Download Anticoagulant-related skin reactions

Review
General
Anticoagulant-related skin
reactions
I Jörg, T Fenyvesi & J Harenberg
1. Introduction
2. Coumarin-induced skin necrosis
3. Heparin-induced skin reactions
4. Hirudin-induced skin reactions
5. Decision rules and perspectives
6. Conclusions
7. Expert opinion
Department of Medicine IV, University Hospital, Faculty of Clinical Medicine Mannheim of the
Ruprecht-Karls-University of Heidelberg, Germany
Cutaneous reactions have been reported during anticoagulant therapy with
coumarin derivatives, unfractionated and low molecular weight heparins,
heparinoids, danaparoid and hirudins. Anticoagulant-induced skin reactions
vary from local allergic manifestations to skin necrosis. In patients with allergic reactions, diagnosis and crossreactions between anticoagulants can be
confirmed by intracutaneous testing. Coumarin- and heparin-induced skin
necrosis are rare, but are important side effects due to their high morbidity
and occasional mortality. Cutaneous tests are contraindicated in these
patients. In the future, anticoagulant strategies may include direct synthetic
thrombin inhibitors (argatroban and melagatran/ximelagatran) and the Factor Xa inhibitor, pentasaccharide (fondaparinux).
Keywords: coumarin, fondaparinux, heparin, hirudin, skin reactions, ximelagatran
Expert Opin. Drug Saf. (2002) 1(3):
1.
Introduction
It is believed that the first description of an anticoagulant-induced skin necrosis was
in 1943, however, the breast necrosis in the 49-year-old woman was, at the time,
attributed to thrombophlebitis migrans disseminate [1]. From the 1950s onwards,
skin necrosis has been associated with oral anticoagulation [2] and, until June 2002,
approximately 400 cases have been reported worldwide, according to Medline-based
research. Heparin-induced skin lesions have been published, although less have been
published for low molecular weight heparin (LMW-heparin), with approximately
100 cases in total [3].
Skin lesions induced by anticoagulants can appear as allergic or necrotic reactions. Local allergic skin reactions often show painful red plaques appearing 2 – 3
days after starting anticoagulant therapy. Immunological reactions start after 7 or
more days [3]. Heparin-induced skin necrosis can occur at the injection site as
well as at any other site of the skin after subcutaneous or intravenous administration, and has been frequently reported in association with heparin-induced
thrombocytopenia (HIT) [3-5].
2.
Coumarin-induced skin necrosis
Coumarin-induced skin necrosis is a rare complication of oral anticoagulation with
a prevalence reported to be between 0.01 and 0.1% of patients [6].
2.1 Aetiology
Ashley Publications
www.ashley-pub.com
The exact aetiology of coumarin-induced skin necrosis is still unknown, but is often
associated with a hypercoagulable state. Protein C or protein S deficiencies have
been reported in patients with coumarin-induced skin necrosis as well as in those
with Factor V Leiden, mutation of the prothrombin gene, lupus anticoagulants and
antiphospholipid syndrome [7-9].
2002 © Ashley Publications Ltd ISSN 1474-0338
1
Anticoagulant-related skin reactions
Protein C deficiency is widely accepted as a major risk factor
for coumarin-induced skin necrosis. Rose et al. examined protein C level antigens in blood samples of 13 patients with a previous warfarin-induced skin necrosis and in 11 patients, a low
protein C level was found, showing the implication of low antigen levels of protein C in the pathogenesis of warfarin necrosis.
After introducing coumarin therapy, vitamin K-dependent
protein C and Factor VII levels drop rapidly, compared with
other factors such as Factor IX and X and prothrombin, leading to a procoagulant/anticoagulant imbalance. The depression of protein C, together with a low blood velocity, leads to
necrosis, particularly in the microvascular system. A similar
mechanism may induce local necrosis in protein S deficiency,
resistance against activated protein C (APC resistance) and
lupus anticoagulants [8].
The transient hypercoagulability leads to local thrombotic
occlusions in the small vessels followed by necrosis. During
steady-state of the vitamin K antagonists, hypercoagulability
leads to haemorrhage in the necrotic area [8].
Microscopic pictures of the necrotic areas show pathological changes in microcirculation-rich areas with thrombosis,
microvascular injury and fibrin deposits in the postcapillary
veins and small vessels, haemorrhage and diffuse necrosis in
the dermis and subcutaneous adipose tissue [8-10].
2.2 Symptoms
Most patients (i.e., more than two thirds) are obese, middleaged women, often treated with coumarin derivatives for a
thromboembolic disease. Predilection sites of the lesions are
areas with increased subcutaneous fatty tissue, e.g., breast,
thigh, abdomen and buttock (Figure 1).
