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 by12 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<50kg

, 10mg 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 3.5Dose• 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 1st and 3rd 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

THANK YOU