Platelet activation secretion

The formation of a platelet aggregate requires the recruitment of additional platelets from the blood stream to the injured vessel wall. This process is executed through a variety of diffusible mediators which act through G-protein-coupled receptors. The main mediators involved in this process are adenosine diphosphate (ADP), thromboxane A2 (TXA2), and thrombin (factor Ila). These mediators of the second phase of platelet activation are formed in different ways. While ADP is secreted from platelets by exocytosis, the release of TXA2 follows its new formation in activated platelets. Thrombin can be formed on the surface of activated platelets (see Fig. 2). 

It is possible that nematode-secreted AChEs act on alternative substrates to ACh. We had previously suggested, on the basis of structural similarity, that platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, might represent such an alternative substrate (Blackburn and Selkirk, 1992b) but subsequent studies demonstrated that purified AChEs did not cleave PAF, and the enzyme responsible for this activity in secreted products of N. brasiliensis, PAF acetylhydrolase, was purified and defined as a distinct heterodimeric protein (Grigg et al., 1996). Although an open mind on the subject sould be kept, the strict substrate specificity of the nematode-secreted AChEs suggests that they most likely act on ACh alone. 

Grigg, M.E., Gounaris, K. and Selkirk, M.E. (1996) Characterisation of a platelet-activating factor acetylhydrolase secreted by the nematode parasite Nippostrongylus brasiliensis. BiochemicalJournal 317, 541-547. 

Mast cell degranulation in response to allergens results in release of mediators such as histamine eosinophil, and neutrophil chemotactic factors leukotrienes C4, D4, and E4 prostaglandins and platelet-activating factor (PAF). Histamine is capable of inducing smooth muscle constriction and bronchospasm and may play a role in mucosal edema and mucus secretion. 

L. W. Tjoelker, C. Eberhardt, J. Unger, H. Letrong, G. A. Zimmerman, T. M. McIntyre, D. M. Stafforini, S. M. Prescott, P. W. Gray, Plasma Platelet-Activating Factor Acetyl-hydrolase Is a Secreted Phospholipase A2 with a Catalytic Triad ,./. Biol. Chem. 1995, 270, 25481-25487. 

The ability of feverfew extract to inhibit 5HT-secretion in platelets was used to identify compounds responsible for the inhibitory effects on platelets [44], A crude feverfew extract was separated by chromatography and fractions were screened for antisecretory activity induced by adrenaline. In five active fractions compounds were identified as the sesquiterpene lactones parthenolide (1), canin (19), artecanin (20), secotanapartholide A (24) and 3 8-hydroxyparthenolide (2). The ability of parthenolide to affect platelet activity induced by other agents was confirmed in a study of direct comparison of crude feverfew extract with parthenolide [43], Parthenolide in the micromolar concentration range inhibited platelet 5HT-secretion. 

Platelets originate by budding off from multinucleate precursor cells, the megakaryocytes. As the smallest formed element of blood (dia. 1 -4 pm), they can be activated by various stimuli. Activation entails an alteration in shape and secretion of a series of highly active substances, including serotonin, platelet activating factor (PAF), ADP, and thromboxane A2. In turn, all of these can activate other platelets, which explains the explosive nature of the process. 

The pathogenesis of TTP is complex, and possibly involves a variety of mechanisms associated with endothelial cell and platelet activation and injury. Recently, however, the deficiency of vWF cleaving prolease aclivily has been idenlified as a hallmark of TTP (67, 68). In normal individuals, vWF is secreted from platelets and endothelial cells as variously sized multimers, resulting from the crosslinking of vWF monomers by disulfide bonds into multimers containing a minimum of 2 to a maximum of 50-100 monomer subunits. 

LPS can provoke a multi-organ failure, due to the secretion of acute-phase reactants such as platelet-activating factor (PAF), TNF-a, and LBP. Multi-organ failure is also due to the secretion of prostaglandin E2 (PGE2) and inflammatory cytokines such as TNF-a, IL-ip, IL-6, whose production may increase the secretion of the acute-phase reactant, LBP [63], thus constituting an amplifying loop. The presence of a tumor may modify this host response as will be discussed below. 

Fig. 1. Schematic diagram showing the different mechanisms of action proposed for the antiulcer action of flavonoids. 1. Blockade of add secretion by decreasing histamine production or inhibiting the proton pump. 2. Bactericidal effect on H. pylori. 3. Antioxidative activity by scavenging free radicals and preventing ROM formation. 4. Potentiation of the mucosal protective factors. PAF platelet activating factor ROM reactive oxygen metabolites H2 histamine receptor 2 M muscarinic receptor G gastrin receptor.

Protease nexin 2 is identical to the secreted form of the amyloid precursor protein containing the Kunitz-type serine protease inhibitor domain (128,129), Protease nexin 2 circulates in blood stored as a platelet a-granule protein, which is secreted upon platelet activation (127). Protease nexin 2 inhibits trypsin- and chymotrypsin-like serine proteases and is also a potent inhibitor of factor Xla (126,127,128). Its location in platelets and its ability to inhibit factor Xla suggests a role in regulating blood coagulation for protease nexin 2. 

Tilly RHJ, SendenJMG, Comfurius R Bevers EM, Zwaal RFA. Increased aminophospholipid translocase activity in human platelets during secretion. Biochem Biophys Acta 1990 1029 188-190. 

P2Y12 receptor is required for complete aggregation response to ADR Nevertheless, both (Fig. 6) receptors interact to lead the full response. ADP potentiates platelet secretion and irreversible aggregation, Enzymatic conversion of released ADP to inactive AMP by endothelial ecto-ADPase limits platelet activation by ADR Thienopyridines (ticlopidine, clopidogrel, prasugrel, cangrelor) are used for inhibiting ADP-induced platelet function in the prevention of acute coronary events,... 

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