COAGULATION & ANTICOAGULATION Dr Rakesh Jain

A set of reactions in which blood is transformed from a liquid to a gel Coagulation follows intrinsic and extrinsic pathways The final three steps of this series of reactions are: – Prothrombin activator is formed – Prothrombin is converted into thrombin – Thrombin catalyzes the joining of fibrinogen into a fibrin mesh Coagulation

Current Concept of coagulation

The “extrinsic” or tissue factor pathway consists of FVIIa/TF complex and FXa/Va complex. It operates on TF-bearing cell to initiate the coagulation process. The “intrinsic” pathway does not include FXII or its cofactors PK and HMWK, which do not appear to be necessary for hemostasis. The “intrinsic” pathway to consist of FXI(a), FIXa/VIIIa complex, and FXa/Va complex. It operates on the platelet surface during the propagation phase to generate a burst of thrombin. Both pathways are needed for hemostasis, because they operate on different surfaces and play distinct roles.

Anticoagulants Parenteral Unfractionated heparin LMWH Fondaparinux Direct Thrombin Inhibitors Hirudin Argatroban Bivalirudin Oral Vitamin K antagonist – Warfarin Thrombin Inhibitor – Dabigatran Xa inhibitor - Rivaroxaban

Parenteral Anticoagulants

Heparin Is a sulfated polysaccharide Commercial heparin is derived from porcine intestinal mucosa Mechanism of Action Activate antithrombin and accelerating the rate at which it inhibits clotting enzymes - thrombin & factor Xa

Pharmacology Requires parenteral administration – s/c or continuous intravenous infusion Intravenous route is most often used for therapeutic purposes Binds to endothelium and plasma proteins Heparin binding to endothelial cells explains its dose- dependent clearance Plasma t 1/2 is 30 to 60 min with bolus iv doses of 25 and 100 U/kg

Levels of heparin - binding proteins in plasma vary from person to person - so anticoagulant response to fixed or weight-adjusted doses of heparin is unpredictable Coagulation monitoring is essential to ensure therapeutic response

Monitoring Anticoagulant Effect of Heparin aPTT or anti–factor Xa level is used aPTT terapeutic range : 2 to 3 fold prolongation Anti factor Xa therapeutic range : 0.3 to 0.7 unit/ml In heparin resistant cases anti factor Xa is prefered - elevated plasma levels of fibrinogen & factor VIII (a/c phase proteins) shorten aPTT but have no effect on anti–factor Xa levels

Dosage Prophylaxis 5000 U s/c twice or thrice daily Therapeutic In ACS : 5000 U / 70 U/Kg bolus followed by 12 to 15 U /Kg/hr infusion In VTE :5000 U / 80 U/kg bolus followed by 18 U /kg/hr infusion

Limitations Poor bioavailability Dose-dependent clearance Variable anticoagulant response Reduced activity in vicinity of platelet-rich thrombi Mechanism Limited absorption of long heparin chains Binds to endothelial cells Binds to plasma proteins Neutralized by PF 4 released fm activated platelets

Side Effects Bleeding Protamine sulfate neutralizes heparin in pts with serious bleeding. 1 mg of intravenous protamine sulfate neutralizes 100 units of heparin Thrombocytopenia HIT is an antibody-mediated process Occurs 5 to 14 d after initiation of therapy Plt count < 100,000 or decrease in plt count of 50% or more from baseline

Osteoporosis In 30% of pts on long-term heparin therapy Elevated Levels of Transaminases

LMWH Smaller fragments of heparin Prepared from UFH by controlled enzymatic or chemical depolymerization Advantages Better bioavailability & ↑ half-life after s/c inj Dose-independent clearance Predictable anticoagulant response Lower risk of HIT and Osteoporosis

Monitoring Usually not required If necessary anti–factor Xa is measured May be done in renal insufficiency, obesity, pregnancy, mechanical valves

Dosing Prophylaxis : 4000 to 5000 U s/c Once daily Treatment : VTE : 150 to 200 U /kg Once daily or 100 U/Kg twice daily ACS : 100 to 120 U /kg twice daily Complication Bleeding, Thrombocytopenia, Osteoporosis - but less than UFH

Fontaparinux Synthetic analogue of the antithrombin-binding pentasaccharide sequence Exhibits complete bioavailability after s/c injection Plasma half-life is 17 hrs Dose Prophylaxis : 2.5 mg once daily Treatment of VTE : 7.5 mg once daily (5mg if wt 100 kg)

Parenteral Direct Thrombin Inhibitors

Oral Anticoagulants Warfarin water-soluble vitamin K antagonist interferes with synthesis of vit Kdependent clotting proteins : factor II,VII, IX, X, proteins C and S Almost completely absorbed fm GI tract Levels peak 90 min after drug administration Plasma half life 36 to 42 hours 97% bound to albumin

Mechanism of Action

Monitoring Prothrombin Time INR Target INR : 2 to 3 in mechanical valves 2.5 to 3.5 Dose 5 to 10 mg Concomitant treatment with parenteral anticoagulant until INR has been therapeutic range for at least 2 consecutive days

Side Effects Bleeding – major side effect If INR 3.5 to 4.5 : Withheld warfarin till normalises INR > 4.5 : vitamin K 1mg sublingual Serious bleeding : 10 mg vit K slow iv, FFP supplementation for Vit K dependent clotting proteins Bleeding in therapeutic range – investigate for cause Skin Necrosis : rare complication Occurs 2 to 5 d after initiation of therapy occurs in pts with deficiencies of protein C or S

Pregnancy – teratogenic nasal hypoplasia & stippled epiphyses Causes fetal bleeding Warfarin is contraindicated in 1 st and 3 rd trimesters

New Oral Anticoagulants

Fibrinolytic drugs Used to degrade thrombi Approved fibrinolytic agents include SK, urokinase, alteplase, tenecteplase and reteplase Act by converting proenzyme, plasminogen, to plasmin SK,UK are not fibrin specific while others are fibrin specific Nonspecific agents, activate circulating plasminogen resulting in generation of unopposed plasmin that can trigger systemic lytic state

Streptokinase Does not directly convert plasminogen to plasmin It forms complex with plasminogen which activate additional plasminogen to plasmin Not fibrin specific Dose : 1.5 million units infusion over 30 to 60 min SK is antigenic Transient hypotension due to plasmin mediated bradikinin release

Urokinase Derived from cultured fetal kidney cells Directly converts plasminogen to plasmin Alteplase Recombinant form of single-chain t-PA Has limited fibrin specificity Given as an iv infusion over 60 to 90 min The total dose of alteplase usually ranges from 90 to 100 mg

Reteplase Recombinant t-PA derivative, reteplase is a single-chain variant Given as two intravenous boluses separated by 30 min

Tenecteplase A genetically engineered variant of t-PA longer half-life than t-PA More fibrin-specific than t-PA For coronary fibrinolysis, tenecteplase is given as a single iv bolus

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