Acute urticaria caused by subcutaneous recombinant hirudin: Evidence for an IgG-mediated hypersensitivity reaction

Bircher, Andreas J.; Czendlik, C.; Messmer, S. Langauer; Müller, Philipp; Howald, H.

doi:10.1016/s0091-6749(96)80018-2

Cited by 34 publications

(18 citation statements)

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“…Also, the patient's IgG antihirudin antibody decreased after administration of PEGhirudin and then increased after elimination of the compound. A decrease in the IgG antihirudin antibody has also been reported in a patient after the ®fth course of subcutaneous hirudin (Bircher et al, 1996).In conclusion, patients with allergic reactions to r-hirudin may receive short-term treatment with PEG-hirudin as a result of a dissociation of the allergic and immunogenic event of pegylated drugs. …”

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“…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).…”

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

et al. 2000

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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...

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

et al. 2000

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“…24,25 One of them was a volunteer who had received desirudin 5 years earlier and who developed urticaria after he was re-exposed twice within a 1-week interval between the subcutaneous injections. 24 The second patient developed symptoms of an allergic response during reexposure to lepirudin. Both patients tested positive for antihirudin antibodies.…”

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Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin

Eichler

Lübenow

Strobel

et al. 2004

Blood

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Bivalirudin is a synthetic antithrombin sharing a sequence of 11 amino acids with the recombinant hirudin lepirudin. We investigated whether antilepirudin antibodies recognize epitopes on bivalirudin. Antilepirudin antibody-positive sera of 43 patients, treated with lepirudin for heparin-induced thrombocytopenia, were analyzed. Lepirudin-and bivalirudincoated microtiter plates were used for antibody testing in an enzyme-linked immunosorbent assay (ELISA) system. Of the 43 sera-containing antibodies binding to lepirudin, 22 (51.2%) contained antibodies that also recognized bivalirudin. Binding of these antibodies to bivalirudin was inhibited by more than 70% by preincubation with high doses of bivalirudin. However, if lepirudin-coated microtiter plates were used, high concentrations of bivalirudin inhibited only 2 of the 43 positive sera by more than 30%. Therefore antihirudin antibodies must be polyspecific.

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“…Möglicher-weise liegt eine Komplementaktivierung oder eine Immunkomplex-Anaphylaxie, wie sie für Dextrane und Hirudine beschrieben wurde, vor [36,37]. Sie treten häufig mit einer Latenz von 5-7 Tagen auf, können aber bereits nach 24 Stunden oder erst nach 14 Tagen manifest werden [1], wahrscheinlich in Abhängig-keit davon, ob bereits IgG-Antikörper vorliegen oder erst neu induziert werden.…”

Section: Igg-assoziierte Reaktionenunclassified

Unerwünschte Arzneimittelreaktionen auf Biologika

Scherer

Spoerl

Bircher

2010

J Deutsche Derma Gesell

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Übersichtsarbeit 411Einleitung Aufgrund der 1975 von Köhler, Milstein und Jerne beschriebenen Hybridomtechnik ist es vor rund 30 Jahren erstmals gelungen monoklonale murine Antikörper primär für die Diagnostik, später auch für therapeutische Zwecke zu entwickeln. Einer der ersten Antikörper war Muromonab, der in der Therapie der Transplantatabstoßung eingesetzt wurde. Bald wurde ein unspezifisches ZytokinRelease-Syndrom, teilweise schon bei der ersten Infusion beobachtet, das in Fieber, Nausea und Exanthemen bis hin zu Multiorganversagen resultierte [1]. Die zunehmende Anwendung von sogenannten Biologika bei Tumoren, Autoimmunkrankheiten und entzündlichen Erkrankungen wie der Psoriasis [2,3] Abbildung 1: Vorgeschlagene Klassifikation unerwünschter Arzneimittelwirkungen auf Biologika (modifiziert nach [7,8]). Bei oft nicht gesichertem Pathomechanismus (z. B. Immunogenität, Immundeviation), ist eine Zuordnung nicht abschließend möglich. Abkürzungen: ADR = unerwünschte Arzneimittelwirkung; CYP = Cytochrom P 450; EGFR = epidermal growth factor receptor; GM-CSF = granulocyte-macrophage colony stimulating factor; ISR = Injektionstellenreaktion; PML = progressive multifokale Enzephalopathie; PRCA = pure red cell aplasia (Erythrozytenaplasie); RCM = Röntgenkontrast-mittel; rHu-EP = rekombinantes humanes Erythropoietin.den UAW ist der Pathomechanismus oft nicht eindeutig geklärt [2]. Typen von BiologikaEs werden drei Gruppen von Biologika unterschieden (Tabelle 1):• Zytokine • Antikörper • Fusionsproteine und lösliche Rezeptorkonstrukte Die Nomenklatur (s. a. http://www.amaassn.org/ama/pub/about-ama/our-people/ coalitions-consortiums/united-statesadopted-names-council.shtml) scheint auf den ersten Blick verwirrend [2,11]. Sie ist folgendermaßen aufgebaut: Das die ersten ein oder zwei Silben umfassende Präfix, ist frei für das Präparat wählbar. Das erste Infix steht für die Zielstruktur oder Krankheitsgruppe, z. B. "-li-" oder "-lim-" steht für Immunsystem, "-tu-" für diverse Tumoren, oder "-kin-" für Zytokinantagonisten. Das zweite Infix in der zweitletzten Silbe steht für die Speziesanteile des Antikör-pers, z. B. "-u-" (humaner Antikörper), "-mo-" (muriner Antikörper) und "-xi-" (chimärer Antikörper) (Tabellen 2, 3). Das Suffix der letzten Silbe "-mab" steht für monoklonaler Antikörper oder Antikörperfragmente. Andere Endsilben sind "-cept" für Rezeptoren und "-inib" für Rezeptorenblocker [11]. So ist der Name des Anti-IgE-Antikörpers Omalizumab folgendermaßen zusammengesetzt: Frei wählbares Präfix "Oma-", "-li-" für das Immunsystem als Target, "-zu-" humanisiert für die Quelle und "-mab" für den monoklonalen Antikörper. Der unterschiedliche Anteil an tierischen und humanen Proteinen hat einen entscheidenden Einfluss auf die Antigenizität und somit auf die Induktion von Antikörpern [12] (Tabellen 2,3). Die vorgeschlagene Nomenklatur für Interleukin (IL)-Antagonisten lautet folgendermaßen: "-nakin" steht für Interleukin-1-Derivate, wie bei Anakinra, "-onakin" für IL-1a, "-benakin" für IL-1b, "-leukin" für IL-2, "-trak...

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Acute urticaria caused by subcutaneous recombinant hirudin: Evidence for an IgG-mediated hypersensitivity reaction

Cited by 34 publications

References 9 publications

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

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

Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin

Unerwünschte Arzneimittelreaktionen auf Biologika

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