More About Blood
Coagulation . . .
Blood
coagulation occurs when the enzyme thrombin is generated and proteolyses
soluble fibrinogen, forming an insoluble fibrin polymer or clot. The
normal role of blood coagulation is to rapidly prevent the loss of
body fluids following vascular injury without compromising blood flow
through either the uninjured or damaged blood vessels. To achieve
this a complex network of reactions have evolved that result in controlled
fibrin deposition only at the site of injury.
Blood coagulation is initiated by the exposure of factor VII (a protein
found in blood) to cells expressing tissue factor (TF) on their plasma
membrane. The primary control of haemostasis is therefore the anatomical
segregation of cells that express functional TF from other components
of the coagulation network present in blood. TF is constitutively
expressed by cells that form biological boundaries such as skin, organ
surfaces and vascular adventitia. This expression pattern has been
described as forming a 'haemostatic envelope', which ensures that
following disruption of vascular integrity FVII/FVIIa in blood is
rapidly exposed to cells that express TF, leading to the initiation
of blood coagulation. The formation of the TF-FVII complex results
in the activation of FIX and FX. In the absence of its cofactor, FVa,
FXa generates only trace amounts of thrombin. Although insufficient
to generate significant fibrin polymerisation, the thrombin generated
in this initiation phase of coagulation is able to activate FV and
FVIII in a positive feedback loop. In the propagation phase FVIIIa
forms a complex with FIXa (tenase complex) and activates further FX
which in complex with its cofactor FVa (prothrombinase complex) leads
to an explosive generation of thrombin that ultimately leads to a
fibrin clot. Thrombin also activates FXI leading to further FIXa generation
independent of the TF-FVIIa complex.
Following the initiation of coagulation, various inhibitory mechanisms
prevent extension of the process beyond the site of vascular injury
which might otherwise result in occlusion of the blood vessel. TFPI
associated with the endothelial cell surface inactivates the initiation
complex by forming a quaternary inhibited complex (TFPI-TF-FVIIa-FXa).
Thrombin generated at the endothelial surface binds the cellular receptor
thrombomodulin and activates protein C. The activation of protein
C is promoted by endothelial protein C receptor (EPCR) which provides
a direct binding site for protein C on endothelial cells and increases
the affinity of the thrombin-thrombomodulin complex for protein C.
Activated protein C in complex with its cofactor protein S, rapidly
inactivates the procoagulant cofactors FVa and FVIIIa by limited proteolysis
forming a negative feedback loop. The activated coagulation proteases
are inhibited by antithrombin, the rate of which is substantially
increased by binding glycosaminoglycans on the surface of endothelial
cells. |
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