Splanchnic venous thrombosis

Etiology, diagnosis, and treatment.


Case presentation

A 56-year-old woman presented to the emergency department with abdominal pain, nausea, and vomiting. Two weeks earlier, she had undergone a laparoscopic right hemicolectomy for a villous adenoma and had tolerated the procedure well. Her medical history consisted of degenerative joint disease, anxiety, and depression. She was on no outpatient medications. She smoked 1 pack of cigarettes a day and was an occasional drinker. Her father had died of stomach cancer.

On physical exam, the patient was afebrile with normal vital signs. The exam was essentially normal except for mild periumbilical tenderness with rebound or guarding. Lab work revealed a hemoglobin level of 13.4 g/dL and a white blood cell count of 5.4 × 109/L with a normal differential. Her platelet count was 480 × 109/L. Her blood chemistries were all normal.

A CT scan of the abdomen demonstrated acute thrombophlebitis of the superior mesenteric vein, with additional thrombus within the portal vein and its intrahepatic branches. The patient was placed on IV heparin and then switched to subcutaneous enoxaparin along within warfarin and was discharged on hospital day 11. Her abdominal pain resolved. The patient received warfarin anticoagulation for 6 months, which was then discontinued. She has had no recurrence of mesenteric venous thrombosis. The cause was felt to be inflammation from surgery.

Background

Splanchnic venous thrombosis involves thrombosis in the mesenteric, splenic, or portal veins (with or without the hepatic veins) (11. Ageno W, Riva N, Schulman S, Beyer-Westendorf J, Bang SM, Senzolo M, et al. Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry. JAMA Intern Med. 2015;175:1474-80. [PMID: 26168152] doi:10.1001/jamainternmed.2015.3184). It should be noted that the superior mesenteric and splenic veins join to form the portal vein, which supplies up to 75% of blood to the liver. The incidence is estimated to be between 1 to 4 cases per million people (22. Ansell J. The subtle benefit of anticoagulant therapy for splanchnic vein thrombosis. JAMA Intern Med. 2015;175:1481-2. [PMID: 26167940] doi:10.1001/jamainternmed.2015.3196.). Budd-Chiari syndrome (hepatic venous thrombosis) is the least common manifestation of splanchnic venous thrombosis, with an incidence of 0.5 to 1 case per million people per year (33. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood. 2014;124:3685-91. [PMID: 25320239] doi:10.1182/blood-2014-07-551515). A multinational registry published in 2015 showed that the most common sites were the portal vein (77%) and the mesenteric vein (44%) (11. Ageno W, Riva N, Schulman S, Beyer-Westendorf J, Bang SM, Senzolo M, et al. Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry. JAMA Intern Med. 2015;175:1474-80. [PMID: 26168152] doi:10.1001/jamainternmed.2015.3184). Mesenteric venous thrombosis was first recognized as a cause of intestinal gangrene more than a century ago by Elliot (44. Kumar S, Sarr MG, Kamath PS. Mesenteric venous thrombosis. N Engl J Med. 2001;345:1683-8. [PMID: 11759648], 55. Elliot JW. II. The operative relief of gangrene of intestine due to occlusion of the mesenteric vessels. Ann Surg. 1895;21:9-23. [PMID: 17860129]) but Warren and Eberhard were the first to show that this condition causes intestinal infarction distinct from mesenteric arterial occlusion (44. Kumar S, Sarr MG, Kamath PS. Mesenteric venous thrombosis. N Engl J Med. 2001;345:1683-8. [PMID: 11759648], 66. Warren S, Eberhard TP. Mesenteric venous thrombosis. Surg Gynecol Obstet. 1935;61:102-21.). Mesenteric venous thrombosis accounts for 5% to 15% of all intestinal ischemic events (44. Kumar S, Sarr MG, Kamath PS. Mesenteric venous thrombosis. N Engl J Med. 2001;345:1683-8. [PMID: 11759648]).

Etiology

The conditions that cause splanchnic venous thrombosis are quite varied. The etiology can be divided into localized and systemic causes. Local causes include hepatic cirrhosis, solid cancer such as hepatocellular carcinoma or gastric and pancreatic adenocarcinomas, inflammatory disorders of the abdomen such as inflammatory bowel disease and diverticulitis, and abdominal surgery. Systemic causes include inherited and acquired thrombophilic conditions. Inherited factors may include the factor V Leiden mutation and the prothrombin gene mutation 20210A. Acquired thrombophilic causes include myeloproliferative neoplasms (especially with positive JAKV617F mutation), the antiphospholipid antibody syndrome, paroxysmal nocturnal hemoglobinuria, hormonal therapy, and abdominal malignancy (77. Sharma AM, Zhu D, Henry Z. Portal vein thrombosis: When to treat and how? Vasc Med. 2016;21:61-9. [PMID: 26584887] doi:10.1177/1358863X15611224).

