Recent articles have reported elevated markers of coagulation, endothelial injury, and microthromboses in lungs from deceased patients with coronavirus 2019 (COVID-19). Platelets are critical in the formation of thrombi, and their most potent trigger is platelet activating factor (PAF). PAF is produced by cells involved in host defense, and its biological actions bear similarities with COVID-19 disease manifestations, including pulmonary microthromboses and inflammation, possibly via activation of mast cells. The histamine1 receptor antagonist rupatadine was developed to have anti-PAF activity and inhibits activation of human mast cells in response to PAF. Rupatadine could be repurposed for COVID-19 prophylaxis.