Splanchnic Vein Thrombosis Patients Research Articles

Efficacy of Direct Oral Anticoagulants Vs Warfarin Vs Low Molecular Weight Heparin in the Treatment of Acute Splanchnic Vein Thrombosis in Patients with Underlying Myeloproliferative Disorder

Introduction: Myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders characterized by clonal proliferation of myeloid-lineage cells. Venous thrombosis poses a significant morbidity risk for MPN patients. The current recommended treatments for acute splanchnic vein thrombosis (SVT) are warfarin and low molecular weight heparin (LMWH). Direct oral anticoagulants (DOACs) are potential alternatives due to their predictable dose response and oral administration, but limited data exists for their use in acute SVTs. This retrospective study aims to assess the efficacy and outcomes of DOACs, LMWH, and warfarin in treating acute SVTs in patients with underlying MPN. Methods: We included patients of all ages with underlying myeloproliferative neoplasms and splanchnic vein thrombosis, with no underlying liver diseases, from Henry Ford Hospital Clinics in metropolitan Detroit, Michigan between 2013 and 2023. Patient data, which included age, gender, race, and BMI were recorded. The primary outcome was complete radiographic resolution (CRR) of the SVT, and secondary outcomes included recanalization, thrombosis progression, recurrent thrombosis, major bleeding, thrombocytopenia, and skin necrosis. The outcomes were compared between the three anticoagulant groups and patients using aspirin. Results: Among the 34 MPN patients with SVT, warfarin was prescribed most frequently (n=19), followed by enoxaparin (n=5) and DOACs (n=5). Although no significant differences were observed, warfarin showed the highest CRR rates (41.2%), while enoxaparin and DOACs had equal CRR rates (25%). DOACs showed recanalization rates similar to warfarin and higher than enoxaparin (44.4% and 47.1% vs. 20.0%, respectively). LMWH was associated with increased recurrent thrombosis rates (50.0%), while DOACs had a higher risk of major bleeding. All three anticoagulants had similar effects on thrombocytopenia and SVT progression. Aspirin use was linked to a higher risk of major bleeding (42.9%), but not using aspirin correlated with complete SVT resolution (30.8%), SVT progression (20.8%), recurrent thrombosis (29.2%), and thrombocytopenia (28.6%). Conclusions: Although limited by a small sample size, our study found no significant differences among the three anticoagulant groups. This contributes to establishing the role of DOACs in treating SVTs in patients with underlying MPN. Further studies with larger sample sizes are needed to explore the efficacy of DOACs compared to warfarin. Additionally, investigating the potential benefits of early thrombolysis in conjunction with anticoagulation for SVT patients with underlying MPN should be pursued, as the rates of complete resolution in these patients were low.

Incidence and outcomes of splanchnic vein thrombosis after diagnosis of COVID-19 or COVID-19 vaccination: a systematic review and meta-analysis.

Coronavirus disease 2019 (COVID-19) and COVID-19 vaccination may cause splanchnic vein thrombosis (SVT), which is potentially fatal. The present study aims to pool the incidence and outcomes of SVT patients with COVID-19 or having received COVID-19 vaccines. The PubMed, EMBASE, and Cochrane databases were searched. Based on the data from cohort studies, meta-analyses were performed to evaluate the incidence of SVT in COVID-19 patients or people having received COVID-19 vaccines. Pooled proportions were calculated. Based on the individual data from case reports, logistic regression analyses were performed to identify factors associated with death in SVT patients. Odds ratios (ORs) were calculated. Among 654 papers initially identified, 135 were included. Based on 12 cohort studies, the pooled incidence of SVT in COVID-19 patients was 0.6%. Data were insufficient to estimate the incidence of SVT after COVID-19 vaccination. Based on 123 case reports, the mortality was 14% (9/64) in SVT patients with COVID-19 and 25% (15/59) in those who received COVID-19 vaccines. Univariate analyses demonstrated that age (OR = 1.061; p = 0.017), diabetes mellitus (OR = 14.00; p = 0.002), anticoagulation (OR = 0.098; p = 0.004), and bowel resection (OR = 16.00; p = 0.001) were significantly associated with death in SVT patients with COVID-19; and anticoagulation (OR = 0.025; p = 0.003) and intravenous immunoglobulin (OR = 0.175; p = 0.046) were significantly associated with death in SVT patients who received COVID-19 vaccines. Multivariate analyses did not identify any independent factor for death in both patients. SVT in COVID-19 patients and in subjects who received COVID-19 vaccines carries a high mortality, but may be improved by anticoagulation. PROSPERO Identifier CRD42022315254.

