com objetivo de aprimorar o
conhecimento, esses questionários irão auxiliar no diagnóstico, desenvolvimento e disseminação do
conhecimento da temática proposta pela pesquisa.
Ao aceitar participar do estudo o(a) senhor(a) autoriza a utilização de suas respostas e dados, em
caráter anônimo, quando essas forem necessárias. Os pesquisadores se comprometem em manter
sigilo e anonimato sobre os dados de cada respondente dos questionários, sendo esses dados
confidenciais, apenas acessíveis para os pesquisadores e o próprio respondente.
A escolha da participação do projeto de pesquisa e dos procedimentos clínicos é uma decisão
compartilhada entre o pesquisador do estudo e o participante de pesquisa. Em caso de danos
decorrentes do estudo, o participante de pesquisa tem direito à indenização de acordo com a
Resolução CNS N° 466 de 2012.
O material com os dados de cada questionário ficará sob os cuidados do professor responsável,
armazenados em arquivo na sala do mesmo, localizada no 5º andar do prédio da Faculdade de
Odontologia da UFPel.
Lembramos que você tem total autonomia em participar ou não da pesquisa, podendo, inclusive,
desistir do estudo em qualquer momento.
Por esse termo, eu ___________________________________, RG no

__________________________ aceito participar do projeto supracitado e autorizo a realização dos
procedimentos descritos acima e a utilização de dados e imagens referentes à minha pessoa pelos
pesquisadores envolvidos no estudo.
Pelotas, ____/____/______
________________________________________
Assinatura do
estudante/profissional
_____________________________ ______________________________
Nome do pesquisador Assinatura do pesquisador
Qualquer dúvida o(a) senhor(a) pode entrar em contato com alguns dos pesquisadores responsáveis
pelo estudo: Mateus Kinalski (53 99990-4838) Mateus Bertolini (53 99934-9134). Cômite de Ética: R.
Gonçalves Chaves 457, Centro, Pelotas, RS-Brasil; website: https://wp.ufpel.edu.br/odontologia/;
telefone: 3260-2821
1ª Via – Paciente 2ª Via - Pesquisador
Relatório do trabalho de campo
No início do projeto de doutorado, iniciamos uma análise da literatura e

verificamos que havia pouca evidência sobre a temática. Com objetivo de realizar um
estudo clínico sobre o uso de implante dentários em pacientes com coagulopatias
hereditárias, primeiramente optamos por realizar uma revisão de escopo sobre
procedimentos cirurgicos (procedimentos invasivos) em pacientes com coagulopatias
hereditárias. Analisamos mais de 220 artigos, verificando que a literatura estava
escassa sobre o uso de implantes nesses indivíduos. Assim, submetemos nosso
projeto aos orgãos responsáveis para dar inicio ao nosso estudo clínico.
Após aprovação do projeto, iniciamos os atendimentos clínicos dos pacientes.
Inicialmente, todos os indivíduos eram submetidos a uma profilaxia prévia no
Hemocentro Regional de Pelotas (Hemopel). Os atendimentos ocorreram
normalmente. No entanto, um paciente apresentou uma complicação hemorrágica
pós operatória. Essa intercorrência e os motivos pelas quais ocorreu fez com que
escrevessemos um artigo relatando a sua causa e suas medidas de controle e
tratamento. Operamos mais alguns pacientes, no entanto, nenhuma complicação
pós-operatória ocorreu durante esse periodo.
No mês de Março de 2020, a pandemia do coronavírus interrompeu as
atividades do projeto de pesquisa, assim como a possibilidade da inclusão de novos
pacientes. Desse modo, optamos por continuar o projeto em suas outras
metodologias sem a necessidade de atendimentos clínicos. Assim, pudemos iniciar
as revisões de escopo sobre outras temáticas, início da avaliação dos Hemocentro
Regionais do país (através de contato via email) e redação dos artigos que
previamente haviamos planejados.
Em virtude das dificuldade do período pandêmico, retornamos os atendimento
alguns meses depois para a realização das próteses sobre implante dos pacientes
operados. No entanto, foi inviavel retornar o atendimento e inclusão de novos
pacientes devido as necessidades de adequação da Faculdade de Odontologia.
Como inicialmente planejado, também não foi possivel avaliar os estudantes e
profissionais, uma vez que não houveram momentos propícios a análise dessas
amostras.
No entanto, é possivel observar nesse projeto de tese que outros caminhos
foram possíveis para a tentativa de aprimorar a evidência científica sobre o tema.
Embora o planejamento inicial tenha sido alterado, esse projeto resultou em sete
artigos científicos redigidos, sendo dois publicados em periódicos internacionais e
quatro artigos submetidos para revistas com alto fator de impacto.
Artigo 1 – Is there a difference in the oral health status of healthy
patients and those with inherited bleeding disorders? A systematic
review and meta-analysis of case-control studies
Authors:
Mateus de Azevedo Kinalski¹, Lucas Peixoto de Araujo², Mateus Bertolini Fernandes dos Santos³
1
Assistant Professor, Faculty of Dentistry, Community University of Chapecó Region, Chapecó, SC, Brazil.
2
Department of Restorative Dentistry, Division of Endodontics, Piracicaba Dental School, State University of
Campinas (UNICAMP), Piracicaba, SP, Brazil
³ Graduate Program in Dentistry, Federal University of Pelotas, Gonçalves Chaves St, 457, 96015-560, Pelotas,
RS, Brazil
Email:
Mateus de Azevedo Kinalski: mateus_kinalsk@hotmail.com
Lucas Peixoto de Araujo: lucaspeixoto94@gmail.com
Mateus Bertolini Fernandes dos Santos: mateus.santos@ufpel.edu.br
Corresponding author:
Mateus Bertolini Fernandes dos Santos
School of Dentistry, Federal University of Pelotas, Pelotas, RS, Brazil
457 Gonçalves Chaves street, room 502, Pelotas, RS, Brazil. 96015-560
Phone: +55 53 999349134 mateus.santos@ufpel.edu.br
Acknowledgments:
This study was partly financed by Coordination for the Improvement of Higher Education Personnel (CAPES)
Finance Code 001.
The authors declare no conflict of interest.
Keywords: inherited bleeding disorders, caries, DMFT, case-control, meta-analysis

Is there a difference in the oral health status of healthy patients and those with inherited
bleeding disorders? A systematic review and meta-analysis of case-control studies
Objectives: The aim of this systematic review and meta-analysis of case-control studies was to
identify the differences in oral health status between inherited bleeding disorders (IBDs) and
healthy patients.
Data: Only case-control studies were included in this review. The risk of bias was assessed
using the NOS tool. The random-effects meta-analysis was performed for DMFT and Oral
Health Index outcomes.
Sources: Online databases were searched to identify studies reporting a comparison between
IBDS oral health conditions (DMFT, Oral Health Index) and healthy patients.
Study selection: Eight case-control studies were included. The majority of the included studies
presented a high degree of methodological quality, while one presented a high risk of bias. A
meta-analysis regarding the mean DMFT between IBDs and healthy patients reported that
children and teenagers (p=0.52; I² = 73%) or adult patients (p=0.96, I²= 0) did not presented
statistically significant differences compared to control groups. The overall DMFT mean
difference between IBDs and healthy patients was -0.18 (p=0.64, I²=0).
Conclusions: There are no differences considering the caries experience of inherited bleeding
disorders compared to healthy patients.
Clinical significance: The available evidence indicates that patients with inherited bleeding
disorders presents similar caries experience with healthy subjects.
Keywords: inherited bleeding disorders, caries, DMFT, case-control, meta-analysis

INTRODUCTION
Inherited bleeding disorders (IBDs) are a heterogeneous group of genetic conditions,
where missing or defective clotting factors prevent normal blood clotting from occurring
(Peyvandi, Duga et al. 2002). Among them, the most common conditions are hemophilia A
(factor VIII [FVIII] deficiency), hemophilia B (factor IX [FIX] deficiency), and von
Willebrand disease (von Willebrand factor [VWF] deficiency), corresponding to more than
95% of all IBDs (Mannucci, Duga et al. 2004).
According to the 3rd guideline of the World Federation of Hemophilia (WFH), for the
maintenance of good oral health in these patients, it is important to avoid the necessity of dental
extractions (Srivastava, Santagostino et al. 2020). Also, it is important to provide dental care
for children and adults, preventing periodontal diseases and dental caries, adapting the
strategies to the individual needs of IBDs patients. In this perspective, the oral health status
becomes important to understand the differences between the conditions of IBDs patients;
While some studies reported that there is a high prevalence of oral bleeding, mainly during the
time of eruption or exfoliation, another reported a low prevalence of dental caries (Salem and
Eshghi 2013, Reddy, Reddy et al. 2019).
Dental caries is one of the most prevalent chronic diseases globally, affecting more than
60% of patients worldwide (Kassebaum, Smith et al. 2017). Considering the epidemiology of
dental caries, the use of specific parameters allows identifying the differences between
experience, prevalence, or incidence of decayed teeth. One of the most applicable methods is
the DMFT (decayed, missed, filled, or treated index), which is used to identify the caries
experience. According to the last ORCA consensus, it could identify “the number of
teeth/surfaces that have caries lesions, restorations, and/or is missing due to caries, accumulated
by an individual”(Machiulskiene, Campus et al. 2020), and is also easy to be applied in large
sample and populational studies.

To the best of our knowledge, there is a lack of well-designed studies identifying the
prevalence of oral conditions in IBDs patients (Zaliuniene, Peciuliene et al. 2014). Moreover,
it is important to identify precisely the status of these conditions to enhance the health policies
for IBDs patients, once the necessity of dental treatment must be performed under specific
medical conditions (e.g., use of factor concentrates) and some procedures (e.g., dental
extractions) could pose risks to the patient integrity (de Azevedo Kinalski, Sarkis-Onofre et al.
2021). Therefore, the present systematic review and meta-analysis of case-control studies aim
to identify the differences in oral health status between IBDs and healthy patients.
MATERIALS AND METHODS

Protocol and registration
The protocol of this study was registered at PROSPERO (CRD42021278228) and the
report written based on the MOOSE (Meta-Analysis of Observational Studies in
Epidemiology) (Stroup, Berlin et al. 2000).
Eligibility and exclusion criteria
The PICO framework was conducted with patients presenting inherited bleeding
disorders (IBDs) compared to healthy patients submitted to oral health examinations (e.g.:
DFMT, dfms, Oral Health Index). Only observational case-control studies that matched the
PICO framework were included for analyses in the present review. No limit regarding the year
of publication or language restriction was applied as excluding factors.
Search strategy
Five electronic databases (PubMed/MedLine, Cochrane Library, Web of Science,
Scopus, and Scielo) were systematically searched until September 2021. The specific keywords
used to carry out the search were selected based on PubMed/MedLine MeSH terms and were
adjusted for the other databases following the search strategy detailed in Supplementary Table
1. The gray literature and the reference lists in the included studies were also carefully searched
to identify any additional eligible studies. All relevant studies retrieved by the search strategy
were imported into a reference manager software (Mendeley Desktop, version 1.17.11,
Mendeley Ltd. George Mason University, USA) to remove duplicates.
Selection process
Titles and abstracts of all studies identified by the search strategy were read and
reviewed independently by two authors (M.A.K and L.P.A). Studies that seemingly met the
eligibility criteria and those classified as unclear by title and abstract reading were selected for
full-text assessment. Among the papers read in full, only those that fulfilled all the eligibility
criteria were included in this systematic review and processed for data extraction, while reasons
for exclusion were recorded (Figure 1). In each search step, the two reviewers compared their
list of papers; in case of disagreement, a final decision of inclusion or exclusion was performed
following discussion and consensus with a third author (M.B.F.S).
Data collection process
Data from included papers were independently extracted and registered by two
researchers. The reviewers inserted data in a spreadsheet in Excel format (Microsoft
Corporation, Redmond, WA, USA), including the authors, publication year, country, total
sample (case and control), the mean age of participants (case and control), diagnosis of
inherited bleeding disorder, and assessed oral health index. The oral health indexes included in
this study were DMFT (decayed, missed, filled, or treated teeth) (mean and standard deviation),
dfms (mean and standard deviation), and Simplified Oral Hygiene Index (OHI-S) (mean and
standard deviation).
Quality assessment
Two researchers (M.A.K and L.A.P) independently conducted a quality assessment of
each study using the Newcastle-Ottawa Scale for case-control studies (NOS) (Stang 2010).
Study quality was graded on a scoring system with a maximum of 9 stars (4 for ‘Selection’, 2
for ‘Comparability’, and 3 for ‘Exposure/Outcome’) spread across nine parameters: definition
of cases; representativeness of the cases; selection of controls; adequate control definition;
comparability of cases; study controls for the basis of the analysis; ascertainment of the
exposure; ascertainment of the same method used for cases and controls; and non-response
rate. Differences in assessment and grading were resolved by discussion with a third researcher
(M.B.F.S). The included studies were considered with high methodological quality when the
overall scores were 8-9; medium quality 7, and poor quality when the study scored six stars or
lower.
Summary measures
The primary outcome of the present study was the mean of the DFMT index. The
quantitative synthesis was performed by a meta-analysis considering the mean differences
between IBDs and healthy patients. Meta-analysis was possible when 2 or more studies
presented the same measures. A subgroup meta-analysis was performed when the studies
presented different age groups between participants. Statistical analysis was performed on the
software RevMan (RevMan 5.3, The Nordic Cochrane Centre, Copenhagen). Heterogeneity
was considered to be high and results unreliable if I² values were >75%.
RESULTS
The details of the search and selection processes are described in the PRISMA
schematic flowchart (Figure 1). The search yielded a total of 370 potentially eligible studies.
The duplicated registers were removed, and 355 studies were left for a title and abstract
screening. Thereafter, the remaining 8 articles fulfilled all the inclusion criteria and are
shortlisted in this review. The various reasons for the exclusion of studies are also available in
Figure 1.
Studies characteristics
This review included a total of eight case-control studies published in the last three
decades. The total sample was composed of 932 patients (Cases = 471; Controls = 461). The
studies were performed in America, Asia, and Europe. Six studies reported data exclusively
from children or teenagers, while two studies also included adult patients.
Quality assessment
According to the parameters established by the NOS quality assessment scale (Table
2), the majority of the included studies (Mielnik-Błaszczak 1999, Sonbol, Pelargidou et al.
2001, Salem and Eshghi 2013, Zaliuniene, Peciuliene et al. 2014, Othman, Sockalingam et al.
2015, Kumar, Pai et al. 2018, Salem, Seyyedkhamesi et al. 2018) presented a high degree of
methodological quality, while one (Benito Urdaneta, Benito Urdaneta et al. 2008) presented
low methodological quality. The parameter that had a low quality was inside the ‘Selection’
domain, in the ‘selection of controls’ subgroup. Most of the studies that scored poorly on this
parameter reported having a convenient control sample since the healthy patients were hospital
controls instead of community controls.
Synthesis of results
The primary outcome assessed in this study was the difference between DMFT
considering IBDs and healthy patients. Six studies were included in the meta-analysis, and
figure 2 shows that there were no statistically significant differences between the mean DMFT
between IBDs and healthy patients considering children and teenagers (p=0.52; I² = 73%) or
adult patients (p=0.96, I²= 0). The overall DMFT mean difference between IBDs and healthy
patients was -0.18 (p=0.64, I²=0).

The secondary outcome assessed in this study was the difference between Oral Hygiene
Index (OHI-S) considering IBDs and healthy patients. Three studies were included in the meta-
analysis, where no statistically significant differences were observed (p=0.54, I² = 94 %)
(Figure 3). However, the heterogeneity in this analysis was considered extremely high.
DISCUSSION
To the best of our knowledge, this systematic review is the first study to compare the
oral health conditions of IBDs and healthy patients. According to the 3rd WFH guidelines, there
is a necessity of education on the importance of good oral hygiene in patients with IBDs, in
order to prevent any dental problems and its possible complications, since these conditions
impose a higher risk of spontaneous gum bleeding, increased risk of bleeding during dental
extractions, and the risk for hospitalization due to oral problems could be up to 27 times greater
than a healthy patient (Othman, Sockalingam et al. 2015, Srivastava, Santagostino et al. 2020).
On the other hand, there is also a necessity of more studies and discussion among dental
professionals regarding the importance of an adequate oral health in IBDs patients, considering
that sometimes treatment to these patients are neglected due to difficulties in finding a dentist
willing to treat these patients (Schaffer, Duong et al. 2016).
Dental caries is the most prevalent disease worldwide, affecting both the quality of life
and the general health conditions of its patients (Schwendicke, Dörfer et al. 2015). In the
present meta-analysis, we used the DMFT as the oral health status index, since its use is already
acknowledged in the dental literature (Machiulskiene, Campus et al. 2020). It was observed
that the mean DMFT comparing IBDs and healthy patients did not present significant
differences among these groups (Figure 2). Also, the overall result demonstrated that there
were no differences irrespective of age (children and teenagers or adults). One could suppose
that caregivers, parents, or even patients with IBDs are already aware of the risks that a poor
oral hygiene can impose to them, such as gum bleeding, dental caries, and the need for other
invasive dental procedures.
The maintenance of adequate oral health of IBDs patients must be a paramount due to
different reasons. First, most non-invasive dental procedures can be performed with the use of
antifibrinolytics only, without the need of factor concentrates infusion (Rasaratnam, Chowdary
et al. 2017). On the other hand, some usual and simple procedures like an anesthetic nerve
block to perform deep dental restorations or root canal treatment might require factor infusion
as prophylactic therapy , which leads to a considerable increase in the medical costs (Brewer,
Roebuck et al. 2003). During the life-course of IBDs patients, it is expected that they will need
factor concentrate infusion for several reasons (Rocha, Carvalho et al. 2015) and it is known
that the indiscriminate use of such concentrates could lead to the development of antibodies,
so-called inhibitors (Xi, Makris et al. 2013). Thus, an adequate follow-up of IBDs patients with
periodic routine visits is advised in order to detect and treat any oral problem in its beginning
without the need of invasive procedures, reducing the risks for developing inhibitors to factor
concentrates. Another important reason is that the factor concentrate infusion therapy is very
expensive and is reported to financially impact public health systems throughout the world
(Rocha, Carvalho et al. 2015, Croteau, Cheng et al. 2019).
Previous studies have indicated the importance of a multidisciplinary staff when
treating IBDs patients, whereas it is highly recommended that these patients should be referred
to a hematologist prior to any dental procedure in order to develop a customized assessment
for risks and need for prophylactic therapy (de Azevedo Kinalski, Brondani et al. 2021, de
Azevedo Kinalski, Sarkis-Onofre et al. 2021).
It is known that systematic reviews and meta-analyses are considered the top level of
scientific evidence due to their study design that gathers and summarizes data from well-
designed and well-conducted studies. However, it is fair to highlight that the present study
presents some limitations. Considering the Oral Health Index (OHI-S), we performed a meta-
analysis including only three studies. Although no statistical differences were found, these
results should be interpreted with caution since an extremely high heterogeneity was observed
(I² = 94 %). Another important limitation is that we could not perform a subgroup meta-analysis
dividing the specific IBDs conditions (Hemophilia A, B, and von Willebrand’s disease) with
the oral health indexes and compare them to the healthy controls due to the lack of published
data.
CONCLUSION
Within the limitations of the present study, it is possible to conclude that there are no
differences considering the caries experience of inherited bleeding disorders compared to
healthy patients.
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TABLES
Table 1. Characteristics of studies
Author (year) Diagnosis Tool Sample Case (group) Case Mean Control Mean
Age (SD) Age (SD)
Simplified Oral Hygiene
200 Hemophilia A
Kumar et al. Index (OHI-S) 20.02 (2.3 –
(Case 100; Control 20.07 (2 – 73)
(2018) 71)
100) Hemophilia B
DMFT
Hemophilia A
Mielnik- Oral Hygiene Index
160 Hemophilia B 4 to 18 years
Blaszczak 4 to 18 years old
(Case 80; Control 80) old
(1999) DMFT
Willebrand's
DMFT
Hemophilia A
Othman et al. Oral Hygiene Index 100
11.74 (0.36) 12.02 (0.22)
(2015) (Case 50; Control 50) Hemophilia B
Modified Gingival Index
(MGI)
Hemophilia A
Hemophilia B
DMFT Von
Salem and 92
Willebrand's 7.6 (4.20) 7.5 (3.4)
Eshghi (2013) (Case 46; Control 46)
Oral Hygiene Index disease
Other
conditions*
DMFT
Hemophilia A
Salem et al. Dmft 106
Hemophilia B 10.49 (4.21) 10.5 (4.07)
(2018) MGI (Case 53; Control 53)
FVII deficiency
Plaque index
DMFT
dmft Hemophilia A
Sonbol et al. 68
DMFS 8.8 (3.4) 9.8 (3.1)
(2001) (Case 38; Control 30)
dmfs Hemophilia B
Plaque index
Simplified Oral Hygiene von
Urdaneta et al. Index (OHI-S) 67 Willebrand’s' 10 to 72 years 10 to 72 years
(2008) (Case 40; Control 27) disease old old
Gingival index
Hemophilia A
Zaliuniene et
DMFT 147† 26.1 (14.4) 26.1 (14.4)
al. (2014) (Case 72; Control 75) Hemophilia B
† based on the DFMT sample
Table 2. Risk of bias (Newcastle-Ottawa Scale)
Study Selection CMP Exposure/Outcome Total
stars
S1 S2 S3 S4 C1 C2 E1 E2 E3
Kumar et al.
* * B * * * * * * 8
(2018)
Mielnik-
* * * * * * * * * 9
Blaszczak (1999)
Othman et al.
* * * * * * * * * 9
(2015)
Salem & Eshghi
* * B * * * * * * 8
(2013)
Salem et al.
* * * * * * * * * 9
(2018)
Sonbol et al.
* * B * * * * * * 8
(2001)
Urdaneta et al.
* * C * * - * * C 6
(2008)
Zaliuniene et al. * * * * * * * * * 9
(2014)
S1: Definition of cases, S2: Representativeness of the cases, S3: Selection of controls, S4: Adequate control
definition; CMP: Comparability, C1: Comparability of cases, C2: Study controls for the basis of the analysis; E1:
Ascertainment of the exposure, E2: Ascertainment of the same method used for cases and controls, E3: Non-
response rate.
FIGURES
Figure 2. Meta-analysis comparing the mean DFMT between IBDs and healthy patients.
Figure 3. Meta-analysis comparing the mean Oral Health Index (OHI-S) between IBDs and healthy
patients.
Artigo 2 - Inherited bleeding disorders in oral procedures.
Assessment of prophylactic and therapeutic protocols: a scoping
review
Running title: Bleeding disorders and dentistry
Mateus de Azevedo Kinalski, M.Sc.; PhD student, Graduate Program in Dentistry, Federal
University of Pelotas (UFPEL), Pelotas, RS, Brazil.
Rafael Sarkis-Onofre, Ph.D; Assistant Professor, Graduate Program in Dentistry, Meridional
University (IMED), Passo Fundo, RS, Brazil.
Mateus Bertolini Fernandes dos Santos, Ph.D; Assistant Professor, Graduate Program in
Densitry, School of Dentistry, Federal University of Pelotas (UFPEL), Pelotas, RS, Brazil.
ACKNOWLEDGEMENTS
This study was financed in part by Coordination for the Improvement of Higher Education
Personnel (CAPES) Finance Code 001. RSO is funded in part by Meriodional Foundation
(Passo Fundo – Brazil).
CONFLICT OF INTEREST
The authors stated that they had no interests which might be perceived as posing a conflict or
bias.
*Artigo publicado no Australian Dental Journal.