Symptoms start within 10 days after the onset of therapy
with pain, oedema and small subcutaneous haematoma, followed by erythematous or haemorrhagic changes in demarcated lesions, that become bullous and can progress to
gangrenous necrosis [11,12]. Symptoms are often associated
with a large initial loading dose of coumarin derivatives.
Delayed onsets have also been reported between day 15 up to
15 years [5] and may reoccur 1 month after discontinuing warfarin without reintroducing therapy [13].
Reports of coumarin-induced skin necrosis are mainly
attributed to warfarin but are also seen with other coumarin
derivatives [14].
Regression of skin necrosis has been described using a protein
C concentrate in patients with protein C deficiency [14].
Successful reintroductions of oral anticoagulation have
been reported [6,15]. To minimise the risk of recurrent skin
necrosis, oral anticoagulation therapy with warfarin was
started at 1 mg/day with a very slow increase in the dose [6].
2.4 Other coumarin-induced cutaneous
reactions
Allergic dermatitis is another complication of coumarin therapy with various clinical manifestations. It appears as urticaria, maculopapular erythematous rash or vesicular rash
between 2 – 3 days or up to months after treatment. The skin
reactions usually disappear when coumarin therapy is discontinued, especially in the case of allergic dermatitis where differential diagnosis of the sensitising agent may be important.
A further unusual complication can be a hypersensitivity
reaction such as vasculitis, which in severe cases can mimic a
skin necrosis [16,17]. In contrast to coumarin-induced skin
necrosis, vasculitis may appear at any time and is accompanied by pathological laboratory values and an inflammatory
infiltrate at histological examination.
Another adverse reaction is the purple toe syndrome, which
was described in 1976 as an acute digital cyanosis secondary
to microembolism from a proximal atheromatous source [18].
An association with anticoagulant therapy was already established in 1961 [19] and the symptoms were attributed to cholesterol emboli released as a result of coumarin-induced
bleeding into atheromatous plaques [19]. Characteristic findings include the sudden development of blue or purple areas
on the sides of feet and toes which are painful and tender to
touch, and usually occur 3 – 8 weeks after introducing coumarin therapy. The lesions are often bilateral and persist for
several weeks [20].
2.5 Prophylactic measures
Anticoagulation should be started with heparin or LMWheparin, while oral anticoagulation with coumarin derivatives should be introduced with small or moderate doses
[21]. Loading doses should be avoided. Heparin/LMWheparin therapy should be maintained until INR > 2 (international normalised ration of the prothrombin time) are
obtained twice on two consecutive days [22].
3.
Heparin-induced skin reactions
2.3 Treatment
As soon as skin reactions appear in a patient treated with
coumarin derivatives, the oral anticoagulant has to be discontinued. Anticoagulant therapy should be continued
with heparin or LMW-heparins until the necrotic lesion
heals [9]. Even though heparin itself can cause a skin necrosis, there are no reports in the literature that heparininduced skin necrosis followed a coumarin-induced skin
necrosis or vice versa.
Small lesions may be treated conservatively, but progression
of the necrotic changes may require surgical intervention.
2
Allergic skin reactions or skin necrosis to heparin and LMWheparin are rare but the incidence is probably underestimated
due to under-reporting [3,23].
3.1 Aetiology and pathogenesis
The aetiology of heparin-induced skin necrosis is unknown but
the occurrence is often associated with HIT (HIT Type II). HIT
Type II is an immunological reaction leading to the binding of
heparin to platelet factor-4 (PF-4), which induces the production of heparin-dependent IgG, IgM and IgA antibodies [3,4].
Expert Opin. Drug Saf. (2002) 1(3)
Jörg, Fenyvesi & Harenberg
heparin [25,26]. The necrosis starts with a small, erythematous
and painful lesion that later extends to areas of necrosis [24].
Histological findings show microvascular thrombi in small
vessels with minimal inflammation [27].
When skin reactions appear, intracutaneous testing should
be performed to confirm diagnosis and to rule out crossreactions between different LMW-heparins and danaparoid.
Importantly, crossreactions between heparin and LMWheparins are observed in 50 and 100% and with danaparoid
in up to 65% of patients [4]. Koch et al. examined 23 patients
with delayed hypersensitivity reactions after subcutaneous
heparin injections and found 19 patients who were sensitised
to all the heparins and LMW-heparins tested [28].
