Anemias

Type

Subtype

2 Subtype

Etiology/Pathogenesis

Clinical Signs/Symptoms

general signs and symptoms of anemia, ie fatigue.

Iron Deficiency
inadequate dietary intake, impaired absorption in duodenum,
Specific to Fe: pica (craving for ingestion of unusual
increased requirement ( ie pregnancy, growing children), chronic
substances), koilonychia (fingernails become thin,
blood loss (ie carcinoma or peptic ulcer)
brittle), blue
sclera
MASSIVE
erythroid
hyperplasia ---> skeletal
abnormalities; impaired bone growth; organomegaly -->
extramedullary hematopoeisis; cachexia (increased
MICROCYTI
nutrients going to the tissues supporting the
C ANEMIAS
qualitative abnormalities of hemoglobin due to genetic
extramedullary and medullary erythropoiesis); iron
major - homozygous, minor - heterozygous
Thalassemias
mutations that cause decreased synthesis or absence of either overload/secondary hemochromatosis; transfusion
(MCV < 70
alpha or beta Hb chains. Aggregation of excess alpha chains
dependence; Beta-minor (heterozygotes) have
fL, decreased
which precipitate --> cell membrane damage, premature
asymptomatic, microcytic anemia (don't confuse w/
removal by spleen, and ineffective erythropoeisis.
Fe deficiency)
Hb

production)
Sideroblastic

Chronic Disease

Diagnostic Criteria

Morphology

decreased hemoglobin, decreased

hematocrit, low MCV,
low serum iron, increased TIBC,
decreased serum ferritin

usually microcytic with high RDW, significant

anisocytosis (variation in size and shape),
RBC's are usually small and hypochromic,
Iron supplements, either oral or parenterally.
elongated RBCS "pencil cells"; basophilic Investigate and treat underlying cause.
stippling
Rule out malignancy in adults.

Treatment

Demographic

Other Key Points

Infants (milk diet = little Fe); Toddlers w/o

balanced diet; Elderly (restricted diets, poor
dentition); Adolescent girls; Women of
childbearing age

Fe aborption inhibited by tea, bran,

medications that pH, foods with phytate.
Fe absoprtion enhanced by Vit C

often microcytic, but may be macrocytic,

hypochromic, target cells are common,
basophilic stippling, poikilocytosis

regular transfusions and use of iron chelators

to prevent iron overload. Patients have
complications of chronic transfusions, iron
overload, hemochromatosi, Congestive
Mediterranean Countries (ie: Italy),
Heart Failure is complication
Africa, SE Asia

Iron becomes trapped in erythroid precursors in patients with

hereditary abnormalities or acquired disorders (alcoholism, lead
poisioning); may also be due myelodysplasia & chronic
inflammation (cytokines mediate macrophage sequestration of
iron)

SIDEROBLASTS: nucleated
erythroblasts, basophilic stippling
(precipatated RNA) whoch inhibits
incorporation of iron into heme. Increased
HgF, iron overload, organ dysfunction.

treat underlying cause

iron cycling is deranged and Fe becomes trapped within

macrophages in bone marrow unavailable for erythropoeisis

variable, may be normocytic; basophilic

stippling

treat underlying cause

very low Hb levels (2.5-6 g/dL),

decreased MCV, increased retic count
high HbF, Hb electrophoresis
confirms diagnosis

High RBW

Alpha-deletion of one of 4 genes

Beta-most causative mutations are
point mutations chromosome 11, beta
major = homozygous, beta minor=
heterozygous, type of hemolytic anemia
(genetic)

sometimes associated with alcohol or

other drugs

inadequate intake (eating/handling raw fish =

diphulobothrium latum), increased requirement, defective

B12 Deficiency absorption in Ileum, defective parietal cell production of IF,

defective metabolism

see pernicious anemia for the following boxes

Folate Deficiency decreased intake, increased requirements, impaired use, excessive RARE to see psych disorders: Irritability, depression,

MACROCYTI Megaloblastic
C ANEMIAS
(MCV > 100
fL, cells are
normochromi
c or
Aplastic
hyperchromi
c)
Myelodysplasia

