Scheme of Coagulation

F XII F XIIa

F XI F XIa

F IX

F X

F IXa

F VIIa F VII

Extrinsic System

Tissue damageRelease of tissue thromboplastine(F III)

Intrinsic SystemForeign surface

F VIII F VIIIaCa2+

PL

Ca2+

PL

F II F IIa F XIIIa

F XIII

Ca2+

Ca2+

Prothrombin Thrombin

Fibrin-monomer

Fibrins-polymerinstabile

Fibrini-polymer stabile

F IFibrino-

gen

Plasmatic Coagulation

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– start-and regulatory

mechanism

Fibrinogen(dissolved)

Fibrin(strong, fibrous

network)

Mechanism of AT III

– inactive complex (TAT)

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Thrombin Thrombin

The effect of AT III is massively increased by heparin

AT III AT III

Most Important Inhibitorsof the Coagulation

•Inhibitors

• Antithrombin III

• Protein C und protein S

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•Inactivation of

• Thrombin

• F Xa

• F XIIa, F XIa, F VIIa

• F VIIIa

• F Va

Regulation of Hemostasis

•Procoagulant Effect:

• release ofplatelet factors

• increase due to coagulationcascade

• accelerating factorsVa and VIIIa

• availability of factorson endothelial surface

•Anticoagulant Effect:

• circulation of factors ininactiv form

• blocking due to inhibitors

• FXII caused activation of fibrinolyses

• micro- undmacrocirculation

• including of plasminogen

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)Ce 1297.80

•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

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)Ce 1297.80

•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

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

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The Physiological Balance of Blood Coagulation

Balance between coagulation factors (F)

and inhibitors (I)

lack of factors

risk of bleeding risk of thromboses

lack of inhibitors

F I

FI F I

Physiology of Coagulation

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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 byinhibitors and endothelium

damage of the vessel wall

vasoconstriction,local decrease of blood pressure

activation of the thrombocytic

system

activation of theplasmatic

coagulation

activationof the

fibrinolyses

Physiological Interactionsof the Coagulation System

Coagulation

Inhibitors Fibrinolyses Wound Healing

ComplementSystem

KininSystem

regulationof coagulation-

processes

degradationof the

clot

activated byF XIII

lysis of bacteria decreased blood pressure,

increased vessel permeability

adequate hemostasis §optimale tissue reconstitution

The Consequences of a Pathophysiological Escalation of the Coagulation System

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Pathological Coagulation

Faktors Inhibitors F XIII Complement Kinin Systeme

bleeding

hypovolemia,shock

organ failure

micro-and macro-thromboses

organ failure,shock

rupture of wounds,fistula

anaphylatoxinsdisturbedwound healing

shock shock

hypotonia

edema,Capillary-Leak-

Syndrom

severe, partly life-threatening diseases

Lability of Hemostasis

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injury of the endothelium

bleeding in the surrounding tissue

physiological reaction pathophysiological escalation

local activationof coagulation and

fibrinolyses

insufficientactivation of coagulation/

ecalating fibrinolyses

escalatingactivation of coagulation/insufficient fibrinolyses

local hemostasis continuous bleeding thromboses

normalwound healing disturbed or absent wound healing

Coagulation Disorder Caused by Sepsis

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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

Diagnostics of Coagulation Disorders

• Function of vessels

• Platelets

• Plasmatic coagulation

• Inhibitors

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• Fibrinolytic system

• Activation parameters ofcoagulation and fibrinolyses

More or less standardized laboratory tests for documentation are existent for the monitoring of the coagulation :

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

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Diagnostics of Coagulation Disorders

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• 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

Minimal Laboratory Programm for Coagulation

• PT

• PTT

• Platelet count

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In case of pathological results or possible coagulation disorders further investigation is mandatory!

Monitoring of Intensive Care Unit Patients

• PT

• PTT

• Platelet count

• Antithrombin III

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• Fibrinogen

• Bleeding time

• Thrombin time

• F XIII and othersingle factors (F V, F II)

Screening Tests of Plasmatic Coagulation

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PTT

XII

XI

IX

PT

V II

V IIIXVIII X IIITT

PT

V II

PTT

XII

XI

IX

Diagnosis of Thrombotic Risk

• Inhibitors:

• Factors:

• Marker of consumption:

• Fibrinolyses:

• Lupus-anticoagulants:

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AT III,Protein C,Protein S

The available parameters detect only a third of all patients at risk:

F XII Fibrinogen,F V (APC-resistance)

TAT, F1+ F2,Fibrin-monomers

Lupus-anticoagulants

PAI, PAP, FSP,D-dimersPlasminogen

Platelet Adhesion•blood platelet WF as binding protein

for collagen and platelets

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TXA2

ADP

damaged endothelium

subendothelial tissue (collagen)

l Damage of endothelium and release of subendothelial structures (collagen)

l Platelet adhesion on collagen influenced by von Willebrand factor

l Activation of adhesed platelets

l Release of Thromboxan A2 (TXA2) and ADP for aggregation of further platelets