Genetic predisposition to vaccine‐induced immune thrombotic thrombocytopenia

Abstract

Vaccine‐induced immune thrombotic thrombocytopenia (VITT) is a rare prothrombotic disorder with a unique clonality‐restricted immunological profile. The study by Petito and Bury et al. provides insight into the role of HLA polymorphisms and an inherent predisposition to VITT.

Commentary on: Petito et al. Association of human leucocyte antigen loci with vaccine‐induced immune thrombotic thrombocytopenia: Potential role of the interaction between platelet factor 4‐derived peptides and MHC‐II. Br J Haematol 2025; 206:290‐295.

Vaccine‐induced immune thrombotic thrombocytopenia (VITT) first emerged as a new thrombotic syndrome that seemed to affect young people at random after receiving the COVID‐19 adenoviral vaccine. With the massive roll‐out of COVID‐19 vaccination campaigns globally in December 2020, millions of people were exposed to adenoviral vector vaccines simultaneously and clusters of VITT patients began to emerge with the sudden onset of thrombocytopenia and thrombosis, often leading to critical illness, stroke and death. Investigators noted similarities between VITT and heparin‐induced thrombocytopenia (HIT), another thrombocytopenic and thrombotic condition and subsequently identified antibodies against platelet factor 4 (PF4) in all affected patients. The recognition of VITT has heightened awareness about clinically similar anti‐PF4 syndromes that can occur in the context of community‐acquired adenoviral infections, monoclonal gammopathy of undetermined significance or spontaneously. ¹ Ongoing research into the immunological mechanisms of VITT is crucial to further our understanding of these related conditions and to elucidate the cause of this unique immune response.

While the incidence of VITT has been widely cited as 1:100 000 vaccinated persons, the frequency appears to differ across countries despite shortcomings in surveillance programmes, reporting bias and variability in access to vaccines. For example, the incidence in Norway (approximately 1 in 26 500) ² appeared to be higher than the United States (approximately 1 in 263 000) ³ and seemingly much higher than India ⁴ These regional differences suggest that, in addition to demographic variations and environmental influences, genetic predisposition may play a role in VITT susceptibility. Additionally, restricted clonality of VITT antibodies has been demonstrated ⁵ with compelling molecular studies showing similar amino acid sequences of VITT antibodies from six VITT patients from across the world. ⁶ , ⁷ These data suggest that a restricted clone of immune cells is responsible for the robust immune response that results in pathogenic anti‐PF4 antibodies.

The immune response in HIT has been well characterized, and it is likely that VITT and other anti‐PF4 syndromes have similar immunological patterns. In HIT, pathogenic anti‐PF4 immunoglobulin G (IgG) antibodies develop rapidly, within 5–10 days after heparin exposure and are frequently accompanied by anti‐PF4 IgM and IgA. The IgG anti‐PF4 antibodies disappear rapidly and do not return even after repeated exposure to heparin. ⁸ This IgG‐predominant pattern resembles a secondary immune response but without the typical immune memory. ⁹ VITT has a similar immune profile, with high titre anti‐PF4 IgG antibodies that develop at the outset with no evidence of recurrence even after re‐exposure to adenoviral vector vaccines. ¹⁰ One notable difference between VITT and HIT immune responses is that VITT antibodies can persist for months or years, ¹¹ whereas HIT antibodies last only 3–4 months. ⁸

The report by Petito and Bury et al. helps elucidate the immunological underpinnings of VITT (REF current paper). The researchers identified three HLA polymorphisms that were overrepresented in Italian patients with VITT compared with a sample from the normal Italian population: HLA‐DPB1*17:01, HLA‐DQA1*05:01 and HLA‐DRB1*11:04. Some of these associations were very strong with odds ratios high enough to move these observations from a probabilistic association (i.e. risk factor) to a more deterministic one (e.g. necessary and/or sufficient). Effect sizes were higher than HLA‐B27 polymorphisms and ankylosing spondylitis, ¹² or HLA‐DRB3*01:01 and alloimmunization to platelet antigen HPA‐1 in fetal neonatal alloimmune thrombocytopenia. ¹³

In addition to HLA polymorphisms, the investigators used in silico analysis to identify a specific PF4‐derived peptide with high binding potential for one of the polymorphisms (HLA‐DRB1*11:04). The peptide was known to be part of the binding site for anti‐PF4 antibodies on PF4. This finding supports the hypothesis that the specific VITT immune response is oligoclonal or potentially monoclonal unlike typical primary immune responses, which are polyclonal in nature. Thus, a single or few existing leucocyte clones could be responsible for the production of VITT antibodies. Taken together, these results indicate that certain individuals may be predisposed to develop clonally restricted VITT antibodies when challenged with adenoviral vector vaccines.

While promising, the results of this case–control study should be considered preliminary until they can be verified externally. With only 16 VITT patients, estimates of effect are unstable. Moreover, the use of a general sample of the population as the control group could have inflated the strength of the associations. Ideally, control populations for genetic studies such as this should be matched for key characteristics (e.g. age, sex, comorbidities) and the technologies used to identify common alleles should be the same for cases and controls. In addition, the inclusion of patients with probable VITT may have obscured the results, since the misclassification of even a single patient could significantly alter the estimates of effect. The authors allude to this fragility in their subgroup analysis of the 11 patients with definite VITT, which identified an additional HLA polymorphism (and HLA‐DQB1*02:01) and strengthened the association with others. Furthermore, while the identification of a single peptide that can bind an HLA molecule may indicate a limited clonal response, in silico determinations are computational predictions only and they do not account for the complexity of biological systems, post‐translational protein modifications and the dynamic nature of peptide‐HLA interactions in vivo. Thus, the results of this singular small study with imperfectly matched controls requires validation, which should be feasible since cohorts of VITT patients continue to be followed longitudinally in other countries including Canada, Australia, United Kingdom and Germany. ¹⁴

In conclusion, the study by Petito and Bury et al. provides insight into the role of HLA polymorphisms in VITT and supports the concepts of (1) an inherent immune predisposition to this rare disease and (2) a unique monoclonal or oligoclonal immune response. Once verified, these results could open a new line of inquiry into the biology of anti‐PF4 disorders and pave the way for immunological risk stratification models for anti‐PF4 disorders including VITT and HIT.

Arnold DM, Paré G, Nazy I. Genetic predisposition to vaccine‐induced immune thrombotic thrombocytopenia. Br J Haematol. 2025;206(1):387–388. 10.1111/bjh.19885