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, whereas amplification 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
. The cell-surface complex of Tissue factor
and activated Coagulation factor VII can be thought of as a
two-subunit enzyme, with Coagulation factor VII 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 . Generated active
Coagulation factor X activates Coagulation
factor V, leading to formation of a prothrombinase complex . Prothrombinase converts prothrombin to Thrombin.
Thrombin feedback amplifies the system by activating not
only Coagulation factor V, but also
Coagulation factor VIII and Coagulation factor
XI . 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 . Tenase complex
converts Coagulation factor X into active
Coagulation factor X and is regarded as a part of the
intrinsic coagulation pathway.
The intrinsic pathway begins with contact activation of Coagulation
factor XII. Coagulation factor XII cleaves
prekallikrein, and the generated Plasma kallikrein catalyses
Bradykinin formation and activates Coagulation
factor XI . The primary function of
Coagulation factor XI is to activate
Coagulation factor IX. Therefore the intrinsic and extrinsic
pathways converge at the level of Coagulation factor X
. Thrombin generated during propagation of
both cascades converts Fibrinogen to a fibrin network.
Thrombin also activates Coagulation factor
XIII, which is a transglutaminase that stabilizes the clot by covalent
cross-linking of fibrin .
Fibrin clots are resorbed during fibrinolysis.
Plasmin, generated from
Pasminogen, is the major fibrinolytic protease.
Plasminogen conversion to Plasmin could be triggered by both
Tissue plasminogen activator (PLAT(TPA)) and by Plasminogen
activator, urokinase (PLAU(UPA)). Under certain conditions,
Coagulation factor XII and Plasma
kallikrein could stimulate Plasmin generation
as well .
Both blood coagulation and fibrinolysis are under fine control of various regulators.
The major class of serine protease inhibitors regulating procoagulant and fibrinolytic
enzymes is the serpin superfamily. Principal enzymes of the serpin family regulating
coagulation/fybrinolytic pathways are Serpin peptidase inhibitor clade C memeber1
(Anthitrombin III), Serpin peptidase inhibitor, clade D
member 1(HCII), Serpin peptidase inhibitor, clade E member 1
(PAI1), Serpin peptidase inhibitor, clade B member 2
(PAI2), Serpin peptidase inhibitor, clade A member 5
(Protein C inhibitor), Serpin peptidase inhibitor, clade E
member 2 (SERPINE2), Serpin peptidase inhibitor, clade F
member 2 (SERPINF2), Serpin peptidase inhibitor, clade A
member 1 (SERPINA1). Antithrombin III binds and inhibits the
principal procoagulant enzymes Thrombin and
Coagulation factor X; HCII
inhibits Thrombin enzymatic activity .
SERPINE2 may function as a non-circulating cell surface
inhibitor of Thrombin, Coagulation factor
X, PLAU(UPA) or
Plasmin, resulting in protease-inhibitor complexes .
PAI1 is the most important and most rapidly acting
physiological inhibitor of both PLAU(UPA) and
PLAT(TPA) . Of special interest is
Protein C inhibitor, which inhibits activity of
Thrombin (Thrombomodulin enhances this effect),
Coagulation factor XI, Plasma
PLAT(TPA) and Protein C . 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 , .
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
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