Alergol Inmunol Clin 2001; 16: 294-296

Alergol Inmunol Clin 2001; 16: 294-296
J. M. Vega,
T. Caro-Patón*,
P. Sánchez,
M. E. Sanchís,
C Martínez,
R. de la Fuente,
A. Armentia,
A. Fernández
Allergy Section and
*Pharmacy Service. "Río
Hortega" University Hospital.
Valladolid (Spain).
Correspondence address:
Dr. J. M. Vega
Sección de Alergia
Hospital Río Hortega
Cardenal Torquemada, s/n
E-47010 Valladolid, Spain
294
Case report
Delayed hypersensitivity reaction
to enoxaparin with sensitisation
to other low-molecular weight and
unfractionated heparins:
tolerance to a recombinant hirudin
The administration of unfractionated heparin (UFH) or of low-molecular weight
heparins (LMWH) may induce a non-necrotic eczematous reaction at the site of
injection that is mediated by a delayed hypersensitivity mechanism. We describe
the case of a 38-year-old woman who, after two episodes of abdominal skin
rash in relation to the administration of enoxaparin, had a negative subcutaneous
challenge test with desirudin, a new recombinant hirudin. In patients evidencing
heparin hypersensitivity, and particularly in those with hypersensitivity
to multiple UFH and LMWH preparations and who require urgent anticoagulation,
recombinant hirudins may represent a safe alternative until allergological
studies can be performed.
Key words: Heparin. Low-molecular weight heparin. Recombinant hirudin.
Allergic reaction.
Reacción de hipersensibilidad retardada
por enoxaparina con sensibilización
a otras heparinas de bajo peso molecular
y no fraccionadas: tolerancia de una
hirudina recombinante
La administración de heparinas no fraccionadas (HNF) o de heparinas de bajo
peso molecular (HBPM) puede ocasionar una reacción eccematosa no necrótica
en el lugar de la inyección, mediada por un mecanismo de hipersensibilidad retardada.
Se describe el caso de una mujer de 38 años que, tras sufrir dos episodios
de erupción cutánea abdominal relacionados con la administración de enoxaparina,
presentó una prueba de provocación cutánea negativa con desirudina,
una nueva hirudina recombinante. En aquellos pacientes que presentan sensibilización
a heparinas, sobre todo cuando es múltiple a HNF y HBPM, en caso de
precisar anticoagulación urgente y a la espera de las pruebas alérgicas las hirudinas
recombinantes pueden constituir una alternativa segura.
Palabras clave: Heparina. Heparina de bajo peso molecular. Hirudina recombinante.
Reacción alérgica.

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.