Blood Cells - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 86

3.6.4 Platelet Activation

Circulating platelets are kept in an inactive state particularly by prostacyclin (PGi2)
and nitric oxide released by endothelial cells (Sect. 9.8 ). Endothelial cells also
express plasmalemmal ectonucleotide pyrophosphatase-phosphodiesterase ENPP1
that inhibits platelet activation by adenosine diphosphate, as it converts ADP into
AMP.
Platelet synthesizes and releases multiple molecules (caspases, osteonectin,
ubiquitin, vimentin, tissue inhibitors of matrix metallopeptidases, etc.). Activated
platelets promote blood coagulation on their surface, produce mediators of inflam-
mation, and cause smooth myocyte proliferation.
In resting platelets, cholesterol is uniformly distributed on the cell surface
and confined to multivesicular bodies, dense granules, and internal membranes of
alpha granules [ 162 ]. Upon interaction with fibrinogen, cholesterol accumulates
at the leading edge during platelet spreading on fibrinogen, especially at tips of
filopodia. Upon stimulation with thrombin receptor-activating peptides (TRAP),
which are synthetic parts of the liberated N-terminal tail of the cleaved, moderate-
affinity, thrombin receptor, cholesterol also redistributes to filopodia. This process
results from the concentration of Src kinase and tetraspanin-30 in these membrane
nanodomains (rafts).
Thrombin, or blood coagulation factor II, is a component of the clotting cascade
and strong activator of platelet aggregation. It targets peptidase-activated receptors
(PAR 1 -PAR 4 ). The serine peptidase thrombin initiates various platelet responses
(shape change, pseudopod extension, eicosanoid production, granule release, ad-
hesive receptor expression, and aggregation) via phospholipase-C, intracellular
calcium flux, and activation of kinases. Another serine peptidase, trypsin, also
activates platelets, stimulating their aggregation and phosphoinositide metabolism.
Both thrombin and trypsin cleave the terminal region of the moderate-affinity throm-
bin receptor, thereby allowing the released C-terminal fragment to subsequently
stimulate the processed receptor. In addition, thrombin acts by a non-proteolytic
mechanism, possibly via a high-affinity receptor such as glycoprotein-1B, which is
not cleaved by thrombin.
Arachidonic acid is enriched in platelet phospholipids, such as phosphatidyl-
choline, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine.
Upon platelet activation, arachidonic acid is released from membrane phospho-
lipids, most likely by cytosolic phospholipase-A2, and converted by the cyclooxyge-
nase axis to thromboxane-A2 that causes full platelet activation (positive feedback
loop) [ 163 ].
At injury sites, platelets adhere to the exposed subendothelium and interact with
collagen, von Willebrand factor, and fibronectin via their receptors, integrins, and
glycoproteic GP1b-GP9 complex. Glycoproteins GP1b (GP1b

dimer),
GP5, and GP9 that are members of the leucine-rich glycoprotein (LRG) family
complex at the platelet surface. Glycoprotein GP1b

α -GP1b β

(encoded by the GP1BA
gene) binds to von Willebrand factor and thrombin on the one hand, and platelet

α