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  • - Dr. E. R. Venkata Subba Reddy
  • Blood coagulation is part of an important  host defense mechanism termed hemostasis.  Hemostasis : arrest or stoppage of bleeding from a blood vessel.  Injury to a blood vessel initiates a series of reactions resulting in hemostasis.  Three stages : 1. Vasoconstriction 2. Formation of platelet plug 3. Coagulation of blood
  • Injury to blood vessel ↓ Endothelial damage and collagen exposure VonWillebrand factor → I ↓ Activation of platelets FIBRINOGEN ↓ ↓ I Serotonin ADP + I I TX A2 I I ↓ I I Aggregation of I more platelets I I I ↓ ↓ Vasoconstriction platelet plug FIBRIN (clot) (STAGE 1) (STAGE 2) (STAGE 3)
  • Definition : The process in which blood  looses its fluidity and becomes a jelly like mass few minutes after its shed out or collected in a container.  The so formed mass is called clot  The clot is a mesh of thin fibrils entangling the blood cells .These fibrils consist of fibrin. The fibrin is formed from fibrinogen.
  • ENZYME CASCADE THEORY  - Factors in inactive proenzyme forms - Series of proenzyme-enzyme conversions ( Zymogen activation reactions ) - At each stage a precursor protein (zymogen) is converted to an active protease by cleavage of one or more peptide bonds - Helped by cofactors, calcium
  • 3 STAGES  1. Formation of Prothrombin Activator 2. Conversion of Prothrombin to Thrombin 3. Conversion of Fibrinogen to Fibrin
  • Two ways  1. Contact activation pathway (formerly known as the intrinsic pathway) 2. Tissue factor pathway (extrinsic pathway)
  • Endothelial damage + collagen exposure I Kallikrein & I ↓ HMW kinogen I XII ------XIIa ↓ HMW kinogen Platelets ↓ XI ------XIa I Calcium I ↓ IX ------------ IXa ↓ VIII & Ca Phospholipid ↓ X------------------ Xa I I I ↓ ↓ PROTHROMBIN ACTIVATOR ( PTA ) (Xa + V + Ca +Phospholipid)
  • Tissue trauma + Tissue thromboplastin ↓ Glycoprotein Phospholipid I VII --------------------------------- VIIa I Ca ↓ Phospholipid X ----------------------------------- Xa I Ca I Factor V I Thrombin ↓ Prothrombin activator (Xa + V + Ca +phospholipid)
  • PROTHROMBIN ACTIVATOR I ↓ PROTHROMBIN-----------------→THROMBIN I ↓ FIBRINOGEN a ←------------------------- FIBRINOGEN I Polymerization I ↓ XIII & Ca LOOSE STRANDS OF FIBRIN-------------------------------→FIBRIN TIGHT BLOOD CLOT
  • The substances necessary for clotting are  called clotting factors Thirteen identified  I – Fibrinogen II – Prothrombin III – Thromboplastin IV – Calcium V – Labile factor ( proaccelerin ) VI – presence not proved VII – Stable factor
  • VIII – Anti hemophilic factor IX – Christmas factor X – Stuart-Prower factor XI – Plasma Thromboplastin antecedent XII – Hageman factor XIII – Fibrin stabilizing factor (Fibrinase)
  • Calcium   Phospholipid  Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factors II, VII, IX and X, as well as protein S, Protein C and protein Z.
  • Five mechanisms keep platelet activation and the  coagulation cascade in check. Protein C is a major physiological anticoagulant.  It is a vitamin K-dependent serine protease . Activated by thrombin with the help of thrombomodulin. The activated form, along with protein S and a phospholipid as cofactors, degrades Va and VIIIa. Antithrombin is a serine protease inhibitor  Tissue pathway factor inhibitor(TFPI)  Plasmin cleaves fibrin into fibrin degradation products  that inhibit excessive fibrin formation. Prostacyclin (PGI2) through cAMP inhibits platelet  activation
  • Clot consists of entrapped  platelets, RBCs, WBCs within the fibrin meshwork.  Clot Retraction : after 30 to 45 min. -Clot contracts. Serum oozes out. -Actin, myosin and Thrombosthenin.  FIBRINOLYSIS : lysis in blood vessel. Requires plasmin (fibrinolysin)
  • Commonly used: aPTT ( activated partial Thromboplastin time) - The  contact factor pathway PT (also used to determine INR)- The tissue factor  pathway Fibrinogen testing (often by the Clauss method)  Platelet count  Platelet function testing (often by PFA-100). 
  • Others: Thrombin clotting time, Bleeding  time, Mixing test (whether an abnormality corrects if the patient's plasma is mixed with normal plasma), Coagulation factor assays, Antiphospholipid antibodies, D- dimer, Genetic tests (factor V leiden), Miscellaneous platelet function tests, Thromboelastography (TEG or ROTEM), Euglobulin lysis test(ELT), .
  • Platelet disorders:  -Inborn or Acquired -congenital: > Glanzmann’s thrombasthenia - It is characterized by a defect in GPIIb/IIIa fibrinogen receptor complex, > Bernard-sourlier syndrome (abnormal glycoprotein Ib-IX-V complex), > Gray platelet syndrome(deficient α-granules), > Delta storage pool deficiency(deficient dense granules). -Acquired: MDS, ITP, TTP, HUS, PNH, DIC, HIT.
  • HAEMOPHILIA: 3 main forms  - Hemophilia A : VIII deficiency - Hemophilia B : IX - Hemophilia C : XI  Von Willebrand disease : most common hereditary bleeding disorder . Def of vWF, that mediates glycoprotein Ib (GPIb) binding to collagen.
  • Thrombosis is the pathological  development of blood clots. May form an embolus or cause occlusionocclusion by embolus or thrombus leads to ischemic necrosis of tissue.  Most cases of thrombosis are due to acquired extrinsic problems (surgery, cancer, immobility, obesity,)  A small proportion of people harbor predisposing conditions known collectively as Thrombophilia (antiphospholipid syndrome, factor V leiden).
  • Adsorbent chemicals, such as zeolites, used for  use in sealing severe injuries quickly (traumatic bleeding secondary to gunshot wounds). Thrombin and fibrin glue are used surgically to  treat bleeding and to thrombose aneurysms. Desmopressin is used to improve platelet function  Prothrombin complex  concentrate, cryoprecipitate and fresh frozen plasma Recoombinant activated human factor VII is  increasingly popular in the treatment of major bleeding. Tranexemic acid and aminocaproic acid inhibit 
  • Anticoagulants and anti-platelets.  Anti platelet agents : aspirin, clopidogrel, dipyridamole  and ticlopidine; the parenteral glycoprotein Iib/IIIa inhibitors are used during angioplasty Anticoagulants, Warfarin (and related coumarins) and  Heparin are the most commonly used. Warfarin affects the vitamin K-dependent clotting factors  (II, VII, IX,X). Heparin and related compounds increase the action of  antithrombin on thrombin and factor Xa. A newer class of drugs, the direct thrombin inhibitors, is  under development; some members are already in clinical use (such as lepirudin). compounds that interfere directly with the enzymatic  action of particular coagulation factors (e.g., rivaroxaban).
  • --- Thankyou