Thrombosis in VEXAS syndrome

Abstract

VEXAS syndrome, an autoinflammatory syndrome due to a Ubiquitin Like Modifier Activating Enzyme 1 (UBA1) somatic mutation, has a high thrombotic burden. We report a case of a 69-year-old male that was diagnosed with VEXAS syndrome who developed venous thromboembolism (VTE). Review of literature of existing VEXAS syndrome cases showed a high thrombotic burden, with the reported incidence of VTE (36.4%) being markedly higher than arterial thrombosis (1.6%), with deep vein thrombosis being more common than pulmonary embolism. Somatic mutation in the UBA1 gene results in decreased ubiquitylation which is a key driver in the development of thrombosis in VEXAS syndrome, due to chronic inflammation and cytokine release from abnormal crosstalk between the intrinsic effector mechanism of innate immune cells, platelets and endothelium resulting in dysregulated haemostasis and endothelial dysfunction. Targeting endothelial dysfunction and reducing inflammatory milieu causing hypercoagulability with immunosuppressants and immunomodulatory agents, together with anticoagulation may be the strategy to prevent recurrent thrombotic events.

Keywords: Genetics; Inflammation; Mutation; Thrombosis; VEXAS Syndrome; Venous Thromboembolism.

Fig. 1

Virchow’s triad showing key molecular and cellular mechanisms of thrombosis in VEXAS syndrome. Somatic mutation of the UBA1 gene on the X chromosome causes decreased ubiquitylation leading to the activation of innate immune pathways. Subsequently, acquired activation of B and T cells gives rise to excess cytokine production, enhanced neutrophil cellular trap formation, uncontrolled monocyte activation, platelet aggregation, and ultimately thrombus formation due to hypercoagulability. Antiphospholipid antibodies contribute towards the activation of platelets and monocytes through complement activation, followed by activation of the coagulation cascade. Accompanying haematologic malignancies such as myeloma and myelodysplastic syndrome will heighten the hypercoagulability favouring the thrombosis in VEXAS syndrome. Medium-sized vasculitis due to multisystem autoinflammation also leads to further endothelial dysfunction, resulting in a higher risk of thrombosis. UPR unfolded protein response, TNF tumour necrosis factor alpha, IL-8 interleukin 8, IL-6 interleukin 6, IFN- γ interferon- γ, IP-10 interferon-inducible protein 10, WPB Weibel − Palade bodies, aPL antiphospholipid antibodies, ®2-GP beta2 glycoprotein, PSGL-1 P-selectin glycoprotein ligand-1

Fig. 2

A: CT thorax showing filling defects (white arrows) in bilateral main pulmonary arteries. B: Bone marrow aspirate with an abnormal myelomonocytic cell (black arrow) with cytoplasmic vacuolation