CME: Bleeding Disorders - Applied Physiology

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CME: Bleeding Disorders - Applied Physiology

  1. 1. Applied Physiology of Bleeding Disorders Dr.B.Gowri Shankar MD pg Prof.Dr.G.Sundaramurthy’s unit(M 7).
  2. 2. Hemostasis <ul><li>Blood must be fluid </li></ul><ul><li>Must coagulate (clot) at appropriate time </li></ul><ul><ul><li>Rapid </li></ul></ul><ul><ul><li>Localized </li></ul></ul><ul><ul><li>Reversible </li></ul></ul><ul><ul><li>Thrombosis…inappropriate coagulation </li></ul></ul>
  3. 3. 3 Major systems involved <ul><li>Vessel wall </li></ul><ul><ul><li>Endothelium </li></ul></ul><ul><ul><li>ECM = BM (type 4 collagen + other proteins) </li></ul></ul><ul><li>Platelets </li></ul><ul><li>Coagulation cascade </li></ul><ul><ul><li>Coagulation factors (proteins) </li></ul></ul><ul><ul><ul><li>Names and numbers </li></ul></ul></ul><ul><ul><ul><li>Active and inactive forms (zymogens) </li></ul></ul></ul>
  4. 4. Antithrombogenic Thrombogenic Vessel injury ( Favors fluid blood ) ( Favors clotting )
  5. 5. Antithrombotic Properties of the Endothelium <ul><li>Anti-platelet properties </li></ul><ul><ul><li>Covers highly thrombogenic basement membrane </li></ul></ul><ul><ul><li>Uninjured endothelium does not bind platelets </li></ul></ul><ul><ul><li>PGI2 (prostacyclin) and NO from uninjured endothelium inhibit platelet binding </li></ul></ul><ul><ul><li>ADPase counters the platelet aggregating effects of ADP </li></ul></ul>
  6. 6. Antithrombotic Properties of the Endothelium Anticoagulant properties * HEPARIN-LIKE MOLECULES: activate anti-thrombin III (inactivates active proteases) * THROMBOMODULIN : changes specificity of thrombin (activates protein C , which inactivates factors Va and VIIIa *Endothelial cells produce tPA which activates fibrinolysis via plasminogen to plasmin
  7. 7. <ul><li>Prothrombotic Properties of the Endothelium </li></ul><ul><li>Synthesis of von Willebrand factor </li></ul><ul><li>Release of tissue factor </li></ul><ul><li>Production of plasminogen activator inhibitors (PAI) </li></ul><ul><li>Membrane phospholipids bind and facilitate activation of clotting factors via Ca bridges </li></ul>
  8. 8. Platelet Response to Agonists Platelets - unstimulated Addition of ADP (mild stimulation) Addition of thrombin (strong stimulation ) Characteristic discoid shape Shape change (elongation and crescents) and Fila form process formation (arrows) Increased spreading, Fila form process extension (arrows) and aggregate formation (stars)
  9. 9. PLATELET
  10. 14. Coagulation Cascade <ul><li>Enzymatic cascade (amplification) </li></ul><ul><li>Several serine proteases </li></ul><ul><ul><li>Produced by liver (most) </li></ul></ul><ul><ul><li>Require Vit K (several) </li></ul></ul><ul><li>3 protein cofactors (not enzymes) </li></ul><ul><li>Requires Ca 2+ </li></ul><ul><li>Localized to site of injury </li></ul><ul><li>Reversible (via production of plasmin) </li></ul>
  11. 15. Fibrinogen Fibrin Thrombin Prothrombin Xa Va VIIa TF Extrinsic Pathway IXa VIIIa XIa XIIa Intrinsic pathway XIIIa Soft clot Fibrin Hard clot V VIII
  12. 16. Fibrinogen Fibrin
  13. 17. Fibrinogen Fibrin Thrombin
  14. 18. Fibrinogen Fibrin Thrombin Prothrombin Xa Va
  15. 19. Fibrinogen Fibrin Thrombin Prothrombin Xa Va VIIa TF Extrinsic Pathway
  16. 20. Fibrinogen Fibrin Thrombin Prothrombin Xa Va VIIa TF Extrinsic Pathway IXa VIIIa XIa XIIa Intrinsic pathway
  17. 21. Fibrinogen Fibrin Thrombin Prothrombin Xa Va VIIa TF Extrinsic Pathway IXa VIIIa XIa XIIa Intrinsic pathway XIIIa Soft clot Fibrin Hard clot
  18. 22. Fibrinogen Fibrin Thrombin Prothrombin Xa Va VIIa TF Extrinsic Pathway IXa VIIIa XIa XIIa Intrinsic pathway XIIIa Soft clot Fibrin Hard clot V VIII
  19. 23. Hemophilia A Deficiency of/nonfunctional VIII Hemophilia B Deficiency of /nonfunctional IX Why do they bleed? Hemophilia C Deficiency of/nonfunctional XI
  20. 24. Thrombin (IIa) Prothrombin (II) Xa VIIa TF IXa Revised Coagulation Pathway (Tissue Factor Pathway) IX NB: production of IXa Interaction of intrinsic and extrinsic pathways
