1. The Fascinating World of Haemostasis and Thrombosis
Susan Louw

2. Haemostasis and Thrombosis

3. Unfortunately Clotting Pathways are IMPORTANT

4. The Role Players
Endothelium
Platelets
Coagulation Factors

5. Steps in Haemostasis Vasoconstriction Platelet Coagulation
activation
adhesion
aggregation
Coagulation
Fibrinolysis

8. The Endothelial Cell: sitting on the fence
Dual role
Anticoagulant
Pro-coagulant

9. Vascular Disorders Inherited Acquired
Hereditary Haemorrhagic Telangiectasia
Connective Tissue disorders
Acquired
Simple benign bruising
Senile purpura
Scurvy
Steroid purpura

10. Blood Dust ? No – They are Platelets!!
Each day produce 1 x 1011 platelets
Production can increased 10- to 20-X
Circulatory half-life = 10 days
Arise from megakaryocyte: each giving rise to to platelets

11. Platelet Granule Content
Dense bodies 
 ADP
653 mM
 ATP
436 mM
 Calcium
2181 mM
 Serotonin
65 mM
 Pyrophosphate
326 mM
 GDP
 Magnesium
-Granule 
 Platelet-specific proteins:
   Platelet factor 4 (PF4)
    -Thromboglobulin ( -TG) family (platelet basic protein, low-affinity platelet factor 4, -thromboglobulin, -thromboglobulin-F)
  Multimerin
  Adhesive glycoproteins
   Fibrinogen
   von Willebrand factor (vWF)
   von Willebrand factor propeptide
   Fibronectin
   Thrombospondin-1
   Vitronectin
 Coagulation factors
   Factor V
   Protein S
   Factor XI
 Mitogenic factors
   Platelet-derived growth factor (PDGF)
   Transforming growth factor- (TGF- )
   Endothelial cell growth factor
   Epidermal growth factor (EGF)
   Insulin-like growth factor 1
 Angiogenic factors
   Vascular endothelial growth factor
   PF4 (inhibitor)
 Fibrinolytic inhibitors 2-Plasmin inhibitor ( 2-PI)  Plasminogen-activator inhibitor-1 (PAI-1)
 Albumin Immunoglobulins
 Angiogenic factors
   Vascular endothelial growth factor
   PF4 (inhibitor)
 Fibrinolytic inhibitors
    2-Plasmin inhibitor ( 2-PI)  Plasminogen-activator inhibitor-1 (PAI-1)
 Albumin
 Immunoglobulins
 Granule membrane-specific proteins
   P-selectin (CD62P)
   CD63 (LAMP-3)
   GMP 33 (thrombospondin fragment)
Other secreted or released proteins6 
 Protease nexin
 Protease nexin I
 Gas6
 Amyloid -protein precursor (protease nexin II)
 Tissue factor pathway inhibitor (TFPI)
 Factor XIII
  1-Protease inhibitor  Cl-inhibitor
 High molecular weight kininogen 2-Macroglobulin   Vascular permeability factor
 Interleukin-1
 Histidine-rich glycoprotein
Chemokines
 MIP-1 (CCL3)
 RANTES (CCL5)

12. Size does NOT matter (we are only 1.5 m in diameter after all)
anucleate cell fragments
adhere to damaged blood vessels
aggregate one with another
and facilitate generation of thrombin

13. Platelet Disorders – Q & Q:
Quantity
Failure of production (Bone Marrow failure)
Increased destruction
ITP
Drug related
Infections
TTP
DIC
Splenomegaly

14. Platelet Disorders – Q & Q:
Quality
Hereditary
Glanzmann’s Thrombasthenia
Bernard-Soulier syndrome
Storage pool disease
Acquired
Anti-platelet drugs
Uraemia
Myeloproliferative and –dysplasic disorders

15. Platelet Disorders
Mucocutaneous bleeding

16. Coagulation factors = Proteins

17. Grouping of Coag Factors
Vit K dependent zymogens
Soluble cofactors
(V & VIII)
Factor XI
Cell-associated factors
Fibrinogen
Factor XIII
Plasma coagulation protease inhibitors

18. Vit K dependent zymogens
Protrombin (Factor II)
Factor VII
Factor IX
Factor X
Protein C

19. Vit K dependent zymogens
Why is Vitamin K called Vitamin K?
What happened to Vitamin F, G, H, I?
Hendrik Dam (1929) - Denmark
Newborn chicks on cholesterol free diet bleed
Corrected by addition of a substance called “Koagulations-Vitamin” to diet

20. Vit K dependent zymogens

21. Coagulation factors achieve result by inducing conformational change in next factor

22. Vit K dependent zymogens
FVIIa & its co-factor: TF = “extrinsic tenase”
FIXa & its co-factor FVIIa: = “intrinsic tenase”
FXa & its co-factor Fva: = “prothrombinase”
Thrombin (FIIa) no co-factor for procoagulant activity but associates with thrombomodulin for its anticoagulant activity = cleaving and activating Protein C

23. Inhibitors
Essential Evil
Life-saving

24. Inhibitors of Coagulation
Tissue Factor Pathway Inhibitor
Antithrombin
Protein Z / Protein Z Dependent Protease Inhibitor

26. Finally - there is fibrinolysis
all blood clots are reorganised and resorbed
main enzyme responsible for this process = plasmin
regulated by various activators and inhibitors

27. Multitude of drugs developed
Physiologist Johannes Müller ( ) described fibrin, the substance of a thrombus
Multitude of drugs developed
To prevent inappropriate thrombus formation
To stop excessive bleeding
To actively lyse clots

28. How important is thrombosis and haemostasis
...”Arterial, cardiac and venous thromboembolism are
major causes of death and disability in developed countries. DVT may also be followed by the post-thrombotic leg syndrome which includes chronic venous ulceration: another major consumer of health service costs”...
...”Deep venous thrombosis (DVT) and its sequela,
pulmonary embolism, are the leading causes of preventable in-hospital mortality”...