Splanchnic vein thrombosis refers to the thrombotic process. Survival and Recurrence in Patients With Splanchnic Vein Thromboses

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2010;8: Survival and Recurrence in Patients With Splanchnic Vein Thromboses MALLIKARJUN R. THATIPELLI,* ROBERT D. MCBANE,*, DAVID O. HODGE, and WALDEMAR E. WYSOKINSKI*, *Division of Cardiovascular Medicine, Division of Hematology, and Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota BACKGROUND & AIMS: Hepatic, splenic, portal, and mesenteric veins are confluent elements within the splanchnic system. It is therefore unclear whether thromboses of isolated segments represent unique entities. We compared etiologies, recurrence, and survival of patients with thromboses of different splanchnic venous segments. METHODS: An inception cohort of individuals was identified with first lifetime incident of splanchnic vein thrombosis between 1980 and We performed a case-controlled comparison of recurrent thrombosis and survival data with those of patients with deep venous thrombosis (DVT). RESULTS: The study (832 patients; mean age, years; 42% women) included patients with isolated portal (n 329), mesenteric (n 76), splenic (n 62), and hepatic (n 45) vein thrombosis and patients with multisegment involvement (n 320). Malignancy (27%) and cirrhosis (24%) were the most common etiologies. Recurrence-free survival 10 years after splanchnic vein thrombosis (76%) was comparable with that after DVT (68%) and not improved by anticoagulant therapy. Hormone therapy was the only independent predictor of recurrence (hazard ratio [HR], 2.2; 95% confidence interval [CI], ; P.03). Major bleeding was 6.9/100 patient-years. Gastroesophageal varices (HR, 2.63; 95% CI, ; P.001) and warfarin therapy (HR, 1.91, 95% CI, ; P.003) were independent predictors of bleeding. The 10-year survival rate of patients with splanchnic vein thrombosis (60%) was lower than that of patients with DVT (68%, P.05). Older age (HR, 1.03; 95% CI, ), active cancer (HR, 2.23; 95% CI, ), and myeloproliferative disorder (HR, 1.92; 95% CI, ) were independent determinants of mortality (P.001). CONCLUSIONS: Splanchnic vein thrombosis depends on the pathology of the organ supplied. On the basis of the low rate of recurrence and substantial rate of major hemorrhage, prolonged anticoagulant therapy does not appear to be justified. Splanchnic vein thrombosis refers to the thrombotic process involving portal, mesenteric, splenic, and hepatic venous segments in isolation or in some combinations. 1 3 These venous segments are confluent elements within the splanchnic system. One might therefore expect similar natural history, recurrence rates, and efficacy of anticoagulation for thrombosis within each segment of this system. On the contrary, given that each of these entities either supply unique organs or have unique drainage pathways, one might anticipate that the natural history would be quite different. It therefore remains unclear from a therapeutic standpoint whether splanchnic vein thrombosis can be viewed as a single entity or whether each constituent differs significantly as to mandate a distinct approach. Given the relative rarity of splanchnic vein thrombosis, data from large prospective randomized trials to guide clinical management are limited. 2,3 Without knowledge of the natural history of splanchnic venous thrombosis, therapeutic decision making remains difficult. To test the hypothesis that venous thrombosis of hepatic, splenic, portal, and mesenteric vein thromboses each represents a distinct clinical entity, we compared the clinical presentation and outcomes of patients with thrombotic involvement of each specific venous segment and with thrombosis of multiple segments. Last, we compared underlying etiology, recurrent rates, and survival of splanchnic vein thrombosis with deep venous thrombosis (DVT) of the lower extremity. Methods Study Population All patients with the diagnosis of hepatic, splenic, portal, superior mesenteric and inferior mesenteric vein thrombosis evaluated at the Mayo Clinic between January 1980 and December 2000 were included. The control group was randomly selected from a group of patients diagnosed with lower extremity DVT at the Mayo Clinic from 1980 to To minimize the impact of year to year variability of clinical evaluation and management, a proportional number of DVT controls were chosen to correspond to the number of splanchnic venous thrombosis cases diagnosed in each calendar year. The study was approved by the Mayo Clinic Institutional Review Board. Data Collection Data were collected from a centralized system that contains complete records of every inpatient hospitalization, outpatient visit, radiology examination, and all laboratory and pathology results (including autopsy reports), death certificates, and relevant correspondence for all patients treated and followed at Mayo Medical Center. Blood collection and thrombophilia test methodology are as outlined in previous reports. 