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Delayed-type hypersensitivity skin reactions caused by subcutaneous unfractionated and low-molecular-weight heparins: Tolerance of a new recombinant hirudin
Delayed-type hypersensitivity skin reactions caused by subcutaneous unfractionated and low-molecular-weight heparins: Tolerance of a new recombinant hirudin Patrick Koch, MD, Thomas Münßinger, MD, Cornelia Rupp-John, and Karen Uhl, MD Homburg/Saar, Germany Background: Eczema-like infiltrated plaques at subcutaneous heparin injection sites are well-documented side effects of these anticoagulants. However, surgical interventions may be problematic if heparin is urgently needed in these patients. Objective: The aims of this study were to perform extensive allergy skin testing in 24 patients, including a pregnant woman in whom subcutaneous infiltrated plaques developed after subcutaneous heparin injections, and to find safe therapeutic alternatives for this group of patients. Methods: Patch, intradermal, and subcutaneous tests were performed with a panel of unfractionated heparins (UFHs), low-molecular-weight heparins (LMWHs), and heparinoids. Since 1997, we have also been performing allergy studies in 8 patients with lepirudin, a new recombinant heparinoid; tolerance of lepirudin was investigated by means of subcutaneous and intravenous injections. The allergy investigations in the pregnant woman were limited to patch tests with heparins and intradermal and subcutaneous tests with pentosanpolysulfate, which are not contraindicated during pregnancy. Results: In our study population 19 of 23 patients were sensitized to all the UFHs and LMWHs tested when intracutaneous and subcutaneous test results were read at up to 96 hours. LMWH was found to be a possible substitute in 4 patients. Five patients were also sensitized to the heparinoid pentosanpolysulfate. Sensitization to the heparinoid danaparoid was observed in 12 of the 13 patients who were tested with this substance. The administration of an intravenous bolus containing a therapeutic dose of lepirudin after negative subcutaneous provocation was tolerated without any side effects in all 8 patients. The pregnant woman was sensitized to LMWH but tolerated subcutaneous pentosanpolysulfate without any side effects. Conclusion: Extensive allergy skin testing should be performed to find safe alternatives. With few exceptions, all patients react to both UFHs and LMWHs, as well as to danaparoid. The subcutaneous provocation test is the most reliable diagnostic measure. Intravenous lepirudin, and in some cases subcutaneous pentosanpolysulfate, appears to be a safe alternative in patients with eczema-like infiltrated plaques at subcutaneous heparin-injection sites. (J Am Acad Dermatol 2000;42:612-9.)
H
eparin-induced nonnecrotic eczematous skin reactions caused by subcutaneous administration of unfractionated heparins (UFHs) or low-molecular-weight heparins (LMWHs) are due to delayed-type hypersensitivity.1-3 These can be easily distinguished clinically from heparin-
From the Department of Dermatology, University of Saarland. Accepted for publication July 22, 1999. Reprint requests: Patrick Koch, MD, Department of Dermatology, University of Saarland, D-66421 Homburg/Saar, Germany. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/101595 doi:10.1067/mjd.2000.101595
612
Abbreviations used LMWH: Low-molecular-weight heparin UFH: Unfractionated heparin
induced skin necrosis4 and from urticaria with angioedema induced by preservative-free LMWHs.5 Between December 1987 and November 1998, 24 patients who presented themselves or were referred to our dermatology department with painful, erythematous, infiltrated skin lesions at the injection sites of different brands of heparins were tested with the
Koch et al 613
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Table I. Anticoagulants tested at the origin of the lesions in 24 patients
Heparins and heparinoids
Unfractionated heparins Heparin calcium 25,000 IU/mL Heparin sodium 5000 IU/mL Heparin sodium 5000 IU/mL Heparin sodium* 8800 IU/mL LMWHs Nadroparin calcium Dalteparin sodium Enoxaparin sodium Reviparin sodium Certoparin sodium Tinzaparin sodium Heparinoids Danaparoid sodium Glycosaminoglycane polysulfate Pentosanpolysulfate Recombinant heparinoid Lepirudin
Heparins inducing the lesions
Origin
Abbreviation
Preservatives
No. of patients tested
Porcine Porcine Bovine Porcine
U1 U2 U3 U4
— Benzyl alcohol Benzyl alcohol —
24 24 11 10
11 3
Porcine Porcine Porcine Porcine Porcine Porcine
L1 L2 L3 L4 L5 L6
— — — — Chlorocresol Benzyl alcohol
24 24 17 14 9 9
3 3 4
Porcine Bovine Beechwood
D H1 H2
— — —
13 10 20
L
—
8
Yeast
1 1
In 2 patients the heparin at the origin of the lesions could not be determined. In 4 patients both enoxaparin sodium and heparin sodium (unfractionated), nadroparin sodium and heparin calcium (unfractionated), dalteparin sodium and nadroparin sodium, and enoxaparin and heparin calcium (unfractionated) induced the lesions. *Heparin in crystalline form diluted in 0.9% NaCl immediately before testing.
aim of finding safe therapeutic alternatives. Since 1997, we have also investigated tolerance to lepirudin, a new recombinant hirudin in 8 patients.
METHODS Patients During an 11-year period from December 1987 to November 1998, we observed 24 patients treated in our department. The study population consisted of 22 women and 2 men, aged 29 to 76 years (mean age, 60 years). Eleven patients in this group had acute or subacute lesions. Twenty-two patients were referred by departments of surgery, gynecology, hematology, and internal medicine for further allergy evaluation with the aim of finding safe alternatives. All patients had received 5000 to 12,000 U of UFH or LMWH subcutaneously 1 to 3 times a day for the treatment or prevention of thromboembolic disease. All patients with acute lesions had typical erythematous, infiltrated, pruritic, and painful plaques at the subcutaneous heparin injection sites on the abdominal wall and thighs. Some of the plaques exhibited vesiculation or bulla formation (Fig 1). There was no thrombocytopenia. In 2 patients (patients 12 and 14), UFHs were administered intravenously outside our dermatology department (12,500 U of heparin sodium). On the following day, a maculopapular rash
predominantly on the trunk developed in these patients, and they were then referred for allergologic investigation. A 33-year-old woman in the seventh month of pregnancy was referred to our department in November 1998 (patient 24). This patient had deep vein thrombosis in September 1997, which was treated with lysis, intravenous heparin sodium, and coumarin. After pregnancy was confirmed in March 1998, the coumarin therapy was discontinued. In October 1998, dalteparin sodium (5000 U daily) was administered to prevent thromboembolism. Two days after the injection, painful, erythematous, and infiltrated lesions developed at the subcutaneous injection sites on the thighs. A subcutaneous injection of nadroparin sodium (1900 U) induced similar lesions. Safe anticoagulants were then requested from the obstetricians for the ninth month of pregnancy. Histologic examination of biopsy specimens taken from skin lesions Samples of affected skin lesions were taken in 5 patients by a 4-mm punch biopsy performed after achievement of local anesthesia and after informed consent had been given. From all patients, hematoxylin-eosin–stained paraffin sections were obtained.
