Abstract
Thromboembolic phenomena have long been known to be an extraintestinal manifestation of inflammatory bowel disease, with the deep veins of the legs and the pulmonary vasculature being the most commonly affected sites. Research has identified factors associated with inflammatory bowel disease that contribute to prothrombotic risk, but understanding of the pathophysiology is incomplete. Symptoms of thromboembolism can be vague, may be overlooked, or may be attributed to the consequences of protracted inflammatory bowel disease and/or side effects of its medications. We present a rare case of combined inferior vena cava and bilateral renal vein thromboses as well as pulmonary embolism in a young woman with ulcerative pancolitis in partial remission. Our patient presented with nonspecific symptoms that would not immediately raise clinical suspicion of severe thromboembolism, and thus we provide our recommendations for diagnosis and treatment.
Introduction
Thromboembolism (TE) is a complication of inflammatory bowel disease (IBD) in 0.7% to 7.7% of patients.[1,2] We present a rare case of combined inferior vena cava (IVC) thrombosis, bilateral renal vein thrombosis, and pulmonary embolism (PE) in a patient with ulcerative colitis (UC). The case highlights the need for vigilance in light of new symptoms since features of thromboembolic events may be subtle or vague. We provide a brief discussion of TE in IBD as well as management recommendations.
Case
Presentation: The patient is a 33-year-old Asian-American woman with a 4-year history of abnormal bowel habits. Six months before admission, she presented to a gastroenterologist with progressively increasing symptoms of abdominal cramping and frequent, loose, bloody bowel movements. Colonoscopy revealed ulcerative pancolitis. She was treated with balsalazide and prednisone for 6 weeks; she had a partial response, as defined by reduced stool frequency and cessation of hematochezia. Attempts to taper prednisone led to full relapse. The patient was heterozygous for the thiopurine s-methyltransferase gene; thus, 6-mercaptopurine was avoided and instead infliximab was added to the balsalazide while prednisone was tapered. Four weeks after her third dose of infliximab, the patient presented to an outside hospital with acute abdominal bloating and leg edema while still in partial response.
Computed tomography of the abdomen and pelvis showed colonic thickening without toxic megacolon or ascites. However, a 9-cm IVC thrombus extending into the renal veins was found incidentally. Subsequent computed tomography angiography (CTA) of the chest revealed PE. The patient was started on unfractionated heparin intravenous (IV) infusion and transferred to a tertiary care hospital for further management.
Upon transfer, the patient continued to have 3 to 5 loose, crampy, nonbloody bowel movements per day. On examination, she appeared ill but was alert and oriented and had no respiratory distress. Pertinent findings included blood pressure 100/60 mm Hg, pulse 120 beats per minute, respiration rate 18 breaths per minute, and no fever. Regular rhythm tachycardia and clear lungs were appreciated. Abdominal examination revealed normal bowel sounds but diffuse moderate tenderness to deep palpation without distention or rebound. Lower extremities had 1+ pitting edema.
Pertinent diagnostic results were white blood cells 15.3*10 3 /microliters (mcL), hemoglobin 10.3 g/dL with mean corpuscular volume 81.8 fL, iron 12 mcg/dL, ferritin 41 ng/mL, and total iron binding capacity of 206 and platelets 341*10 3 /mcL. Chemistries were normal, and liver tests were remarkable for isolated alkaline phosphatase elevation at 138 U/L (normal 31 to 103 U/L). Coagulation parameters while the patient was on IV heparin infusion included international normalized ratio 1.1; partial thromboplastin time 67.4 seconds (normal 24.6 to 32.4 seconds); fibrinogen 597 mg/dL (normal 210 to 443 mg/dL); factor VIII 414 IU/dL (414% activity); and negative hypercoagulability panel for antiphospholipid antibodies, factor V Leiden mutation, prothrombin 20210A mutation, and hyperhomocysteinemia. Antinuclear antibodies were negative, and erythrocyte sedimentation rate was slightly elevated at 26 mm/hr.
Repeated chest CTA showed persistent IVC thrombus (Figures 1 and 2) and minor PE in the lingular and left lower truncus basalis arteries. IVC venography through the right jugular vein confirmed the persistence of a large IVC thrombus extending into the right renal vein (Figures 3 through 5) with resolution of the left renal vein thrombus.
Hospital course: IV unfractionated heparin infusion was continued. In addition, a suprarenal retrievable Optease IVC filter (Figure 4) was placed through the right jugular vein and the patient underwent local thrombolysis of the IVC and renal vein thrombi with 2 days of tenecteplase infusion. At the completion of thrombolysis, repeat venography revealed resolution of the IVC thrombus and 30% to 40% reduction of the right renal vein thrombus. Tachycardia and edema resolved within 1 week of admission. Bowel movements remained unchanged from admission while the patient was on balsalazide and infliximab. The patient was transitioned to warfarin before discharge, and continued gastroenterologic follow-up and surgical consultation were arranged.
