1. HEMOSTAZ Yard. Doç. Dr. Murat ÖRMEN

2. Vessels Platelets Fibrinolysis/Inhibitors Coagulation Proteins BleedingClotting Hemostaz

3. Endothelial Cells Basement Membrane Red Blood CellsPlateletsWhite Cells Vascular System

4. Platelets Fibrinolysis/Inhibitors Coagulation Proteins Vessels

5. PRİMER HEMOSTAZ

9. Platelet Rich Plasma (PRP) Aggregatin g Reagent Aggregat e Clumping Baseline Light Transmission Increased Light Transmission + Platelet Aggregation

10. Function HEMOSTASİS BLEEDİNG AGREGOMETRİ ANİMASYON

11. Platelets Coagulation Proteins Fibrinolysis/Inhibitors Vessels

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

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

14. 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

15. Factor VIIIa Tissue Factor Phospholipid (Platelet Factor 3) Factor IXa Factor VIIa Factor X Factor Xa Anti- thrombin III Heparin Anti- thrombin III Ca++ Heparin Activation Procoagulant Anticoagulant Inhibition or Extrinsic X-ase Complex Intrinsic X-ase Complex Tissue Factor Factor III, Thromboplastin Biosynthesis: Brain, lung, subendothelium MW: 45,000 daltons 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

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

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

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

19. Ca++ High Molecular Weight Kininogen Factor XIIa Factor XIa Factor XI Factor XIa Activation Procoagulant Anticoagulant Inhibition  1- Anti- trypsin  1- 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

20. Ca++ Tissue Factor VIIa Factor IXa Factor IX Factor IXa Activation Procoagulant Anticoagulant Inhibition Factor XIa or Anti- thrombin III Heparin Anti- thrombin III Heparin Factor IX Christmas Factor 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

21. 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 Factor IIa Factor VIII Activated Protein C Protein S Phospholipi d (Platelet Factor 3) Inactive Fragments Ca++ Factor VIIIa Protein C Complex Activation Procoagulant Anticoagulant Inhibition Factor Xa or

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

23. 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

24. Fibrinogen Factor I Biosynthesis: Liver MW: 340,000 daltons Plasma Concentration: 2500 mg/L In Vivo Half-Life: 20 hours Pathology: Afibrinogenemia, autosomal recessive. Dysfibrinogenemia, autosomal dominant Factor IIa Factor IIa Fibrinopeptid e A Fibrinopeptid e B Fibrinogen Factor II Fibrin Monomer Procoagulant Activation Factor IIa Activation Procoagulant Fibrin Polymer CA+ Factor XIII Factor XIIIa Soluble Fibrin Polyme r Plasmin Anticoagulant Inhibition Procoagulant Activation Fibrin (Factor Ia) Stable Thrombus (Clot) Activate d Platelet s FDPs Fibrinogen Degradatio n Products FDPs & XDPs (Cross-linked DPs) (e.g. D-dimers) 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

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

26. Ca++ Patient’s Plasma Factors I II V VIII IX X XI XII Phospholipid and Activator Activated Partial Thromboplastin Time

27. Quantitative Fibrinogen High concentration of thrombin 1:10 dilution patient’s plasma Time (in seconds) Fibrinogen in mg/dL 204060100200400600 60 30 10 6 3 1:4 0 1:3 0 1:2 0 1:1 0 1:5

28. Heparin/AT-III Complex

29. Minimum Plasma Levels MinorMajor FactorSpontaneousTrauma Hemorrhageor Surgery I Fibrinogen50-100100 mg/dL II10-1520-40% V5-1525% VII5-1010-20% VIII5-1010-20% Hemophilia A15-2025% von Willebrand2525% IX10-1520-25% X5-1015-20% XI5-1515-25% XII1010% XIII15% Williams, W. J., Hematology, 1972

30. Platelets Fibrinolysis/Inhibitors Coagulation Proteins Vessels

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

32. Plasminogen 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 Urokinase Kallikrein tPA (tissue Plasminogen Activator) Plasminogen  2 - Anti- plasmin  2 - Anti- plasmin Activation Procoagulant Anticoagulant Inhibition Plasmin or

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

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

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

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

37. Protein C 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 (?) * Requires Protein S for functional activity Thrombo- modulin Factor IIa Protein C Activated Protein C Inhibitor Protein C Inhibitor Activated Protein C* Protein C Activation Peptide Activation Procoagulant Anticoagulant Inhibition

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

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

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