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Fig 1. Bullous lesion at the subcutaneous injection site of heparin-calcium.
Fig 2. Positive intradermal test results to heparin calcium, heparin sodium (unfractionated), and dalteparin sodium after 96 hours.
Table II. Histologic changes of 9 biopsy specimens taken from the sites of positive intradermal and subcutaneous tests in 8 patients with delayed-type hypersensitivity to heparins and heparinoids Test reactions
Subcutaneous test reactions
Intradermal test reactions
Days after injection
Patient
Anticoagulants
Histologic changes
3 4 5 3 3 3 3 2 2
8 16 16 3 5 6 14 15 23
Heparin-calcium Dalteparin sodium Pentosanpolysulfate Nadroparin sodium Heparin calcium Heparin calcium Heparin calcium Reviparin sodium Certoparin sodium
Eczematous Drug reaction Drug reaction Drug reaction Eczematous Eczematous Drug reaction Eczematous Drug reaction
Drug reaction, Perivascular lymphocytic infiltrates with some eosinophils in the superficial and in one patient (dalteparin-sodium, D4) also in the deep dermis, compatible with a drug-induced reaction; Eczematous, eczematous histologic changes.
Allergy studies Patch testing was performed with the standard series of the German Contact Dermatitis Group; preservatives used in different brands of heparins, including the heparin responsible for the lesions; and different brands of undiluted UFHs, LMWHs, and heparinoids made by several manufacturers when available (Table I). Methods recommended by the German Contact Dermatitis Group for this testing were used.6 The test substances of the standard series (Hermal, Reinbek, Germany), as well as the heparins and heparinoids, were applied to the patients’ upper backs for 24 hours by using Leukotest (Beiersdorf, Germany) and fixed with Mefix (Mölnlycke, Hilden, Germany). Readings were taken after 24, 48, and 72 hours. The patch test reaction was considered to be an allergic reaction when a score of +, ++, or +++ was given at 48 and 72 hours or at 72 hours.
Intradermal tests were performed on the flexural side of the forearm with 0.05 mL of similar undiluted brands of UFHs, LWMHs, and heparinoids used for patch testing. Readings were taken after 20 minutes to rule out immediate hypersensitivity and after 24, 48, 72, and 96 hours. The test result was considered positive when an infiltrated eczematous reaction was noted at 24, 48, 72, or 96 hours. This was consistent with delayed-type hypersensitivity. Intradermal tests were performed in 10 volunteers with undiluted preservative-free heparin calcium. This resulted in negative results at 24, 48, and 72 hours, as reported previously.3 Subcutaneous tests were performed on the abdominal wall with 0.1 mL of undiluted brands of UFHs, LMWHs, and heparinoids that had produced negative results in the intradermal test. The tests were read up to 96 hours. A therapeutic dose of glycosaminoglycane polysulfate, pentosanpolysulfate (1
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ampule), and lepirudin (1 mL of a solution of 5 mg/mL) was injected subcutaneously in the abdominal wall or in the thighs when the subcutaneous test result was negative. In 2 patients (patients 13 and 22) anticoagulants were urgently needed, and only subcutaneous tests were performed. The pregnant woman underwent patch testing as described earlier, and then an intradermal, a subcutaneous, and a subcutaneous provocation test were performed only with pentosanpolysulfate to minimize possible side effects. Glycosaminoglycane polysulfate has been withdrawn from the German market and has thus been tested in only 10 patients. Histologic examination of biopsy specimens taken from the sites of positive intradermal and subcutaneous tests to UFHs, LMWHs, and pentosanpolysulfate Nine biopsies were performed in 8 patients by using a 4-mm punch biopsy. From all cases, hematoxylin-eosin–stained paraffin sections were obtained. Results of histologic examination of these specimens is shown in Table II. Intravenous provocation with lepirudin A solution of 5 mg/mL was prepared according to the manufacturer’s instructions. A therapeutic bolus containing 0.4 mg/kg of lepirudin was then injected intravenously over a 2-minute period. The patient was subsequently observed for 24 hours in our dermatology department.
RESULTS Histologic examination of biopsy specimens of lesions The spectrum of histopathologic changes could be subdivided into 2 main patterns. The first pattern consists of changes with features of allergic contact dermatitis with spongiosis of the epidermis and lymphohistiocytic infiltrates with some eosinophils around the dilated vessels of the dermis (3 patients). The second pattern is changes compatible with a drug reaction, such as perivascular lymphohistiocytic infiltrates with eosinophils in the superficial dermis (2 patients). Sensitization to heparins and heparinoids Delayed-type hypersensitivity reactions to both UFH and LMWH were observed in 23 patients tested. Results are shown in Table III. In our study population 19 of 23 patients were sensitized to all types of UFH and LMWH tested. In addition, 5 patients were sensitized to pentosanpolysulfate. Sensitization to danaparoid was observed in 12
Koch et al 615
of the 13 patients tested. In 5 patients the intradermal test produced positive results only after 96 hours (Fig 2). An LMWH was considered as a possible therapeutic alternative in only 4 patients: dalteparin sodium in patient 9; certoparin, dalteparin, reviparin, and tinzaparin sodium and danaparoid in patient 17; tinzaparin sodium in patient 21; and dalteparin, reviparin, and tinzaparin sodium in patient 22. However, no consecutive therapy was carried out with these anticoagulants because it was not necessary at this time. Patch and intradermal tests were performed before subcutaneous tests in 21 patients. Sensitization to heparin was detected by these methods in 9 of 21 and 17 of 21 patients, respectively. The entire spectrum of sensitization to heparin and heparinoids was detected only by the subcutaneous tests. As shown in Table III, subcutaneous tests were also performed in patients in whom the intradermal test results to some UFHs and LMWHs were positive. This indicates that intradermal tests produced false-negative results to one or more heparins in 9 of 21 patients. The pregnant woman (patient 24) was sensitized to all the LMWHs but not to the UFHs. However, only patch tests were performed. The subcutaneous provocation test with pentosanpolysulfate was tolerated without any side effects. Intravenous provocation with lepirudin No side effects were observed in any of the 8 patients tested (Table III). Further anticoagulation Nine patients currently required anticoagulation for the prevention of thromboembolism or in conjunction with surgery (Table III). Subcutaneous glycosaminoglycan polysulfate and pentosanpolysulfate proved to be safe therapeutic alternatives in 2 and 3 patients, respectively. Two weeks after the initiation of treatment with pentosanpolysulfate (50 mg twice daily), however, erythematous lesions at the subcutaneous injection sites developed in patient 12. Patient 13 received coumarin. Four patients urgently required surgery. As reported previously,7 intravenous anticoagulation during coronary bypass surgery could be achieved in patient 9 with intravenous dalteparin sodium. Subcutaneous test results were negative with this LMWH; in addition, methylprednisolone and clemastine hydrogen fumarate were administered as anaphylactoid prophylaxis. It was possible to perform coronary bypass surgery in patients 2 and 8 with ancrod.8 Lepirudin was administrated intravenously twice daily for 8 days after an osteosynthesis procedure in patient 18 without any side effects.
