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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 (Palta S et al., 2014).

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. This patch is temporary
and will be replaced by a clot during coagulation, in the phase of secondary
haemostasis (Gale AJ, 2011).

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Platelets
derived from megakaryocytes are the main player in the primary haemostasis
(Schulze et al., 2005). 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 (Hou Y et
al., 2015).

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 (Rivera J
et al., 2009; Clemetson KJ & Clemetson JM, 2007).

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 (Van Ommen CH & Peters M, 2012).

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) (D’Andrea G et al.; 2009).

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 (Roberts HR, 2003; Riddell JP Jr. et al., 2007; Palta S et
al., 2014). The waterfall-cascade hypothesis was later modified as the function
of the clotting factors, which were better investigated and defined (Saito H et
al., 2011).

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 (Lane DA et
al., 2005; Gale AJ, 2011).

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 (Palta S et al., 2014).

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 (Kirchhofer et al.,
1996). 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 (Steen M , 2002; Gale AJ, 2011; Palta S et al., 2014). 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 (Chernysh IN et al., 2012).

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 (Gale AJ, 2011; Palta S et al., 2014).

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 (Gale AJ, 2011; Palta S et al., 2014).

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 (Dahlbäck B & Villoutreix BO, 2005).

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 (Broze GJ Jr, 2001; Palta
S et al., 2014).

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 their affinity for factor V/Va (FV/FVa)
and protein S (PS), their expression in platelets and endothelial cells, their
mechanism for association with cell surfaces, and their 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 (Wood JP et al., 2014).

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) (Chapin JC & Hajjar KA, 2015). 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 (Lijnen HR, 2001; Gale AJ, 2011).

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