Abdominal thromboses of splanchnic, renal and ovarian veins

Best Practice & Research Clinical Haematology 25 (2012) 253–264

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Abdominal thromboses of splanchnic, renal and ovarian veins Valerio De Stefano, MD, Professor of Hematology, Director of the Hematology Service a, *, Ida Martinelli, MD, PhD, Consultant Hematologist, Responsible of the Thrombosis Center b a

Institute of Hematology, Catholic University, Largo Gemelli, 8, 00168 Rome, Italy Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine and Medical Specialities, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Via Pace, 9, 20122 Milan, Italy b

Keywords: Budd–Chiari syndrome extrahepatic portal vein thrombosis mesenteric vein thrombosis renal vein thrombosis ovarian vein thrombosis

Thromboses of abdominal veins outside the iliac–caval axis are rare but clinically relevant. Early deaths after splanchnic vein thrombosis occur in 5–30% of cases. Sequelae can be liver failure or bowel infarction after splanchnic vein thrombosis, renal insufficiency after renal vein thrombosis, ovarian infarction after ovarian vein thrombosis. Local cancer or infections are rare in Budd–Chiari syndrome, and common for other sites. Inherited thrombophilia is detected in 30–50% of patients. Myeloproliferative neoplasms are the main cause of splanchnic vein thrombosis: 20–50% of patients have an overt myeloproliferative neoplasm and/or carry the molecular marker JAK2 V617F. Renal vein thrombosis is closely related to nephrotic syndrome; finally, ovarian vein thrombosis can complicate puerperium. Heparin is used for acute treatment, sometimes in conjunction with systemic or local thrombolysis. Vitamin K-antagonists are recommended for 3–6 months, and long-term in patients with Budd-Chiari syndrome, unprovoked splanchnic vein thrombosis, or renal vein thrombosis with a permanent prothrombotic state such as nephrotic syndrome. Ó 2012 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: þ39 06 30154968; Fax: þ39 06 3051343. E-mail address: [email protected] (V. De Stefano). 1521-6926/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.beha.2012.07.002

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Introduction Thrombosis of abdominal venous vessels causes a wide spectrum of clinical pictures: patients can be totally asymptomatic or can present with acute abdominal pain. Key organs as liver, bowel, or kidneys bear the burden of thrombosis, developing chronic or acute impairment in function. Acute thrombosis of visceral veins is associated with a consistent early mortality rate; moreover, in survivors long-term consequences can dramatically affect the quality of life. Resulting liver disease can lead to cirrhosis, portal hypertension, and development of esophageal varices with a high bleeding risk. Short-bowel syndrome can develop in patients who required extensive resection of the small bowel due to thrombosis of superior mesenteric vein. Impairment of renal function due to renal vein thrombosis can require dialysis therapy. Therefore, prompt diagnosis and treatment are warranted to limit or avoid important clinical consequences. In this review we will describe abdominal thromboses of venous vessels outside the iliac–caval axis and discuss the clinical implications and the strategies of treatment. Splanchnic vein thrombosis Epidemiology and clinical manifestations The term splanchnic vein thrombosis encompasses occlusions of the hepatic veins (Budd–Chiari syndrome) or the veins forming the portal vein system. Budd–Chiari syndrome (BCS), extrahepatic portal vein obstruction (EHPVO), and mesenteric vein thrombosis (MVT) are three different diseases but the concomitant involvement of more than one venous district is frequent. BCS is defined as the obstruction of the hepatic venous outflow at any level, spanning from the small hepatic veins to the junction of the inferior vena cava and the right atrium. Outflow obstruction caused by hepatic veno-occlusive disease or hepatic disorders associated with congestive heart failure are not included in this definition [1]. The annual incidence of BCS is less than 1 per million individuals [2,3]. BCS is considered primary in the presence of thrombus or web, and secondary in the presence of endoluminal material other than thrombus (tumors or parasitic mass) or of extrinsic compression (abscesses, cysts, tumors) [1]. Membraneous webs that obstruct the terminal portion of the inferior vena cava can be either congenital or, more likely, the late sequelae of inferior vena cava thrombosis [4]. These are rare causes of BCS in the Western countries, but account for the large majority of cases in Oriental and South African cohorts [2], caused by recurrent bacterial infections and filariasis. However, the improvement in hygienic and sanitary conditions in India has made isolated inferior vena cava obstruction much rarer than in the past [5]. In Western countries, two-thirds of the patients are women [6,7], whereas in Asia there is a slight prevalence of men [2]. Symptoms of BCS depend on the extent and rapidity of the hepatic outflow obstruction, as well as on the degree of liver decompression via a collateral blood flow. Accordingly, presentation can be fulminant, acute, subacute or chronic [1]. Fulminant BCS is rare (5% of cases) and is associated with a rapid onset, extensive hepatocellular necrosis and hepatic encephalopathy; the acute form accounts for 20% of cases, with rapid development of ascites and hepatic necrosis with little or no formation of venous collaterals. The subacute or chronic forms are the most common, occurring in 60% of patients [8]. The remaining 15% of patients are and remain asymptomatic, perhaps because the hepatic outflow is preserved by a patent hepatic vein or large collaterals [9]. However the prevalence of the asymptomatic forms was notably lower (3%) in a recent survey [10]. Hepatomegaly, splenomegaly, right upper abdominal quadrant pain and ascites occur in the majority of patients, whereas mild jaundice and slight elevation of the aminotransferases are seen only in a minority of patients and in the chronic forms [6,7,10]. The mortality rate at 6 months is 10% [10]. After 10 years of follow-up, the survival of patients with BCS is 57–62%, and prognosis is worse in the 14% of cases with concomitant EHPVO [6,11,12]. EHPVO is defined as the obstruction of the extrahepatic portal vein that may occur with or without the involvement of the intrahepatic portal, splenic or superior mesenteric veins, formation of portal cavernoma and development of portal hypertension. Isolated occlusion of the splenic or superior mesenteric vein and portal vein thrombosis associated with chronic liver disease or tumor are not included in EHPVO [13]. In the 1980s the annual incidence of portal vein thrombosis was estimated at