Pediatric Splanchnic Vein Thrombosis: Systematic Review and Meta-Analysis

Background: The clinical characteristics of splanchnic vein thrombosis (SVT) in pediatric patients and its optimal treatment strategies are unknown. Aim: We aimed to study the risk factors for pediatric SVT and the efficacy and safety of anticoagulant therapy. Methods: MEDLINE and EMBASE were searched up to December 2021. We only included studies which reported SVT treatment and outcomes, including rates of SVT re-canalization, progression or recurrence, as well as rates of bleeding and mortality. SVT anticoagulation responsewas pooled using inverse variance and generalized linear mixed and random-effects models. Results: A total of 508 patients were included across 17 studies. Of pediatric SVT cases, 308 presented with portal vein thrombosis, 175 with Budd-Chiari syndrome, 3 with splenic vein thrombosis, 2 with mesenteric vein thrombosis, and 20 with thromboses involving multiple sites. Anticoagulant therapy was prescribed in 187 patients; However, outcome was reported only in 153 of these patients. Of 321 patients who did not receive anticoagulation, outcome was reported in 139. The pooled proportion of response to anticoagulant therapy (assessed by any recanalization) was 55.9% (95% confidence interval (CI): 39%-71%, I2 = 56%) (Figure 1). In patients who did not receive anticoagulation, recanalization rate was 43.7% (95% confidence interval (CI): 13%-80%, I2 = 81%) (Figure 2). Major bleeding was reported in 3.7% (7/187) of patients who received anticoagulant therapy and 0.6 % (2/321) in patients who did not receive anticoagulant therapy, and non-major bleeding was reported in 4.8% (9/187) and 14.3% (46/321) respectively. Mortality was reported in 10.4% (53/508) of pediatric SVT patients (42 were treated with anticoagulation and 11 did not). VTE recurrence was rare, and reported in 0.8% of SVT patients (4/508) all of whom received anticoagulant therapy. Conclusions: In pediatric patients with SVT, anticoagulant therapy appears to be associated with high recanalization rates and low risk of thrombus progression and bleeding. The incidence of VTE recurrence remains low and comparable to the risk of VTE recurrence in pediatric patients with other types of VTE. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Presentation, Risk Factors and Outcome of Splanchnic Venous Thrombosis: A Report on 305 Cases

Background and Aims: Splanchnic vein thrombosis (SVT) is a manifestation of unusual site venous thromboembolism. Most common predisposing factors for SVT include liver cirrhosis, solid abdominal cancer, myeloproliferative neoplasms (MPN), and abdominal infection or inflammatory diseases. Complex balance between bleeding risk and the risk of thrombus extension or recurrence makes the management of SVT a clinical challenge. In this study, we reported clinical presentation and outcome data of patients with SVT followed in our center from January 2000 to December 2021, with a focus on MPN and cirrhotic patients. Methods: We performed a retrospective review of clinical reports of 305 SVT patients. According to PLT count in patients with no active bleeding, anticoagulation treatment was started as soon as possible with: no treatment for a platelet count <30.000/μl; prophylactic dose of LMWH or related drugs for a platelet count range 30.000 -50.000/μl and therapeutic dose low-molecular-weight heparin (LMWH) followed by early initiation of vitamin-K antagonist (VKA; INR range 1.8-2.5) for a platelet count >50.000/μl. Moreover, cytoreductive therapy was administered in MPN patients and prophylaxis with beta-blockers and endoscopic therapies were applied in cirrhotic SVT. Cox regression analysis was used to identify independent predictors of recanalization and overall survival. The Kaplan-Meier method was performed to estimate the overall survival and the time to reach vessel recanalization. Results: In a median follow up of 16.1 months (range, 1-346), 305 patients experienced a SVT (median age 59 years; 68.2% males). Isolated portal vein thrombosis was the most common site of thrombosis (55.1%), followed by multiple venous involvement (28.9%). Six patients developed a Budd-Chiari syndrome. SVT were associated to chronic liver disease, solid cancer and abdominal infections in 212 (69.5%), 100 (32.8%) and 34 (11.5%) patients, respectively. Ninety-seven patients had splenomegaly. MPN was identified in 38 (12.5%) patients. Among these patients, JAK2 and CALR mutation were detected in 81.6% and 13.2%, respectively, and abnormal karyotype in 10.5%. Ascites and esophageal varices were present in 47.5% and 48.8% of patients, respectively. Therapeutic decisions were taken as a multidisciplinary team, involving the use of VKA and LMWH in 70 and 163 patients, respectively. In addition, trans-jugular intrahepatic portosystemic (TIPS) or other surgical shunting was undertaken in 12% and variceal banding in 11%. In a median duration therapy of 9.6 months, bleeding complications and recanalization were reported in 9.5% and 35.4% of patients, respectively. At univariate analysis, VKA exposure was associated with a significantly lower risk of bleeding events compared to LMWH (p=0.039), while esophageal varices (p=0.049), leukocytosis at time of thrombosis (p=0.048), liver cirrhosis (p=0.010) and solid tumor (p=0.021) were associated with lack of recanalization. Only one death was attributed to fatal bleeding, whereas 76 patients died for causes not related to anticoagulation (cirrhosis, cancer, MPN evolution) with a median OS was not reached (range, 107,89-NR). Factors associated with poor survival included age (p<0.001), MPN (p=0.047), recurrent thrombosis (p=0.041), alkaline phosphatase (p=0.013), gamma-GT (p<0.001), albumin (p=0.021), MELD score (p=0.004), lack of recanalization (p<0.001), bleeding event (p=0.043), ascites (p=0.009), and antithrombotic therapy (p=0.006, Figure 1). Among MPN patients, poor survival outcome was also associated with driver mutations (p=0.034), hemoglobin level at thrombosis (p<0.001), splenomegaly (p=0.019), and cytoreductive therapy (p=0.019). Conclusions: Outcome in SVT patients mostly depends on the presence of an underlying MPN, liver failure, active bleeding, recurrence and recanalization rate. Moreover, the anticoagulant treatment was associated with a low bleeding incidence also in patients with major risk factors for bleeding (i.e. liver cirrhosis, cancer or esophageal varices). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment of Portal, Mesenteric, and Splenic Vein Thrombosis with Rivaroxaban: A Pilot, Prospective Cohort Study

