The Fascinating World of Haemostasis and Thrombosis

1. The Fascinating World of Haemostasis and Thrombosis Susan Louw

2. Haemostasis and Thrombosis

3. Unfortunately Clotting Pathways are IMPORTANT

4. Endothelium Platelets Coagulation Factors The Role Players

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

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

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

10. Blood Dust ? No – They are Platelets!! • Each day produce1 x 1011 platelets • Production can increased 10- to 20-X • Circulatory half-life = 10 days • Arise from megakaryocyte: each giving rise to 1000 to 3000 platelets

11. 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 inhibitors2-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  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 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) Platelet Granule Content

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

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. Physiologist Johannes Müller (1801-1858) 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”...