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.

SARS-CoV-2 Vaccine and Thrombosis: An Expert Consensus on Vaccine-Induced Immune Thrombotic Thrombocytopenia

“…The appearance of these autoantibodies in cases of exaggerated inflammatory response probably by the adenoviral vector, which triggers the release of PF4 contained in the platelets, could be responsible for multicellular activation with massive generation of thrombin, platelet consumption and severe thrombogenicity (36).The inflammatory reaction can cause "NETosis" or "immunothrombosis" with the release of leukocytic DNA, which supports the formation of microthrombi (37)(38)(39). Disproportionate post-vaccination inflammation can also increase endothelial adhesiveness and the release of tissue factor, a real trigger of the generation of thrombin, a key enzyme in coagulation (33,36). An important point is that this thrombotic and thrombocytopenic symptomatology occurred after the first vaccine injection, with intervals to detection ranging from 4 to 28 days (40).…”

“…Of note, particular care should be taken to ensure that these reported cases of thrombosis are not related to a SARS-CoV-2 infection concomitant with the vaccination. Not all the reported patients were tested for other immune and systemic conditions that might be responsible for complement pathway activation, inflammation and coagulation in order to explain an idiosyncratic reaction (36). All UK patients had a negative SARS-Cov-2…”

The Role of CLEC-2 and Its Ligands in Thromboinflammation

“…Besides, Btk is essential for platelet CLEC-2 (88). In heparin-induced thrombocytopenia, Btk inhibitors reduce CLEC-2-and GPIb-mediated platelet activation, monocyte interaction and activation, and neutrophil extracellular trap release (89). In addition, Btk inhibitors likely to reduce the microvascular and venous thrombosis in COVID-19 by blocking platelet CLEC-2, and well reduce thrombosis without an associated increase in bleeding (90), providing a new idea for the selective targeting of thrombotic inflammatory diseases.…”

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

“…Whether for COVID-19 or vaccine-related thrombosis, the use of alternate anticoagulants, and possibly IVIG, should be considered [111,112,122,190,[192][193][194]. More likely than not, once the pathogenesis of this phenomenon is better understood, other forms of therapy will emerge [122,195]. Furthermore, changes as to how the vaccines will be recommended and used are likely to occur [196].…”