Hypercoagulability and intravascular thrombosis are well recognized but uncommon complications of inflammatory bowel disease (IBD) (1-3). Both arterial and venous thromboses have been described as early as the 1930s by Bargen and Barker (4). Intravascular thrombosis can affect various organ systems including the pelvic plexuses, lungs, central nervous system, spleen and kidneys, leading to congestion, ischemia or infarction (2-5). A few case reports on hepatic venous involvement with subsequent Budd Chiari syndrome (BCS) are found in the literature, mainly describing adult patients with ulcerative colitis (UC) (5-8). Bowel ischemia secondary to vascular thrombosis in pediatric patients with IBD has never been described before. Response of hepatic venous thrombosis to anticoagulation and colectomy has not been studied either.
We describe a 14-year-old girl with known UC. She was hospitalized at a local hospital with bloody diarrhea, fatigue and weight loss. She was started on methylpred-nisolone, ceftriaxone and parenteral nutrition. Her stool culture and C. difficile toxin were negative. Three days into her hospitalization, she developed progressive abdominal distension. A CT scan of the abdomen showed significant ascites and hypoechoic regions in her liver. She was then transferred to our facility for further management.
Upon admission, her vital signs were stable and her physical exam revealed a soft distended abdomen without tenderness or organomegaly. There was evidence of free fluid with shifting dullness. The remainder of the exam was unremarkable. Her laboratory examinations revealed normal electrolytes and liver function tests except for mild hypokalemia and prothrombin time of 16 seconds with an INR of 1.3. Results of other tests included C reactive protein 1.5 mg/dl, hemoglobin concentration 9.2 g/dl, platelet count 289,000/mm3 and white cell count 6800/mm3 with 68% neutrophils and 25% lymphocytes. Prednisone, 5-ASA, spironolactone, metronidazole and intravenous fluids were started. Abdominal X-rays were normal. Paracentesis was performed revealing >5000 WBC/mm3. The ascitic fluid grew Enterococcus for which she was placed on antibiotics.
She developed progressively worsening abdominal distension, tenderness and fever and was transferred to the pediatric intensive care unit. Radiologic studies showed intra abdominal free air. Exploratory laparotomy revealed a 5 cm circumferentially gangrenous and perforated section of the distal transverse colon. It was resected and a transverse colostomy was performed. Her resected colon sample (Fig. 1A, B) showed multiple thrombi at different stages of development with evidence of ischemia. No changes suggestive of vasculitis were found. Her hypercoagulabity workup included a fibrinogen level of 742 mg/dl, a platelet count of 426,000/mm3, a normal protein C level, antithrombin III assay and no factor V Leiden or prothrombin G20210A gene mutations. Her functional protein S level was initially low but later normalized. Protein S levels in both parents were normal. The patient was hemodynamically unstable after surgery and remained in intensive care. Post operative course was complicated by fungal sepsis and persistent ascites. Her liver function tests worsened with an ALT 70 U/L, GGT 179 U/L, total bilirubin 1.2 mg/dl and a prothrombin time of 19 seconds. As signs of hemodynamic instability were only evident around the time of perforation, we do not think her gradually worsening hepatic dysfunction was related to sepsis. The patient was started on enoxaparin subcutaneously. The medication was discontinued because of worsening rectal bleeding. Repeat paracentesis was performed revealing an elevated serum-ascitic fluid albumin gradient of 1.4 g/dl suggesting portal hypertension.
A transjugular liver biopsy was performed with venography and measurement of wedged hepatic vein pressure. A free hepatic vein pressure of 6 mmHg and a wedged hepatic vein pressure of 11 mmHg were obtained. The liver biopsy showed small vessel venous occlusion with no evidence of fatty change, significant inflammation or fibrosis. A CO2 portogram was obtained, demonstrating normal appearing portal vein branches within the liver. The hepatic venograms (Fig. 2) revealed substantial narrowing of the inferior vena cava below the junction of the hepatic vein and multiple filling defects in all three hepatic veins, consistent with intravascular coagulation and Budd Chiari syndrome. Enoxaparin was re-intiated. An upper endoscopy showed superficial grade 0-1 esophageal varices and portal hypertensive gastropathy. The patient was discharged on enoxaparin, 5-ASA, prednisone and spironolactone. Two months after hospital discharge, a CT of the abdomen showed no narrowing in the inferior vena cava or hepatic veins.