Pernicious
Anemia

Disorders ass'd
w/ decreased
BM function

loss (dialysis); absorbed in Jejunum

forgetfulness (diff than B12 CNS problems); Glossitis

due to intrinsic factor deficiency --> autoimmune destruction of

gastric mucosa --> IF deficiency; also causes neurological
problems due to degeneration of myelin (from increased MMA)

atrophic gastritis; Glossitis (smooth/red tongue),

intestinal metaplasia, glossitis, diarrhea, spastic
paraparesis, sensory ataxia, severe parasthesias,
often mild jaundice, fatigue, pallor, weight loss

leukopenia with hypersegmented

neutrophils, anisocytosis, cells are large
and oval , increased MCV, increased RDW,
bone marrow changes: enlarged nuclei in red treat with oral or IM B12--cure anemia and
cell precursors, immature chromatin, no
Increased levels of serum
stop neurological changes, never give
nuclear pyknosis, N/C asynchrony
homocysteine and MMA, decreased
folate without B12 (B12 needed for
hematocrit, increased MCV, serum B12
absorption of folate, folate may mask
levels, Schilling test--> decreased
B12 deficiency), patients should be
B12 excretion (1st dose)
followed and screened for gastric cancer
Increased levels of serum
homocysteine, serum folate, RBC
folate levels

reduced hematopoeisis in bone marrow due to radiation, chemicals,

benzene, can be hereditary or idiopathic

diminished RBCs, platelets,

granulocytes, WBCs

drugs, toxins, liver, thyroid disease

Decreased reticulocyte count

common in alcoholics and drug addicts

occurs in adult patients 50-70

bone marrow will be mostly fat, largely

acellular

Chronic Alcohol Use

consider myelophthisic (infiltrative process in bm) like metastatic
tumor or primary hematological malignancy ie leukemia,
lymphoma

General

qualitative defect due to a point mutation in 6th position of beta

globin chain that leads to replacement of glutamate with valine
--abnormal physiochemical properties of Hb that lead to sickling
Sickling: abnormal RBC shape, viscous and sticky, occurs due to
deoxygenation, dehydration. Vaso-occlusion: occurs in capillaries,
causing microinfarcts and end organ damage, sickled RBC's
express high levels of adhesion molecules, NO may be inactivated,
WBC adhesion due to inflammation. predisposition to
vasocontriction + platlet aggregation.
Hemolysis:damaged and abnormal cells removed by spleen,
ultimately become asplenic

Sickle Cell Anemia

Chronic Disease

General
Concepts

NORMOCYTIC ANEMIAS

accelerated RBC turnover, either intravascularly or extravascularly

(within spleen, liver, or BM), most hemolysis occurs in spleen
and occurs due to an abnormal environment, RBC membrane
defects, RBC metabolic defects, or abnormal Hb structurecan occur.
intravascularly: mechanical injuries, infections/toxins,
burns, or complement fixation

Hb electrophoresis, peripheral
smear --> low Hb (5-9 g/dL), variable
MCV

decreased hematocrit, increased

reticulocyte count, increased total and
indirect bilirubin (not conjugated) ,
decreased haptoglobin
(intrasvascular),
fatigue, pallor, jaundice, hemoglobinemia,
elevated Lactate dehydrogenase
hemoglobinuria, acute: fever, chills, headache, chronic: (marker of turnover). Dark blood &
hepatosplenomegaly, gallstones, back pain (Hb
urine (Hb unbound because
damages kidney)
haptoglobin saturation)

DAT (Direct antiglobulin/Coombs test);

Indirect test: positive indicated
alloantibodies

prevention is best therapy, stop

immediately if there is suspicion of a
transfusion reaction, screen mothers for are
Rh negative and given then RhIG to prevent
disease

Immune
patient produces antibodies against his or her own RBCs.
Warm type (Extravascular) assoc. w/ malignancies,
Hemolysis-autoantibodies autoimmune disorders, viral infections or idiopathic. Cold-type
(Intravascular) assoc. w/ lymphomas, viruses, mycoplasma
(AIHA)

Warm Type (70 %): more severe, with abrupt onset at

37 degrees, IgG mediated, splenomegaly, jaundice,
extravascular removal. Cold type (30 %): insidious
onset, IgM mediated, activate complement, reacts at 4
degrees, can be episodic or chronic