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Table III. Results of allergy evaluation and therapy with alternative anticoagulants in 24 patients with local reactions at the subcutaneous heparin injection sites Patient No.
Sex
Age (y)
1
F
66
2
F
76
3
F
37
4
F
47
5
F
73
6
F
76
7
F
49
8
M
72
9
F
67
10
F
29
11
F
69
12
F
45
13
F
56
14
F
62
Heparins/ Heparinoids tested
Patch
Intradermal
Subcutaneous
U1→U4 L1, L2 H1 U1→U4
– – – –
+ + – –
ND ND – +
L1, L2 H1 U1→U4 L1, L2 H1 U1→U4 L1, L2 H1, H2 U1→U4 L1, L2 H1, H2 U1→U4 L1→L3 H1, H2 U1→U4 L1→L3 H1, H2 U1, U3, O L1→L3 H1, H2 U1→U4, O
– – – – – – – – – + – + + – – – – – – – –
– – + + – – – – + + – + + – + + – + + – –
+ – + + – + + – ND ND – ND ND – ND ND – ND + – +
– – – + – + – – – + – – ND ND ND ND – – – –
– – + + – – – – + + + – ND ND ND ND + + + –
L1+, L2– – + + – + + – ND ND ND – + + + – ND + ND –
L1, L2 H1 U1→U4 L1, L2 H1, H2 U1→U3 L1→L4 H2 U1→U4 L1→L4 D H2 U1, U2 L1→L4 D H2 U1, U2 L1→L4 D H2
Therapy after the allergy investigations
(1) Coronary surgery with ancrod; (2) H1 subcutaneous
Coronary surgery with ancrod
(1) Coronary surgery with dalteparin; (2) H1 subcutaneous
H2 subcutaneous*
Coumarin
H2 subcutaneous
D, Danaparoid; H1, glycosaminoglycan polysulfate; H2, pentosanpolysulfate; L, lepirudin; L1, nadroparin calcium; L2, dalteparin sodium; L3, enoxaparin sodium; L4, reviparin sodium; L5, certoparin sodium; L6, tinzaparin sodium; O, other heparins tested; U1, heparin calcium 25,000 IU/mL; U2, porcine heparin sodium 5000 IU/mL; U3, bovine heparin sodium 5000 IU/mL; U4, heparin sodium 8800 IU/mL. *Erythematous lesions at the subcutaneous injection sites 2 weeks after the initiation of treatment.
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Table III. Cont’d Patient No.
Sex
Age (y)
15
F
75
16
M
56
17
F
58
18
F
69
19
F
72
20
F
59
21
F
59
22
F
71
23
F
60
24
F
33
Heparins/ Heparinoids tested
Patch
Intradermal
Subcutaneous
U1, U2 L1→L6 D H2 U1, U2 L1→L4 D H2 L U1, U2, O L1→L6 D H2 L U1, U2 L1→L6 D H2 L U1, U2 L1→L6 D H2 L U1, U2 L1→L6 D H2 L U1, U2 L1→L6 D H2 L U1, U2 L1→L6 D H2 L U1, U2 L1→L6 D H2 L U1, U2 L1→L6 D H2
– – – – – + – – – – – – – – + + + – – – – – – – + + + – – – – – – – ND ND ND ND ND – + – – – – + + –
+ + + – + + + – – + L1, L3+ – + – + + + + – + + + – – + + + + – + + – – – ND ND ND ND ND + + + – – ND ND ND –
+ + ND – + + ND + – + L2, L4→L6– – + – ND ND ND + – ND ND ND – – ND ND ND + – ND L1→L5+, L6– + + – + L1, L3, L5+ + – – ND + ND – – ND ND ND –
Therapy after the allergy investigations
H2 subcutaneous
Lepirudin intravenous twice daily
H2 subcutaneous
618 Koch et al
Histologic examination of biopsy specimens from patients with positive test reactions The patients’ lesions and the test reactions showed the following histologically similar changes: (1) an eczematous reaction that was more pronounced in the intradermal and subcutaneous tests than in the patients’ lesions and (2) perivascular lymphocytic infiltrates with some eosinophils in the superficial, and in some cases also in the deep, dermis, which were compatible with a drug-induced reaction (Table II).
