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 Normalised ratio (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)

Explain common disorders of coagulation, their diagnosis and treatment.

Too little coagulation Inherited Disorders: Haemophilia A: Factor VIII, B: Factor IX Give purified/recombinant Factor VII Aquired Disorders Liver disease (Alcoholic liver disease) or Vitamin K deficiency (Haemorrhagic disease of newborn) Give vitamin K supplement Too much coagulation: Venous Disorders: Caused by artificial surfaces, prolonged stasis (post-surgery), arterial fibrillation, deficiency in reg factors, smoking, cancer, obesity Oral Anti-coagulants Warfarin (Vitamin K antagonist) Injectable Anti-coagulants Heparin (acts as an anti Thrombin)

Arterial Thrombosis Induced Disorders MI, angina, stroke, peripheral artery disease Excessive demand of coagulation - Severe wounds Prevention: antiplatelet drugs New drug: NOVA 7, functions where TF Treatment: Thrombolytic drugs: tissue present at wound site, 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 Coumarins o 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 lowmolecular weight heparins with oral anticoagulants: warfarin and the newer (oral) anti-coagulants: direct thrombin inhibitors Dabigatrin.
Warfarin Oral, very slow onset/offset Long term use, cheap Careful monitoring by INR Treats: venous thrombosis Heparin (LMWH) 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.

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 fibrinogen o 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 expressed on the surface of intact cells. Enhances the inhibitory potency of Antithrombin III o 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