DOI: 10.1111/adj.12813
Abstract
Background: This scoping review aimed to map available evidence regarding
minor/major oral procedures in patients with inherited bleeding disorders (IBDs).
Methods: Studies in medicine or dentistry that reported minor and major oral
procedures in individuals presenting IBDs (e.g. hemophilia A or B, von Willebrand
disease) were selected. Search and screening were performed in PubMed/Medline,
Scopus, Web of Science, and Cochrane Library by two independent researchers.
Results: Initial search yielded 4152 citations, of which 257 were included in the final
analysis. Most of the evidence for prophylaxis use was derived from observational
studies and the most-commonly reported prophylactic protocols were fresh frozen
plasma and factor VIII concentrate. A considerable number of studies reported
postoperative complications and hospitalizations.
Conclusion: The present study identified that (1) there is room for new studies to
assess the use of antifibrinolytic agents with no factor replacement; (2) to date the use
of factor replacement therapy is the most indicated approach when treating patients
with IBDs with adjunct systemic or local antifibrinolytic agents to reduce post-operative
complications; and (3) there is a critical need for high-quality evidence studies since
much of the conclusions of the included studies are not supported by statistical
analysis.
Keywords: complication; hemophilia; inherited bleeding disorders; prophylaxis; von

Willebrand’s disease.
INTRODUCTION
Inherited bleeding disorders (IBDs) are a heterogeneous group of genetic
conditions, where missing or defective clotting factors prevent normal blood clotting
from occurring (Peyvandi, Duga et al. 2002). Among them, the most common
conditions are hemophilia A (factor VIII [FVIII] deficiency), hemophilia B (factor IX [FIX]
deficiency), and von Willebrand disease (von Willebrand factor [VWF] deficiency)
corresponding to more than 95% of all IBDs (Mannucci, Duga et al. 2004).
IBDs can present as mild, moderate, or severe depending on the levels of
clotting factors in the blood. The severity of such conditions is directly related to the
increase in episodes of spontaneous or traumatic bleeding, impacting patients’ lives.
Easy bruising, epistaxis, joint bleeding with evolution to hemarthrosis at a young age,
and menorrhagia in women are among the most frequent symptoms and complications
observed in patients with IBDs (Kruse-Jarres, Oldenburg et al. 2019, Winikoff, Scully
et al. 2019).
For invasive procedures in this patient group, replacement therapy is widely
recommended and is considered key to reaching adequate hemostasis (Srivastava,
Brewer et al. 2013, Aledort, Mannucci et al. 2019). However, due to the high costs of
clotting factor concentrates, different protocols have been employed for similar elective
procedures, which could lead to increased risk of bleeding complications when low
dosages are used, increased costs due to unneeded over-dosage, or development of
clotting factor antibodies (so-called inhibitors) (Mannucci and Tuddenham 2001,
Berntorp and Shapiro 2012). Treatment of IBDs is also linked to increased secondary
and indirect costs, such as hospitalizations, need for additional therapies, and reduced
work productivity for the patients (Chen 2016). Alternative approaches with lower
costs, such as the use of antifibrinolytics, can contribute to reduced adverse effects
after invasive procedures without the need for replacement therapy (van Galen,
Engelen et al. 2019).
Although some of the challenges have been highlighted in the last few decades,
there is still a lack of evidence on the performance of oral invasive procedures in
patients with IBDs. These procedures can involve higher rates of excessive bleeding
and a higher incidence of complications, including the need for hospitalization
(Hewson, Daly et al. 2011, Laffan, Lester et al. 2014). Likewise, a recent retrospective
study presented at the 2020 World Federation of Hemophilia (WFH) Virtual Summit
(Lim 2020) suggests that dental extractions can be safely conducted when
antifibrinolytic agents are used, with no factor replacement. Nevertheless, the last
WFH Guideline suggests that oral invasive procedures must consider the hemostasis
management individually under the advisement of a hematologist (Srivastava,
Santagostino et al.). Therefore, the present study was designed as a scoping review,
to assess the available evidence regarding minor and major oral procedures (dental
extractions, implant placements, orthognathic surgery, and periodontal treatments) in
patients with IBDs considering the study design, methodological standards, studied
IBD, main outcome, type of anesthesia, reported use of prophylaxis and protocol,
reported complication, and need of hospital admission.

The protocol of this study was based on the framework proposed by Peters et
al (Peters, Godfrey et al. 2015) in a publication of the Joanna Briggs Institute, and is
available at the Open Science Framework at the following link: (https://osf.io/4k6e8/).
The report of this scoping review was based on PRISMA Extension for Scoping
Reviews (Tricco, Lillie et al. 2018).
To standardize the wide variability of oral procedures, we divided the studies
into two wide areas (oral surgery and periodontics), and we further grouped into minor
and major oral procedures based on a previous classification (Solimeno, Escobar et
al. 2018). Minor procedures were considered to be those performed with lower
invasiveness (Oral surgery: ≤3 teeth extracted, or ≤3 implant placements;
Periodontics: Scaling or root planing) and major procedures those with surgical-level
invasiveness (Oral surgery: ≥3 teeth extracted, third molar extraction, or ≥3 implant
placements; Periodontics: Periodontal surgeries, crown augmentation, subgingival
scaling, or root planing).
We selected studies in medicine or dentistry that reported minor and major oral
procedures in individuals presenting any IBDs (e.g. hemophilia A or B, von Willebrand
disease). Studies were included regardless of methodological design, previous IBDs
diagnosed, or prophylaxis protocols.
The search was performed in four databases (PubMed/Medline, Scopus, Web
of Science and Cochrane Library) without date restrictions (the last search was
performed on 11 November 2019) and limited to articles written in the English
language. The adopted search strategy was drafted using PubMed/Medline MeSH
terms and was adapted for the other databases (Supplementary 1).
The search was made using reference manager software (EndNote X7,
Thomson Reuters, New York, NY). Two researchers independently (M.A.K and R.S.O)
identified the articles by first analyzing titles and abstracts. Retrieved records were
then classified following the eligibility criteria as include, exclude, or uncertain. Full-
text articles of the included and uncertain records were screened by the same two
reviewers and criteria. Discrepancies in the screening of titles/abstracts and full-text
articles were resolved through discussion. In case of disagreement, the opinion of a
third reviewer (M.B.F.S) was garnered.
A Microsoft Excel spreadsheet was created to allow data extraction. This
spreadsheet was tested and discussed by the reviewers to standardize data collection.
Then, one of the reviewers (M.A.K) extracted the data and another reviewer (R.S.O)
double-checked it. The following data were collected: study design (cases studies,
observational studies, cohort studies, clinical studies, reviews or systematic reviews,
and guidelines/consensus) and methodological aspects (publication year, country,
and when applicable, study registration, sample size calculation, IBDs studied, main
outcome, type of anesthesia, reported use of prophylaxis and its protocol, reported
complication, and hospital admission). Observational and clinical trial studies were
further classified according to the specific trial design (e.g. retrospective, prospective,
non-randomized, or randomized).
The level of evidence was determined according to the original evidence
pyramid (Friedman, Furberg et al. 2010). Also, it is important to state that although
Consensus/Guidelines are not present in the pyramid, we opted to add it at the top of
our evidence level assessment considering that such papers are usually published as
a result of experts’ consensus conferences or following high-quality clinical studies
(Djulbegovic and Guyatt 2017).
A descriptive analysis was performed that considered: (1) study design; (2)
patients’ IBD; (3) if the condition was previously diagnosed (yes or not); (4) the specific
area (oral surgery or periodontics); (5) the type of procedure (minor or major, as
described above) (6) type of anesthesia (local or general); (7) prophylaxis (performed
or not performed); (8) prophylaxis protocol (blood transfusion, replacement therapy, or
medications); (9) complications (occurred or absent); and (10) hospitalization (yes, no,
or not reported). Tables and figures were created to present the synthesis of results.
Finally, we created a word cloud figure to illustrate the frequency of adopted
prophylactic protocol according to the level of evidence of the included studies.
RESULTS
SEARCH FINDINGS
Figure 1 presents the flow chart for the study selection. The search initially yielded
4152 potentially relevant studies. After the removal of duplicates (979) and irrelevant
articles (2827), 346 studies met the eligibility criteria based on title and abstract. These
were obtained and full-text screened, resulting in 257 studies being included in the
analysis (Supplementary 2). The included studies were classified by year and level of
evidence (Figure 2) and will be reported in this section according to the study design.
CASE REPORTS
Seventy-eight oral surgery (OS) and two periodontics (PE) case report studies
were included (Table 1). Hemophilia A (32·1%) was the most prevalent studied
condition, and the vast majority of the patients were previously diagnosed (OS 92·3%;
PE 100%).
Most of the case report studies reported major procedures (≥3 extracted teeth,
third molar extraction, periodontal surgery, or ≥3 implant placements) (OS 43%; PE
50%), under general anesthesia (OS 52·5%), and reported prophylaxis (OS 77·3%;
PE 50%), of which replacement therapy (OS 53·4%; PE 100%) was the most common
prophylactic protocol. Postoperative complications were reported in 44·3% of OS case
reports, while the two PE case reports reported complications after the procedures.
CASE SERIES
Twenty-eight studies reporting OS procedures and four studies reporting PE
procedures were included (Table 2). Hemophilia A (35·7%) was the most-reported
condition, while hemophilia B (3·6%) was the least. Most of the patients were
previously diagnosed (OS 96·4%, PE 100%).
Tooth extraction (OS 96%) and periodontal surgery (PE 75·0%) were the most-
reported procedures. The type of anesthesia was not cited in 42·8% of OS studies,
while 50% of PE studies reported local anesthesia. Prophylaxis was performed in most
of the case series studies (OS 85·2%; PE 100%), for which replacement therapy (OS
60·9%; PE 50%) and medications (OS 21·7%; PE 25%) were the most common
approaches. Half of the OS studies reported complications, while no PE study reported
any. Procedures performed in hospital settings were reported in 32·2% of OS and 50%
of PE case series studies.
OBSERVATIONAL STUDIES
Forty-four OS and three PE observational studies were included (Table 3). Most
of them were retrospective studies (OS 70·5%; PE 100%). Most of the studies included
patients with hemophilia and von Willebrand disease (OS 34·1%; PE 33·3%), followed
in frequency by hemophilia (FVIII, FIX, or both) (OS 29·6%; PE 0%).
The main reported outcomes were clinical (OS 81·8%; PE 100%). In studies
that reported clinical outcomes, the type of anesthesia was not cited in 58% of OS
studies, while general anesthesia was performed in all PE studies. Prophylaxis was
performed in the majority of the observational studies (OS in 89·7%; PE 100%), where
replacement therapy was reported to be the most prevalent prophylactic protocol (OS
53·8%, PE 33·3%). Most studies reported complications (OS 77·4%, PE 100%), and
66·7% of OS patients were treated in hospital settings.
COHORT STUDIES
Two cohort studies were included in our analysis. Both addressed OS outcomes
while one of them also addressed PE outcomes.
Hemophilic patients undergoing OS had higher rates of postoperative bleeding
events and VWF-affected subjects presented higher odds ratios of bleeding
complications after tooth extraction than non-affected VWF non affected; In the same
analysis, root scaling and/or planing presented 8·9-fold higher odds of postoperative
bleeding in PE patients.
CLINICAL STUDIES
Twenty-four OS clinical studies and two PE clinical studies were included (Table
4). OS clinical studies included slightly more non-randomized (54·2%) than non-
randomized studies, whereas both of the PE studies were randomized clinical trials.
Hemophilia (FVIII, FIX, or both) was the most cited IBD condition (OS 33·3; PE
100%). The main outcomes of OS studies were therapeutics (OS 45·8%) while both
of the PE studies addressed the adjunctive use of local hemostatic agents along with
prophylactic measures. More than half of the OS clinical studies did not report the type
of anesthesia used, but 90·9% reported the use of prophylaxis, with replacement
therapy being the most common approach (31·6%). Also, 73·7% of the OS studies
reported complications, and 23·8% reported hospitalization. Local anesthesia was
reported in both of the PE clinical studies and neither reported hospitalization.
Although it was reported that some patients presented bleeding as a complication,
none required factor replacement therapy to manage it.
REVIEWS
Forty OS reviews were included, the first published in 1939, and the last in
2019. Of the included reviews, 90% were narrative literature reviews, three (7·5%)
were systematic reviews of clinical studies, and one (2·5%) was a guideline review.
Among the interventions, the other is the update from a previous version from the
same authors. Hemophilia (FVIII, FIX, or both) was most commonly reported (52·4%
of patients), followed by all-cause IBDs (any diagnosed IBD; 35·7%) and von
Willebrand disease (11·9%). The main study outcomes were patient’s management
(57·1%), followed by therapeutics (23·8%), and local hemostatic therapies (9·5%).
Five reviews addressing PE were included, the first published in 1973 and the
last in 2018. All PE studies were narrative literature reviews, of which three had non-
standardized hemophilia (FVIII, FIX, or both) subjects, while the other two described
non-standardized IBDs. Among them, four addressed the management of the patients,
while one described treatment outcomes.
CONSENSUS/GUIDELINES
Two consensuses were included in our analysis. One addressed patients with
any IBD and was written by hospital-based dentists in Australia regarding OS
procedures (tooth extraction and implants placement). Another considered patients
with hemophilia and clotting factor inhibitors and the need for tooth extraction,
recommending doses of bypassing agents for such patients. Also, it is reported that
single tooth extractions must be considered minor surgeries and multiple teeth
extractions as major surgeries in that specific group.
Four guidelines were included in our analysis. One addressed subjects with
IBDs receiving PE treatment. The authors suggested that when PE treatment must be
performed, routine supragingival scaling and prophylaxis is unlikely to cause
prolonged bleeding. However, additional therapies are recommended when more
invasive periodontal procedures or procedures on patients with severe stages of
periodontal disease would be performed. Of the three reviews which focused on OS,
one addressed patients with von Willebrand disease and other hemophilic patients,
while the others addressed patients with IBDs in general. These guidelines reported
the management of IBDs subjects prior and after OS, while one, in particular, reported
the necessity of a hospital environment to treat moderate and severe cases.
OTHER STUDY DESIGN ELEMENTS
Letters to the editor (n = 19) were also included in our study. The first published
letter was in 1957 and the last in 2019. The most-reported outcome was tooth
extraction with prolonged bleeding.
Six editorials addressed OS treatments, the first in 1959, and the last in 2013.
Three addressed tooth extractions, one the need for general anesthesia, and the other
two hemostasis in patients with IBDs. Also, another editorial was published in 1960
regarding PE treatment. This editorial suggested that in the case of periodontal
inflammation and infection, where spontaneous hemorrhage is apparent, hospital
admission and replacement therapy is advised.
Figure 3 presents a word cloud illustration of the prophylactic therapeutics adopted in
the included studies. We highlight that most of the evidence about prophylactic
protocols are from observational studies and that the most-reported prophylactic
protocols included fresh frozen plasma or factor VIII concentrate.
REPORTED COMPLICATIONS
Table 5 presents the descriptive analysis of complications (number, absolute,
and relative frequencies) according to each study design. Bleeding was the main
complication reported by the studies, presenting high values of absolute frequencies
and 100% of relative frequencies in all study designs. Edema and swelling were also
reported in some studies, as well as apnea, bronchopneumonia, dysphagia, dry
socket, and seizure.
DISCUSSION
The present scoping review was performed to summarize existing evidence on
minor and major oral procedures in patients with IBDs. This review thus sheds some
light on this important topic that was not yet fully addressed in either medical or dental
journals. IBDs represent a considerable number of conditions, all of them with complex
networks of physiopathology and management. It is necessary to consider problems
both on an individual basis, concerning the health conditions of the patient (e.g. risk of
complications, need of additional therapies, hospitalization, and death risk) and, in a
broader context, the impact of the high cost of IBDs on national health systems.
It is important to highlight that some oral problems, such as caries or periodontal
disease, are cumulative, beginning in the early stages of life. During the childhood of
healthy patients, tooth exfoliation does not present any substantive complication;
however, patients with IBDs have a greater risk of spontaneous and constant bleeding
(Salem, Seyyedkhamesi et al. 2018). In fact, in some cases, primary tooth exfoliation
or extraction leads to the diagnosis of an IBD (Martinez-Rider, Garrocho-Rangel et al.
2017). It has been reported previously that teenagers with or without IBDs present
similar oral problems (e.g. caries and gingivitis) (Salem and Eshghi 2013, Othman,
Sockalingam et al. 2015). However, the oral health of patients with IBDs over their
lifetime is sometimes neglected due to several reasons, including financial issues and
difficulties in finding a dentist willing to treat these patients (Schaffer, Duong et al.
2016). The refusal to treat patients with IBDs might be related to the lack of
standardization of treatment and prophylactic protocols, type of anesthesia, or need
for patient admission in hospital settings, which were evidenced by our study.
The concept of evidence-based medicine mandates the use of best evidence
in making decisions about the care of individual patients to optimize clinical practice
(Djulbegovic and Guyatt 2017). The pyramid of evidence was proposed to categorize
evidence in hierarchical order according to study design (Friedman, Furberg et al.
2010). In our study, we were able to identify a growing interest in studies addressing
the oral treatment for patients with IBDs; however, many of these studies were
classified as low-quality evidence (Figure 2). Thus, the absence of high-quality
evidence could make the decision-making process difficult and, sometimes, biased
decisions or inadequate approaches could be made (Fanaroff, Califf et al. 2019).
Likewise, the lack of robust evidence could explain the wide variation in prophylactic
and therapeutic protocols reported here, and also the higher percentages of reported
complications.
The management of IBDs has changed its course during the last century, and
the introduction of factor concentrates containing coagulation factors has provided
significant improvements in the treatment and life expectancy of patients with IBDs
(Mannucci and Tuddenham 2001, Lee 2009). Although for most patients with IBDs the
administration of factor concentrates is episodic, some subjects require continuous
prophylactic administration of clotting factors due to the severity of their condition,
mainly to reduce musculoskeletal bleeding (Srivastava, Brewer et al. 2013). These
requirements are not only challenging in medical terms but also represent an issue for
health systems, as the factor concentrates represent more than 90% of the direct
medical care costs of a hemophilic patient (Rodriguez-Merchan 2020). The need for
oral treatments for patients with IBDs is relatively frequent and the present scoping
review identified that the administration of factor concentrates perioperatively appears
to be standard of care. In the literature presented here, importance should be given to
the fact that bleeding occured in 100% of studies that reported complications and that
there is no standardization of prophylactic protocols, where a high variance of doses
was observed (Figure 3). Besides their high cost, the indiscriminate use of factor
concentrates could lead to the development of antibodies against the factor
concentrates, so-called inhibitors (Xi, Makris et al. 2013). Inhibitors can dramatically
reduce the effectiveness of factors concentrates, which in turn leads to the need for
even more expensive medications and an increased risk of complications.
Research involving gene therapy and hemophilia dates back to the early 2000s
and it is expected that this method will be the key to the resolution of hemophilia.
Promising results were recently presented by Pasi et al.,(Pasi, Rangarajan et al. 2019)
where patients with hemophilia A who received a single dose of valoctocogene
roxaparvovec gene therapy significantly reduced annual bleeding rates and increased
FVIII activity levels after 3 years of follow-up. The authors also reported no major
safety issues during the trial, with no inhibitor development. There is no doubt that
gene therapy will revolutionize how patients with IBDs are treated, improving their
quality of life, and reducing life-threatening risks from minor or major elective
procedures. However, it should be highlighted that gene therapy is still in the initial
phases of clinical studies, and being conducted in very small samples. Other gene
therapy studies also should be conducted to ameliorate the long list of IBDs, such as
factor V deficiency, factor VII deficiency, factor X deficiency, factor XI deficiency,
Bernard-Soulier syndrome, and Glanzmann’s thrombasthenia. Therefore, when
considering minor and major oral procedures in the short- and mid-term, there is still
a need for evidence to support the decision-making process to avoid extra costs and
the risk of postoperative complications.
A limitation of this scoping review is that we have considered consensus and
guidelines as top evidence, as such papers are usually published as a result of experts’
consensus conferences or by specialized international organizations. However, a
recent study evaluated guidelines from the European and American Cardiology
Associations demonstrated that only a small part of the evidence for these guidelines
was obtained from high-quality randomized controlled trials (Fanaroff, Califf et al.
2019). In our study, four guidelines were included, but there is no mention of whether
they have based their decisions on such study designs. Decisions made on guidelines
without adequate evidence can expose patients to unnecessary risks, thus
contradicting ethical principles. Another limitation that worths mentioning is the fact
that the majority of the included studies reported only the occurrence of the
complications (e.g. bleeding) but without mentioning its severity.
In summary, it important to emphasize that patients with IBDs require a careful
assessment before treatment and that prophylactic and therapeutic protocols should
be discussed in a multi-professional team. Although a recent study (Lim 2020) have
reported that minor oral procedures can be safely conducted with antifibrinolytic
agents with no factor replacement, the present scoping review identified a lack of
standardization considering the management of minor and major oral procedures in
patients with IBDs, whereas the indication of general or local anesthesia, prophylaxis
agent and protocol were based on primary studies with low-level of evidence and,
sometimes, low methodological standards.
CONCLUSIONS
The present scoping review identified that (1) there is room for new studies to
assess the safety and risk of complications when antifibrinolytic agents are used as a
prophylactic measure with no factor replacement; (2) to date the use of factor
replacement therapy is the most indicated approach when treating patients with IBDs
with adjunct systemic or local antifibrinolytic agents to reduce post-operative
complications; and (3) there is a critical need for high-quality evidence studies since
much of the outcomes and conclusions of the included studies are not supported by
statistical analysis.
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26. Lee CA. The best of times, the worst of times: a story of haemophilia. Clin Med
(Lond) 2009;9:453-458.
27. Rodriguez-Merchan EC. The cost of hemophilia treatment: the importance of
minimizing it without detriment to its quality. Expert Rev Hematol 2020;13:269-274.
28. Xi M, Makris M, Marcucci M, Santagostino E, Mannucci PM, Iorio A. Inhibitor
development in previously treated hemophilia A patients: a systematic review, meta-
analysis, and meta-regression. J Thromb Haemost 2013;11:1655-1662.
29. Pasi K, Rangarajan S, Mitchell N, et al. First-in-human Evidence of Durable
Therapeutic Efficacy and Safety of AAV Gene Therapy Over Three-years with
Valoctocogene Roxaparvovec for Severe Haemophilia A (BMN 270-201 Study).
Abstract LB 01.2. Presented at the International Society of Thrombosis and
Haemostasis 2019 Congress 2019;3:2.
30. Fanaroff AC, Califf RM, Windecker S, Smith SC, Jr., Lopes RD. Levels of
Evidence Supporting American College of Cardiology/American Heart Association and
European Society of Cardiology Guidelines, 2008-2018. JAMA 2019;321:1069-1080.
TABLES
Table 1. Characteristics of case reports studies (1930-2019).
Condition Oral Surgery Periodontics
N % N %
Hemophilia A 25 32.1 - -
Hemophilia B 6 7.7 1 50.0
Hemophilia A or B 10 12.8 - -
Von Willebrand’s 10 12.8 1 50.0
disease
Other conditions§ 27 34.6 - -
Previously
diagnosed?
Yes 72 92.3 1 -
No 6 7.7 1 -
Main procedure
Minor procedures† 29 37.1 1 50.0
Major procedures‡ 34 43.6 1 50.0
Orthognathic surgery 7 9.0 - -
Prolonged bleeding 8 10.3 - -
Type of anesthesia
General anesthesia 31 52.5 0 0
Local anesthesia 28 47.5 2 100
Prophylaxis
Performed 58 77.3 1 50.0
Not performed 17 22.7 1 50.0
Type of prophylaxis
Blood transfusion 19 32.7 - -
Replacement therapy 31 53.4 1 100

