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HEMOSTAZ

HEMOSTAZ. Yard. Doç. Dr. Murat ÖRMEN. Hemosta z. Vessels. Bleeding. Clotting. Coagulation Proteins. Platelets. Fibrinolysis/Inhibitors. Basement Membrane. Endothelial Cells. Red Blood Cells. Platelets. White Cells. Vascular System. Vessels. Coagulation Proteins. Platelets.

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HEMOSTAZ

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  1. HEMOSTAZ Yard. Doç. Dr. Murat ÖRMEN

  2. Hemostaz Vessels Bleeding Clotting Coagulation Proteins Platelets Fibrinolysis/Inhibitors

  3. Basement Membrane Endothelial Cells Red Blood Cells Platelets White Cells Vascular System

  4. Vessels Coagulation Proteins Platelets Fibrinolysis/Inhibitors

  5. PRİMER HEMOSTAZ

  6. Platelet Rich Plasma (PRP) Aggregate Clumping Aggregating Reagent + Baseline Light Transmission Increased Light Transmission Platelet Aggregation

  7. Function HEMOSTASİS BLEEDİNG AGREGOMETRİ ANİMASYON

  8. Vessels Coagulation Proteins Platelets Fibrinolysis/Inhibitors

  9. Prekalli- krein Kalli- krein VII HMWK Extrinsic Pathway (PT) Kinins XII XIIa Tissue Factor XIa Intrinsic Pathway (aPTT) XI VIIa IXa IX Pro- Urokinase X Xa X VIIIa Fibrinolysis Ure- Kinase T-PA II Va VIII IIa Plas- minogen V Plasmin XIII XIIIa Common Pathway Fibrin Polymer Fibrinogen Fibrin Clot + Platelet Plug

  10. Extrinsic Pathway (PT) VII Tissue Factor VIIa X Xa II Va IIa Common Pathway V XIII XIIIa Fibrin Polymer Fibrin Clot + Platelet Plug Fibrinigen

  11. High Molecular Weight Kininogen Ca++ Phospholipid (Platelet Factor 3) Factor XIIa Factor Xa Factor IXa or or Procoagulant Procoagulant Factor VII Activation Factor Xa Factor VIIa Tissue Factor Inhibition Anticoagulant Ca++ Factor VIIa *Tissue Factor Pathway Inhibitor TFPI* TFPI* Factor VII Proconvertin, Stable Factor Biosynthesis: Liver, Vitamin K dependent MW: 55,000 daltons Plasma Concentration: 1 mg/L In Vivo Half-Life: 5 hours Pathology: Hypoproconvertinemia, autosomal recessive

  12. Factor VIIIa Ca++ Intrinsic X-ase Complex Extrinsic X-ase Complex Ca++ Tissue Factor Phospholipid (Platelet Factor 3) or Factor VIIa Factor IXa Procoagulant Activation Factor X Factor Xa Inhibition Factor Xa Anticoagulant Anti- thrombin III Anti- thrombin III Heparin Heparin Factor X Stuart-Prower Factor Biosynthesis: Liver, Vitamin K dependent MW: 55,000 daltons Plasma Concentration: 5 mg/L In Vivo Half-Life: 65 hours Pathology: Stuart disease, autosomal recessive Tissue Factor Factor III, Thromboplastin Biosynthesis: Brain, lung, subendothelium MW: 45,000 daltons

  13. Kalli- krein Prekalli- krein HMWK Kinins XII XIIa XIa Intrinsic Pathway (aPTT) XI IXa IX Xa X VIIIa II Va VIII IIa V XIII Common Pathway XIIIa Fibrin Polymer Fibrin Clot + Platelet Plug Fibrinogen

  14. Negatively Charged Activating Surface High Blood Pressure and Inflammation (e.g., kaolin, ellagic acid silica) Kalli- krein High Molecular Weight Kininogen Factor XII Fragments* Kinins Procoagulant Factor XII Activation Factor XIIa Inhibition Factor XIIa Anticoagulant HMWK C1 Esterase Inhibitor C1 Esterase Inhibitor * FXIIf alter vascular permeability Biosynthesis: Liver MW: 80,000 daltons Plasma Concentration: 29 mg/L In Vivo Half-Life: 60 hours Pathology: Hageman trait, autosomal recessive Factor XII Hageman Factor High Molecular Weight Kininogen (HMWK) Fitzgerald Factor MW: 120,000 daltons Plasma Concentration: 70 mg/L Pathology: Fitzgerald trait, autosomal recessive

