Factor V Leiden and venous thrombosis in a 4-yr-old girl with Behçet's syndrome

J. Ihle3, J. Kümmerle-Deschner, T. Orlikowsky, E. Albert1, D. Niethammer and G. E. Dannecker

Universitätskinderklinik, Hoppe-Seyler-Straße 1, D-72076 Tübingen and
1 Labor für Immungenetik, Poliklinik der Universität München, Pettenkoferstraße 8a, D-80336 München, Germany

Sir, Behçet's syndrome (BS) was originally described as a triad of aphthous stomatitis, genital ulcers and iritis, but many additional manifestations of the disease are well known. The aetiology is unknown, but an association with HLA-B51 has been described in patients of Oriental and Mediterranean origin. In Japanese patients with BS, an association with MIC-A*009 (MHC class I chain-related gene A), which is even stronger than that with HLA-B51, has been reported recently [1].

Onset of BS in childhood is very rare and the most common clinical manifestation in the paediatric age is oral ulcerations, found in virtually all patients. Other signs, such as cutaneous symptoms and gastrointestinal manifestations, follow in decreasing frequency [2]. Non-specific vasculitis with perivascular infiltration of CD4+ lymphocytes and other mononuclear cells is a well-known feature of BS, resulting in venous thrombosis in 10–25% of adult patients [3] and 8–15% of children [2]. Earlier studies of the coagulation system did not show any specific abnormalities for BS patients. Recently, an association of BS and venous thrombosis with factor V Leiden has been suggested in adults [4, 5].

Factor V Leiden is due to a single base pair mutation resulting in a substitution of Arg506 to Gln in the factor V gene product. This mutation is located at the putative cleavage site of factor V, resulting in resistance to activated protein C (APCR) [6, 7]. The anticoagulant action of APC is diminished and APCR has been identified as an important thrombophilic factor in a high percentage of adults and children with thrombotic events [8].

In addition to the recently reported association of BS with thrombosis and factor V Leiden in adults, we report on a 4-yr-old Turkish girl with BS developing deep venous thrombosis associated with factor V Leiden.

She presented initially at the age of 3 yr with painful and swollen ankles and knees. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were raised; all other laboratory tests, including antinuclear antibodies and rheumatoid factor, were negative. Ophthalmological examination was normal. A presumptive diagnosis of JA was made, but treatment with naproxen, methotrexate and prednisolone did not result in complete remission.

Six months after the onset of her symptoms, a single painless ulceration was noted on the left side of her tongue, which disappeared after 6 weeks. The ulceration recurred 4 months later and the patient developed erythema nodosum on her calves. A concurrent vasculitic lesion is shown in Fig. 1Go. Biopsy showed unspecific vasculitis with pericapillary lymphocytic infiltrates and endothelial proliferation.



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FIG. 1. Photograph showing the vasculitic lesions on both feet of the patient, which were slightly elevated, and along the sides of her feet as well as the back of her feet.

 
Two months later she presented with thrombosis of the left femoral vein. An extensive coagulation screen showed increased APCR with a heterozygous factor V Leiden mutation G1691A. No other coagulation abnormalities were found.

With regard to the combination of recurrent oral ulceration, arthritis and unspecific vasculitis with thrombosis, a presumptive diagnosis of BS was made. No other organ system was found to be involved. As determined by sequencing, HLA-B*5101 and MIC-A*009 were positive [9], but the pathergy phenomenon was negative. She was treated with colchicine 1 mg/day and azathioprine 1 mg/kg/day. This treatment regimen resulted in immediate improvement of all symptoms with only one recurrence of an ulceration at the pharynx. Currently, azathioprine has been stopped, but colchicine is intended as long-term therapy.

Thrombosis was treated with i.v. heparin and subsequently with low-molecular-weight heparin. Four months after the onset of thrombosis, her left femoral vein was completely recanalized. Anticoagulation was stopped 5 months later without the D-dimers increasing subsequently.

The most likely diagnosis in our patient is BS, considering the combination of recurrent oral ulceration with arthritis and vasculitis, the presence of the immunogenetic markers HLA-B*0501 and MIC-A*009, and the immediate improvement after colchicine and azathioprine had been added to the therapeutic regimen.

The only abnormality found in the patient's coagulation system was an increased APCR due to factor V Leiden. The importance of this mutation in the development of thrombosis in children has only recently been recognized. In paediatric patients, 23% of 125 children with thrombosis carried the mutation [8]. Factor V Leiden may be sufficient to cause thrombosis without any additional risk factors, but the prevalence of factor V Leiden in the normal paediatric population is 2.5–12%, suggesting that the defect alone is not necessarily sufficient for vascular occlusion, but is an important cofactor [8]. In a recent report in adults, factor V Leiden was present in three out of eight patients with BS and thrombosis, whereas none of 15 Behçet's patients without thrombosis carried the mutation [4]. In contrast, factor V Leiden was also reported in BS patients without thrombosis, but with a much lower frequency than in BS patients with thrombosis [5].

In children as well as in adults with BS, the defect may be an important trigger for the development of thrombosis. In our opinion, the diagnostic evaluation of BS should therefore include an extensive coagulation screen with APCR and factor V Leiden. If the BS is active, anticoagulation might be considered in the presence of factor V Leiden, although it has to be noted that recurrent venous thrombosis might occur despite anticoagulant therapy [10]. Disease control therefore seems to be the most important factor in preventing thromboembolic complications. Although guidelines are missing, it seems justified to discontinue thrombosis prophylaxis when disease is in remission, unless there is recurrent vascular occlusion.

Notes

3 Correspondence to: J. Ihle, Universitätskinderklinik, Hoppe-Seyler-Straße 1, 72076 Tübingen, Germany. Back

References

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  2. Kone-Paut I, Yurdakul S, Bahabri SA, Shafae N, Ozen S, Oezdogan H et al. Clinical features of Behçet's disease in children: an international collaborative study of 86 cases. J Pediatr 1998;132:721–5.[ISI][Medline]
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  8. Aschka I, Aumann V, Bergmann F, Budde U, Eberl W, Eckhof-Donovan S et al. Prevalence of factor V Leiden in children with thrombo-embolism. Eur J Pediatr 1996;155:1009–14.[ISI][Medline]
  9. Yao Z, Volgger A, Helmberg W, Keller E, Fan LA, Chandanayingyong D et al. Definition of new alleles of MIC-A using sequencing based typing (SBT). Eur J Immunogenet 1999;26:225–32.
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Accepted 22 June 1999





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