DISCUSSION Erythematous, infiltrated, and painful plaques overlying sites of subcutaneous heparin injection represent a distinctive reaction and are probably a more common side effect than is generally realized. The clinical appearance in the cases previously described1,2 is almost identical and closely resembles that in our patients. Skin biopsy specimens of the lesions and of the test reactions reveal typically eczematous changes in some patients; these are compatible with delayed-type hypersensitivity, as has been reported by other investigators.1,2 The histologic and allergy evaluation in our study population indicates that the delayed-type hypersensitivity is probably caused by or associated with the heparin molecule itself. Most of the heparins tested were free of preservatives. Heparins are complex mixtures of mucopolysaccharides produced from porcine or bovine intestine and lungs. Molecular weight discriminates UFHs (10-20 kd) from LMWHs (4-6 kd).9 Heparin, a negatively charged mucopolysaccharide hapten, binds strongly to proteins, resulting in a complete antigen.10 However, the heparin fractions that induce the sensitization have not been determined. In our study population 19 of 23 patients were sensitized to all the UFHs and LMWHs tested, including preparations recently put on the market in Germany, indicating cross-reactivity of the different preparations. Because of the structural similarities of the UFHs and the LMWHs, all available heparin preparations may thus elicit positive reactions. However, as reported in this study and in studies by other authors, some patients with delayed-type hypersensitivity to UFHs11,12 or LMWHs10 may tolerate 1 or 2 LMWHs without any side effects, indicating usefulness of extensive skin testing. Twelve of 13 patients were sensitized to danaparoid. Because this heparinoid is a mucopolysaccharide derived from porcine intestinal mucosa, it may share identical allergens with heparin.13 As reported previously, danaparoid may induce similar lesions in patients with delayed-type cutaneous reactions caused by UFHs and LMWHs13,14 and cannot be recommended
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as a substitute. In some patients intravenous heparin may cause a generalized maculopapular rash,15 whereas it is well tolerated by others.16 The results of our studies and other studies indicate that heparinoids, such as pentosanpolysulfate or glycosaminoglycan polysulfate (now withdrawn from the German market), may be an alternative for some groups of patients15,17,18 but not for others.16 Recently, in a patient sensitized to 4 UFHs, danaparoid, pentosanpolysulfate, and 3 LMWHs, no side effects were observed after intravenous therapy with lepirudin.19 Hirudin is a small polypeptide that acts directly on thrombin and does not depend on antithrombin III for its action. Recombinant hirudin has been shown to be safe, effective, and well tolerated when administrated for anticoagulation by intravenous and subcutaneous routes.20 It is used in Germany for the treatment of heparin-induced thrombocytopenia type II. Recombinant hirudin is, however, contraindicated during pregnancy. It also appears to be a therapeutic alternative for patients undergoing hemodialysis who have heparin necrosis.21 Our results indicate that lepirudin appears to be a safe therapeutic alternative in patients with delayedtype hypersensitivity to heparins and heparinoids. An intravenous bolus containing a therapeutic dose of lepirudin was tolerated and produced no side effects in our group of 8 patients. In patient 18, who was sensitized to heparin sodium, heparin calcium, all 6 LMWHs tested, danaparoid, and pentosanpolysulfate, therapy with lepirudin during an 8-day period proved to be effective and well tolerated. However, recombinant hirudin may also induce immediate- and delayed-type hypersensitivity reactions.22,23 Neither patch nor intradermal tests alone are suitable methods for revealing the entire spectrum of heparin hypersensitivity. Subcutaneous provocation, in contrast, is highly reliable and may reveal tolerance to some LMWHs. However, the whole allergy procedure, with a panel of different UFHs, LMWHs, and 3 heparinoids (danaparoid, pentosanpolysulfate, and lepirudin), is very time consuming. Often patients require anticoagulation immediately and cannot wait for the delay of 4 days for the reading of the test results. Because the reaction is not lifethreatening, in these cases the therapy can be changed immediately to lepirudin, and specific symptomatic treatment can be initiated. REFERENCES 1. Klein GF, Kofler H, Wolf H, Frisch PO. Eczema-like, erythematous, infiltrated plaques: a common side effect of subcutaneous heparin therapy. J Am Acad Dermatol 1989;21:703-7. 2. Bircher AJ, Flückinger R, Büchner SA. Eczematous infiltrated plaques to subcutaneous heparin: a type IV allergic reaction. Br J Dermatol 1990;123:507-14.
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3. Koch P, Schäfer H, Bahmer FA. Allergische Hautreaktionen gegen Standard- und niedermolekulare Heparine. Gute Verträglichkeit von Heparin-Analogen. Z Hautkr 1991;66:428-35. 4. Bredlich RO, Stracke S, Gall H, Proebstle TM. Heparinassoziiertes Thrombozyten-Aggregationssyndrom mit Hautnekrosen bei Hämodialyse. Dtsch Med Wochenschr 1997;122:328-32. 5. Odeh M, Oliven A. Urticaria and angioedema induced by lowmolecular-weight heparin. Lancet 1992;340:972-3. 6. Brehler R, Hellweg B. Beurteilung von Epikutantestreaktionen nach Empfehlungen der Deutschen Kontaktallergie-Gruppe. Dt Dermatol 1995;43:688-90. 7. Koch P, Bahmer FA, Schäfer H.Tolerance of intravenous low-molecular-weight heparin after eczematous reaction to subcutaneous heparin. Contact Dermatitis 1991;25:205-6. 8. Smith RE, Townsend GE, Berry BR, Bowen T. Enoxaparin for unstable angina and ancrod for cardiac surgery following heparin allergy. Ann Pharmacother 1996;30:476-80. 9. Hirsch J, Levine MN. Low molecular weight heparin. Blood 1992;79:1-17. 10. Bircher AJ, Itin PH, Tsakiris DA, Surber C. Delayed hypersensitivity to one low-molecular-weight heparin with tolerance of other low-molecular-weight heparins. Br J Dermatol 1995;132: 461-3. 11. De Boer K, Heyboer H, Ten Cate JW, Borm JJJ, Van Ginkel CJW. Low molecular weight heparin treatment in a pregnant woman with allergy to standard heparins and heparinoid. Thromb Haemost 1989;61:148. 12. Gallais V, Bredoux H, Rancourt MF, Dallot A, Salama J, Laroche L. Toxidermie à l’héparine. Presse Med 1996;25:1040. 13. Korstanje MJ, Bessems PJM, Hardy E, Van De Staak WJBM. Delayed-type hypersensitivity to heparin. Contact Dermatitis 1988;20:383-4. 14. Sivakumaran M, Ghosh K, Munks R, Gelsthorpe K, Tan L, Wood JK. Delayed cutaneous reaction to unfractionated heparin, lowmolecular-weight heparin and danaparoid. Br J Haematol 1994;86:893-4.