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less than 4 per million individuals [14], but a recent autopsy study found EHPVO in approximately 3 individuals per thousand [15]. Presentation of EHPVO can be acute or chronic. Acute thrombosis is characterized by abdominal pain, fever and diarrhea, with no evidence of portal hypertension. When the mesenteric veins are also obstructed, there is a substantial risk of intestinal ischemia and bowel infarction. However, EHPVO may also be asymptomatic, and diagnosed incidentally. The chronic form [13,16,17] is characterized by portal cavernoma, portal hypertension with splenomegaly, and a frequency of bleeding from esophageal varices as high as 12% patient-years [18]. The overall survival of patients with portal vein thrombosis is 54% after 10 years, but in the absence of cancer, cirrhosis and thrombosis of the mesenteric vein it is 81%, with a mortality rate at one year of 5% [19]. The annual incidence of superior MVT is 2.7 per 100,000 individuals [20], and its presentation can be acute, subacute or chronic [21]. Symptoms of acute and chronic forms mimic those of EHPVO, that occurs concomitantly with MVT in 65–72% of patients [22]. Acute thrombosis is associated with a definite risk of bowel infarction and surgical resection in 23–33% of patients, with an early mortality rate of 20–30% [20,22]. The rate of recurrent thrombosis is 9.1%, in most cases in the absence of anticoagulant therapy [23]. Diagnosis The key imaging findings of BCS are occlusion of the hepatic veins, inferior vena cava, or both. Other typical findings are caudate lobe enlargement that may compress the inferior vena cava, liver enhancement due to portal and sinusoidal stasis and, in the subacute and chronic forms, intrahepatic collateral vessels and hypervascular nodules [24]. Doppler ultrasound has a sensitivity as high as 89% in EHPVO and near 100% in BCS, whereas in MVT sensitivity is much smaller because the quality of the test is often limited by overlying bowel gas [25–27]. Contrast-enhanced computed tomography and magnetic resonance imaging are the techniques of first choice and, in case of uncertain diagnosis, hepatic venography and liver biopsy are warranted [1,24,28]. Venography allows for pressure measurements, while liver biopsy helps to rule out other liver diseases [1]. Risk factors Risk factors for splanchnic vein thrombosis can be local or systemic (Table 1). Multiple risk factors are present in 10–46% of patients with BCS [7,10,29,30] and in 10–64% of those with portal vein thrombosis [17,19,29–31]. A local precipitating factor is rarely present in patients with BCS [7,29,30], but is found in 21–60% of those with portal vein thrombosis [26,27,31], mainly liver cirrhosis, hepatocarcinoma or other abdominal tumors, inflammatory diseases and abdominal surgery (Table 1). EHPVO develops in 5–8% of patients after splenectomy, especially in those with underlying myeloproliferative neoplasms (MPNs) or hemolytic anemia [32,33]. The leading cause of splanchnic vein thrombosis are MPNs, diagnosed in half of the patients with BCS and in one third of those with EHPVO [10,19,29,30,32,34,35]. The JAK2 V617F mutation, the main molecular marker of the Philadelphia-negative chronic MPNs, is found in nearly all patients with polycythemia vera and in about half of those with essential thrombocytemia [36]. The close relationship between MPNs and splanchnic vein thrombosis is confirmed by the high prevalence of the JAK2 V617F mutation among patients with BCS and EHPVO [10,31,37–40] (Table 1). Among patients with splanchnic vein thrombosis and JAK2 V617F positivity as the sole marker of hematologic disease at the time of thrombosis, the rate of development of an overt MPN during follow-up is 52% [39]. Enhanced platelet and leukocyte activation and plasma hypercoagulability associated with JAK2 V617F positivity have been postulated as pathogenic mechanisms of thrombosis [41,42]. In the absence of MPNs, the mutation is extremely rare in patients with venous thrombosis other than those of the splanchnic district [39,43]. Preliminary data show that the mutation is found in the endothelial cells of patients with BCS and polycythemia vera, suggesting a possible contribution of endothelial abnormality to the prothrombotic state [44]. Inherited thrombophilia is found in patients with splanchnic vein thrombosis, although diagnosis of deficiencies of antithrombin, protein C, and protein S is difficult in patients with liver function impairment [35,45]. A high prevalence of prothrombin G20210A mutation but not of factor V Leiden

