The Role of Platelet-Activating Factor in the Pathogenesis of Necrotizing Enterocolitis
David J. Hackam in Necrotizing Enterocolitis, 2021
Platelet-activating factor (PAF) is an endogenous phospholipid mediator with multiple potent effects (1). It was known in the late 1970s that a compound was present in the circulation and tracheal fluid that resulted in platelet aggregation and degranulation, and by 1979, Benveniste and others identified this molecule as an acyl glycolipid that they called PAF (2). This glycolipid was shown to have a very short half-life in vivo and was present in most cells, fluids, and tissues (3). PAF is synthesized following the hydrolysis of phosphatidylcholine by phospholipase A2 into lyso-PAF with the following acetyl-transferase conversion into PAF. Lyso-PAF has minimal biologic activity, though PAF has potent effects following ligand binding to the PAF receptor that is present on most cells and tissues. PAF is converted back to the inactive lyso-PAF by the enzyme PAF-AH, and as discussed later in this chapter, this important enzyme is relatively deficient in the newborn circulation (4). It has been suggested that endogenous PAF functions in part to protect the intestine from invasive pathogen exposure by activating an intense self-limited inflammatory response. If the organism or local environment lacks appropriate PAF-AH activity to down-regulate PAF activation, severe intestinal necrosis may result.
Immunologically Mediated Diseases and Allergic Reactions
Julius P. Kreier in Infection, Resistance, and Immunity, 2022
The second class of mediators released by activated mast cells are the newly formed mediators. Generation of lipid mediators begins with the activation of the enzyme phospholipase A2, which catalyzes the release of arachidonic acid from the membrane phospholipids. Arachidonic acid is then sequentially metabolized by the enzymes in one of two separate pathways: the cyclooxygenase pathway that produces the prostaglandins or the 5-lipoxygenase pathway that forms the leukotrienes. During allergic reactions, prostaglandin D2 induces vasodilation and bronchoconstriction. The leukotrienes C4, D4, and E4, previously referred to as slow-reacting substance of anaphylaxis, mediate prolonged bronchoconstriction, vasopermeability, and mucus secretion. Another derivative of phospholipid is platelet activating factor, which aggregates platelets, leading to microthrombi. Platelet activating factor also causes severe bronchoconstriction, increases vasopermeability, and augments chemotaxis of neutrophils. Whereas mast cells have been shown to produce prostaglandin D2, the leukotrienes, and PAF, basophils apparently synthesize only the leukotrienes (See chapter 4).
Effects of Antithrombotic and Results of Drug Screening
Josef Hladovec in Antithrombotic Drugs in Thrombosis Models, 2020
Two newly emerging groups of drugs have to be mentioned here. The first is inhibitors of platelet-activating factor, PAF. Even though main attention was paid to other roles of this mediator than in thrombogenesis (shock, allergic reactions, bronchial tonus control, etc.) some of its inhibitors (or rather, PAF receptor antagonists) such as BN 52021, BN 50 341, L-652731, triazolam, and alprazolam,712, 713 as well as kadsurenone714 were not only tested on platelet function in vitro, but also in animal models. Etienne et al.715 tested BN 50 341 in a model with electric current-induced carotid artery thrombosis in the rat. The drug was effective at doses of 50 mg/kg/h. In the mesenteric microcirculation, the drug was effective at a dose of 3 mg/kg i.v. against topical ADP administration.
Evaluation of maternal plasma platelet activating factor acetylhydrolase activity and mRNA expression in pre-eclampsia: a case control study
Published in Journal of Obstetrics and Gynaecology, 2021
Preeti Gupta, Rachna Agarwal, Sruthi Bhaskaran, Seema Garg, Mohit Mehndiratta, Gita Radhakrishnan, Alpana Singh, Richa Agarwal, Divya Narang
Preeclampsia is a complication of pregnancy closely related to placental dysfunction. Platelet-activating factor (PAF) is a biologically potent Ether phospholipid, generated by many types of cells including neutrophils, monocytes/macrophages, platelets, and endothelial cells (Prescott et al. 2000). PAF-like oxidised phospholipids are oxidatively modified phospholipids that could be produced by oxidative stress. Both PAF and PAF-like oxidised phospholipids are potent proinflammatory mediators, production and accumulation which are associated with various inflammatory diseases such as asthma, sepsis, cardiac infarction, cerebral ischaemia, and hypertension (Karasawa 2006). In this observational case-control study we made an effort to understand the pathogenesis of preeclampsia using PAF-AH, as the aetiology and pathogenesis remain elusive.
Association of acute thrombocytopenia with anaphylaxis
Published in Baylor University Medical Center Proceedings, 2021
Vihitha Thota, Sudheer Konduru, Sana Mulla, Samia Hossain, Manaswitha Thota, Rajesh Thirumaran
Anaphylaxis is an acute, potentially lethal systemic process resulting from an inflammatory reaction to medications, among other agents.3 The mechanism behind most cases of anaphylaxis is immunoglobulin E–mediated.4 In anaphylaxis, platelets, among other cells, are activated and release platelet-activating factor. Platelet-activating factor causes platelet aggregation and further release of potent vasoconstrictors in the inflammatory response,5 causing increased vascular permeability, circulatory collapse, and decreased cardiac output.6 Platelets, once activated, are in a procoagulant state by binding to collagen through glycoprotein VI. Platelets also contribute to the activation of coagulation by providing binding sites for prothrombin and factor XI.2
Disseminated intravascular coagulation: an update on pathogenesis and diagnosis
Published in Expert Review of Hematology, 2018
Marcel Levi, Suthesh Sivapalaratnam
Platelets are crucial in the development of coagulation abnormalities in DIC [26]. Activated platelets provide a surface on which activation of coagulation factors is greatly facilitated. Direct platelet activation can occur through pro-inflammatory chemokines, such as platelet activating factor [30]. Thrombin that is generated as a result of tissue factor-initiated activation of coagulation may further activate platelets [31]. Platelet activation accelerates further fibrin formation by expression of P-selectin, which potentiates expression of tissue factor on monocytes and orchestrates adherence of platelets to leukocytes and to the vessel wall [32]. P-selectin is readily released from the activated platelet membrane and soluble P-selectin levels are accurate markers of systemic inflammation [32].