Vaccine-induced immune thrombotic thrombocytopenia (VITT): targeting pathomechanisms with Bruton tyrosine kinase inhibitors.

Abstract

A series of cases with rare thromboembolic incidents including cerebral sinus vein thrombosis (some of them fatal) and concomitant thrombocytopenia occurring shortly after vaccination with the COVID-19 vaccine AZD1222 (Vaxzevria) has caused significant concern and led to its temporary suspension in many countries. Immediate laboratory efforts in four of these patients have identified a tentative pathomechanism underlying this syndrome termed vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) or vaccine-induced thrombosis with thrombocytopenia (VITT), which encompasses the presence of platelet-activating antibodies to platelet-factor 4/heparin complexes, possibly emulated by polyanionic constituents of AZD1222, and thus resembles heparin-induced thrombocytopenia (HIT). Because these immune complexes bind and activate platelets via Fcγ-receptor IIA (FcγRIIA), high-dose intravenous immunoglobulin G has been suggested for treatment of VIPIT in addition to non-heparin anticoagulants. Here we propose inhibitors of Bruton tyrosine kinase (Btk) approved for B-cell malignancies (e.g. ibrutinib) as another therapeutic option in VIPIT, as they are expected to pleiotropically target multiple pathways downstream of FcγRIIA-mediated Btk activation, e.g. as demonstrated for the effective inhibition of platelet aggregation, dense granule secretion, P-selectin expression and platelet-neutrophil aggregate formation stimulated by FcγRIIA cross-linking. Moreover, CLEC-2- and GPIb-mediated platelet activation, the interactions and activation of monocytes and the release of neutrophil extracellular traps, as encountered in HIT, could be attenuated by Btk inhibitors. As a paradigm for emergency repurposing of approved drugs in COVID-19, off-label use of Btk inhibitors in a low dose range not affecting haemostatic functions could thus be considered as a sufficiently safe option to treat VIPIT.