4 Thrombophilia panel included lupus anticoagulant, protein C, protein S, antithrombin, activated protein C resistance (1995; with reflexive testing for factor V Leiden), prothrombin G20210A mutation (1998), disseminated intravascular coagulation, fibrinogen, fibrin D-dimer, dysfibrinogenemia, plasminogen, anticardiolipin antibodies, and homocysteine. Abbreviations used in this paper: CI, confidence interval; DVT, deep venous thrombosis; HR, hazard ratio by the AGA Institute /10/$36.00 doi: /j.cgh

2 February 2010 SPLANCHNIC VEIN THROMBOSIS 201 Table 1. Demographic Characteristics and Underlying Etiology Variable (%) Total (n 832) Hepatic (n 45) Portal (n 329) Mesenteric (n 76) Splenic (n 62) Multiple (n 320) DVT (n 236) P value Age (mean SD) Female (%) Idiopathic Cancer Myeloproliferative Leukemia/lymphoma Inflammatory bowel disease Pancreatitis OCP/HRT Cirrhosis Surgery Infection Connective tissue disease Thrombophilia No. positive (no. tested) 105 (319) 10 (25) 20 (86) 22 (43) 4 (12) 49 (153) NA.03 Note: DVT group not included in P values or column totals. OCP/HRT, oral contraceptive pill/hormonal replacement therapy. Follow-up The follow-up period began at the time of the initial patient encounter and ended with the most recent medical evaluation or at the time of death. Causes of death were determined by a review of medical records, death certificates, and autopsy results, when available. Major Event Definition and Adjudication A major thrombotic event was defined as DVT, pulmonary embolism, or atypical venous thrombosis occurring within venous segments such as renal, mesenteric, ovarian vein thrombosis, or cerebral venous sinuses thrombosis and had to be confirmed by well-accepted imaging modalities as previously described. 4,5 A recurrent thrombotic event within the same vascular territory was distinguished from the original thrombus by comparing serial imaging modalities. A major hemorrhage was defined as visible bleeding and a fall in hemoglobin of 2 g/dl, hemorrhage requiring transfusion of 2 units of blood, or intraocular, intracerebral, or retroperitoneal hemorrhage. Statistical Analysis Baseline data are presented as a percent of the total or as a mean and standard deviation. Differences between splanchnic vein thrombosis and DVT were tested for statistical significance by using Pearson 2 test for categorical data or Student t test for continuous variables. Differences between the groups in the thrombophilia prevalence were tested with Fisher exact test. The Kaplan Meier product limit estimator was used to calculate unadjusted event rates. Differences between the unadjusted curves were tested by using log-rank tests. Expected mortality was estimated by using age-specific and sex-specific mortality rates from the US white population. 6 These expected rates were compared with the observed mortality rates by using a one-sample log-rank test. Multivariate Cox proportional hazards models were fit to model the time to recurrence and the time to death in the splanchnic vein thrombosis patients. Covariate incorporated into the model included age, gender, cancer, antecedent surgery (within 3 months of splanchnic vein thrombosis diagnosis), infection, and history of DVT or pulmonary embolism. Warfarin use was modeled as a time-dependent covariate in the time to recurrence models. Results Demographic Characteristics and Underlying Etiology A total of 832 patients with splanchnic vein thrombosis (mean age, years; 42% women) including isolated portal (n 329), mesenteric (n 76), splenic (n 62), and hepatic (n 45) vein thrombosis and 320 patients with multisegmental involvement underwent evaluation at the Mayo Clinic and had complete follow-up data (Table 1). Imaging modalities used to make the diagnosis included computed tomography (n 327), duplex ultrasonography (n 258), angiography (n 104), and contrast-enhanced magnetic resonance imaging (n 15). Diagnosis was established at surgery in 70 cases and at autopsy in 58 cases. Venous segments involved with thrombosis