Haemostasis between pro-coagulant pathway, and the mechanisms that

 

Haemostasis
is a physiological process of blood clotting and dissolution of the clot,
following by repair of the injured tissue. It results from interplay of
vascular endothelium, platelets, coagulation factors, anti coagulation
mechanisms and fibrinolytic system. The fluidity of blood in the absence of
injury is maintained by the balance between pro-coagulant pathway, and the
mechanisms that inhibit the pro-coagulant pathway. Imbalance between the two
mechanisms, for example during clinical illnesses or preoperative period,
predisposes a patient to either bleeding or thrombosis. To stop bleeding after injury a complex process is initiated within
seconds. After vasoconstriction, which reduces blood flow, begins the first
phase of haemostasis –primary haemostasis. The primary haemostasis leads to the
formation of initial platelet plug. Activated platelets adhere to the site of
injured tissue and to each other, plugging the injury. However, this initial
platelet plug is unstable and will be stabilized during coagulation-process, in
the phase of secondary haemostasis. Platelets derived from megakaryocytes are the main player in the primary
haemostasis. In health they do not adhere to surfaces of vessels or to each
other, but after injury platelets are exposed to subendothelial matrix that
leads to activation and adhesion of platelets into haemostatic plug. Platelets
play a central role in haemostasis providing proper flow of sequential events
after injuries: platelet adhesion, activation, aggregation, and expression of
procoagulant activity. Thus, they are involved in cell-based thrombin
generation, which amplifies the blood coagulation cascade, by supplying a
procoagulant surface provided by the phospholipids of the platelet plasma membrane
on which the coagulation enzyme complexes can be assembled. Different
transmembrane receptors are embedded in the platelet membrane, which act in
cell signalling providing activation and adhesion of thrombocytes: integrins
(?IIb?3, ?2?1, ?5?1, ?6?1, ?V?3), leucine-rich repeated (LRR) receptors
(Glycoprotein GP Ib/IX/V, Toll-like receptors), G-protein coupled seven
transmembrane receptors (PAR-1 and PAR-4 thrombin receptors, P2Y1 and P2Y12ADP
receptors, TP? and TP? TxA2 receptors), proteins belonging to the
immunoglobulin super family (GP VI, Fc?RIIA), C-type lectin receptors
(P-selectin), tyrosine kinase receptors (thrombopoietin receptor, Gas-6,
ephrins and Eph kinases) and a lot of other types (e.g. CD63, CD36, P-selectin
ligand 1, TNF receptor) (Figure 2) (Rivera J et al, 2009). It has been also
known that some of receptors are involved in other platelet functions such as
inflammation, tumor growth and metastasis, or immunological response. Upon
endothelial injury plasma protein called von Willebrand factor (VWF) binds to
the exposed collagen. Platelets move to the site of injury and become activated
through the binding to the VWF via glycoprotein (GPIb) and to the collagen via
GPVI and ?2?1receptors. After activation, the GPIIb:IIIa (?IIb?3)-receptor
changes conformation and binds fibrinogen or VWF, initiating platelet
aggregation. To support the aggregation and to recruit unactivated circulating
platelets , thrombocytes release proteins imported for their proper haemostatic
function such as VWF, fibrinogen, P-selectin, PECAM-1, CD40 ligand (CD154),
platelet factor-4, ?-thromboglobulin, thrombospondin, platelet derived growth
factor (PDGF), FV, as well as ADP, thromboxane A2 (TXA2), serotonin, histamine,
pyrophosphate, and calcium .

