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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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Presentation Transcript
  • 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
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
  • 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
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



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


In 30% of pts on long-term heparin therapy

  • Elevated Levels of Transaminases
  • 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)
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
  • 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
Pregnancy – teratogenic
  • nasal hypoplasia & stippled epiphyses
  • Causes fetal bleeding
  • Warfarin is contraindicated in 1st and 3rd trimesters
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
  • 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