Thrombosis and Haemostasis Café Cardiologique 29/10/2014

Thrombosis and Haemostasis Thrombosis: The formation of a blood clot within a vessel that obstructs the flow in the circulatory system Haemostasis: A process which causes bleeding to stop with the intention of keeping blood within a damaged vessel

A balancing act Constant balance to maintain the blood in its normal state Various overlapping factors play a role A variety of cell types within the circulation play a multitude of roles in the outlined processes Thrombosis Haemorrhage

Thrombosis Alterations in blood flow e.g.: Prolonged immobility Venous stasis Mitral stenosis Varicose veins STASIS Endothelial Injury Hypercoagulability Injury or trauma to the vascular wall e.g.: Shear stress Hypertension Alterations to the constitution of blood, caused by: Hyperviscosity, antithrombin III deficiency, trauma e.g. burns, age, smoking, obesity. *Also known as Virchow’s triad

Haemostasis Circulate in the blood in a resting state Activated by a variety of agonists Platelets Present in the plasma as zymogens Rapidly activated after contact with tissue factor Tissue Factor Clotting Factors Present in the sub-endothelium Required for the activation of clotting factors

Key cell types Platelets Vascular Endothelium Anuclear 1-3µm x 10 8 /mL Circulate for 8-10 days Bud from megakaryocytes in the bone marrow Nucleated 1-3µm ~5 x cells Total surface area of ~7m 2 Line all of the circulatory system from capillaries to the heart.

Video of thrombus formation can be found Thrombus formation Laser injury thrombus formation vide – Dr. Christophe Dubois

Thrombus structure Aggregated platelets form a platelet plug at site of injury. Activated platelets bind fibrin through their fibrinogen receptor Other circulating cells get caught up in the thrombus Platelets Erythrocyte Fibrin Electron micrograph image – Prof. John Weisel

Coagulation cascade Initiated by exposure of blood to abnormal surface The clotting factor complexes associate on cell surfaces The cascade significantly amplifies a small initiating stimulus Generation of thrombin is the focal event

Thrombus formation Thrombus formation figure – Prof. Alison Goodall

Inhibition and Fibrinolysis Circulating factors: Antithrombin degrades the serine proteases FIXa, FXa, FXIa and FIIa (Thrombin) Tissue Factor Pathway Inhibitor (TFPI) limits the action of Tissue Factor Protein C is activated via Thrombin and works with Protein S to degrade FVa and FVIIIa Plasmin is activated by FXIa, XIIa and tPA, acts to dissolve Fibrin (fibrinolysis) Endothelial bound/released: Nitric Oxide and Prostacyclin act to inhibit platelet activation Heparan Sulphate binds to antithrombin causing a conformational change allowing it to target FIXa, FXa, FXIa and FIIa Thrombomodulin expressed on the endothelial surface and acts as a cofactor in the activation of Protein C TFPI is also present in the Endothelium

Summary Thrombosis Haemorrhage Coagulation Clot Stability Aggregation Anticoagulation Fibrinolysis Maintaining the liquid state of blood