L47 Anticoagulation

An overview of the clotting cascade: 1. Initiation: Platelets adhere to vessel and [blank_start]recruit[blank_end] more circulating platelets to [blank_start]aggregate[blank_end]. This provides a surface where clotting factors assemble. Some clotting factors are [blank_start]released[blank_end]. TF initiates coagulation. TF activates [blank_start]X and IX[blank_end], forming Xa and IXa. 2. Amplification IXa amplifies the activation of [blank_start]X[blank_end]. The [blank_start]Xa/Va[blank_end] complex is a critical component, activating [blank_start]FIIa[blank_end] (thrombin) 3. Propagation A burst of activated thrombin then converts [blank_start]fibrinogen to fibrin[blank_end], to form a mesh.

The clotting cascade has an "[blank_start]intrinsic[blank_end] pathway" activated by trauma inside the vascular system. It is [blank_start]slower[blank_end] than the “extrinsic pathway”. The initiation involves XII, XI, IX, VIII.

Warfarin is a Vitamin K “antagonist” that targets Vitamin K epoxide reductase in the liver.

NOACs (novel oral anticoagulants) like dabigatran and rivaroxaban target thrombin and Xa.

Choose the incorrect statement.

By inhibiting vitamin K epoxide reductase, warfarin increases the production of clotting factors II, VII, IX, X.

The half-life of the FII is longer than warfarin and is the rate limiting step in the time course of the warfarin effect.

Unfractionated heparin is found naturally in [blank_start]mast[blank_end] cells. It is a large [blank_start]polymer[blank_end] with alternating disaccharide units of variable lengths. - No [blank_start]intrinsic[blank_end] anticoagulant activity - Not [blank_start]orally[blank_end] available so given intravenously and subcutaneously - Half-life of about [blank_start]1[blank_end] hour The antidote is a reversal agent called [blank_start]protamine sulphate[blank_end]. It binds to [blank_start]antithrombin II[blank_end]I, and induces a conformational change that enhances binding to [blank_start]activated[blank_end] clotting actors, helping to inhibit coagulation.

Low molecular weight heparins (LMWH) • Given [blank_start]subcutaneous[blank_end] • Enoxaparin halfe life ~ [blank_start]5hrs[blank_end] • Mainly [blank_start]renally[blank_end]-cleared • Effect [blank_start]partially[blank_end] reversed by giving protamine sulphate • Target is mostly anti-[blank_start]Xa[blank_end], some anti-IIa

Novel oral anticoagulants (NOACs): 1. Dabigatran etexilate • Competitive and reversible inhibition of free and clot bound [blank_start]thrombin[blank_end] • Prodrug converted to active compound (dabigatran) • [blank_start]Low[blank_end] oral availability (~7%) • ~80% [blank_start]renally[blank_end] cleared, ~20% glucuronidation • Half life: ~12 hours 2. Rivaroxaban • Competitive and reversible inhibition of free and clot bound [blank_start]Xa[blank_end] • [blank_start]Good[blank_end] oral availability (>80%) • ~35% renally cleared, ~65% [blank_start]metabolised[blank_end] (CYP3A4 and others) • Half life: ~7-10 hours

PT, prothrombin time, is the time taken for plasma to clot in [blank_start]vitro[blank_end] after the addition of [blank_start]tissue factor & CaCl[blank_end]. Normally it is 12-15 seconds. The PT ratio is the [blank_start]patient's[blank_end] PT over the normal [blank_start]average[blank_end] PT. The International Normalised ratio (INR) is a “correction” of the PT ratio, or rather a correction of the large variability in the [blank_start]sensitivity of the reagents[blank_end]. Low INR indicates a risk for [blank_start]clotting[blank_end] while high INR indicates a risk for [blank_start]bleeding[blank_end]. The usual range is 2-3.

Which of these is not a major determinant of warfarin dose requirements:

Most clinically important interactions with warfarin are well understood and can be predicted. I.e these drugs: • Inhibition of CYP2C9, e.g. [blank_start]amiodarone, fluconazole[blank_end] • Induction of CYPs, e.g. [blank_start]phenytoin, rifampin[blank_end] • Inhibition if CYP3A4, 1A2 e.g. [blank_start]quinolones, macrolides, azoles[blank_end] Will affect the warfarin metabolism significantly.

Occasional consumption of vitamin K rich food is unlikely to be important in most patients but in the elderly and malnourished, vitamin K deficiency may increase risk of bleeding.

Thrombolytic drugs (also called fibrinolytics) work by activating [blank_start]plasminogen[blank_end], to produce plasmin. [blank_start]Plasmin[blank_end] breaks cross-links between [blank_start]fibrin[blank_end] molecules, disrupting the structural integrity of blood clots. They restore blood flow more [blank_start]quickly[blank_end] than anticoagulants but carry a much higher [blank_start]risk[blank_end] of bleeding.

t-PA binds to fibrin, converts plasmin to plasminogen, which digests fibrin.