1. Scheme of Coagulation F XIIF XIIa F XIF XIa F IX F X F IXa F VIIaF VII Extrinsic System Tissue damage Release of tissue thromboplastine (F III) Intrinsic System Foreign surface F VIIIF VIIIa Ca 2+ PL Ca 2+ PL F IIF IIaF XIIIa F XIII Ca 2+ ProthrombinThrombin Fibrin- monomer Fibrin s - polymer instabile Fibrin i - polymer stabile F I Fibrino- gen

2. Plasmatic Coagulation Ce 1297.76 –start- and regulatory mechanism Fibrinogen (dissolved) Fibrin (strong, fibrous network)

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

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

5. Regulation of Hemostasis Procoagulant Effect: release of platelet factors increase due to coagulation cascade accelerating factors Va and VIIIa availability of factors on endothelial surface Anticoagulant Effect: circulation of factors in inactiv form blocking due to inhibitors FXII caused activation of fibrinolyses micro- und macrocirculation including of plasminogen

6. Regulatory Effect of the Endothelium on 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) Ce 1297.80 Anticoagulant Effect: neutralisation/binding of thrombin activation of the protein C/S systems release of „tissue factor pathway inhibitor“ (versus F VIIa, F Xa) Fibrinolytic Effect: release of tpA

7. Regulatory Effect of the Endothelium on 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) Ce 1297.80 Anticoagulant Effect: neutralisation/binding of thrombin activation of the protein C/S systems release of „tissue factor pathway inhibitor“ (versus F VIIa, F Xa) Fibrinolytic Effect: release of tpA

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, inhibitors and fibrinolytic system Ce 1297.82

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

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

11. Physiological Interactions of the Coagulation System Coagulation InhibitorsFibrinolyses Wound Healing Complement System KininSystem regulation of coagulation- processes degradation of the clot activated by F XIII lysis of bacteriadecreased blood pressure, increased vessel permeability adequate hemostasis § optimale tissue reconstitution

12. The Consequences of a Pathophysiological Escalation of the Coagulation System Ce 1297.87 Pathological Coagulation FaktorsInhibitorsF XIIIComplement Kinin Systeme bleeding hypovolemia, shock organ failure micro- and macro- thromboses organ failure, shock rupture of wounds, fistula anaphylatoxinsdisturbed wound healing shock hypotonia edema, Capillary-Leak- Syndrom severe, partly life-threatening diseases

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

14. Coagulation Disorder Caused by Sepsis Ce 1297.89 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

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

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 Ce 1297.92 Fibrinolyses:- Plasminogen - Plasminogen activator inhibitor (PAI) Marker of hyperfibrinolyses:-Fibrin(ogen) degradation product (FDP) -Fibrin degradation products (FDP) - Plasmin- antiplasmin complex (PAP) Marker of activation of the coagulation:-Fibrin-monomers -Prothrombin fragments F 1 + F 2 -Thrombin-antithrombin (TAT) complex

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

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

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

21. Diagnosis of Thrombotic Risk Inhibitors: Factors: Marker of consumption: Fibrinolyses: Lupus-anticoagulants: Ce 1297.96 AT III, Protein C, Protein S The available parameters detect only a third of all patients at risk: F XIIFibrinogen, F V (APC-resistance) TAT, F 1 + F 2, Fibrin-monomers Lupus-anticoagulants PAI, PAP, FSP, D-dimers Plasminogen

22. Platelet Adhesion blood plateletWF as binding protein for collagen and platelets Ce 1297.73 TXA 2 ADP 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 A 2 (TXA 2 ) and ADP for aggregation of further platelets