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HIS 11,12 - Anticoagulant Drugs

Compare and contrast the different types of blood clotting tests.

 Both require blood that is freshly drawn or stored in an appropriate anti-coagulant (EDTA,

Citrate, ACD or thrombin inhibitors such as hepatin)

1. Assess Extrinsic Pathway (Tissue factor pathway)

i. Prothrombin time / PT test / INR

  Whole blood in glass tube would result in clotting in 5-11 minutes  Whole blood in a vaccutainer w/ anti-coagulant it would not clot  However, you can also add back Ca++ to overcome anticoagulant  If you also add tissue factor, it will clot very fast (12-14 seconds this is refered to

as the Prothrombin time or PT = extrinsic pathway of CC)   Time will determine if blood clots properly.  Since PT varies, the prothrombin ratio (PR) is the PT of patient / PT of normal

 pooled plasma, 0.8-1.2 is considered normal.

  Recombinant human proteins are used to calculate the International Normalisedratio (INR) which is the reference of PR and can be effected by smoking, alcohol,

drugs, illness (liver disease), stress, and climate. 

2. Assess Intrinsic Pathway

i.  Activated partial thromboplastin time   Anti-coagulated whole blood and calcium, phospholipid, silica, celite, kaeolin or

ellagic acid, (Partial because NO TF), the clot forms within 33 s = activated

partial thromboplastin time (aPTT) 

ii.  D-Dimer test   D-dimer is a specific degradation fragment of cross-linked fibrin.   Produced naturally as part of the wound healing process by plasmin degradation 

of thrombus (Long half-life) 

  Measurement used to aid diagnosis of systemic thrombosis   A positive D-dimer result may indicate the presence of an abnormally high level

of fibrin degradation products (Recent thrombotic event) 

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Explain common disorders of coagulation, their diagnosis and treatment.

Too little coagulation Too much coagulation:

Inherited Disorders:

Haemophilia A: Factor VIII, B: Factor IX

  Give purified/recombinant Factor VIIAquired Disorders

Liver disease (Alcoholic liver disease) or

Vitamin K deficiency (Haemorrhagic disease of

newborn)

  Give vitamin K supplementInduced Disorders

Excessive demand of coagulation - Severe wounds

   New drug: NOVA 7, functions where TF present at wound site,

Venous Disorders:

Caused by artificial surfaces, prolonged stasis 

(post-surgery), arterial fibrillation, deficiencyin reg factors, smoking, cancer, obesity

  Oral Anti-coagulants –  Warfarin (Vitamin K antagonist)

  Injectable Anti-coagulants –  Heparin (acts as an anti Thrombin)

Arterial Thrombosis

MI, angina, stroke, peripheral artery disease

  Prevention: antiplatelet drugs  Treatment: Thrombolytic drugs: tissue

 plasminogen activator (tPA), streptokinase

Summarize the different classes of anti- coagulant drugs, their mode of

administration and side effects.

  Many drugs are vitamin K antagonists which inhibit coagulation cascade from proceeding at (II, VII, IX, X)

  Warfarin and other Coumarinso  Treatment of venous thrombosis (long flight, or immobile hospital patient) or

secondary prophylaxia (individuals who have already formed a blood clot to prevent future blood clots) 

o  Admin'd orally but takes a long time (8h to 4 days) to deplete stores in body o  99% plasma protein bound (Can interact with other drugs and their activity) o  Metabolized by cytochrome P450 in liver. o  Warfarin dosage needs careful monitoring by (PT) test 

  Vitamin K is necessary for coagulation and is synthesized by bacteria in the gut.Compare and contrast Intravenous anticoagulants: Heparin and low-

molecular weight heparins with oral anticoagulants: warfarin and the

newer (oral) anti-coagulants: direct thrombin inhibitors Dabigatrin.

Warfarin Heparin (LMWH)

  Oral, very slow onset/offset  Long term use, cheap  Careful monitoring by INR    Treats: venous thrombosis

  Intravenous, immediate onset of action  Short term use, cheap  Careful monitoring by aPTT and HIT  Treats: DVT, Pul embolism, acute MI

Dabigatrin 

  Direct thrombin inhibitor, prodrug, does not need careful monitoring, more expensive  No antidote for it but allows predictable anticoagulation.

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Explain the role of intact endothelium in regulating haemostasis.

  Thrombomodulin is expressed on the surface of intact endothelial cells.  Binds to thrombin and forms a 1:1 (TT) complex which functions to:

o  TT cannot activate fibrinogeno  TT converts regulatory protein, Protein C, to its active form (APC)o  APC and Protein S degrade Factors Va and VIIIa

  Heparan sulphate proteoglycans are synthesized by endothelial cells and expressedon the surface of intact cells.

  Enhances the inhibitory potency of Antithrombin IIIo  AT-III weak inhibitor of thrombin,

  Combined w/ AT-III to be a more potent inhibitor (1000 fold)o  Heparen and AT-III complex inhibits both Thrombin and Xa

Identify the drugs that impact on the thrombolytic pathway.

**IIa inhibitor include Dabigatran