Haemostasis

Describe the process and regulation of haemostasis, coagulation and fibrinolysis

Haemostasis describes the physiological processes that occur to stop bleeding. It involves three processes:

• Vessel constriction
  Decreases flow, which limits further haemorrhage and reduces the shear stresses which break up forming clot
• Platelet plug formation or Primary Haemostasis
  Platelets adhere to the damaged vessel wall and aggregate
• Fibrin formation or Secondary Haemostasis
  Fibrin is formed from fibrinogen (via the coagulation cascade), which stabilises the platelet plug

Primary Haemostasis

Following a vascular injury, the exposure of subendothelial proteins stimulates platelets to form an occlusive plug via several processes:

• Adhesion
  Exposed collagen binds to GPIa receptor on platelets.
  vWF also binds to platelets.

• Activation
  Metabolic activation, increasing Phospholipase A₂ and Phospholipase C, increasing platelet intracellular Ca²⁺ and initiating a transformation from a disc to a sphere with long projections.
  • Metabolic activation is stimulated by:
    • Collagen
    • Adrenaline
    • ADP
    • Thrombin
  • Additionally, platelets release ADP and thromboxane A₂ from their alpha granules and dense bodies, amplifying further platelet aggregation and adhesion

• Aggregation
  With other platelets - held together by fibrin - forming a plug.

• Contraction
  After some time platelets contract, retracting the clot and sealing the wall.

Secondary Haemostasis

The coagulation cascade is an amplification mechanism which activates clotting factors in order to produce fibrin.

Participating factors in the coagulation cascade can be either enzymes or cofactors:

• Enzymes circulate in their inactive form, and become active (e.g. VII ⇒ VIIa) when hydrolysed by their precursor factor
• Cofactors amplify the cascade

Pathways

The cascade is divided into the intrinsic pathway and extrinsic pathway, which join to form the common pathway. In vitro, the intrinsic and extrinsic pathways operate separately. This is an artifact of lab measurement - in vivo the pathways are co-dependent.

Extrinsic Pathway

The extrinsic pathway contains two factors, and the process of activation occurs in seconds:

• Tissue Factor
  Membrane protein on sub-endothelial cells, which is exposed when the vessel is damaged (it is found in a few other places as well). It binds to factor VII to form VIIa, and thus activates the extrinsic pathway.
• Factor VII

Intrinsic Pathway

The intrinsic pathway is activated over minutes, and contains:

• Contact factors
  Only important in vitro when conducting lab testing - deficiency of these factors does not cause a coagulopathy.
  • HMWK
    HMWK activates factor XII.
  • Factor XII
    Factor XIIa activates factor IX, as does thrombin.
• Factor XI
• Factor IX
• Factor VIII
  Factor VIII circulates in a complex with vWF, preventing it from degradation. When activated by thrombin, it acts as a cofactor for factor IXa to activate factor X.

The intrinsic pathway is activated by:

• Thrombin
  Main activator of the intrinsic pathway in vivo.
• Collagen
• Glass
  In vitro.

Common Pathway

The common pathway contains:

• Factor X
• Factor V
  Cofactor (similar to factor VIII), which when activated by thrombin allows factor Xa to convert prothrombin into thrombin.
• Factor II (prothrombin)
  Has several key roles:
  • Cleaves fibrinogen to fibrin
  • Activates factor XIII
    Factor XIIIa stabilises clot by forming cross-bridges between fibrin in a platelet plug.
  • Amplification of the clotting cascade by activating factors V and VIII
  • Activates protein C
    Thrombin binds with thrombomodulin to form a complex which inhibits coagulation.
• Factor I (fibrinogen)

The Cell-Based Model of Coagulation

• The cascade model (above) accurately describes the process of clotting in vitro, but not in vivo
• The cell-based model has several changes, noting the central role of the platelet:
  • Initiation phase
    Coagulation begins with tissue factor being exposed, which also activates platelets.
  • Amplification phase
    A positive feedback loop occurs:
    • Production of Xa causes production of thrombin (IIa), priming the system
    • Thrombin then activates factors V, VIII, and IX, accelerating Xa production and further thrombin generation
  • Propagation phase
    Platelets bind activated clotting factors, causing high rates of thrombin formation around them.

References

1. Krafts K. Clot or Bleed: A Painless Guide for People Who Hate Coag. Pathology Student.
2. Chambers D, Huang C, Matthews G. Basic Physiology for Anaesthetists. Cambridge University Press. 2015.
3. Clotting Cascade 22/4/2007. (Image). By Joe D (Own work). CC BY 3.0 , via Wikimedia Commons.