DAT (Direct antiglobulin/Coombs test);

Indirect test: positive indicated
alloantibodies
larger bluish reticulocytes

steroids, IV Ig; rule out malignancies

hemolysis in the blood vessels (microangiopathic

Non-immune
hemolytic anemia- MAHA) is assoc. with DIC,
hemolysis
(Intravascular) mechanical stresses either inside (see next box) or outside vessels hypertension, TTP, or disseminated cancers, increased
(prosthetic valves)

Hereditary
mutations in RBC cytoskeletal proteins--> membrane integrity,
Spherocytosis flexibility, stability defects -->lodged in spleen and prematurely
(Extravascular) destroyed. Mostly ankyrin protein, also spectrin protein

most people are asymptomatic and normal in

steady state, episodic and extravascular hemolysis
G6PD Deficiency defects in this enzyme prevent NAPDH production needed for
(Extravascular) glutathione reduction, RBCs at more risk for oxidative damage and incited by oxidant drugs (anti-malarials,
Hb denaturation--makes membrane more deformable cells are
sulfonamides), ingestion of fava beans, infections
prematurely removed by spleen
(viral hepatitis, pneumonia, typhoid fever)

Deficiencies result in impaired DNA synthesis and defective nuclear maturation with a block in cell division.
RNA and protein synthesis (cytoplasmic maturation) are unaffected

many meds can cause hemolytic anemia,

should be considered when no other
explanation can be found. Mechanisms
include: oxidation of Hb, antibody
destruction of RBCs (hapten),
thrombotic microangiopathies

RBCs appear fragmented (schistocytes);

helmet cells

fibrin, increased thrombin production

many are asymptomatic (1/3), some will have chronic

hemolysis, aplastic crisis (w/ Parvovirus infxn)

sub-Sahara Africa, Cuba, South/Central

Homozygous has almost 100 % abnormal Hb;
America, Saudi Arabia, India, Turkey, Greece, heterozygous has 40 % abnormal Hb;
Italy
type of genetic hemolytic anemia

polychromatophilia, shistocytes, spherocytes

(small RBCs lacking central pallor), sickle
cells, target cells, increased accumulation of
RBC catabolic products
splenectomy helpful in some cases

acute transfusion reaction: fever, diaphoresis,

hypotension/shock, dyspnea, tachycardia, chills, rigor,
vomiting, urticaria, hemoglobinemia, hemoglobinuria
Rh incompatibility: baby is anemic,
erythroid hyperplasia, extramedullary hematopoiesis,
unconjugated bilirubin, hydrops fetalis

infection

megaloblastic

target cells and sickled cells

hydroxyurea used to reduce pain crises by

producing HbF instead of HbS; bone marrow
transplant; long-term complications include:
impaired growth, occasional narcotic
dependence

Immune
Hemolysis-alloantibodies
(Extra-/Intravas
ABO transfusion reactions (IgM mediated), Rh incompatibility (IgG
cular)
mediated)

Hemolytic

painful crises (vaso-occlusion), end organ damage,

autosplenectomy --> predisposed to encapsulated
bacterial infection; avascular necrosis (bone); acute
chest syndrome--hypoxia, fever, cough, chest pain;
peripheral ulcers, hyperbilirubinemia
gallstones, endothelial dysfunction, pulmonary HTN,
extramedullary hematopoeisis, stroke, renal disease,
typical symptoms of anemia, sequestration crisis-->
rapid splenic enlargement, hypovolemia

spherical shape, less surface area, less

clinical history, family history, specific flexibility; Howell-Jolly Bodies (after
lab tests
splenectomy)

splenectomy corrects anemia, but doesn't

correct RBC defect

mostly AD inheritance

clinical suspicion, specific lab test

peripheral smear

avoid meds and foods that cause hemolysis,

infants may require exchange
transfusions,
most do NOT have
chronic complications

mostly X-linked inheritence (female

heterozugote possible), affects people of
Middle Eastern descent and black
Americans

Heinz bodies*--aggregations of denatured

Hb in the periphery of cells; 'bite-cells'

*Heinz bodies also seen In ALPHAthalassemia (NOT on this test)