varied considerably among this cohort with respect to location and extent (Figure 1). The age distribution at time of diagnosis spanned the entire spectrum from the first day of life to 94 years (Figure 2), and specific characteristics of age and gender division were apparent for each specific venous segment. The most common underlying pathology was cancer, present in 221 (27%) patients (Table 1). The three most common sites of malignancy were pancreatic (n 84), hepatobiliary (n 70), and gastrointestinal (n 41). Myeloproliferative disorder, present in 88 cases, was a prominent cause of hepatic vein thrombosis and commonly resulted in multifocal thrombosis. Nearly half of all patients with splenic vein thrombosis had underlying pancreatitis. Nearly one third of patients with portal vein thrombosis had associated cirrhosis. Other etiologies included sepsis of intra-abdominal origin (n 83), inflammatory bowel disease (Crohn s disease, n 17, ulcerative colitis, n 34), and various collagen vascular and autoimmune disorders (n 51). Paroxysmal nocturnal hematuria was associated with

3 202 THATIPELLI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8, No. 2 Figure 1. Splanchnic venous thrombus location. Number and location of isolated venous segment thrombosis are presented. Where thrombosis extended to an additional venous segment, the number is presented in parentheses for each location. venous thrombosis (3.5/100 patient-years), with a median time to recurrence of 19 months. Only 3 patients experienced more than 1 recurrence. Thirty-four recurrent events involved the splanchnic veins, and additional sites included lower extremity (n 19), pulmonary embolism (n 9), and axillary-jugularsubclavian veins (n 8). Recurrence-free survival at 10 years (74%) did not differ significantly compared with DVT group (68%; P.68; Figure 3A). Recurrence-free survival was marginally lower for those patients with multiple compared with those with isolated venous segment thrombosis (64% vs 80%; P.07; Figure 3B). Recurrence-free survival rates were marginally lower in patients with mesenteric (60%) and hepatic vein (76%) thrombosis compared with splenic (97%) and portal (85%) vein thrombosis (P.09; Figure 3C). By multivariate analysis, only estrogen/ progesterone therapy was the independent predictor of recurrence (hazard ratio [HR], 2.2; 95% confidence interval [CI], ; P.02). Recurrence-free survival was not significantly improved for patients receiving warfarin compared with those who were not (0.89 vs 0.77; P.38; Figure 3D). There were 354 patients with neither cirrhosis nor malignancy. Of these, 143 (40.4%) were treated with warfarin. Within this splanchnic vein thrombosis in 9 cases. Seventy-six thrombotic events occurred after recent surgery, of which only 2 were remote from abdominal cavity (laminectomy and thoracotomy). The most common surgeries associated with splanchnic vein thrombosis were splenectomy (n 20) and liver transplantation (n 21). Thrombophilia testing was performed in 318 patients. Of these, a congenital or acquired thrombophilia was detected in 115 patients. The most common symptom was abdominal pain, and less than one fifth of patients were asymptomatic (Table 2). Although ascites (29%) was the most common sign, its prevalence varied considerably, depending on thrombus location. Gastrointestinal bleeding, present in one fourth of patients, was associated with gastroesophageal varices. Nearly half of patients with mesenteric vein thrombosis presented with signs and symptoms of acute abdomen. Asterixis was found only in patients with hepatic vein thrombosis. Anticoagulant Therapy Warfarin therapy was provided for 28% of patients (n 235) with splanchnic vein thrombosis. The percentage of those on anticoagulation varied considerably, depending on both the location (hepatic, 51%; portal, 16%; mesenteric, 54%; splenic, 5%) and extent of involvement (multisegmental, 49% vs isolated, 23%). Of these, 199 patients received warfarin for at least 6 months, and 175 continued treatment lifelong. Twenty-four patients were treated with aspirin only. Three patients received fibrinolytic therapy. Recurrent Venous Thromboembolism During the mean follow-up period of months (a total of 1847 patient-years), 65 patients experienced recurrent Figure 2. Age decile at diagnosis by gender. Differences in age distribution and gender at time of diagnosis are apparent for each venous segment involved. These data represent isolated venous thrombosis at the various locations only.