Introduction: Anticoagulation plays a crucial role in the treatment of splanchnic vein thrombosis (SVT), including thrombosis of the portal (PVT), mesenteric (MVT) and splenic (SpVT) veins. Rivaroxaban is a potential alternative to heparins and vitamin K antagonists (VKA) in these patients, but data to support its use are scant. Several recent guidelines highlighted the limited evidence available for the use of the direct oral anticoagulants in these patients. In addition, despite anticoagulation, SVT patients carry high risk of recurrent venous thromboembolic events.The aim of this study was to evaluate the safety and efficacy of rivaroxaban for the acute-phase treatment of SVT (first 3 months of treatment).Methods: RIVASVT-100 (NCT02627053) was a prospective cohort study of adult patients with a first episode of symptomatic, objectively diagnosed PVT, MVT or SpVT. Exclusion criteria were known liver cirrhosis, Budd-Chiari syndrome, previous or ongoing variceal bleeding, portal cavernoma, thrombocytopenia, severe renal failure, life expectancy <3 months, concomitant interfering medications, treatment with therapeutic dose of heparins for >7 days, ongoing VKA treatment.Patients received rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily for a total of 3 months. Afterwards, the decision to continue any available anticoagulant drug was left to the discretion of the attending physicians. Follow-up was performed at 3 weeks, 2 months, 3 months and 6 months.Primary outcome was the occurrence of ISTH-defined major bleeding events during the 3 months of active treatment and up to 2 days after the end of study treatment. Secondary outcomes included death, clinically relevant non-major bleeding (CRNMB), recurrent SVT or symptomatic venous thromboembolism in other sites. We here report the results of the 3-month follow-up.Results: Between June 2015 and March 2021, 103 patients were enrolled from 18 participating centres. After excluding 3 patients who did not meet the criteria for eligibility, 100 patients were included in the analysis. Mean (SD) age was 54.4 (± 15.5) years; 64% were males. Overall, 74% of patients had PVT, 61% MVT and 48% SpVT; 53% of SVT occurred in multiple sites. The most common risk factors were abdominal inflammation/infection (26%), followed by solid cancer (9%), overt myeloproliferative neoplasms (9%) and oestrogen hormonal therapy (9%), while 43% of cases were unprovoked. The JAK2 V617F mutation was detected in 13 out of 50 tested patients (26%).Rivaroxaban was the sole anticoagulant agent used in 21% of patients, whereas the remaining received a combination of anticoagulants, which included low molecular weight heparin, unfractionated heparin or fondaparinux for a median of 5.0 days before transitioning to rivaroxaban.Three patients were lost to follow-up but known to be alive at the end of the study. At 3-month follow-up, 1 (1.0%) patient died due to a non-SVT related cause. Two patients (2.06%; 95% CI, 0.57-7.21) had major bleeding events (both gastrointestinal), while 3 patients (3.09%) had CRNMB. There were 2 recurrent SVT (2.06%) during rivaroxaban treatment, one of these occurred in a patient with metastatic solid cancer. The 6-month follow-up for the last enrolled patient is ongoing.Conclusions: Rivaroxaban appears to be safe and effective for the acute-phase treatment of SVT in non-cirrhotic patients. DisclosuresBeyer-Westendorf: Bayer: Other: Personal fees; Daiichi Sankyo: Other: Personal fees; Pfizer: Other: Personal fees; Portola-Alexion: Other: Personal fees. Carrier: BMS: Honoraria, Research Funding; Leo Pharma: Honoraria, Research Funding; Bayer: Honoraria; Pfizer: Honoraria, Research Funding; Servier: Honoraria; Sanofi: Honoraria. Bertoletti: BMS: Honoraria, Other: Personal Fees; Pfizer: Honoraria, Other: Personal fees; Aspen: Other: Personal Fees; Bayer: Other: Personal Fees; Leo Pharma: Other: Personal Fee. Di Nisio: Bayer, Daiichi Sankyo, BMS-Pfizer, Leo Pharma, and Sanofi: Other: Personal fees. Ageno: Bayer: Research Funding; Bayer, Portola, Janssen, Aspen, Norgine, Sanofi.: Other: Advisory Board. OffLabel Disclosure:The use of rivaroxaban in splanchnic vein thrombosis is off label in most countries.

Anticoagulation and Vessel Recanalization in Cirrhotic Patients with Splanchnic Vein Thrombosis: A Multidisciplinary "Real Life" Experience.

Background and AimSplanchnic vein thrombosis (SVT) is a potentially life-threatening complication of liver cirrhosis. This study aimed to evaluate the impact of a multi-disciplinary approach and early anticoagulation therapy (AT) on bleeding/thrombotic events, recanalization rates and outcome of cirrhotic patients with SVT.MethodsThis is a single-center, registry-based cohort study. Over 17 years, 149 SVT patients were enrolled and prospectively evaluated. Regarding cirrhotic-SVT, a pre-specified algorithm, guiding initial posology of AT and follow-up visits schedule, was performed. Major bleeding (MB), thrombotic events, functional liver scores and all cause-mortality were investigated. Efficacy of AT was evaluated by radiological imaging.ResultsIn cirrhotic-SVT, the incidence rate of MB was 8.4 per 100 patient-year (95% CI, 3.83–15.97), while the incidence rate of thrombosis was 5.6 per 100 patient-year (95% CI, 2.05–12.2). In incidental SVT treated with AT, MB incidence was 6.5 per 100 patient-year (95% CI: 2.8–12.82), while in symptomatic SVT was 2.2 per 100 patient-year (95% CI: 0.25–8.02). All thrombotic recurrences occurred in incidental SVT (7.7 per 100 patient-years; 95% CI, 3.71–14.26). Overall survival was significantly higher in patients who had at least a partial recanalization (p < 0.01) and partial/total recanalization was independently associated with improved MELD score at multivariate analysis (HR 2.62, 95% CI 1.1–6.47, p = 0.03).ConclusionIn cirrhotic SVT patients, partial or total resolution of thrombosis ameliorates liver function and is associated with higher overall survival. A multidisciplinary approach together with radiological follow-up at pre-fixed time improves patient selection and monitoring.