  15. Ca++ Factor XIIa High Molecular Weight Kininogen Procoagulant Prekalli- krein Activation Inhibition Kallikrein Anticoagulant C1 Esterase Inhibitor Kalli- krein C1 Esterase Inhibitor Prekallikrein Fletcher Factor Biosynthesis: Probably Liver MW: 107,000 daltons Plasma Concentration: 50 mg/L Pathology: Fletcher trait, autosomal recessive

  16. Ca++ Factor XIIa High Molecular Weight Kininogen Factor XI Procoagulant Activation Factor XIa Inhibition Anticoagulant a1- Anti- trypsin Factor XIa a1- Anti- trypsin Factor XI Plasma Thromboplastin Antecedent Biosynthesis: Liver MW: 158,000 daltons Plasma Concentration: 4 mg/L In Vivo Half-Life: 65 hours Pathology: Hemophilia C, autosomal recessive

  17. Ca++ Tissue Factor Ca++ Factor VIIa Factor XIa or Factor IX Procoagulant Activation Factor IXa Inhibition Anticoagulant Anti- thrombin III Factor IXa Heparin Anti- thrombin III Heparin Biosynthesis: Liver, Vitamin K dependent MW: 57,000 daltons Plasma Concentration: 4 mg/L In Vivo Half-Life: 20 hours Pathology: Hemophilia B, (Christmas disease) x-linked recessive Factor IX Christmas Factor

  18. Factor VIII Antihemophilic Factor vWF von Willebrand Factor Biosynthesis: Liver, endothelium; Factor VIII Related Antigen, megakaryocyte MW(FVIII + vWF): 1.2-2 million daltons (6-10 subunits – 200,000 daltons each) Plasma Concentration: 7 mg/L (vWF) In vivo Half-Life: 10 hours (Factor VIII) Pathology: Factor VIII-Hemophilia A, x-linked recessive. vWF-von Willebrand’s disease, autosomal dominant Ca++ Factor IIa Factor Xa or Procoagulant Factor VIII Activation Factor VIIIa Inhibition Anticoagulant Inactive Fragments Protein C Complex Activated ProteinC Protein S Phospholipid (Platelet Factor 3)

  19. Prothrombinase Complex Phospholipid (Platelet Factor 3) Factor Va Factor Xa Activation Fragments Factor II Procoagulant Activation Factor IIa (Thrombin) Factor IIa Inhibition Anticoagulant Anti- thrombin III Ca++ Anti- thrombin III * Heparin *or Heparin CofactorII Heparin Biosynthesis: Liver, Vitamin K dependent MW: 70,000 daltons Plasma Concentration: 100 mg/L In Vivo Half-Life: 100 hours Pathology: Hypoprothrombinemia, autosomal recessive Factor II Prothrombin

  20. Factor IIa Procoagulant Factor V Activation Factor Va Inhibition Anticoagulant Inactive Fragments Activated ProteinC Ca++ Protein S Phospholipid (Platelet Factor 3) Protein C Complex Factor V Proaccelerin, Labile Factor Biosynthesis: Liver, megakaryocytes MW: 330,000 daltons Plasma Concentration: 5-12 mg/L In Vivo Half-Life: 25 hours Pathology: Parahemophilia, autosomal recessive

  21. Biosynthesis: Liver MW: 340,000 daltons Plasma Concentration: 2500 mg/L In Vivo Half-Life: 20 hours Pathology: Afibrinogenemia, autosomal recessive. Dysfibrinogenemia, autosomal dominant CA+ Fibrin Polymer Factor IIa Fibrinopeptide A Factor IIa Factor IIa Fibrinopeptide B Factor XIII Fibrin Monomer Procoagulant Procoagulant Activation Fibrinogen Factor II Activation Activation Procoagulant Factor XIII Fibrin Stabilizing Factor (FSF) Biosynthesis: Megakaryocytes, liver MW: 320,000 daltons Plasma Concentration: 10mg/L In Vivo Half-Life: 12 days Pathology: FSF deficiency, autosomal recessive Activation Factor XIIIa Soluble Fibrin Polymer Anticoagulant Plasmin Anticoagulant Inhibition Inhibition Plasmin Procoagulant Anticoagulant Activation Inhibition Plasmin Fibrin (Factor Ia) FDPs Fibrinogen Degradation Products Activated Platelets Anticoagulant FDPs & XDPs (Cross-linked DPs) (e.g. D-dimers) Inhibition Stable Thrombus (Clot) Fibrinogen Factor I