Low RBW

PLATELETS
lab values

Quantitative
Disorders

thrombycytopenia is < 150 x10^9/L

normal is 150-450
Thrombocytosis is > 450 x 10^9/L

Type

Subtype

Etiology/Pathogenesis
underproduction from bone marrow: leukemia,
myelodysplastic syndromes, congenital BM failure
decreased survival: autoimmune destruction,
intravascular consumption
blood loss, extravascular consumption

General Thrombocytopenia
Congenital Platelet Disorders
Fanconi's Anemia

defect in DNA repair

Schwachman-Diamond Syndrome

SBDS gene mutation leads to bone marrow failure

CAMT

genetic mutation of thrombopoeitin receptor gene (cmpl) prevents platelet formation

Wiskott-Aldrich Syndrome

dense granule defect

Immune/Idiopathic Thrombocytopenia Purpura (ITP)

anti-platelet IgG antibodies against platelet receptor

Iib-IIIa results in splenic destruction
thought
to follow infection/MMR vaccine, cross-reaction with
anti-viral antibody

Thrombotic Thrombocytopenic Purpura (TTP)

reversible aggregation of platelets in

microvasculature--ischemia of organs, involves
MAHA
congenital and acquired-ADAMS13 deficiency (cleaves vWF)

Hemolytic-Uremic Syndrome (HUS)

assoc. with MAHA, related to TTP but

pathophysiology located to kidney

Disseminated Intravascular Coagulopathy (DIC)

assoc. with MAHA, trauma, severe infections, OB

complications, malignancy, shock, hypoxia
consumptive coagulopathy due to thrombin
activation

hypercoaguable state from reaction to heparin in a

small amount of patients after therapy is started -IgG antibody reacts with platelet factor 4

Heparin-Induced Thrombocytopenia (HIT)

Other

HIV-associated

immune destruction of platelets or ineffective

platelet production

drug-associated

drugs trigger auto-antibody like penicillin, quinine,

IFN-alpha that bind platelet membrane proteins

Bernard-Soulier Syndrome

defect in platelet glycoprotein Ib-IX which disrupts

the adhesion of platelets to subendothelium

Glanzmann's Thombasthenia

deficiency in platelet glycoprotein Iib/IIIa which

disrupts the cross-linking of fibrinogen needed for
platelets to aggregate

Gray platelet syndrome

alpha granule deficiency

Drug-Induced

ASA/NSAIDs due to COX1 inhibition of TXA2, also

penicillin and psychotropic drugs like valproic acid

Critical Illness, Hypothermia

renal failure, cardiopulmonary bypass surgery,

dialysis -- platelets are only transiently activated

Clinical
Signs/Epidemiology

Diagnostic Criteria/Lab
Values

short stature, abnormal facies, thumb

hypoplasia usually presents at 4-7 YO,

thrombocytopenia preceding pancytopenia

Morphology

Treatment/Outcomes

pancreatic insufficiency
bleeding in newborn period

thrombocytopenia progressing to pancytopenia

and possibly AML

significant bleeding at a young age

thrombocytopenia with small platelets

BM transplant

80 % of children with acute ITP recover

spontaneously
adults present more
insidiously, considered chronic if > 6 mos. (< 5 %
spontaneous remission)
treat if
platelets < 20, high risk of spontaneous
bleed > 10
treatment is symptomatic: IV IgG, anti-RH
(competitive inhibition of destruction in spleen),
prednisone, splenectomy for chronic cases or
rituximab

97% of children present with

petechiae/purpura, intercranial hemorrhage
is rare
otherwise
normal Hb, normal WBC abnormally low platelet
appear well
count (<20,000)

fever, neurological abnormalities likes

headaches and strokes
renal failure

diagnostic pentad: thrombocytopenia, MAHA

(elevated LDH), fever, neurological
abnormalities, renal failure (increased Cr), DIClike (decreased fibrinogen, elevated D-dimer,
elevated Pt/PTT)

fever, bloody diarrhea (ie E.coli poisoning)