4 February 2010 SPLANCHNIC VEIN THROMBOSIS 203 Table 2. Signs and Symptoms at Clinical Presentation Relative to Venous Segment Involvement Hepatic (n 45) Portal (n 329) Mesenteric (n 76) Splenic (n 62) Total (n 512) P value Asymptomatic 15% 21% 10% 17% 18%.21 Abdominal pain 64% 40% 63% 57% 48%.001 Nausea 13% 16% 16% 23% 16%.54 Diarrhea 2% 8% 7% 8% 7%.54 Fever 9% 13% 8% 10% 12%.52 Gastrointestinal bleed 11% 28% 20% 29% 26%.05 Ascites 71% 31% 11% 11% 29%.001 Jaundice 16% 13% 4% 11% 11%.15 Anorexia 24% 8% 4% 8% 9%.001 Acute abdomen 4% 12% 47% 15% 17%.001 Encephalopathy 9% 9% 3% 7% 8%.25 Asterixis 16% 0% 0% 0% 1%.001 Gastroesophageal varices 18% 35% 7% 18% 27%.001 group, there were 31 recurrences. There was no effect of anticoagulation on recurrence rate in this group either. Hemorrhagic Events During the 1847 patient-years of follow-up, there were 127 major bleeding events (6.9/100 patient-years). Of these, 60 of 320 events occurred in patients with multisegmental thrombosis, 43 of 329 with portal, 14 of 76 with mesenteric, 6 of 62 with splenic, and 4 of 45 with hepatic vein thrombosis. Major bleeding occurred more frequently in patients currently receiving warfarin (n 55/210) compared with those not anticoagulated (n 72/380; P.05). The most common site of bleeding was the gastrointestinal tract (n 97) followed by genitourinary (n 14) and retroperitoneal (n 7). Multivariate analysis revealed gastroesophageal varices (HR, 2.63; 95% CI, ; P.001) and warfarin therapy (HR, 1.91; 95% CI, ; P.003) as independent predictors of major hemorrhages. Survival During the time period of this study, there were 346 deaths. In general, patients with splanchnic vein thrombosis had worse survival compared with patients with leg DVT (60% vs 68%, respectively; P.02) and with the age-matched and sex-matched controls (P.004; Figure 4A). Patients with isolated segment thrombosis had significantly better survival compared with those with multisegmental involvement (68% vs 48%, respectively; P.001; Figure 4B) and identical to leg DVT patient survival. Patients with splanchnic vein thrombosis and active malignancy had much lower survival than those without active malignancy (36% vs 69%, respectively; P.001; Figure 4C). Patients with isolated hepatic vein thrombosis had the highest 10-year survival rate (82%; Figure 4D), whereas patients with isolated portal vein thrombosis had the lowest (63%; P.045). Survival rates among patients receiving anticoagulation were higher compared with those who did not (64% vs 58%, respectively; P.01; Figure 3E). Fifty-four patients underwent emergent laparotomy for resection of ischemic bowel complicating venous thrombosis. One of these patients died within 30 days of surgery. Surgery did not significantly impact mortality. Multivariate analysis revealed that age (HR, 1.03; 95% CI, ; P.001), active cancer (HR, 2.23; 95% CI, ; P.001), and myeloproliferative disorder (HR, 1.92; 95% CI, ; P.001) were independent predictors of mortality. Discussion The principal findings of this study include an estimate of the rate of recurrent thrombosis in individuals identified with first lifetime incident of splanchnic vein thrombosis. There were 65 recurrent thrombotic events (34% within splanchnic circulation) for a survival-free recurrence rate at 10 years of 74% or a recurrence rate of 3.5/100 patient-years. These recurrence rates were similar to those for the lower extremity DVT control group and not significantly different for patients receiving warfarin. By multivariate analysis, hormonal therapy was the only independent predictor of recurrent venous thrombosis. We furthermore provide an estimate of thrombus recurrence for each specific venous segment within the splanchnic circulation. Recurrence-free survival rates varied from 60% (mesenteric vein thrombosis) to 97% (splenic vein thrombosis) at 10 years. Moreover, patients with isolated involvement experienced higher recurrence-free survival compared with those with multisegmental involvement (80% vs 64%). Previous reports of this nature have been limited to mesenteric and portal vein thrombosis recurrence and varied considerably In the biggest series of 136 adults with portal vein thrombosis, the recurrence rate was 5.5/100 patient-years. 