To Clot or Not to Clot? Ad is the Question - Insights on Mechanisms Related to Vaccine Induced Thrombotic Thrombocytopenia

Abstract

Vaccine-induced immune thrombotic thrombocytopenia (VITT), or thrombotic thrombocytopenic syndrome (TTS), has caused global concern. VITT is characterized by thrombosis and thrombocytopenia following COVID-19 vaccinations with the AstraZeneca ChAdOx1 nCov-19 and the Janssen Ad26.COV2.S vaccines. The clinical features of VITT include thrombosis, typically cerebral venous thrombosis, and severe thrombocytopenia developing 5 to 24 days following first dose of vaccine, with elevated D-dimer, and antibodies specific to platelet factor 4 (PF4), signifying platelet activation. As of June 1, 2021, over 1.93 billion COVID-19 vaccine doses had been administered worldwide. Currently, 467 VITT cases (0.000024%) have been reported across the UK, Europe, Canada and Australia. Clinically, VITT presents similarly to a rare autoimmune condition called “spontaneous/autoimmune heparin Induced Thrombocytopenia” (HIT) without prior heparin exposure. Guidance on diagnosis and management of VITT has been reported but the pathogenic mechanism of VITT is not fully elucidated. A definite causal relationship with the vaccine material is yet to be confirmed. To date, it is established that IgG antibodies recognizing PF4 activate platelets through FcγRIIA, however it remains unclear what triggers production of these antibodies. The fact that VITT, has only been described in association with adenoviral vector-based DNA virus vaccines, but not mRNA/lipid-based vaccines, raises the likelihood that the syndrome is somehow linked to the vector or other constituents in the vaccine preparation. Here, we propose and discuss potential mechanisms in relation to adenovirus induction of VITT. We discuss adenovirus immunogenicity and interactions with platelets and other host proteins, the role of PF4 and platelet activation. Whilst confirming a single mechanism underpinning VITT is challenging, we provide insights and clues into areas warranting investigation into the mechanistic basis of VITT, highlighting the unanswered questions. Further research is required to help solidify a pathogenic model for this condition.

Emerging Concepts in Immune Thrombotic Thrombocytopenic Purpura

“…A similar remark can be made of COVID vaccines, where, at the time of writing, only 2 cases of relapsing iTTP (134,135) and 8 de novo iTTP cases (136)(137)(138)141) were identified, among many millions of doses administered currently in the world. In this context, it is important not to confuse iTTP with vaccineinduced thrombotic thrombocytopenia (VITT), which has different mechanisms compared to iTTP (142,143). Arguments for molecular mimicry in development of autoimmunity can still be made in the context of vaccines (144).…”

Mechanisms of Thrombosis in Heparin-Induced Thrombocytopenia and Vaccine-Induced Immune Thrombotic Thrombocytopenia

“…12 Comparatively, VITT is exceedingly uncommon, with published incidences ranging between 0.87 per million in central Europe to 8.6 per million in the United Kingdom. 14 The incidence of VITT appears to be 3 to 10 times higher following a dose of ChAdOx nCoV-19 compared with post-Ad26.COV2.S vaccination. 15 16 VITT generally occurs following the first, but not subsequent, dose of the vaccine, 17 with cases after the second dose being rare.…”

COVID-19 Vaccine-Associated Immune Thrombosis and Thrombocytopenia (VITT): Diagnostic Discrepancies and Global Implications

“…1 The autoantibodies bind to complexes of PF4, free deoxyribonucleic acid, and coating proteins of adenoviruses via the Fc portion of autoantibodies then onto platelet membranes to trigger activation and aggregation. 19 Following this, prothrombotic molecules are released and thrombin generation is promoted, and PF4 binds to heparin sulfate and chondroitin sulfate on vascular endothelial cells. Seven theories have been proposed recently to explain VITT.…”

“…Seven theories have been proposed recently to explain VITT. 19 However, the knowledge in this area is still developing to delineate the exact mechanism(s) behind VITT.…”