Splanchnic Vein Thrombosis Treatment with Rivaroxaban - a Case Series from the Prospective Dresden Noac Registry (NCT01588119)

Background : Although rivaroxaban is not specifically approved to be used in patients with splanchnic vein thrombosis (SVT), it may offer advantages due the oral intake and the specific pharmacological profile. As a consequence, off-label use of rivaroxaban in single cases has been reported. However, the effectiveness and safety of rivaroxaban in SVT remains to be established.Patients and methods : Using data from the prospective, non-interventional multicentric Dresden NOAC we evaluated a subgroup of patients receiving rivaroxaban for acute or chronic SVT treatment. All patients in the registry undergo long-term follow-up by quarterly phone calls and suspected thromboembolic and bleeding outcome events are centrally adjudicated using standard definitions.Results: Until June 30th 2017, 23 patients receiving rivaroxaban for SVT treatment were enrolled (65% male, median age 56 years). In these, SVT manifested as portal vein thrombosis in 15 cases (65.2%), mesenteric vein thrombosis in 2 (8.7%) and in both localizations in 6 (26.1%) cases. Idiopathic SVT was diagnosed in 78% of cases; 13% had intra- abdominal infections and 9% had cancer (table 1).Median time between diagnosis and initiation of rivaroxaban was 32 days (25th/75th percentile 11.5-125.5 days). Mean exposure time of rivaroxaban was 13 months (range 1-43 months), during which no thromboembolic event occurred. Ten patients had a total of 19 bleeding complications during treatment with rivaroxaban, which (according to International Society of Thrombosis and Haemostasis definition) were minor bleeding in 8 cases, clinically relevant non-major bleeding in 6 and major bleeding in 5 cases (3 x gastrointestinal, 1 x hemorrhoid; 1 x traumatic intracranial bleeding).During follow-up (mean 23 months; range 1-59 months), 7 patients had a scheduled end of rivaroxaban treatment, 2 patients were electively switched to prophylactic dosages of apixaban for long-term secondary prevention and 5 patients had unplanned permanent discontinuation of oral anticoagulation. Five patients died during follow-up (2x traumatic intracranial bleeding, 3 terminal malignant diseases).Detailed information on thrombus burden at baseline and during follow-up was available for 17/23 patients (table 2). Of these, 9 patients initiated rivaroxaban in the first 30 days after SVT diagnosis and demonstrated complete clot resolution in 8 and stable thrombus in 1 case. In contrast, those 8 patients who initiated rivaroxaban later than 30 days were found to have complete resolution or improvement in only two cases and stable thrombus burden without improvement in the remaining 6 cases.Conclusions: Our cohort of 23 consecutive patients currently represents the largest prospectively collected case series of rivaroxaban treatment for SVT. In this cohort treatment with rivaroxaban demonstrated high effectiveness to prevent thromboembolic complications but bleeding complications are common, which is known for SVT patients. Therefore, careful risk-benefit assessments are especially needed in this indication. Early initiation of rivaroxaban resulted in fast thrombus resolution in the majority of cases, whereas late initiation tended to achieve stable clot burden only. A fast SVT resolution with oral direct factor Xa inhibitors may be supported by their first-pass effect, which, compared to LMWH or VKA, should result in high drug concentrations at the site of thrombus in the splanchnic system. It remains to be seen if the fast clot resolution in early initiators of rivaroxaban will reduce late sequelae such as gastrointestinal bleeding from varicose veins, which is the most feared clinical consequence of residual clot in SVT. [Display omitted] DisclosuresMarten:Bayer HealthCare: Honoraria; Daiichi Sankyo: Honoraria. Beyer-Westendorf:Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria, Research Funding.

Clinical history of cancer‐associated splanchnic vein thrombosis

BackgroundCancer represents a risk factor for splanchnic vein thrombosis (SVT) and usual site venous thromboembolism (VTE). ObjectivesTo compare characteristics and outcomes of patients with cancer‐associated SVT and usual site VTE. Patients/MethodsPatients with solid cancer and SVT were enrolled in an international, prospective registry between May 2008 and January 2012. The comparison cohort included (1:1 ratio) patients with solid cancer and usual site VTE treated at two thrombosis centers who had a minimum of 12 months follow‐up at December 2019 or experienced one of the outcomes within 12 months follow‐up. Recurrent VTE, major bleeding, and all‐cause mortality were evaluated at 12‐month follow‐up. ResultsA total of 264 patients (132 in each cohort) were enrolled. Patients with SVT were less likely to have metastatic disease (36.1% vs 72.5%) or receive cancer therapy at thrombosis diagnosis (29.6% vs 64.9%). The most frequent cancer types were hepatobiliary and pancreatic in the SVT cohort and gastrointestinal in the usual site VTE cohort. Fewer patients with SVT received anticoagulation (68.9% vs 99.2%), and treatment duration was shorter (6.0 vs 11.0 months). The cumulative incidence of major bleeding (2.3% vs 4.7%) was nonsignificantly lower in the SVT cohort, whereas recurrent thrombosis (4.7% vs 5.5%) and all‐cause mortality (41.7% vs 39.4%) were comparable between the two cohorts. ConclusionsThe risk of recurrent thrombosis and bleeding appears to be similar in cancer patients with SVT and cancer patients with usual site VTE, despite some differences in baseline characteristics and anticoagulant treatment. Further prospective studies are warranted to confirm these findings.

