Proposed mechanism for rare thrombotic events after use of some Covid-19 vaccines

Abstract

Administration of AstraZeneca/Oxford and Johnson & Johnson/Janssen Covid-19 vaccines which use an adenovirus vector for DNA delivery has been associated with very rare thromboembolic complications coupled with an immune response to platelet factor 4 protein. The cause of this has not yet been identified. It is known that binding of coagulation factor proteins to the surface of some adenoviruses can protect their function. Here I propose that the thromboembolic events are caused by impairment of coagulation factor X binding to the virus capsid. The unprotected capsid then stimulates an immune response leading to platelet activation, increased thrombogenicity and formation of an antibody complex with platelet factor 4. Impaired binding of factor X may be due to an undiagnosed mutation in affected individuals. Options to test this mechanism experimentally and potential remedial actions to resolve the hazard are described. This mechanism offers a remedial route to address concerns about the safety of these vaccines, which are otherwise well-positioned to deliver global Covid-19 immunity across diverse healthcare economies.

Keywords: Adenoviridae; COVID-19 vaccines; Factor X; Thrombocytopenia; Venous thrombosis.

Fig. 1

Schematic of mechanisms for thrombotic response to adenovirus Covid-19 vaccine. Panel A, normal mechanism: adenovirus vector binds endogenous factor X, preventing interaction with IgM, complement and platelet factor 4 (PF4). Outcome: no VITT. Panel B, adverse mechanism 1: adenovirus is unprotected by factor X, allowing interaction with IgM, promoting complement activation and activated/aggregated platelet-release of prothrombotic components including PF4 and polyphosphate. PF4-IgG immune complexes are formed. Outcome: up-regulation of coagulation and VITT.Panel C, adverse mechanism 2: adenovirus is unprotected by factor X, allowing PF4 binding to the polyanionic (possibly polysulfated) capsid surface. Adenovirus-PF4-IgG complexes are formed, activating complement and platelets. Outcome: up-regulation of coagulation and VITT.