One month later, the patient underwent total proctocolectomy with an ileoanal pull-through anastomosis and a diverting loop ileostomy. Her postoperative course was uneventful. Histologic sections of the colonic mucosa showed distortion of crypt architecture, cryptitis and crypt abscesses. In several foci the mucosa showed surface ischemic damage characterized by loss of upper portion of crypt with fibrin and abundant neutrophils attached to the surface. Four months after her total colectomy, she underwent ileostomy take down. Her diuretic was discontinued as there was no evidence of ascites. She continued to do well on subcutaneous enoxaparin. The patient elected to stop her anticoagulation therapy 11 months after total colectomy and has remained in stable condition with normal liver function tests and without any evidence of ascites.
Ischemic colitis was found on the histologic examination of the patients resected bowel. This is extremely rare in the pediatric population with IBD. A 13-year-old patient with Crohn disease was reported by Talbot et al., with necrosis of the ileum, cecum and ascending colon and who later died of sepsis (2). This has been noted in very few adult patients. It is theoretically possible that such a process can possibly affect any part of the arterial system, including the mesenteric vessels. Therefore, ischemic colitis should be included on the growing list of complications of UC.
Patients with IBD can develop thromboembolic complications. A hypercoagulable state has been postulated and hemostatic abnormalities have been sometimes identified. These include elevated platelet counts and coagulation factors such as fibrinogen, factor V and factor VIII. Others include decreased blood clotting activation inhibitors such as antithrombin III, protein S and protein C and decreased fibrinolytic activity (1,5,7-11). Thrombophilic mutations such as factor V Leiden, prothrombin or methylene tetrahydrofolate reductase have also been implicated (12). Coagulation abnormalities have been observed in 60% in a series of 7,199 adult patients with UC and Crohn disease (2,13).
Hemostatic abnormalities are not found in all patients who develop thrombosis. Conversely, hemostatic abnor-malities have been described with IBD patients with no obvious thromboembolic phenomenon. Thromboembolic complications have been described in only 1.3 to 6.4% of cases of IBD patients in several series (2,9,14). Thus, it is difficult to accurately relate coagulation abnormalities to the occurrence of thromboembolism. There are possibly other factors that contribute to the risk of thromboembolism in such patients, including dehydration, immobilization, infection and surgery.
In our patient, fibrinogen rose to a peak of 742 mg/dl (normal 160-340 mg/dl) and the platelet count increased to 426,000. She tested negative for factor V Leiden and Prothrombin G20210A gene mutations. Functional protein C level was 71% (normal, 64-116%) and anti-thrombin III assay measured 101% (normal, 80-137%). Functional protein S level was initially low at 28% (normal, 63-136%) but gradually normalized 11 months after proctocolectomy. The initially low level was ascribed to a consumptive state. Thus our case did not have any identifiable cause of hypercoagualtion other than having active UC.
Antiphospholipid antibodies, which are a heterogeneous group of polyclonal immunoglobulins, are also thought to play a role in hypercoagulability in a small percentage of this patient population. Antiphospholipid syndrome includes a wide variety of clinical entities including arterial or venous thrombosis, strokes, recurrent abortion and thrombocytopenia (1,3,14). This consideration was ruled out in our case as she tested negative for such antibodies.
The most common sites for venous thrombosis in IBD patients are the pulmonary vasculature, the pelvis and the deep veins of the legs (5,9,15). Involvement of the splenic, portal, renal and central nervous systems have been described. Hepatic vein thrombosis has rarely been reported. Risk factors for thrombosis include polycythemia, malignancies, myeloprolifrative disorders, homocystinuria, inherited deficiency of antithrombin III, protein C or protein S and medication intake such as oral contraceptives and L-Asparaginase (9,10,14). Our patient did not have any such risk factors. She was, however, initially dehydrated, and probably had low grade sepsis with an intra abdominal infection. This would have placed her at a higher risk for a thromboembolic event.
Arterial thrombosis is a known but infrequent complication in patients with IBD. Thrombosis within the renal arteries with subsequent ischemia and partial or complete kidney infarction has been reported. Similar mechanisms have led to pulmonary, retinal and central nervous system infarctions (9,10,13). Peripheral arterial thromboembolic complications have developed, resulting in ischemic finger tips, lower extremity claudication, limb loss, and infarction of the glans penis (2). Such events have been associated in the adult population with pancolonic disease and poorer prognosis in UC patients (13). Young adults with active UC have developed myocardial ischemia and infarction in rare cases (16). Osteonecrosis has been described with IBD patients, however such a population is commonly on steroids and that might be the predisposing factor.
