key: cord-0068411-ikeijj9n authors: Corica, Bernadette; Cacciani, Antonella; Cangemi, Roberto; Visentini, Marcella; Recchia, Fabrizio; Grillo, Rosalba; Vano, Marco; Sperduti, Nicolò; Cincione, Alessandro; Buoninfante, Giovanni; Pulcinelli, Fabio; Chistolini, Antonio; De Santis, Adriano; Flego, Davide; Romiti, Giulio Francesco; Basili, Stefania; Stefanini, Lucia title: Clinical course, management, and platelet activity assessment of splanchnic VITT: A case report date: 2021-10-13 journal: Thromb Res DOI: 10.1016/j.thromres.2021.10.008 sha: 6ade0c3fc694723f5572a7c266ced3f4ec6fc2d4 doc_id: 68411 cord_uid: ikeijj9n nan The Coronavirus Disease (COVID- 19) pandemic imposes a high burden of morbidity and mortality worldwide. Several vaccines have been developed to curb the plague and currently represent the most important weapon for this fight. The currently available SARS-CoV-2 vaccines are either lipid nanoparticle/mRNA-based or adenoviral vector vaccines. These vaccines proved effective in preventing severe disease and death in phase-III randomized clinical trials, without significant safety warnings. (1, 2) This led to worldwide approval and mass administration. Shortly after, a rare syndrome characterized by atypical thrombosis and thrombocytopenia was described. (3) (4) (5) (6) This syndrome, defined as "vaccine-induced immune thrombotic thrombocytopenia" (VITT) (7, 8) , mainly occurred among otherwise healthy adultsmostly women, all vaccinated with SARS-CoV-2 adenoviral vector vaccines (3) , with an estimated prevalence of approximately 1 every 100.000 vaccinated adults (9) . Cerebral venous thrombosis was the most frequent type of thrombosis recorded, with splanchnic thrombosis described only in exceptional cases (5) . The pathogenesis, diagnosis, and optimal treatment of VITT are largely unknown. A role for anti-platelet factor 4 (PF4) antibodies in its pathogenesis has been postulated(10), with high uncertainty on the underlying mechanisms, and poor knowledge of the platelet reactivity throughout the disease course. Interim guidance has been developed to aid physicians in treating this syndrome, with anticoagulation and high dose intravenous immunoglobulin (IVIG) currently proposed as first-line therapies (11) . Plasma exchange (PE) has been described once as a tentative treatment for patients with refractory VITT (12) , but further confirmation are urgently needed to validate its use. Physical examination showed cutaneous purpura with a blister in the right arm, and diffuse tenderness of the abdomen, without rebound or rigidity; bowel sounds were present, without jaundice or pallor. The patient was discharged on day 39 in good clinical conditions, on treatment with fondaparinux 10 mg/die, prednisolone 25 mg, and is now attending scheduled follow-up visits. PLTs count remained above 170.000/mm 3 during follow-up, and we also observed normal levels of PAC1-FITC and active/total integrin ratio. The patient is still treated with fondaparinux and is currently undergoing steroids tapering. No relapsing or new thrombotic events were observed during follow-up. VITT is a rare adverse event of viral vectored SARS-CoV-2 vaccines. Most cases occurred in young adults (typically <60 years old), particularly women, without overt risk factors or known thrombophilia (14) . In our case, three major remarks should be made: first, the epidemiology and natural history of VITT is still largely unknown (our case occurred in a middle-aged man, and the thrombosis involved an uncommon and extensive vein district); second, refractory VITT may be treated effectively with PE, as previously described in a recent case series (12) ; third, knowledge on the platelet activation state during the course Beyond that, the mechanisms underlying VITT are still largely unknown (15) . Similar platelet signalling patterns have been reported among patients with COVID-19-related thrombosis and VITT, suggesting that common mechanisms may be involved (16, 17) . A recent report demonstrated that the different binding properties of anti-PF4 antibodies detected in VITT and heparin-induced thrombocytopenia patients could explain why in the former, but not in the latter, antibodies do not need heparin to crosslink the FcγIIA receptor and activate platelets (18) . Alternatively, one could envisage that the nucleic acids contained in the vaccines promote the antibody crosslinking since previous reports showed that nucleic acids can bind PF4 (19) . All these hypotheses, however, still need confirmation in vivo, and insights on platelet activation during VITT course are urgently needed. In our case, the median fluorescence intensity of PAC1-FITC (that binds active αIIbβ3 on platelets), and the ratio of active/total integrin followed the thrombotic evolution mediated by anti-PF4 antibodies. Thus, we postulate that platelet integrin activation could represent a promising tool to diagnose and monitor the progression of VITT. This case underlines the high uncertainty surrounding our knowledge of VITT, particularly regarding risk factors, clinical presentation, and treatment, as for COVID-19 (20) . While VITT is a rare event, and further studies are required to confirm our findings on PE efficacy and platelet reactivity, we believe that granular reporting of VITT cases is helpful to inform clinical practice and tackle the burden of VITT during this vaccination campaign. This case contributes to expand the knowledge on VITT and PE approach and suggests that flow cytometric analysis of integrin activation could be used to improve the surveillance of Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, singleblind, randomised controlled trial Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination Successful treatment of acute spleno-portomesenteric vein thrombosis after ChAdOx1 nCoV-19 vaccine. 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Qeios [Internet] 2021 Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19 Antibody epitopes in vaccine-induced immune thrombotic thrombocytopenia Complex formation with nucleic acids and aptamers alters the antigenic properties of platelet factor 4 Embracing the Uncertainty: an Important Lesson from COVID-19 We thank the patient, who reviewed the manuscript, for giving his consent to publication.We thank Prof. Antonio Angeloni, Dr. Shafii Bafti Mahnaz, Dr. Martina Di Palma and the Immunohematology and Transfusion Medicine Unit of Policlinico Umberto I, SapienzaUniversity of Rome, Italy for their involvement in the case management.