Trends and In-Hospital Outcomes of Splanchnic Vein Thrombosis Associated with Gastrointestinal Malignancies: A Nationwide Analysis

Introduction: Gastrointestinal cancers have a strong association with splanchnic vein thrombosis (SVT), yet the hospitalization data is unknown. Objective and Methods: We analyzed around 78 million discharges from the 2007–2017 Nationwide Inpatient Sample with an inclusion criterion of adult patients admitted for portal or hepatic vein thrombosis as a primary diagnosis with a gastrointestinal or hepatobiliary malignancy as a secondary diagnosis. The outcomes were in-hospital mortality, complication rates, and resource utilization. Odds ratios (OR) and means were adjusted for confounders using multivariate regression analysis models. Results: Out of the total 32,324 hospitalizations for SVT, 3,220 (10%) were associated with a GI malignancy, of which hepatocellular carcinoma (HCC) and pancreatic cancer were the most common. Portal vein thrombosis accounted for 95% of these hospitalizations. Admissions for pancreatic cancer-associated SVT have increased by 7.2 times from 2007 to 2017. Patients with SVT and concomitant GI malignancies were significantly older and had a higher comorbidity score than those with SVT without GI malignancy. Risk of inpatient mortality for SVT patients were significantly higher for patients with gastric cancer (rate: 12.1%, OR 8.6, 95% CI: 1.8–39.7) and HCC (rate: 7.6%, OR 2.77, 95% CI 1.5–4.8) as compared to non-GI malignancy-related SVT. Odds of variceal bleeding were significantly higher for patients with HCC (OR 1.67, 95% CI: 1.2–2.34) than patients without GI malignancy. Conclusions: Digestive cancer-associated SVTs constitute 10% of all SVT related hospitalizations and are significantly increasing in the past decade. We report the baseline characteristics and predictors of inpatient mortality in this study.

Outcomes of long-term anticoagulant treatment for the secondary prophylaxis of splanchnic venous thrombosis.

Splanchnic vein thrombosis (SVT) is an uncommon but potentially life-threatening disease usually related to different underlying clinical conditions. The risk of SVT recurrences is high over time in patients with an underlying permanent prothrombotic condition. Vitamin K antagonists (VKA) represent the mainstay of treatment for SVT. Data about the efficacy and safety of direct oral anticoagulants (DOACs) are reported in the literature for the treatment of acute SVT, but less is known about their application for the secondary prophylaxis of venous thromboembolism (VTE). The aim of this study was to assess the efficacy and safety of long-term DOACs therapy in patients at high-risk of thrombosis, compared to VKA. This is a retrospective single-centre study including 70 patients with SVT on long-term anticoagulant treatment with VKA followed-up at our Units between January 2017 and December 2019. All the patients were at high thrombotic risk defined as the presence of a permanent prothrombotic condition requiring long-term anticoagulation. During follow-up, 28 patients were shifted to DOACs and their clinical outcomes were compared to those of the patients who continued VKA therapy. All the arterial and venous thrombotic events of the splanchnic and extra-splanchnic districts as well as the haemorrhagic adverse events occurring during follow-up were recorded. Of the seventy patients enrolled in the study, 36 patients (51.4%) had a single-segment involvement thrombosis (28.5% of portal vein, 7.1% of superior mesenteric vein, 4.3% of splenic vein, 11.5% of hepatic veins) and 34 patients (48.6%) had multi-segment involvement at the time of diagnosis. 42 patients (60%) continued VKA therapy and 28 (40%) were switched to DOACs. Median follow-up was 6years (range 2-8) during VKA and 1.9years (range 1-5.2) during DOACs. The incidence of thrombotic events was similar between patients on VKA and those on DOACs. Patients on VKA developed deep vein thrombosis (DVT), and of the patients on DOACs 1 developed NSTEMI and 1 DVT. No major haemorrhagic events occurred. Minor bleedings occurred in 26% of patients on VKA and in none of the DOACs patients (P: 0.09). Our results highlight that DOACs could represent an effective and safe alternative to the VKA for secondary prophylaxis in SVT patients at high risk of thrombosis.

Prevalence of prothrombotic factors in patients with Budd-Chiari syndrome or non-cirrhotic nonmalignant portal vein thrombosis: A hospital-based observational study.

