Physiology: Blood coagulation & Hemostasis

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  1. Thrombogenic
    Favoring or inducing the formation to clot
  2. Coagulopathy
    Defect due to abnormal conc. or function of coagulation factors
  3. Petechia
    Small pinpoint hemorrhages in skin/mucous membranes
  4. Ecchymoses
    Larger hemorrhages in skin/mucous membranes
  5. Thrombocytopenia
    Reduced number of Thrombocytes
  6. Thrombocytopenia
    Defect (congential/acquired) in platelet function
  7. Fibrinolysis
    Normal or pathologic dissolution of a fibrin clot
  8. DIC
    Disseminated intravascular coagulation
  9. vWD
    von Willebrand disease
  10. OSPT
    One stage prothrombin time
  11. APTT
    Activated partial thromboplastin time
  12. ACT
    Activated clotting time
  13. Major Stages of Hemostasis
    • 1. Blood vessel constriction (neural)
    • 2. Platelet activation (primary (temporary) hemostatic plug & Secondrry (stable) hemostatic plug)
    • 3. Coagulation activation (tissue factors, thromboplastin)
    • 4. Dissolution of fibrin clot
    • 5. Endothelial repair
  14. Hemostasis
    • Arrest of bleeding. There are 5 stages.
    • 1. Vascular damage>vasoconstriction>platelet adhesion
    • 2. Platelet recruitment>aggregation>fibrin formation>primary hemostatic plug (fragile)
    • 3. Reinforcement of stable plug with fibrin>secondary hemostatic plug (thrombus)
    • 4. Dissolution of fibrin clot: clot retraction & activation of fibronolysis
    • 5. Endothelial repair>degradation of fibrin clot.
  15. Components of the hemostatic system
    • 1. Vascular endothelium
    • 2. Platelets
    • 3. Plasma proteins
  16. Vascular endothelium (both anti and pro-coagulant properties)
    • Anti-coagulant properties
    • 1. Smooth surface, -ve charge (single protein layer)
    • 2. Secretion of inhibitors of platelet function and fibrin formation: PGI2, NO, ADPase, Tissue factor pathway inhibitor (TFPI), Thrombomodulin
    • 3. Secretion of activators of fibrinolysis: Tissue plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA)
    • Pro-coagulant properties
    • 1. Synthesis & secretion of tissue factor (III Thromboplastin) to initiate clot formation
    • 2. Adhesive proteins (von Wilebrand factor) that attach activated platelets to surface
    • 3. Secretion of inhibitors of fibrinolysis: Plasminogen activator inhibitor (PAI), Thrmobin activatable fibrinolytic inhibitor (TAFI)
  17. Evulate Primary hemostasis (3 ways)
    • 1. Platelet tests
    • Platelet counts: Normal Dogs & Cats > 200,000/ul; Cattle, horse >100,000/ul
    • Thombocytopenia: <20,000/ul > bleeding from small vessels
    • Platelet function: measure platelet adhesion, aggregation, platelet release reaction
    • 2. von Willebrand factor
    • Large glycoprotein in vessel wall, made of protein polymers (multimers)
    • Assays: ELISA for von Willebrand factor antigen, multimeric analyses, functional tests, genetic tests
    • 3. Buccal mucosal bleeding time (BMBT)
    • in vivo test for primary hemostasis (platelets, wall defects & vWF) in small animals.  Normal dogs clot in less then 4 min
  18. Primary Hemostasis disorders
    • Acquired
    • Thrombocytopenia (<20,000/ul eg. bone marrow dysfunction, immune-mediated)
    • Acquired Thrombopathies (eg. liver failer, uremia, drug induced)
    • Congenital
    • von Willebrand disease (dogs, cats, pigs: delayed clotting after trauma due to weak platelet aggregates)
    • Inherited Thrombopathies
  19. Clotting Factors
    • Factor I Fibrinogen (liver)
    • Factor II Prothrombin (liver) (Vitamin K-dependent)
    • Factor III Thromboplastin (tissue factor) (VE)
    • Factor IV Calcium
    • Factor V Proaccelerin, Labile factor, Accelerator globulin (VE)
    • Factor VII Proconvertin, SPCA, Stable factor (liver)
    • Factor VIII Antihemophilic factor (AHF, AHF-A), Antihemophilic globulin (VE)
    • Factor IX Plasma thromboplastic component (PTC), Christmas factor, AHF-B (liver)
    • Factor X Stuart-Prower factor (VE)
    • Factor XI Plasma thromboplastin antecedent (PTA), AHF-C (liver)
    • Factor XII Hageman factor, Glass factor (liver)
    • Factor XIII Fibrin stabilizing factor, Laki-lorand factor (liver)
    • vWH von Willebrand factor (VE)
    • Pre-Ka Prekallikrein (PK), Fletcher factor (liver)
