Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT): Targeting Pathomechanisms with Bruton Tyrosine Kinase Inhibitors

Thromb Haemost. 2021 Nov;121(11):1395-1399. doi: 10.1055/a-1481-3039. Epub 2021 May 28.


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 coronavirus disease 2019 (COVID-19) vaccine AZD1222 (Vaxzevria) have 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 initially vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) and renamed recently vaccine-induced immune thrombotic thrombocytopenia (VITT). It 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 VITT 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 VITT, as they are expected to pleiotropically target multiple pathways downstream of FcγRIIA-mediated Btk activation, for example, 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, C-type lectin-like receptor 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 a sufficiently safe option to treat VITT.

Publication types

  • Review

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase / antagonists & inhibitors*
  • Agammaglobulinaemia Tyrosine Kinase / metabolism
  • Animals
  • Autoantibodies / blood
  • Blood Platelets / drug effects*
  • Blood Platelets / enzymology
  • Blood Platelets / immunology
  • COVID-19 Vaccines / administration & dosage
  • COVID-19 Vaccines / adverse effects*
  • ChAdOx1 nCoV-19
  • Humans
  • Molecular Targeted Therapy
  • Platelet Activation / drug effects*
  • Platelet Factor 4 / immunology
  • Protein Kinase Inhibitors / therapeutic use*
  • Purpura, Thrombocytopenic, Idiopathic / blood
  • Purpura, Thrombocytopenic, Idiopathic / drug therapy*
  • Purpura, Thrombocytopenic, Idiopathic / enzymology
  • Purpura, Thrombocytopenic, Idiopathic / immunology
  • Receptors, IgG / metabolism
  • Signal Transduction
  • Vaccination / adverse effects*


  • Autoantibodies
  • COVID-19 Vaccines
  • FCGR2A protein, human
  • PF4 protein, human
  • Protein Kinase Inhibitors
  • Receptors, IgG
  • Platelet Factor 4
  • ChAdOx1 nCoV-19
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human