Describe the process and regulation of haemostasis, coagulation
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
Platlets 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
Following a vascular injury, the exposure of subendothelial proteins stimulates platelets to form an occlusive plug via several processes:
Exposed collagen binds to GPIa receptor on platelets.
vWF also binds to platelets.
Metabolic activation, increasing phospholipase A2 and phopholipase C, increasing platelet intracellular Ca2+ and initiating a transformation from a disc to a sphere with long projections.
With other platelets - held together by fibrin - forming a plug.
After some time platelets contract, retracting the clot and sealing the wall.
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 precusor factor
- Cofactors amplify the cascade
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.
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
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 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:
Main activator of the intrinsic pathway in vivo.
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 crossbridges between fibrin in a platelet plug.
- Amplification of the clotting cascade by activating factors V and VIII
- Activates protein C
Thrombin binds with thombomodulin 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.
- Initiation phase