Q J Med 2002; 95: 253-255
© 2002 Association of Physicians
Correspondence |
Recurrent venous thromboses, anti-cardiolipin antibodies and Crohn's disease
Department of Rheumatology, Allergy and Immunology, Tan Tock Seng Hospital, Singapore
Singapore National Eye Centre, Singapore
Raffles Hospital, Singapore
Sir,
Inflammatory bowel disease (IBD), which is relatively uncommon in Orientals, is associated with an increased frequency of thromboembolism. Thromboembolic disease is a significant cause of morbidity and mortality in patients with IBD. The mechanism of enhanced procoagulant activity is not well understood. We report a case of a middle-aged Chinese man who presented with bilateral central retinal vein occlusions (CRVO), deep venous thrombosis, anticardiolipin antibodies (ACA) and intermittent per rectal bleeding as the predominant manifestations of Crohn's disease (CD).
A 43-year-old Chinese businessman first presented in June 1994 with acute onset of visual blurring in the left eye. He was diagnosed with CRVO and was treated topically by the attending ophthalmologist. Six months later, he developed neovascular glaucoma which resulted in evisceration of the left eye. He remained well for a year until April 1996, when he presented with his first episode of painless per rectal bleeding. This was not associated with any change in bowel habit or weight loss, nor with constitutional symptoms. Colonoscopy showed a mass at the ileocecal junction which was suggestive of a malignancy. A modified right hemicolectomy, was done with the terminal ileum, caecum and proximal 12 cm of the ascending colon removed. The histology of both the colonic biopsy and the hemicolectomy specimen were reported as non-specific inflammatory changes, with no malignancy seen.
Following surgery, he remained well for the next two years. In July 1998, he again developed per rectal bleeding on two occasions, each episode lasting 2 days. Gastroscopy, colonoscopy and small bowel series were normal. The bleeding resolved spontaneously. In April 1999, he developed acute pain and swelling of the right calf. A venogram of the right leg showed deep venous thrombosis. However, he decided to seek alternative therapy (traditional Chinese medications) and the swelling resolved after two weeks. In November 1999, he developed sudden onset of blurring of vision in the right eye associated with daily episodes of per rectal bleeding for 3 days. Apart from recurrent painful oral ulcers, he did not have genital ulcers, skin rash, inflammatory back pain or arthritis. There was no significant past or family history of any rheumatic or gastrointestinal disorder or colorectal malignancy.
Clinical examination revealed a well-built man who was neither pale nor jaundiced. His blood pressure was 130/70 mmHg, pulse rate was 78 bpm and regular. The abdomen was distended, non-tender with no palpable masses and paucity of bowel sounds. Per rectal examination revealed fresh blood uniformly mixed with stools. There were no perianal skin tags or fistulae seen, and no masses were felt. Fundoscopy showed non-ischaemic CRVO of the right eye with visual acuity 6/36. A left glass eye was present.
Investigations revealed haemoglobin of 11.9 g/dl (normochromic and normocytic), white cell count 9.9x109/l with normal differential counts and platelets 399x109/l. The erythrocyte sedimentation rate (ESR) was 35 mm/h and serum albumin 38 g/l. Renal function, liver function tests and coagulation profile were normal. Urine microscopy was normal. Antinuclear antibody (ANA), anti-double stranded DNA (anti-dsDNA), anti-neutrophil cytoplasmic antibody (ANCA) and lupus anticoagulant were negative. Anticardiolipin (ACA) IgG was positive (17 GPL U/ml, normal range <10) and ACA IgM was negative. Protein C, Protein S and antithrombin III were normal. The other tests for thrombophilia, including plasma fibrinogen, activated protein C resistance, homocysteine and plasminogen activator inhibitor levels were not done in view of the patient's financial constraints. Chest and abdominal radiographs and a repeat colonoscopy were normal. The histopathological slides from 1996 were reviewed specifically for features of IBD. The specimen from the modified right hemicolectomy showed an ileocecal ulcer with fissuring, patchy lymphoplasmacytic inflammatory infiltrate in the adjacent small bowel and colon, and goblet cell depletion. The current colonic biopsy in showed a granuloma in relation to the crypt. There was no vasculitis. The histopathological features were consistent with CD. The patient subsequently returned to his home country for further treatment.
IBD is relatively uncommon in Orientals. The prevalence of UC has been estimated to be 8.6 per 100 000, and for CD, 1.3 per 100 000 people in Singapore,1 much lower than those reported for Western populations. In our patients with IBD, there were more Indians than Chinese or Malays, particularly for ulcerative colitis (UC) but not for CD.2 The clinical manifestations of IBD were similar to the those in a Western population, except that extra-intestinal manifestations were rare.3
Patients with IBD frequently suffer from thromboembolic events. The development of thrombosis seems to be related to active inflammatory disease in most patients with CD, but apparently not in those with UC. Retinal vein occlusion has rarely been reported in association with inflammatory bowel disease (IBD).4,5 In our patient, the CRVO preceded the first gastrointestinal manifestation of IBD, an uncommon presentation. Many prothrombotic mechanisms have been proposed in IBD. These include thrombocytosis, hyperfibrinogenemia, elevated prothrombin fragment F1+2, decreased factor XIII, high plasminogen activator inhibitor levels and Protein S, Protein C or antithrombin III deficiency. Some of these have been reported in association with large-vessel venous or arterial thromboses in single sites. Factor V Leiden mutation, prothrombin gene G20210A mutation and MTHFR gene mutation are not more prevalent in IBD patients compared to healthy controls.6–8
Elevated levels of anti-cardiolipin antibodies (ACA) are associated with an increased risk for venous and arterial thrombosis. ACA was first implicated in the thrombotic events associated with CD in a 21-year-old female with recurrent thromboses preceding the onset of Crohn's disease.9 ACA was subsequently found in one study, in half of the patients with CD who had active disease.10 Two later studies, each comparing more than 100 IBD patients and healthy controls, showed no correlation between ACA and anti-ß2 glycoprotein I cofactor levels, disease activity and the number of thromboembolic events.11,12 It is difficult to conclude whether the ACA in our patient's case was truly pathogenetic or merely an epiphenomenon, as it was of a relatively low titre. A repeat ACA done 2–3 months after commencing immunosuppressive therapy for the CD would have been helpful.
Over the past year, research on the mechanisms for thrombophilia in IBD has shifted from ACAs to hyperhomocysteinemia. Although hyperhomocysteinemia is a common phenomenon in IBD and correlates with serum folate, cobalamin, creatinine, and pyridoxine concentrations, there is little correlation with thrombotic events.13 Hyperhomocysteinemia has, however, been found to be associated with age, sex, smoking, serum cobalamin and ileal resection, of which smoking and serum cobalamin are potentially reversible risk factors.14
This case highlights an atypical presentation of CD with predominantly thrombotic events. Central retinal venous thrombosis is an unusual site for thrombosis in CD. There is a need for a high index of suspicion and careful histopathological review of endoscopic biopsies, especially in Orientals with per rectal bleeding, as IBD is uncommon.
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