LAUSR

To the Editor, Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT) (also termed vaccine-induced thrombotic thrombocytopenia or vaccine-induced immune thrombocytopenia or thrombosis with thrombocytopenia syndrome (TTS) by the CDC and FDA) is characterized by (i) venous or arterial thrombosis; (ii) mild to severe thrombocytopenia ; (iii) positive antiplatelet factor 4 (PF4)–polyanion antibodies or anti-PF4-heparin antibodies detected by the HIT (heparininduced thrombocytopenia) ELISA assay (iv) occurring five to 24 days after ChAdOx1 nCoV-19 or Ad26.COV2.S vaccination [1]. In initial reports, patients were likely young and under 50 years, female (more than two thirds), median platelet counts at diagnosis about 20 to 30 × 109 L−1, no risk factors for thrombosis and faced unusual sites for thrombosis including cerebral sinus venous thrombosis (more than two thirds) or portal vein with high fatality rates. VITT is associated with the detection of anti-PF4 antibodies, unrelated to previous use of heparin therapy. Heparin-independent platelet activation, known as autoimmune heparin-induced thrombocytopenia (aHIT) was previously described in patients with positive antiPF4–polyanion antibodies [2]. Similarly to aHIT, PF4 antibodies are sought to activate platelets via the platelet FcγRIIA receptors, but there is to date no clear data supporting that PF4 is either a bystander component within an immune complex that activates platelets, or directly contribute directly to platelet aggregation [3]. Based on current evidence, the precise mechanisms and molecular pathways triggering the production of anti-PF4 antibodies after adenovirus vectored vaccines remain to be determined. The Ad26.COV2.S and ChAdOx1 nCoV-19 vaccines have different vaccine phenotypes with different host cell receptors and biological effects making unclear which component of the vaccine (adenoviral sequence, spike protein, other component) may be held responsible for the production of anti-PF4 antibodies. Potential risk factors for VITT may include young age and female sex while estrogen-replacement therapy or oral contraceptives were inconstantly reported among women. Moreover, no evidence to date is sufficient to establish a causal relationship between these events and hormonal therapy. The unusual topography and rare incidence for acute cerebral sinus venous thrombosis (CSVT), have led us to the hypothesis that procoagulant microparticles (MPs) enriched in phosphatidylserine (PS) and tissue factor (TF) may be important cofactors in the pathogenesis of VITT. Microparticles (MPs) refer to small vesicles, ranging from 0.1 to 2 μm, originating from the plasma membrane of stimulated or apoptotic cells including, platelets, * Olivier Morel [email protected]