3.3 Treatment
Figure 1. Bruising and skin necrosis on the torso of a patient
receiving warfarin therapy. Taken with permission from [11].
Figure 2. Allergic skin reaction to subcutaneous heparin
administered in the subcutaneous tissue of the abdominal
wall. Taken with permission from [23].
When local cutaneous allergic reactions to heparin appear,
therapy can be continued until the results of cutaneous testing
are available. The therapy should then be changed according
to the test results (Figure 4).
Discontinuation of medication is mandatory if systemic
allergic reactions have occurred [3]. Switches from subcutaneous to intravenous administration of heparin have been
described but this, in turn, can cause generalised reactions [29].
Anticoagulant therapy should be changed to hirudin and/or
coumarins and cutaneous testing should be performed.
Depending on the results of the test, anticoagulant therapy
may be continued or should be changed. In the future, argatroban, melagatran or fomdaparinux may be adopted.
Heparin PF-4 antibodies should be determined and a thrombophilic screening performed. Prophylactic, low doses of the
alternative anticoagulant are recommended for patients without
thrombophilic tendency and who test negative for heparin PF-4
antibodies. Therapeutic high doses are recommended for
patients who test positive for heparin PF-4 antibodies [3,4].
3.4 Other
Elevated IgG antibody titres were also observed in patients
with heparin-induced skin lesions irrespective of whether
they developed thrombocytopenia, suggesting an immunological mechanism in these patients [3]. A high association
between heparin-induced cutaneous lesions with positive
testing for LMW-heparin and danaparoid in intracutaneous
tests, circulating antiheparin IgG antibodies and HIT Type II
has been described [4].
3.2 Clinical
picture
There is a broad spectrum of cutaneous reactions from erythematous pruritic areas to large symptomatic plaques
(Figure 2) to heparin-induced skin necrosis (Figure 3). Women
are more affected than men [23].
Heparin-induced skin necrosis starts between day 5 and
10 after introduction of intravenous or subcutaneous
administration. Late onsets, i.e., up to day 16, have been
reported [24]. Skin necrosis occurs more often in patients
treated with unfractionated heparin than with LMW-
heparin-induced skin reactions
Skin lesions may appear at the injection site but can also be
generalised. Immediate as well as delayed hypersensitivity
reactions may occur [5]. Skin reactions have been reported as
urticarial rash or as a Type I immediate hypersensitivity reaction and usually appear 2 – 5 days after the start of treatment.
They can also occur as Type III Arthus reaction with vasculitis. Delayed hypersensitivity reactions may be present with
localised skin reactions [30] or with a generalised maculopapular rash [31], within days 3 and 14 of therapy [30].
3.5 Differential
diagnosis
Local allergic reactions to sprays or other ingredients of
subcutaneous heparin formulations have also been
described [32].
4.
Hirudin-induced skin reactions
Hirudin is an enzyme produced by the salivary glands of the
leech Hirudo medicinalis and acts as a specific direct
Expert Opin. Drug Saf. (2002) 1(3)
3
Anticoagulant-related skin reactions
4.2 Symptoms
LMWH 1
LMWH 3
LMWH 2
LMWH 4
Figure 3. Heparin-induced skin necrosis on abdomen and
thighs using four LMW-heparin preparations of different
origins. Taken with permission from [23].
LMWH: Low molecular weight heparin.
Allergic reactions after hirudin exposure appear as urticaria
after systemic administration [34] or as contact allergy following topical use [35].
Re-exposure to hirudins was investigated in healthy subjects. Out of 200 volunteers, only 3 experienced an allergic
reaction after the second course of subcutaneous r-hirudins.
Thus, the conclusion was that Type I allergic reactions to
r-hirudin are rare (< 1%) after a second exposure and limited
to the skin [36].
In a case report, an allergic reaction to r-hirudin was
described in a patient with a history of HIT [37]. Twenty mins
after subcutaneous injection of r-hirudin, the patient developed pruritus, erythema and a generalised flush reaction.
After therapy with cortisone and histamine antagonists, the
symptoms disappeared. Under treatment with pegylated-hirudin 50 mg s.c. o.d., no side effects occurred.
Another report in the literature described a patient with a
history of HIT Type II. During bolus injection of hirudin,
extravasation in the surrounding tissue occurred. Infusion was
restarted at a different site for 10 days. After 4 weeks, the
patient developed skin reactions with erythema and induration at the site of extravasation. Histopathological findings
showed an epitheloid granulomatous infiltrate. The findings
and delayed onset were consistent with a delayed hypersensitivity reaction to hirudin [38].
