Splanchnic vein thrombosis and/or Budd-Chiari Syndrome after SARS-COV-2 vaccination
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.
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.
COVID-19 Vaccine Efficacy and Safety in patients with Vascular Liver Disease
Vascular liver diseases (VLD) are a group of rare liver disorders consequence of alterations in the liver venous tree and of unknown etiology.
SARS-CoV-2 pandemic has led to a huge number of research studies in patients with liver disease that have demonstrated an increased risk of severe disease and death in patients with chronic liver disease (CLD). However, data on COVID-19 susceptibility, thrombotic risk and outcome in patients with VLD is not totally known.
In the last months, the Pfizer/BioNTech® BNT162b2 mRNA, Moderna® mRNA-1273, and the AstraZeneca®/University of Oxford ChAdOx1-nCoV-19 chimpanzee adenovirus vector vaccines have each reported excellent safety profiles have all gained rapid regulatory approval.
Due to the impact of SARS-CoV-2 in patients with CLD and the safe profile of vaccines, the European Reference Network (ERN) for hepatological disorders recommend and encourage vaccination of patients with rare liver disorders, including (VLD) (https://rare-liver.eu).
To better understand the profile and impact of SARS-CoV-2 vaccination in patients with VLD we propose to create a VALDIG-ERN registry to include VLD patients receiving COVID-19 vaccines with the aim of evaluating:
- Vaccine Efficacy
- frequency of post-vaccination SARS-CoV-2 infection
- Patient response (when available)
- anti-spike IgG antibodies and spike-specific CD4+ and CD8+ T cells
- Adverse events
- Liver-related complication and decompensation
- Due to the enhance thrombotic risk in patients with VLD, special interest will be paid on coagulation parameters and thrombotic events (both splanchnic and systemic)
The international nature of the study and the different vaccination policies in the participating countries, will allow to evaluate the impact of vaccine type. Moreover, having a big sample size will allow to group patients based on VLD phenotype and underlying disease.
Splanchnic vein thrombosis in patients with COVID-19 infection
The novel coronavirus pandemic leads to rapid dissemination around the world. COVID-19 has been causing death primarily due to pneumonia and respiratory failure. One of the complications which has been described in COVID-19 infection is the increased systemic inflammatory response from the virus which leads to a higher risk of hypercoagulability and associated thromboembolic disease [1, 2].
Splanchnic vein thrombosis occurring outside the setting of cirrhosis is a rare condition which is thought to account for 5% to 10% of all patients with portal hypertension in developed countries . It can be associated with severe complications such as gastrointestinal bleeding, portal biliopathy, and intestinal ischemia [4, 5]. Currently, only a few cases of splanchnic vein thrombosis have been reported in patients with COVID-19 . Considering the high risk of thrombotic events in patients with COVID-19 infection, the burden of splanchnic vein thrombosis should be assessed in a large series of patients.
- To assess the burden of splanchnic vein thrombosis in patients with COVID-19 infection
- To evaluate which splanchnic vein (hepatic, portal, mesenteric, splenic veins) are at risk of thrombosis during COVID-19 infection
- To assess the prevalence of other prothrombotic conditions than the hypercoagulable state induced by COVID-19
- To assess the impact of splanchnic vein thrombosis on the prognosis of patients with COVID-19 infection
- To assess the prognosis factors associated with poor outcome
- To assess the rate of recanalization without or under anticoagulation therapy
International Registry of Congenital Porto-Systemic Shunts (IRCPSS)
A multi-center, retrospective and prospective registry of neonates, children and adults with congenital porto-systemic shunts
Congenital portosystemic shunts (CPSS) are a rare malformation in humans the systemic repercussions of which are potentially severe. They include signs and symptoms such as hepatic encephalopathy, pulmonary vascular diseases, benign or malignant liver tumors and biological and metabolic disorders. The true incidence of CPSS is not known. CPSS can be diagnosed at any age either because the patient is symptomatic or as an incidental finding.
AIMS AND OBJECTIVES:
Given their rarity, patients presenting with symptoms of systemic complications may experience significant diagnostic delay. Understanding the pathophysiology and natural history in human subjects is paramount for management, something which this registry aims to capture by garnering important clinical, demographic, radiological, and biological information about patients with CPSS. Therefore, the aim of the International registry of congenital porto-systemic shunts (IRCPSS) is to characterize the natural history of CPSS, to identify subjects at risk of developing complications, with the overarching goal to improve and standardize care of patients with CPSS.