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15. Koch P, Uhl K, John S. Dermite allergique de contact et exanthème généralisé induit par héparines standard et de bas poids moléculaire: absence de sensibilisation à un héparinoïde. Ann Dermatol Venereol 1997;124(Suppl I):236. 16. Boehncke WH, Weber L, Gall H.Tolerance to intravenous administration of heparin and heparinoid in a patient with delayedtype hypersensitivity to heparins and heparinoids. Contact Dermatitis 1996;35:73-5. 17. Zimmermann J, Harenberg J, Weber E, De Vries X, Jarass W, Schmidt W. Behandlung bei Heparin-induzierter kutaner Reaktion mit einem niedermolekularem Heparin-Analog. Dtsch Med Wochenschr 1984;109:1326-28. 18. Gall H, Leiter U, Peter RU. Spättyp-Allergie auf Heparine bei guter Verträglichkeit von Natriumpentosanpolysulfat. Dermatosen 1998;46:212-5. 19. Erdmann S, Hertl M, Merk HF. Spättypreaktionen auf Heparine und Heparinoïde-Hirudin als therapeutische Alternative: eine Fallbeschreibung. Z Hautkr 1998;73:505-10. 20. Schiele F, Lindgaerde F, Eriksson H, Bassand JP, Wallmark A, Hansson PO, et al. Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective dose-ranging randomized trial. Thromb Haemost 1997;77:834-8. 21. Zimmermann-Schröder J, Castedello Th, Bahmer FA. Heparininduzierte Nekrosen bei dialysepflichtiger Niereninsuffisienz. Z Hautkr 1998;73:272-8. 22. Bircher AJ, Czendliki CH, Langauer Messmer SW, Müller PH, Howald H. Acute urticaria from subcutaneous recombinant hirudin. J Allergy Clin Immunol 1996;98:994-6. 23. Zollner TM, Gall H, Volpel H, Kaufmann R. Type IV allergy to natural hirudin confirmed by in vitro stimulation with recombinant hirudin. Contact Dermatitis 1996;35:59-60.
H
eparin-induced nonnecrotic eczematous skin reactions caused by subcutaneous administration of unfractionated heparins (UFHs) or low-molecular-weight heparins (LMWHs) are due to delayed-type hypersensitivity.1-3 These can be easily distinguished clinically from heparin-
From the Department of Dermatology, University of Saarland. Accepted for publication July 22, 1999. Reprint requests: Patrick Koch, MD, Department of Dermatology, University of Saarland, D-66421 Homburg/Saar, Germany. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/101595 doi:10.1067/mjd.2000.101595
612
Abbreviations used LMWH: Low-molecular-weight heparin UFH: Unfractionated heparin
induced skin necrosis4 and from urticaria with angioedema induced by preservative-free LMWHs.5 Between December 1987 and November 1998, 24 patients who presented themselves or were referred to our dermatology department with painful, erythematous, infiltrated skin lesions at the injection sites of different brands of heparins were tested with the
Koch et al 613
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Table I. Anticoagulants tested at the origin of the lesions in 24 patients
Heparins and heparinoids
Unfractionated heparins Heparin calcium 25,000 IU/mL Heparin sodium 5000 IU/mL Heparin sodium 5000 IU/mL Heparin sodium* 8800 IU/mL LMWHs Nadroparin calcium Dalteparin sodium Enoxaparin sodium Reviparin sodium Certoparin sodium Tinzaparin sodium Heparinoids Danaparoid sodium Glycosaminoglycane polysulfate Pentosanpolysulfate Recombinant heparinoid Lepirudin
Heparins inducing the lesions
Origin
Abbreviation
Preservatives
No. of patients tested
Porcine Porcine Bovine Porcine
U1 U2 U3 U4
— Benzyl alcohol Benzyl alcohol —
24 24 11 10
11 3
Porcine Porcine Porcine Porcine Porcine Porcine
L1 L2 L3 L4 L5 L6
— — — — Chlorocresol Benzyl alcohol
24 24 17 14 9 9
3 3 4
Porcine Bovine Beechwood
D H1 H2
— — —
13 10 20
L
—
8
Yeast
1 1
In 2 patients the heparin at the origin of the lesions could not be determined. In 4 patients both enoxaparin sodium and heparin sodium (unfractionated), nadroparin sodium and heparin calcium (unfractionated), dalteparin sodium and nadroparin sodium, and enoxaparin and heparin calcium (unfractionated) induced the lesions. *Heparin in crystalline form diluted in 0.9% NaCl immediately before testing.
aim of finding safe therapeutic alternatives. Since 1997, we have also investigated tolerance to lepirudin, a new recombinant hirudin in 8 patients.
METHODS Patients During an 11-year period from December 1987 to November 1998, we observed 24 patients treated in our department. The study population consisted of 22 women and 2 men, aged 29 to 76 years (mean age, 60 years). Eleven patients in this group had acute or subacute lesions. Twenty-two patients were referred by departments of surgery, gynecology, hematology, and internal medicine for further allergy evaluation with the aim of finding safe alternatives. All patients had received 5000 to 12,000 U of UFH or LMWH subcutaneously 1 to 3 times a day for the treatment or prevention of thromboembolic disease. All patients with acute lesions had typical erythematous, infiltrated, pruritic, and painful plaques at the subcutaneous heparin injection sites on the abdominal wall and thighs. Some of the plaques exhibited vesiculation or bulla formation (Fig 1). There was no thrombocytopenia. In 2 patients (patients 12 and 14), UFHs were administered intravenously outside our dermatology department (12,500 U of heparin sodium). On the following day, a maculopapular rash
predominantly on the trunk developed in these patients, and they were then referred for allergologic investigation. A 33-year-old woman in the seventh month of pregnancy was referred to our department in November 1998 (patient 24). This patient had deep vein thrombosis in September 1997, which was treated with lysis, intravenous heparin sodium, and coumarin. After pregnancy was confirmed in March 1998, the coumarin therapy was discontinued. In October 1998, dalteparin sodium (5000 U daily) was administered to prevent thromboembolism. Two days after the injection, painful, erythematous, and infiltrated lesions developed at the subcutaneous injection sites on the thighs. A subcutaneous injection of nadroparin sodium (1900 U) induced similar lesions. Safe anticoagulants were then requested from the obstetricians for the ninth month of pregnancy. Histologic examination of biopsy specimens taken from skin lesions Samples of affected skin lesions were taken in 5 patients by a 4-mm punch biopsy performed after achievement of local anesthesia and after informed consent had been given. From all patients, hematoxylin-eosin–stained paraffin sections were obtained.
614 Koch et al
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Fig 1. Bullous lesion at the subcutaneous injection site of heparin-calcium.
Fig 2. Positive intradermal test results to heparin calcium, heparin sodium (unfractionated), and dalteparin sodium after 96 hours.