DIC not typical

thrombocytopenia, MAHA, fever with acute renal

failure

treatment is supportive, may need dialysis but

patients usually recover

consumption of clotting factors fibrinogen is low

elevated PT/pTT, D-dimer
thrombocytopenia
schistocytes

treatment with plasma can replenish factors but

can exacerbate clotting so it is only given for
severe cases and bleeding

schistocytes, platelet aggregation

treat with fresh, frozen plasma every 3 weeks

goal is to treat BEFORE neurological
symptoms appear

can see skin lesions with hypercoaguable

state

platelet count can drop 50 %, diagnose by HIT

assay

mild and often not treated, but

thrombocytopenia can be presenting
symptom in children

mild drop in platelets (often in 50's)

mucocutaneous bleeding ie epistaxis,

menorrhagia, GI bleeding-- bleeding is out
of proportion to the level of their
mild thrombocytopenia, abnormal platelet
thrombocytopenia
aggregation study
mucocutaneous bleeding similar to B-S
syndrome, sever bleeding can occur in
infancy

similar to ITP, splenectomy in refractory cases

giant platelets

abnormal platelet aggregation study

mild bleeding but can progressive and cause

splenomegaly

DIC?

creates heparin-antibody complexes stop heparin

microthrombocytes, platelets look

pale and gray

thrombocytopenia

platlets are fragmented

remove offending agent, treat underlying disease,

DAVP--desmopression is a sympathetic
stimulator that stimulated factor 8 and vWF release
to 4x increase and stop bleeding symptoms
aminocaproic acid, a fibrinolytic inhibitor
that binds plasminogen and promotes clotting
platelet transfusions can be used in issues with
major bleeding

Other Key Points

this one is here because apparently

sometimes it appears on the boards

also appears on boards

sometimes seen with SLE

occurs in about 2 % of patients on

heparin therapy

rare AR disorder-consanguinity?

rare AR disorder
AR disorder

COAGULOPATHIES
Differential Diagnoses

Lab Value

Disorders Considered

Rationale

Elevated PT Only

warfarin ingestion

warfarin inhibits vitamin K so it inhibits

activity of vitamin K dependent factors

congenital factor VII deficiency

clinically variable

Liver Disease

underproduction of clotting factors

Heparin effect

activated antithrombin

Elevated PTT only

vW disease

Elevated Pt and PTT

deficiency of factor 8, 9, 11, or 12

factor 23 deficiency doesn't cause bleeding

disorder

lupus anticoagulant

falsely elevates PTT

high-dose heparin
vitamin K deficiency
factor 2,5, or 10 deficiency

factor 10 is rare

dysfibrinogenemia
DIC/hemangioma
Elevated TT

if w/ thrombocytopenia

fibrinogen defects
heparin effect

Normal PT, PTT, platelet count with

bleeding

qualitative disorders
vW disease

may have elevated PFA

Factor 13 deficiency, PAI-1 deficiency

rare congential defects

vasculitis, connective tissue diseases

cause vessel weakness

Etiology/Pathogenesis

Clinical
Signs/Epidemiology

Type 1 (80%)

reduced levels of the vWF protein

usually mild, and often asymptomatic in

heterozygotes
mucocutaneous bleeding: prolonged,
recurrent epistaxis, easy bruising,
menorrhagia, increased bleeding postprocedure

Type II, Type III

rare and more severe AR with abnormal vWF

protein

Coagulopathy DisorderSubtype

von Willebrand Disease

Hemophilia A

bleeding into deep tissues like joints,

muscle groups, vital organs-- can be
delayed due to pooling, and often lifethreatening and often spontaneous
more mild forms may
only experience bleeding with trauma
affected infants may
have circumsion bleeds, bleeding of
deficiency in factor VIII, may be due to large tongue, and bleeding after venopuncture
deletion, body may recognize synthetic
recurrent synovial bleeds could
factor 8 as foreign because their factor 8 is damage joints
concerns
so mutated
more for intracranial, retinal, GI and renal
mild forms may have smaller mutations
bleeding

Hemophilia B

Factor IX deficiency

Contact Pathway Disorders

Factor XI and XII deficiencies

clinically sim
not typically assoc. with bleeding
problems, but possible thrombosis risk