Comprehensive investigations on the prothrombotic factors of splanchnic vein thrombosis (SVT), including Budd-Chiari syndrome (BCS) and non-cirrhotic nonmalignant portal vein thrombosis (PVT), in Eastern patients are scarce. Between March 2012 and July 2017, 812 consecutive patients, including 418 BCS and 394 non-cirrhotic nonmalignant PVT patients, were admitted to Xijing Hospital (a Chinese tertiary academic hospital) and screened for prothrombotic factors. Odds ratios (ORs), 95% confidence intervals (CIs), and P-trends were calculated by using conditional logistic regression. The prevalence of myeloproliferative neoplasms (MPNs) was only 6.3% among BCS patients but 28.3% among PVT patients. Notably, the presence of MPNs was associated with a higher risk of hepatic vein-type BCS (OR 9.9, 95% CI 3.6-26.7, P-trend <0.001) and extensive thrombosis in PVT (OR 4.1, 95% CI 1.9-8.9, P-trend <0.001). Calreticulin mutations existed in 2.7% of SVT patients. Furthermore, the prevalence of antiphospholipid antibody syndrome and protein C, protein S, or antithrombin deficiency in BCS patients was 7.3% and 22.5%, respectively, similar to that in patients with PVT (7.4% and 25.7%). In addition, factor V Leiden mutation, prothrombin G20210A mutation, and paroxysmal nocturnal hemoglobinuria were identified in <1% of both BCS and PVT patients. There is a significant positive association between MPNs and hepatic vein-type BCS or non-cirrhotic nonmalignant PVT with extensive thrombosis. Additionally, calreticulin mutations should be tested in JAK2V617F -negative SVT patients in China. However, screening for factor V Leiden mutation, prothrombin G20210A mutation, and paroxysmal nocturnal hemoglobinuria may be unnecessary.

PB2200 PREVALENCE OF JAK2V617F, CALR AND MPL MUTATIONS IN PATIENTS OF MYELOPROLIFERATIVE NEOPLASMS AND SPLANCHNIC VEIN THROMBOSIS IN INDIA

Background:Recurrent somatic mutations in the JAK2, MPL, and CALR genes have been described in patients diagnosed with Philadelphia‐negative Myeloproliferative neoplasms (MPNs), including Polycythemia vera (PV), Essential thrombocythemia (ET) and Primary myelofibrosis (PMF). MPN is also the most common etiology in splanchnic vein thrombosis (SVT). MPNs account for approximately 40% of Budd Chiari syndrome (BCS) and 31% of portal vein thrombosis (PVT).The present study was aimed at studying the prevalence of JAK‐2V617F, MPLW515L/K and CALR exon 9 mutations in BCR‐ABL1 negative myeloproliferative neoplasms (MPNs) and splanchnic vein thrombosis (SVT) patients. There is paucity of such data in the Indian patients.Aims:The study had two aims: Identification of incidence of JAK2V617F, CALR exon 9 mutations and MPLW515L/K mutations in BCR‐ABL1 negative MPNs in India Identification of incidence of JAK2V617F, CALR exon 9 mutations and MPLW515L/K mutations in Indian patients of SVT MethodsA total number of 60 patients of SVT and 59 MPN patients (10 PV, 19 ET, and 30 PMF) were included in the study. The mutation analysis for JAK2V617F, CALR exon 9 and MPLW515L/K mutations were performed using the Allele specific oligonucleotide‐polymerase chain reaction (ASO‐PCR) was used to detect JAK‐2, CALR and MPL mutations.Results:Among 59 patients of MPNs and 60 SVT; JAK‐2 mutation was found in 61.0% (36/59) and 23.3% (14/60) respectively. On sub‐classification, JAK‐2 mutation was detected in 80.0% (8/10) of PV; 42.1% (8/19) of ET and 66.7% (20/30) of PMF patients.All the patients of MPNs and SVT were subjected to CALR mutation analysis. The overall rate of CALR mutations in PMF and ET was 10% (3/30) and 21.0% (4/19) respectively. Limiting the analysis to JAK2V617F negative patients of PMF and ET, it was seen that 30% (3/10) PMF and ∼36.36% (4/11) ET cases were CALR mutated. Of these 7 CALR mutations; L367fs∗46 (type‐1) and K385fs∗47 (type‐2) mutations were found in 5 and 2 patients respectively. MPL mutation was identified in 5.26% (1/19) ET cases. Triple negative ET and PMF were ∼31.5% (∼6/19) and ∼23.3% (7/30) respectively. None of the SVT patients were observed to be CALR mutated and none showed the MPLW515L/K mutations.Summary/Conclusion:Indian patients exhibit a lower incidence of CALR mutations in Primary myelofibrosis than that seen in the western literature. However, the incidence of CALR mutations is the same as that reported earlier in Indian patients of Essential thrombocythemia. Triple negative cases constitute 31.5% of all cases of Essential thrombocythemia and 23.3% of Primary myelofibrosis Indian patients show a Testing for CALR mutations and MPLW515L/K mutations in splanchnic vein thrombosis is not justified.

Splanchnic vein thrombosis and myeloproliferative neoplasms: molecular-driven diagnosis and long-term treatment.

Splanchnic vein thrombosis (SVT) encompasses Budd-Chiari syndrome (BCS), extrahepatic portal vein obstruction (EHPVO), and mesenteric vein thrombosis. Philadelphia-negative myeloproliferative neoplasms (MPNS) are the leading systemic cause of non-cirrhotic and non-malignant SVT and are diagnosed in 40% of BCS patients and one-third of EHPVO patients. In SVT patients the molecular marker JAK2 V617F is detectable up to 87% of those with overt MPN and up to 26% of those without. In the latter, other MPN molecular markers, such as mutations in JAK2 exon 12, CALR and MPL genes, are extremely rare. Immediate anticoagulation with heparin is used to treat acute patients. Upon clinical deterioration, catheter-directed thrombolysis or a transjugular intrahepatic portosystemic shunt is used in conjunction with anticoagulation. Orthotopic liver transplantation is the only reliable option in BCS patients with a lack of a response to other treatments, without contraindication due to MPN. Long-term oral anticoagulation with vitamin K-antagonists (VKA) is recommended in all SVT patients with the MPN-related permanent prothrombotic state; the benefits of adding aspirin to VKA are uncertain. Cytoreduction is warranted in all SVT patients with an overt MPN, but its appropriateness is doubtful in those with molecular MPN without hypercythaemia.

