Antibody-mediated procoagulant platelets in SARS-CoV-2-vaccination associated immune thrombotic thrombocytopenia

Abstract

The COVID-19 pandemic has resulted in significant morbidity and mortality worldwide. To prevent severe infection, mass COVID-19 vaccination campaigns with several vaccine types are currently underway. We report pathological and immunological findings in 8 patients who developed vaccine-induced immune thrombotic thrombocytopenia (VITT) after administration of SARS-CoV-2 vaccine ChAdOx1 nCoV-19. We analyzed patient material using enzyme immune assays, flow cytometry and heparin-induced platelet aggregation assay and performed autopsies on two fatal cases. Eight patients (5 female, 3 male) with a median age of 41.5 years (range, 24 to 53) were referred to us with suspected thrombotic complications 6 to 20 days after ChAdOx1 nCoV-19 vaccination. All patients had thrombocytopenia at admission. Patients had a median platelet count of 46.5 x109/L (range, 8 to 92). Three had a fatal outcome and 5 were successfully treated. Autopsies showed arterial and venous thromboses in various organs and the occlusion of glomerular capillaries by hyaline thrombi. Sera from VITT patients contain high titer antibodies against platelet factor 4 (PF4) (OD 2.59±0.64). PF4 antibodies in VITT patients induced significant increase in procoagulant markers (P-selectin and phosphatidylserine externalization) compared to healthy volunteers and healthy vaccinated volunteers. The generation of procoagulant platelets was PF4 and heparin dependent. We demonstrate the contribution of antibody-mediated platelet activation in the pathogenesis of VITT.

Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia

“…However, other serum factors could also contribute to platelet activation. Previous studies have demonstrated antibodies from VITT patients were able to activate platelets and cause platelet aggregation in the presence of adenoviral particles in a dose-dependent manner 1,23,24 . Thus, it is possible platelet activation caused by anti-PF4 antibodies in VITT patients may not be the only factor leading to the development of thrombotic events.…”

No Correlation between Anti-PF4 and Anti–SARS-CoV-2 Antibodies after ChAdOx1 nCoV-19 Vaccination

“… To the Editor: Vaccine-induced immune thrombotic thrombocytopenia (VITT), also known as thrombosis with thrombocytopenia syndrome, is a rare but potentially fatal complication of vector-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. 1-3 The clinical picture and the serologic findings in patients with VITT resemble heparin-induced thrombocytopenia. 1-3 Several groups have reported the presence of platelet factor 4 (PF4)–reactive antibodies in patients with VITT.…”

Untangling the Intricacies of Infection, Thrombosis, Vaccination, and Antiphospholipid Antibodies for COVID-19

“…Tiede et al detail another five patients but include more variant presentations of thrombosis for arterial, venous, and small vessel disease [112]. Althaus et al comment on a series of eight patients which included deaths [115]. The latter facilitated postmortem studies which provided evidence of arterial and venous thrombotic events as well as occlusion of renal capillaries.…”

“…There may be a strong and direct role of platelet factor 4 antibodies, and again an association with antigenic conformational change is posed [115]. Lesser considered components will be the excipients or adjuvants that accompany the same if any.…”