Discussion
IBD-related TE was first described in the literature over 70 years ago.[1] It has been reported from the cerebral sinuses all the way to the digits of the feet, producing features that may either be specific to the target organ or nonspecific and vague. The overall mortality of such complications in patients with IBD has been estimated to be as high as 25%.[2] Appropriate management of TE begins with rapid diagnosis. However, in the context of an ill patient who is often on multiple oral and intravenous drugs (i.e., prednisone or infliximab), new symptoms can easily be overlooked as part of the disease itself or side effects of medications.
What makes patients with IBD susceptible to TE has been investigated but is still not well understood. Aside from conventional risk factors for TE, such as recent surgery, immobilization, central venous catheters, cigarette smoking, and oral contraceptive use, prothrombotic factors hypothesized to be implicated in IBD include activity of disease, extent of disease, and changes in factors of hemostasis.
The largest study of patients with IBD and TE to date showed that approximately 66% had active disease at the time of TE.[2] A more recent study, however, suggested that only 45% of patients with UC had active disease at the time of TE as opposed to nearly 90% with Crohn’s disease (CD).[3] An even newer study of 59 patients with UC and 39 with CD has shown that 80% of both UC and CD patients had active disease during the time of TE.[4] Some patients may also have subclinical disease, and thus subclinical endothelial and hematologic changes, which contribute to thromboembolic events.[5] Therefore, it appears that disease activity correlates with TE in most patients with IBD.
The aforementioned study of 59 patients with UC and 39 with CD showed that the vast majority of patients with TE had extensive disease as opposed to a small affected area.[4] This association might imply that disease extension may be a risk factor for TE. However, it remains to be seen if, for example, mild pancolitis would pose greater risk than severe proctosigmoiditis.
Prothrombotic hematologic abnormalities in IBD were first described in 1968 and are now known to involve factor V, factor VIII, antithrombin III, protein S, plasminogen activator inhibitor, fibrinogen, leukocyte-endothelial cell adhesion molecules, and platelet quantity and function.[3,5-9,10] Significant elevations in factor VIII may occur in nearly 50% of patients with active UC, while prothrombotic abnormalities in the other hematologic factors may be seen in an even greater percentage of patients with active IBD.[11] To an extent, such changes may be secondary to inflammatory cytokines that, in addition to driving acute phase reactions, have been shown to affect the coagulation cascade at numerous points as well as alter platelet parameters.[3,11] However, some of these hematologic abnormalities are not specific to the setting of IBD, but rather occur in the general population. To date, no particular abnormality has been shown to be a consistent surrogate marker for thrombotic risk in IBD.[12] Overall, the cause of prothrombotic hematologic changes is probably multifactorial and it is possible that such changes may normalize as inflammation subsides.
Active disease, extensive disease, and hematologic abnormalities, namely elevated factor VIII and fibrinogen, were 3 likely major contributors to out patient’s TE. She had no known conventional risk factors for thrombosis. Given the magnitude of the thromboembolic burden, limited response to heparin, and fear of further thrombus formation and propagation with risk for hemodynamic instability, it was felt that more effective anticoagulation therapy with local thrombolysis using highly fibrinoselective tenecteplase and an IVC filter would have the best results.[13,14] While our patient did very well clinically — especially considering we were unable to find any previous reports of combined inferior vena cava and bilateral renal vein thrombosis in IBD — further studies are needed to verify the success, safety, and long-term outcome of such treatment.
Conclusion
We recommend that physicians caring for patients with IBD be mindful of the following:
- Although thromboembolic complications are most common in persons with active disease, these complications are also seen in patients with partial or full remission.
- When patients with IBD present with new symptoms, consider thromboembolic disease of the anatomical area. Our patient’s bloating and leg edema, for example, were nonspecific and could have been attributed to colitis, low albumin level, or side effects of corticosteroid or infliximab therapy.
- Appropriate diagnostic testing should be performed early in the course to improve outcome.
- Gastrointestinal hemorrhage as a consequence of anticoagulation or thrombolytic therapy is often a concern in active IBD. However, if the benefit is believed to outweigh the risks for TE (eg, hemodynamic instability or tissue ischemia), such therapy should not be withheld.
Figure 1.
Inferior vena cava (IVC) thrombus seen on axial computed tomography.
Figure 2.
IVC thrombus seen in coronal computed tomography.
Figure 3.
IVC venogram demonstrating IVC filling defect secondary to thrombus.
IVC venogram demonstrating filling defect in proximal right renal vein secondary to thrombus.
Figure 4.
IVC venogram demonstrating IVC filling defect, superior to right renal vein, secondary to thrombus; also visualized are Optease IVC filter and catheter in distal right renal vein.
Figure 5.
IVC venogram demonstrating filling defect in proximal right renal vein secondary to thrombus.