Bleeding is
the common cause of platelet disorders. They can be caused by a reduction in
the number of platelets or thrombocytopenia (e.g. Wiskott-Aldrich syndrome,
Fechtner syndrome, May-Hegglin anomaly) as well as by platelet function defects
or thrombocytopathies (e.g. Glanzmann’s thrombasthenia, vonWillebrand’s
disease-platelet type, Bernard-Soulier syndrome. Further, the initial platelet
plug must be stabilized via fibrin – clot formation- through secondary
haemostasis. In 1964 Davie, Ratnoff, and Macfarlane published separately
articles in Nature and Science outlining the basic principle of a “waterfall”
and a “cascade” of proenzymes activated through proteolytic cleavage that in
turn activate downstream enzymes. The waterfall-cascade hypothesis was later
modified as the function of the clotting factors, which were better
investigated and defined. Secondary haemostasis is the cascade of coagulation
serine proteases that results in cleavage of fibrinogen by thrombin to fibrin
(Figure 3). It leads to stabilization of the instable primary platelet plug at
the site of an injury and formation of a blood clot. Remarkable, that the
process of fibrin generation occurs coincident to the process of platelet
aggregation.Two different models of coagulation cascade have been accepted: the
traditional classification into extrinsic and intrinsic pathway, both of which
converge on factor X activation, and the modern model of coagulation pathway.
The modern model describes coagulation pathway with following phases:
initiation, amplification and propagation. Tissue factor (TF) is a
transmembrane glycoprotein and the cofactor for the serine protease factor
VIIa. Its contact with blood leads to binding and activation of FVII in the
presence of calcium. This TF-VIIa-Ca2+-complex considered as the initiator of
coagulation cascade activates factors IX and X. The coagulation factor Xa
converts prothrombin (factor II) to thrombin. This small amount of thrombin
(trace level) is sufficient and crucial for activation of factor XI, which then
activates factor IX, and factors V and VIII. Upon activation, factors FXI, FV
and FVIII promote the amplification of the coagulation pathway. In the
propagation phase of coagulation cascade, conversion of prothrombin to thrombin
by prothrombinase complex (FVa-FXa-Ca2+) takes place. Then thrombin cleaves
soluble fibrinogen into fibrin monomers, which are insoluble. The fibrin
monomers polymerize producing a stable clot. Factor XIIIa (plasma
transglutaminase) activated by thrombin cross-links glutamine and lysine residues
between fibrin molecules completing the process of secondary haemostasis. Not
only coagulation but also mechanisms which inhibit pro-coagulant pathway play a
significant role in providing haemostasis. Anticoagulant mechanisms have a
regulatory and control function in maintaining haemostasis. Thus, these
mechanisms promote blood fluidity in the absence of injury, localize the
formation of clot at the site of injury, as well as perform degradation of
blood clot after injury. The balance between procoagulant system and
anticoagulant system is critical for proper haemostasis and the avoidance of
pathological bleeding or thrombosis. The main action of anticoagulant
mechanisms is to reduce production and activity of thrombin. Antithrombin (AT),
also known as AT III is an inhibitor of the coagulation serine proteases such
as thrombin, factor IXa, Xa, XIa and XIIa. Heparin enhances the enzymatic
activity of antithrombin. Furthermore, heparin cofactor II, ?2 macroglobulin
and ?1-antitrypsin are also inhibitors of thrombin. Another physiological
anticoagulant mechanism is represented by the protein C pathway. Protein C is a
vitamin K-dependent serine protease which is activated by thrombin and
regulates activity of coagulation factors Va and VIIIa. Once activated by
thrombin, it forms activated protein C (APC) and inhibits activated factors V
and VIII. Protein S and phospholipids act in this pathway as cofactors. Protein
Z-dependent protease inhibitor (ZPI) is a serine protease inhibitor, which
inactivates FXa in the presence of protein Z (PZ) (vitamin K-dependent
glycoprotein) as cofactor, phospholipids and Ca2+-ions. ZPI also inhibits
factors IXa and XIa, in protein Z independent pathway. The primary inhibitor of the initiation of blood coagulation process is
the tissue factor (TF) pathway inhibitor. TFPI acts as a high-affinity
inhibitor of two coagulation proteases, such as TF-factor VIIa (TF-FVIIa) and
factor Xa (FXa). There are two isoforms of TFPI known: TFPI? and TFPI?. These
two isoforms differ in several characteristics: in affinity for factor V/Va
(FV/FVa)
and protein S (PS), in expression in platelets
and endothelial cells, in mechanism for association with cell surfaces,
and in ability to influence early steps of blood coagulation through distinct mechanisms
of inhibition of TF-FVIIa activity or inhibition of prothrombinase. Protein S is needed as
cofactor for optimal inhibition of factor Xa by TFPI?, but is not required for FXa-dependent TF-FVIIa inhibition. As mentioned above, fibrin plays an
essential role in secondary haemostasis as the primary product of the
coagulation cascade. Degradation of fibrin is termed fibrinolysis. The
fibrinolytic pathway is a complex physiological pathway controlled by action of
a series of cofactors, inhibitors, receptors. Dysregulation of this pathway is
associated with different pathologies (e.g. coagulopathies, disseminated
intravascular coagulation (DIC) or congenital bleeding disorders). Degradation
of fibrin is performed by serine protease plasmin, which is present in blood as
a proezyme plasminogen and need to be activated by tissue plasminogen activator
(tPA) and urokinase.

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