Shedding Light on the Pathogenesis of Splanchnic Vein Thrombosis.

Splanchnic vein thrombosis is a rare but potentially life-threatening manifestation of venous thromboembolism, with challenging implications both at the pathological and therapeutic level. It is frequently associated with liver cirrhosis, but it could also be provoked by myeloproliferative disorders, cancer of various gastroenterological origin, abdominal infections and thrombophilia. A portion of splanchnic vein thrombosis is still classified as idiopathic. Here, we review the mechanisms of splanchnic vein thrombosis, including new insights on the role of clonal hematopoiesis in idiopathic SVT pathogenesis, with important implications from the therapeutic standpoint.

Acute Necrotizing Pancreatitis Complicated by Multiple Splanchnic Venous Thromboses and Bilateral Renal Infarctions in a Patient With Recent COVID-19 Infection: A Case Report.

Splanchnic vein thrombosis (SVT) is a well-known complication of pancreatitis, but extra-splanchnic thrombosis is rarely seen. We report a case of acute necrotizing pancreatitis complicated by portal vein thrombosis and resultant hepatic infarction, splenic vein thrombosis, bilateral renal infarction, and bowel hypoperfusion in an 81-year-old man with recent coronavirus disease 2019 (COVID-19) infection. To the best of our knowledge, this is the first documented case of such extensive intra-abdominal thromboses complicating severe acute pancreatitis. Despite multi-organ support and systemic anticoagulation, he deteriorated into multiple organ failure and died after 72 hours. He had no prior history of thrombotic disorders. COVID-19 infection can cause sustained prothrombotic changes, while severe acute pancreatitis also produces an inflammatory response that promotes coagulation. Together, the two concurrent disease processes may have resulted in the particularly extensive intra-abdominal thromboses and infarctions seen in this patient. Physicians should be mindful of the elevated risk of severe vascular complications in acute pancreatitis patients with concurrent or recent COVID-19 infection.

Thrombosis patterns and clinical outcome of COVID-19 vaccine-induced immune thrombotic thrombocytopenia: A Systematic Review and Meta-Analysis.

OBJECTIVES: To meta-analyse the clinical manifestations, diagnosis, treatment, and mortality of vaccine-induced immune thrombotic thrombocytopenia (VITT) after adenoviral vector vaccination. METHODS: Eighteen studies of VITT after ChAdOx1 nCoV-19 or Ad26.COV2.S vaccine administration were reviewed from PubMed, Scopus, Embase, and Web of Science. The meta-analysis estimated the summary effects and between-study heterogeneity regarding the incidence, manifestations, sites of thrombosis, diagnostic findings, and clinical outcomes. RESULTS: The incidence of total venous thrombosis after ChAdOx1 nCoV-19 vaccination was 28 (95% CI 12-52, I2=100%) per 100,000 doses administered. Of 664 patients included in the quantitative analysis (10 studies), the mean age of patients with VITT was 45.6 years (95% CI 43.8-47.4, I2=57%), with a female predominance (70%). Cerebral venous thrombosis (CVT), deep vein thrombosis (DVT)/pulmonary thromboembolism (PE), and splanchnic vein thrombosis occurred in 54%, 36%, and 19% of patients with VITT, respectively. The pooled incidence rate of CVT after ChAdOx1 nCoV-19 vaccination (23 per 100,000 person-years) was higher than that reported in the pre-pandemic general population (0.9 per 100,000 person-years). Intracranial haemorrhage and extracranial thrombosis accompanied 47% and 33% of all patients with CVT, respectively. The antiplatelet factor 4 antibody positivity rate was 91% (95% CI 88-94, I2=0%) and the overall mortality was 32% (95% CI 24-41, I2=69%), and no significant difference was observed between heparin- and non-heparin-based anticoagulation treatments (risk ratio 0.84, 95% CI 0.47-1.50, I2=0%). CONCLUSIONS: Patients with VITT after SARS-CoV-2 vaccination most frequently presented with CVT following DVT/PE and splanchnic vein thrombosis, and about one-third of patients had a fatal outcome. This meta-analysis should provide a better understanding of VITT and assist clinicians in identifying VITT early to improve outcomes and optimise management.