The disorder can also be idiopathic. However, emerging risk factors have decreased the proportion of events that are truly idiopathic to about 15% to 27% of cases (33. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood. 2014;124:3685-91. [PMID: 25320239] doi:10.1182/blood-2014-07-551515). In an international registry published in 2015, the most common causes were liver cirrhosis (27.8%) and solid cancer (22.7%) (11. Ageno W, Riva N, Schulman S, Beyer-Westendorf J, Bang SM, Senzolo M, et al. Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry. JAMA Intern Med. 2015;175:1474-80. [PMID: 26168152] doi:10.1001/jamainternmed.2015.3184). Myeloproliferative neoplasms have emerged as the leading systemic cause (33. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood. 2014;124:3685-91. [PMID: 25320239] doi:10.1182/blood-2014-07-551515). Among the inherited causes, factor V Leiden is more associated with Budd-Chiari syndrome while the prothrombin gene mutation has a stronger association with portal venous thrombosis (88. Shetty S, Ghosh K. Thrombophilic dimension of Budd Chiari syndrome and portal venous thrombosis—a concise review. Thromb Res. 2011;127:505-12. [PMID: 20961602] doi:10.1016/j.thromres.2010.09.019).

The location of the thrombus is usually related to its cause. Clots seen in larger vessels are usually due to intra-abdominal causes, which start at the site of compression and then progress distally to involve smaller vessels. When an underlying thrombophilic disorder is the cause, the thrombosis often begins in smaller vessels and progresses to involve larger vessels (44. Kumar S, Sarr MG, Kamath PS. Mesenteric venous thrombosis. N Engl J Med. 2001;345:1683-8. [PMID: 11759648]).

Clinical presentation

The hallmark of mesenteric ischemia, be it arterial or venous, is abdominal pain out of proportion to the physical exam (44. Kumar S, Sarr MG, Kamath PS. Mesenteric venous thrombosis. N Engl J Med. 2001;345:1683-8. [PMID: 11759648]). Splanchnic venous thrombosis can be acute, subacute, or chronic, which are actually different stages of the same disease. In acute splanchnic venous thrombosis, abdominal pain will begin suddenly and is associated with a risk of bowel infarction and peritonitis. The subacute form is characterized by abdominal pain lasting for days to weeks without bowel infarction. The pain pattern in acute and subacute thrombosis is mid-abdominal and colicky.

Acute Budd-Chiari syndrome will present differently and is associated with ascites and hepatic necrosis (33. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood. 2014;124:3685-91. [PMID: 25320239] doi:10.1182/blood-2014-07-551515). Patients who have chronic splanchnic venous thrombosis do not exhibit pain, often develop extensive venous collateral circulation, and are at risk for complications such as bleeding esophageal varices if there is portal venous thrombosis (44. Kumar S, Sarr MG, Kamath PS. Mesenteric venous thrombosis. N Engl J Med. 2001;345:1683-8. [PMID: 11759648]). A significant number of chronic thromboses are detected incidentally (99. Thatipelli MR, McBane RD, Hodge DO, Wysokinski WE. Survival and recurrence in patients with splanchnic vein thromboses. Clin Gastroenterol Hepatol. 2010;8:200-5. [PMID: 19782767] doi:10.1016/j.cgh.2009.09.019). The initial physical findings may be normal. However, patients can develop fever, guarding, and rebound tenderness and progress to bowel infarction and peritonitis.

Imaging

A CT scan is the best test for diagnosing splanchnic venous thrombosis. An acute thrombus will appear as a central lucency in the mesenteric vein. Other CT findings include enlargement of the superior mesenteric vein and a sharply defined vein wall with a rim of increased density (44. Kumar S, Sarr MG, Kamath PS. Mesenteric venous thrombosis. N Engl J Med. 2001;345:1683-8. [PMID: 11759648]). If well-developed collateral circulation is seen in the mesentery and retroperitoneum, the thrombosis has been present for more than a few weeks (44. Kumar S, Sarr MG, Kamath PS. Mesenteric venous thrombosis. N Engl J Med. 2001;345:1683-8. [PMID: 11759648]). MRI is also very sensitive for diagnosis, but it is more cumbersome.

Ultrasound is not useful in splanchnic venous thrombosis because its accuracy is limited by overlying bowel gas (33. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood. 2014;124:3685-91. [PMID: 25320239] doi:10.1182/blood-2014-07-551515). Doppler ultrasound has a sensitivity of about 90% for the diagnosis of Budd-Chiari syndrome and portal venous thrombosis. However, CT and MRI still have better accuracy for diagnosing these conditions and can also show concomitant diseases and alternative diagnoses (33. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood. 2014;124:3685-91. [PMID: 25320239] doi:10.1182/blood-2014-07-551515).