CALR mutation analysis is not indicated in patients with splanchnic vein thrombosis without evidence of a myeloproliferative neoplasm: a micro-review

Th e recent discovery of exon 9 insertion and/or deletion mutations of the CALR gene in up to 80% of JAK2and MPL-unmutated essential thrombocythemia and primary myelofi brosis patients compels the incorporation of CALR mutational analysis into the molecular diagnostic algorithm for these myeloproliferative neoplasms (MPN). MPN are a major cause of splanchnic vein thrombosis (SVT) which encompasses Budd-Chiari syndrome, portal and mesenteric vein thrombosis. Up to 40% of SVT patients are diagnosed with an overt or latent MPN [1]. While the MPN-associated JAK2 V617F mutation is consistently reported in cohorts of SVT patients, several studies have investigated the role of CALR mutation analysis for MPN diagnosis in the presence of SVT with some debate existing [2-10]. Here, all reports published to date are summarized (Table 1). Briefl y, of 944 patients studied only eight (0.8%) had evidence of a CALR mutation and of whom seven already had a previous diagnosis of an MPN. MPN patients with CALR mutations have a signifi cantly lower overall risk of thrombosis than their counterparts harboring the JAK2 V617F and this is clearly the case with respect to SVT. While CALR mutated MPN patients may develop SVT, summarizing those published studies to date, routine investigation for these mutations appears not to be indicated in the diagnostic algorithm for SVT where no clinical or hematological features of an MPN are present. References

PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q, and Prothrombin 20210A in Splanchnic Vein Thrombosis: Analysis of Individual Patient Data From Three Prospective Studies

There are no univocal opinions on the role of genetic thrombophilia on splanchnic vein thrombosis (SVT). We defined genetic thrombophilia the presence of one of these thrombophilic genetic factors (THRGFs): PAI-1 4G-4G, MTHFR 677TT, V Leiden 506Q, and prothrombin 20210A. To evaluate the frequencies of these THRGFs in SVT patients, we analyzed individual data of 482 Caucasian patients, recruited from 2000 to 2014 in three prospective studies. SVT was defined as the presence of thrombosis of portal (PVT), mesenteric (MVT), splenic (SPVT), cava (CT), and hepatic vein (Budd Chiari syndrome, BCS). Pre-hepatic SVT (pre-HSVT) was defined as PVT with or without MVT/SPVT, without BCS. Post-hepatic SVT (post-HSVT) was BCS with or without PVT/MVT/SPVT. We compared 350 patients with liver cirrhosis (LC), 47 hepatocellular carcinoma (HCC), 37 myeloproliferative neoplasm (MPN), 38 associated disease (AD), 10 without any associated disease (WAD), vs 150 healthy controls (HC); 437 patients showed pre-HSVT and 45 post-HSVT. Thrombophilia was present in 294/482 (60.9%) patients: 189/350 LC (54.0%), 31/47 (66.0%) HCC, 29/39 (74.4%) MPN, 35/38 AD (92.1%), and 10/10 (100%) WAD, and 54/150 (36.0%) in HC. In the total group, we found 175 PAI-1 4G-4G, 130 MTHFR 677TT, 42V Leiden 506Q, and 27 prothrombin 20210A; 75 patients showed presence of >1 TRHGF; the more frequent association was PAI-1 4G-4G/MTHFR 677TT, in 36 patients. PAI-1 4G-4G and MTHFR 677TT were significantly more frequent in patients with SVT (P values <0.005), whereas V Leiden Q506 and prothrombin G20210A were not. PAI-1 4G-4G and MTHFR 677TT distributions deviated significantly from that expected from a population in Hardy-Weinberg equilibrium. Thrombophilia was significantly less frequent in patients with pre-HSVT (250/437, 57.2%) than in patients with post-HSVT (44/45, 97.8%). Our study shows the significant prevalence of PAI-1 4G-4G and MTHFR 677TT in SVT, mainly in post-HSVT.

Risk Factors, Diagnosis, Management, and Outcome of Splanchnic Vein Thrombosis: A Retrospective Analysis.

This study aims to determine the risk factors, diagnostic methods employed, treatment modalities, and outcome in patients with splanchnic vein thrombosis (SVT). A retrospective chart review of patients, age 18 to 90 years, diagnosed with SVT at a single institution from January 1, 2010 to November 10, 2012. They were grouped as portal vein thrombosis (PVT)-including those combined with splenic vein thrombosis (SPVT) or mesenteric vein thrombosis (MVT)-and Budd-Chiari syndrome (BCS). Overall 246 SVT patients were identified, including 225 PVT and 21 BCS. Risk factors were liver disease, upper abdominal (regional) cancer and surgery, pancreatitis, and hereditary thrombophilia. The most common symptom was abdominal pain and most patients had abnormal liver function. Among those tested, the JAK2 V617F mutation was present in only 20% of the patients with PVT and 14% of the patients with BCS. Most patients were diagnosed by computed tomography. Anticoagulants were given to 30% of the patients with PVT and to 60% of the patients with BCS, with recurrence of SVT in 15% of the patients with PVT and 24% of the patients with BCS, regardless of anticoagulation. As compared with published literature on SVT, we found a higher incidence of regional cancer and surgery and a lower incidence of the JAK2 V617F mutation.