Abdominal surgery in patients with chronic extra-hepatic portal vein obstruction
This retrospective case-control study aims to evaluate the outcome after abdominal surgery in patients with non-cirrhotic chronic extra-hepatic portal vein obstruction (EHPVO), when compared to patients without EHPVO. Patients with known EHPVO who underwent abdominal surgery between 2000 and 2020 will be included, and compared with patients without EHPVO who had a similar surgical intervention. A special attention will be paid to portal-hypertension related complications, and bleeding complications.
- To retrospectively assess the outcome of adult patients with EHPVO who underwent abdominal surgery (except surgical portosystemic shunt).
- To retrospectively assess the impact of portal decompression (either surgical portosystemic shunt or radiological shunt) before or at the time of surgery on postoperative outcome.
Long-term outcome of patients with Budd-Chiari Syndrome
Background: Budd Chiari Syndrome is a rare vascular liver disease with major deleterious complications if not treated and intervened on time. Current literature recommends stepwise treatment of BCS, based on a progressively escalating invasiveness with a good overall Overt Liver Transplantation free survival.
However currently there are no definite consensus on long-term follow-up studies to aid to protocolize management on the choice of best treatment for each individual and the correct timing on when make the clinical decision of stepping up on the treatment algorithm.
Methods: European Retrospective multicentric study
AIMS AND PURPOSE OF THE STUDY:
- To assess the long-term outcome of patients with BCS.
- To evaluate the incidence and predictive factors of interventions in patients with BCS on the long-term outcome.
- Establish the best treatment for patients with BCS that initially received a TIPS in whom during follow-up an asymptomatic thrombosis/dysfunction of TIPS occurs.
Incidence and predictive factors of recurrent thrombosis in non-cirrhotic portal vein thrombosis. VALIDATION COHORT.
Background: Recurrent thrombosis (or rethrombosis, RT) is one of the main threats of chronic non-cirrhotic portal vein thrombosis (NC-PVT). Clinical guidelines only recommend long-term anticoagulation to prevent rethrombosis in patients with a recognized prothrombotic disorder or with a previous history of intestinal venous ischemia or thrombosis.
To describe the rate of rethrombosis in NC-PVT and to identify its predictive factors.
Previous results: We included 114 patients with NC-PVT due to myeloproliferative neoplasm (n=29), thrombophilia disorders (n=12), exclusively local factors (n=36) or idiopathic PVT (n=37). According to current guidelines, patients with prothrombotic disorders were on long-term anticoagulation (except for those with specific contraindications) while most patients with idiopathic/local factor were not anticoagulated. Patients were followed-up with regular scheduled imaging studies, and RT was identified in 17 patients, with a cumulative probability of rethrombosis of 2.6%, 12.9% and 19.2% at 1, 5 and 10 years respectively. Most RT (82%) occurred in the subgroup of patients with idiopathic/local etiology not receiving long-term anticoagulation. In this subpopulation, factor V ≥90% and factor VIII≥150% were independently associated with RT.
VALIDATION COHORT: We aim at validating these results that suggest that patients with idiopathic or associated with chronic PVT not receiving long term anticoagulation that present high levels of Factor V and/or factor VIII are at higher risk of re-thrombosis.
Methods: enrollment of patients with idiopathic/local factor chronic PVT that have not received long-term anticoagulation in which the extension of the thrombosis has been thoroughly established at baseline and that have had a periodical imaging follow-up that ensured the detection of asymptomatic re-thrombosis during follow-up.
Regarding the determination of factor V and VIII, as they are not routinely included in most thrombophilia studies these patients will need to have a biobank plasma sample to do this analysis. The biobank sample should have been obtained not long after the chronic PVT diagnosis.
Percutaneous Portal Vein Recanalization using Self-Expandable Nitinol Stents in Patients with Non-cirrhotic Non-tumoral Portal Vein Occlusion
This retrospective study tries to determine when portal vein recanalization (PVR) is useful in case of symptomatic portal vein occlusion (PVO). Based on previous experience, portal vein recanalization (PVR) could be a therapeutic option in patients with symptomatic portal vein obstruction (PVO) when at least a portion of the segmental branches of the largest liver segments (V or VIII) remained patent. In the present study, we would like extend our experience in this field by collecting data from patients with PVO from the European vascular disease of the liver group VALDIG. Patients with PVO who underwent PVR after 2010 will be included. Data from patients with PVO from the European vascular disease of the liver group VALDIG will be retrospectively reviewed and follow-up data will be updated. We will classify patients according to the vascular extent of PVO before PVR and assess long-term stent patency in patients with and without TIPS insertion, in those who received and who did not receive anticoagulation therapy, and to the type and duration of treatment.
The main aim of this study will be to validate the usefulness of the classification of PVO according to the vascular extent of PVO to decide when PVR is feasible. In addition, we also aim to assess the effect of anticoagulation therapy on long-term stent patency and to assess the benefit of TIPS in addition to PVR on long-term stent patency.
