Haemostatic Regulation

Describe the mechanisms of preventing thrombosis including endothelial factors and natural anticoagulants

Haemostasis must be controlled to prevent rampant clotting of the vascular tree. This involves both endothelial factors and proteins.

Endothelial Regulation

Intact endothelium and the glycocalyx prevent clotting in a number of ways:

• Minimise stasis
  • High blood flow
    Especially where flow is turbulent (large arteries).
  • Maximise laminar flow
    Glycocalyx smooths flow.

• Inhibition of platelet adhesion and activation
  NO, prostacyclin, and ectonucleotidases (which degrade ADP) inhibit platelet activation.

• Membrane-bound anticoagulant proteins
  • Heparan (not heparin)
    Activates antithrombin III.
  • Thrombomodulin
    Binds thrombin, preventing cleavage of fibrinogen to fibrin. The thrombin-thrombomodulin complex activates protein C (which in turn inactivates factors Va and VIIIa).

• Prevent exposure of procoagulant protein
  • Collagen
  • vWF
  • Tissue Factor

• tPA secretion (see 'Clot Lysis')

Clot Regulation

• Effect of blood flow
  • Dilutes clotting factors
    Activated clotting factors are washed away and metabolised by the RES.
  • Laminar flow
    Causes axial streaming of platelets, minimising endothelial contact and chance of activation.fa
• Activation of anticoagulant factors
  • Tissue Factor Pathway Inhibitor
    Inhibits VIIa, antagonising the action of tissue factor
  • Antithrombin III
    Inhibits the serine proteases, i.e. the non-cofactor factors in all three pathways - IIa, VIIa, IXa, Xa, XIa, XIIa.
  • Protein C
    Inactivates protein Va and VIIIa, and is activated by thrombin.
  • Protein S
    Cofactor which helps protein C.

Clot Lysis

Clot breakdown is performed by:

• Tissue Plasminogen Activator (tPA)
  Binds to fibrin, and then cleaves plasminogen to plasmin. This keeps the plasmin formation in the vicinity of the clot, limiting its systemic spread of.

• Plasmin cleaves fibrin into fibrin degradation products
  FDPs conveniently inhibit further thrombin and fibrin formation.

References

1. Krafts K. Clot or Bleed: A Painless Guide for People Who Hate Coag. Pathology Student.
2. Van Hinsbergh VWM. Endothelium—role in regulation of coagulation and inflammation. Seminars in Immunopathology. 2012;34(1):93-106.