PB0586 - Repurposing of Montelukast in COVID-19 patients in order to modulate platelet activation

Background: Sustained platelet activation, thrombosis, vascular damage, fibrotic response as well as inflammatory overload are typical features of COVID-19 pathology. Common denominator in these processes is leukotrienes (LTs). Elevated levels of LTE4 have been detected in bronchoalveolar lavage of COVID-19 patients so the use of LT receptor antagonists as a potential therapeutic for COVID-19 patient treatment has been hypothesized. A first phase III randomized double-blind clinical trial testing montelukast in COVID-19 patients has been indeed proposed.

Aims: To investigate whether montelukast affects the expression of the major markers of platelet activation such as tissue factor (TF), P-selectin, as well as the formation of platelet-leukocyte aggregates and microvesicle (MV) release observed in COVID-19 syndrome.

Methods: Blood from healthy subjects (HS; n=4-6) was plasma-depleted and reconstituted with plasma pools (n=3) from COVID-19 patients (4 patients/pool) or from the same HS blood donors. To assess the effect of montelukast on cell activation, blood from HS was preincubated for 30 minutes with the drug. Circulating cell-associated TF expression, platelet activation markers, and MV release were analyzed by flow cytometry.

Results: Plasma from COVID-19 patients significantly increased (4-fold) the number of TF+- and P-selectin+-platelets of HS recapitulating the platelet activation status of COVID patients. Montelukast prevented platelet activation induced by plasma from COVID-19 patients and it reduced the formation of circulating monocyte- and granulocyte-platelet aggregates, decreasing the number of those TF+ by 4-times. Finally, it completely inhibited the release of TF+ circulating MVs, reducing by more than 2-times those derived from platelets.

Conclusion(s): Our data indicate that leukotrienes contribute to sustain platelet activation occurring in the COVID-19 patient, which can however be prevented by treatment with montelukast. Until results from ongoing trials will be available, our data provide the molecular basis by which the drug may be effective in the treatment of COVID-19.