Medications 8 13.9 - -
Complications
Occurred 31 44.3 2 100
Absent 39 55.7 0 0
Hospitalization
Yes 44 75.9 0 0
† ≤3 No 14 24.1 2 100 teeth

extracted; ≤3
implants placement; ‡ ≥ 3 teeth extracted; third molar extraction; ≥3 implants placement; Factor §VII
deficiency; Glanzmann's thrombasthenia; Factor X Friuli disorder; Bernard-Soulier syndrome; Congenital
factor V (FV) deficiency; Factor Xl (PTA) deficiency; combined deficiency of the vitamin K-dependent
clotting factors (VKCFD); Combined factor V and VIII deficiency; Factor XII deficiency; Congenital F5F8
deficiency; Congenital deficiencies of both factor V and factor VIII.
Table 2. Characteristics of case series studies (1941-2019).
Oral Surgery Periodontics
Condition N % N %
Hemophilia A 10 35.7 - -
Hemophilia B 1 3.6 1
Hemophilia A or B 5 17.8 - -
Von Willebrand’s disease 5 17.8 1
Von Willebrand’s and Hemophilia 1 3.6 1
Other conditions† 6 21.5 1
Previously diagnosed?
Yes 27 96.4 4 100%
No‡ 1 3.6 - -
Main procedure
Scaling and root planning - - 1
Tooth extraction 27 96.4 - -
Orthognathic surgery 1 3.6 - -
Periodontal surgery - - 3
Type of anesthesia
General anesthesia 8 28.6 1
Local anesthesia 8 28.6 2
Not reported 12 42.8 1
Prophylaxis
Performed 23 85.2 4
Not performed 4 14.8 0
Type of prophylaxis
Blood transfusion 4 17.4 1
Replacement therapy§ 14 60.9 2
Medications¶ 5 21.7 1
Complications
Occurred 10 35.7 -
Absent 14 50.0 4
Not reported 4 14.3 -
Hospitalization
Yes 9 32.2 2
No 5 17.8 1
Not reported 14 50.0 1
† Hemophilia and Glanssmann Disease; Heterozygous factor XI deficiency; Glanzmann thrombasthenia; Factor
IX deficiency; Bernard–Soulier syndrome; FVII deficiency
‡Delayed diagnosis of VWD;
§Recombinant FVII activated; Factor VIII Concentrate; Factor IX Concentrate;
¶ DDVAP, EACA, Tranexamic Acid
Table 3. Characteristics of observational studies considering surgical procedures
(1961-2019).
Oral surgery Periodontics
Methodological aspects N % N %
Cross-sectional 11 25.0 -
Retrospective 31 70.5 3 100
Prospective 2 4.5 -
Trial registration
Yes 1 2.2 0 0
No 43 97.8 3 100
Sample size calculation
Yes 0 0 0 0
No 44 100 3 100
Condition
Hemophilia A 6 13.6 1
Hemophilia B 1 2.3 -
Hemophilia A or B 13 29.6 -
Von Willebrand’s disease 7 15.9 1
Von Willebrand’s and Hemophilia 15 34.1 1
†
Other conditions‡ 2 4.5 -
Main study outcome
Surgical outcomes 36 81.8 3
Bleeding complication 3 6.8 -
Questionnaires 2 4.5 -
Others 3 6.8 -
Type of anesthesia
General anesthesia 8 25.8 3
Local anesthesia 5 16.2 -
Prophylaxis
Performed 26 89.7 3 100
Not performed 3 10.3 0 0
Type of prophylaxis
Blood transfusion 1 3.84 -
Replacement therapy 14 53.84 1
Medications 8 30.76 2
Combination (replacement or 3 11.53 -
Medications)
Complications
Occurred 24 77.4 3
Absent 7 22.6 0
Hospitalization
Yes 12 66.7 1
No 6 33.3 2
† two studies presented other unspecified conditions ‡FV deficiency; FVII deficiency
Table 4. Characteristics of clinical studies considering surgical procedures (1967-
2015).
Oral surgery Periodontics
Specific design N % N %
Non-randomized clinical trial 13 54.2 - -
Randomized clinical trial 1 4.2 2 100
Double-blind trial 3 12.5 - -
Prospective trial 2 8.3 - -
Pilot study 2 8.3 - -
Others 3 12.5 - -
Trial registration
Yes 3 12.5 2 100
No 21 87.5 -
Sample size calculation
Yes 0 0 0 0
No 24 100 2 100
Condition
Hemophilia A 5 20.8 -
Hemophilia B 2 8.3 -
Hemophilia A or B 8 33.3 2
Von Willebrand’s disease 1 4.2 -
Von Willebrand’s and Hemophilia 7 29.2 -
Other conditions† 1 4.2 -
Main study outcome
Local hemostatic agents 7 29.1 -
Local hemostatic + Therapeutics 3 12.5 2
Therapeutics 11 45.8 -
Surgical outcomes 3 12.5 -
Type of anesthesia
General anesthesia 4 23.5 -
Local anesthesia 4 23.5 2
Prophylaxis
Performed 20 90.9 2
Not performed 2 9.1 0
Type of prophylaxis
Blood transfusion 4 21.0 -
Replacement therapy 6 31.6 2
Medications 4 21.0 -
Combination (Replacement and 5 -
26.4
medications)
Complications
Occurred 14 73.7 1
Absent 5 26.3 1
Hospitalization
Yes 5 23.8 1
No 2 9.5 1
Not reported 14 66.7
†Hemophilia A, Hemophilia B, von Willebrand’s disease, FVII deficiency, FXI deficiency, Glanzmann
Thrombasthenia
Table 5. Number of complications, absolute†, and relativeⱡ frequencies according to study design.
Case reports Case series Observational studies Clinical studies

Relative Absolute Relative Absolute Relative Absolute Relative Absolute
n n n n
frequency frequency frequency frequency frequency frequency frequency frequency
Bleeding 33 100% 45,8% 10 100% 31,3% 27 100% 57,4% 15 100% 57,7%
Edema 1 3,0% 1,4% 1 10% 3,1% 0 0% 0% 0 0% 0%
Swelling 3 9,1% 4,2% 1 10% 3,1% 0 0% 0% 0 0% 0%
Others* 2 6,1% 2,8% 0 0% 0% 2 7% 4,3% 0 0% 0%
†Number of included studies according to each study design: Case reports=72; Case series=32; Observational studies=47;
Clinical studies=26.
ⱡNumber of studies that reported complications: Case reports=33; Case series=10; Observational studies=27; Clinical
studies=15.
*Apnea, broncopneumonia, disphagya, dry socket, seizure.
FIGURE LEGENDS
Figure 1 – PRISMA Flowchart.
Figure 2 – Bubble graphic presenting the included studies in this scoping review
according to its level of evidence and year. *Consensus/Guidelines were considered
as top evidence level considering that such papers are usually a result of experts’
consensus conferences or published by specialized international organizations.
Figure 3 – Word cloud illustration of the prophylactic therapeutics adopted in the
included studies. The size of the therapeutic agent follows the frequency of
appearance in the included studies and the color is related to the study design: case
report and case series (green), observational studies (orange), and clinical studies
(red).
Artigo 3 - Endodontic therapy in patients with inherited bleeding
disorders: a scoping review
Mateus A Kinalski, M.Sc.; Ph.D. Assistant Professor, Faculty of Dentistry, Community
University of Chapecó Region, Chapeco, SC, Brazil.
Lucas P Araújo, DDS, M.Sc.; Ph.D. student, Department of Restorative Dentistry,
Division of Endodontics, Piracicaba Dental School, State University of Campinas
(UNICAMP), Piracicaba, SP, Brazil
Rafael Sarkis-Onofre, Ph.D.; Assistant Professor, Graduate Program in Dentistry,
Meridional University (IMED), Passo Fundo, RS, Brazil.
Mateus BF dos Santos, Ph.D.; Assistant Professor, Graduate Program in Dentistry,
School of Dentistry, Federal University of Pelotas (UFPEL), Pelotas, RS, Brazil.
Running title: Bleeding disorders and endodontics

Scientific field: Endodontics
Article type: Review Article
* Artigo submetido ao periódico Giornale Italiano de Endodonzia

Abstract
This scoping review aimed to map available evidence regarding endodontic therapy in
patients with IBDs. Studies in medicine or dentistry that reported endodontic therapy
in individuals presenting IBDs (e.g., hemophilia A or B, von Willebrand disease) were
selected. Search and screening were performed in PubMed/Medline, Embase,
Scopus, Web of Science, and Cochrane Library by two independent researchers. The
search initially yielded 676 potentially relevant studies, of which 14 were included final
analysis. Most of the evidence for prophylaxis use was derived from observational
studies. The most-reported procedure was endodontic therapy, while one reported a
surgical endodontic procedure. Regarding the type of anesthesia, most studies
reported these procedures could be performed under local anesthesia. Three studies
reported patient’s complication after endodontic therapy. The available evidence
seems to indicate the following aspects: 1) Endodontic therapy in patients with IBDs
can be considered a low-risk procedure; 2) Local anesthesia should be performed
when treating IBDs subjects, and the prophylaxis should be preferred when there is
the necessity of nerve block anesthesia; 3) Endodontic therapy can be conducted in a
clinical setting (no need for hospital admittance); 4) Although a reduced number of
complications was reported, it should not be neglected.
Keywords: inherited bleeding disorders; hemophilia; von Willebrand's disease;
prophylaxis; complication.
1. INTRODUCTION
conditions, where missing or defective clotting factors prevent normal blood clotting
from occurring (Peyvandi, Duga et al. 2002). Among them, the most common
conditions are hemophilia A (factor VIII [FVIII] deficiency), hemophilia B (factor IX [FIX]
deficiency), and von Willebrand disease (von Willebrand factor [VWF] deficiency),
corresponding to more than 95% of all IBDs (Mannucci, Duga et al. 2004). These IBDs
can be presented as mild, moderate, or severe, depending on the levels of clotting
factors in the blood. Also, the severity of such conditions is directly related to the
increase of spontaneous or traumatic bleeding episodes, directly impacting patients'
quality of life (Scalone, Mantovani et al. 2006).
Root canal treatment is considered a non-invasive procedure that aims to
maintain or restore the periradicular tissues affected by an injured or infected dental
pulp; in the scope of endodontic therapies, there are other procedures like vital pulp
therapy that aims to maintain dental pulp vitality or even surgical root canal treatment,
even though it is considered an invasive procedure (Kinalski, Sarkis-Onofre et al.
2020). Bleeding during endodontic treatment is not uncommon, generally occurring
when the pulp is vital or during apical enlargement or establishment of apical patency.
Considering that IBDs individuals present an increased risk of bleeding, one must
ponder that IBDs might represent an important concern to the dentists during the
endodontic procedures since it could impair the hemostasis achievement required for
the successful indication of root canal sealers, resulting in impaired sealing of the
filling. Also, excessive bleeding could not solely jeopardize the treatment but offer risk
to the patients once they present a higher incidence of complications, including the
need for hospitalization (Hewson, Daly et al. 2011, Laffan, Lester et al. 2014, Kinalski,
Sarkis-Onofre et al. 2020).
A previous systematic review suggested that some systemic conditions may be
correlated with endodontic outcomes, impairing the success rates of these endodontic-
treated teeth, although IBDs were not included in the analysis (Aminoshariae, Kulild
et al. 2017). Also, a case-control reported that IBDs subjects presents higher
prevalence of radiolucent periapical lesions and lower frequency of root canal
treatment than than control patients (Castellanos-Cosano, Machuca-Portillo et al.
2013). On the other hand, the last World Federation of Hemophilia (WFH) guidelines
stated that importance should be given to ensure that people with IBDs have access
to dental treatment according to evidence-based protocols (Srivastava, Santagostino
et al. 2020). Considering that there is no consensus in the literature about the
performance of endodontic therapy in patients with IBDs and in some situations this
topic is neglected or did not include in the recommendations, a summary of the
available evidence would be highly useful. Thus, the present study was designed as
a scoping review to map the available evidence regarding endodontic therapy in
patients with IBDs.
2. MATERIALS AND METHODS