Successful surgical-multimodal treatment for vaccine-induced complete splanchnic vein thrombosis after ChAdOx1 nCoV-19 vaccination

Objective Thrombotic-thrombocytopenic events are rare, but life-threatening, complications after ChAdOx1 nCoV-19 vaccination and sometimes present as symptomatic splanchnic vein thrombosis with critical illness. Life-saving aggressive and multimodal treatment is essential in these cases. Design We report on a critically ill 40-year-old male patient with complete splanchnic (portal/mesenteric/splenic) vein thrombosis, becoming symptomatic 7 days after ChAdOx1 nCoV-19 vaccination and diagnosed on day 12. Laparotomy for abdominal compartment syndrome and repeated transjugular/ transhepatic interventional and open surgical thrombectomy procedures were performed. Additional therapy consisted of thrombolysis with recombinant tissue-type plasminogen activator over 5 days, anticoagulation (argatroban), platelet inhibition (Acetylsalicylic acid /clopidogrel), immunoglobulins and steroids. Results This aggressive treatment included 5 laparotomies and 4 angiographic interventions, open abdomen for 8 days, transfusion of 27 units of packed red cells, 9 abdominal and 4 cerebral CT scans, thrombolysis therapy for 5 days, mechanical ventilation for 15 days, and an ICU stay of 25 days. Full patient recovery and near complete recanalization of splanchnic veins was achieved. Conclusion Without treatment, ChAdOx1 nCoV-19 vaccination-induced total splanchnic vein thrombosis has serious consequences with a high risk for death. The case described here shows that an aggressive multimodal surgical-medical treatment strategy in a specialized center can save these patients and achieve a good outcome.

A Case of Extensive Splanchnic Vein Thrombosis in a COVID-19 Patient and a Review of the Literature

Splanchnic vein thrombosis is one of the rare complications of coronavirus disease 2019 (COVID-19). A 43-year-old woman presented with splanchnic vein thrombosis as a rare extrapulmonary complication of COVID-19. She was previously healthy without a medical history of coagulopathy before hospital admission. She complained of epigastric pain, along with nausea and vomiting. Enhanced abdominopelvic computed tomography (CT) scan demonstrated extensive acute thrombosis in the portal, superior mesenteric, and splenic veins with total occlusion. Intestinal ischemia or infarction was not clinically observed. All thrombophilia screening tests yielded negative results. Under anticoagulation therapy, she recovered dramatically and was discharged from the hospital. Imaging findings can be used to confirm splanchnic vein thrombosis when a COVID-19 patient has abdominal symptoms. © 2021, Author(s).

Vaccine-induced immune thrombotic thrombocytopenia with atypical vein thrombosis: Implications for clinical practice.

OBJECTIVES: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a new and rare syndrome resulting from the largest vaccination campaign against SARS-CoV-2 in the history of mankind. The aim of this review is to clarify underlying mechanisms, pathology, diagnosis, and therapy, with the related clinical implications. METHODS: We performed a comprehensive literature review in order to collect the clinical and treatment data about patients suffering from VITT. PubMed, Ovid Medline, Ovid EMBASE, Scopus, and Web of Science were screened regarding patients who developed VITT. Last search was launched on June 30th 2021. RESULTS: Abdominal and/or neurological symptoms develop between 5 and 20 days after vaccine administration and do not involve the lower extremities. VITT is suspected if the platelet count is lower than 100.000/mm3 and D-dimer is higher than the age-adjusted range. Medical treatment is mainly based on intravenous immunoglobulins, corticosteroids, and anticoagulant drugs with a short plasma half-life, but the complete avoidance of low molecular weight heparin is recommended. Endovascular treatment and/or decompressive craniectomy might be an option in a minority of cases. CONCLUSION: Due to widespread vaccination concerns, the vascular specialist and phlebologist are increasingly consulted to prevent or diagnose VITT. The latter has peculiar and completely different localizations, symptoms, and treatment compared to the common pictures of venous thrombosis.

Splanchnic venous thrombosis in a nephrotic patient following COVID-19 infection: a case report.

BACKGROUND: As the COVID-19 pandemic spread worldwide, case reports and small series identified its association with an increasing number of medical conditions including a propensity for thrombotic complications. And since the nephrotic syndrome is also a thrombophilic state, its co-occurrence with the SARS-CoV-2 infection is likely to be associated with an even higher risk of thrombosis, particularly in the presence of known or unknown additional risk factors. Lower extremity deep vein thrombosis (DVT) and pulmonary embolism (PE) are the most common manifestations of COVID-19-associated hypercoagulable state with other venous or arterial sites being much less frequently involved. Although splanchnic vein thrombosis (SVT) has been reported to be 25 times less common than usual site venous thromboembolism (VTE) and rarely occurs in nephrotic patients, it can have catastrophic consequences. A small number of SVT cases have been reported in COVID-19 infected patients in spite of their number exceeding 180 million worldwide. CASE PRESENTATION: An unvaccinated young adult male with steroid-dependent nephrotic syndrome (SDNS) who was in a complete nephrotic remission relapsed following contracting SARS-CoV-2 infection and developed abdominal pain and diarrhea. Abdominal US revealed portal vein thrombosis. The patient was anticoagulated, yet the SVT rapidly propagated to involve the spleno-mesenteric, intrahepatic and the right hepatic veins. In spite of mechanical thrombectomy, thrombolytics and anticoagulation, he developed mesenteric ischemia which progressed to gangrene leading to bowel resection and a complicated hospital course. CONCLUSION: Our case highlights the potential for a catastrophic outcome when COVID-19 infection occurs in those with a concomitant hypercoagulable state and reminds us of the need for a careful assessment of abdominal symptoms in SARS-CoV-2 infected patients.