  21. 25. Tissue Factor Pathway Inhibitor <ul><li>Kunitz-type protease inhibitor (kringles) </li></ul><ul><li>34 and 41 KD forms in plasma (C-term truncation) </li></ul><ul><li>Directly inhibits Xa </li></ul><ul><li>Inhibits VIIa-TF complex in a [Xa]-dependent manner </li></ul><ul><li>Bound to LDL, HDL and Lp (a) </li></ul><ul><li>~10% present in platelets (endothelium also) </li></ul>
  22. 26. Thrombin (IIa) Prothrombin (II) Xa VIIa TF IXa Tissue Factor Pathway Inhibitor IX TFI TFPI NB: Inhibition of Xa and VIIa
  23. 27. Proposed Mechanism of Tissue Factor Pathway Inhibitor (TFPI) Activity F-Xa Endothelium Tissue factor F-VIIa TFPI F-Xa TFPI TFPI F-Xa
  24. 28. Physiologic Inhibitors of coagulation <ul><li>Antithrombin III (serpin) </li></ul><ul><li>Activated Protein C + protein S </li></ul><ul><ul><li>Inactivates Va and VIIIa (via proteolysis) </li></ul></ul><ul><ul><li>NB: Factor V Leiden </li></ul></ul><ul><li>Thrombomodulin (EC glycoprotein) </li></ul><ul><ul><li>Binds to thrombin </li></ul></ul><ul><ul><li>Decreases ability to produce fibrin </li></ul></ul><ul><ul><li>Increases ability to activate Protein C </li></ul></ul>
  25. 29. Proposed Mechanism of AT III-Heparin System Heparin Thrombin Antithrombin Lysine sites Serine site Arginine site H Th H AT III AT III Th
  26. 30. Proposed Mechanism of Thrombomodulin, Protein C and Protein S (TM-PC-PS) System Thrombin Prothrombin Protein C Thrombomodulin Thrombin F-Xa Activated platelet PS F-Va x Ca ++ Ca ++ Activated Protein C
  27. 31. Role of vitamin K Some clotting factors require a post-translational modification before they are active in clotting These factors are II, VII, IX, X, proteins C and S This PTM involves the addition of a COO- to certain Glu residues in the clotting factors This PTM results in the formation of several  -carboxy glutamates = Gla This PTM requires vitamin K
  28. 32. Role of vitamin K <ul><li>Vit K is altered in carboxylation Rx and must be regenerated before reuse </li></ul><ul><li>Regeneration involves 2 reductases which convert vit K epoxide to vit K </li></ul><ul><li>Vit K antagonists inhibit these reductases </li></ul><ul><li>Vit K-dependent PTM provides sites on modified coag factors for Ca bridging </li></ul>
  29. 33. Non-physiologic inhibitors of coagulation <ul><li>Vitamin K antagonists (in vivo only) </li></ul><ul><li>Ca chelators (in vitro only) </li></ul><ul><ul><li>EDTA </li></ul></ul><ul><ul><li>Citrate </li></ul></ul><ul><ul><li>Oxalate </li></ul></ul><ul><li>* Heparin (in vivo and in vitro) </li></ul>
  30. 35. Clot removal
  31. 36. Fibrin Fibrin Split Products (FSP) Plasmin Fibrinolysis
  32. 37. Fibrin Fibrin Split Products (FSP) Plasmin Plasminogen tPA Fibrinolysis
  33. 38. Inhibitors of fibrinolysis <ul><li>Plasminogen activator inhibitors (PAIs) </li></ul><ul><li> 2 -antiplasmin (serpin) </li></ul>
  34. 40. Pathophysiology of DIC <ul><li>loss of localization of coagulation process </li></ul><ul><li>caused by abnormalities in any of four major components of hemostasis </li></ul><ul><ul><li>1. vascular integrity </li></ul></ul><ul><ul><li>2. platelets </li></ul></ul><ul><ul><li>3. coagulation cascade </li></ul></ul><ul><ul><li>4. clot lysis </li></ul></ul>
  35. 41. Pathophysiology of DIC Disruption of Vascular Integrity <ul><li>vascular endothelial damage can initiate coagulation and DIC </li></ul><ul><ul><li>causes platelet adhesion and aggregation </li></ul></ul><ul><ul><ul><li>vasculitis (infectious, systemic lupus) </li></ul></ul></ul><ul><ul><ul><li>burns </li></ul></ul></ul><ul><ul><ul><li>dissecting aortic aneurysms </li></ul></ul></ul>
  36. 42. Pathophysiology of DIC Abnormal Platelet Function
  37. 43. Pathophysiology of DIC Abnormal Platelet Function <ul><li>altered platelet aggregation causes DIC </li></ul><ul><ul><li>platelets coated with immune complexes or bacteria aggregate without vascular injury </li></ul></ul><ul><ul><ul><li>immune complex disease </li></ul></ul></ul><ul><ul><ul><li>pregnancy toxemia (immune complexes) </li></ul></ul></ul><ul><ul><ul><li>viraemia </li></ul></ul></ul><ul><ul><ul><li>sepsis or bacteremia </li></ul></ul></ul><ul><ul><li>diffuse platelet consumption and destruction </li></ul></ul>
  38. 44. Pathophysiology of DIC Clotting Factor Abnormalities
