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Coagulation Factor

Friction force. vWF. platelet. Coagulation Factor. platelet. platelet. fibrin. platelet. platelet. platelet. Antithrombotic pathway. Fibrinolytic pathway. contact Pathway. Tissue f. Pathway. TFPI. X. Protein C pathway. AT III pathway. V. Thrombin. Fibrinogen. FDP.

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Coagulation Factor

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  1. Friction force vWF platelet Coagulation Factor platelet platelet fibrin platelet platelet platelet Antithrombotic pathway Fibrinolytic pathway

  2. contact Pathway Tissue f. Pathway TFPI X Protein C pathway AT III pathway V Thrombin Fibrinogen FDP D-dimer Fibrinolytic Pathway plasminogen

  3. Hemarthrosis Hemophilia 혈우병

  4. Pathologic bruising in von Willebrand’s disease platelet (혈소판) vessel (혈관)

  5. 12 7 11 9 8 10 5 2 1 Fibrin clot Tissue Factor HMKN PK Extrinsic pathway Intrinsic pathway Tissue Factor thromboplastin Activator Kaolin Silica Platelet phospholipid Common pathway thrombin fibrinogen

  6. 7 12 11 9 8 10 5 2 Antithrombin III pathway Heparin + ATIII + Heparin like Substance + HCII + Dermatan Sulfate

  7. Protein C pathway 7 12 11 aVIII 9 8 10 aV 5 2 PC + Thrombomodulin + Thrombin APC resistence Factor V Leiden: Arg506Gln Activated PC + PS free PS free -- PS + C4b-BP * Thrombomodulin: thrombin receptor on endothelial cell * Cleavage site of Factor V 306,506,679

  8. 7 12 11 9 8 10 5 2 Damaged endothelial cell Tissue factor VWf PF4 activated PLT Beta-TG Tissue Factor Pathway Inhibitor

  9. Antithrombin Tissue Factor Pathway Inhibitor 4 major antithrombotic pathways Protein C Protein S Fibrinolytic System

  10. Thrombi (혈전) Thromboemboli Hypercoagulable state Protein C Protein S Antithrombin III Plasminogen Factor V Leiden

  11. Collagen fibronectin VWf Factor VIII VWf GpIb receptor fibrinogen PLT GpIIb/IIIa

  12. Factor VIII and VWF terminology Old term New term VIII VIII:Ag VIII:C VIII:C VIIIC:Ag Factor VIII Protein Antigen Function VWF VWF:Ag VWF Activity vWF Protein Antigen Function VIIIR:Ag VIIIR:Ag VIIIR:RCo

  13. Damaged endothelial cell VWf PF4 activated bacterial glycopeptide ristocetin viper venome protein PLT Beta-TG

  14. Gp IIb/IIIa receptor

  15. IIIa Heterodimer IIb Transmembrane domain Intracytoplasmic tail domain Intracellular actin cytoskeleton organization fluxes in intracellular Ca pH focal adhesion kinase 세포의 기능 motility growth 분화

  16. Gp IIb /IIIa Decrease amount of Gp IIb/IIIa Genetic defect of Gp IIb/IIIa Platelet aggregation test absence of response to ADP, collagen, epinephrine impaired response to ristocetin

  17. Collagen fibronectin VWf Factor VIII VWf GpIb receptor fibrinogen PLT GpIIb/IIIa

  18. Gp Ib Platelet adhesion to damaged vessel subendothelial matrix - vWF - GpIb sheet formation Genetic defect of Gp Ib gene: Bernard Soulier syndrome Platelet aggregation test impaired response to ristocetin normal response to ADP, collagen, epinephrine

  19. Fibrinogen FpA X Fibrin monomer D D Y+D D E E F.XIII Fibrin polymer Fibrin clot YY/DYD YD/DY DD/E Plasminogen system D-dimer

  20. Plasmin A1-antiplasm Plasminogen activator Plasminogen Fibrin Fibrin A1-antiplasmin + plasmin

  21. Plasminogen System fibrinolytic system • Vascular biology • Matrix remodelling • Tumor growth • Dissemination of tumor • Wound healing