  22. Prothrombin Time Factors Thromboplastin and Calcium I II V VII X Patient’s Plasma

  23. Factors I II V VIII IX X XI XII Ca++ Phospholipidand Activator Patient’s Plasma Activated PartialThromboplastin Time

  24. 60 1:40 1:30 30 1:20 Time (in seconds) High concentration of thrombin 1:10 10 6 1:5 3 1:10 dilution patient’s plasma 20 40 60 100 200 400 600 Fibrinogen in mg/dL Quantitative Fibrinogen

  25. Heparin/AT-III Complex

  26. Minor MajorFactor Spontaneous Trauma Hemorrhage or SurgeryI Fibrinogen 50-100 100 mg/dL II 10-15 20-40% V 5-15 25% VII 5-10 10-20% VIII 5-10 10-20% Hemophilia A 15-20 25% von Willebrand 25 25% IX 10-15 20-25% X 5-10 15-20% XI 5-15 15-25% XII 10 10% XIII 1 5% Williams, W. J., Hematology, 1972 Minimum Plasma Levels

  27. Vessels Coagulation Proteins Platelets Fibrinolysis/Inhibitors

  28. Fibrinolysis Activators: t-PA,u-PA, STK, XII, HMWK, PK Plasminogen Plasmin Fibrin Fibrinogen Degradation Products R.E.S.

  29. Biosynthesis: Liver MW: 90,000 daltons Plasma Concentration: 120 mg/L In Vivo Half-Life: 48 hours Pathology: Plasminogen deficiency, autosomal dominant. Dysplasminogenemia, autosomal recessive Plasminogen tPA (tissue Plasminogen Activator) or or Kallikrein Urokinase Anticoagulant Plasminogen Activation Plasmin Procoagulant Inhibition Plasmin a2 - Anti- plasmin a2 - Anti- plasmin

  30. Prekalli- krein Kalli- krein VII HMWK Extrinsic Pathway (PT) Kinins XII XIIa Tissue Factor XIa Intrinsic Pathway (aPTT) XI VIIa IXa IX Pro- Urokinase X Xa X VIIIa Fibrinolysis Ure- Kinase T-PA II Va VIII IIa Plas- minogen V Plasmin XIII XIIIa Common Pathway Fibrin Polymer Fibrinogen Fibrin Clot + Platelet Plug

  31. Lysine Site Heparin Thrombin, Antithrombin-III and Heparin Acidic Site Serine Site Antithrombin-III (Nonactivated) Thrombin (Active) Arginine Site Heparin Inactivation of Thrombin Antithrombin-III (Complexed) Thrombin (Inhibited) Antithrombin-III Heparin Thrombin Complex Antithrombin-III Inhibitionof Thrombin

  32. Antithrombin-III Decreased Levels 1. Congenital 2. Acquired – decreased synthesis 3. Acquired – increased utilization 4. Drug-induced

  33. Protein C • Vitamin K-dependent plasma protein • Inactivates Factors V and VIII • Stimulates fibrinolysis

  34. Biosynthesis: Liver, Vitamin K dependent MW: 56,000 daltons Plasma Concentration: 3-5 mg/L In Vivo Half-Life: 6-7 hours Pathology: Protein C deficiency, autosomal recessive (?) Protein C Thrombo- modulin Factor IIa Protein C Activation Peptide Protein C Anticoagulant Activation Activated Protein C* Inhibition Activated Protein C Procoagulant Protein C Inhibitor * Requires Protein S for functional activity Protein C Inhibitor

  35. Deficiencies of Protein C I. Congenital Hereditary autosomal dominant II. Acquired A. DIC B. Liver disease C. During post-operative period D. Anticoagulant therapy

  36. Clinical Manifestations • Superficial thrombophlebitis • Venous thromboses in adolescents or young adults • Arterial thromboses rarely observed • Skin necrosis during onset of oral anticoagulant therapy

  37. Protein S • Cofactor for Protein C • Vitamin K-dependent protein • Enhances binding of Protein C to phospholipid surfaces

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