Treatment of an acute flush reaction caused by subcutaneous r‐hirudin with pegylated hirudin

Abstract

Summary. We report a patient who was treated with recombinant (r)-hirudin for heparin-induced thrombocytopenia and developed a¯ush reaction twice upon re-exposure to 25 mg of subcutaneous r-hirudin. Antihirudin IgG antibodies developed. The patient received 50 mg of PEG-hirudin subcutaneously over 2 days. No side-effects occurred. The level of IgG antihirudin antibodies increased. Ecarin clotting time and thrombin inhibition S2238 assay were not in¯uenced by the patient's IgG antihirudin antibody. PEG-hirudin may be used in patients with intolerance to r-hirudin because of a dissociation of the allergenic and immunogenic properties of the pegylated drug.Keywords: r-hirudin, allergy, PEG-hirudin, heparin-induced thrombocytopenia.Hirudin is extracted from the salivary glands of the leech Hirudo medicinalis and inhibits blood coagulation by binding to and inactivating thrombin (Markwardt, 1994). Today, it is produced by recombinant technology. Recently, an acute urticaria reaction caused by subcutaneous recombinant (r)-hirudin (Bircher et al, 1996) and contact allergy to hirudin contained in topical medications have been reported (Dejobert et al, 1991).Heparin-induced thrombocytopenia (HIT) and thrombosis is treated with danaparoid or r-hirudin (Harenberg et al, 1997;Greinacher et al, 1999). Pegylated (PEG) hirudin was developed to increase the half-life of r-hirudin (Esslinger et al, 1997). The pegylation of drugs also results in reduced allergenicity. Here, we report the use of PEG-hirudin in a patient with¯ush reaction to subcutaneous r-hirudin. CASE REPORTA 62-year-old male patient, with a history of HIT in 1992, presented in December 1996 with unstable angina and received 0?1 mg/kg/h r-hirudin intravenously for a period of 7 days. Treatment was well tolerated, and the activated partial thromboplastin time (aPTT) was prolonged by 1?5±2 times the normal range. r-Hirudin was switched to oral anticoagulation.In June 1997, the patient was again referred to the hospital for recurrent cardiac ischaemia. Oral anticoagulation was switched to r-hirudin, because cardiac catheterization was planned. By 2 h after the subcutaneous administration of 25 mg of hirudin, the patient developed a generalized¯ush reaction. The allergic reaction disappeared within 2 h. Antibodies against r-hirudin did not develop. Six weeks later, the patient was referred to another hospital for operation on nifedipin-induced gingivitis. Anticoagulation was switched again from phenprocoumon to r-hirudin. Twenty minutes after the subcutaneous injection of 25 mg of r-hirudin, pruritus, erythema and a generalized¯ush reaction appeared. Symptoms disappeared within 1 h with cortisone and histamine blockers. Ecarin clotting time, which speci®cally determines the inhibition of hirudins on the conversion of meizothrombin to thrombin, increased from 54 s before subcutaneous administration to 106 s and 94 s at 2 h and 6 h, respectively, after subcutaneous administration of r-hirudin (normal range < 55 s). Inhibition of thrombin was measured using the chromoge...

Treatment of Patients with a History of Heparin-Induced Thrombocytopenia and Anti-Lepirudin Antibodies with Argatroban

“…This is supported by results in the literature demonstrating an interaction of the antibodies of the patient with those of the ELISA perhaps through formation of multiple hirudin complexes. These resulted in higher plasma concentrations of lepirudin in the ELISA compared to the concentrations of lepirudin determined by the chromogenic method or ecarin clotting time assay [5].…”

“…Lepirudin is established for the treatment of these patients [3,4]. However, as a protein, recombinant hirudin is antigenic and may generate in 40 to 70% of patients antibodies of the IgG, IgM and IgA class [5]. The antibodies may increase or decrease the anticoagulant effect of hirudin and hereby influence the variability of the dosage [5].…”

“…However, as a protein, recombinant hirudin is antigenic and may generate in 40 to 70% of patients antibodies of the IgG, IgM and IgA class [5]. The antibodies may increase or decrease the anticoagulant effect of hirudin and hereby influence the variability of the dosage [5]. Therefore we prospectively have determined lepirudin antibodies in the past in all patients treated with lepirudin due to HIT type II [4,5].…”

“…The antibodies may increase or decrease the anticoagulant effect of hirudin and hereby influence the variability of the dosage [5]. Therefore we prospectively have determined lepirudin antibodies in the past in all patients treated with lepirudin due to HIT type II [4,5]. Argatroban is a synthetic, non-protein small molecule direct thrombin inhibitor used for treatment of HIT type II patients [6].…”

Anaphylactic and Anaphylactoid Reactions Associated With Lepirudin in Patients With Heparin-Induced Thrombocytopenia

“…4 -6 However, until now, only 2 patients with allergic reactions to hirudins have been reported. 7,8 In 2002, 3 patients with potential anaphylactic reactions associated with lepirudin treatment were identified by the manufacturer's (Schering AG) pharmacosurveillance system. We therefore reassessed the risk of allergic and anaphylactic reactions potentially caused by lepirudin.…”