  39. 45. Pathophysiology of DIC I. Abnormal Factor Activation <ul><li>intravascular tissue phospholipid causes abnormal activation of clotting factors </li></ul><ul><ul><li>provides surface for factor activation </li></ul></ul><ul><ul><ul><li>massive trauma </li></ul></ul></ul><ul><ul><ul><li>necrotic tumor </li></ul></ul></ul><ul><ul><ul><li>red cell hemolysis of any cause </li></ul></ul></ul><ul><ul><ul><li>obstetric complications: retained dead fetus, placental abruption, amniotic fluid embolus </li></ul></ul></ul>
  40. 46. Pathophysiology of DIC I. Abnormal Factor Activation <ul><li>widespread activation of coagulation leads to formation of fibrin </li></ul><ul><li>coagulation factors consumed </li></ul><ul><ul><li>concentrations of fibrinogen and labile cofactors (V and VIII) decline first </li></ul></ul><ul><ul><ul><li>used once and destroyed </li></ul></ul></ul><ul><ul><li>serine proteases capable of catalyzing multiple reactions </li></ul></ul>
  41. 47. Pathophysiology of DIC II. Abnormal Factor Control <ul><li>hemostasis controlled by antithrombin (AT) and protein C </li></ul><ul><ul><li>antithrombin inhibits active serine proteases </li></ul></ul><ul><ul><li>protein C regulates thrombin formation </li></ul></ul><ul><li>deficiencies lead to excess clot formation and factor consumption </li></ul><ul><ul><li>precipitate or exacerbate DIC </li></ul></ul>
  42. 48. Pathophysiology of DIC Accelerated Fibrinolysis <ul><li>fibrinolysis -> fibrin split products (FSPs) </li></ul><ul><ul><li>also called fibrin degradation products (FDPs) </li></ul></ul><ul><li>clearance mechanisms may be overwhelmed </li></ul><ul><ul><li>FSPs normally cleared by Kupffer cells </li></ul></ul><ul><li>excess FSPs cause decreased clot formation </li></ul><ul><ul><li>coat platelets and inhibit aggregation </li></ul></ul><ul><ul><li>inhibit fibrin cross-linking </li></ul></ul>
  43. 49. Pathophysiology of DIC Accelerated Fibrinolysis <ul><li>urokinase lyses fibrin clots </li></ul><ul><ul><li>catalyzes synthesis of plasmin from plasminogen </li></ul></ul><ul><ul><li>leads to excess FSP production </li></ul></ul><ul><ul><ul><li>promotes DIC </li></ul></ul></ul><ul><ul><li>prostate disease, urinary tract surgery </li></ul></ul>
  44. 50. Heparin Induced Thrombocytopenia <ul><li>HIT ( heparin-induced thrombocytopenia) </li></ul><ul><li>HAT ( heparin-associated thrombocytopenia) </li></ul><ul><li>White- clot syndrome </li></ul>
  45. 51. HIT <ul><li>An immunoglobulin-mediated adverse drug reaction characterized by: </li></ul><ul><ul><li>platelet activation </li></ul></ul><ul><ul><li>thrombocytopenia </li></ul></ul><ul><ul><li>thrombotic complications </li></ul></ul>
  46. 52. Pathogenesis of HIT <ul><li>Most commonly caused by IgG antibodies (designated HIT-IgG) that activate platelets through their Fc receptors </li></ul>
  47. 53. Antigenic Heparin/PF4 Complex <ul><li>antigen in HIT is a complex of “-” charged heparin polysaccharide and “+” charged protein tetramer (platelet factor 4 or PF4) </li></ul><ul><li>PF4 - released from platelet storage granules during platelet activation </li></ul><ul><li>unfractionated heparin wraps around PF4 to a greater extent than LMWH </li></ul>
  48. 54. Effects on the coagulation system <ul><li>Binding of heparin to PF4 neutralizes the anti-coagulant effect of heparin </li></ul><ul><li>Immune complexes composed of heparin, PF4, and IgG binds to platelet Fc receptors, resulting in strong platelet activation, and ultimate increase in thrombin generation </li></ul>
  49. 55. Iceberg Model 10/98 medslides.com Multiple thrombosis (white clot syndrome) 0.01-0.1% Isolated thrombosis 30-80% of below groups Asymptomatic thrombocytopenia 30-50% of below group HIT - IgG seroconversion 0-10% Warkentin TE, et al. 1994;75-127
  50. 56. Pathophysiology of Drug-induced thrombocytopenia <ul><li>Certain drugs(quinine, quinidine, sulfa antibiotics) link non-covalently to platelet membrane glycoproteins </li></ul><ul><li>very rarely, IgG antibodies are produced that recognize these drug-glycoprotein complexes </li></ul><ul><li>macrophages remove the complexes causing severe thrombocytopenia </li></ul>
  51. 57. Thank You

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