Biomedical Engineering Reference
In-Depth Information
Platelet behavior with regard to the vasculature wall is also based on a balance
between stimulation and inhibition of the different stages of the coagulation reaction
chain. In particular, endoperoxides, precursors of prostaglandins, are used either by
platelet enzymes to produce thromboxane-A2 (TxA2), which supports aggregation,
or by endothelial enzymes to synthesize PGi2, which inhibits platelet aggregation.
Platelets express 2 receptors for subendothelial collagen, such as collagen-1
and -3: integrin-
α
2
β
1
is overexpressed in
pathological clot formation [
1030
]. As its underexpression only causes a mildly
prolonged bleeding time, it is a good target for antithrombotic therapy.
Type 1A phosphoinositide 3-kinase
141
α
2
β
1
and GP6 glycoprotein. Integrin-
PI3K
c1β
isoform regulates the formation
and stability of
α
2B
β
3
-integrin adhesion bonds, involved in shear activation of
platelets [
1031
]. Inhibitors of PI3K
c1β
have been developed to preclude thrombus
formation.
Serpins, inhibitors of peptidases, include serpin-A1, or
1-antitrypsin, that
reduces the activity of elastase, serpin-C1, or antithrombin, that prevents blood
coagulation, serpin-E1, or plasminogen activator inhibitor-1, serpin-B2, or plas-
minogen activator inhibitor-2, etc. Peptidase binding cleaves an exposed serpin
amino acid sequence (reactive-center loop [RCL]) that is incorporated into the
central
α
-sheet. Some serpins can spontaneously undergo a similar conformational
rearrangement without RCL cleavage to form an inactive protein. Serpins are able to
swap domains as well as to misfold. In addition, domain swap can happen between
different monomers, as an RCL portion of one monomer can be incorporated into
the
β
-sheet linkages.
Accumulation of misfolded serpin multimers create conformational diseases or
serpinopathies that cause thrombosis (and also emphysema, liver cirrhosis, and
neurodegenerative lesions such as Alzheimer's, Huntington's, and Parkinson's
diseases, as well as prion-induced encephalopathy).
In atherothrombotic diseases, inhibition of peptidase-activated receptor PAR
1
of thrombin prevents thrombin-mediated platelet activation, but does not interfere
with thrombin-dependent fibrin generation for hemostasis, i.e., does not raise the
bleeding risk [
1033
].
142
β
-sheet of another [
1032
]. Serpins can actually polymerize via
β
141
Class-1 PI3Ks that produce second messengers phosphoinositide PI(3,4,5)P
3
and PI(3,4)P
2
regulate platelet responses, such as the activation of integrin-
3
, a major platelet integrin
that mediates platelet-vessel wall and platelet-platelet adhesions via multiple ligands, such as von
Willebrand factor, fibrinogen, fibronectin, and TNFSF5 protein. Platelets contain all class-1 PI3K
isoforms.
142
Platelet activation that is needed for hemostasis is mediated by multiple agents. Platelet integrins
bind to exposed extracellular matrix proteins, such as collagen and von Willebrand factor to
ensure thrombocyte adhesion. The following release of adenosine diphosphate, thromboxane-A2,
serotonin, and catecholamines (adrenaline and noradrenaline [
1036
]), as well as local production of
thrombin prime autocrine and paracrine platelet activation. These agents connect to their cognate
GPCRs, such as Gq-coupled P2Y
1
and Gi-coupled P2Y
12
for ADP, 2 TP receptor subtypes that are
generated by alternative splicing of the primary transcript (Gq-coupled TP
α
β
2B
α
and Gi-coupled TP
β
)
for TxA2, Gq-coupled 5HT
2A
for serotonin, Gi/o-coupled
2a adrenoceptors for catecholamines,
and Gi/z-, Gq-, and G12/13-coupled peptidase-activated receptor PAR
1
for thrombin. Resulting
α
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