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Functional Aspects of

Functional Aspects of. Vessels. Coagulation Proteins. Platelets. Fibrinolysis/Inhibitors. Homeostasis:. State of fluid equilibrium within the blood vessels. Hemostasis Homeostasis. Vessels. Bleeding. Clotting. Coagulation Proteins. Platelets. Fibrinolysis/Inhibitors. Vessels.

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Functional Aspects of

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  1. Functional Aspects of

  2. Vessels Coagulation Proteins Platelets Fibrinolysis/Inhibitors Homeostasis: State of fluid equilibrium within the blood vessels

  3. Hemostasis Homeostasis Vessels Bleeding Clotting Coagulation Proteins Platelets Fibrinolysis/Inhibitors

  4. Vessels Coagulation Proteins Platelets Fibrinolysis/Inhibitors

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

  6. Vessels Coagulation Proteins Platelets Fibrinolysis/Inhibitors

  7. Disk-shaped “cells” produced in the megakaryocytes of the bone marrow Mature Platelet Megakaryocyte Bone Marrow What are Platelets?

  8. Dense Body ADP Serotonin ATP Calcium Dense Tubular System Microtubular System Plasma Membrane PF3 Glycogen Exterior Coat (Glycocalyx) Alpha Granules PF4 Fibrinogen Factor V Fibronectin Factor VIII R:ag b Thromboglobulin (vWF) Mitochondria Surface Connecting System Cytosol Factor XIII Anatomy of a Platelet

  9. Quantity - 200,000 - 400,000/mm3 Life Span - 10 days 33% pooling 67% in the circulation Spleen Megakaryocyte Storage and Circulation

  10. A Adhesion ADP Release Shape Change Release 3 seconds Aggregation B 10 seconds C Coagulation Fibrin Formation 5 minutes Platelet Function

  11. Peripheral Smear Platelet Count Platelet Aggregation Bleeding Time Platelet Testing

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

  13. Platelet Rich Plasma Platelet Poor Plasma 100 90 80 70 60 50 40 30 20 10 0 Secondary Response (Release) Primary Response Lag Injection Point Typical Biphasic Pattern

  14. Cut 1 mm deep5 mm long Constant Pressure Expected Range 2 - 10 minutes 40 mm Bleeding Time

  15. Vessels Coagulation Proteins Platelets Fibrinolysis/Inhibitors

  16. Factor I Fibrinogen Factor II Prothrombin Factor III Tissue Thromboplastin Factor IV Calcium Ions Factor V Labile Factor, Proaccelerin Factor VII Stable Factor, Proconvertin Factor VIII Antihemophilic Factor Factor IX Christmas Factor Factor X Stuart-Prower Factor Factor XI Plasma Thromboplastin Antecedent Factor XII Hageman Factor Factor XIII Fibrin Stabilizing Factor Coagulation Factors

  17. 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

  18. Fibrinogen Group Factors I, V, VIII and XIII Prothrombin Group Factors II, VII, IX and X Contact Group Factors XI, XII Prekallikrein (Fletcher Factor) High Molecular Weight Kininogen (Fitzgerald Factor) Coagulation Factors

  19. 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

  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 Biosynthesis: Liver, megakaryocytes MW: 330,000 daltons Plasma Concentration: 5-12 mg/L In Vivo Half-Life: 25 hours Pathology: Parahemophilia, autosomal recessive Factor V Proaccelerin, Labile Factor

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

  22. 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 Cofactor II 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

  23. 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 Ca++ Anticoagulant Factor VIIa *Tissue Factor Pathway Inhibitor (a.k.a. LACI or EPI) 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

  24. 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 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

  25. 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

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

  27. 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

  28. 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 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 High Molecular Weight Kininogen (HMWK) Fitzgerald Factor MW: 120,000 daltons Plasma Concentration: 70 mg/L Pathology: Fitzgerald trait, autosomal recessive

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

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

  31. 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

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

  33. 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

  34. Screens for effects of • Heparin • FDPs Low concentration of thrombin Undiluted patient’s plasma Thrombin Clotting Time

  35. MonitoringAnticoagulant Therapy Vitamin K Antagonists Antithrombin III Accelerators

  36. Vitamin K Antagonists • Coumarin, Dicumarol, Warfarin • Oral Administration • Long-Acting Effect • Factors IIa, VIIa, IXa, Xa • PT

  37. AT-III Accelerators • Heparin, Heparinoids, LMW Heparin • Parenteral Administration • Short-Acting Effect • Factors IIa, IXa, Xa • APTT

  38. Heparin/AT-III Complex

  39. Variables inMonitoring Heparin • Time of Specimen Collection • Type of Anticoagulant • Centrifugation of Specimen • Instrumentation and Reagents

  40. Diagnosis Factor Assays Therapy

  41. Plasma with 0% F.VII has a Prolonged Prothrombin Time By adding various concentrations of Factor VII Standard the Prothrombin Time is corrected The degree of correction is proportional to the concentration 0.1 mL F.VII Deficient Substrate 0.1 mL F.VII Standard or patient’s plasma dilution 0.2 mL Thromboplastin Calcium Chloride Mixture Factor Assays of the Extrinsic Proteins II, V, VII, X

  42. Plasma with 0% Factor VIII has a prolonged APTT 0.1 mL Phospholipid and Activator 0.1 mL Factor VIII Deficient Plasma The degree of correction is proportional to the concentration By adding various concentrations of Factor VIII Standard the APTT is shortened 0.1 mL Factor VIII Standard or patient’s plasma dilution 0.1 mL Calcium Chloride Factor Assays of the Intrinsic Proteins VIII, IX, XI, XII

  43. Dilution % Activity Clotting Time 1:5 20.0% 14.3 seconds 1:10 10.0% 17.3 seconds 1:20 5.0% 21.0 seconds 1:40 2.5% 26.0 seconds 30 25 20 15 10 5 2 5 10 20 The Standard Curve

  44. 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

  45. Vessels Coagulation Proteins Platelets Fibrinolysis/Inhibitors

  46. Activators Plasminogen Plasmin Fibrin Fibrinogen Degradation Products R.E.S. Fibrinolysis

  47. 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

  48. • t-PA • Streptokinase • Urokinase • Anaphylaxis • GI Bleeding • Intracranial Hemorrhage Thrombolytic Therapy

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