Splanchnic vein thrombosis and/or Budd-Chiari Syndrome after SARS-COV-2 vaccination

Jul 30, 2021

The Coronavirus disease 2019 (Covid-19) pandemic and the coronavirus SARS-CoV-2 have dominated health care systems during the last 1.5 years. Worldwide, almost 200 million people were infected, leading to approximately 4 million deaths. In Europe, almost 33 million people were tested positive for Covid-19, leading to 750.000 deaths. The quick spread around the globe stimulated pharmaceutical companies to develop highly effective vaccines, which are currently widely in use. Safety data did not lead to major warnings, other than very rare cases of anaphylaxis. However, first reports on the ‘real-life’ use of ChAdOx1 nCoV-19 (Vaxzevria by AstraZeneca) described a new syndrome, characterized by severe thrombosis at unusual sites such as cerebral venous sinus thrombosis, splanchnic vein thrombosis, hepatic vein thrombosis or arterial thrombosis , all combined with thrombocytopenia. This syndrome is named Vaccine-induced immune Thrombotic Thrombocytopenia (VITT) (1, 2), or Thrombosis with Thrombocytopenia Syndrome (TTS).  These patients typically present with signs of diffuse intravascular coagulation (DIC) with highly elevated D-dimer, low or normal fibrinogen levels, normal or prolonged activated partial thromboplastin time (aPTT) or prothrombin time (PT), and an acute onset thrombocytopenia without other clear causes. Interestingly, in all patients, platelet-activating antibodies against platelet factor 4 (PF4) were found, similarly to those observed in heparin-induced thrombocytopenia (HIT), even though there was no heparin exposure (2). The majority of these cases occurred within the first 2-4 weeks following the first vaccination and occur mostly in women under 60 years of age. In these patients, administration of heparin and platelet transfusion should be avoided as it can cause disease progression.

As of June 27 2021, 51.4 million doses of ChAdOx1 nCoV-19 have been administered in the EU. Amongst these, a total of 479 cases (0.9 per 1 million) of suspected VITT have been reported to the European Medicines Agency (EMA) drug safety database EudraVigilance, of whom 100 (21%)  with fatal outcome (source: https://www.ema.europa.eu/en/documents/covid-19-vaccine-safety-update/covid-19-vaccine-safety-update-vaxzevria-previously-covid-19-vaccine-astrazeneca-14-july-2021_en.pdf). Moreover, similar thrombotic cases have been reported, albeit in smaller frequency, after the Johnson & Johnson/Janssen Ad26.CV2.S adenoviral vector vaccine, the Pfizer BioNTech mRNA vaccine, and the Moderna mRNA vaccine.

So far, only a fraction of these EMA reported cases have been further described in more detail by the scientific community. Several case reports and a handful of case series, the largest including 23 patients (Scully et al NEJM 2021), have been published so far. These primarily reported on VITT related cerebral vein sinus thrombosis  as this site appears most commonly affected (3). In several cases however, thrombosis occurs simultaneously at multiple sites with patients presenting with, for instance, combined cerebral venous sinus thrombosis, pulmonary emboli and splanchnic vein thrombosis. Patients with splanchnic or hepatic vein thrombosis have not been separately described in detail and little is known about their frequency, clinical presentation, comorbidities, disease progression, complications such as portal hypertension, or specific treatments other than anticoagulation such as vascular recanalization procedures. Moreover, most series have focused on describing this new entity with an emphasis on the diagnostic dilemma’s, laboratory results and general outcome in terms of survival and hospitalization, while more specific data on prothrombotic risk factors, treatment, portal hypertension  and mid-term outcome are lacking.

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The primary aim of the current study is to investigate the incidence of hepatic, portal, superior mesenteric and/or splenic vein thrombosis or Budd-Chiari syndrome (i.e. hepatic vein thrombosis) in the setting of VITT and to describe these cases in detail regarding 1) clinical presentation, 2) diagnostic work-up including other prothrombotic risk factors and exposure to one of the SARS-CoV-2 vaccines, 3) use of vascular recanalization procedures, 4) portal hypertensive complications or liver failure, 6) choice of anticoagulant treatment and response of thrombosis to anticoagulation, and 7) clinical mid-term / long-term outcome and treatment duration.

The secondary aim is to compare VITT cases of splanchnic, hepatic or portal vein thrombosis to cases of splanchnic and/or hepatic vein thrombosis unrelated to SARS-CoV-2 vaccination from the international Vascular Liver Disease Group (VALDIG), with regards to clinical and laboratory presentation, (other) risk factors for thrombosis, (anticoagulant) treatment and outcome.

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