Makindo Medical Notes

1. Endothelial Injury

In situ thrombosis often begins with damage to the endothelial lining of the blood vessel, which can result from various triggers such as atherosclerosis, trauma, or inflammation.

• Common Causes:
  • Atherosclerotic plaque rupture
  • Mechanical injury (trauma or surgical intervention)
  • Inflammation of the vessel wall (e.g., vasculitis)
• Consequence: Exposure of subendothelial structures like collagen, von Willebrand factor (vWF), and tissue factor (TF) to circulating blood.

Platelet Adhesion

• After endothelial injury: platelets rapidly adhere to the exposed subendothelial collagen and von Willebrand factor at the injury site.
• Platelet Activation: Once adhered, platelets are activated and undergo shape change, releasing various granules containing ADP, thromboxane A₂, and serotonin, which further recruit and activate more platelets.

Platelet Aggregation

• The release of ADP and thromboxane A₂ promotes platelet aggregation.
• Fibrinogen links activated platelets together by binding to their GPIIb/IIIa receptors, forming a temporary platelet plug.
• Thromboxane A₂: A potent vasoconstrictor and promoter of platelet aggregation.
• Fibrinogen: Acts as a bridge between activated platelets to form the initial plug.

Coagulation Cascade Activation

• Tissue Factor:Simultaneously, tissue factor (TF) is exposed due to endothelial injury. This activates the coagulation cascade, a series of proteolytic reactions that ultimately lead to the formation of fibrin, a protein that stabilizes the platelet plug.
• Intrinsic and Extrinsic Pathways: The coagulation cascade has two pathways (intrinsic and extrinsic), both of which converge at the common pathway, leading to thrombin activation.
• Thrombin: A central enzyme that converts fibrinogen to fibrin, stabilizing the growing thrombus.

Formation of Stable Thrombus

• Thrombin converts fibrinogen into fibrin strands, which weave through the platelet plug to form a stable thrombus.
• This meshwork of fibrin and platelets forms the final clot, effectively sealing the site of injury.
• Stable Clot Formation: Fibrin strengthens the platelet plug, turning it into a stable clot that remains attached to the site of endothelial damage.

Regulation and Dissolution (Fibrinolysis)

• The formation of a thrombus is tightly regulated to prevent excessive clotting.
• Once the vessel wall begins to heal, fibrinolysis is activated to dissolve the clot and restore normal blood flow.
• Tissue Plasminogen Activator (tPA): Activates plasminogen to plasmin, which breaks down fibrin and dissolves the clot.
• Plasmin: The enzyme responsible for degrading fibrin, leading to clot breakdown and removal.
• Note: Imbalance between pro-thrombotic and anti-thrombotic mechanisms can lead to pathological thrombosis, such as arterial thrombosis, which can result in ischaemia or infarction.