Jappe et al. reported the occurrence of a local Arthus reaction after subcutaneous application of r-hirudin in a female
patient with delayed-type hypersensitivity to several heparins
and heparinoids. The patient was then challenged with intravenous heparins and heparinoids for 3 days and tolerated this
treatment well [39].
4.3 Treatment
If skin reactions to r-hirudin appear, treatment may be continued with argatroban, melagatran or pentasaccharide. Subcutaneous or intravenous administration of heparin/LMW-heparin,
danaparoid or dermatansulfate may also be an alternative if the
patient had no adverse events or positive cutaneous testing.
Figure 4. Positive intracutanous tests to unfractionated
heparins, LMW-heparins, and danaparoid (orgaran). Taken
with permission from [23].
thrombin inhibitor. Today, recombinant DNA technology is
used for production. Pegylated-hirudin was developed to
increase the half-life of r-hirudin [33] and to reduce the antigenicity of hirudin.
4.1 Aetiology
The polypeptidic nature of hirudins can cause an immunogenic reaction in some individuals. IgG and IgE antibodies
against r-hirudin develop in 40 – 70% of patients with hirudin-induced skin reactions. Immediate as well as delayed
hypersensitivity reactions have also been reported.
4
5.
Decision rules and perspectives
Skin reactions are rare adverse effects of anticoagulant therapy
and can occur with treatment with coumarin-derivatives,
heparins, LMW-heparins, danaparoid and hirudins. Coumarin- and heparin-induced skin necrosis are serious complications and are associated with a high morbidity and
occasional mortality [40,41]. Patients with coumarin-induced
skin reactions can continue anticoagulant therapy safely and
effectively by switching to heparin treatment. Rules for deciding an alternative therapy when cutaneous allergic and
necrotic reactions occur are summarised in Figures 5 and 6.
In cases of heparin-induced skin reactions, intracutaneous testing should be performed before switching to
another LMW-heparin or danaparoid sodium to rule out
Expert Opin. Drug Saf. (2002) 1(3)
Jörg, Fenyvesi & Harenberg
Anticoagulant-induced allergic skin reactions
Local
Systemic
Continue therapy
Stop medication
Cutaneous testing
Heparins/hirudin
Coumarins
Change to
Change to
heparins
hirudins..
heparins..
Change to therapy
according to test result
..or Factor Xa or
thrombin inhibitor
Cutaneous testing
Continue/change
according test result
Coumarin if indicated
Figure 5. Decision rules for treatment of anticoagulant-induced allergic reactions.
Expert Opin. Drug Saf. (2002) 1(3)
5
Anticoagulant-related skin reactions
Anticoagulant skin necrosis
Heparin-induced
Coumarin-induced
Stop of anticoagulant medication
Heparin PF4 antibodies
+ thrombophilic screening
Protein C level
< 10%
> 20%
Protein C
concentrate
Positive
High dose
Low dose
Factor Xa- or thrombin inhibitor
and, if indicated, coumarin
Heparins, thrombin inhibitor
or Factor Xa inhibitor
Figure 6. Decision rules for treatment of anticoagulant-induced skin necrosis.
6
Negative
Expert Opin. Drug Saf. (2002) 1(3)
Jörg, Fenyvesi & Harenberg
crossreactions. If positive cutaneous testing is found for all
tested agents, anticoagulant therapy with hirudin should
be offered as an alternative ( Figures 5 and 6). In the future,
pentasaccharides or oral thrombin inhibitors may be the
alternatives.
6. Conclusions
The aim of this article was to briefly review the most relevant issues of anticoagulant-related skin reactions and the
management for diagnosis and further anticoagulation. A
local manifestation of allergic skin reactions should not
immediately lead to therapeutic changes of anticoagulant
therapy. In these patients, cutaneous testing is advisable due
to crossreactions between coumarins and heparins/LMWheparins/danaparoid.
If systemic allergic reactions occur, then alternative anticoagulant therapies should be used although cutaneous testing
is still advised. In contrast, if coumarin- and heparininduced skin necrosis should occur, then there should be an
immediate termination of the anticoagulant, and treatment
should be changed to therapeutic doses of an alternative
anticoagulant (Figure 6). Cutaneous testing is contraindicated in these patients.
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Website
101. http://dx.doi.org/10.1046/j.1365-
2168.2000.01352.x.
Affiliation
I Jörg MD, T Fenyvesi MD & J Harenberg MD†
†Author for correspondence
Department of Medicine IV, University Hospital
Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167
Mannheim, Germany
Tel: +49 621 383 3378; Fax: +49 621 383 3808;
E-mail: [email protected]