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

Thrombosis Haemorrhage

• • • 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

• • • •

Alterations in blood flow e.g.:

Prolonged immobility Venous stasis Mitral stenosis Varicose veins

STASIS

Thrombosis Endothelial Injury

Injury or trauma to the vascular wall e.g.:

• Shear stress • Hypertension Hypercoagulability *Also known as Virchow’s triad •

Alterations to the constitution of blood, caused by:

Hyperviscosity, antithrombin III deficiency, trauma e.g. burns, age, smoking, obesity.

Haemostasis

• • Circulate in the blood in a resting state Activated by a variety of agonists

Platelets

Haemostasis • Clotting Factors Present in the plasma as zymogens • Rapidly activated after contact with tissue factor Tissue Factor • • Present in the sub-endothelium Required for the activation of clotting factors

Platelets

Key cell types

Vascular Endothelium

• • • • • Anuclear 1-3µm 1.5-4.5 x 10 8 /mL Circulate for 8-10 days Bud from megakaryocytes in the bone marrow • • • • • Nucleated 1-3µm ~5 x 10 13 cells Total surface area of ~7m 2 Line all of the circulatory system from capillaries to the heart.

Thrombus formation

• Video of thrombus formation can be found https://www.youtube.com/watch?v=E3y2kXGI1LY 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

• • • Coagulation Clot Stability Aggregation

Thrombosis

Summary

• • • Anticoagulation Fibrinolysis Maintaining the liquid state of blood

Haemorrhage