8 In summary, the recurrence rates of splanchnic vein thrombosis are low in general. Rates vary, depending on the site and extent of involvement and the use of hormonal therapy as a causative agent. The second important finding of this study is an estimate of the rate of major hemorrhage in patients with splanchnic vein thrombosis both with and without anticoagulant therapy. Within our entire cohort, there were 127 major bleeding events for a rate of 6.9/100 patient-years. As anticipated, the most common source of bleeding was from the gastrointestinal tract and specifically from gastroesophageal varices and was more common for patients receiving warfarin. Previously quoted retrospective analysis 8 of 136 adults (62% on anticoagulation) with portal vein thrombosis showed a similar rate of thromboembolic complications (5.5 per 100 patient-years) but nearly twice the observed bleeding rates (12.5 per 100 patient-years) compared with our findings. In contrast to our series, anticoagulant therapy did not increase either the risk or the severity of bleed-

5 204 THATIPELLI ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8, No. 2 ing. This discrepancy could be related to the higher incidence of gastroesophageal varices reported in this series, the selected group of patients (nonmalignant, noncirrhotic), and the higher proportion of patients receiving warfarin. The authors of this study concluded that the benefit/risk favors anticoagulant treatment. We would temper these recommendations and advocate individualization of anticoagulant therapy. For example, anticoagulation might be desirable in patients with aggressive thrombophilic markers and should be minimized in those with a history of gastrointestinal variceal bleeding (particularly in those with cirrhosis). Overall survival at 10 years was 60% for the entire cohort, which was much lower than expected and lower than in patients with leg DVT. Predictors of poor survival included location and extension of venous segment involvement, underlying malignancy, and myeloproliferative disorder. Portal vein thrombosis carries the worse prognosis, most likely related to the high prevalence of malignancy. We and others 8 have shown improved survival with anticoagulant therapy. However, the retrospective nature of these data is likely clouded by selection bias and requires confirmation by randomized controlled trial design. As with other venous thrombi occurring at atypical locations, 6,17,18 we have found that splanchnic vein thrombosis largely results from pathology of the organ supplied related to underlying malignancy, inflammation, infection, or surgery. This study also shows that there are unique features of venous thrombosis for each specific segment of splanchnic circulation. Hepatic vein thrombosis affects primarily younger women, has myeloproliferative disorder as a prominent cause, Figure 3. Recurrent venous thromboembolism. Recurrence-free survival of patients with splanchnic vein thrombosis at 10 years (A) did not differ significantly compared with those with lower extremity DVT (P.68). Recurrence-free survival at 10 years (B) was marginally greater for isolated venous segment involvement compared with those with multisegmental involvement (P.07). Patients with mesenteric and hepatic vein thrombosis experienced marginally lower recurrence-free survival rates (60% and 76%, respectively) compared with splenic (97%) and portal (85%) vein thrombosis (C), but these differences have not reached statistical significance (P.08). Recurrence-free survival at 10 years was similar for patients receiving warfarin (D) compared with those not anticoagulated. Figure 4. Survival. Overall survival at 10 years (A) for patients with splanchnic vein thrombosis was lower compared with DVT patients (P.02) or age-matched and gender-matched individuals from the US white population (P.004). Patients with isolated venous segmental involvement (B) had higher overall survival compared with those with multisegmental involvement (P.001). Patients with splanchnic vein thrombosis and underlying active malignancy (C) had much lower survival than those without active malignancy (P.001). Patients with isolated hepatic vein thrombosis had the highest 10-year survival rate (D), whereas patients with isolated portal vein thrombosis had the lowest (P.045). Overall survival at 10 years was greater for patients receiving warfarin (E) compared with those not anticoagulated (P.01).

