Antibody-induced procoagulant platelets in severe COVID-19 infection

Abstract

The pathophysiology of COVID-19 associated thrombosis seems to be multifactorial. We hypothesized that COVID-19 is accompanied by procoagulant platelets and platelet apoptosis with subsequent alteration of the coagulation system. We investigated depolarization of mitochondrial inner transmembrane potential (ΔΨm), cytosolic calcium (Ca2+) concentration, and phosphatidylserine (PS) externalization by flow cytometry. Platelets from intensive care unit (ICU) COVID-19 patients (n=21) showed higher ΔΨm depolarization, cytosolic Ca2+ concentration and PS externalization, compared to healthy controls (n=18) and COVID-19 non-ICU patients (n=4). Moreover significant higher cytosolic Ca2+ concentration and PS was observed compared to septic ICU control group (ICU control). In ICU control group (n=5; ICU non-COVID-19) cytosolic Ca2+ concentration and PS externalization was comparable to healthy control, with an increase in ΔΨm depolarization. Sera from ICU COVID-19 patients induced significant increase in apoptosis markers (ΔΨm depolarization, cytosolic Ca2+ concentration and PS externalization) compared to healthy volunteer and septic ICU control. Interestingly, immunoglobulin G (IgG) fractions from COVID-19 patients induced an Fc gamma receptor IIA dependent platelet apoptosis (ΔΨm depolarization, cytosolic Ca2+ concentration and PS externalization). Enhanced PS externalization in platelets from ICU COVID-19 patients was associated with increased sequential organ failure assessment (SOFA) score (r=0.5635) and D-Dimer (r=0.4473). Most importantly, patients with thrombosis had significantly higher PS externalization compared to those without. The strong correlations between procoagulant platelet and apoptosis markers and increased D-Dimer levels as well as the incidence of thrombosis may indicate that antibody-mediated platelet apoptosis potentially contributes to sustained increased thromboembolic risk in ICU COVID-19 patients.

Platelet‐activating immune complexes identified in critically ill COVID‐19 patients suspected of heparin‐induced thrombocytopenia

“…Our findings are supported by previous work showing significantly increased platelet apoptosis, secondary to IgG-mediated FcγRIIA signaling, in critically ill COVID-19 patients. 21 It is important to note that the plateletactivating ICs in our cohort were identified using a buffer control (i.e., no addition of heparin). This step should thus be included in all SRA testing, as it can both identify atypical HIT and non-HIT platelet-activating ICs.…”

Hypotheses behind the very rare cases of thrombosis with thrombocytopenia syndrome after SARS-CoV-2 vaccination

“…It has been reported by Althaus et al that severe COVID-19 was associated with antibody-mediated upregulation of platelet apoptosis and that IgG from severe COVID-19 patients induces procoagulant platelets and thus contribute to the increased risk for thromboembolic complications. [ 62 ] In particular, sera from COVID-19 patients in the ICU cause IgG-mediated platelet apoptosis via cross-linking FcɣRIIa. [ 62 ] To explore the mechanism of platelet apoptosis in COVID-19, patients’ sera were incubated with washed platelets from healthy donors, and these samples induced a significantly higher mitochondrial inner membrane potential depolarization compared with sera from healthy donors.…”

“…[ 62 ] In particular, sera from COVID-19 patients in the ICU cause IgG-mediated platelet apoptosis via cross-linking FcɣRIIa. [ 62 ] To explore the mechanism of platelet apoptosis in COVID-19, patients’ sera were incubated with washed platelets from healthy donors, and these samples induced a significantly higher mitochondrial inner membrane potential depolarization compared with sera from healthy donors. [ 62 ] More importantly, IgG-mediated platelet apoptosis was inhibited by blocking FcɣRIIa with the IV.3 monoclonal antibody.…”

“…[ 62 ] To explore the mechanism of platelet apoptosis in COVID-19, patients’ sera were incubated with washed platelets from healthy donors, and these samples induced a significantly higher mitochondrial inner membrane potential depolarization compared with sera from healthy donors. [ 62 ] More importantly, IgG-mediated platelet apoptosis was inhibited by blocking FcɣRIIa with the IV.3 monoclonal antibody. [ 62 ] These data also indicate that IgG contribute to the increased phosphatidylserine expression on platelets of patients with severe COVID-19 infection.…”

Challenges and Issues of Anti-SARS-CoV-2 Vaccines

“…At the time of writing this paper, the causality could not be formally established, but the problem is under thorough investigation by EMA experts and international surveillance is ongoing 5 . This concern should be all the more seriously considered that COVID-19 is associated with a high prevalence of thromboembolic complications for which an immunological origin through the formation of anti-platelets antibodies has already been hypothesized (36).…”