Scheme of Coagulation

1. F XII F XIIa Scheme of Coagulation Intrinsic System Extrinsic System Foreign surface Tissue damage Release of tissue thromboplastine (F III) F XI F XIa F X F VIIa F VII F IX F IXa Ca2+ PL F VIII F VIIIa F XIII Ca2+ PL Ca2+ F II F IIa F XIIIa Prothrombin Thrombin Ca2+ F IFibrino-gen Fibrin- monomer Fibrins- polymer instabile Fibrini- polymer stabile

2. Plasmatic Coagulation • start-and regulatorymechanism • Fibrin(strong, fibrousnetwork) • Fibrinogen(dissolved) Ce 1297.76

3. Mechanism of AT III • inactive complex (TAT) • AT III • AT III • Thrombin • Thrombin • The effect of AT III is massively increased by heparin Ce 1297.77

4. Most Important Inhibitorsof the Coagulation • Inhibitors • Antithrombin III • Protein C und protein S • Inactivation of • Thrombin • F Xa • F XIIa, F XIa, F VIIa • F VIIIa • F Va Ce 1297.78

5. Regulation of Hemostasis • Anticoagulant Effect: • circulation of factors ininactiv form • blocking due to inhibitors • FXII caused activation of fibrinolyses • micro- undmacrocirculation • including of plasminogen • Procoagulant Effect: • release ofplatelet factors • increase due to coagulationcascade • accelerating factorsVa and VIIIa • availability of factorson endothelial surface

6. Regulatory Effect of the Endotheliumon Hemostasis • Procoagulant Effect: • surface/receptors for activation of coagulation factors • release of tissue thromboplastine • neutralisation of heparin • activation of F XII • Antifibrinolytic Effect: • release of plasminogen-activatorinhibitor 1 (PAI 1) • Anticoagulant Effect: • neutralisation/bindingof thrombin • activation of the protein C/S systems • release of „tissue factorpathway inhibitor“(versus F VIIa, F Xa) • Fibrinolytic Effect: • release of tpA Ce 1297.80

7. Regulatory Effect of the Endotheliumon Hemostasis • Procoagulant Effect: • surface/receptors for activation of coagulation factors • release of tissue thromboplastine • neutralisation of heparin • activation of F XII • Antifibrinolytic Effect: • release of plasminogen-activatorinhibitor 1 (PAI 1) • Anticoagulant Effect: • neutralisation/bindingof thrombin • activation of the protein C/S systems • release of „tissue factorpathway inhibitor“(versus F VIIa, F Xa) • Fibrinolytic Effect: • release of tpA Ce 1297.80

8. The Plasmatic Coagulation • Start mechanism: - contact with foreign surface (F XII, F XI) - release of tissue thromboplastin • Course: - cascading activation of different coagulation factors • Goal: - conversion of fibrinogen into fibrin • Regulation: - interaction of endothelium, platelets,plasmatic coagulation system, inhibitorsand fibrinolytic system Ce 1297.82

9. The Physiological Balance of Blood Coagulation Balance between coagulation factors (F)and inhibitors (I) F I • lack of factors • lack of inhibitors F I I F • risk of bleeding • risk of thromboses

10. Physiology of Coagulation • damage of the vessel wall • vasoconstriction,local decrease of blood pressure • activation of the thrombocytic system • activation of theplasmatic coagulation • activationof thefibrinolyses regulation by inhibitors and endothelium • formation of a fibrin-platelet-clot • wound closure/hemostasis • tissue reconstitution/wound healing • In case of coagulation disorders bleedings, thromboses and/or disturbed wound healing might occur! Ce 1297.85

11. Physiological Interactionsof the Coagulation System Coagulation ComplementSystem Wound Healing Inhibitors Fibrinolyses KininSystem activated byF XIII regulation of coagulation-processes degradationof the clot lysis of bacteria decreased blood pressure, increased vessel permeability adequate hemostasis §optimale tissue reconstitution

12. The Consequences of a Pathophysiological Escalation of the Coagulation System Pathological Coagulation Kinin Systeme Faktors Inhibitors F XIII Complement micro- and macro-thromboses edema, Capillary-Leak- Syndrom disturbedwound healing anaphylatoxins bleeding hypovolemia,shock hypotonia organ failure, shock rupture of wounds,fistula shock shock organ failure severe, partly life-threatening diseases Ce 1297.87

13. Lability of Hemostasis injury of the endothelium bleeding in the surrounding tissue physiological reaction pathophysiological escalation insufficient activation of coagulation/ ecalating fibrinolyses escalating activation of coagulation/ insufficient fibrinolyses local activationof coagulation andfibrinolyses continuous bleeding thromboses local hemostasis normal wound healing disturbed or absent wound healing Ce 1297.88

14. Coagulation Disorder Caused by Sepsis Infection Sepsis Severe sepsis with refractive hypotonia Activation of coagulation (DIC) Bleeding Micro- and Macro- thromboses Shock Multiple organ failure In case of severe infections the consequences of sepsis and coagulation disorders are increasing Ce 1297.89

15. Diagnostics of Coagulation Disorders More or less standardized laboratory tests for documentation are existent for the monitoring of the coagulation : • Function of vessels • Platelets • Plasmatic coagulation • Inhibitors • Fibrinolytic system • Activation parameters ofcoagulation and fibrinolyses Ce 1297.90

16. Diagnostics of Coagulation Disorders • Global tests: - Thrombelastogramm(plasmatic coagulation, fibrinolyses, platelets) - Bleeding time (number and function of platelets, plasmatic coagulation) • Function of vessels: - Rumpel-Leede-Test • Platelets: - Counting - Tests for adhesion and aggregation • Plasm. coagulation: - Screening tests (PT, PTT, TT) - Single factors - Inhibitors Ce 1297.91

17. Diagnostics of Coagulation Disorders • Fibrinolyses: - Plasminogen - Plasminogen activator inhibitor (PAI) • Marker ofhyperfibrinolyses:-Fibrin(ogen) degradation product (FDP) - Fibrin degradation products (FDP) - Plasmin- antiplasmin complex (PAP) • Marker of activationof the coagulation: - Fibrin-monomers - Prothrombin fragments F1+ F2 - Thrombin-antithrombin (TAT) complex Ce 1297.92

18. Minimal Laboratory Programm for Coagulation • PT • PTT • Platelet count In case of pathological results or possible coagulation disorders further investigation is mandatory! Ce 1297.93

19. Monitoring of Intensive Care Unit Patients • PT • PTT • Platelet count • Antithrombin III • Fibrinogen • Bleeding time • Thrombin time • F XIII and othersingle factors (F V, F II) Ce 1297.94

20. Screening Tests of Plasmatic Coagulation PTT XII XI IX PTT XII XI IX PT V II PT V II V III X V II I TT X III Ce 1297.95

21. Diagnosis of Thrombotic Risk The available parameters detect only a third of all patients at risk: • Inhibitors: • Factors: • Marker of consumption: • Fibrinolyses: • Lupus-anticoagulants: AT III,Protein C,Protein S F XII Fibrinogen, F V (APC-resistance) TAT, F1+ F2, Fibrin-monomers PAI, PAP, FSP, D-dimers Plasminogen Lupus-anticoagulants Ce 1297.96

22. Platelet Adhesion TXA2 ADP • blood platelet WF as binding proteinfor collagen and platelets damaged endothelium subendothelial tissue (collagen) • Damage of endothelium and release of subendothelial structures (collagen) • Platelet adhesion on collagen influenced by von Willebrand factor • Activation of adhesed platelets • Release of Thromboxan A2 (TXA2) and ADP for aggregation of further platelets Ce 1297.73