    • HMW-K High molecular weight kininogen (HMWK, HF), Fitzergald factor (liver)
    • t-PA Tissue-type plasminogen activator (liver)
    • u-PA Urokinase-type plasminogen activator
    • PL Platelet phospholipid
  20. Intrinsic Pathway
    • Factor XII Collagen, Trauma, other activators XIIa
    • Factor XI
    • Factor IX XIA & Calcium IXs
    • Which combines with VIIIa, ca2 and PL, to make the tenase complex, activating X in the common pathway
    • Most Factors except XII get positve feedback from thrombin
  21. Extrinsic Pathway
    • Tissue factor (III) trauma
    • VII (Xa can give positive feedback here)
    • III & VIIa can either directly activate X to Xa in the common pathway or go to Factor IXa to form the Tenase complex
  22. Common Pathway
    • Factor X activated by Tenase complex or III & VIIA Xa
    • Factor Xa with prothrombin (II), Ca2, PL, Va form Prothrombinase complex
    • Thrombin activated by prothrombinase complex
    • Activates Fibrinogen (I) to Fibrin
    • Thrombin also activates XIII to XIIIa
    • Fibrin and XIIIa, with calcium, form Fibrin polymers
  23. Factor's dependent on Vit. K for hemostasis
    Biosynthesis of Factor II, VII, IX, and X are dependent on Vit. K
  24. Factors affected by heparin
    Factors IX, X, XI, XII and Thrombin
  25. Secondary Hemostasis summary (8)
    • 1. There are 2 major pathways: intrinsic pathway or contact pathway and extrinsic pathway or tissue factor pathway
    • 2. Both converge at a common point
    • 3. ~13 (?) soluble factors are involved in clotting
    • 4. Biosynthesis of II, VII, IX and X are dependent on vitamin K
    • 5. Heparin affects factors IX, X, XI, XII and Thrombin
    • 6. Most of these factors are proteases - normally inactive and sequentially activated
    • 7. In birds, reptiles and marine animals, Factor XII (intrinsic pathway) is deficient - resulting in prolonged clotting time
    • 8. Acquired defects (platelet defects, liver diseases, DIC) more common than hereditary defects (hemophilia) in animals
  26. Evaluation of secondary hemostasis
    • 1. One stage Prothrombin time (OSPT or PT)
    • 2. Activated Partial Thromboplastin time (APTT)
    • 3. Activated Clotting time (ACT)
  27. One stage Prothrombin time (OSPT or PT)
    • For evaluating extrinsic & common pathways (defects in factor VII, V, K, Prothrombin, Fibrinogen, eg. rodenticie poisioning)
    • Plasma + tissue factor + ca -> clotting time (dogs < 10 sec)
  28. Activated Partial Thromboplastin time (APTT)
    • For evaluating intrinsic & common pathways (defects in Factors XII, XI, X, IX, VIII, Prothrombin, Fibrinogen)
    • Plasma + Activator of XII + PL + Ca -> clotting time (dogs < 45 sec)
  29. Activated Clotting time (ACT)
    • Activator (diatomaceous earth) +  whole blood -> clotting time (normal: dogs 60-90 sec. cats 160 sec): Less sensitive than APTT
    • For evaluating intrinsic and common pathways (decreased platelet count)
  30. Secondary Hemostasis Disorders
    • Vit K antagonism/deficiency
    • rodenticide poisoning (dicoumarol)
    • cholestatic liver disease
    • Sever malabsorption
    • Liver failure
    • Disseminated intravascular coagulation (DIC)
    • pathological activation of both coagulation mechanism & fibrinolytic system in blood vessels -> decreased thrombocytes + FDPs (eg, cause cancer, infectious diseases)
    • Coagulation factor deficiency (Dogs, cats. Congenital)
    • FVIII deficiency - Hemophilia A
    • FIX deficiency - Hemophilia B
  31. Dissolution of Fibrin clot
    • 1. Clot retraction - shrinking of fibrin clot
    • a. mediated by platelet contractile proteins -actin, myosin, thrombosthenin
    • b. Functions - stablize clot, promote tissue repair, activate fibrinolysis
    • 2. Fibinolysis - degradation of fibrin clot by plasmin
  32. Fibrinolytic system (tertiary hemostasis)
    Plasminogen has to be activated to plasmin. It has both inhibitors and activators.

    • Inhibitors: Plasminogen activator inhibitors (PAI 1,2,3)
    • Activators: Extrinsic: Urokinase, tPA
    • Intrinsic: Kallikrein, XIIa, XIa
    • Exogenous: Streptokinase

    The Plasmin, with alpha2-antiplamin and alpha2-macroglobulin, change fibrin to fibrin degradation products
Card Set:
Physiology: Blood coagulation & Hemostasis
2013-10-31 21:54:01
Lecture 13

L:13 Blood Coagulation & Hemostasis
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