Table II. Histologic changes of 9 biopsy specimens taken from the sites of positive intradermal and subcutaneous tests in 8 patients with delayed-type hypersensitivity to heparins and heparinoids Test reactions
Subcutaneous test reactions
Intradermal test reactions
Days after injection
Patient
Anticoagulants
Histologic changes
3 4 5 3 3 3 3 2 2
8 16 16 3 5 6 14 15 23
Heparin-calcium Dalteparin sodium Pentosanpolysulfate Nadroparin sodium Heparin calcium Heparin calcium Heparin calcium Reviparin sodium Certoparin sodium
Eczematous Drug reaction Drug reaction Drug reaction Eczematous Eczematous Drug reaction Eczematous Drug reaction
Drug reaction, Perivascular lymphocytic infiltrates with some eosinophils in the superficial and in one patient (dalteparin-sodium, D4) also in the deep dermis, compatible with a drug-induced reaction; Eczematous, eczematous histologic changes.
Allergy studies Patch testing was performed with the standard series of the German Contact Dermatitis Group; preservatives used in different brands of heparins, including the heparin responsible for the lesions; and different brands of undiluted UFHs, LMWHs, and heparinoids made by several manufacturers when available (Table I). Methods recommended by the German Contact Dermatitis Group for this testing were used.6 The test substances of the standard series (Hermal, Reinbek, Germany), as well as the heparins and heparinoids, were applied to the patients’ upper backs for 24 hours by using Leukotest (Beiersdorf, Germany) and fixed with Mefix (Mölnlycke, Hilden, Germany). Readings were taken after 24, 48, and 72 hours. The patch test reaction was considered to be an allergic reaction when a score of +, ++, or +++ was given at 48 and 72 hours or at 72 hours.
Intradermal tests were performed on the flexural side of the forearm with 0.05 mL of similar undiluted brands of UFHs, LWMHs, and heparinoids used for patch testing. Readings were taken after 20 minutes to rule out immediate hypersensitivity and after 24, 48, 72, and 96 hours. The test result was considered positive when an infiltrated eczematous reaction was noted at 24, 48, 72, or 96 hours. This was consistent with delayed-type hypersensitivity. Intradermal tests were performed in 10 volunteers with undiluted preservative-free heparin calcium. This resulted in negative results at 24, 48, and 72 hours, as reported previously.3 Subcutaneous tests were performed on the abdominal wall with 0.1 mL of undiluted brands of UFHs, LMWHs, and heparinoids that had produced negative results in the intradermal test. The tests were read up to 96 hours. A therapeutic dose of glycosaminoglycane polysulfate, pentosanpolysulfate (1
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ampule), and lepirudin (1 mL of a solution of 5 mg/mL) was injected subcutaneously in the abdominal wall or in the thighs when the subcutaneous test result was negative. In 2 patients (patients 13 and 22) anticoagulants were urgently needed, and only subcutaneous tests were performed. The pregnant woman underwent patch testing as described earlier, and then an intradermal, a subcutaneous, and a subcutaneous provocation test were performed only with pentosanpolysulfate to minimize possible side effects. Glycosaminoglycane polysulfate has been withdrawn from the German market and has thus been tested in only 10 patients. Histologic examination of biopsy specimens taken from the sites of positive intradermal and subcutaneous tests to UFHs, LMWHs, and pentosanpolysulfate Nine biopsies were performed in 8 patients by using a 4-mm punch biopsy. From all cases, hematoxylin-eosin–stained paraffin sections were obtained. Results of histologic examination of these specimens is shown in Table II. Intravenous provocation with lepirudin A solution of 5 mg/mL was prepared according to the manufacturer’s instructions. A therapeutic bolus containing 0.4 mg/kg of lepirudin was then injected intravenously over a 2-minute period. The patient was subsequently observed for 24 hours in our dermatology department.
RESULTS Histologic examination of biopsy specimens of lesions The spectrum of histopathologic changes could be subdivided into 2 main patterns. The first pattern consists of changes with features of allergic contact dermatitis with spongiosis of the epidermis and lymphohistiocytic infiltrates with some eosinophils around the dilated vessels of the dermis (3 patients). The second pattern is changes compatible with a drug reaction, such as perivascular lymphohistiocytic infiltrates with eosinophils in the superficial dermis (2 patients). Sensitization to heparins and heparinoids Delayed-type hypersensitivity reactions to both UFH and LMWH were observed in 23 patients tested. Results are shown in Table III. In our study population 19 of 23 patients were sensitized to all types of UFH and LMWH tested. In addition, 5 patients were sensitized to pentosanpolysulfate. Sensitization to danaparoid was observed in 12
Koch et al 615
of the 13 patients tested. In 5 patients the intradermal test produced positive results only after 96 hours (Fig 2). An LMWH was considered as a possible therapeutic alternative in only 4 patients: dalteparin sodium in patient 9; certoparin, dalteparin, reviparin, and tinzaparin sodium and danaparoid in patient 17; tinzaparin sodium in patient 21; and dalteparin, reviparin, and tinzaparin sodium in patient 22. However, no consecutive therapy was carried out with these anticoagulants because it was not necessary at this time. Patch and intradermal tests were performed before subcutaneous tests in 21 patients. Sensitization to heparin was detected by these methods in 9 of 21 and 17 of 21 patients, respectively. The entire spectrum of sensitization to heparin and heparinoids was detected only by the subcutaneous tests. As shown in Table III, subcutaneous tests were also performed in patients in whom the intradermal test results to some UFHs and LMWHs were positive. This indicates that intradermal tests produced false-negative results to one or more heparins in 9 of 21 patients. The pregnant woman (patient 24) was sensitized to all the LMWHs but not to the UFHs. However, only patch tests were performed. The subcutaneous provocation test with pentosanpolysulfate was tolerated without any side effects. Intravenous provocation with lepirudin No side effects were observed in any of the 8 patients tested (Table III). Further anticoagulation Nine patients currently required anticoagulation for the prevention of thromboembolism or in conjunction with surgery (Table III). Subcutaneous glycosaminoglycan polysulfate and pentosanpolysulfate proved to be safe therapeutic alternatives in 2 and 3 patients, respectively. Two weeks after the initiation of treatment with pentosanpolysulfate (50 mg twice daily), however, erythematous lesions at the subcutaneous injection sites developed in patient 12. Patient 13 received coumarin. Four patients urgently required surgery. As reported previously,7 intravenous anticoagulation during coronary bypass surgery could be achieved in patient 9 with intravenous dalteparin sodium. Subcutaneous test results were negative with this LMWH; in addition, methylprednisolone and clemastine hydrogen fumarate were administered as anaphylactoid prophylaxis. It was possible to perform coronary bypass surgery in patients 2 and 8 with ancrod.8 Lepirudin was administrated intravenously twice daily for 8 days after an osteosynthesis procedure in patient 18 without any side effects.
