Systemic platelet exhaustion in critically-ill COVID-19 patients

Background : Infection with SARS-CoV-2 leads to an altered hemostatic system and Covid-19 associated coagulopathy (CAC). Platelet counts remain overall unaltered, but thromboembolic events are frequently reported. Studies on the contribution of platelets to CAC are emerging but still lacking precise cohort comparison and broad analyses of platelet markers. Aims : We aimed to analyze platelet receptor expression and function on platelets and biomarkers in platelet-poor plasma to investigate the role of platelets in the onset of critical progression of CAC. Methods : Extensive platelet function analyses were performed on 34 critically-ill patients with Covid-19 and data was compared to sepsis patients ( n = 24) and non-SARS-CoV-2 acute infection ( n = 18). Tests included PFA-200, aggregometry, flow cytometry and whole mount TEM. Plasma levels of TPO, sCD62P and sGPVI were determined by ELISA. For all patients, relatives, and for healthy controls ( n = 10) informed consent was obtained. Results : While platelet counts in patients of our Covid-19 cohort were expectably unaltered, platelet function was severely impaired in multiple assays. Platelets failed to aggregate in response to ADP or TRAP-6 and could not activate integrin response or release α-granules. The amount of platelet-leukocyte aggregates was markedly elevated, indicating previous platelet activation in line with higher levels of sCD62P and sGPVI. Remarkably, we observed platelet exhaustion in Covid-19 patients using whole mount TEM by means of a lack of dense granules corroborating with impaired uptake of mepacrine. Conclusions : Our data imply that SARS-CoV-2 infection leads to a sub-threshold activation of platelets in a way that they become activated already before critical disease progression, without being cleared from the circulation, which is in striking contrast to sepsis. The platelet pool appears to be exhausted with detrimental consequences for thrombus stability and the risk of thromboembolic events. The mere platelet count in Covid-19 does thus not reflect progression to CAC, whereas platelet function is of high prognostic relevance.