Coagulation anticoagulation
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COAGULATION & ANTICOAGULATION. Dr Rakesh Jain. Coagulation. 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

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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

Current concept of coagulation

Current Concept of coagulation

Coagulation anticoagulation

  • 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/VIIIacomplex, 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.




  • Unfractionated heparin

  • LMWH

  • Fondaparinux

    Direct Thrombin Inhibitors

  • Hirudin

  • Argatroban

  • Bivalirudin


  • Vitamin K antagonist – Warfarin

  • Thrombin Inhibitor – Dabigatran

  • Xa inhibitor - Rivaroxaban

Parenteral anticoagulants

Parenteral Anticoagulants



  • 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



  • 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

Coagulation anticoagulation

  • 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

Monitoring Anticoagulant Effect of Heparin

  • aPTT or anti–factor Xa level is used

  • aPTTterapeutic 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



  • 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

Coagulation anticoagulation



Limited absorption of long heparin chains

Binds to endothelial cells

Binds to plasma proteins

Neutralized by PF 4 released fm activated platelets

  • Poor bioavailability

  • Dose-dependent clearance

  • Variable anticoagulant response

  • Reduced activity in vicinity of platelet-rich thrombi

Side effects

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

Coagulation anticoagulation

  • Osteoporosis

    In 30% of pts on long-term heparin therapy

  • Elevated Levels of Transaminases

Coagulation anticoagulation


  • 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



  • Usually not required

  • If necessary anti–factor Xa is measured

  • May be done in renal insufficiency , obesity , pregnancy , mechanical valves



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



  • Synthetic analogue of the antithrombin-binding pentasaccharide sequence

  • Exhibits complete bioavailability after s/c injection

  • Plasma half-life is 17 hrs


  • 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

Parenteral Direct Thrombin Inhibitors

Oral anticoagulants

Oral Anticoagulants


  • water-soluble vitamin K antagonist

  • interferes with synthesis of vitKdependent

    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

Mechanism of Action



  • Prothrombin Time

  • INR

  • Target INR : 2 to 3

    in mechanical valves 2.5 to 3.5


  • 5 to 10 mg

  • Concomitant treatment with parenteral anticoagulant until INR has been therapeutic range for at least 2 consecutive days

Side effects1

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

Coagulation anticoagulation

Pregnancy – teratogenic

  • nasal hypoplasia & stippled epiphyses

  • Causes fetal bleeding

  • Warfarin is contraindicated in 1st and 3rd trimesters

New oral anticoagulants

New Oral Anticoagulants

Fibrinolytic drugs

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



  • 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

Coagulation anticoagulation


  • Derived from cultured fetal kidney cells

  • Directly converts plasminogen to plasmin


  • 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



  • Recombinant t-PA derivative, reteplase is a single-chain variant

  • Given as two intravenous boluses separated by 30 min



  • 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

Coagulation anticoagulation


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