ANTICOAGULAÇÃO

Tampão hemostático
COMPONENTES DA HEMOSTASIA
Vasos
Proteinas cascata coagulação
Plaquetas
Cascata de coagulação
 Coagulation Factors
Factor Name Plasma half-life
(h)
I Fibrinogen 72-96
II Prothrombin 60
III Tissue Factor or thromboplastin --
IV Ca2+ --
V Proaccelerin 15
VII Proconvertin 5
VIII Antihemophilic A factor 10
IX Antihemophilic B factor or Christmas 25
factor
X Stuart factor 40
XI Plasma thromboplastin antecedent 45-65
XII Hageman factor 60
XIII Fibrin Stabilising Factor 150
Prekallikrein --
High-Molecular Weight Kininogen 156
Rede de fibrina
Contact Activation - The Role of Kallikrein
Negative Charged Surface

XII

HK XII
FXIIa PKK
HK XII HK
FXIIa
PKK FXI
Kallikrein
FXIIa FXIIa

Bradykinin Kallikrein XIa

Thrombin Generation
Esfregaço sanguíneo
Equilíbrio endotélio - plaquetas
Plaquetas Endotélio
Fibrinolysis
Formação de trombo intravascular
Formação de trombo intravascular
 Pathophysiology
Dislodgement of a blood clot:

 Lower Extremities: 65% to 90%

 Pelvic venous system
 Renal venous system
 Upper Extremity
 Right Heart
 Risk Factors for Thrombosis
Hereditary Atherosclerosis Acquired
thrombophilia thrombophilia

Thrombosis Surgery
Immobility trauma

Estrogens
Inflammation
Malignancy
Epidemiologia da Tromboembolia

Adapted from: Andrew, Monagle, Brooker, Eds. “Thromboembolic

Complications during Infancy and Childhood”: © 2000 BCDecker.
Virchow’s Triad
Objetivos Terapeuticos

1 - Prevenir expansão do trombo ou a embolia

2 - Restaurar fluxo sanguineo

3 - Minimizar sequelas a longo termo

 Anticoagulantes
Excreção

Heparina Hepático

Dalteparina
Enoxaparina
Polissacarídeos sulfatados LMWH Fraxiparina Renal
Tinzparina

Pentassacarídeo - Fondaparinux

Hirudina

Peptídicos Leperudina Renal

Inibidores diretos da Trombina Bivalirudina

Sintéticos - Argatroban Hepático

Heparina
Fracionamento da heparina
Fracionamento da heparina
Fondaparinux
 Anticoagulantes
Excreção

Heparina Hepático

Dalteparina
Enoxaparina
Polissacarídeos sulfatados LMWH Fraxiparina Renal
Tinzparina

Pentassacarídeo - Fondaparinux

Hirudina

Peptídicos Leperudina Renal

Inibidores diretos da Trombina Bivalirudina

Sintéticos - Argatroban Hepático

L- Arginine

Argatroban

Inibidor da Trombina
Reversível
Secreção Biliar
 Anticoagulantes
Excreção

Heparina Hepático

Dalteparina
Enoxaparina
Polissacarídeos sulfatados LMWH Fraxiparina Renal
Tinzparina

Pentassacarídeo - Fondaparinux

Hirudina

Peptídicos Leperudina Renal

Inibidores diretos da Trombina Bivalirudina

Sintéticos - Argatroban Hepático

Via de ação da heparina não fracionada
 Unfractionated Heparin
Extracted from porcine gut or bovine lung

Binds to factors IIa, IXa, Xa, XIa, XIIa (slow)

Binds and ↑ anti - thrombin III (AT III) activity to 1,000 fold →binds & inactivates
factors IIa and Xa.

Degree of inhibition: F Xa = IIa

* LMWH inhibition of Xa > IIa

Lesser inhibition on F IXa, XIa and F XIIa

Implication:

Heparin has almost NO anticoagulant action without AT III

The therapeutic range for UF heparin is 0.3-0.7 IU/ml.