2.1. Protocol
The protocol of this study was based on the framework proposed by Peters et
al. (Peters, Godfrey et al. 2015) and is available at the Open Science Framework at
the following link: (https://osf.io/4k6e8/). The report of this scoping review is based on
PRISMA Extension for Scoping Reviews. (Tricco, Lillie et al. 2018)
2.2. Eligibility criteria
We selected studies in medicine or dentistry that reported endodontic
procedures in individuals presenting any IBDs (e.g., hemophilia A or B, von Willebrand
disease). Studies were included regardless of methodological design, previous IBDs
diagnosis, or prophylaxis protocols.
2.3. Information sources and Search
The systematic search was performed in five databases (PubMed/Medline,
Embase, Scopus, Web of Science, and Cochrane Library) without date restrictions
(the last search was conducted on July 15th, 2021) and limited to articles written in
English. The adopted search strategy was drafted using PubMed/Medline MeSH terms
and was adapted for the other databases (Supplementary 1).
2.4. Selection of sources of evidence
The search was made using a reference manager software (EndNote X7,
Thomson Reuters, New York, NY). Two researchers (MAK and LPA) independently
identified the articles by first analyzing titles and abstracts. Retrieved records were
then classified following the eligibility criteria as include, exclude, or uncertain. Full-
text articles of the included and uncertain papers were screened by the same two
reviewers and criteria. Discrepancies in the screening of titles/abstracts and full-text
articles were resolved through discussion. In case of disagreement, the opinion of a
third reviewer (MBFS) was garnered.
2.5. Data charting process and Data items
A Microsoft Excel spreadsheet was created for data extraction. This
spreadsheet was tested and discussed by the reviewers to standardize data collection.
Two of the reviewers (MAK, LPA) extracted the data, and another reviewer (RSO)
double-checked it. The following data were collected: study design (cases studies,
observational studies, cohort studies, clinical studies, reviews or systematic reviews,
and guidelines/consensus) and methodological aspects (publication year, IBDs
studied, endodontic diagnosis, procedure or main outcome, reported use of
prophylaxis and its protocol, type of anesthesia, reported complication, and main
findings of the study). Observational and clinical trial studies were further classified
according to the specific trial design (e.g., retrospective, prospective, non-randomized,
or randomized).
The level of evidence was determined according to the original evidence
pyramid. (Friedman, Furberg et al. 2010) Also, it is essential to state that although
Consensus/Guidelines are not present in the pyramid, we opted to add it at the top of
our evidence level assessment, considering that such papers are usually published as
a result of experts' consensus conferences or following high-quality clinical studies
and systematic reviews. (Djulbegovic and Guyatt 2017, Kinalski, Sarkis-Onofre et al.
2020)
2.6. Synthesis of results
A descriptive analysis was performed that considered: (1) study design; (2)
patients' Inherited Bleeding Disorder (e.g. Hemophilia A, Hemophilia B, von Willebrand
disease); (3) endodontic diagnosis; (4) endodontic therapy; (5) the type of anesthesia
(local or general; (6) prophylaxis (performed or not performed); (7) prophylaxis
protocol (blood transfusion, replacement therapy, or medications); (8) complications
(occurred or absent); and (10) summary of study’s findings. Tables and figures were
created to present the synthesis of results.
3. RESULTS
3.1. Search findings
Figure 1 presents the PRISMA 2020 flowchart for the study selection. The
search initially yielded 676 potentially relevant studies. After removing duplicates
(n=94) and irrelevant articles (n=550), 32 studies met the eligibility criteria based on
title and abstract. These were obtained and full text screened, resulting in 14 included
studies in the analysis (Supplementary 2). Considering the level of evidence according
to the studies design, three were classified as consensus/guidelines (Brewer, Roebuck
et al. 2003, Pasi, Collins et al. 2004, Hewson, Daly et al. 2011), three as an observational
study (Franchini, Rossetti et al. 2005, Castellanos-Cosano, Machuca-Portillo et al. 2013,
Givol, Hirschhorn et al. 2015), two as reviews (Evans and Aledort 1978, Gupta, Epstein
et al. 2007), five as case reports (Leeb 1977, Vire and Barrett 1982, Dudek, Helewski
et al. 2013, Dudeja, Dudeja et al. 2014, Ngoc, Van Nga et al. 2018), and one as
editorial (Rubin, Levine et al. 1959).
Of the included studies, six reported endodontic therapy in patients with
inherited bleeding disorders in general, another five with Hemophilia, and three von
Willebrand disease. From studies that reported endodontic diagnosis (case reports,
observational, and clinical studies), three studies reported endodontic therapy
involving vital pulp and two studies necrotic pulps. Considering the endodontic
treatment, four studies reported endodontic therapy, while one performed a surgical
endodontic procedure (apicectomy). Also, one study reported Periapical Index (PAI)
score comparing patients with IBDs and healthy subjects.
In Table 2, the data regarding prophylaxis protocols adopted for endodontic
therapy is presented. One review reported that the endodontic surgical procedures
(e.g., apicectomy) could require factor replacement therapy (Gupta, Epstein et al.
2007), whereas an observational study with 72 endodontic treatments reported that
such therapy was managed only with local antifibrinolytic (tranexamic acid
mouthwash, 10 mL of 5% solution for 2 min) for periods between 4-8 days after the
procedure (Franchini, Rossetti et al. 2005). Despite that, this study also cited that
endodontic surgeries have been performed; however, they did not report data about
these procedures and prophylactic measures adopted to conduct them.
Regarding the type of anesthesia, most studies reported that endodontic
therapy could be performed under local anesthesia. Also, according to the guidelines
from the UK Haemophilia Centre Doctor's Organization, when an inferior dental block
is performed in mild responsive patients of von Willebrand disease, a single dose of
DDAVP given with tranexamic acid is usually sufficient, without need for factor infusion
(Pasi, Collins et al. 2004). Only one study reported that the endodontic therapy was
performed under general anesthesia, although more than one procedure was
performed at the same session.
Table 3 presents the reported complications in patients submitted to endodontic
therapy. One study reported a case of severe hemorrhage during endodontic
treatment, resulting in an acute swelling on the left side of the face that decreased in
24 hours. In another study, the patient reported a minor discomfort, with a reported
bruise on the anesthetic injection site. An observational study with IBDs patients
reported that 5 of the 40 events of delayed postoperative pain occurred during ‘low
risk’ procedures. Still, the authors did not specify if it was after the endodontic
procedure or not.
Two literature reviews reported no contraindication for performing endodontic
therapy in patients with IBDs, and that such procedures could be performed routinely
(Evans and Aledort 1978, Gupta, Epstein et al. 2007). A consensus statement by
hospital-based dentists providing dental treatment for patients with inherited bleeding
disorders stated that endodontic therapy could be considered a low-risk procedure,
irrespective of IBDs severity (Hewson, Daly et al. 2011).
4. DISCUSSION
This scoping review is the first to summarize the available evidence of

endodontic therapy in patients with IBDs. This paper included studies with different
methods, highlighting the available evidence of different diagnoses and treatments,
prophylactic protocol, type of anesthesia, and complications. Although several
systemic conditions have been reported to influence endodontic treatment
(Aminoshariae, Kulild et al. 2017), there is still a lack of information regarding
endodontic therapy in patients with IBDs.
The last WFH consensus reported the importance of maintenance of oral health
of IBDs patients to improve quality of life and to avoid the need for tooth extraction
(Srivastava, Santagostino et al. 2020). However, one could suppose that dentists that
are not used to treat patients with these conditions might find it challenging to gather
evidence to the prophylactic measures as well as technical specifics (e.g. type of
anesthesia) to perform endodontic therapy in such patients. A recent scoping review
on invasive oral procedures (e.g. tooth extraction) indicated the importance of a
multidisciplinary team when treating patients with IBDs, highlighting the importance of
adjunct systemic or local antifibrinolytic agents to reduce postoperative complications
(Kinalski, Sarkis-Onofre et al. 2020). Likewise, the evidence gathered in the present
study suggests that endodontic therapy appears to be considered a low-risk procedure
and could be an interesting approach for IBDs patients. However, this procedure must
be discussed and planned within a multidisciplinary team. Finally, it appears the
endodontic therapy can be conducted in a clinical setting (no need for hospital
admittance).
Another important factor that should be considered when endodontic therapy is
indicated is related to the type of anesthesia (local or general). As observed in our
results, local anesthesia was the preferred approach in the included studies that
treated IBDs patients. However, this must be subdivided into two categories: infiltration
anesthesia (when there are no muscle or tissue injuries) and nerve block (e.g. inferior
alveolar, posterior superior alveolar). There is no consensus regarding the prophylaxis
protocol for dental therapies needing anesthesia. Some studies suggest that the
infiltration anesthesia did not represent a risk (Hewson, Daly et al. 2011, Dougall,
Apperley et al. 2019), while others reported that it requires a prophylactic treatment to
increase the clotting factor levels above 30-50% of normal (Harrington 2000,
Zaliuniene, Peciuliene et al. 2014). On the other hand, when nerve block is
recommended, the use of factor concentrates must be made since the anesthesia
itself could increase the risk of bleeding or complications (Stubbs and Lloyd 2001,
Hewson, Daly et al. 2011, Zaliuniene, Peciuliene et al. 2014).
According to our results, most of the observed complications were not explicitly
associated with endodontic therapy. Among the endodontic-related complications, one
study reported an “undiagnosed bleeding condition” that led to a severe hemorrhagic
complication on the left side of the patient face after 24 hours. In this case, after the
initial file was placed into the canal, profuse bleeding was noted. However, after the
first session, a root perforation was found, explaining the reason and extension of this
complication. Importance should be given to the fact that this patient was not
previously diagnosed, and for this reason, did not receive any prophylactic measures.
One important topic that could lead to doubts regarding endodontic therapy in
IBDs patients is related to the instrumentation beyond the apex. Although no
recommendation was explicitly stated, it is known that the instrumentation beyond the
apex can injury the periapical tissues, resulting in bleeding (Evans and Aledort 1978,
Brewer, Roebuck et al. 2003, Hewson, Daly et al. 2011); hence this approach is not
advisable. When bleeding occurs in the root canal, a consensus recommendation is
4% sodium hypochlorite irrigation and calcium hydroxide dressing of the root canal
(Hewson, Daly et al. 2011).
A limitation of the present scoping review is that we included studies with
different methods and designs, and also the fact that we considered consensus and
guidelines as top-level evidence, considering that international associations and
experts draft such papers. However, the present study found that most of the evidence
on the topic is based on primary studies (e.g. case reports). Also, the follow-up of the
included cases was not performed or not reported by the studies, and, for this reason,
the success rates of endodontic therapy in patients with IBDs are not available.
Therefore, there is an urgent need to further studies considering endodontic therapy
and its specificities when treating IBDs patients, developing more accurate treatment
strategies, and reducing complications.
5. CONCLUSIONS
Within the limitation of the present study, the following conclusion can be drawn:
 There is a lack of well-designed studies related to the topic.
 The most available evidence is based on observational studies and case
reports.
 The available evidence seems to indicate the following aspects: 1) Endodontic
therapy in patients with IBDs can be considered a low-risk procedure; 2) Local
anesthesia should be performed when treating IBDs subjects, and the
prophylaxis should be preferred when there is the necessity for nerve block
anesthesia; 3) Endodontic therapy can be conducted in a clinical setting (no
need for hospital admittance); 4) Although a reduced number of complication
was reported, it should not be neglected.
 This review serves as a starting point from which future research initiatives
related to managing patients with IBDs should be prioritized.
The authors stated that they had no interests which might be perceived as
posing a conflict or bias.
ROLE OF THE FUNDING SOURCE

This study was financed in part by Coordination for the Improvement of Higher
Education Personnel (CAPES) Finance Code 001. RSO is funded in part by
Meriodional Foundation (Passo Fundo – Brazil).
REGISTRATION
Available at the Open Science Framework at the following link: https://osf.io/4k6e8/
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TABLES
Table 1. Characteristics of Studies Assessing the Relationship between Inherited bleeding disorders and Endodontic Outcomes
Endodont
Procedure or
Author Conditi Sample ic Prophyla Anesthes Complicati
Study Design Study Summary of Findings
(Year) on Size Diagnosi xis ia ons
Outcome
s
Consensus (by
Endodontic treatment is a low-risk procedure; Pulpectomy is carried
Inherited hospital-based dentists
out carefully within the working length of the root canal to ensure that
Hewson et bleeding providing dental Not
- - - - - the instruments do not pass through the apex of the root canal;
al. (2011) disorder treatment for patients reported
Bleeding can usually be controlled with 4% sodium hypochlorite
s with inherited bleeding
irrigation, and calcium hydroxide dressing of the root canal.
disorders)
Von
Guideline (UK
Pasi et al. Willebra
Haemophilia Centre - - - - - - Prophylaxis should be given if an inferior dental block is to be used.
(2004) nd
Doctor's Organization)
disease
Inherited Endodontic treatment should not cause problems, although vital
Brewer et bleeding teeth could bleed for some time. Treatment under hospital
Guideline - - - - - -
al. (2003) disorder environment should be preconized considering the IBDs severity
s (moderate or severe).
Hemophili
Inherited Root canal treatment was considered a low-risk of bleeding
a A, B,
Givol et al. bleeding Not Endodontic procedure. Alveolar nerve block may induce intramuscular bleeding
Observational (Cohort) and von Yes Local Yes**
(2015) disorder reported therapy in patients suffering from hemophilia and thus was not performed
Willebrand
s unless proper factor concentrate replacement was applied.
(n=125)
Haemophi
lia A
(n=121);
Inherited Hemophili The protocol for the dental management followed at our three
Franchini Endodontic
bleeding Observational a B Not hemophilia centers during these last 10 years has been
et al. therapy Yes Local None
disorder (Retrospective Study) (n=14); reported demonstrated safe and effective, with low incidences of hemorrhagic
(2005) (n=72)
s von and treatment-related complications.
Willebrand
disease
(n=95)
Inherited
Endodontic therapy does not usually pose any significant risk of
Gupta et bleeding Endodontic
Literature Review - - - - - bleeding and can be performed routinely. Endodontic surgical
al. (2007) disorder therapy
procedures may require factor replacement therapy.
s
Evans & There is generally no contraindication for performing endodontic
Hemoph Endodontic
Aledort Literature Review - - - - - therapy for hemophilic patients. Instrumentation and filling beyond
ilia therapy
(1978) the apex of the vital root should be avoided.
Endodontic
therapy for
tooth 85;
Necrotic
preventive
pulp Hemophilia A patients can have their treatment safely performed
Ngoc et al. Hemoph diode laser Not
Case report 1 without General No under general anesthesia as long as the dental surgeon,
(2018) ilia A pulpotomy for reported
periapical hematologist, and anesthesiologist cooperate well with one another.
teeth 55, 74,
lesion
75, and 84;
indirect pulp
capping
If done carefully, endodontic treatment usually does not pose any
Dudeja et Hemoph Endodontic
Case report 1 Vital pulp Yes Local No significant risk of bleeding. It is usually preferred over extraction
al .(2014) ilia A therapy
wherever possible.
Von Necrotic Endodontic inflammations requiring
Dudek et Willebra pulp with endodontic microsurgeries do not obligatorily need hematologic
Case report 1 Apicectomy No Local None
al. (2013) nd periapical preparations and surgery can be successfully undertaken in
disease lesion outpatient conditions
Von
Vire & Endodontics can be completed successfully if the clinician consults
Willebra Endodontic
Barret Case report 1 Vital pulp Yes Local Yes with the hematologist to minimize the patient's trauma during
nd therapy
(1982) treatment.
disease
Endodontics enables the patient to retain needed teeth and avoid
Rubin et Hemoph extractions in many cases. Care is taken not to instrument beyond
Editorial - - - - - -
al. (1959) ilia the apex as this may cause bleeding. It could be difficult to control
and jeopardize the dentist to obtain a dry canal for filling purposes.
Table 2. Characteristics of studies considering endodontic therapy and prophylactics
protocols.
Author Endodontic
Condition Study Design Procedure Prophylaxis Type of Prophylaxis
(Year) Diagnosis
Vire and Von

Endodontic One unit of cryoprecipitate the
Barret Willebrand Case report Vital pulp Yes
treatment day before.
(1982) disease
Oral tranexamic acid 500 mg (4

times a day) one day prior
Dudeja
Hemophilia Endodontic procedure.
et al Case report Vital pulp Yes
A treatment Intravenous infusion of factor
(2014)
VIII one night before so as to
build up the level to 50%.
Mouthwashes of tranexamic
Franchini Inherited Observational Endodontic acid, 10 mL of 5% solution for
et al bleeding (Retrospective Not reported therapy Yes 2 min) four times a day for 4–8
(2005) disorders Study) (n=72) days (median 5.7 days) after
the procedure.
Periprocedure
Inherited haematological replacement
Givol et Observational Endodontic
bleeding Not reported Yes therapy was applied at the
al (2015) (Cohort) therapy
disorders discretion
of a haematology consultant
Endodontic therapy does not

usually pose any significant
Inherited risk of bleeding and can be
Gupta et Literature Not Endodontic
bleeding Reccomended performed routinely.
al (2007) Review applicable therapy
disorders Endodontic surgical
procedures may require factor
replacement therapy.
Table 3. Reported complications in the included studies.
Procedure
Author Study Endodontic Type of
Condition or Study Prophylaxis Complications
(Year) Design Diagnosis complication
Outcome
Profuse intracanal
Hemorrhagea bleeding that led to a
Leeb J during firm and severe
Hemophilia Case report Vital pulp No Yes
(1977) endodontic swelling of the left
treatment side of the face in a
24-hour period.
Minor discomfort.
Vire Bruise was noted 18
Von
and Endodontic hours after the
Willebrand Case report Vital pulp Yes Yes
Barret treatment procedure on the
disease
(1982) anesthetic injection
site.
5 of 40 events of
delayed
postoperative
bleeding occurred
Givol Inherited
Observational Endodontic during dental
et al bleeding Not reported Yes Yes
(Cohort) therapy procedures that were
(2015) disorders
defined as ‘low risk’.
However, it did not
specify if it was after
endodontic therapy.
Artigo 4 - Are dental implants a feasible technique to replace tooth
loss in patients with inherited bleeding disorders? A clinical
comparative study with 1-year of follow-up
Mateus de Azevedo Kinalski,1 DDS, M.Sc
Otávio Amaral de Andrade Leão,2 BPE, M.Sc.
Lucas Pradebon Brondani,3 DDS, M.Sc., Ph.D.
Augusto Luis Mendes de Mattos Carpena,4 DDS
César Dalmolin Bergoli,5 DDS, M.Sc., Ph.D.
Mateus Bertolini Fernandes dos Santos,5 DDS, M.Sc., Ph.D.
1
PhD student, Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Brazil
2
PhD student Graduate Program in Epidemiology, Federal University of Pelotas, Pelotas,
Brazil
3
Private Practice, Pelotas, Brazil
M.Sc. student, Graduate Program in Dentistry, Federal University of Pelotas, Pelotas, Brazil
5
Assistant Professor, Graduate Program in Dentistry, Federal University of Pelotas, Pelotas,
Brazil
Running title: Dental implants and Bleeding disorders
Word count: 2,751
Disclosure: The authors stated that they had no interests which might be perceived as posing
a conflict or bias.
Authorship
Mateus A Kinalski - design of the study, data collection, data analysis/interpretation,
manuscript draft, critical revision of article, approval of article.
Otávio AA Leão - data analysis/interpretation, manuscript draft, critical revision of article,
approval of article.
Lucas P Brondani - data collection, data analysis/interpretation, manuscript draft, critical
revision of article, approval of article.
Augusto LMM Carpena - data collection, data analysis/interpretation, manuscript draft,
critical revision of article, approval of article.
César D Bergoli - data collection, data analysis/interpretation, manuscript draft, critical
revision of article, approval of article.
Mateus BF dos Santos - design of the study, data collection, data analysis/interpretation,
manuscript draft, critical revision of article, approval of article.
Abstract
Aim: This pilot study assessed clinical and radiographic outcomes of dental implants placed in
patients with inherited bleeding disorders (IBDs) (e.g., Hemophilia A or B, or von Willebrand’s
disease) and compared it to healthy patients after 1-year of follow-up.
Methods: A prospective comparative clinical study was designed according to the SPIRIT and
reported following the CONSORT. Patients were allocated to IBDs and control groups.
Primary outcome (implant survival) and secondary outcomes (implant stability and
radiographic peri-implant alterations) were evaluated. Chi-square was used to check
differences between groups and logistic regression to obtain the odds ratio between groups.
Results: A total of 163 (20 IBDs /140 control) implants were placed in 84 (6 IBDs / 78 control)
patients according to the allocation process. The survival rates of implants placed in IBDs
patients was 89.47%, while the control presented 94.41% after one year of evaluation.
Regarding the radiographic alterations, both groups presented a reduction in the distances when
comparing the implant placement (T0) and the abutment selection phase (Ta) without
statistically significant difference (p=0.52). Although IBDs patients presented an increased risk
of implant failure (Odds Ratio 1.98), no statistically significant differences were found
(p<0.41).
Conclusions: Dental implant therapy in IBDs patients seems to be a feasible option for oral
rehabilitation.
Keywords: Haemophilia, osseointegration, von Willebrand's disease, rare diseases.