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Table 1 Risk factors for Budd–Chiari syndrome and portal vein thrombosis in adults. The percent estimates are the ranges from single studies [3,6,7,10,17,19,29–31,35,37,45,49] and revision papers [34,38–40,46].

Local risk factors (%) Acquired Cancer Cirrhosis Abdominal infection Liver abscess Inflammatory bowel diseases Pancreatitis Cholecystitis Appendicitis Tuberculous lymphadenitis Membranous web Neonatal omphalitis Circumstantial Abdominal surgery Splenectomy Cholecystectomy Gastrectomy Liver transplantation Abdominal trauma Systemic risk factors (%) Inherited Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden Prothrombin G20210A Acquired Myeloproliferative neoplasms JAK2 V617F (with overt myeloproliferative neoplasms) JAK2 V617F (without overt myeloproliferative neoplasms) Antiphospholipid antibodies Behcet disease Autoimmune diseases Paroxysmal nocturnal hemoglobinuria Circumstantiala Oral contraceptives Hormone replacement therapy Pregnancy or puerperium a

Budd–Chiari syndrome

Portal vein thrombosis

6–7 8–14 7 2 3–8 – – – – 1–4 (West)–30 (East) –

13–24 17–18 10 3–5 1–4 6–19 2–7 1 3 – 1–6

2–23 2 – – – 10

10–30 7 3–12 3 2 1–3

2–5 2–9 3–7 4–26 3–8

1–2 1–9 1–5 3–8 3–22

23–49 57–100 26–44 1–11 4–9 10–13 2–19

6–33 78–100 19–27 3–13

15–50 14 4–16

15–30 3 2–3

1–4 1–2

Percentage calculated on the number of women.

has been consistently reported in patients with EHPVO [31,35,45,46], whereas factor V Leiden is more common in those with BCS [10,30]. Case control studies found an 8-fold increased risk of EHPVO for prothrombin G20210A mutation [35] and an 11-fold increased risk of BCS for factor V Leiden [30]. A recent meta-analysis showed a 4-fold and 3-fold increased risk of EHPVO for prothrombin G20210A and factor V Leiden, respectively [46]. A BCS is the most frequent thrombotic complication of paroxysmal nocturnal hemoglobinuria (41% of the occlusive events) [47] and of Behçet’s disease (26% of the occlusive events) [48]. Established circumstantial risk factors for BCS are pregnancy, puerperium and the use of oral contraceptives [49,50]. A case control study showed that oral contraceptives were associated with a 2.4 increased risk of BCS [50], but further estimations are needed. Reports on the risk factors associated with MVT were mostly anedoctal until recently, when an autopsy series and a population-based study were published [20,51]. The former showed the presence of abdominal cancer in 22% and liver cirrhosis in 17% of cases. The latter showed thrombophilia markers in 67%, a local factor (surgery or inflammation) in 25%, cancer in 24%, and use of oral contraceptives in 6% of patients.