Vaccine-induced thrombotic thrombocytopenia (VITT)

Introduction: An unexpected accumulation of thrombotic events with thrombocytopenia emerged in association with the AZD1222 vaccine against COVID-19. We report our initial experience with emphasis on presenting characteristics, treatment, and short-term outcome. Methods: This is a retrospective, consecutive cohort of all patients admitted to Hannover Medical School between 8th March and 4th April 2021 with known or suspected thromboembolic events and thrombocytopenia within 2 weeks after vaccination with AZD1222. Results: Five patients were admitted during the observation period. These were women between 41 and 67 years of age, who had received AZD1222 5 to 11 days before. Clinical manifestations ranged from cerebral sinus vein thrombosis, splanchnic vein thrombosis, arterial ischemic stroke, and thrombotic microangiopathy (TMA) to mild symptoms without abnormal imaging results. Thrombocytopenia ranged between 12 and 105 /nl. All patients had markedly elevated D-Dimer. Heparin-induced thrombocytopenia (HIT) workup revealed anti-platelet factor 4 autoantibodies in sera from all patients. Platelet aggregation by these antibodies was observed in the presence of buffer or AZD1222 but suppressed by heparin. Treatment consisted of anticoagulation (heparin or argatroban), dexamethasone and, in severe cases, intravenous immunoglobulin (IVIG) or eculizumab. Two patients treated with anticoagulation, dexamethasone and IVIG had subsequent major thromboembolic events. One patient presenting with a picture of TMA responded to anticoagulation and eculizumab. Another patient responded to thrombolysis and eculizumab after failure of anticoagulation and IVIG. Long-term sequelae are expected in two patients with severe cerebrovascular events while remaining three patients have fully recovered. Anti-PF4 antibodies declined in recovering patients over a period of 8 weeks. Conclusions: The triad of thromboembolic events, thrombocytopenia and anti-PF4 autoantibodies is characteristic of VITT. The spectrum of clinical manifestations ranged from mild to unusually severe. Anticoagulation alone is not always sufficient to prevent recurrent or progressive thromboembolic events. IVIG and eculizumab are potential treatment options but their effects are currently uncertain.

Impact of SARS-CoV-2 Pandemic on Vascular Liver Diseases.

BACKGROUND & AIMS: Vascular liver diseases (VLDs) are represented mainly by portosinusoidal vascular disease (PSVD), noncirrhotic splanchnic vein thrombosis (SVT), and Budd Chiari syndrome (BCS). It is unknown whether patients with VLDs constitute a high-risk population for complications and greater coronavirus disease 2019 (COVID-19)-related mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our objective was to assess the prevalence and severity of SARS-CoV-2 infection among patients with VLDs, as well as to assess its impact on hepatic decompensation and survival. METHODS: This is an observational international study analyzing the prevalence and severity of SARS-CoV-2 infection in VLDs between March 2020 and March 2021, compared with the general population (GP). Patients from Spain (5 centers; n = 493) and France (1 center; n = 475) were included. RESULTS: Nine hundred sixty-eight patients were included: 274 with PSVD, 539 with SVT, and 155 with BCS. Among them, 138 (14%) were infected with SARS-CoV-2: 53 with PSVD, 77 with SVT, and 8 with BCS. The prevalence of SARS-CoV-2 infection in patients with PSVD (19%) and SVT (14%) was significantly higher than in the GP (6.5%; P < .05), whereas it was very similar in patients with BCS (5%). In terms of infection severity, patients with VLDs also presented a higher need of hospital admission (14% vs 7.3%; P < .01), intensive care unit admission (2% vs 0.7%; P < .01), and mortality (4% vs 1.5%; P < .05) than the GP. Previous history of ascites (50% vs 8%; P < .05) and post-COVID-19 hepatic decompensation (50% vs 4%; P < .05) were associated with COVID-19 mortality. CONCLUSIONS: Patients with PSVD and SVT could be at higher risk of infection by SARS-CoV-2 and at higher risk of severe COVID-19 disease.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) - a novel clinico-pathological entity with heterogeneous clinical presentations.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a novel entity that emerged in March 2021 following reports of unusual thrombosis after ChAdOx1 nCoV-19, (AstraZeneca) vaccination. Following the recognition of this syndrome, multiple consensus guidelines have been released to risk stratify patients presenting with possible symptoms after ChAdOx1 nCoV-19 vaccination. All guidelines rapidly identify VITT in patients with the complete triad of thrombocytopenia, thrombosis and elevated D-dimers after ChAdOx1 nCoV-19 vaccination. However, with earlier recognition of the associated symptoms, the clinical manifestations are likely to be more heterogeneous and represent an evolving spectrum of disease. In this setting, current guidelines may lack the sensitivity to detect early cases of VITT and risk missed or delayed diagnoses. The broad clinical phenotype and challenges associated with diagnosis of VITT are highlighted in our present case series of four patients with confirmed VITT. Dependent on the guidance used, each patient could have been classified as a low probability of VITT at presentation. The present study highlights the issues associated with the recognition of VITT, the limitations of current guidance and the need for heightened clinical vigilance as our understanding of the pathophysiology of this novel condition evolves.

