Low allergenic potential with fondaparinux: results of a prospective investigation

Abstract

Objective: To determine the incidence and causes of skin reactions to the synthetic pentasaccharide fondaparinux.

Patients and methods: Patients who received prophylactic/therapeutic subcutaneous fondaparinux treatment for more than 7 days were prospectively examined for cutaneous adverse effects between September 1, 2008, and April 30, 2009. When indicated, other procedures, such as skin biopsy, allergy testing, and clinical/laboratory assessment for thrombosis and heparin-induced thrombocytopenia, were performed.

Results: Overall, 231 patients were enrolled. No patient developed typical delayed type IV hypersensitivity (DTH) erythematous skin lesions. However, one female patient experienced abdominal pruritus at sites of injection. Histology revealed a mild lymphohistiocytic infiltrate, confirming a DTH reaction. Heparin-induced thrombocytopenia, as another possible underlying pathomechanism for cutaneous lesions, was ruled out clinically and serologically. Hence, the overall incidence of fondaparinux-induced allergic skin lesions was 0.4% (95% confidence interval, 0.01%-2.4%). No cross-allergies were observed in patients with DTH reaction to heparins.

Conclusion: Fondaparinux has a low allergenic potential. The incidence of allergic cutaneous DTH reactions is almost 20 times lower compared to that with commonly used heparins. These results, together with the known low prevalence of secondary thrombotic events or heparin-induced thrombocytopenia during fondaparinux therapy, suggest that in selected patients fondaparinux might substantially improve patient care, therapeutic safety, and cost-effectiveness of anticoagulant therapy.

Trial registration: clinicaltrials.gov identifier: NCT00510432.

FIGURE 1.

Top, Typical presentation of a patient with delayed type IV hypersensitivity (DTH) reaction to nadroparin. The patient had pruritus at the injection areas and appearance of a single red plaque, with few papules at the heparin injection site 4 to 6 hours after subcutaneous application. Middle, Clinical presentation of the only study patient with a DTH reaction to fondaparinux. The patient had pruritus at the injection areas, but the skin appeared normal without erythematous lesions. Bottom, Clinical presentation of a patient with cutaneous necrosis due to underlying heparin-induced thrombocytopenia. Histologic study confirmed microthromboses in the necrotic areas.

FIGURE 2.

A, Skin biopsy specimen from a patient with typical delayed type IV hypersensitivity (DTH) reaction to heparin, showing epidermal spongiosis and dermal infiltration with lymphocytes and eosinophils, characteristic of a DTH reaction (hematoxylin-eosin; original magnification, x200). B-D, Skin biopsy specimens from the only study patient with a DTH reaction to fondaparinux, showing a mild, mainly perivascular dermal infiltration, predominantly with lymphocytes and to a low degree with eosinophils, typical of a DTH reaction. There are no microthromboses in dermal vessels; these would be suggestive of the presence of heparin-induced thrombocytopenia (B-D, hematoxylineosin; original magnification, x100, x200, x400, respectively).

FIGURE 3.

Molecular structures of the antithrombin-binding pentasaccharide sequence of heparin (top) and fondaparinux (bottom).