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Therapy In the acute phase patients should be treated promptly with low-molecular or unfractionated heparin followed by oral anticoagulant therapy with vitamin K antagonists (VKA), sodium restriction, diuretic therapy and paracentesis, if needed. In the case of clinical deterioration despite anticoagulation, patients should be considered for such invasive procedures as angioplasty with or without stenting, transjugular intrahepatic portosystemic or surgical portosystemic shunt [1,28]. In patients with BCS, systemic thrombolytic therapy with tissue plasminogen activator is of little value, whereas catheter-directed thrombolysis seems to be effective in acute and partially occlusive thrombosis [52]. Local thrombolysis may also be effective in patients with EHPVO and MVT [53–55]. Transjugular intrahepatic portosystemic shunt is minimally invasive, has a low morbidity and mortality, improves survival of patients with BCS [56] and has been used also for patients with noncavernomatous EHPVO [57]. However, owing the 23% of perioperative mortality [11] and the unknown improvement in patients’ survival, surgical shunting is rarely performed [10]. Failure of the aforementioned interventions occurs in 10–20% of patients with BCS [9,29], who are therefore candidate to liver transplantation. Also acute EHPVO and MVT require prompt anticoagulation. There is limited evidence that oral anticoagulant therapy with VKA favours recanalization and reduces the recurrence rate, without increasing the risk and severity of variceal bleeding [18,31,58]. A recent prospective study showed that at 1 year of follow-up the recanalization rate in patients with initial obstruction of the portal vein, superior mesenteric vein, and splenic vein receiving anticoagulant therapy with VKA was 38%, 61% and 54%, respectively [31]. The optimal duration of anticoagulant treatment is unknown, but a minimum of 3–6 months for EHPVO and life-long for BCS are suggested; patients with EHPVO should receive lifelong anticoagulation in the presence of permanent risk factors for thrombosis or thrombus extension into mesenteric veins [1,13,16,59,60].

Renal vein thrombosis Epidemiology and clinical manifestations The annual incidence of renal vein thrombosis (RVT) in the general population is less than 1 per million [61]. RVT is the most prevalent noncatheter-related thrombosis during the neonatal period and accounts for 16–20% of all thromboembolic events in newborns [62]. The reported incidence of RVT from a German registry is 2.2 per 100,000 live births [63], due to the occurrence of neonatal dehydration or prolonged hypotension. Males are more commonly affected than females. The classic presentation of RVT includes microscopic or gross hematuria, flank pain, a painful palpable mass (in infants), and a decline in renal function. However, this presentation is typical of acute thrombosis and is rather rare. Commonly, RVT has an insidious onset and can be completely asymptomatic. The rapidity of the venous occlusion and the development of venous collateral circulation that takes several days, are determinant of the clinical presentation and renal function impairment. The spectrum of occlusion varies from acute complete to chronic incomplete, with different clinical picture. Acute RVT may be uni-or bilateral, the latter occurring in almost two thirds of patients. In patients with unilateral thrombosis, the left renal vein is more commonly involved than the right one. Only in children one or both kidneys can be palpable and painful, with overlying tenderness and muscle spasm. Hematuria, proteinuria, and a reduction in glomerular filtration rate are often present. Acidosis, leukocytosis and high plasma lactate dehydrogenase may be found. The affected kidney rapidly increases in size due to marked congestion and capsule distension, and the absence of collateral circulation may result in hemorrhagic infarction [64,65]. In a series of 218 adult patients the most common symptoms were flank pain (73%) and gross hematuria (36%). Nonspecific symptoms (anorexia, nausea, and fever) were present in more than 40% of patients. On examination, asterixis was noted in nearly half. A palpable flank mass was present in 9% of cases. Four percent of patients with RVT presented with peritoneal signs suggestive of an acute abdomen. Anemia was present in 38%. More than half patients had impaired renal function at the time of diagnosis, and 5%

