Controlled Clinical Trials — Necessity and Progress
James L. MacPherson, Duke O. Kasprisin in Therapeutic Hemapheresis, 2019
The leading “missing factor” theory focuses upon the inhibitor of platelet aggregation, prostacyclin (PGl2).3Prostacyclin may act by increasing cyclic AMP levels in platelets thus making internal calcium unavailable for the calcium-dependent platelet reactions that are involved in adherence, shape, change, aggregation, and release. During the formation of hemostatic plugs and thrombi, platelet aggregation gives rise to thromboxane A2 (TXA2), a substance that augments platelet aggregation and the release reaction; in normal platelet-endothelial interaction, the platelet aggregating tendency of thromboxane A2 is balanced by the inhibitor of platelet aggregation, prostacyclin (PG12). A number of investigators have suggested that patients with TTP have either a deficiency of PG12 or a precursor of this prostaglandin.3It is hypothesized that the clinical response to plasma therapy in TTP is due to the fact that the plasma supplies this “missing factor”.
Critical Care and Anaesthesia
Tjun Tang, Elizabeth O'Riordan, Stewart Walsh in Cracking the Intercollegiate General Surgery FRCS Viva, 2020
What are the causes of coagulopathy in a surgical patient?Hypothermia causes platelet dysfunction.Massive blood transfusion: packed RBCs do not contain platelets, and stored blood rapidly loses the function of V and VII. Citrate may also cause hypocalcaemia which impairs coagulation.Aspirin reduces platelet function by interfering with thromboxane A2 synthesis.Heparin directly interferes with clotting and can also lead to thrombocytopenia (HIT).Sepsis can lead to DIC or bone marrow suppression.Postoperative acute renal or liver failure can occur.
Haemostasis: Normal Physiology, Disorders of Haemostasis and Thrombosis
John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie in Basic Sciences Endocrine Surgery Rhinology, 2018
Aspirin acts by irreversibly inhibiting cyclo-oxygenase (COX) 1 and 2 (in contrast to some NSAIDs that reversibly act). Aspirin in low dose blocks the formation of thromboxane A2 in platelets for the life of the platelet; however, there is little effect on prostacyclin (because endothelial cells have a nucleus to produce further enzyme to produce more prostacyclin). The balance of increasing prostacyclin and reducing thromboxane A2 inhibits platelet aggregation. Platelet transfusion is the only way to reverse the effects of antiplatelet agents and only really helps if the drug has not been taken recently (otherwise the transfused platelets will also be affected).
What can we learn from the platelet lipidome?
Published in Platelets, 2023
Gaëtan Chicanne, Jean Darcourt, Justine Bertrand-Michel, Cédric Garcia, Agnès Ribes, Bernard Payrastre
Another important pathway in platelets involves PLA2. Among the fatty acyls generated by PLA2, arachidonic acid is a major precursor for oxidative transformation to eicosanoids by lipoxygenase and cyclooxygenase pathways. Following stimulation, platelets produce a number of eicosanoids, including thromboxane A2 (TXA2), a proaggregatory lipid. T×A2 released by activated platelets acts as an auto- and paracrine molecule through the G-protein coupled receptor TP-receptor [7,8]. The calcium-sensitive cytosolic PLA2α isoform (cPLA2α) has a major role in human platelets as demonstrated in a rare inherited human deficiency of this enzyme leading to impaired platelet eicosanoid generation associated with platelet dysfunction [21]. A platelet lipidomic profiling study has highlighted the importance of PLA2α (cPLA2α) in platelet activation and clarified the substrates of this PLA2 isoform [22]. Moreover, the lysophospholipids generated by cPLA2 were identified but their role in platelet remains poorly understood. This study also suggested the involvement of cPLA2 in the production of a unique eicosanoid downstream of PAR4 and GPVI triggering.
Nonsteroidal anti-inflammatory drugs in end-stage kidney disease: dangerous or underutilized?
Published in Expert Opinion on Pharmacotherapy, 2021
The predominant mechanism of action of NSAIDs is the inhibition of COX enzymes, prohibiting prostanoid synthesis from arachidonic acid (Figure 1) [1,15,16]. Arachidonic acid metabolism is a multi-step enzymatic process that follows platelet aggregation and activation of membrane phospholipases. Thromboxane A2 (TXA2), a platelet prostanoid product of arachidonic acid metabolism, acts as a vasoconstrictor and platelet aggregant. This platelet-activating cascade is initiated by COX-1, an enzyme that is constituently expressed in mature platelets as well as various organ tissues including the gastric mucosa, kidneys, and vascular endothelium [17]. In contrast, COX-2 is only transiently expressed in immature platelets [18] or in vascular endothelial cells during inflammatory states and is largely involved in the production of prostaglandins, most notably prostacyclin (PGI2). Inhibition of prostacyclin’s vasodilatory and platelet anti-aggregant effects contribute to increased risk for adverse cardiovascular events in patients taking NSAIDs and selective COX-2 inhibitors [19,20].
The molecular basis of platelet biogenesis, activation, aggregation and implications in neurological disorders
Published in International Journal of Neuroscience, 2020
Abhilash Ludhiadch, Abhishek Muralidharan, Renuka Balyan, Anjana Munshi
Thromboxane A2 is a molecular signal which provides the stimulus for increasing platelet aggregation. In association with ADP it increases the size of the platelet aggregate and results in the formation of a platelet plug, which acts as a temporary remedy for the vascular injury. In presence of agonists like ADP, arachidonic acid stored in the plasma membrane of the platelets are converted to thromboxane A2 by a series of oxygenations reactions. The released thromboxane A2 recruits more platelets to cross-link and strengthen the platelet plug [61,62]. ADP binding also causes a conformational change in GpIIb/IIIa receptors present on the surface of platelets causing deposition of circulatory glycoprotein called fibrinogen. Thrombin generation further catalyzes the conversion of this fibrinogen to the fibrous protein fibrin, which increases the stability of the platelet plug [63].
Related Knowledge Centers
- Degranulation
- Fibrinogen
- Hemostasis
- Integrin
- Platelet
- Thrombus
- Thromboxane
- Thromboxane Receptor
- Vasoconstriction
- Variant Angina