DISCUSSION
The patient presented with the unusual combination of diarrhea that became bloody, thrombocytopenia, markedly elevated liver enzymes, and prolonged prothrombin time. A number of diagnoses were considered and excluded by the treating team after testing. These included hemolytic uremic syndrome, acute infectious hepatitis, malignancy, and chronic liver disease. None of these diagnoses fully explained the constellation of findings. Inflammatory bowel disease certainly could have caused diarrhea that became bloody, but an additional explanation was needed for the thrombocytopenia, marked elevation of liver enzymes, and abnormal prothrombin time. Active inflammatory bowel disease resulting in a secondary hypercoagulable state leading to portal and mesenteric vein thrombosis explains all of the key findings of the case.
It is difficult to make a clinical diagnosis of acute portal vein thrombosis. The common presenting symptoms are extremely vague—abdominal pain, anorexia, and vomiting.1 Extension of the thrombus into the mesenteric venous system may progress to intestinal ischemia and infarct,2,3 with marked abdominal pain and development of peritoneal signs. The marked elevation of liver enzymes seen in this patient is not a reported feature of acute portal vein thrombosis,4 except in the immediately post-liver-transplantation setting.5,6 In the case at hand with extensive clot formation, the degree of elevation may represent ischemic insult from diffuse clotting in small intrahepatic vessels as well. (The heterogeneous enhancement of the liver seen at CT scanning would be compatible with this.) Portal hypertension may develop if the thrombus persists, leading to related signs of splenomegaly, esophageal varices, and gastrointestinal bleeding.3 If the tests are done, the diagnosis is easily made by ultrasonography with Doppler scanning and computed tomography.3 Both anticoagulant therapy with heparin and thrombolytic therapy with urokinase have been successfully used to prevent progression to portal hypertension and intestinal infarct.2,3,7 Peritonitis and signs of intestinal infarction require excision of necrotic bowel.2
Deep vein thromboses are uncommon in childhood and always raise the question of a hypercoagulable state. Hypercoagulable states may occur as a result of inherited coagulation disorders or acquired coagulation risk factors.8,9 The most common inherited procoagulant disorder would be factor V resistance to the anticoagulant activity of activated protein C, caused by the Leiden mutation in factor V. Somewhat less common is the procoagulant G20210A mutation in the prothrombin gene. Deficiency of or resistance to the anticoagulant proteins antithrombin III, protein C, and protein S are recognized causes of hypercoagulability. Hyperhomocystinemia can predispose to thrombosis. An inherited cause of hyperhomocystinemia is deficiency of methylenetetrahydrofolate reductase. Paroxysmal nocturnal hemoglobinuria is an acquired genetic mutation in the multipotential hematopoietic stem cell, which predisposes to thrombosis.9,10 Antiphospholipid antibodies are well-recognized risk factors for thromboses.
Secondary causes of hypercoagulation must also be kept in mind when evaluating any patient with thrombosis. These acquired risk factors include infection, dehydration, immobility, prior surgery, placement of a central venous catheter, and medications such as corticosteroids and oral contraceptives.8 Disease states that involve protein loss such as nephrotic syndrome 8,9,11 (or colitis—see below) are associated with an increased risk of thrombosis. Inflammatory diseases such as malignancies, systemic lupus erythematosis, and inflammatory bowel disease are also associated with a prothrombotic state.9
Deep vein thrombosis is a recognized complication of inflammatory bowel disease (IBD). The reported incidence of thrombotic complications in IBD to ranges from 1% to 6.7%.12 The prevalence in one postmortem study was 39%.12 Thrombosis with IBD tends to occur in younger patients 13,14 and is associated with a high mortality rate (8%).14 Nine percent of thromboembolic events in IBD are found in the portal venous system, and this is associated with a mortality rate as high as 50%.15 Cerebral vascular events, including cerebral venous thrombosis, carotid artery thromboembolism, and retinal branch artery occlusion, account for 10% of thrombotic events in IBD and are associated with high mortality and neurologic morbidity rates.15 Thrombi affecting the pulmonary, gonadal, cardiac, and peripheral vessels have also been described.15 Because of the increased risk of thrombosis, thromboprophylaxis with low-molecular-weight heparin of all hospitalized patients with IBD has been suggested, although it has not yet been studied.16 The pathogenesis of the thrombotic complications of IBD appears to be multifactorial. Some studies cite a high incidence of inherited procoagulant disorders in patients with IBD 17; however, no inherited disorder has been found more frequently in patients with IBD than in the general population.12,16 Inflammation results in elevated platelet counts and elevated levels of the procoagulant factors V, VIII, fibrinogen, and von Willebrand factor.16 It decreases levels of the clot-stabilizing factor XIII, which may counter the procoagulant effects of inflammation.16 Fecal losses and consumption in the microvasculature of anticoagulant factors protein C, protein S, and antithrombin III could increase clotting tendency.16 Folic acid and vitamin B12 deficiency can be seen in patients with IBD and can contribute to elevated homocysteine levels, which promote thrombosis through an unknown mechanism.16 Antiphospholipid antibodies are somewhat more common in patients with IBD.16 Other prothrombotic factors common in patients with IBD include dehydration, immobility, central venous catheters, steroid use, and prior surgery.
Recent evidence suggests that although greater than 50% of children with portal vein thrombosis are deficient in 1 or more anticoagulant proteins, they do not appear to have a higher prevalence of hereditary prothrombotic disorders.18 Inflammation, dehydration, and decreased levels of protein S, protein C, and antithrombin III likely contributed to the thrombosis in this case.
Although it seems hazardous to treat a patient bleeding from colitis with heparin, heparin has actually been used in therapeutic trials to treat ulcerative colitis. These trials were based on the theory that thromboses in the microvasculature and resultant ischemia contributed to the disease process.19 One prospective study with unfractionated heparin resulted in improvement of ulcerative colitis clinical activity, inflammatory laboratory values, and histologic changes.20 In one small randomized trial the efficacy of heparin in treating active colitis was similar to that of steroids, and the heparin did not exacerbate the bleeding.21 The apparently beneficial effect of heparin in ulcerative colitis has been hypothesized to be related to anticoagulant effect, enhanced mucosal repair by promotion of growth factor activity, and antiinflammatory effects.22