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Table III. Results of allergy evaluation and therapy with alternative anticoagulants in 24 patients with local reactions at the subcutaneous heparin injection sites Patient No.
Sex
Age (y)
1
F
66
2
F
76
3
F
37
4
F
47
5
F
73
6
F
76
7
F
49
8
M
72
9
F
67
10
F
29
11
F
69
12
F
45
13
F
56
14
F
62
Heparins/ Heparinoids tested
Patch
Intradermal
Subcutaneous
U1→U4 L1, L2 H1 U1→U4
– – – –
+ + – –
ND ND – +
L1, L2 H1 U1→U4 L1, L2 H1 U1→U4 L1, L2 H1, H2 U1→U4 L1, L2 H1, H2 U1→U4 L1→L3 H1, H2 U1→U4 L1→L3 H1, H2 U1, U3, O L1→L3 H1, H2 U1→U4, O
– – – – – – – – – + – + + – – – – – – – –
– – + + – – – – + + – + + – + + – + + – –
+ – + + – + + – ND ND – ND ND – ND ND – ND + – +
– – – + – + – – – + – – ND ND ND ND – – – –
– – + + – – – – + + + – ND ND ND ND + + + –
L1+, L2– – + + – + + – ND ND ND – + + + – ND + ND –
L1, L2 H1 U1→U4 L1, L2 H1, H2 U1→U3 L1→L4 H2 U1→U4 L1→L4 D H2 U1, U2 L1→L4 D H2 U1, U2 L1→L4 D H2
Therapy after the allergy investigations
(1) Coronary surgery with ancrod; (2) H1 subcutaneous
Coronary surgery with ancrod
(1) Coronary surgery with dalteparin; (2) H1 subcutaneous
H2 subcutaneous*
Coumarin
H2 subcutaneous
D, Danaparoid; H1, glycosaminoglycan polysulfate; H2, pentosanpolysulfate; L, lepirudin; L1, nadroparin calcium; L2, dalteparin sodium; L3, enoxaparin sodium; L4, reviparin sodium; L5, certoparin sodium; L6, tinzaparin sodium; O, other heparins tested; U1, heparin calcium 25,000 IU/mL; U2, porcine heparin sodium 5000 IU/mL; U3, bovine heparin sodium 5000 IU/mL; U4, heparin sodium 8800 IU/mL. *Erythematous lesions at the subcutaneous injection sites 2 weeks after the initiation of treatment.
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Table III. Cont’d Patient No.
Sex
Age (y)
15
F
75
16
M
56
17
F
58
18
F
69
19
F
72
20
F
59
21
F
59
22
F
71
23
F
60
24
F
33
Heparins/ Heparinoids tested
Patch
Intradermal
Subcutaneous
U1, U2 L1→L6 D H2 U1, U2 L1→L4 D H2 L U1, U2, O L1→L6 D H2 L U1, U2 L1→L6 D H2 L U1, U2 L1→L6 D H2 L U1, U2 L1→L6 D H2 L U1, U2 L1→L6 D H2 L U1, U2 L1→L6 D H2 L U1, U2 L1→L6 D H2 L U1, U2 L1→L6 D H2
– – – – – + – – – – – – – – + + + – – – – – – – + + + – – – – – – – ND ND ND ND ND – + – – – – + + –
+ + + – + + + – – + L1, L3+ – + – + + + + – + + + – – + + + + – + + – – – ND ND ND ND ND + + + – – ND ND ND –
+ + ND – + + ND + – + L2, L4→L6– – + – ND ND ND + – ND ND ND – – ND ND ND + – ND L1→L5+, L6– + + – + L1, L3, L5+ + – – ND + ND – – ND ND ND –
Therapy after the allergy investigations
H2 subcutaneous
Lepirudin intravenous twice daily
H2 subcutaneous
618 Koch et al
Histologic examination of biopsy specimens from patients with positive test reactions The patients’ lesions and the test reactions showed the following histologically similar changes: (1) an eczematous reaction that was more pronounced in the intradermal and subcutaneous tests than in the patients’ lesions and (2) perivascular lymphocytic infiltrates with some eosinophils in the superficial, and in some cases also in the deep, dermis, which were compatible with a drug-induced reaction (Table II).
DISCUSSION Erythematous, infiltrated, and painful plaques overlying sites of subcutaneous heparin injection represent a distinctive reaction and are probably a more common side effect than is generally realized. The clinical appearance in the cases previously described1,2 is almost identical and closely resembles that in our patients. Skin biopsy specimens of the lesions and of the test reactions reveal typically eczematous changes in some patients; these are compatible with delayed-type hypersensitivity, as has been reported by other investigators.1,2 The histologic and allergy evaluation in our study population indicates that the delayed-type hypersensitivity is probably caused by or associated with the heparin molecule itself. Most of the heparins tested were free of preservatives. Heparins are complex mixtures of mucopolysaccharides produced from porcine or bovine intestine and lungs. Molecular weight discriminates UFHs (10-20 kd) from LMWHs (4-6 kd).9 Heparin, a negatively charged mucopolysaccharide hapten, binds strongly to proteins, resulting in a complete antigen.10 However, the heparin fractions that induce the sensitization have not been determined. In our study population 19 of 23 patients were sensitized to all the UFHs and LMWHs tested, including preparations recently put on the market in Germany, indicating cross-reactivity of the different preparations. Because of the structural similarities of the UFHs and the LMWHs, all available heparin preparations may thus elicit positive reactions. However, as reported in this study and in studies by other authors, some patients with delayed-type hypersensitivity to UFHs11,12 or LMWHs10 may tolerate 1 or 2 LMWHs without any side effects, indicating usefulness of extensive skin testing. Twelve of 13 patients were sensitized to danaparoid. Because this heparinoid is a mucopolysaccharide derived from porcine intestinal mucosa, it may share identical allergens with heparin.13 As reported previously, danaparoid may induce similar lesions in patients with delayed-type cutaneous reactions caused by UFHs and LMWHs13,14 and cannot be recommended
