1. HAEMOSTASIS AND THROMBOSIS Regulation of coagulation
Vessel wall injury
Vasoconstriction, local blood pressure drop
Activation of platelets
Activation of plasmatic coagulation
Activation of fibrinolysis
Regulation by
inhibitors
and
endothelial
cells
Formation of fibrin-platelet-thrombus
Wound closure / cessation of bleeding
Tissue regeneration / wound healing
Disturbed coagulation may lead to bleeding, thromboembolism and/or impaired wound healing!

2. What is haemostasis? Coagulation Fibrinolysis
Maintains blood in a fluid state in circulation and provides defence mechanism against bleeding when injury occurs
Vasoconstriction of the damaged vessel
Coagulation
Fibrinolysis
Platelet plug formation primary haemostasis
Key messages:
Haemostasis is a physiological mechanism – normal state of blood and defense
Vasoconstriction:
In order to minimize blood loss. Vasoconstrictors produced by endothelium
Adrenergic vasoconstriction (epinephrine)
Platelet plug formation:
Caused by interaction between platelet and blood vessel wall/wound
Caused by effect of the functions of platelets (thrombocytes)
Platelet glycoproteins:
GP Ib binds to vWF lack of Bernard Soulier
GP Ia/IIa binds to collagen
GP IIb/IIIa binds to fibrinogen, vWF and other lack of Glanzmann
For normal primary haemostasis the following is needed:
normal vWF, amount and function
adequate number and function of thrombocytes, see above
normal activation of thrombocytes, can be blocked with thrombocyte function inhibitors (ASA, dipyridamol, clopidogrel)
normal aggregation of thrombocytes
normal collagen
pharmacological interaction:
heparin inhibits binding of GP Ib binding to vWF
GP IIb/IIIa inhibitors inhibits binding of GP IIb/IIIa to fibrinogen and vWF
ASA, dipyridamol, clopidogrel metabolic inhibition of activiation of thrombocytes
Fibrin clot formation secondary haemostasis
Fibrinolysis tertiary haemostasis

3. What is the function of thrombin?
Necessary for haemostasis
Activates platelets
Activates FVIII and FV
Activates FXIII necessary for the formation of fully stabilized fibrin clots/plugs
Activates FXI (feed-back loop leading to more thrombin formation via FIX)
Activates TAFI (thrombin activatable fibrinolysis inhibitor)
TAFI (carboxypeptidase) prevents the conversion of GLU-plasminogen into LYS-plasminogen

4. Summary Initiation Amplification Propagation
TF complexes with FVIIa, which activates FX to FXa
FXa generates small amount of thrombin on surface of TF-bearing cells with FVa as co-enzyme
FVIIa also activates FIX to FIXa
Amplification
Thrombin activates platelets
Thrombin cleaves FVIII from vWF and FVIII is activated to FVIIIa
Thrombin activates FXI and FV
Propagation
FIXa-FVIIIa complex generates FXa on the surface of activated platelets
This FXa generates a huge thrombin burst
Thrombin converts fibrinogen to fibrin

5. Platelet Function Adherence Only Aggregation & Release
Direction of Blood Flow

6. Bernard-Soulier Syndrome
Platelet Adherence
von Willebrand Disease
vWF
Gp Ib
vWF
Bernard-Soulier Syndrome
Gp Ib
vWF
vWF

7. Platelet Release Function
Wiskott-Aldrich syndrome
ADP
Hermansky-Pudlak
syndrome
ß-thromboglobulin
Platelet factor 4
DenseGranule
Platelet-derived Growth Factor
Alpha-granule
Gray platelet syndrome
Lysosome
Fibrinogen
Chédiak-
Higashi anomaly
Factor V
Hydrolase

8. Platelet Aggregation IIIa IIIa IIIa Release Defects Thrombasthenia ADP
vWF
IIIa
IIb
Gp Ib
Release Defects
Dense Granule
ADP
Thrombasthenia
Fibrinogen E D
IIIa
IIb
IIIa
IIb
Afibrinogenemia

9. Antithrombotic Properties of the Endothelium
Anti-platelet properties
Healthy endothelium does not bind platelets
Produce PGI-2 (prostacyclin) and NO (Nitric Oxide), which inhibit platelet binding
Produce ADP-ase which counters the platelet aggregating effects of ADP

10. Antithrombotic Properties of the Endothelium (cont
Antithrombotic Properties of the Endothelium (cont.) Anticoagulant properties Produce Heparin-like proteoglycans which activate anti-thrombin Produce Thrombomodulin which make a complex with thrombin (TM.T complex ) and activates protein C , Produce tPA which activates fibrinolysis by activating plasminogen to plasmin

11. Prothrombotic Properties of the Endothelium
Synthesis of von Willebrand factor
Release of tissue factor
Production of plasminogen activator inhibitors (PAI)
Membrane phospholipids bind and facilitate activation of clotting factors via Ca++ bridges

12. Procoagulant
Anticoagulant

13. Procoagulant
Anticoagulant

14. Virchow’s Triad Endothelial injury Abnormal blood flow
Pathogenesis of a Thrombus
Endothelial injury
Abnormal blood flow
Hypercoagulability
Genetic
acquired

15. Intrinsic pathway XIIa Extrinsic Pathway XIa TF Prothrombin IXa VIIa
VIII
VIIIa Xa Va V
Soft clot
Thrombin
Fibrinogen
Fibrin
XIIIa
Hard clot
Fibrin

16. Folate and Homocysteine Metabolic Pathways