Safety of vitamin K antagonist treatment for splanchnic vein thrombosis: a multicenter cohort study

The treatment of splanchnic vein thrombosis (SVT) is challenging, due to the increased risk of bleeding and potentially life-threatening complications. Current recommendations are based on evidence from the treatment of venous thrombosis in usual sites, but small observational studies in SVT population suggest that the bleeding risk may offset the benefit of anticoagulant treatment in this setting. The aim of this study was to evaluate the safety of vitamin K antagonists (VKAs) in SVT patients. We retrospectively included SVT patients treated with VKAs followed by 37 Italian anticoagulation clinics, until June 2013. The primary outcome was the incidence of major bleeding (MB), according to the ISTH definition, during VKA treatment. Vascular events, including both arterial and venous thrombosis, and mortality were also documented. Three hundred and seventy-five patients were included (median age 53 years; 54.7% males). During a median VKA treatment duration of 1.98 years, 15 MB events occurred, corresponding to an incidence rate of 1.24 (95% confidence interval [CI], 0.75-2.06) per 100 patient-years. Gastrointestinal bleeding represented 40% of all MB events. At multivariate analysis, the presence of esophageal varices emerged as independent predictor of MB (hazard ratio 5.4; 95% CI, 1.4-21.1). The incidence rate of vascular events on treatment was 1.37 (95% CI, 0.84-2.23) per 100 patient-years and the mortality rate was 0.83 (95% CI, 0.44-1.54) per 100 patient-years. Selected SVT patients followed by anticoagulation clinics for the management of VKA treatment show a low rate of major bleeding and vascular events.

Diagnostic value of the JAK2 V617F mutation for latent chronic myeloproliferative disorders in patients with Budd-Chiari syndrome and/or portal vein thrombosis.

The diagnosis of an underlying myeloproliferative neoplasm (MPN) is often problematic in patients with Budd Chiari syndrome (BCS) or portal vein thrombosis (PVT). This study aimed to assess the diagnostic value of the JAK2 gene V617F gain-of-function mutation for MPN in splanchnic vein thrombosis patients. One hundred eleven patients (80 with PVT, 27 with BCS, and 4 with BCS and PVT) were investigated. The control group included 56 volunteers without any known diseases. LightCycler SNP genotyping was performed to detect the JAK2 V617F mutation in DNA extracted from peripheral blood. The JAK2 V617F mutation was identified in six of 28 patients (21.4%) with idiopathic PVT or BCS and in eight of 45 patients (17.8%) with PVT or BCS secondary to a known prothrombotic factor, but in only one of 38 patients (2.6%) with PVT and cirrhosis (p=0.049). The JAK2 V617F mutation is a noninvasive molecular marker for occult MPNs and can be used for the diagnosis of latent MPNs presenting with thrombotic events. Analysis of JAK2 mutation in the patients with idiopathic PVT or BCS showed that 20% had latent MPNs. In addition to this JAK2 mutation, prothrombotic events were observed in a significant number of patients with splanchnic vein thrombosis. JAK2 gene analysis should be included in the research panel for BCS and PVT patients without cirrhosis.

Recurrent Thrombotic Events after Discontinuation of Vitamin K Antagonist Treatment for Splanchnic Vein Thrombosis: A Multicenter Retrospective Cohort Study

It is generally recommended that patients with splanchnic vein thrombosis (SVT) should receive a minimum of 3 months of anticoagulant treatment. However, little information is available on the long-term risk of recurrent thrombotic events. The aim of this study was to evaluate the risk of venous and arterial thrombosis after discontinuation of vitamin K antagonist (VKA) in SVT patients. Retrospective information from a cohort of SVT patients treated with VKA and followed by 37 Italian Anticoagulation Clinics, up to June 2013, was collected. Only patients who discontinued VKA and did not receive any other anticoagulant drug were enrolled in this study. Thrombotic events during follow-up were centrally adjudicated. Ninety patients were included: 33 unprovoked SVT, 27 SVT secondary to transient risk factors, and 30 with permanent risk factors. During a median follow-up of 1.6 years, 6 venous and 1 arterial thrombosis were documented, for an incidence of 3.3/100 patient-years (pt-y). The recurrence rate was highest in the first year after VKA discontinuation (8.2/100'pt-y) and in patients with permanent risk factors (10.2/100'pt-y). Liver cirrhosis significantly increased the risk of recurrence. In conclusion, the rate of recurrent vascular complications after SVT is not negligible, at least in some patient subgroups.

How I treat splanchnic vein thrombosis

AbstractAntithrombotic treatment of splanchnic vein thrombosis (SVT) is a clinical challenge. Depending on the site of thrombosis, patients are at risk of developing liver insufficiency, portal hypertension, or bowel infarction and may experience recurrence in both the splanchnic veins and other vein segments. To prevent recurrence, anticoagulant therapy should be started as soon as possible after diagnosis and is often continued for an indefinite period of time. However, active bleeding is not infrequent at the time of SVT diagnosis, and major risk factors for bleeding, such as esophageal varices or a low platelet count, are frequently present in these patients. In real-world clinical practice, a proportion of SVT patients are left untreated because the risks associated with anticoagulant therapy are felt to exceed its benefits. However, the majority of patients receive anticoagulant drugs, with heterogeneous timing of initiation, drug choice, and dosages. Evidence to drive treatment decisions is limited because no randomized controlled trials have been carried out in these patients. This review provides practical guidance for the use of anticoagulant drugs in patients presenting with SVT, including symptomatic as well as incidentally detected events.