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as a substitute. In some patients intravenous heparin may cause a generalized maculopapular rash,15 whereas it is well tolerated by others.16 The results of our studies and other studies indicate that heparinoids, such as pentosanpolysulfate or glycosaminoglycan polysulfate (now withdrawn from the German market), may be an alternative for some groups of patients15,17,18 but not for others.16 Recently, in a patient sensitized to 4 UFHs, danaparoid, pentosanpolysulfate, and 3 LMWHs, no side effects were observed after intravenous therapy with lepirudin.19 Hirudin is a small polypeptide that acts directly on thrombin and does not depend on antithrombin III for its action. Recombinant hirudin has been shown to be safe, effective, and well tolerated when administrated for anticoagulation by intravenous and subcutaneous routes.20 It is used in Germany for the treatment of heparin-induced thrombocytopenia type II. Recombinant hirudin is, however, contraindicated during pregnancy. It also appears to be a therapeutic alternative for patients undergoing hemodialysis who have heparin necrosis.21 Our results indicate that lepirudin appears to be a safe therapeutic alternative in patients with delayedtype hypersensitivity to heparins and heparinoids. An intravenous bolus containing a therapeutic dose of lepirudin was tolerated and produced no side effects in our group of 8 patients. In patient 18, who was sensitized to heparin sodium, heparin calcium, all 6 LMWHs tested, danaparoid, and pentosanpolysulfate, therapy with lepirudin during an 8-day period proved to be effective and well tolerated. However, recombinant hirudin may also induce immediate- and delayed-type hypersensitivity reactions.22,23 Neither patch nor intradermal tests alone are suitable methods for revealing the entire spectrum of heparin hypersensitivity. Subcutaneous provocation, in contrast, is highly reliable and may reveal tolerance to some LMWHs. However, the whole allergy procedure, with a panel of different UFHs, LMWHs, and 3 heparinoids (danaparoid, pentosanpolysulfate, and lepirudin), is very time consuming. Often patients require anticoagulation immediately and cannot wait for the delay of 4 days for the reading of the test results. Because the reaction is not lifethreatening, in these cases the therapy can be changed immediately to lepirudin, and specific symptomatic treatment can be initiated. REFERENCES 1. Klein GF, Kofler H, Wolf H, Frisch PO. Eczema-like, erythematous, infiltrated plaques: a common side effect of subcutaneous heparin therapy. J Am Acad Dermatol 1989;21:703-7. 2. Bircher AJ, Flückinger R, Büchner SA. Eczematous infiltrated plaques to subcutaneous heparin: a type IV allergic reaction. Br J Dermatol 1990;123:507-14.
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3. Koch P, Schäfer H, Bahmer FA. Allergische Hautreaktionen gegen Standard- und niedermolekulare Heparine. Gute Verträglichkeit von Heparin-Analogen. Z Hautkr 1991;66:428-35. 4. Bredlich RO, Stracke S, Gall H, Proebstle TM. Heparinassoziiertes Thrombozyten-Aggregationssyndrom mit Hautnekrosen bei Hämodialyse. Dtsch Med Wochenschr 1997;122:328-32. 5. Odeh M, Oliven A. Urticaria and angioedema induced by lowmolecular-weight heparin. Lancet 1992;340:972-3. 6. Brehler R, Hellweg B. Beurteilung von Epikutantestreaktionen nach Empfehlungen der Deutschen Kontaktallergie-Gruppe. Dt Dermatol 1995;43:688-90. 7. Koch P, Bahmer FA, Schäfer H.Tolerance of intravenous low-molecular-weight heparin after eczematous reaction to subcutaneous heparin. Contact Dermatitis 1991;25:205-6. 8. Smith RE, Townsend GE, Berry BR, Bowen T. Enoxaparin for unstable angina and ancrod for cardiac surgery following heparin allergy. Ann Pharmacother 1996;30:476-80. 9. Hirsch J, Levine MN. Low molecular weight heparin. Blood 1992;79:1-17. 10. Bircher AJ, Itin PH, Tsakiris DA, Surber C. Delayed hypersensitivity to one low-molecular-weight heparin with tolerance of other low-molecular-weight heparins. Br J Dermatol 1995;132: 461-3. 11. De Boer K, Heyboer H, Ten Cate JW, Borm JJJ, Van Ginkel CJW. Low molecular weight heparin treatment in a pregnant woman with allergy to standard heparins and heparinoid. Thromb Haemost 1989;61:148. 12. Gallais V, Bredoux H, Rancourt MF, Dallot A, Salama J, Laroche L. Toxidermie à l’héparine. Presse Med 1996;25:1040. 13. Korstanje MJ, Bessems PJM, Hardy E, Van De Staak WJBM. Delayed-type hypersensitivity to heparin. Contact Dermatitis 1988;20:383-4. 14. Sivakumaran M, Ghosh K, Munks R, Gelsthorpe K, Tan L, Wood JK. Delayed cutaneous reaction to unfractionated heparin, lowmolecular-weight heparin and danaparoid. Br J Haematol 1994;86:893-4.
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15. Koch P, Uhl K, John S. Dermite allergique de contact et exanthème généralisé induit par héparines standard et de bas poids moléculaire: absence de sensibilisation à un héparinoïde. Ann Dermatol Venereol 1997;124(Suppl I):236. 16. Boehncke WH, Weber L, Gall H.Tolerance to intravenous administration of heparin and heparinoid in a patient with delayedtype hypersensitivity to heparins and heparinoids. Contact Dermatitis 1996;35:73-5. 17. Zimmermann J, Harenberg J, Weber E, De Vries X, Jarass W, Schmidt W. Behandlung bei Heparin-induzierter kutaner Reaktion mit einem niedermolekularem Heparin-Analog. Dtsch Med Wochenschr 1984;109:1326-28. 18. Gall H, Leiter U, Peter RU. Spättyp-Allergie auf Heparine bei guter Verträglichkeit von Natriumpentosanpolysulfat. Dermatosen 1998;46:212-5. 19. Erdmann S, Hertl M, Merk HF. Spättypreaktionen auf Heparine und Heparinoïde-Hirudin als therapeutische Alternative: eine Fallbeschreibung. Z Hautkr 1998;73:505-10. 20. Schiele F, Lindgaerde F, Eriksson H, Bassand JP, Wallmark A, Hansson PO, et al. Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective dose-ranging randomized trial. Thromb Haemost 1997;77:834-8. 21. Zimmermann-Schröder J, Castedello Th, Bahmer FA. Heparininduzierte Nekrosen bei dialysepflichtiger Niereninsuffisienz. Z Hautkr 1998;73:272-8. 22. Bircher AJ, Czendliki CH, Langauer Messmer SW, Müller PH, Howald H. Acute urticaria from subcutaneous recombinant hirudin. J Allergy Clin Immunol 1996;98:994-6. 23. Zollner TM, Gall H, Volpel H, Kaufmann R. Type IV allergy to natural hirudin confirmed by in vitro stimulation with recombinant hirudin. Contact Dermatitis 1996;35:59-60.