Treatment

The quality of evidence guiding treatment for splanchnic venous thrombosis is low and is based only on observational studies (33. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood. 2014;124:3685-91. [PMID: 25320239] doi:10.1182/blood-2014-07-551515). Current guidelines recommend anticoagulation for all patients with splanchnic venous thrombosis for at least 3 months, longer in patients with permanent thrombotic conditions and a low bleeding risk (11. Ageno W, Riva N, Schulman S, Beyer-Westendorf J, Bang SM, Senzolo M, et al. Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry. JAMA Intern Med. 2015;175:1474-80. [PMID: 26168152] doi:10.1001/jamainternmed.2015.3184). These recommendations are based only on the results of a few observational studies in patients with splanchnic venous thrombosis and rely more on evidence from studies of patients with deep venous thrombosis of the legs or pulmonary embolism (11. Ageno W, Riva N, Schulman S, Beyer-Westendorf J, Bang SM, Senzolo M, et al. Long-term clinical outcomes of splanchnic vein thrombosis: results of an international registry. JAMA Intern Med. 2015;175:1474-80. [PMID: 26168152] doi:10.1001/jamainternmed.2015.3184, 99. Thatipelli MR, McBane RD, Hodge DO, Wysokinski WE. Survival and recurrence in patients with splanchnic vein thromboses. Clin Gastroenterol Hepatol. 2010;8:200-5. [PMID: 19782767] doi:10.1016/j.cgh.2009.09.019).

The ninth edition of the American College of Chest Physicians (CHEST) guidelines on antithrombotic therapy and prevention of thrombosis recommend anticoagulation over no anticoagulation in patients with symptomatic splanchnic venous thrombosis, but no anticoagulation for incidentally detected thrombosis (1010. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e419S-94S. [PMID: 22315268] doi:10.1378/chest.11-2301). Treatment of 3 months' duration is recommended for provoked thrombosis, and treatment of longer than 3 months' duration is recommended for unprovoked thrombosis, provided the bleeding risk is low or moderate. Extended anticoagulation is recommended for cancer-associated thromboembolism (1010. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e419S-94S. [PMID: 22315268] doi:10.1378/chest.11-2301).

The American Association for the Study of Liver Diseases recommends anticoagulation for patients with acute portal venous thrombosis and Budd-Chiari syndrome. For patients with acute and chronic portal venous thrombosis, anticoagulation is recommended for at least 3 months. Patients with permanent risk factors or clot extension into the mesenteric veins should receive anticoagulation indefinitely, as should all patients with Budd-Chiari syndrome (33. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood. 2014;124:3685-91. [PMID: 25320239] doi:10.1182/blood-2014-07-551515, 1111. DeLeve LD, Valla DC, Garcia-Tsao G; American Association for the Study Liver Diseases. Vascular disorders of the liver. Hepatology. 2009;49:1729-64. [PMID: 19399912] doi:10.1002/hep.22772). Thrombolytic therapy should be reserved for select patients with severe symptoms, such as mesenteric venous thrombosis with ischemia, and a low risk of bleeding (33. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood. 2014;124:3685-91. [PMID: 25320239] doi:10.1182/blood-2014-07-551515).

Direct oral anticoagulant drugs have the potential to make splanchnic venous thrombosis treatment easier due to their short half-life and predictable dose response. However, patients with splanchnic venous thrombosis have not been enrolled in clinical trials and there is a concern for increased gastrointestinal bleeding with some direct oral anticoagulants (33. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood. 2014;124:3685-91. [PMID: 25320239] doi:10.1182/blood-2014-07-551515).

The risk for both recurrence and bleeding is higher in patients with portal venous thrombosis than in patients with isolated mesenteric venous thrombosis. There are no data on the risk of recurrence in patients who have incidentally detected portal venous thrombosis and are not treated (33. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood. 2014;124:3685-91. [PMID: 25320239] doi:10.1182/blood-2014-07-551515).

Available data indicate that anticoagulation may improve survival, decrease the recurrence rate, and improve recanalization. Improving recanalization in portal venous thrombosis may prevent subsequent development of portal hypertension and thus lower the risk of long-term bleeding from consequences of portal hypertension (33. Ageno W, Dentali F, Squizzato A. How I treat splanchnic vein thrombosis. Blood. 2014;124:3685-91. [PMID: 25320239] doi:10.1182/blood-2014-07-551515).