Spontaneous HIT syndrome: Knee replacement, infection, and parallels with vaccine-induced immune thrombotic thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is characterized clinically by thrombocytopenia, hypercoagulability, and increased thrombosis risk, and serologically by platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies. Heparin-"induced" acknowledges that HIT is usually triggered by a proximate immunizing exposure to heparin. However, certain non-heparin medications (pentosan polysulfate, hypersulfated chondroitin sulfate, fondaparinux) can trigger "HIT". Further, naturally-occurring polyanions (bacterial lipopolysaccharide, DNA/RNA) can interact with PF4 to recapitulate HIT antigens. Indeed, immunologic presensitization to naturally-occurring polyanions could explain why HIT more closely resembles a secondary, rather than a primary, immune response. In 2008 it was first reported that a HIT-mimicking disorder can occur without any preceding exposure to heparin or polyanionic medications. Termed "spontaneous HIT syndrome", two subtypes are recognized: (a) surgical (post-orthopedic, especially post-total knee arthroplasty, and (b) medical (usually post-infectious). Recently, COVID-19 adenoviral vector vaccination has been associated with a thrombotic thrombocytopenic disorder associated with positive PF4-dependent enzyme-immunoassays and serum-induced platelet activation that is maximal when PF4 is added. Vaccine-induced immune thrombotic thrombocytopenia (VITT) features unusual thromboses (cerebral venous thrombosis, splanchnic vein thrombosis) similar to those seen in spontaneous HIT syndrome. The emerging concept is that classic HIT reflects platelet-activating anti-PF4/heparin antibodies whereas spontaneous HIT syndrome and other atypical "autoimmune HIT" presentations (delayed-onset HIT, persisting HIT, heparin "flush" HIT) reflect heparin-independent platelet-activating anti-PF4 antibodies-although the precise relationships between PF4 epitope targets and the clinical syndromes remain to be determined. Treatment of spontaneous HIT syndrome includes non-heparin anticoagulation (direct oral Xa inhibitors favored over direct thrombin inhibitors) and high-dose immunoglobulin.

Vaccine induced thrombotic thrombocytopenia: The shady chapter of a success story.

The recognition of the rare but serious and potentially lethal complication of vaccine induced thrombotic thrombocytopenia (VITT) raised concerns regarding the safety of COVID-19 vaccines and led to the reconsideration of vaccination strategies in many countries. Following the description of VITT among recipients of adenoviral vector ChAdOx1 vaccine, a review of similar cases after Ad26.COV2·S vaccination gave rise to the question whether this entity may constitute a potential class effect of all adenoviral vector vaccines. Most cases are females, typically younger than 60 years who present shortly (range: 5-30 days) following vaccination with thrombocytopenia and thrombotic manifestations, occasionally in multiple sites. Following initial incertitude, concrete recommendations to guide the diagnosis (clinical suspicion, initial laboratory screening, PF4-polyanion-antibody ELISA) and management of VITT (non-heparin anticoagulants, corticosteroids, intravenous immunoglobulin) have been issued. The mechanisms behind this rare syndrome are currently a subject of active research and include the following: 1) production of PF4-polyanion autoantibodies; 2) adenoviral vector entry in megacaryocytes and subsequent expression of spike protein on platelet surface; 3) direct platelet and endothelial cell binding and activation by the adenoviral vector; 4) activation of endothelial and inflammatory cells by the PF4-polyanion autoantibodies; 5) the presence of an inflammatory co-signal; and 6) the abundance of circulating soluble spike protein variants following vaccination. Apart from the analysis of potential underlying mechanisms, this review aims to synopsize the clinical and epidemiologic features of VITT, to present the current evidence-based recommendations on diagnostic and therapeutic work-up of VITT and to discuss new dilemmas and perspectives that emerged after the description of this entity.