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required dialytic therapy. Nephrotic-range proteinuria was present in 22.5% of patients at presentation and 20% of patients during follow-up [66]. Diagnosis The sonographic features of RVT include renal enlargement, increased echogenicity, loss of corticomedullary differentiation and echogenic interlobular streaking related to interlobular and interlobar thrombus. After the first week, renal enlargement associated with the formation of disorganized patchwork of hyper-echoic and hypo-echoic appearances occurs, representing hemorrhage and either edema or resolving hemorrhage, respectively. Adrenal hemorrhage can also be associated and may be identified ultrasonically [67]. Doppler ultrasound may reveal increased blood velocity and turbulence in narrowed sections of the renal vein or cessation of blood flow if the lumen is completely obstructed. The sensitivity of ultrasound is 85% and the specificity 56%. Power Doppler ultrasound has ameliorated the diagnosis of RVT and also of caval tumor thrombus [68,69]. Contrast computed tomography remains the imaging of choice for diagnosing RVT. Indirect radiographic signs suggesting RVT include increased renal size; renal vein enlargement; delayed, diminished, or absent opacification of the collecting system; a persistent nephrogram attributable to poor venous washout; prolonged cortico-medullary differentiation; thickening of renal fascia; and stranding of perinephric fat. The sensitivity and specificity are almost 100%. It can also show renal tumours and other renal pathologies. The disadvantages of computed tomography include exposure to radiation and use of nephrotoxic iodinated contrast media [70]. Magnetic resonance angiography is an alternative imaging, with a slightly lower sensitivity and specificity than computed tomography [71]. Inferior venacavography and selective renal venography are the gold-standard tests, although invasive and involving radiation exposure and injection of iodinated contrast [65]. A patent inferior vena cava without any filling defects in conjunction with clearance of the contrast by the renal vein rules out the diagnosis of RVT. Findings indicative of RVT include lack of washout of contrast or obvious filling defects due to the presence of thrombus. Risk factors In adults, RVT not cancer-related occurs almost always in patients with nephrotic syndrome, that is per se associated with an increased risk of venous thromboembolism. Deep venous thrombosis of the lower extremities can occur in up to 15% of patients. The incidence of RVT in patients with nephrotic syndrome ranges from 5% to 62% and is most common in membranous nephropathy [72]. In a large prospective study assessing RVT in 151 patients with nephrotic syndrome, it was identified in 22% of cases [73]. Conversely, nephrotic syndrome was present in about 20% of patients with RVT, mainly due to membraneous glomerulopathy [66]. Thrombotic diathesis in nephrotic syndrome may arise from preferential loss of naturally occurring anticoagulant proteins (mainly antithrombin), increased synthesis of procoagulant factors (fibrinogen, factors V and VIII), decreased fibrinolytic activity, or from local activation of the glomerular hemostasis system [72]. Extrinsic or intrinsic involvement of the renal vascular pedicle that can evolve in RVT is encountered in adults and is usually due to cancer, being observed in more than 50% of cases of renal cell carcinoma, as well as retroperitoneal tumours and lymphomas [64]. In a series of 218 patients with RVT, malignancy was the underlying condition in 66% of cases, 51% of which with renal cell carcinoma [66] (Table 2). RVT can be caused by either blunt or surgical trauma. An under-appreciated cause is iatrogenic, due to the presence of an inferior vana cava filter in the suprarenal position, femoral vein catheterization or, in neonatal intensive care, umbilical vein catheterization [64]. Finally, RVT complicates 0.1–0.5% of renal transplantations [74,75] and can be somewhat favoured by the presence of factor V Leiden [76]. A case–control study in newborns found a 9-fold increased risk of RVT for heterozygous factor V Leiden and an 8-fold increased risk for high lipoprotein (a) levels, whereas the presence of prothrombin G20210A was not associated with the disease [77]. In adults, inherited thrombophilia has been reported in approximately half patients with RVT, similar to what observed in patients with deep venous thrombosis of the legs [66] (Table 2).

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Table 2 Risk factors for renal vein thrombosis in a series of 218 adult patients referred to a single center [66]. Local risk factors (%) Acquired Cancer Infection Urogenital infection Sepsis Other infections Circumstantial Surgery General Colorectal Urological Vascular Systemic risk factors (%) Inheriteda Antithrombin deficiency Protein C deficiency Protein S deficiency Factor V Leiden Prothrombin G20210A Acquired Nephrotic syndrome Antiphospholipid antibodiesb Circumstantialc Hormone therapy Pregnancy or puerperium a b c

66 14 4 6 4 7 0.5 1 5 0.5

9 12 14 12 17 20 10 0.4 3

36 patients tested. 16 patients tested. Percentage calculated on the number of women.