Thrombophilia

(aka hypercoaguable states)

thrombotic Disorder
Congenital

Subtype

Etiology/Pathogenesis

common

does not respond to inhibition by

activated protein C, so essentially a
protein C deficiency

common

elevated prothrombin level promotes

enhanced thrombin and leads to
thrombophilia

common

mutations reduce enzyme activity, which

leads to build up of homocysteine that
injures blood vessels and causes vessels
to become prothrombotic

rare

clinically similar to Protein C/S deficiency

because antithrombin normally
inactivates thrombin and factor Xa

Protein C/Protein S Deficiency

rare

Protein C normally inhibits factors Va and

VIIIa and Protein S is the cofactor.
Deficiencies in either of theses increase
clot formation because they are unable
to inhibit the procoagulant system

Fibrinogen Disorders

Dysfibrinogenemia

AD mutation of fibrinogen

Afibrinogenemia

complete absence of fibrinogen

Hypofibrinogenemia

lower levels of fibrinogen

Factor V/Leidin Mutation

Prothrombin Mutation

MTHFR Mutation

Antithrombin III deficiency

Acquired

prolonged immobiliztion

high risk

tissue injury/trauma

high risk

Cancer, Inflammator Diseases

high risk

DIC

high risk

Atrial fibrillation

high risk

prosthetic cardiac valves

high risk

HIT

high risk

nephrotic syndrome

low risk

hyperestrogenic states

low risk

oral contraceptive use

low risk

smoking

low risk

antiphospholipid antibody

high risk

autoantibodies that interfere with

coagulation factors leading to
endothelial damage and platelet
activation

Diagnostic Criteria/Lab
Values

Treatment/Outcomes

low levels of vWF antigen, vWF activity, F VIII,

usually only mildly depressed (40-49 % of
normal)

DDAVP used to increase vWF factor,

activity, and FVIII levels-- can be used for
prolonged bleeding episodes or preprocedure
can
most common inherited bleeding
also used vWF concentrate prior to a
disorder! 1-3% of population, AD
major operation
inheritance

thrombocytopenia

Other Key Points

may require prophylactic recombinant

FVIII infusions 3x/week (half-life is 12 hrs)
tingling in joints= immediate
FVIII transfusion 1-2x/day until it resolves
family history-- 30 % have no family history
for those who
severely prolonged PTT
develop antibodies to FVIII may treat
check FVIII and PTT levels for newborns of with synthetic FVII or immune tolerance
mothers who are carriers
therapy
clinically similar to Hemophilia A

Factor XI common in Ashkenazi Jews

treat with fresh frozen plasma, typically

10 mL/kg

most common hereditary

disorder assoc. with SEVERE
bleeding
X-linked
inheritance severe cases have <1 %
FVIII

Clinical Signs/Epidemiology

Diagnostic Criteria/Lab
Values

Treatment/Outcomes

measure activated protein C resistance

by functional assay

approx. 130 % normal prothrombin levels

increased venous and arterial thrombotic
events, thought to be worse with folic acid
deficiency but supplementation has not proven
to reduce risk

severe deficiency leads to purpura, DIC and

sepsis in infants

may be heparin resistant (normally

enhances antithrombin function)

bleeding and clotting problems

bleeding often occurs with trauma
lifelong bleeding disorder assoc. with splenic
rupture and umbilical cord bleeding in newborn

treat with fibrinogen concentrate

mild disorder, assoc. with possible OB problems

signs of venous thrombotic event: gradual

onset of pain with swelling, swollen extremity,
erythema
signs of arterial thrombotic
event: pain, cool, pale distal to thrombus

can image thrombus/clot through

doppler ultrasound or echocardiogram if
in subclavian, run labs to screen for
underlying risk: CBC and DIC profile
also need to consider
anatomical complications: PagetSchroetter or May-thurner syndromes

discontinue any aggravating factors

or triggers then begin anti-coag
therapy with heparin and replace any
deficient factors with concentrates
consider tPA if
large and occlusive heparin therapy
can last 3-6 mos

signs of venous thrombotic event: gradual

onset of pain with swelling, swollen extremity,
erythema
signs of arterial thrombotic
event: pain, cool, pale distal to thrombus

in subclavian, run labs to screen for

underlying risk: CBC and DIC profile
also need to consider
anatomical complications: PagetSchroetter or May-thurner syndromes

thrombosis and atherosclerosis

false increase in PTT

assoc. with SLE

often

therapy with heparin and replace any

deficient factors with concentrates
consider tPA if
large and occlusive heparin therapy
can last 3-6 mos