Alergol Inmunol Clin 2001; 16: 294-296

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$Prueba de uso con guante de látex como método de diagnóstico ...$

The administration of unfractionated heparins (UFH) or of low-molecular weigh heparins (LMWH) may induce a non-necrotic eczematous reaction at the site of injection, in which a delayed hypersensitivity mechanism is involved 1 . Cross-reactivity has often been observed in these cases between the various heparins 2-5 or even with heparinoids 3-5 . This may constitute a problem, particularly when faced with an urgent need for anticoagulant therapy. There have recently been reports of cases in which the new recombinant hirudins represent a safe alternative for patients with this type of reaction 3,6,7,9 . CASE REPORT A 38-year old woman, obese but with no other salient features in her past history, was referred to the Allergy Outpatient Clinic because of two episodes of abdominal skin rash which she described as vesicular-blistering within the past two years. The first episode had occurred ten days after the subcutaneous administration into the abdominal wall of enoxaparin (Clexane ® ) 40 mg, one dose every 24 hours, because of a tibioperoneal fracture suffered during a motoring accident. The administration of this low-molecular weight heparin was continued for five further days; the skin rash progressed to involve the whole abdomen, and remitted gradually in a number of days after withdrawal of the drug. The second episode occurred after the administration of the same low-molecular weight heparin because of a new tibial fracture after a further traumatism. In this case, the skin rash in the abdomen began several hours after the administration of the first dose and, as the drug was not immediately withdrawn, progressed to involve the whole abdomen with greater severity than in the previous occasion. The rash again remitted gradually after withdrawal of the drug. After recovering from this second episode the patient was seen for the first time at the Allergy Outpatient Clinic, and the following allergologic study was performed (Table I): (1) skin prick tests at 1:1 dilution with unfractionated heparin (heparin sodium) and with two LMWH [enoxaparin and nadroparin (Fraxiparin ® )], which were read after 20 minutes, 48 hours and 96 hours, and (2) epicutaneous tests, again at 1:1 dilution, with the same heparin preparations, which were read after 48 and 96 hours. Positive results were observed in the epicutaneous tests with all the heparin preparations used, but the reactions were stronger with the Delayed hypersensitivity to enoxaparin Table I. Results of the skin prick and epicutaneous tests and of the subcutaneous tolerance tests with various heparin preparations and with desirudin Prick Epicutaneous Subcutaneous 1:1, 20 min 1:1, 48 h/96 h 1:1, 20 min/48 h Unfractionated heparin Heparin sodium Low-molecular weight heparins – +/++ NT Nadroparin (Fraxiparin ® ) – ++/++ NT Enoxaparin (Clexane ® ) Recombinant hirudin – +++/+++ NT Desirudin (Revasc ® ) NT = Not tested. – – – LMWH and particularly with enoxaparin (Fig. 1); the parallel tests in control patients were negative. The possibility of tolerance to a recombinant hirudin, desirudin, was considered as two similar case reports were Fig. 1. Results of the epicutaneous tests with various heparin preparations (1:1 dilution) at the second reading (96 hours). 295
J. M. Vega, et al found in the literature with good tolerance to that drug 6,7 . Skin prick and epicutaneous tests were thereupon performed with desirudin, with negative results; after the patient had given her informed consent, a subcutaneous challenge test with desirudin (Revasc ® , 15 mg) was carried out, with full tolerance and with no immediate or delayed reaction. DISCUSSION Delayed skin reactions in the form of eczematous plaques at the site of injection of LMWH appear after several days (3 – 13 days); they are more frequent in obese women with protracted treatments 5 , as in the present case, and in diabetics, and they may be more frequent than generally suspected 3 . Using skin tests (intradermal or epicutaneous) and skin biopsies, these lesions have been demonstrated to be consistent with delayed hypersensitivity reactions, probably elicited by the heparin molecule itself as most heparin preparations are devoid of conservants 3 . Various