Therapy Current management of RVT has shifted from surgical (thrombectomy or nephrectomy) to medical. Regardless of etiology, anticoagulant therapy is the mainstay of treatment of acute RVT, using low-molecular or unfractionated heparin followed by oral anticoagulant therapy with VKA. Lowmolecular-weight heparins should be used with caution in patients with renal insufficiency due to the risk of drug accumulation and potential increased risk for bleeding. Patients with a transient and removed recognized risk factor for RVT should be treated with a standard regimen of VKA (INR range from 2.0 to 3.0) for 3–6 months. Although the overall rate of recurrent RVT is low [66], patients with a permanent hypercoagulable state, those with idiopatic RVT and those with a severe, unremitting nephrotic syndrome (particularly with membranous nephropathy and with a serum albumin <20 g/L) should receive long-term anticoagulation [64,65]. Selected cases of RVT are suitable for thrombectomy and/or systemic or catheter-directed local thrombolysis [65]. These interventions should be performed at an early stage, to prevent irreversible damage to the kidney. Thrombolytic therapy results in rapid improvement of renal function and has low morbidity. However, such invasive procedures are reserved to patients with an acute and marked deterioration in renal function, bilateral RVT, thrombosis of a solitary native kidney or a renal transplant and to patients in which medical treatment was ineffective [78,79]. Ovarian vein thrombosis Epidemiology and clinical manifestations Ovarian vein thrombosis (OVT) is a rare condition, commonly identified in the postpartum period. It is characterized by inflammation or thrombosis of one or both ovarian veins. Ovarian veins have

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extensive communications with the uterine and vaginal plexuses, thus facilitating entry for infection. In 90% of cases OVT occurs in the right ovarian vein. The predominant right localization is partly due to the dextrotorsion of the puerperal enlarged uterus, which causes compression of the ovarian vein or to the incompetent valves of the right ovarian vein that induce blood flow stasis. Furthermore, the right ovarian vein is also longer than the left one and its valves are less competent. At term, the diameter of the ovarian vein increases up to 3 times that in the nonpregnant state and blood flow in the ovarian vein sharply declines immediately after delivery. This may lead to partial collapse of the veins and create significant venous stasis [80,81]. Overall, OVT complicates 1:500 to 1:2000 deliveries [82]. In a prospective observation on 40,353 deliveries, the incidence of OVT was 0.02% for vaginal deliveries and 0.1% for cesarean deliveries; 0.7% of twin deliveries via caesarean section was complicated by OVT and none of twin deliveries via the vaginal route. Thus, the risk for twin versus single delivery was 21-fold, and for cesarean section versus vaginal delivery was 7-fold. Perhaps, the size of the uterus during twin pregnancy resulted in compression of the ovarian veins [83]. The clinical picture of postpartum OVT is represented by lower quadrant and flank pain, fever in the first 48–96 h after delivery (41%), and occasionally by a palpable tender lower abdominal mass (50–67%) [81]. Uterine infection is present or suspected in the majority of cases before or at the onset of symptoms of OVT; despite antibiotics, fever persists, often accompanied by rigor. The abdominal pain can worsen and localize to the side of the affected vein, and may radiate to the groin, upper abdomen, or flank. Patients have direct tenderness on the affected side in association with both voluntary and involuntary guarding. The mass, consisting of a thrombosed vein with a surrounding phlegmon, may reach diameters of 8–10 cm. Additional signs and symptoms are nausea and vomiting, malaise, dyspnea, tachypnea, tachycardia, and ileus. The differential diagnosis must include appendicitis, pyelonephritis, broad ligament hematoma, adnexal torsion, or tubo-ovarian abscess. Complications arising from OVT include extension into the inferior vena cava and renal veins, ovarian infarction, sepsis, embolization of the thrombus and rarely, death. In one patient series pulmonary embolism was reported in 13% of the patients with postpartum OVT with a mortality of approximately 4% [84]; in a more recent single center series of 13 patients, no pulmonary embolism was observed [83]. Diagnosis Historically, before the introduction of modern imaging techniques, in most cases diagnosis was based on laparotomy. Ultrasound findings of OVT include an anechoic to hypo-echoic mass between the adnexa and the inferior vena cava and the absence of blood flow within the mass. Sonographic images can be limited as a result of overlying bowel gas in the puerperal and postsurgical abdomen, as well as frequent nonspecific findings. Computed tomography and magnetic resonance imaging usually show a tubular mass between the adnexa and renal hilum. Contrast-enhanced images of the ovarian vein reveal a low-density lumen with sharply defined walls. The sensitivity of computed tomography, magnetic resonance and Doppler ultrasonography has been reported 100%, 92% and 52%, respectively [85,86]. However, if the diagnosis remains uncertain after evaluation of both clinical presentation and objective testing, it is reasonable to consider a surgical approach, usually a diagnostic laparoscopy. This minimizes the risk of missing other underlying conditions that require surgery [81]. Risk factors Pregnancy-related hypercoagulability likely contributes to the development of postpartum OVT. Other common associations with OVT include gynecological malignancy, surgery, pelvic inflammatory disease, sepsis and hypercoagulable states. Rarely OVT has no recognized cause and there are only single case reports of idiopathic OVT worldwide [87]. In a series of 35 patients, 34% had an underlying malignancy, 34% assumed hormone therapy, 23% experienced recent pelvic infection, 20% underwent recent surgery, and 14% had postpartum OVT [88]. Inherited thrombophilia is present in 23–32% of patients with postpartum OVT, not different from the rate found in patients with deep venous thrombosis of the lower limbs [82,83] (Table 3). There are