INTRODUCTION
Dental implants are considered the gold-standard approach to replace missing teeth,
presenting high survival and success rates in the overall population (Dos Santos, Agostini et
al. 2019, Sarkis-Onofre, Marchini et al. 2019). In the early years of oral implantology, some
medical conditions (e.g.: osteoporosis, HIV, and diabetes) were considered as contraindication
factors and the recommendation was to avoid the therapy with dental implants (Donos and
Calciolari 2014, de Medeiros, Kudo et al. 2018). However, in the last decades, clinical studies
have provided enough evidence to support the feasibility of dental implants in patients with
different systemic diseases (Donos and Calciolari 2014, Gomez-de Diego, Mang-de la Rosa
Mdel et al. 2014). Under these circumstances, the indication of dental implants in patients with
systemic diseases must be assessed on a patient-basis and the specific conditions must be
considered since some may pose increased risks for implant failures (Vissink, Spijkervet et al.
2018).
In this context, some rare medical conditions still remain without sufficient evidence to
support the indication or the survival rates of dental implant therapy. This is the case of
inherited bleeding disorders (IBDs). IBDs are a group of heterogeneous genetic conditions,
where missing or defective clotting factors prevent normal blood clotting from occurring
(Peyvandi, Duga et al. 2002). The most common IBDs are hemophilia A (factor VIII [FVIII]
deficiency), hemophilia B (factor IX [FIX] deficiency), and von Willebrand’s disease (von
Willebrand factor [VWF] deficiency), representing more than 95% of all IBDs (Mannucci,
Duga et al. 2004).
It is well-known that invasive procedures in IBDs patients present higher risks of
complications (de Azevedo Kinalski, Sarkis-Onofre et al. 2020) . The clotting factor
replacement therapy is advisable to adequately obtain patients’ hemostasis (Aledort, Mannucci
et al. 2019) and to avoid postoperative complications or hospitalizations (de Azevedo Kinalski,
Brondani et al. 2021). Considering dental implant therapy, a consensus suggested that implant
placement would pose no more risk for IBDs patients than the extraction of impacted third
molars (Hewson, Daly et al. 2011). Also, according to the 3rd World Federation of Hemophilia
(WFH) guideline, implant placement should be performed only with a personalized plan for
hemostasis management in consultation with a hematologist (Srivastava, Santagostino et al.
2020). It is important to emphasize that such invasive procedures are also associated with
higher rates of postoperative bleeding and a higher incidence of complications, whereas some
cases need hospitalization (Hewson, Daly et al. 2011, Laffan, Lester et al. 2014, de Azevedo
Kinalski, Brondani et al. 2021).
The osseointegration process starts with the initial contact of blood cells with the
implant surface, creating a dynamic state of cellular activity, that activates platelets and
leukocytes in the peri-implant clot and binds the transient structural proteins, such as fibrin, to
the surface of the implant (Davies et al., 2008). The osseointegration process then evolves
through the formation of bone callus, lamellar compaction, interface remodeling, and
maturation (Misch, 2014). It is worth noting that IBDs physiopathology might affect the
osseointegration process due to the deficient coagulation resulting from these conditions.
Considering that, there is a scientific gap whether any of the stages of osseointegration
is affected by IBDs, which would consequently affect implant survival and success rates. Thus,
the aim of this comparative clinical trial was to assess clinical and radiographic outcomes of
IBDs patients and to compare those outcomes with healthy individuals treated with dental
implant therapy at the same service. The primary outcome of the present study was the implant
survival rate and the secondary outcomes were implant stability and radiographic peri-implant
bone alterations.

Study design
This is a prospective comparative clinical study. The study protocol was approved by
the institutional ethics committee (Protocol 3.725.570) and the trial was registered prior to its
beginning (ReBEC TRIAL: RBR-2YPZFW). This study is reported following the CONSORT
guidelines (Schulz, Altman et al. 2010).
Setting
All dental procedures were carried by oral implantology specialists at the dental clinic
of the School of Dentistry of the Federal University of Pelotas (UFPEL), Brazil. The
recruitment of patients started in October 2019 and the patients were treated and then followed-
up for at least 1-year. The last follow-up and data collection appointments were conducted in
January, 2021.
Study groups:
Inherited bleeding disorders patients
Considering that IBDs are rare conditions, IBDs patients were recruited from the
Regional Blood Center of Pelotas (HEMOPEL) where the Brazilian National Health System
(Sistema Unico de Saude – SUS) holds a register of all patients with inherited bleeding
disorders in the region. The total number of patients nested in the HEMOPEL was 222 subjects,
from whom 172 were older than 18 years old and could be invited to participate in this study.
A public advertisement was displayed at the HEMOPEL facilities to recruit those who
had need for dental implant therapy. To be enrolled in this study, patients had to satisfy the
inclusion criteria, which was to be diagnosed with any IBDs (e.g.: Hemophilia A, Hemophilia
B, or von Willebrand’s disease) and to have indication for dental implant therapy.
Control
Adult patients without IBDs diagnose that sought for treatment at School of Dentistry
of the Federal University of Pelotas (UFPEL), Brazil, were included in the control group.
Eligibility criteria
The adopted inclusion criteria were: 1) At least twenty-one years old; 2) Need for dental
implant therapy; 3) Adequate bone dimensions for implant placement without the need for
guided bone regeneration procedures; 4) Good general health, which allows for dental implant
surgery; 5) Availability for dental appointments at the institution; and 6) Signed informed
consent given by the patient.
Exclusion criteria: 1) Any uncontrolled systemic diseases that prevent surgery for
dental implant placement (e.g.: hypertension, metabolic bone disease, diabetes); 2) Need for
guided bone regeneration or sinus lift for implant placement, and; 3) history of radiation
therapy in head and neck.
Clinical procedures
All surgeries were carried out by the same group of surgeons who were specialists in
oral implantology and have adopted the same protocol for implant placement. Implant length
and diameter were chosen based on bone availability assessed by cone-beam computed
tomography.
As for patients with IBDs, they were referred to the Regional Blood Center of Pelotas
(HEMOPEL) and a standardized prophylaxis protocol was prescribed, consisting of the
infusion of 2,500 IU of plasmatic Factor VIII (Fanhdi, Grifols, Barcelona, Spain) followed by
oral administration of 500mg tranexamic acid (EMS S/A, Hortolândia, Brazil) (24 hours prior
to the surgery and every 8 hours for 4 days). The same prophylaxis protocol was adopted in all
appointments that required any invasive procedure.
Antibiotic prophylaxis was prescribed for all patients using 2g of amoxicillin 1 hour prior to
the surgery and 500mg of amoxicillin every 8 hours for 7 days. (Lobato, Kinalski et al. 2020,
Kinalski, Agostini et al. 2021) All procedures were performed at the dental office under local
infiltrative anesthesia, buccal, and intra-papillary anesthetic injections. Local anesthesia was
induced by articaine 4% with epinephrine (1:100,000), and the implant placement followed the
manufacturer recommendations (Neodent Straumann, Curitiba, Brazil) using specific drills
with increased diameters, and the implant platforms were positioned 2mm below the bone crest.
The insertion torque was measured by a torque ratchet during the implant placement (N.cm)
and implant stability was assessed with a resonance frequency analysis device (Osstell®,
IntegrationDiagnostics AB, Gothenburg, Sweden) by means of implant stability quotient
(ISQ).
Digital periapical radiographs were made at implant placement (T0) and at the abutment
selection phase (Ta) and were used to assess radiographic peri-implant alterations during the
osseointegration period (4 to 6 months).
Primary outcome
Implant survival was the primary outcome of our study. In this way, we considered the
definition of implant survival when the implant was present at the follow-up examination
(Albrektsson and Donos 2012).
Secondary outcomes
Implant stability was assessed by means of ISQ through the use of a resonance
frequency analysis device (Osstell®). The device was handled by a single operator and
calibrated following the manufacturer’s instructions. The smartpegs were attached to the
implants and measurements were performed in triplicate on the mesial, distal, buccal, and
lingual surfaces of each implant at the following intervals: baseline (T0 – implant placement)
and at the abutment selection phase (Ta). Whenever inconsistency was observed during the ISQ
assessment (e.g.: lack of proper grip of the smartpegs, ISQ resulting in 0) they were excluded
from the analysis.
Digital radiographs for T0 and Ta were imported into specific software (ImageJ 1.47v,
NIH, USA) (dos Santos, Caldas et al. 2015, Lobato, Kinalski et al. 2020) to assess the
radiographic peri-implant alterations. To do so, the previously known implant length and
diameter were used as references using the software tool “Set scale” to define the length and
diameter of the radiographic image. The distance between the implant platform and the alveolar
bone crest was defined by a straight-line segment in both mesial and distal points, in
millimeters (mm). All images were assessed by a previously calibrated operator (MAK).
Statistical analyses
Sample description was performed using frequency distribution (%) according to
research group (IBDs or control group), using chi-square test to check difference between
groups. Age and implants characteristics were described using t-test, comparing the mean and
standard deviation of those characteristics between groups. For implant stability and
radiographic peri-implant bone alterations, a delta (difference between two-time evaluations)
of those variables were also calculated and tested according groups. Stripplots graphs were
used to obtain visual distribution of implant stability and radiographic peri-implant bone
alterations according to the different groups. Lastly, logistic regression was used to obtain the
odds ratio of dental implant failure for IBDs patients, using the control group as reference.
All statistical procedures were performed using Stata Software 16.0 (Stata Corporation,
College Station, TX, USA), considering the implants as unit of analysis and an alpha level of
0.05.
RESULTS
A total of 163 implants were placed in 84 patients according to the allocation process,
where 20 implants were placed in 6 patients that were previously diagnosed with any IBD and
143 were placed in healthy patients. The mean age of the IBDs patients was 48.0 years old (SD
±9.25) while 51.8 years old (SD±11.2) was the mean age of the control group. The CONSORT
flow diagram describing the enrollment characteristics of this study is presented in Figure 1.
The distribution of implants and patients’ characteristics between IBDs and control
groups are presented in Table 1. A statistical analysis was made on these outcomes to check
for similar distribution between the groups, where no statistically significant difference was
observed for general health (diabetes and hypertension), patients’ age, smoking habits, implant
length, or type of implant placement (healed site or extraction socket); however, our study
failed to equally distribute the region where the implants were placed, with less implants in the
anterior region of IBDs patients (p=0.001). The insertion torque values assessed at the implant
placement ranged from 10 to 60 N.cm (mean 33.5; SD ±17.3) in IBDs patients and from 15 to
60 N.cm (mean 43.6; SD ±16.3) in the control group (p<0.01).
Table 2 presents the trans and postoperative implant-related outcomes of IBDs patients
and the control group. At Ta, two implants of the IBDs group failed to osseointegrate; the
implants were removed and a new implant was placed in the region; however, these implants
were excluded from our study. An increase in the mean ISQ values was observed at Ta
compared to T0 both in IBDs patients and control group, but no statistically significant
difference was found when comparing the groups (p=0.99). Figure 2 demonstrates the
comparison of ISQ values at T0 and Ta, where it can be inferred a similar distribution pattern
for IBDs patients compared to the control group. Regarding the radiographic peri-implant bone
alterations, both groups presented a reduction in the distances when comparing T0 and Ta (IBDs
mean -1.2mm, SD 0.8; Control mean -1.0 SD 1.2); however, no statistically significant
difference was found between groups (p=0.52). In the Figure 3, it is also possible to identify a
similar pattern for radiographic peri-implant bone alterations at T0 and Ta for IBDs patients
compared to the control group.
The 1-year survival rates of implants placed in IBDs patients was 89.47%, while the
control group presented a survival rate of 94.41% (Figure 4). Table 3 also presents the survival
rates, including the analysis of the risk of failure of implants placed in IBDs patients and control
groups after one year of evaluation. Although IBDs patients presented an increased risk of
implant failure (OR 1.98), no statistically significant differences were found (p<0.41).
DISCUSSION
IBDs are rare conditions that affect about to 1:125.000 people worldwide (males with
Hemophilia A or B) (Srivastava, Santagostino et al. 2020). Considering the rarity of these
conditions and the increased risks of bleeding-related complications that may vary from
spontaneous bleeding to postoperative hospitalizations, dental therapy in IBDs patients is still
a topic that remains under the shadow of evidences (de Azevedo Kinalski, Sarkis-Onofre et al.
2020). In regard to the prescription of dental implant therapy in IBDs patients, the scientific
literature points to controversial pathways, where some studies indicates that such therapy
should be carefully indicated (Donos and Calciolari 2014, Srivastava, Santagostino et al. 2020)
while others suggests multiple implants placement including sinus lift elevation procedures
performed at the dental office (de Azevedo Kinalski, Brondani et al. 2021). In this context, this
is, to the best of our knowledge, the first prospective clinical study to assess dental implant
outcomes in patients with IBDs and to compare it with a control group of healthy patients.
The primary outcome of this study was implant survival and our results demonstrated
that patients with IBDs present lower survival rates (89.47% vs 94.41%.) and a higher odds
ratio for implant failure (OR 1.98) compared to healthy subjects. Although these results were
inferior in the IBDs patients, no statistically significant difference was observed. The absence
of such statistically significant difference should be considered when interpreting our results
since the sample of this study is small due to the rarity of IBDs and the absence of previous
studies on the topic to provide data for a proper sample size calculation. Conversely, the
absence of statistically significant difference is a very important finding of this study, since this
study demonstrate that IBDs patients are able to be treated with dental implants with slightly
lower survival rates compared to previous clinical studies conducted in the overall population
(Albrektsson, Buser et al. 2012).
It is known that early failures, when the implant fails before implant loading, are
expected to occur in about 2–6% of placed implants (Krisam, Ott et al. 2019). However, it is
still unclear whether IBDs influence the osseointegration process and/or the early failure rates
of dental implants. Although medical papers report short- to mid-term follow-up of hemophilic
patients submitted to total knee arthroplasty(Bae, Kim et al. 2020), the fixation of such
orthopedic implants is different than of dental implants and, therefore, extrapolation must be
made with caution.
According to our results, the variation of implant stability and radiographic
measurements between the implant platform to the alveolar bone crest at the implant placement
and at the abutment selection phase were similar for IBDs patients and healthy controls. A
previous systematic review suggested that a mean marginal bone loss of 1.3 mm after loading
should be considered normal while an optimal value should be lower than 2 mm compared to
the implant placement moment (Moraschini, Poubel et al. 2015). In our study, the radiographic
peri-implant bone alterations for IBDs patients were within this threshold (1.2mm, SD 0.8),
suggesting that when integrated, dental implants could behave similarly for IBDs patients.
Considering that most failures occur in the first year, it can be speculated that dental
implants can be performed in IBDs patients with safeness and predictability. However, it is
mandatory that an adequate diagnosis and a multi-professional team must manage and discuss
each IBDs patients’ specificities in order to assess and define the treatment individually. In the
present study, all patients were assessed by a medical staff (hematologists and nurses), which
prescribed and performed the prophylactic treatment and postoperative recommendations. It
should be highlighted that dental professionals that are considering the prescription of dental
implants in IBDs patients should be aware to hemostasis maintenance during and after the
procedures since bleeding episodes could be life-threatening to these patients (Heiland, Weber
et al. 2003). A recent scoping review about oral surgeries in IBDs patients identified
replacement therapy as the most indicated approach, with adjunct systemic or local
antifibrinolytic agents to reduce postoperative complications (de Azevedo Kinalski, Sarkis-
Onofre et al. 2020).
As stated earlier, the most important limitation of the present study is the small sample
size. However, due to the rarity of such conditions and the absence of similar studies, we do
believe that the piece of evidence provided by this study would contribute to shed some light
on dental implant therapy in IBDs patients. Also, the mean sample size of clinical studies
involving implant dentistry and compromised patients is reduced (Diz, Scully et al. 2013, Jiang,
Zhu et al. 2021). In this context, we suggest that dental implant therapy in IBDs patients seems
to be a feasible option for the oral rehabilitation. Further studies to improve our knowledge on
dental implant therapy in IBDs patients must be conducted, with special attention to the
assessment of mid- and long-term marginal bone loss and complications since the peri-implant
bone could be subjected to micro fractures during function, which can consequently cause
micro bleedings and there is still no available evidence whether such micro bleeding would
affect implant survival, success rates, or marginal bone loss.
CONCLUSION
Within the limitations of the present study, it is concluded that dental implant therapy
in IBDs patients seems to be a feasible option for the oral rehabilitation, with similar implant
stability and radiographic peri-implant bone alterations at implant placement and the abutment
selection phase and a slightly lower 1-year survival rates compared to a control group.
ACKNOWLEDGMENTS
Education Personnel (CAPES) Finance Code 001.
CONFLICT OF INTEREST STATEMENT
The authors stated that they had no interests which might be perceived as posing a
conflict or bias.
REFERENCES
Albrektsson, T., D. Buser, and L. Sennerby

2012 Crestal bone loss and oral implants. Clin Implant Dent Relat Res 14(6):783-91.
Albrektsson, T., and N. Donos
2012 Implant survival and complications. The Third EAO consensus conference
2012. Clin Oral Implants Res 23 Suppl 6:63-5.
Aledort, L., et al.
2019 Factor VIII replacement is still the standard of care in haemophilia A. Blood
Transfus 17(6):479-486.
Bae, Jung-Kwon, et al.
2020 Mid-to Long-Term Survival of Total Knee Arthroplasty in Hemophilic
Arthropathy. Journal of Clinical Medicine 9(10):3247.
de Azevedo Kinalski, M., et al.
2021 Delayed bleeding in a hemophilic patient after sinus floor elevation and
multiple implant placements. J Oral Implantol.
de Azevedo Kinalski, M., R. Sarkis-Onofre, and M. B. F. Dos Santos
2020 Inherited bleeding disorders in oral procedures. Assessment of prophylactic
and therapeutic protocols: a scoping review. Aust Dent J.
de Medeiros, Fcfl, et al.
2018 Dental implants in patients with osteoporosis: a systematic review with meta-
analysis. Int J Oral Maxillofac Surg 47(4):480-491.
Diz, P., C. Scully, and M. Sanz
2013 Dental implants in the medically compromised patient. J Dent 41(3):195-206.
Donos, N., and E. Calciolari
2014 Dental implants in patients affected by systemic diseases. Br Dent J
217(8):425-30.
dos Santos, M. B., et al.
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on the stress distribution--a laboratory and 3D FEA. J Biomech 48(1):8-13.
Dos Santos, M. B. F., et al.
2019 Industry sponsorship bias in clinical trials in implant dentistry: Systematic
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Gomez-de Diego, R., et al.
2014 Indications and contraindications of dental implants in medically compromised
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Heiland, M., M. Weber, and R. Schmelzle
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inhibitors to factor VIII: a case report. J Oral Maxillofac Surg 61(11):1350-3.
Hewson, I. D., et al.
2011 Consensus statement by hospital based dentists providing dental treatment for
patients with inherited bleeding disorders. Aust Dent J 56(2):221-6.
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in Healed Sites: A Randomized Controlled Trial. International Journal of Implant
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Tables
Table 1 – Distribution of implants and patient’s characteristics in the studied groups.
IBDs Control
n % n % p-value
Implant region 0.001
Anterior 1 5.0 61 42.7
Posterior 19 95.0 82 57.3
Implant type 0.44
Healed site 15 75.0 95 66.4
Extraction socket 5 25.0 48 33.6
Implant length 0.33
<10mm 9 45.0 81 56.6
≥10mm 11 55.0 62 43.4
Smoking 0.11
Yes 0 0 16 12.2
No 20 100 127 88.8
Diabetes 0.10
Yes 0 0 17 11.9
No 20 100 126 88.1
Hypertension 0.90
Yes 5 25.0 34 23.8
No 15 75.0 109 76.2
mean SD mean SD
Age 48.0 9.25 51.8 11.2 0.16
Insertion torque (N.cm) 33.5 17.3 43.6 16.3 0.01
Table 2 – Post-operative implant related outcomes between IBDs patients and control group.
IBDs Control
p-value‡
Mean SD Mean SD
ISQ
T0 ISQ 66.7 8.6 63.5 14.0 0.34
Ta ISQ 69.1 9.0 64.9 10.9 0.14
ISQ difference (T6-T0) 1.9 9.1 2.0 16.3 0.99
Marginal bone*
Implant platform-bone crest T0† 2.2 0.6 2.6 2.0 0.43
Implant platform-bone crest Ta† 1.0 1.1 1.6 1.9 0.23
Peri-implant alterations (T0-Ta) † -1.2 0.8 -1.0 1.2 0.52

†
radiographical measures. ‡obtained from t-test.
Table 3 – Survival rates and risk of implant failure between IBDs and control groups after one year of
evaluation.
Groups
N % Survival rates (%) Odds ratio† 95%CI p-value
0.41; 10.13 0.41
IBDs 20 12.3 89.47 1.98
Control 143 87.7 94.41 1

†
Values were evaluated using failure rates obtained through logistic regression
Figure legends
Figure 1 – CONSORT flowchart.
Figure 2 – Stripplots graph comparison between ISQ values at T0 and Ta in IBDs patients and
the control group.
Figure 3 – Stripplots graphs comparison between the radiographic peri-implant bone alterations
values at T0 and Ta in IBDs patients and the control group.
Figure 4 – Graphic comparison of the 1-year survival rates (gray implants were lost) of dental
implants placed in IBDs patients (red) and the control group (blue).
Supplemental Materials
Supplemental Material 1 – CONSORT checklist.

