Blood clotting

• Stages of blood clotting

  1. Formation of the unstable clot (primary haemostasis)

  2. Formation of the fibrin clot (secondary haemostasis)

  3. Clot degradation (fibrinolysis)
• Haemostasis


  The balance between blood clotting and clot dissolution
• Factors which precipitate clotting are described by Virchow’s triad: Clotting = thrombosis, Clot = thrombus
• Formation of the unstable clot

  Platelets play a key role in the formation of the soft or unstable clot. They adhere to collagen, undergo activation, change shape, aggregate, adhere, and degranulate
• Formation of the fibrin clot


  The initial platelet plug is stabilised by the formation of a mesh of fibrin. Fibrin is produced from fibrinogen. Fibrin cross-linking helps to stabilise and solidify the clot
• Factor XIIIa


  A transglutaminase that catalyses the formation of covalent cross-links between fibrin molecules
• Activation of Thrombin


  Factor X is activated to Xa, leading to the activation of prothrombin to thrombin. Thrombin activity must be tightly regulated
• Source: 'Image taken from eClinPath: https://eclinpath.com/hemostasis/physiology/coagulation-cascade-new-model/'
• Key factors in the clotting cascade

  • Proteases: XII, XI, X, IX, VII, thrombin
  • Accessory factors: VIII, V
  • PS = phosphatidylserine, a negatively charged membrane lipid found on the surface of activated platelets
  • TF = tissue factor
• Some clotting factors (factors II, VII, IX, and X) are modified by gamma-carboxylation when they are synth
• Eases of thrombin


  • XII
  • XI
  • X
  • IX
  • VII
• Accessory factors


  • VIII
  • V
• PS


  Phosphatidylserine, a negatively charged membrane lipid found on the surface of activated platelets
• TF


  Tissue factor
• Importance of coagulation complexes


  • Some clotting factors (factors II, VII, IX and X) are modified by gamma-carboxylation when they are synthesized in the liver. This reaction requires vitamin K
• Gamma-carboxylation


  CO2 and O2 react with glutamate in the presence of Ca2+ and Vitamin K to form g-carboxyglutamate (g-GLA)
• 1. GLA-modified clotting factors binding calcium

  2. GLA-modified clotting factors bind calcium found bound to platelet membranes, forming coagulation complexes
• 1. GLA-modified clotting factors binding calcium


  Makes clotting much more efficient than if they were free in the circulation
• Limiting clot formation


  1. Antithrombin inactivates thrombin and factors VIIa, IXa, Xa, XIa, XIIa

  2. ii. α1-antitrypsin and α2-macroglobulin act as protease inhibitors

  3. iii. Protein C degrades factors V and VIII (protein C is activated by thrombin)
• Clot breakdown (fibrinolysis)


  Plasminogen activators, e.g., tissue plasminogen activator (tPA), urokinase, convert plasminogen to plasmin which degrades fibrin. Plasmin inhibitors like α2 antiplasmin inhibit this process
• Vitamin K antagonists (e.g., warfarin, dicoumarol) inhibit the gamma carboxylation of clotting factors and decrease the efficiency of clotting. Their effects are only apparent over the long term as only newly synthesized clotting factors are affected
• Heparin is a negatively charged polysaccharide that enhances antithrombin activity
• Aspirin prevents platelet aggregation by inhibiting an enzyme, cyclooxygenase, involved in platelet adhesion. It can be toxic to cats
• Clotting disorders causing increased clotting time

  • Hageman deficiency (Factor XII deficiency)
  • Haemophilia A (Factor VIII deficiency)
  • Haemophilia B (Factor IX deficiency)
  • Von Willebrand’s disease (decreased platelet aggregation due to lack of von Willebrand’s factor)
  • Thrombocytopenia (decreased platelet count)
  • Vitamin K deficiency (decreased carboxylation of clotting factors)
  • Severe liver disease (decreased clotting factor production)
  • Rodenticide poisoning (warfarin ingestion)
• Conditions may present as nasal, oral, or anal bleeding