key: cord-0987119-jp7sn5ro
authors: Geeraerts, Thomas; Montastruc, François; Bonneville, Fabrice; Mémier, Vincent; Raposo, Nicolas
title: Oxford-AstraZeneca COVID-19 vaccine-induced cerebral venous thrombosis and thrombocytopaenia: A missed opportunity for a rapid return of experience
date: 2021-05-24
journal: Anaesth Crit Care Pain Med
DOI: 10.1016/j.accpm.2021.100889
sha: 14ac246cd2deb2cf7f1722e37240b53676311cf8
doc_id: 987119
cord_uid: jp7sn5ro

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We were aware of the possibility of cerebral venous thrombosis after COVID-19 vaccination, and the declaration to our regional pharmacovigilance centre was made on the 23 rd of March 2021. We would like, however, to share the difficulties we had to find reliable clinical information in this context.

Our knowledge of the pathophysiology and therapeutic possibilities was very limited. Several major issues were questioned as the performances of detection methods for antibodies against platelet factor 4 (PF4)/heparin complex, possible efficacy of steroids, intravenous immunoglobulins, plasma exchange, or choice of anticoagulants. In case this test is negative, a heparin-induced thrombocytopaenia (HIT)-like specific immunological cause of thrombosis/thrombocytopaenia can be ruled out… and critical thromboses such as sinus/cerebral or splanchnic vein thrombosis, the prothrombotic pathomechanism can very likely be interrupted by the administration of high-dose intravenous immunoglobulins… "

This was the only reliable information we had at this time. Without information and feedback from similar cases, we felt like engaging in shady dealings without really understanding the pathophysiological processes of the disease and the risks/benefits balance of therapeutic options.

In the first days of the management of these patients, we organised videoconference meetings with the local and national experts (vascular neurologists, neuro-intensivists, neuroradiologists, haemostasis specialists, internal medicine and virologists) sharing the knowledge and the possible cases occurring in France and around the world.

In our two patients, the anti-PF4 antibodies were negative (Latex Immunoturbidimetric Assay HemosIL® HIT-Ab (PF4-H) performed using the ACL TOP® instrument). Despite early and aggressive treatment of these two cases of severe cerebral venous thrombosis, the medical management of anticoagulant therapy and thrombocytopaenia in this specific postvaccination context was complex. The predominantly thrombotic clinical expression and the absence of anti-PF4 antibodies, which could have been evidence of spontaneous heparininduced thrombocytopaenia, led to consider that thrombocytopaenia was of autoimmune mechanism that may be induced by vaccine. Thrombotic anti-phospholipid syndrome was ruled out in both patients by negative testing for Lupus anticoagulants, anticardiolipin antibodies (ELISA), and anti-β2-glycoprotein I antibodies in plasma. The JAK2 V617F mutation was not present. Paroxysmal nocturnal haemoglobinuria was ruled out in both patients by absence of haemolytic anaemia and normal levels of bilirubin, haptoglobin and reticulocytes.

In the hypothesis of immunological thrombocytopaenia, heparin was continued and associated with corticosteroids followed by intravenous immunoglobulins in one patient.

Later, we had the confirmation of a definite case of a Vaccine-induced Immune cerebral venous Thrombosis and Thrombocytopaenia (VITT syndrome) with the help of an expert laboratory and the detection of significant levels of IgG antibodies to PF4 by ELISA when the samples were analysed with the method using polyvinylsulfonate-PF4 (LIFECODES PF4 IgG, Immucor®) and with strong platelet activation confirmed by a sensitised PF4-supplemented Serotonin Release Assay [1] .

Unfortunately, both patients had unfavourable outcome with refractory intracranial hypertension leading to death. More than 10 days after the death of our two patients, cases of VITT were published online the 9 th and 16 th of April [2] [3] [4] , representing a total of 39 cases. (https://www.theguardian.com/society/2021/apr/13/how-uk-doctor-marie-scully-bloodclotting-link-astrazeneca-covid-jab-university-college-london-hospital). Exchange of information on a daily basis was performed through e-mails to colleagues and creation of a WhatsApp group. This probably allowed an effective exchange of information between members of this group, but did not allow an effective feedback to those outside the group.

Professional networks, sometimes linked to scientific societies, can probably contribute a lot by allowing contact between physicians, quickly drafting guidelines and disseminating them through their usual network. They are however highly dependent on effective early warning systems.

We propose that, in the case of serious and life-threatening conditions, pharmacovigilance agencies, in addition to collecting and analysing serious events, should propose the possibility of a rapid contact between clinicians who have reported similar events via an exchange of e-mail addresses or the creation of discussion forums, on a global and

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