Chronic urticaria responding to subcutaneous heparin sodium

SIR, A 43-year-old woman was referred to the dermatology department in 2002 because of a 5-year history of relentless, debilitating urticaria. Her past medical history was unremarkable but there was a family history of hypothyroidism (mother), multiple sclerosis (sister) and coeliac disease (daughter). Blood tests including full blood count, erythrocyte sedimentation rate, C-reactive protein, urea, creatinine, electrolytes, liver function tests, thyroid function tests, antinuclear antibodies, thyroid autoantibodies and C4 were all normal or negative. Autologous serum skin testing was not carried out. Cetirizine, loratadine, fexofenadine, hydroxyzine, chlorpheniramine, ketotifen, montelukast, cimetidine and doxepin were all tried in standard doses in various combinations. Cetirizine and loratadine were also tried at 20 mg daily with additional sedating antihistamines at night. None of these treatments conferred any significant benefit. Ciclosporin 4 mg kg was given for 6 weeks. This cleared her urticaria but relapse occurred as soon as the dose was reduced below 3 mg kg. Ciclosporin was not continued long term as the risks were felt to outweigh the benefits. A course of psoralen plus ultraviolet A (PUVA) was then tried twice weekly. This was effective but only during treatment. Urticaria relapsed within a week of discontinuing PUVA. Methotrexate was tried for 10 weeks, initially at 10 mg weekly, increasing to 15 mg weekly after 4 weeks. It made no difference to her urticaria. Warfarin was also tried in view of two case reports and a double-blind placebocontrolled study in eight patients describing its effectiveness. It had no beneficial effect in our patient, as noted in another published study of four patients with chronic urticaria. In 2003, she was admitted with suspected appendicitis. Prophylactic subcutaneous heparin sodium was given at a dose of 5000 IU twice daily for 3 days during her admission. Her urticaria cleared dramatically and completely, but relapsed immediately when heparin was discontinued. She requested continued treatment with heparin and after a discussion about the risks was recommenced on self-administered subcutaneous heparin sodium 5000 IU twice daily, with the same dramatic effect. The patient remains completely clear of urticaria after 15 months of treatment. If heparin is discontinued or the dose reduced, the urticaria returns. The activated partial thromboplastin time, as expected, was not prolonged by 5000 IU of heparin administered subcutaneously at 12-h intervals. She has not so far experienced significant adverse side-effects of heparin such as excessive bleeding tendency, heparin-induced thrombocytopenia, skin necrosis or osteoporosis. Baseline bone densitometry was normal. Heparin is a naturally occurring glycosaminoglycan in the secretory granules of mast cells and basophils. It is able to interact with various plasma and cell surface proteins, conferring upon it numerous biological properties. Heparin has been shown to have a role in the modulation of mast cell mediator release both in vitro and in vivo. It has a dose-dependent inhibitory effect on the in vitro release of histamine from basophils induced by serum as well as plasma from patients with chronic urticaria. Forty per cent of patients with chronic urticaria have an acute weal and flare response to intradermal injections of autologous serum. It has been proposed that this is due to IgG autoantibodies against the high-affinity IgE receptor FceRIa on mast cells. However, heat decomplemented and IgG-depleted serum has also been observed to elicit a weal and flare response. Fagiolo et al. have demonstrated that mixing heparin with autologous serum immediately prior to intradermal injection diminishes the weal and flare reaction in patients with chronic urticaria. As the action of heparin was immediate, the authors felt it was unlikely to be mediated by second messenger intracellular pathways. Acute cutaneous reactions of sheep to intradermal injection of an allergen but not histamine have been reduced by pretreatment with intravenous heparin, demonstrating the ability of heparin to modulate mast cell mediator release rather than end organ response. The exact mechanism of action of heparin in the context of urticaria is therefore still unknown. To our knowledge, there have been no published reports of the effectiveness of heparin as a treatment for chronic urticaria.