Lecture 5.2 - Haemostasis

Haemostasis

• Haemostasis is the process of stopping blood loss after injury
• It consists of two parts: primary haemostasis (platelet plug formation) and secondary haemostasis (fibrin clot formation)

Primary Haemostasis

• Platelets are derived from megakaryocytes and have a discoid shape with no nucleus
• Platelets contain glycoproteins that interact with specific ligands
• Primary haemostasis involves the interaction of platelets, subendothelium, and fibrinogen
• Platelet granules are present in three types: alpha, dense, and lysosomal granules

Platelet Adhesion

• Endothelial injury exposes subendothelial matrix proteins to circulating blood
• Vasoconstriction occurs first, reducing blood loss, with nitric oxide helping in the process
• Von Willebrand factor (vWF) is released by endothelial cells and is important for platelet adhesion
• Initial platelet adhesion involves the interaction of vWF and the GP1b receptor on the platelet surface

Platelet Activation and Shape Change

• Binding of platelets to vWF triggers their activation, causing:
  • Thromboxane generation (vasoconstrictor)
  • Granule release (containing ADP, PAF, and fibrinogen)
  • Activation of GPIIb/IIIa receptor (allowing platelets to bind to fibrinogen)
  • Platelet shape change (swelling, forming extensions, and spreading across the subendothelium)

Platelet Aggregation

• Nearby platelets are recruited and become activated
• Following activation of GPIIb/IIIa, platelets begin cross-linking
• Nearby platelets bind to each other via the GP IIb/IIIa receptor, mediated by fibrinogen, and form a plug

Secondary Haemostasis

• Secondary haemostasis forms a stable mesh network and a permanent thrombus
• It involves a series of reactions involving coagulation factors (enzymes made by the liver) to produce thrombin
• Thrombin cleaves fibrinogen and forms fibrin

Coagulation Cascade

• The coagulation cascade has three pathways: extrinsic, intrinsic, and common
• The extrinsic pathway is activated by tissue factor (TF) released by endothelial cells after external damage
• The intrinsic pathway begins when factor XII becomes activated after exposure to subendothelial collagen
• The common pathway results in the formation of thrombin, which cleaves fibrinogen to form fibrin

Fibrin Clot and Fibrinolysis

• Fibrinolysis is the process of breaking down a fibrin clot
• The central protein involved in fibrinolysis is plasminogen, which is converted to its active form, plasmin
• Plasmin works by converting insoluble fibrin into soluble degradation products
• Fibrinolysis is an important process to prevent excessive clotting

Bleeding Disorders

• Bleeding disorders involve a deficiency in clotting factors or proteins important in the coagulation cascade
• Examples of bleeding disorders include:
  • Von Willebrand disease (deficiency in vWF)
  • Haemophilia (deficiency in factor 8, 9, or 11)
  • Thrombocytopenia (low platelet count)

Thrombophilia

• Thrombophilia is a predisposition to thrombosis due to inherited or acquired defects of haemostasis
• Examples of thrombophilias include:
  • Factor V Leiden
  • Antithrombin deficiency
  • Protein C or protein S deficiency
  • Antiphospholipid syndrome

Laboratory Testing

• Laboratory tests used to diagnose bleeding disorders include:
  • Prothrombin time (PT)
  • Activated partial thromboplastin time (APTT)
  • Platelet count
  • Bleeding time
  • D-dimer (detects thrombus formation)