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 Mayo Clin Proc. 2010;85(10):913-919 BMI = body mass index; DTH = delayed type IV hypersensitivity; DVT = deep venous thrombosis; HIT = heparin-induced thrombocytopenia; LMWH = low-molecular-weight heparin; PE = pulmonary embolism; UFH = unfractionated heparin

Pharmacology of Heparin and Related Drugs

“…Histologic analysis has shown infiltration by neutrophils and eosinophils, which is characteristic of delayed type hypersensitivity reactions (Grassegger et al, 2001;Schindewolf et al, 2010a). There is some evidence that the hypersensitivity reaction is molecular weight dependent (Ludwig et al, 2005), with the pentasaccharide having a much lower incidence compared with other heparins (Schindewolf et al, 2010b).…”

Non‐immediate heparin and heparinoid cutaneous allergic reactions: a role for fondaparinux

“…Based on the current literature, fondaparinux has been a useful alternative in at least 40 cases of non‐immediate cutaneous reactions from heparins and heparinoids . Various studies and case reports from centres in Germany, Austria and Spain demonstrated that cross‐reactivity is not uncommon between various types of UFH and LMWH and between heparins and heparinoids.…”

“…Various studies and case reports from centres in Germany, Austria and Spain demonstrated that cross‐reactivity is not uncommon between various types of UFH and LMWH and between heparins and heparinoids. In a total of 48 cases where patients with confirmed non‐immediate reactions to heparins or heparinoids were challenged with fondaparinux, 43 did not demonstrate any non‐immediate cutaneous reaction to fondaparinux . There are only five cases of cross‐reactivity to fondaparinux reported, with three of these reactions occurring only after rechallenge .…”

“…Fondaparinux has potential to cross‐react, because it represents the shortest sequence within the heparin molecule that is required to interact with factor Xa. The difference between these classes of anticoagulants in regards to their antigenicity and ability to induce non‐immediate cutaneous reactions has been postulated to be related to their molecular heterogeneity, with heparins comprising large molecular weight structures (Mr 3000–58 000 Da) of high heterogeneity . This heterogeneity is not surprising given they are naturally occurring molecules sourced from various tissues of different species (porcine and bovine).…”

“…Closer monitoring for cutaneous reactions after subcutaneous administration of heparins should be performed in those with risk factors of obesity, female sex and prolonged therapy. Fondaparinux is an anticoagulant with low allergic potential, likely owing to its fully synthetic pentasaccharide structure which has fewer potential epitopes compared to the heterogeneous mix of glycosaminoglycans that constitute heparins and heparinoids. It has emerged as a useful alternative for subjects with non‐immediate cutaneous reactions to heparins, which can be used for both prevention and treatment of venous thromboembolism.…”