Table 1.

Categorization of pathology that contributes to morbidity and mortality in severe COVID-19 with a direct comparison to the known physiological effects of Platelet Activating Factor in human or animal models.

COVID-19 Complication Category	Physiological Effects of Platelet Activating Factor	References
Acute Respiratory Syndrome/Pneumonia	Increase of vascular permeability in lung tissues resulting in pulmonary edema.8,9 PAF promotes bronchoconstriction, mucus secretion, and bronchial inflammation in asthmatic individuals.10-13	[10] Miwa M., Miyake T., Yamanaka T., et al.: Characterization of serum platelet-activating factor (PAF) acetylhydrolase. Correlation between deficiency of serum PAF acetylhydrolase and respiratory symptoms in asthmatic children. J Clin Invest. 1988;82(6):1983 to 1991. [11] Hsieh K.H., Ng C.K.: Increased plasma platelet-activating factor in children with acute asthmatic attacks and decreased in vivo and in vitro production of platelet-activating factor after immunotherapy. J Allergy Clin Immunol. 199; Feb;91(2):650 to 7. [12] Kowalski M.L, Agache I., Bavbek S., et al.: Diagnosis and management of NSAID-Exacerbated Respiratory Disease (N-ERD)-a EAACI position paper. Allergy 2019; Jan;74(1):28 to 39. [13] Busse W.W.: Leukotrienes and inflammation. Am J Respir Crit Care Med. 1998; Jun;157(6 Pt 1):S210 to 3.
Thrombosis	Signals platelet reactivity and aggregation that results in construction of atherosclerotic plaques. Promotes vascular inflammation and remodeling.16-21	[16] Hajra A., Mathai S.V., Ball S., et al.: Management of Thrombotic Complications in COVID-19: An Update. Drugs 2020;80(15):1553 to 1562. [17] Piazza G., Campia U., Hurwitz S., et al.: Registry of Arterial and Venous Thromboembolic Complications in Patients With COVID-19. J Am Coll Cardiol. 2020; Nov 3;76(18):2060 to 2072. [18] Palur Ramakrishnan A.V., Varghese T.P., Vanapalli S., et al.: Platelet activating factor: A potential biomarker in acute coronary syndrome? Cardiovasc Ther. 2017; Feb;35(1):64 to 70. [19] Marcus A.J., Safier L.B., Ullman H.L., et al.; Effects of acetyl glyceryl ether phosphorylcholine on human platelet function in vitro. Blood. 1981; 58 (5): 1027 to 1031. [20] Cazenave J.P., Benveniste J., Mustard J.F.: Aggregation of rabbit platelets by platelet-activating factor is independent of the release reaction and the arachidonate pathway and inhibited by membrane-active drugs. Lab Invest. 1979 Sep;41(3):275 to 285. [21] Golino P., Ambrosio G., Ragni M., et al.: Short-term and long-term role of platelet activating factor as a mediator of in vivo platelet aggregation. Circulation. 1993 Sep;88(3):1205 to 1214.
Hemodynamic Instability/Septic Shock	In response to infection or allergic stimuli, PAF stimulates degranulation of mast cells and recruitment of inflammatory mediators. The net result is increased vascular permeability and vasodilation that can lead to hypotensive shock.25,26	[25] Vadas P., Gold M., Perelman B., et al.: Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis. N Engl J Med. 2008; Jan 3;358(1):28 to 35. [26] Munoz-Cano R.M., Casas-Saucedo R., Valero Santiago A., et al.: Platelet-Activating Factor (PAF) in Allergic Rhinitis: Clinical and Therapeutic Implications. J Clin Med. 2019; Aug 29;8(9):1338.
Multi-Organ Failure/SIRS	Promotes inflammation and fibrosis in renal tissue.31,33 PAF serum levels elevated under conditions of acute kidney failure. 32 PAF represents an element of the inflammatory cascade that leads to the development of SIRS.28-30	[28] Kajiwara N., Sasaki T., Bradding P., et al.: Activation of human mast cells through the platelet-activating factor receptor. J Allergy Clin Immunol. 2010; May;125(5):1137 to 1145. [29] Mokhtari T., Hassani F., Ghaffari N., et al.: COVID-19 and multiorgan failure: A narrative review on potential mechanisms. J Mol Histol. 2020;51(6):613 to 628. [30] Zaim S., Chong J.H., Sankaranarayanan V., et al.: COVID-19 and Multiorgan Response. Curr Probl Cardiol. 2020;45(8):100618. [31] Raza A., Estepa A., Chan V., et al.: Acute Renal Failure in Critically Ill COVID-19 Patients With a Focus on the Role of Renal Replacement Therapy: A Review of What We Know So Far. Cureus. 2020;12(6):e8429. Published 2020; Jun 3. [32] Mariano F., Guida G., Donati D., et al.: Production of platelet-activating factor in patients with sepsis-associated acute renal failure. Nephrology Dialysis Transplantation. 1999; May;14(5): 1150 to 1157. [33] Correa-Costa M., Andrade-Oliveira V., Braga T.T., et al.: Activation of platelet-activating factor receptor exacerbates renal inflammation and promotes fibrosis. Lab Invest. 2014; Apr;94(4):455 to 66.

Abbreviations: PAF, Platelet Activating Factor; SIRS, Systemic Inflammatory Response Syndrome