Figures
Figure 1 – CONSORT flowchart.
Figure 4 – Graphic comparison of the 1-year survival rates (gray implants were lost)
of dental implants placed in IBDs patients (red) and the control group (blue).
Supplemental Material 1 – CONSORT checklist.
Artigo 5 - Dental implant therapy on a patient with von Willebrand’s
disease: A case report of 2-years of follow-up
Running title: Dental implants and Bleeding disorders
Mateus de Azevedo Kinalski, MSc; PhD student, Graduate Program in Dentistry, Federal
University of Pelotas, Pelotas, Brazil
Lucas Pradebon Brondani, DDS; M.Sc., Ph.D., Graduate Program in Dentistry, Federal
University of Pelotas, Pelotas, Brazil
Mateus Bertolini Fernandes dos Santos, PhD; Assistant Professor, Graduate Program in
Dentistry, Federal University of Pelotas, Pelotas, Brazil
No conflict of interest.
Abstract
The present study reports the 2-year follow-up of a case where a maxillary left second premolar
was extracted and a dental implant was placed in the extraction socket with immediate loading
in the provisional crown of a patient with von Willebrand’s disease. Dental implant therapy in
patients with von Willebrand’s disease seems to be an adequate treatment option for oral
rehabilitation. However, multi-disciplinary assessment is advised.
Clinical significance: Clinical and radiographic outcomes after 2-years of dental implant
rehabilitation in a patient with von Willebrand’s disease were adequate and compatible with
those expected when treating healthy patients.
Keywords: osseointegration, von Willebrand's disease, rare diseases.

INTRODUCTION
Von Willebrand’s disease is the most common inherited bleeding disorder, affecting
primary hemostasis (platelet adhesion) and coagulation (protection of Factor VIII) (Fénelon,
Castet et al. 2018). As other inherited bleeding disorders, patients with this condition are more
prone to spontaneous bleeding, among them the increased risk for excessive bleeding of oral
mucosa, where dental management requires a close collaboration of a multi-professional staff
in order to avoid complications and the need for patients admittance (de Azevedo Kinalski,
Sarkis-Onofre et al. 2021).
When considering tooth loss, dental implants are considered the gold-standard therapy,
presenting high survival and success rates in the overall population (Dos Santos, Agostini et
al. 2019, Sarkis-Onofre, Marchini et al. 2019). Although some papers reported the placement
of implants in patients with inherited bleeding disorders (Fénelon, Castet et al. 2018, Kang and
Kang 2018, de Azevedo Kinalski, Brondani et al. 2021), there is still no study in the literature
reporting the mid- and long-term success of dental implants in such patients (de Azevedo
Kinalski, Sarkis-Onofre et al. 2021).
In this way, we could hypothesize that the short-term success is related to the
osseointegration process, which starts with the initial contact of blood cells at the implant
surface and subsequent formation of a peri-implant clot (Davies et al., 2008). The
osseointegration process might be affected by von Willebrand’s disease and other inherited
bleeding disorders due to the deficient coagulation; however, the infusion of clotting factors as
a prophylactic approach to the surgery might reduce the risks of osseointegration problems. On
the other hand, when considering the mid- and long-term success of dental implants, it can be
supposed that during function the peri-implant bone might be subjected to micro fractures and
bleedings that could also affect the behavior of peri-implant tissues in a patient with von
Willebrand’s disease. Considering that, the present study aims to report the 2-years follow-up
of an implant rehabilitation made in a patient with von Willebrand’s disease.
CASE REPORT
This clinical report was written in agreement with the CARE guidelines(Gagnier,
Kienle et al. 2013, Gagnier, Kienle et al. 2013) and informed consent was obtained from the
patient, acknowledging the use of the photographs to be used in this manuscript.
A 62-year-old female sought for treatment complaining about a loosen single-crown
and metallic post cast in the maxillary left second premolar in September 2019. During medical
history taking, the patient reported to have von Willebrand’s’ disease with reported history of
hemorrhage at third molar extraction and the birth of her second child. The patient also reported
to have controlled hypertension (with regular intake of losartan potassium 50mg with
hydrochlorothiazide 12.5 mg tablets). The patient did not smoke or report any other general
health conditions.
During clinical examination (Fig. 1), it was possible to identify that the crown was not
properly fitted to the remaining root with excessive cement in the buccal region. A cone-beam
computed tomography (CBCT) was made to assess bone availability to place an implant, where
it was possible to identify a short post cast and resorbed root with adequate bone height and
width (Fig. 2). The proposed treatment plan included the root extraction and placement of an
implant in the fresh extraction socket.
The patient was then referred to a hematologist for treatment plan assessment,
considering possible risks and the need of prophylactic measures. The prophylaxis protocol
prescribed by the hematologist consisted in the oral administration of 500mg tranexamic acid
(EMS S/A, Hortolândia, Brazil) every 8 hours starting 24 hours prior the procedures and
maintained after 4 days.

The tooth extraction was made using a minimally invasive technique (Fig. 3), and a
3.5x13mm implant with morse taper connection (Alvim CM Acqua, Neodent Straumann,
Curitiba, Brazil) was placed in the fresh extraction socket. The implant was placed 2-mm
subcrestally (Fig. 4), with 32 N.cm of insertion torque assessed by a manual ratchet. Also,
implant stability was assessed by a resonance frequency analysis device (Ostell, Ostell Inc.)
and, considering that the implant presented an ISQ of 66, we opted to perform immediate
loading of the implant.
The immediate loading temporary crown was made using a temporary prosthesis
abutment (PRO-PEEK, Neodent Straumann) installed directly in the implant platform (Fig. 5).
Four months later, the patient returned to the clinics to change her temporary crown to
the definitive restoration. At this appointment, an x-ray was performed to assess the
osseointegration (Fig. 6) and the abutment selection was performed according to the peri-
implant soft tissue height. A cementable abutment was selected for this case (Munhão
Universal CM, 0.8mm transmucosal height x 3.3mm diameter x 6mm of height, Neodent
Straumann, Curitiba, Brazil). The abutment was installed with 32 N.cm torque and a new
temporary crown was made in order to obtain adequate peri-implant tissue conditioning.
Impression was made using polyvinylsiloxane (Futura AD, Nova DFL, Rio de Janeiro, Brazil)
in an open-tray. The putty and light-bodied material were handled simultaneously and the
impression occurred in a single step. The cast was then poured with Type IV dental stone (Fuji-
rock, GC America, IL, USA) and a metal-ceramic restoration was manufactured using a
castable plastic coping for cement-retained restorations in the shade A3.5 (Vita Classic) (Vita
VMK Master®, Vita Zahnfabrik GmbH, Germany) through the burn-out technique (Figure 7).
It is worth mentioning that, none of the prosthetic procedures needed any kind of prophylactic
measure and there was no excessive bleeding or reported complication throughout the
prosthetic phase of the treatment.

During the whole year of 2020 until September 2021, due to the COVID-19 pandemic,
the patient was not reassessed for follow-up, but phone contact was periodically made to assess
for complications. In the 2-year follow-up appointment, it was possible to observe that the final
restoration is in position with no significant marginal bone loss, assessed by an x-ray image
(Fig. 8).
DISCUSSION
Dental implant therapy is a very important topic in Dentistry; however, it is still under-
reported when considering the treatment of patients with inherited bleeding disorders. In this
perspective, this study reported a successful dental implant rehabilitation after two years in a
von Willebrand’s disease patient. Although some papers have already reported dental implant
therapy in patients with inherited bleeding disorders (Fénelon, Castet et al. 2018, Kang and
Kang 2018, de Azevedo Kinalski, Brondani et al. 2021), their report is mainly related to the
surgical treatment and prostheses manufacture, with no mid- or long-term assessment of the
survival rates or marginal bone loss.
It is known that von Willebrand’s disease affects coagulation and exposes these
individuals to a higher risk of complications following dental procedures. When considering
the impact of von Willebrand’s disease in the dental implant therapy it should be considered
that such increased risk of bleeding and difficulties in the clot formation (Ruggeri 2007) could
jeopardize the initial osseointegration process after implant placement. Although not directly
associated to endanger the osseointegration, a reduced bone metabolism and density might be
expected due to the effects of von Willebrand’s disease (e.g recurrent hemarthrosis and lower
physical activities) (Mansouritorghabeh and Rezaieyazdi 2017).
To the best of our knowledge, this is the second study to present a follow-up of implant
placement in von Willebrand’s disease patients. While our study reported an immediate implant
placement with a provisional crown in the maxillary, the other performed an implant in the
posterior mandible with conventional loading (Kang and Kang 2018). Although there are some
differences in the survival rates between mandibular and maxillary implants, both studies
reported a success after 18 and 24 months respectively. Also, the marginal bone alterations
observed in our case report after 2-years of follow-up were within the successful marginal bone
loss threshold for dental implants in healthy patients (<2mm radiographic bone loss from initial
surgery) (Misch, Perel et al. 2008).
In this context, although previous studies suggest that patients with inherited bleeding
disorders must be treated with general anesthesia and in hospital setting (Weinstock,
Onyejiuwa et al. 2015), the present study proposes the treatment of such patients at a dental
office level under local anesthesia, reducing the costs related to patient’s admittance. Likewise,
when planning dental implants in patients with von Willebrand’s disease, it is important to
consider that a multi-disciplinary staff or hematologist must be consulted in order to prepare a
customized prophylactic approach to avoid the risk of complications. In our case, the patient
received a prophylactic treatment with an antifibrinolytic (tranexamic acid) which is positively
associated with a reduced risk of postoperative bleeding (Ma, Han et al. 2020, de Azevedo
Kinalski, Sarkis-Onofre et al. 2021). It is important to highlight also that, depending on the
severity of the case, even non-invasive procedures such as impression taking and prosthesis
installation should be discussed with the medical staff in order to assess the risk of bleeding
and need of any prophylactic approach.
Observational studies on the topic are needed in order to improve our knowledge on
dental implant therapy in IBDs patients, with special attention to the assessment of mid- and
long-term marginal bone loss and complications since the peri-implant bone could be subjected
to micro fractures and bleedings that might affect the implant survival or success rates.
CONCLUSION
Within the limitations of the present study, it is concluded that dental implant therapy
in von Willebrand patient presented success after 2-years of follow-up. It should be emphasized
that a hematologist or multi-disciplinary staff assessment is advised.

REFERENCES
de Azevedo Kinalski, M., Brondani, L. P., de Mattos Carpena, A. L. M., & Dos Santos, M. B.
F. (2021). Delayed bleeding in a hemophilic patient after sinus floor elevation and
multiple implant placements. J Oral Implantol. doi:10.1563/aaid-joi-D-20-00043
de Azevedo Kinalski, M., Sarkis-Onofre, R., & Dos Santos, M. B. F. (2021). Inherited
bleeding disorders in oral procedures. Assessment of prophylactic and therapeutic
protocols: a scoping review. Aust Dent J, 66(2), 150-158. doi:10.1111/adj.12813
de Azevedo Kinalski, M., Sarkis-Onofre, R., & Dos Santos, M. B. F. (2021). Inherited
bleeding disorders in oral procedures. Assessment of prophylactic and therapeutic
protocols: a scoping review. Australian dental journal, 66(2), 150-158.
doi:10.1111/adj.12813
Dos Santos, M. B. F., Agostini, B. A., de Moraes, R. R., Schwendicke, F., & Sarkis-Onofre,
R. (2019). Industry sponsorship bias in clinical trials in implant dentistry: Systematic
review and meta-regression. J Clin Periodontol. doi:10.1111/jcpe.13100
Fénelon, M., Castet, S., Fricain, J. C., & Catros, S. (2018). Guided Implant Surgery to
Reduce Morbidity in Von Willebrand Disease Patients: A Case Report. Open Dent J,
12, 80-86. doi:10.2174/1874210601812010080
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Disease: A Case Study. Implant Dent, 27(5), 599-601.
doi:10.1097/id.0000000000000821
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Mansouritorghabeh, H., & Rezaieyazdi, Z. (2017). Bone Density Status in Bleeding
Disorders: Where Are We and What Needs to Be Done? Journal of bone metabolism,
24(4), 201-206. doi:10.11005/jbm.2017.24.4.201
Misch, C. E., Perel, M. L., Wang, H. L., Sammartino, G., Galindo-Moreno, P., Trisi, P., . . .
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17(1), 5-15. doi:10.1097/ID.0b013e3181676059
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Sarkis-Onofre, R., Marchini, L., Spazzin, A. O., & Santos, M. (2019). Randomized
Controlled Trials in Implant Dentistry: Assessment of the Last 20 Years of
Contribution and Research Network Analysis. J Oral Implantol, 45(4), 327-333.
doi:10.1563/aaid-joi-D-18-00276
Weinstock, R. J., Onyejiuwa, A., Shnayder, G., & Clarkson, E. I. (2015). Use of recombinant
factor VII for tooth extractions in a patient with severe congenital factor VII
deficiency: a case report. J Am Dent Assoc, 146(4), 271-275.
doi:10.1016/j.adaj.2014.12.022
Figure legends
Figure 1 – Initial clinical examination. It is possible to observe that the crown is not properly
fitted to the remaining root, with excessive cement in the buccal region.
Figure 2 – Bone height and width assessed by CBCT image.
Figure 3 – Remaining root, during the extraction it was possible to identify a longitudinal
fracture.
Figure 4 – Dental implant final position, with the implant platform placed 2-mm below the
bone crest.
Figure 5 – Temporary crown after suture removal. One-week after the implant placement.
Figure 6 – Four months radiographic image of the dental implant.
Figure 7 – Final metal-ceramic restoration.
Figure 8 – Two years radiographic follow-up, where no significant marginal bone loss was
observed.
Supplemental Material 1 – CARE checklist.
Figure legends
Figure 1 – Initial clinical examination. It is possible to observe that the crown is not
properly fitted to the remaining root, with excessive cement in the buccal region.
Figure 2 – Bone height and width assessed by CBCT image.
Figure 3 – Remaining root, during the extraction it was possible to identify a
longitudinal fracture.
Figure 4 – Dental implant final position, with the implant platform placed 2-mm below
the bone crest.

Figure 5 – Temporary crown after suture removal. One-week after the implant
placement.
Figure 6 – Four months radiographic image of the dental implant.

Figure 7 – Final metal-ceramic restoration.
Figure 8 – Two years radiographic follow-up, where no significant marginal bone loss
was observed.
Artigo 6 - Delayed bleeding in a hemophilic patient after sinus floor
elevation and multiple implant placements: A case report
Running title: Post-operative complications
Mateus de Azevedo Kinalski,a DDS

Lucas Pradebon Brondani,a DDS, MSc, PhD
Augusto Luis Mendes de Mattos Carpena,a DDS, MSc
Mateus Bertolini Fernandes dos Santos,b DDS, MSc, PhD
a Graduate student, Graduate Program Prosthodontics, School of Dentistry, Federal

b Assistant Professor, Graduate Program Prosthodontics, School of Dentistry, Federal
457 Gonçalves Chaves street, room 502, Pelotas, RS, Brazil . 96015-560
Phone: +55 53 999349134 mateusbertolini@yahoo.com.br
Artigo publicado no Journal of Oral Implantology.