6 February 2010 SPLANCHNIC VEIN THROMBOSIS 205 recurrence-free survival rates are relatively low, yet overall survival exceeds thromboses in other splanchnic locations. Portal vein thrombosis, the most common thrombosis within the splanchnic territory, has poor survival because of the relatively high incidence of malignancy; nearly one third of patients had associated cirrhosis. Isolated splenic vein thrombosis is uncommon, mainly occurs in middle-aged men with pancreatitis, and has the highest recurrence-free survival rate (97%). Last, mesenteric vein thrombosis is commonly manifested as acute abdomen and has the lowest recurrence-free survival of all splanchnic vein thromboses and relatively high bleeding incidence. On the basis of this data set and data reported by others, prolonged anticoagulant therapy does not appear to be justified by the low rate of recurrence and considerable rate of major hemorrhage. We therefore conclude that DVT treatment guidelines are not readily applicable to these patients. For patients at increased risk of recurrence (mesenteric vein thrombosis), therapy must be individualized, and prolonged secondary prophylaxis with warfarin might be warranted. For these patients, anticoagulation decisions could include endoscopic screening for varices to assess bleeding risk. References 1. Mushlin PS, Gelman S. Hepatic physiology and pathophysiology: hepatic anatomy and circulation. In: Miller s anesthesia. 6th ed. New York: Churchill Livingstone, McBane RD, Wysokinski WE. Treatment of venous thrombosis at unusual sites. Curr Treat Options Cardiovasc Med 2008;10: Wysokinski WE, McBane RD. Mesenteric vein thrombosis. In: Gloviczki P, ed. 3rd ed. Handbook of venous disorders. London, UK: Hodder Arnold, 2009: Wysokinska EM, Wysokinski WE, Brown RD, et al. Thrombophilia differences in cerebral venous sinus and lower extremity deep venous thrombosis. Neurology 2008;70: Wysokinski WE, Gosk-Bierska I, Greene EL, et al. Renal vein thrombosis: incidence of venous thrombosis recurrence and survival. Am J Kidney Dis 2008;51: Therneau T, Sicks J, Bergstralh E, et al. Expected survival based on hazard rates: technical report series. No. 52. Section of biostatistics. Rochester, MN: Mayo Clinic, Condat B, Pessione F, Helene Denninger M, et al. Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy. Hepatology 2000;32: Condat B, Pessione F, Hillaire S, et al. Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy. Gastroenterology 2001;120: Jona J, Cummins GM Jr, Head HB. Recurrent primary mesenteric venous thrombosis. JAMA 1974;227: Abdu RA, Zakhour BJ, Dallis DJ. Mesenteric venous thrombosis: 1911 to Surgery 1987;101: Rhee RY, Gloviczki P, Mendonca CT, et al. Mesenteric venous thrombosis: still a lethal disease in the 1990s. Vasc Surg 1994; 20: Kumar S, Kamath PS. Acute superior mesenteric venous thrombosis: one disease or two? Am J Gastroenterol 2003;98: Morasch MD, Ebaugh JL, Chiou AC, et al. Mesenteric venous thrombosis: a changing clinical entity. J Vasc Surg 2001;34: Janssen HL, Wijnhoud A, Haagsma EB, et al. Extrahepatic portal vein thrombosis: aetiology and determinants of survival. Gut 2001;49: Ahn SS, Yellin A, Sheng FC, et al. Selective surgical therapy of the Budd-Chiari syndrome provides superior survivor rates than conservative medical management. J Vasc Surg 1987;5: de Franchis R. Evolving consensus in portal hypertension: report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005;43: Gosk-Bierska I, Wysokinski WE, Brown RD, et al. Cerebral venous sinus thrombosis: incidence of venous thrombosis recurrence and survival. Neurology 2006;67: Wysokinska EM, Hodge D, McBane RD 2nd. Ovarian vein thrombosis: incidence of recurrent venous thromboembolism and survival. Thromb Haemost. 2006;96: Reprint requests Address requests for reprints to: W. E. Wysokinski, MD, Division of Cardiovascular Medicine, Mayo Clinic and Foundation for Education and Research, 200 First Street SW, Rochester, Minnesota wysokinski.waldemar@mayo.edu; fax: (507) Conflicts of interest The authors disclose no conflicts. Funding Biostatistical support was provided by an internal grant from the Mayo Clinic Division of Cardiology.