Development of portal hypertension after acute portal vein thrombosis. A long-term follow-up study
Background: A few studies have evaluated the long-term evolution of patients after APVT. Previously studies the follow-up was relatively short (a median of 4 years follow-up in patients with a much longer life expectancy).
Hypothesis: Patients with APVT have a risk of developing long-term PHS, regardless of recanalization. Also, recanalized patients can develop PHS due to liver parenchyma distortion after APVT, presence of portal sinusoidal vascular disease, micro-thrombosis or failure to identify small vessel thrombosis by conventional imaging studies.
• Main Objective of the study : Evaluate in a large cohort of patients with Non-cirrhotic APVT, with at least 12m of follow up after diagnosis, the risk of developing PHS in relation to the degree of recanalization achieved with treatment.
• Objective 2: Identificacion of factors predicting recanalization, survival, high-risk esophageal varices, variceal bleeding, ascites, hepatic encephalopathy, portal cholangiopathy, presence of porto-systemic shunts and re-thrombosis episodes.
• One of main inclusion criteria: Is to have one contrast-enhanced CT scan or MRI staging the extension of APVT at diagnosis and other image study during follow-up, more than 12m.
Menopause, female hormones and PSVD
Background: Although the exact pathogenetic mechanism of PSVD is not fully understood but a possible key element is formation of microthrombi in the small portal branches causing presinusoidal portal hypertension.
Before menopause, women are reasonably protected against venous thrombosis by their circulating estrogens; nevertheless, this protection ends after menopause.
On the other hand hormonal therapy (oral contraceptives and postmenopausal replacement therapy) increases the risk of venous thromboembolism and whether it may impact PSVD development is unknown.
- Evaluate the impact of female hormones in PSVD onset/progression
- Evaluate the association between PSVD onset and menopausal state
- Evaluate the frequency of hormone therapy in women with PSVD, both in pre and postmenopausal women
- Determine the impact of hormone therapy in the severity of PSVD
Natural history of Portosinusoidal Vascular Disease (PSVD) and Liver Transplantation
Background: Patients with PSVD usually have preserved liver function, however sometimes liver transplantation is required.
Factors predicting the need of OLT and the real applicability in IPH patients are not known.
Post-OLT outcome has never been reported in a large cohort of patients.
Methods: European Retrospective multicentric study
- To evaluate in a large international cohort of consecutive patients diagnosed of IPH followed in centers of the VALDIG.
- Factors predicting the need of OLT and the applicability in real life.
- Evaluate the long term outcome of patients with PSVD that had been submitted to LT (survival, recurrence..).
Medically assisted reproduction in women with vascular liver diseases
This retrospective study tries to determine the safety and efficacy of medically assisted reproduction in women with known Budd-Chiari syndrome, portal vein thrombosis or porto-sinusoidal vascular disease. Women with vascular liver diseases who underwent medically assisted reproduction between 2000 and 2018 will be included. This includes controlled pharmacologic stimulation of ovarian follicles, paired or not with assisted reproduction technologies. Vascular liver disease should be diagnosed prior to medically assisted reproduction.
The aim of this retrospective study is thus to determine the safety and efficacy of medically assisted reproduction in women with known Budd-Chiari syndrome, portal vein thrombosis or vascular porto-sinusoidal disease.
PNH and Splanchnic Vein Thrombosis
Data from patients with PNH and splanchnic vein thrombosis from the European vascular disease interest group VALDIG and French vascular network will be retrospectively reviewed. Only patients with a diagnosis of splanchnic vein thrombosis made between 2000 and 2016 will be included.
We will compare the evolution of thrombosis in patients who received a “curative” treatment for PNH, including eculizumab and bone marrow transplantation, to patients who did not receive one of these 2 types of treatments, either because it was not available or when the patient did not have HLA compatible donor.
VALDIG Database and Registry
Vascular diseases of the liver are a heterogeneous group of rare and if untreated fatal disorders that include portal vein thrombosis, Budd-Chiari syndrome, non-cirrhotic portal hypertension, sinusoidal obstruction syndrome, hereditary hemorrhagic teleangiectasia and others.
Current knowledge about patients suffering from these disorders is insufficient and no biological samples are available to study the mechanisms of these diseases and the effects of treatments.
Therefore, with the support of a grant from EASL, we are running this cohort study by including and following up patients on the platform redcap.ctu.unibe.ch. If you are member of VALDIG you can request a password and username (contact email@example.com) to participate to this study by including patients from your center into the database (a complete set of data) or into the registry (a limited set of data).
- To characterize the population with vascular liver disease in Switzerland by defining history, outcome and risk factors.
- To build a bio-bank with blood from these patients.
For more information and the study descriptions see here