DOI: 0.1563/aaid-joi-D-20-00043
INTRODUCTION
Hemophilia A is an inherited bleeding disorder in which the blood does not clot
properly due to the lack or low levels of proteins called clotting factors, more
specifically the factor VIII. This condition affects approximately 1 in 5,000 male children
worldwide.(2018). This condition is divided into three levels of severity: mild (5–40%
of clotting factor XIII), moderate (1–5%) or severe (<1%). The management and
indication of elective dental procedures in patients with Hemophilia A must consider
the severity of the disorder, the type of the dental procedure, and the patients’ medical
history to choose the more adequate therapy.(Valera, Kemoun et al. 2013)
Considering the risk of prolonged or excessive bleeding, oral procedures could
be divided into minor (e.g. restorations, orthodontic treatment, single tooth extraction)
or major oral procedures (e.g. removal of impacted third molar).(Brewer and Correa
2006) It is well known that dental implants are the gold standard treatment when
considering the rehabilitation of missing teeth.(Sarkis-Onofre, Marchini et al. 2019)
Likewise, in some cases with insufficient bone height and width, bone graft
procedures, such as sinus floor elevation, could be indicated to allow the placement
of implants.
A consensus article, published in 2017, suggested that implant placement
would pose no more risk for the patients than the extraction of impacted third
molars,(Hewson, Daly et al. 2011) whereas bone grafting and sinus floor elevation
procedures were not indicated.(Hewson, Daly et al. 2011, Donos and Calciolari 2014,
Laino, Cicciu et al. 2019) Considering that most of the recommendations in the
literature are made by consensus statements or non-systematic reviews, the evidence
about implant's survival, success rates and complication risks of these approaches in
hemophilic patients are still scarce. Thus, to the best of our knowledge, this is the first
clinical case describing a case of multiple dental implants with atraumatic sinus floor
elevation procedures in a patient with mild hemophilia A (16% factor VIII level)
performed at dental office under local infiltrative anesthesia (buccal and intra-papillary
injections).
DESCRIPTION OF THE CASE

This clinical report was written in agreement with the CARE guidelines(Gagnier,
Kienle et al. 2013) and informed consent was obtained from the patient acknowledging
the use of data and photographs to be used in this manuscript.
History taking
A 46-year-old caucasian male sought for specialized treatment with dental
implants at the Dental School of the Federal University of Pelotas (UFPel) complaining
about the absence of posterior teeth (Figure 1). During anamnesis, the patient
reported to have hemophilia A and to be registered in the Regional Blood Center of
Pelotas (HEMOPEL) where the Brazilian National Health Service (Sistema Único de
Saúde – SUS) provides multi-disciplinary monitoring for all patients with inherited
bleeding disorders. At the medical history taking the patient also reported already
having one implant in the upper right canine and that all his past teeth extractions were
performed in a hospital under general anesthesia. He did not have the habit of
smoking, alcohol or other substances consumption. At clinical examination, the patient
presented the absence of the first and second right molar and a periodontally
compromised right second premolar in the upper arch and the absence of both lower
first molars and the right second molar (Fig. 1 and 2). After this first appointment, the
blood center multidisciplinary team (BCMT) was contacted and the medical record of
the patient was obtained (Table 1). A discussion with the BCMT approached the
viability and possible risks of the treatment with dental implants and adjunctive
therapies.
Treatment plan
As the procedures were authorized by the BCMT, the patient was informed
about the treatment possibilities and a cone-beam computed tomography (CBCT) was
made to assess bone availability to place the implants. With the CBCT images, we
proposed a treatment plan that included the placement of 3 implants in the lower arch
in previously healed sites and the extraction of the upper left second premolar and
placement of one implant at the fresh extraction socket and atraumatic sinus floor
elevation and placement of another 2 implants in the posterior healed sites, due to the
low bone height observed in the CBCT. The patient agreed with the proposed
treatment and the procedures were scheduled to be made at the dental office
environment under local anesthesia in two different appointments.
Prophylaxis
The prophylaxis protocol prescribed by the BCMT consisted in the infusion of
2,500 IU of plasmatic Factor VIII (Fanhdi, Grifols, Barcelona, Spain) and oral
administration of 500mg tranexamic acid (EMS S/A, Hortolândia, Brazil) every 8 hours
starting 24 hours prior the procedures and maintained after 4 days. The same
prophylaxis protocol was adopted in both appointments.
Clinical procedures
The first scheduled procedure was the placement of the lower implants (Fig. 3)
and after one week the patient was assessed for post-operative pain and wound
healing (Fig. 4). At the same appointment the procedures on the upper arch were
made (Figs. 5). No complication nor excessive bleeding was observed during the
procedures, even when the sinus floor elevation was performed. All implants were of
the same model and brand (Alvim CM, Neodent Straumann, Curitiba, Brazil) and, in
the region of upper left first and second molars the sinus floor elevation was made
using an atraumatic sinus floor elevation technique(Summers 1998) with biphasic
calcium-phosphate synthetic biomaterial (Nanosynt, Arcsys, Joinville, Brazil). Data of
placed implants are presented in Table 2. Figure 6 presents the panoramic x-ray
demonstrating the position of the placed implants. As the BCMT suggested that even
for suture removal the patient should be submitted to prophylaxis, we have opted to
use 5-0 catgut sutures (Ethicon, Johnson and Johnson, USA) in the second surgery
to avoid the need of infusions.
The team kept phone contact with the patient after all the procedures and the
patient reported to have felt 0 in a zero-to-ten scale of post-operative pain and reported
using analgesic drugs just for two days after each procedure.
Delayed bleeding and its management
After nine days of the last procedure, the patient observed a low volume, but
constant, bleeding in the mouth that persisted for 12 hours starting at the beginning of
the night. The patient later reported also to wake-up sometimes during the night
suffocating with his blood. During the morning the patient contacted the dental team
and was immediately referred to the blood center. He received an infusion of 2,500 IU
of plasmatic Factor VIII (Fanhdi, Grifols, Barcelona, Spain), which was also prescriber
for the day after, and oral administration of 500mg tranexamic acid every 8 hours for
5 days.
After the infusion, the patient was assessed in the dental office, where the
wound site was inspected. The bleeding had stopped after the infusion and it was
possible to observe the presence of a dense clot throughout the whole wound, where
some of the catgut sutures were still present (Fig. 7). The wound was cleansed and
rinsed with 0.9% sodium chloride solution and the reminiscent sutures were removed.
In figure 8 it is possible to observe that no infection was presented, and the wound
healing process was compatible with nine-day postoperative healing of an ordinary
patient. When asked about the reason for the post-operative bleeding, the patient did
not recall any important situation other than eating regular food instead of soft food
usually recommended after oral surgeries. The wound site after 21 days of the
procedure is presented in Figure 9, where is possible to observe proper healing, with
no other reported complication.
DISCUSSION
To the best of our knowledge, this is one of the few case reports where dental
implants were placed in patients with an inherited bleeding disorder and is the first
case report of sinus floor elevation procedure in a hemophilic patient.
Dental treatments in hemophilic patients are challenging and the absence of
adequate preparation for the procedures can be life-threatening.(Brewer, Roebuck et
al. 2003) Considering the current literature, there is no consensus on the need for
hospital admittance and/or general anesthesia(Weinstock, Onyejiuwa et al. 2015) or
the performance of the procedures in outpatient clinics (e.g. dental offices) under local
anesthesia.(Hewson, Daly et al. 2011) As the costs of patient’s admittance, general
anesthesia, and operating room use are high and could be unaffordable for some
patients,(Weinstock, Onyejiuwa et al. 2015) the present manuscript is also one of the
few reports on the treatment of a hemophilic patient at a dental office level under local
anesthesia. Although some national health systems provide the plasmatic factors for
free, as it is the case of Brazil, the costs of it should not be neglected, since the
plasmatic factor used in the prophylaxis and management of the complications are
very expensive (1,000 IU = U$500).(Kazancioglu, Cakir et al. 2013)
Considering the type of procedure, there is also no consensus on the indication
of dental implants and sinus floor elevation procedures in patients with inherited
bleeding disorders. Valera et al.(Valera, Kemoun et al. 2013) suggested that dentists
should consider different prosthetic alternatives, and implant treatment should be
prescribed only when an obvious indication is observed, while other authors suggested
that placement of dental implants could be placed but bone grafting and sinus floor
elevation procedures were not indicated.(Hewson, Daly et al. 2011, Donos and
Calciolari 2014, Laino, Cicciu et al. 2019) The meaning of obvious indication is not
clear and recent studies suggests that with appropriate consultation, patients with
inherited bleeding disorders can undergo surgical procedures safely and
predictably.(Weinstock, Onyejiuwa et al. 2015) Hence, the indication of such
procedures depends on the patients’ needs and willingness and, when facing a
situation like that, a discussion with a hematologist or a BCMT to assess the risks and
viability of the treatment plan is advised.(Escobar, Brewer et al. 2018)
In the presented clinical case, we described the placement of six implants in a
hemophilic patient where sinus floor elevation was performed in the placement of two
implants. Delayed bleeding was observed 9-days after this procedure; however, no
sign of infection was observed, and the wound healing process was compatible with
the postoperative healing of an ordinary patient. The patient reported to ate regular
consistency instead of soft food, usually recommended after oral surgeries, being one
of the possible causes of the delayed bleeding. Although eating hard or regular food
does not pose any problem to ordinary patients, bruising in the surgical wounds could
result in non-stoppable bleeding that could impact the patient’s general health. Thus,
it is recommended that when treating patients with inherited bleeding disorders special
attention should be given when explaining to the patient the do’s and don’ts to avoid
the occurrence of such complications.
CONCLUSION
According to the presented clinical case and pertinent literature discussion, the
following suggestions can be drawn:
 A multi-disciplinary team, including a hematologist, should study,
discuss and elaborate the treatment plan;
 Patients should be advised to report any complication observed after the
procedures;
 Close contact between the professional and the patient should be
maintained even after the first postoperative days;
 It should be highlighted to the patients that extreme care should be taken
including the avoidance of hard foods until the final healing of the
surgical wound.
ACKNOWLEDGEMENTS
The authors would like to thank the Regional Blood Center of Pelotas
(HEMOPEL) and its staff by their contribution and support in managing the presented
case. This study was financed in part by Coordination for the Improvement of Higher
Education Personnel (CAPES) Finance Code 001.
All authors declare no conflict of interest.
REFERENCES
1. World Federation of Hemophilia Report on the Annual Global Survey 2017.
Montreal: World Federation of Hemophilia; 2018.
2. Valera MC, Kemoun P, Cousty S, Sie P, Payrastre B. Inherited platelet
disorders and oral health. Journal of oral pathology & medicine : official
publication of the International Association of Oral Pathologists and the
American Academy of Oral Pathology. Feb 2013;42(2):115-124.
3. Brewer A, Correa ME. Guidelines for dental treatment of patients with inherited
bleeding disorders. Montreal: World Federation of Hemophilia; 2006.
4. Sarkis-Onofre R, Marchini L, Spazzin AO, Santos M. Randomized Controlled
Trials in Implant Dentistry: Assessment of the Last 20 Years of Contribution and
Research Network Analysis. The Journal of oral implantology. Aug
2019;45(4):327-333.
5. Hewson ID, Daly J, Hallett KB, et al. Consensus statement by hospital based
dentists providing dental treatment for patients with inherited bleeding
disorders. Australian dental journal. Jun 2011;56(2):221-226.
6. Donos N, Calciolari E. Dental implants in patients affected by systemic
diseases. British dental journal. Oct 2014;217(8):425-430.
7. Laino L, Cicciu M, Fiorillo L, et al. Surgical Risk on Patients with
Coagulopathies: Guidelines on Hemophiliac Patients for Oro-Maxillofacial
Surgery. International journal of environmental research and public health. Apr
17 2019;16(8).
8. Gagnier JJ, Kienle G, Altman DG, et al. The CARE guidelines: consensus-
based clinical case reporting guideline development. BMJ case reports. Oct 23
2013;2013.
9. Summers RB. Sinus floor elevation with osteotomes. Journal of esthetic
dentistry. 1998;10(3):164-171.
10. Brewer AK, Roebuck EM, Donachie M, et al. The dental management of adult
patients with haemophilia and other congenital bleeding disorders. Haemophilia
: the official journal of the World Federation of Hemophilia. Nov 2003;9(6):673-
677.
11. Weinstock RJ, Onyejiuwa A, Shnayder G, Clarkson EI. Use of recombinant
factor VII for tooth extractions in a patient with severe congenital factor VII
deficiency: a case report. Journal of the American Dental Association. Apr
2015;146(4):271-275.
12. Kazancioglu HO, Cakir O, Ak G, Zulfikar B. The Effectiveness of a New
Hemostatic Agent (Ankaferd Blood Stopper) for the Control of Bleeding
following Tooth Extraction in Hemophilia: A Controlled Clinical Trial. Turkish
journal of haematology : official journal of Turkish Society of Haematology. Mar
2013;30(1):19-24.
13. Escobar MA, Brewer A, Caviglia H, et al. Recommendations on multidisciplinary
management of elective surgery in people with haemophilia. Haemophilia : the
official journal of the World Federation of Hemophilia. Sep 2018;24(5):693-702.
TABLES
Table 1 – Patient medical record.
Bleeding disorder Hemofilia A – Factor VIII deficiency
Severity Mild
HIV – ELISA Not reagent
HCV – ELISA Reagent
HBsAG Not reagent
Syphilis Not reagent
American Not reagent
trypanosomiasis
HTL – Elisa Not reagent
Table 2 – Implant placement specifics.
Implant region 36 46 47 25 26 27
Implant
3.5x8mm 3.5x8mm 3.5x8mm 3.5x11.5mm 3.5x8mm 3.5x8mm
diameter/length
Buccal gap - - - 2.5mm - -
Implant platform-
bone crest 2 2 1.5 5 1 1
distance (mm)
Insertion torque
32 60 45 10 20 10
(N.cm)
Implant stability
77.5 53 61 60 62 -
(ISQ)
Healing Healing Healing Healing Cover Cover
Covering
abutment abutment abutment abutment screw screw
Sutures Nylon Nylon Nylon Catgut Catgut Catgut
*Implant platform-bone crest distances refers to subcrestally positioned implants
assessed during the surgery.
FIGURES
Figure 1 – Oral condition of the patient at the first appointment.
Figure 2 – Panoramic x-ray demonstrating the patient condition when he sought for
treatment.
Figure 3 – Surgical site immediately after the placement of implants in the lower arch.
Figure 4 – Fifteen days of post-op. The sutures were removed in the same
appointment of the implant placement in the upper arch.
Figure 5 – The 2nd bicuspid was extracted and one implant was placed in its fresh
extraction socket. Another two implants were placed in the posterior region
concomitant to atraumatic sinus floor elevation.
Figure 6 – Panoramic x-ray demonstrating the post-operative outcome

Figure 7 – Wound site when the patient arrived at the dental office. It is possible to
observe the presence of a dense clot throughout the whole wound, where some of the
catgut sutures were still present.
Figure 8 – After sutures removal and wound cleansing, the healing process was
compatible with a nine-day postoperative healing of an ordinary patient.
Figure 9 – Wound site after 21 days of the procedure, showing proper healing of the
surgical site.
SUPPLEMENTAL MATERIALS
Supplemental Material 1 – CARE checklist.
Artigo 7 - One-year follow-up of endodontic retreatment in a patient
with severe Hemophilia A: a case report
Running title: Bleeding disorders and endodontics
Keywords: Inherited bleeding disorders, hemophilia A, root canal retreatment, case
report
Lucas Peixoto de Araújo, DDS, M.Sc.; Ph.D. student, Department of Restorative

Dentistry, Division of Endodontics, Piracicaba Dental School, State University of
Campinas (UNICAMP), Piracicaba, SP, Brazil
Mateus de Azevedo Kinalski, DDS, M.Sc.; Ph.D.; Assistant Professor, Faculty of
Dentistry, Community University of Chapecó Region (UNOCHAPECÓ), Chapecó, SC,
Brazil.
Lucas Pinto Carpena, DDS, M.Sc.; Ph.D. student, Graduate Program in Dentistry,
Federal University of Pelotas (UFPEL), Pelotas, RS, Brazil
Caio Cézar Randi Ferraz, DDS, M.Sc.; Ph.D.; Associate Professor, Department of
Restorative Dentistry, Division of Endodontics, Piracicaba Dental School, State
University of Campinas (UNICAMP), Piracicaba, SP, Brazil
Mateus Bertolini Fernandes dos Santos, DDS, M.Sc.; Ph.D.; Assistant Professor,
Graduate Program in Dentistry, School of Dentistry, Federal University of Pelotas
(UFPEL), Pelotas, RS, Brazil.
ACKNOWLEDGEMENTS
Education Personnel (CAPES) – Finance Code 001.
* Artigo submetido ao periódico Journal of Endodontics

Introduction
conditions in which missing or defective clotting factors prevent normal blood clotting
from occurring (Peyvandi, Duga et al. 2002). Among those conditions, Hemophilia A
(deficiency of factor VIII) is the most prevalent, representing about 85% of all inherited
bleeding disorders (Srivastava and Santagostino 2020). Accordingly to the severity,
this condition can be divided into mild (up to 5% of FVIII in the blood), moderate (1-
5%), or severe (<1%). In this way, a proper diagnose and severity classification is
important since such a condition is directly related to an increased number of
spontaneous or traumatic bleeding episodes (Chen 2016).
Endodontic treatment is considered a non-invasive dental procedure (Hewson,
Daly et al. 2011). Although the risk of excessive bleeding during treatment is not
common, it can sometimes occur during apical enlargement, removal of reminiscent
of vital pulp, or during apical patency establishment. When treating hemophilic
patients, a higher risk of bleeding is expected, with also an increased risk of
postoperative complications (Berntorp and Shapiro 2012). Therefore, root canal
treatment should be performed with caution and under previous medical advice in
order to avoid any further complications.
In this perspective, a previously published consensus reported that root canal
procedures in mild and moderate hemophilic patients could be performed under dental
office settings (Hewson, Daly et al. 2011); however, this very consensus also
suggested that adults with severe hemophilia must have endodontic treatments
performed at hospital settings (Brewer, Roebuck et al. 2003). Such recommendation
is based on the assumption that excessive bleeding in severe hemophilic patients
might impose the necessity of additional replacement therapies. Also, some studies
reported complications as minor discomforts to acute swelling (Leeb 1977, Vire and
Barrett 1982)
When planning an endodontic intervention in a hemophilic patient, the dentist
should consider some important challenges: (1) to reduce or eliminate the risk of
bleeding during the procedure and post-treatment, and (2) to achieve hemostasis and
root canal dryness in order to properly fill the root canal (Marashdeh, Friedman et al.
2019). Likewise, the scientific literature about root canal procedures in hemophilic
patients is still scarce. Therefore, the aim of the present case report was to describe
the planning and treatment of a patient with severe hemophilia A at a dental office
setting, with a multi-professional approach to, including hematological advice and
clotting factor replacement therapy, and to report specific endodontic considerations.
Material and Methods