degrees of cross-reactivity have been reported between the two forms of heparin (UFH and LMWH) and the heparinoids: only between some LMWH, between LMWH and UFH, or between heparins and heparinoids 1-9 . In a recent study on 23 patients with delayed hypersensitivity reactions to heparins, most were sensitised to both types of heparins and to heparinoids 3 . Both types of heparins and daparinoid (a heparinoid type) are derived from the porcine intestinal mucosa, so that, when it is intended to test heparinoid tolerance, other alternative drugs are recommended, even though there have been reports of cases evidencing cross-reactivity to the latter 3 . The recombinant hirudin derivatives are polypeptides acting through direct inhibition of thrombin. Desirudin is administered subcutaneously for the prophylaxis of postsurgical deep venous thrombosis. Lepirudin is administered intravenously, and it has been used in heparin-induced type II thrombocytopenia and in haemodialysis patients with heparin-induced necrosis. However, these drugs are contraindicated during pregnancy and may also trigger immediate or delayed hypersensitivity reactions, even though no cross-reactivity has been demonstrated between them and heparins or heparinoids. Thus, therapy with recombinant hirudin derivatives may be indicated without awaiting the results of allergologic studies when the indication for anticoagulation is urgent 3 . Delayed hypersensitivity to heparins and heparinoids may be demonstrated through epicutaneous or intradermal 296 tests (up to 1:1 dilution) with delayed reading; greater sensitivity has been observed with the latter 3 , although in that case positive results were seen with all the heparin preparations tested epicutaneously. Challenge tests with the alternative drug(s) are required despite the negativity of the skin tests. In the case here reported, tolerance to a recombinant hirudin was demonstrated in a patient with delayed eczematous reactions in the area of subcutaneous administration of enoxaparin, with sensitisation to this LMWH, to other LMWH and to UFH. This case agrees with previously published ones of delayed hypersensitivity reactions to heparins with tolerance to recombinant hirudins (desirudin 6,7 or lepirudin 3,7 ). In delayed reactions induced by heparins with evidence of sensitisation to these drugs, and particularly when the sensitisation is multiple to LMWH and UFH or when the allergic tests must be postponed because anticoagulation is urgently required, recombinant hirudins may represent a safe alternative. REFERENCES 1. Bircher AJ, Flückinger R, Büchner SA. Eczematous infiltrated plaques to subcutaneous heparin: a type IV allergic reaction. Br J Dermatol 1990; 123: 507-514. 2. Méndez J, Sanchís ME, de la Fuente R, Stolle R, Vega JM, Martínez C, et al. Delayed-type hypersensitivity to subcutaneous enoxaparin. Allergy 1998; 53: 999-1003. 3. Koch P, Munssinger T, Rupp-John C, Uhl K. Delayed-type hypersensitivity skin reactions caused by subcutaneous unfractionated and low-molecular-weight heparins: tolerance of a new recombinant hirudin. J Am Acad Dermatol 2000; 42: 612-619. 4. Sivakumaran K, Ghosh K, Munks R, Gelsthorpe K, Tan L, Wood JK. Delayed cutaneous reaction to unfractionated heparin, low molecular weight heparin and danaparoid. Br J Haematol 1994; 86: 893-894. 5. Szolar-Platzer C, Werner A, Kränke B. Delayed-type skin reaction to heparin-alternative daparinoid. J Am Acad Dermatol 2000; 43: 920-922. 6. Koch P, Reinhold S, Bush C. Delayed allergic skin reactions to subcutaneous heparins. Tolerance of 2 recombinant hirudins. Contact Dermatitis 2000; 42: 278-279. 7. Martín L, Machet L, Gironet N, Pouplard C, Gruel Y, Vaillant L. Eczematous plaques related to unfractionated and low-molecularweight heparins: cross-reaction with danaparoid but not with desirudin. Contact Dermatitis 2000; 42: 295-296. 8. Méndez J, de la Fuente R, Stolle R, Vega JM, Sanchís ME, Armentía A, et al. Delayed hypersensitivity skin reaction to enoxaparin. Allergy 1996; 51: 853-854. 9. Bircher AJ, Itin PH, Tsakiris DA, Surber C. Delayed hypersensitivity to one low-molecular-weight heparin with tolerance of other lowmolecular-weight heparins. Br J Dermatol 1995; 132: 461-463.
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Alergol Inmunol Clin 2001; 16: 294-296

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