The Fascinating World of Haemostasis and Thrombosis Susan Louw

Haemostasis and Thrombosis

Unfortunately Clotting Pathways are IMPORTANT

The Role Players Endothelium Platelets Coagulation Factors

Steps in Haemostasis Vasoconstriction Platelet Coagulation activation adhesion aggregation Coagulation Fibrinolysis

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

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

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 1 000 to 3 000 platelets

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)

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

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

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

Platelet Disorders Mucocutaneous bleeding

Coagulation factors = Proteins

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

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

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

Vit K dependent zymogens

Coagulation factors achieve result by inducing conformational change in next factor

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

Inhibitors Essential Evil Life-saving

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

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

Multitude of drugs developed 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

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”...