One unit of heparin (the "Howell Unit") is the quantity required to

keep 1 mL of cat's blood fluid for 24 hours at 0 °C.
 Low Molecular Weight Heparin (LMWH)

4,000-6,500 daltons (vs. standard heparin

3,000 -30,000 daltons)
Retains anti-Xa activity
Less anti -IIa than standard heparin
Enhances AT-III interaction with F IIa & F Xa
Degree of inhibition: F Xa > IIa

The range for LMW heparin is less clearly

defined. Some clinicians maintain that is 0.4-
1.1 IU/ml (anti-FXa method).
Ligação heparina – antitrombina III
Interação entre heparans e Fatores IIa e Xa
Standard Heparin vs. LMWH
Standard Heparin vs. LMWH
Heparina de baixo peso molecular
Karl Link
Warfarin – uso como raticida
 Oral Anticoagulants
Warfarin

Inhibits synthesis of vitamin - k dependent

factors II, VII, IX, X and protein C & S

Reversal:
Stopping medication and waiting for ~4
days for PT normalization vitamin K PO or
IV (1-2mg)
Immediate: rFVIIa, FFP (1-2 units),
prothrombin complex concentrate

Check PT prior to surgery

Warfarin—Mecanismo de Ação
Vitamina K
Fatôres

VII

Utilização reduzida de IX Proteina C

Vitamin K
X Proteina S

II

Warfarin
Meia-vida dos fatôres dependentes de
vitamina K

Proteina Meia-vida

Fator VII 4–6 horas

Fator IX 24 horas
Fator II 60 horas
Fator X 48–72 horas
Proteina C 8 horas
Proteina S 30 horas
 HIT Syndrome
 Type I
 associated with an early (within 4 days) and usually
mild decrease in platelet count (rarely <100 x 109/L)
 typically recovers within 3 days despite continued
use of heparin
 nonimmunologic mechanisms (mild direct platelet
activation by heparin)
 not associated with any major clinical sequelae
 occurs primarily with high dose iv heparin

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 HIT Syndrome
 Type II
 substantial fall in platelet count (> 50%)
 count in the 50,000 - 80,000 /mm range
 typical onset of 4-14 days
 occurs with any dose by any route
 induced by immunologic mechanisms
 rarely causes bleeding (think of alternative Dx)
 potential for development of life-threatening
thromboembolic complications

10/98 medslides.com 41
Clinical signs of HIT

Erythematous plaques 1 Deep venous thrombosis 1

Skin necrosis 1 Venous gangrene 2

1 Reproduced with permission Blackwell Publishing (Warkentin TE. Br J Haematol 1996

2 Warkentin TE et al. Ann Intern Med 1997
 Cascade of events leading to formation of HIT antibodies and
prothrombotic components

www.thrombosite.com
10/98 medslides.com 43
 Risks for HIT
 Type I
 intravenous high-dose heparin
 Type II
 varies with dose of heparin
 unfractionated heparin > LMWH
 bovine > porcine
 surgical > medical patients

10/98 medslides.com 45
 Frequency of HIT
 Unfractionated heparin 1
 Low molecular weight heparin 2
 3% and 1% orthopedic patients who received UFH for one
and two weeks, respectively

HIT antibodies HIT syndrome

UFH 7.8% 3%
LMWH 2.2% 0%

1. Thromb Hemost 1998;79:1-7

2. NEJM 1995;332:1330-1335
10/98 medslides.com 46
 Do’s and Don’ts of HIT Management

Drug Do Don’t Comments

Warfarin x warfarin in the absence of an anticoagulant

can precipitate venous limb gangrene
Platelet x infusing platelets merely “adds fuel to the fire”
Vena caval filter x often results in devastating caval, pelvic, and
lower leg venous thrombosis
LMWH x low molecular weight heparin usually cross-
react with unfractionated heparin after HIT or
HITTS (HIT thrombosis syndrome) has occurred
Ancrod x not readily available; difficult to titrate dose
Danaparoid x cross-reacts with UFH in about 10-15% of
cases; titrate with unwieldy anti-factor Xa levels
Hirudin x Beware renal insufficiency, antibody formation
Plasmapheresis x removes micro-particles formed from platelet
activation; not a standard indication
Argatroban x FDA approved June 30, 2000

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Tempo de sangramento
Relação entre plaquetas e sangramento
Adesão e agregação plaquetária
Ativação plaquetária
Ativação plaquetária
Ativação plaquetária
Endothelium Platelets
Prostaglandin Synthesis
ASPIRIN

NSAIDS
Mecanismo de ação da aspirina
 Antiplaquetários

Aspirina (irreversivel)
Inibidores de COX
Anti-inflamatórios não estereoidais

Inibidores de fosfodiesterase Dipiridamol

Ticlopidina
Inibidores do receptor P2Y (ADP) (irreversivel)
Clopidogrel

Eptifibatide (peptídico)
Inibidores do receptor GPIIa-IIIa
Abciximab (anticorpo monoclonal)

Inibe ligação fibrinogeneo- GPIIa-IIIa - Tirofiban (análogo Tyr – irreversível)

Plasmina