Well recognized hepatic complications of UC include fatty liver changes, pericholangitis, sclerosing cholangitis, chronic active hepatitis and rarely cirrhosis and hepatic failure (5-8). Hepatic vein thrombosis or BCS has been described in very few case reports as a rare complication of IBD. Most such cases are adults with UC. Classically, BCS presents with hepatomegaly, ascites and right upper quadrant abdominal pain. BCS can present acutely or insidiously over months or years. Other causes of BCS in children include ventriculoatrial shunt, sickle cell disease, systemic lupus erythrematosus, antiphos-pholipid antibody syndrome, toxins, webbed inferior vena cava and malignancies (6,7). None of these were present in our patient. BCS is usually progressive with rare spontaneous resolution. Definitive treatment with side to side portocaval shunt, mesocaval shunts or hepatic transplantation may be needed (7,8). Our patient is the youngest described in the literature with BCS as a complication of UC. She is also unique in her complete recovery after anticoagulation and total colectomy.
Intravascular thrombosis can involve multiple organ systems in UC patients even in the pediatric population. It is rare to see BCS in such an age group as a complication of UC in the absence of other predisposing factors. Such a complication can often be managed successfully by medical therapy alone. In this case, anticoagulation was safe and effective. Other possible etiologies of intravascular thrombosis should be investigated and ruled out as that can affect the duration of anticoagulation therapy. Colectomy may be helpful in some cases especially those refractory to medical treatment.
1. Lam A, Borda IT, Inwood MJ, Thompson S. Coagulation studies in ulcerative colitis and Crohn's disease. Gastroenterology
2. Talbot RW, Heppell J, Dozois RR, Beart RW. Vascular complications of inflammatory bowel disease. Mayo Clin Proc
3. Chiarantini E, Valanzano R, Liotta AA, et al. Hemostatic abnormalities in inflammatory bowel disease. Thromb Res
4. Bargen JA, Baker MW. Extensive arterial and venous thrombosis complicating chronic ulcerative colitis. Arch Intern Med
5. Chesner IM, Muller S, Newman J. Ulcerative colitis complicated by Budd-Chiari syndrome. Gut
6. Praderio L, Dagna L, Longhi P, Rubin G, Sabbadini MG. Budd-Chiari syndrome in a patient with ulcerative colitis: association with anticardiolipin antibodies. J Clin Gastroenterol
7. Kraut J, Berman JH, Gunasekaran TS, Allen R, McFadden J, Messersmith R, Pellettiere E. Hepatic vein thrombosis (Budd-Chiari syndrome) in an adolescent with ulcerative colitis. J Pediatr Gastroenteol Nutr
8. Brinson RR, Curtis WD, Schuman BM, Mills LR. Recovery from hepatic vein thrombosis (Budd-Chiari syndrome) complicating ulcerative colitis. Dig Dis Sci
9. Lloyd-Still JD, Tomasi L. Neurovascular and thromboemboembolic complications of inflammatory disease in childhood. J Pediatr Gastroenterol Nutr
10. Del Rosario JF, Orenstein SR, Bhargava S, Putman PE. Thrombotic complications in the pediatric inflammatory bowel disease. Clin Pediatr
11. Maccini DM, Berg JC, Bell GA. Budd-Chiari syndrome and Crohn's disease. An unreported association. Dig Dis Sci.
12. Kader HA, Berman WF, Al-Seraihy AS, Ware RE, Ulshen MH, Treem WR. Prevalence of factor V G1691A (Leiden), prothrombin G20210A, and methylene tetrahydrofolate reductase C677T thrombophilic mutations in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr
13. Novotny DA, Rubin RJ, Slezak FA, Porter JA. Arterial thromboembolic complications of inflammatory bowel disease: Report of three cases. Dis Colon Rectum
14. Papi C, Ciaco A, Acierno G, et al. Severe ulcerative colitis, dural sinus thrombosis, and the lupus anticoagulant. Am J Gastroenterol
15. Paradis K, Bernstein ML, Adelson JW. Thrombosis as a complication of inflammatory bowel disease in children: A report of four cases. J Pediatr Gastroenterol Nutr
16. Mutlu B, Ermeydan CM, Enc F, Fotbolcu H, Demirkol O, Basaran Y. Acute myocardial infarction in a young woman with severe ulcerative colitis. Internat J Card