This case report has been written according to Preferred Reporting Items for
Case reports in Endodontics (PRICE) 2020 guidelines (Nagendrababu, Chong et al.
2020).
A 21-years-old caucasian male patient diagnosed with severe congenital
hemophilia A was referred by the Regional Blood Center of Pelotas (HEMOPEL) to
the School of Dentistry of the Federal University of Pelotas. The patient's chief
complaint was 'pain when chewing hard food' in the region of the left mandibular first
molar.
The visual inspection of the patient identified restorations in multiple teeth and
the clinical examination of the tooth with referred pain presented moderate sensitivity
to vertical percussion, with no discomfort at palpation or extra-oral abnormalities as
described in Table 1. The intraoral periapical digital radiographic (CDR Elite size 2,
Dentsply Sirona, Charlotte, NC, USA) image showed a previous endodontic treatment
with insufficient root canal fillings, persistency of periapical radiolucency and an apical
widening of the periodontal ligament space characterizing a periradicular pathological
condition due to the failure of the previous root canal treatment (Figure 1). Based on
these pieces of information, a diagnosis of symptomatic apical periodontitis was made
to the left mandibular first molar, and root canal retreatment was indicated.
After reviewing the risks, benefits, and treatment options, written informed
consent from the patient was obtained for the proposed treatment and followed the
ethical principles of the World Medical Association’s Declaration of Helsinki. The
patient was referred back to the Blood Center for medical assessment and a
prophylactic treatment plan. The results of the blood tests are presented in Table 2.
The prophylactic protocol consisted of infusion of 3000 UI/dL recombinant
factor VIII concentrate (Hemo-8R, Hemobrás, Federal District, Brazil) one hour before
the root canal treatment due to the necessity of alveolar nerve block anesthesia and
to reduce the risk of intraoperative bleeding or complications.
The alveolar nerve block was performed using 1.8mL of 2% lidocaine with
1:100.000 epinephrine (Alphacaine 2%, Nova DFL, Rio de Janeiro, Brazil), and
supplementary anesthesia was carried out with a buccal infiltration of 1.8mL of 4%
articaine with 1:100.000 epinephrine (Nova DFL). After that, a rubber dam was placed
to isolate the operating field. The access cavity was opened with high-speed diamond
burs and refined under magnification provided by a dental operating microscope
(OPMI Pico, Zeiss, Oberkochen, Germany) using an E6D pear diamond ultrasonic tip
(Helse Ultrasonics, Sao Paulo, Brazil) to carefully remove interferences and previous
restorative materials. Initial root fillings removal was performed using a Reciproc R25
file (VDW GmbH, München, Germany), and apical patency was achieved in all root
canals with small size C-Pilot files (VDW GmbH) and was maintained at a size 15 K-
file (VDW GmbH). Chlorhexidine gluconate gel at 2% (LenzaFarm, Minas Gerais,
Brazil) was used as a chemical auxiliary substance associated with 0.9% sterile saline
solution as an irrigation substance.
The root canals length measures were determined electronically by a
RomiApex A-15 apex locator (Romidan LTD, Kiryat Ono, Israel) and were as follows:
mesiolingual 21mm; mesiobuccal 21mm; and distal 22mm. Working length was
established at the "0.0" reading of the electronic apex locator, and the glide path was
conducted in all canals with an R-Pilot reciprocating file (VDW GmbH) prior to the
apical enlargement using a Reciproc R25 file. At the end of the root canal
repreparation, three cycles of passive ultrasonic irrigation were performed in each
canal using an E1 Irrisonic ultrasonic tip (Helse Ultrasonic) associated with 1mL of
EDTA 17% (Biodinamica, Parana, Brazil), renewing this substance at the end of each
cycle. A final flush of 0.9% sterile saline solution was carried out to remove any trace
of the previous substances, and the canals were dried with sterile paper points. The
root canals were obturated with the single-cone obturation technique using a
calibrated gutta-percha point in each canal, associated with Bio-C Sealer (Angelus,
Parana, Brazil), a tricalcium silicate-based root canal sealer. After cutting and
condensing the gutta-percha points, the tooth received an immediate coronal
restoration with Opus A2 (FGM, Santa Catarina, Brazil) bulk-fill resin-based
composite. Finally, a radiograph was taken to assess the quality of the root canal filling
(Figure 2).
No complication occurred during or after the procedure, and a telephone inquiry
was made with the patient after 48 hours and three months as an initial follow-up
method to evaluate the patient's comfort and symptom conditions.
The patient was then recalled after twelve months for periapical healing
assessment, and the one-year clinical and radiographic follow-up showed complete
periapical healing with reestablished radiographic regular periapical bone density
(Figure 3), no sensitivity on percussion or palpation, and the patient reported adequate
function of the tooth with no pain. Figure 4 is a schematic flowchart that summarizes
the steps involved in this case report and its clinical outcome, and Table 3 represents
the treatment timeline.
Discussion
The present study reports a case of persistent apical periodontitis resolved with
root canal retreatment on a severe hemophilic A patient. There is still a lack of studies
reporting endodontic therapy in IBDs patients. In this way, the present case report
provides important information regarding root canal retreatment and the radiographic
assessment of one year of follow-up with adequate periapical bone repair without the
presence of any signs or symptoms.
According to a case-control study, hemophilic patients present a 2.2 higher
odds ratio of presenting teeth with apical periodontitis but about 70% less prevalence
of endodontic treated teeth when compared to patients without IBDs (Castellanos-
Cosano, Machuca-Portillo et al. 2013). In this perspective, another survey on IBDs
patients in hemophilia treatment centers across the United States identified that
financial barriers, lack of skilled providers, and patient anxiety contribute directly to
less access to oral health care (Schaffer, Duong et al. 2016). On the other hand, it is
well-known that root canal treatment is a conservative technique that reduces the need
for tooth extractions, providing high long-term survival rates (Ng, Mann et al. 2011).
The maintenance of teeth in IBDs patients is extremely important once it reduces the
need for more invasive procedures such as tooth extraction and dental implant
placement, which are more prone to intra and postoperative complications.
Importance should be given to the adequate management of IBDs subjects,
especially those with high severities due to the increased risk of bleeding episodes
during their lifetime (Srivastava and Santagostino 2020). Considering the possible
implications of IBDs, dental professionals might be afraid of providing invasive
procedures in IBDs patients, such as anesthetic nerve block and other specific
endodontic procedures. A consensus statement by hospital-based dentists suggests
that endodontic therapy in patients with IBDs could be considered a low-risk procedure
and can be performed routinely (Hewson, Daly et al. 2011). On the same perspective,
a recent scoping review on invasive oral procedures (e.g., tooth extraction and
anesthesia) highlighted the importance of a multidisciplinary team when treating
patients with IBDs to reduce complications and provide a safe treatment (Kinalski,
Sarkis-Onofre et al. 2020). In this sense, dentists willing to perform endodontic therapy
on IBD patients should be aware of some particularities in order to reduce the risk of
bleeding-related complications. In this way, it can be suggested that infiltrative
anesthesia and the maintenance of the working length within the root canal region
should be preferred in IBDs subjects.
It has been suggested that a single dose of 0.1 mg desmopressin acetate tablet
associated with 250 mg tranexamic acid could be used as a prophylactic protocol to
perform inferior alveolar nerve block in IBDs patients (Pasi, Collins et al. 2004).
However, considering the severity of our patient and the increased risk of
complications, our multi-professional team decided to prescribe the infusion of clotting
factor VIII one hour prior to the dental appointment; Also, 2% chlorhexidine gluconate
gel was chosen as the preferred irrigation substance instead of sodium hypochlorite
due to the necessity of avoiding intraoperative accidents in patients with this special
healthcare need, since there is no difference regarding clinical and radiographic
outcomes when comparing those two irrigation substances (Zandi, Petronijevic et al.
2019). The root canal retreatment was conducted following the gold standard
endodontic procedures with apical patency achievement in all root canals. Considering
that adequate hemostasis and dryness in the root canal were obtained, the treatment
was performed in a single session to avoid the need for a second appointment and,
consequently, the need for another clotting factor infusion. A cost-analysis study
revealed that the treatment of hemophilia patients is very expensive and may also
affect public policies adopted by health systems. (Ferreira, Brum et al. 2020). For this
reason, it is important to correctly administrate the clotting factor replacement therapy
in order to reduce the occurrence of complications during and after the procedures,
impacting the patient's health positively and reducing the costs to the public health
systems.
Although IBDs are considered rare, it is important to highlight that dental
professionals must consider inquiring all patients about their health condition and signs
of abnormal or excessive bleeding, including family background assessment and,
whenever treating patients with diagnosed or suggestive signs and symptoms of IBDs,
these patients must be referred to hematologists or blood centers with a multi-
professional team prior to any dental therapy in order to assess the specific patient's
conditions as well as to plan the need of prophylactic measures and the performance
of the treatment in a dental office setting.
Conclusion
Although no complications or excessive bleeding was observed, proper
multidisciplinary planning must be carried when treating patients severe hemophilia A.
Further clinical investigations should focus on the need for prophylactic protocols in
order to safely perform endodontic treatment on patients diagnosed with different
severity levels of IBDs.
REFERENCES
Berntorp E, Shapiro AD (2012) Modern haemophilia care. Lancet 379(9824), 1447-

1456.
Brewer AK, Roebuck EM, Donachie M et al. (2003) The dental management of adult
patients with haemophilia and other congenital bleeding disorders. Haemophilia
9(6), 673-677.
Castellanos-Cosano L, Machuca-Portillo G, Sanchez-Dominguez B, Torres-Lagares
D, Lopez-Lopez J, Segura-Egea JJ (2013) High prevalence of radiolucent
periapical lesions amongst patients with inherited coagulation disorders.
Haemophilia 19(3), e110-115.
Chen SL (2016) Economic costs of hemophilia and the impact of prophylactic
treatment on patient management. Am J Manag Care 22(5 Suppl), s126-133.
Ferreira AA, Brum IV, Souza JVdL, Leite ICG (2020) Cost analysis of hemophilia
treatment in a Brazilian public blood center. Cadernos Saúde Coletiva 28, 556-
566.
Hewson ID, Daly J, Hallett KB et al. (2011) Consensus statement by hospital based
dentists providing dental treatment for patients with inherited bleeding
disorders. Aust Dent J 56(2), 221-226.
Kinalski MA, Sarkis-Onofre R, dos Santos MBF (2020) Inherited bleeding disorders in
oral procedures. Assessment of prophylactic and therapeutic protocols: a
scoping review. Australian Dental Journal [epub ahead of print].
Leeb IJ (1977) Severe hemorrhage as an endodontic complication. J Endod 3(12),
465-467.
Marashdeh MQ, Friedman S, Lévesque C, Finer Y (2019) Esterases affect the
physical properties of materials used to seal the endodontic space. Dental
materials : official publication of the Academy of Dental Materials 35(8), 1065-
1072.
Nagendrababu V, Chong BS, McCabe P et al. (2020) PRICE 2020 guidelines for
reporting case reports in Endodontics: a consensus-based development. Int
Endod J 53(5), 619-626.
Ng YL, Mann V, Gulabivala K (2011) A prospective study of the factors affecting
outcomes of non-surgical root canal treatment: part 2: tooth survival. Int Endod
J 44(7), 610-625.
Pasi KJ, Collins PW, Keeling DM et al. (2004) Management of von Willebrand disease:
A guideline from the UK Haemophilia Centre Doctor's Organization.
Haemophilia 10(3), 218-231.
Peyvandi F, Duga S, Akhavan S, Mannucci PM (2002) Rare coagulation deficiencies.
Haemophilia 8(3), 308-321.
Schaffer R, Duong MT, Wachter B, Arana E, Frances D (2016) Access to dental care
for people with bleeding disorders: survey results of hemophilia treatment
centers in the U.S. Spec Care Dentist 36(6), 295-299.
Srivastava A, Santagostino E (2020) WFH Guidelines for the Management of
Hemophilia, 3rd edition. 26 Suppl 6, 1-158.
Vire DE, Barrett KC (1982) Endodontic Rx for the von Willebrand patient. J Endod
8(11), 514-516.
Zandi H, Petronijevic N, Mdala I et al. (2019) Outcome of Endodontic Retreatment
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Figure legends
Figure 1 – Initial radiographic assessment of the left mandibular first molar.
Figure 2 – Immediate postoperative periapical radiograph.

Figure 3 – One-year follow-up periapical radiograph of the root canal retreatment.
Figure 4 – Schematic PRICE 2020 flowchart
Tables
Table 1 – Diagnostic assessment results.
Tooth Cold Heat Percussio Palpation Mobilit Extra-oral
numbe n y
r
#36 No No Moderate No Within No
respons respons abnormalitie normal abnormalitie
e e s limit s
Table 2 – Hematology tests
Blood assay Result Reference values
Activated partial 103.3 seconds 34.3 seconds
thromboplastin time
Prothrombin time 13.5 seconds 13.4 seconds
Factor VIII activity (FVIII:C) Less than 0.01 IU/ml At least 0.25 IU/ml
von Willebrand factor 1.19 IU/ml 0.90-1.20 IU/ml
activity (FvW:Ag)
Anti-factor VIII inhibitor 1.3 UB/ml At least 0.6 UB/ml
antibody
Table 3 – Timeline of the patient planning, treatment, and follow-up
Time Event Symptons
0 Patient visited the clinic, Moderate pain at vertical
history, clinical and percussion in the left
radiographic mandibular first molar
examination.
+24 hours Factor XIII prophylactic -
treatment
+1 hour Endodontic retreatment -
of tooth #36
+12 hours 1st Follow-up No pain, no swelling
(Phone inquiry) (sympton free)
+12 hours 2nd Follow-up No pain, no swelling
+24 hours 3rd Follow-up No pain, no swelling
+3 months 4th Follow-up No pain, no swelling
+9 months 5th Follow-up No pain, no swelling
(clinical and (sympton free)
radiographic Radiographic evidence
assessment) of complete periapical
repair
Considerações Finais
causadas por deficiência quantitativa e/ou qualitativa de fatores de coagulação.
Embora essas condições sejam conhecidas há bastante tempo, as evidências
científicas quanto ao tratamento odontológico em pacientes apresentando essas
condições ainda se apresenta escassa e amparada em estudos com baixo poder de
evidência. Neste contexto, a proposta da presente tese de realizar análise da
evidência científica disponível e de gerar conhecimento para aplicação na prática
clínica através de estudos clínicos se finda com a realização de três estudos de alto
poder de evidência, sendo uma revisão sistemática com meta-análise e duas revisões
de escopo, um estudo clínico observacional com 1 ano de acompanhamento e três
relatos de casos clínicos abordando a realização e acompanhamento de tratamento
endodôntico e de implantodontia, bem como a descrição de uma complicação pós-
operatória. Diante disso e amparado pelo exposto no corpo desta tese de doutorado,
as considerações finais da presente tese serão apresentadas com recomendações
específicas sobre:
1. Saúde oral de pacientes com coagulopatias hereditárias:
Através da realuzação de meta-análise, foi possivel concluir que não há
diferenças entre a experiência de cárie de pacientes com coagulopatias hereditárias
comparados à pacientes saudáveis. No entanto, é importante frisar que a prevenção
e o cuidado com a saúde bucal se fazem ainda mais relevantes diante de pacientes
com coagulopatias hereditárias, uma vez que em havendo diagnóstico de doença
cárie, os procedimentos restauradores podem exigir procedimentos com certo grau

de invasividade e/ou risco de sangramento, o que podem impactar negativamente o
tratamento ou a saúde do paciente.
2. Procedimentos cirúrgicos (exodontias e periodontais):
A presente tese evidenciou que a terapia de reposição de fatores de
coagulação com utilização simultânea de antifibrinolíticos sistêmicos, que atuam para
reduzir complicações pós-operatórias, é a abordagem mais indicada para o
tratamento de indivíduos com coagulopatias hereditárias. Entretanto, observa-se na
literatura um alto número de complicações pós-operatórias registradas em diferentes
desenhos e metodologia dos estudos.
Essa elevada prevalência de complicações pode estar associada ao fato de
ainda haver abordagens sem respaldo de evidências científicas fortes e a existência
de dúvidas quanto à melhor abordagem quando do atendimento odontológico de
pacientes com coagulopatias hereditárias. Portanto, há ainda necessidade de novos
estudos avaliando a segurança e o risco de complicações através da utilização de
diferentes abordagens profiláticas, sendo a utilização de apenas antifibrinolíticos
sistêmicos sem o uso de reposição de fatores de coagulação uma das possíveis
abordagens.
3. Procedimentos de implantodontia:
Evidenciou-se que o tratamento com implantes dentários em pacientes com
coagulopatias herditárias se apresentam como opção viável e segura para
reabilitação de dentes perdidos possuindo valores de estabilidade do implantes (ISQ)
no ato cirúrgico e no momento da cirurgia de reabertura similares à pacientes sem
qualquer tipo de coagulopatia hereditária bem como imagens radiográficas de

acompanhamento de um ano do tratamento condizentes com os critérios de sucesso
estabelecidos para a população geral. Embora a literatura aponte não haver riscos
maiores do que extrações dentárias, ressalta-se a importância de um manejo
individualizado dos pacientes após o período pós-operatório, uma vez que
sangramentos podem ocorrer devido à traumas mastigatórios, principalmente quando
houver realização de procedimentos de enxertia.
4. Procedimentos endodônticos:
Os procedimentos endodônticos podem ser considerados de baixo risco,
sendo que o procedimento de maior risco está relacionado ao processo de anestesia
por bloqueio e não ao tratamento endodôntico propriamente dito. Assim, recomenda-
se a utilização de anestesia local infiltrativa sempre que possível de modo à reduzir
ainda mais o risco de complicações. No entanto, quando houver necessidade de
bloqueio anestésico, a realização de profilaxia com infusão de fator de coagulação
deve ser realizada.
Outro ponto importante identificado na presente tese diz respeito à
possibilidade de realização de procedimentos endodônticos em consultório, sem a
necessidade de internação hospitalar.
5. Recomendações à cirurgiões dentistas:
Recomenda-se que sempre que o profissional se deparar com pacientes com
coagulopatias hereditárias, principalmente quando o tratamento envolver a realização
de procedimentos invasivos, estes procedimentos devem ser discutidos e avaliados
preferencialmente por equipe multidisciplinar ou ao menos por um médico
hematologista. É importante que o cirurgião-dentista em conunto com esta equipe

multidisciplinar avalie a condição e a severidade da coagulopatia de maneira
personalizada para cada indivíduo, de modo a reduzir o risco de complicações.
Por fim, é importante que o profissional realize acompanhamento pós-
operatório individualizado, estando à disposição do paciente para eventuais dúvidas
ou intercorrências e, assim, reduzindo as chances de possíveis complicações com
necessidade de hospitalização.
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UNIVERSIDADE FEDERAL DE PELOTAS

Coagulopatias Hereditárias em Odontologia:

Mateus de Azevedo Kinalski

Coagulopatias Hereditárias em Odontologia:

Tese apresentada ao Programa de Pós-

Orientador: Prof. Dr. Mateus Bertolini Fernandes dos Santos

Coagulopatias Hereditárias em Odontologia:

Tese aprovada, como requisito parcial, para obtenção do grau de Doutor em

Data da Defesa: 24/09/2021

Prof. Dr. Mateus Bertolini Fernandes dos Santos (Orientador)

Prof. Dr. Rafael Ratto de Moraes (Titular interno)

Prof. Dr. Gabriel Kalil Rocha Pereira (Titular externo)

Prof. Dr. Andre Webber Rosa (Titular externo)

Prof. Dr. Lucas Pradebon Brondani (Suplente externo)

Prof. Dr. Cesar Dalmolin Bergoli (Suplente interno)

À Faculdade de Odontologia, em nome da direção e de seus funcionários,

Instuição a qual vesti a camiseta e sentirei orgulho de me considerar egresso durante

toda a minha trajetória de vida.

Ao Programa de Pós-Graduação em Odontologia, aos coordenadores Prof. Dr.

Ao Hemocentro Regional de Pelotas, em nome de sua equipe, pelo suporte

bucal de todos os seus pacientes.

Ao meu orientador, Mateus Bertolini Fernandes dos Santos. De um encontro na

obrigado por tudo!

imprescindíveis nesta caminhada. Agradeço-lhes por demonstrar que é sempre possível

possuo nesse universo. A minha familia, por acreditarem e compreenderem a ausência

amor depositado em mim.

Aos meus mestres, agradeço por toda a dedicação ao ensinar e confiança

depositada em mim. Um bom aluno é sempre fruto de um bom educador.

não é, apenas, formalidade.

A presente dissertação foi redigida segundo o Manual de Normas para

KINALSKI, Mateus de Azevedo. Coagulopatias Hereditárias em Odontologia: Uma

Hereditárias e sua relação com a Odontologia. As coagulopatias hereditárias são um

qualitativa de fatores de coagulação, sendo as principais a Hemofilia A, Hemofilia B e

doença de von Willebrand. No entanto, há uma lacuna quanto as condições orais,

tratamentos e particularidades em relação aos individuos com coagulopatias hereditárias

e uma meta-analise sobre a experiência de cárie comparando individuos com

conhecimento e contribuir para a evidência científica sobre essa temática, a fim de

reduzir as possíveis complicações pós-operatórias apos procedimentos odontológicos

em pacientes com coagulopatias hereditárias.

Palavras-chave: Coagulopatias hereditárias; Hemofilia A; Hemofilia B; Doença de von

KINALSKI, Mateus de Azevedo. Inherited bleeding disorders: An analysis of the

are a heterogeneous group of genetic conditions in which missing or defective clotting

aiming to reduce postoperative complications after dental procedures in patients with

inherited bleeding disorders.

Key-words: Inherited bleeding disorders; Hemophilia A; Hemophilia B; von Willebrand´s

Definição das Coagulopatias Hereditárias

Doença de von Willebrand

Coagulopatias Hereditárias e aspectos relacionados aos pacientes

Condições de saúde orais

Terapia com Implantes dentários

UNIVERSIDADE FEDERAL DE PELOTAS

Avaliação do nível de conhecimento de estudantes e profissionais da

Palavras-chave: Coagulopatias Hereditárias, Fator VIII, Fator IX, Hemofilia A, Hemofilia

1.2 Definição das Coagulopatias Hereditárias

1.2.1 Doença de von Willebrand

1.3 Coagulopatias Hereditárias e aspectos relacionados aos pacientes

1.3.2 Condições orais

1.3.3 Implantes dentários

2.2 Objetivos específicos

4.2 Amostra e recrutamento

4.2.2 Estudantes e profissionais

4.3 Critérios de Elegibilidade

4.3.2 Estudantes e profissionais