Splanchnic vein thrombosis in patients with myeloproliferative neoplasms: The Mayo clinic experience with 84 consecutive cases
Authors: Sravanthi Lavu, Natasha Szuber, Mythri Mudireddy, Meera Yogarajah, Naseema Gangat, Animesh Pardanani, Curtis A. Hanson, Rhett P. Ketterling, Aneel A. Ashrani, Patrick S. Kamath, Ayalew Tefferi
Journal: American Journal of Hematology (2017)

Myeloproliferative neoplasms (MPN) constitute the most frequent cause of Budd–Chiari syndrome (BCS) and non-malignant, non-cirrhotic portal vein thrombosis (PVT), and it is currently assumed that JAK2 mutations might contribute to the increased risk of thrombosis in MPN.1 In a population-based cohort study from Denmark, including 1915 first-time cases of splanchnic vein thrombosis (SVT), the affected veins were portal in 78% (median age 63 years), hepatic (median age 54 years) in 11%, and mesenteric in 11% (median age 73 years); the respective incidence rates were 21, 3, and 3/100 000 persons per year, and the risk appeared to similar in the two sexes.2 The particular study documented recent surgery (90-day window) in 40% of the SVT cases, including 15% with abdominal surgery; other associated conditions included liver cirrhosis (11%), pancreatitis (11%), and extra-intestinal abdominal cancer (10%).2 In another large prospective study of 604 patients from an international registry, SVT involved the portal vein in 77% of the cases, mesenteric vein in 44%, hepatic vein 9%, splenic vein 23%, and multiple veins in 38%.3 The most frequently listed associated conditions in the particular study were liver cirrhosis (28%), solid cancer (23%), hormonal therapy (11%), intra-abdominal infection or inflammation (10%), abdominal surgery (9%), and MPN (8%); the event was felt to be unprovoked in 27% while the frequencies of JAK2V617F, prothrombin G20210A, and factor V Leiden mutations were 20%, 12%, and 11%, respectively.3 In one of the largest studies of MPN-associated SVT, 181 cases were retrospectively recruited from 23 European centers: polycythemia vera (PV) 37%, essential thrombocythemia (ET) 37%, and primary myelofibrosis (PMF) 26%; driver mutational frequencies were JAK2 in 93%, CALR 16%, and MPL 4%4; 65% of the patients were women and median age at diagnosis was 48 years.4 Also in the same study, median time from initial diagnosis of MPN to diagnosis of SVT was 2 years and the distribution of events included portal vein in 60%, hepatic vein 17%, splenic vein 13%, and mesenteric vein 10%; history of thrombosis before the index event of SVT was documented in only 8% of the patients, including venous thrombosis history in 4%; among tested patients, 18% had evidence of inherited thrombophilia.4 All patients in the particular study were reported to have received low-molecular-weight heparin therapy followed by warfarin therapy in the majority; at a median 3.2 years follow-up time, recurrent thrombotic events were recorded in 31 patients (17%), including SVT in 45% of the recurrent events.4 Reported risk factors for SVT recurrence included history of thrombosis, BCS, splenomegaly, and marked leukocytosis.4 There was no clear evidence of value for warfarin therapy, with or without concomitant aspirin or cytoreductive therapy, in terms of venous thrombosis recurrence.4 The current study constitutes a single center experience with 107 consecutive cases of SVT in patients with overt MPN (Table 1). The study was approved by the Mayo Clinic institutional review board and patients were recruited from institutional databases with additional cases identified through the Mayo Clinic Advanced Cohort Explorer Tool. Diagnosis of MPN was according to World Health Organization diagnostic criteria5 and SVT was confirmed in all cases by imaging studies. Cases with MPN, unclassifiable, or evidence of other neoplasms were excluded. Twenty-three patients were excluded from final analysis due to the temporal proximity of their SVT (within 3 months) to splenectomy. The clinical characteristics of the 84 study patients, at the time of their SVT diagnosis at our institution, are summarized in Table 1. At the time of SVT, active aspirin use was documented in only 20% of the patients. A history of previous thrombosis was recorded in 58% and included antecedent SVT in 46%. SVT type was portal ± splenic (n = 58; 26 MF, 19 PV, 13 ET), followed by portal + mesenteric ± splenic (n = 16; 11 ET, 2 MF and 3 PV), BCS ± other vessels (n = 9; 6 PV, 2 ET and 1MF), and splenic vein only (n = 1 PV). Comparison of these three SVT categories disclosed significant associations with MPN sub-category (P = .001; BCS with PV and "portal + mesenteric" with ET) and occurrence of ascites (P = .008; with BCS). It was also observed that the majority of BCS cases (7 of 8) occurred in patients younger than age 60 (P = .07). Initial treatment included systemic anticoagulation (SA) only in 35% of the patients, SA + ASA in 4%, SA + cytoreductive drug (principally hydroxyurea) in 24%, SA + ASA + cytoreductive drug in 2%, and no SA in the remaining 36%. In addition, trans-jugular intrahepatic portosystemic shunt (TIPS) or other surgical shunting was undertaken in 16% of patients and variceal banding in 17%. At a median follow up of 2.7 years, 22 deaths and 3 leukemic transformations were recorded. The cause of death was liver failure in three individuals (all MF), upper GI bleed in one (MF), leukemic transformation in one (MF), and thrombosis in one (ET), while it was felt to be unrelated to SVT in 12 instances and unknown in 4. As expected, post-SVT survival was significantly shorter in patients with MF, compared to those with PV or ET (HR 4.5, 95% CI 1.9–10.9). Other significant risk factors for overall survival, in multivariable analysis, included older age (HR 5.0, 95% CI 1.6–14.5) and abnormal cytogenetics (HR 3.9, 95% CI 1.4–11.3); when survival analysis was restricted to the 55 patients with PV/ET, advanced age (P < .01) and abnormal cytogenetics (P = .04) again predicted shortened survival. Fourteen patients (16%) had recurrent vascular events, including 8 (10%) with recurrent SVT. Only male sex (P = .02) predicted shorter thrombosis-free survival (Supporting Information Table 1). Similarly, post-SVT thrombosis-free survival and recurrence rate were not affected by type of SVT or initial treatment strategy (Supporting Information Table 1). In the current study, post-SVT survival in MPN was primarily influenced by the expected natural history of the underlying MPN, rather than the SVT event per se. Unlike the case with the aforementioned multicenter European study,4 we were not able to identify reliable predictors of SVT recurrence, in our patient cohort. On the other hand, both studies were in agreement in terms of their failure to demonstrate the therapeutic value of systemic anticoagulation, and the non-trivial rate of event recurrence. Accordingly, it is reasonable to query the value of alternative forms of systemic anticoagulation, such as the use of direct-acting oral anticoagulants, despite the challenge of securing optimal anti-thrombotic effect against the ever present risk of bleeding. In our opinion, primary prevention through avoidance of precipitating factors and aggressive management of high risk patients remains the best treatment approach.6 The authors have no conflict of interest to declare. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.