The haemostatic system maintains blood in a fluid state under normal conditions and
responds to vessel injury by the rapid formation of a clot consisting of platelets and
Fibrin. The traditional view of the regulation of blood coagulation is that the
initiation phase is triggered by an extrinsic pathway, and the amplification phase
requires an intrinsic pathway. The extrinsic pathway begins with disruption of the
endothelium, which exposes Coagulation factor III (Tissue factor), expressed in
adventitial cells, to the plasma allowing it to bind circulating Coagulation factor VII
[1]. This cell-surface complex of Tissue factor and activated
Coagulation factor VII can be thought of as an enzyme with
two-subunitswhere Coagulation factor VII acts as the
catalytic subunit and Tissue factor as the regulatory subunit. The Tissue factor/Coagulation factor VII complex activates two serine
protease zymogens Coagulation factor X and
Coagulation factor IX by limited proteolysis [2]. The newly generated active Coagulation factor X
activates Coagulation factor V, leading to the formation of
a prothrombinase complex [3]. Finally, Prothrombinase converts prothrombin
to Thrombin, which feedbacks to amplify the system by
activating not only Coagulation factor V, but also
Coagulation factor VIII [4].
Coagulation factor VIII circulates while bound to
von Willebrand factor, which is an adhesive protein
important for the generation of the initial platelet plug. After activation,
Coagulation factor VIII dissociates from von
Willebrand factor and forms a so-called 'tenase complex' with
Coagulation factor IX [5]. The tenase complex
converts Coagulation factor X into active
Coagulation factor X and is regarded as a part of the
intrinsic coagulation pathway.
Thrombin is also responsible for the conversion of
Fibrinogen to a fibrin network [6]. Fibrin clots are resorbed during fibrinolysis,
mainly by Plasmin.
Both blood coagulation and fibrinolysis are under fine control of various regulators.
In particular,
the class of the inhibitors of serine proteases the serpin superfamily (e.g. Serpin
peptidase inhibitor, clade F member 2 (SERPINF2)) play the
major role in regulating procoagulant and fibrinolytic enzymes. The Serpin peptidase
inhibitor, clade C (antithrombin), member 1 (Antithrombin
III) binds and inhibits the principal procoagulant enzymes
Thrombin and Coagulation factor
X [7], [8]. Serpin
peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), specifically member 1
(Alpha 1-antitrypsin) together with Alpha-2-macroglobulin
(A2M) bind and suppress Thrombin
and Plasmin [9], [10].
The Protein C system is activated on the surface of
intact endothelial cells by Thrombin bound to
Thrombomodulin. Protein S
supports the anticoagulant activity of Protein C. Activated
Protein C cleaves phospholipid-membrane bound
Coagulation factor V and Coagulation factor
VIII [4], [11].
Tissue factor pathway inhibitor (TFPI) is the only
physiological inhibitor of the F3/Coagulation
factor VII complex. TFPI binds to the
Coagulation factor VII active site and to
Coagulation factor X, forming a totally inactive complex
[12], [13].