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Table 3 Risk factors for ovarian vein thrombosis. The percent estimates are from three series of 22 [82], 13 [83], and 35 [88] patients. Local risk factors (%) Acquired Cancer Pelvic infection Inflammatory bowel diseases Circumstantial Cesarean delivery Twin delivery Surgery Trauma Systemic risk factors (%) Inherited Protein S deficiency Factor V Leiden Prothrombin G20210A Acquired Hormone therapy Puerperium Antiphospholipid antibodies

34 23–53 6 36–70 46 20 3

14 15–23 8 34 14 8

anedoctical cases with lupus anticoagulant or other antiphospholipid antibodies [89,90]. The rate of recurrent OVT is 3% patient-years, comparable that of recurrent deep venous thrombosis of the lower limbs, and may involve the contralateral ovarian vein, left renal vein, and inferior vena cava [88].

Therapy Broad-spectrum antibiotics and anticoagulation are the mainstay of treatment. Oral anticoagulation is usually recommended for 3–6 months, and antibiotic therapy is often recommended for one week. However, no standard evidence-based protocol exists for the use of antibiotics or for the length of anticoagulation. A favourable outcome with secondary antithrombotic prophylaxis with lowmolecular-weight heparin for 3 months has been reported in a series of 12 patients [83]. Conclusions Abdominal venous thromboses occurring outside the iliac–caval axis are rare but clinically relevant. Acute thrombosis of visceral veins is associated with a consistent early mortality rate of 5–10%, as high as 30% in patients with MVT. Progress in diagnostic imaging has improved rapidity of diagnosis in acute forms, and allowed to recognize much more frequently asymptomatic or chronic forms. Differential diagnosis of abdominal pain should always consider abdominal thrombosis, especially in the presence of circumstantial risk factors such as oral contraceptive use, pregnancy and puerperium, recent abdominal surgery, liver cirrhosis or inflammatory bowel diseases. Conversely, diagnosis of abdominal venous thrombosis should prompt to investigate thoroughly the presence of possible underlying common causes, such as inherited thrombophilia, or less common causes, such as MPNs or paroxysmal nocturnal hemoglobinuria. Anticoagulant therapy in patients with splanchnic venous thrombosis is challenging because of the increased bleeding risk of these patients, who often have an impaired liver function and esophageal varices due to portal hypertension. However, long-term treatment with VKA should be considered in patients with unprovoked splanchnic venous thrombosis, in those with severe thrombophilia (antithrombin, protein C or protein S deficiency, homozygous factor V Leiden or prothrombin G20210A mutation, antiphospholipid antibodies or combined abnormalities) or MPNs, and in those with recurrent thrombosis. Also patients with RVT and persistent nephrotic syndrome are candidates to long-term anticoagulant therapy.

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Conflict of interest statement The authors have no conflict of interest to disclose.

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