  22. Single Cell Vital Organ Endothelial cell Inflammatory cytokine Growth factor Circulating hormons Bacterial product Shear stress Hydrostatic pressure Cyclic strain Friction force Gross modification of cell shape Reorganization of cytoskeletal elements SSRE expression Differential display of mRNA transcript eNOS (endothelial isoform of nitric oxide synthetase) COX-2 (inducible isoform of cyclo-oxygenase) MnSOD (manganase-dependent superoxide dismutase) vasoprotective anti-atherogenic Anti-thromboptic anti-adhesive anti-proliferative anti-oxidant

  23. Platelet test • Bleeding time • Platelet count • Platelet adhesion test • Platelet aggregation test • ADP, epinephrine, collagen, ristocetin • Gp IIb/IIIa receptor measurement

  24. Screening test for coagualtion pathway • Platelet count • Bleeding Time • PT, aPTT, fibrinogen • Thrombin time

  25. Diagnostic tests: Coagulation assay • factor I, II, V, VII, VIII, IX, X, XII • prekallikrein • HMWK • factor XIII

  26. Fibrinolytic system test • Fibrinogen, FDP, D-dimer • Plasminogen, Plasminogen activator • Plasminogen activator inhibitor • a2-antiplasmin

  27. Antithrombotic pathway • Antithrombin III • Protein C, Protein S • Factor V Leiden • Plasminogen

  28. 12 7 11 9 8 10 5 2 1 Fibrin clot HMKN PK Tissue Factor thrombin Heparin + ATIII fibrinogen

  29. 12 7 11 9 8 10 5 2 1 Fibrin clot PT APTT Tissue Factor HMKN PK Tissue Factor thromboplastin Activator Kaolin Silica Platelet phospholipid CaCl2 CaCl2

  30. 왜 aPTT만을 기준으로 할 수 없는지? aPTT의 증가 : 효과적으로 anticoagulation 되었다고 판단할 수 없다. aPTT 검사 방법, 시약 종류, 검사 기기에 따른 차이 : standardized method 라는 것이 없다는 문제점 Heparin 종류에 따른 차이: 종류가 다른 약을 사용할 경우 같은 aPTT 수치를 보여도 antithrombotic effect는 현저히 다르다. Surrogate assay for heparin concentration

  31. History of Heparin Monitoring 1967 JAMA : Replacement of WBCT by aPTT 1972 NEJM : Historical TR of ratio of 1.5 - 2.5 1st prospective clinical study 1977 Blood : TR 0.2 - 0.4 U/ml by protamine titration 1986 NEJM : TR 0.3 - 0.7 U/ml by anti-Xa activity ‘ Gold Standard’ Reports on the problems in using Fixed Ratio d/t different responsiveness of different reagents 1980, 1985, 1988, 1990 AM J Clin Pathol 1990 Thromb Haemost

  32. Anti-Xa Heparin Assay Free AT + Heparin -> AT-Heparin AT-Heparin + Fxa (in excess) -> AT-Heparin-Fxa + Fxa (residual) Fxa (residual) + Substrate -> Signal

  33. Heparin 투여 환자에서 사용전 점검할 항목 Platelet Count Heparin antibody screening AT III level

  34. Consensus Recommendations : HIT Heparin 투여환자의 혈소판수 검사 - Naïve paient 투여전 & 투여 4일후부터 격일로 14일간 혈소판수 검사 - prior heparin exposure 투여전 & 투여 1일째부터 격일로 14일간 혈소판수 검사 Confirm by assay for heparin mediated antibody if - 혈소판수치가 heparin 투여전의 50% 이하로 감소 혈소판 수<100,000/ul - 혈소판 수치가 감소하지 않더라도 arterial or venous thrombosis가 진행될 경우

  35. Q & A about LMWH LMWH은 UH와 무엇이 다른가? US: mixture of polysacchride chains(3,000-30,000) LMWH: UH의 분획, potent anti-Xa activity LMWH의 장점은? Decreased binding to nonanticoagulant-related plasma protein Greater bioavailability longer half life lower incidence of HIT Predictable anticoagulant activity: No monotoring LMWH injection route Subcutaneous injection (self)

  36. 12 7 11 9 8 10 5 2 1 Fibrin clot PT APTT Tissue Factor HMKN PK Tissue Factor thromboplastin Activator Kaolin Silica Platelet phospholipid CaCl2 CaCl2

  37. Prothrombin Time (PT) • sec • % • International Normalized Ratio • 정상 0.8 - 1.2 • Therapeutic Range 2.0 - 3.0

  38. Anticoagulant Warfarin 복용환자의 뇌출혈 Therapeutic Range monitor by PT

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