Cutaneous adverse events associated with heparin

Authors


  • Conflict of interest: none declared.

Dr Paola Maldonado Cid, Department of Dermatology, Hospital Universitario La Paz, P° de la Castellana 261, 28046 Madrid, Spain
E-mail: pmaldonadocid@gmail.com

Summary

Heparin use is associated with various cutaneous reactions, with the most common being immune-mediated skin lesions and bleeding complications. In this review, we compile the dermatological side-effects of heparin reported in the literature, and provide a clear approach to their adequate management.

Heparin use and mechanism of action

Heparin (and its analogues) and warfarin are the traditional anticoagulants used for the prevention and treatment of thromboembolic disease. Table 1 shows a simplified classification of anticoagulants.

Table 1.   Classification of most commonly used anticoagulants.
  1. *Clexane® (Sanofi-Aventis, Paris, France); †Hibor® (Laboratorios Farmaceuticos ROVI SA, Madrid, Spain); ‡XARELTO (Bayer Healthcare AG, Leverkusen, Germany; §Sintrom® (Novartis Farmacéutica, Barcelena, Spain).

Unfractionated heparinsHeparin calcium
Heparin sodium
Low-molecular weight heparinsEnoxaparin sodium*
Bemiparin sodium†
Danaparinoid sodium
Synthetic pentasaccharide (anti-Xa)Fondaparinux sodium
Direct thrombin inhibitorsHirudins (lepirudin, etc.)
Synthetic inhibitors (e.g. rivaroxaban‡)
CoumarinsAcenocoumarol§

Heparin is an indirect thrombin inhibitor that binds to anti-thrombin, converting this cofactor from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa and IXa. Low-molecular weight heparin (LMWH) drugs have less anti-thrombin activity than does unfractionated heparin (UFH).1

Unfractionated heparin is used intravenously, and requires monitoring using the activated partial thromboplastin time (APTT). By contrast, LMWH is administered by subcutaneous injection, and the dose can be weight-adjusted without monitoring.1

Epidemiology of cutaneous adverse events associated with heparin

Owing to under-reporting, the real incidence of heparin-induced skin lesions is unknown.2 However, AEs are reported less often with LMWH than with UFH.3 In a recent prospective study,2 the incidence and causes of heparin-induced skin lesions were evaluated in a large cohort of patients. An incidence of 7.5% was found, much higher than the 1–2% previously estimated. Delayed-type hypersensitivity reactions were found to be the commonest cutaneous side-effect related to heparin use. Most patients enrolled in the study received LMWH.

Classification, aetiology and management

Skin lesions related to heparin use can be classified as: immune-mediated reactions, which covers (i) type I immediate hypersensitivity reactions; (ii) type IV delayed hypersensitivity reactions: (iii) skin necrosis; and non-immune-mediated reactions, covering (iv) bleeding diathesis and (iv) other, less common reactions (Table 2).

Table 2.   Classification, aetiology and management of frequent immune-mediated cutaneous reactions induced by heparin.
TypeType I immediate hypersensitivity reactionsType IV delayed hypersensitivity reactionsSkin necrosis
CharacteristicsPruritus
Urticaria
Angio-oedema
Conjunctivitis
Rhinitis
Bronchial asthma
Anaphylaxis
At injection sites
Maculopapular exanthems
Necrotic cutaneous plaques
AetiologyIgE-mediated hypersensitivityCell-mediated hypersensitivityHIT II
Vasculitis
ManagementStop heparin
Start alternative anticoagulant (anti-Xa, hirudin)
Prick test
Modify treatment according to results
Stop heparin
Start alternative anticoagulant (anti-Xa, hirudin)
Prick/epicutaneous test: if positive, modify treatment according to results; if negative, subcutaneous test and modify treatment according to results
Stop heparin
Start alternative anticoagulant (anti-Xa, hirudin)
Allergy tests contraindicated

Immune-mediated reactions

Type I immediate hypersensitivity reactions

Immediate hypersensitivity reactions to heparins,3–5 e.g. pruritus (including palmoplantar pruritus), urticaria (Fig. 1), angio-oedema, conjunctivitis, rhinitis, bronchial asthma and anaphylaxis, are probably IgE-mediated. These reactions were first reported in the 1940s, after the introduction of heparin for clinical use, and were attributed to contaminant proteins and preservatives. They are now rare because of improved purification procedures.

Figure 1.

 Type IV delayed hypersensitivity reaction at heparin injection sites.

Type IV delayed hypersensitivity reactions

Type IV delayed hypersensitivity reactions (also referred to as cell-mediated hypersensitivity)3–5 require a sensitization period of about 10 days, although an interval of several months is also possible. A shorter latency period, of only a few days, has been reported in previously sensitized patients. Pruriginous erythematous plaques located at injection sites are the commonest type of reaction, sometimes with subsequent formation of vesicles or bullae. Less common maculopapular exanthems have also been reported. Female gender, obesity, and long duration of heparin therapy have been identified as risk factors for this type of reaction. Histopathological studies show spongiosis of the epidermis and a lymphohistiocytic perivascular infiltrate with predominantly CD4 cells.

Skin necrosis

Skin necrosis related to heparin use develops after 5–9 days of treatment. There are various pathogenic explanations for this phenomenon.3 One of these is heparin-induced thrombocytopenia (HIT) type II, caused by production of heparin-dependent antibodies (mainly IgG) that bind to a platelet factor 4–heparin complex, leading to platelet activation and aggregation; for diagnosis, a score taking into account clinical and analytical parameters should be used.6 Another possibility is vasculitis induced by type III hypersensitivity reaction (deposit of immune complexes on endothelial structures).

Lesions start as erythematous painful plaques with rapid evolution towards necrosis.4,7 Skin necrosis is usually located at injection sites, although distant lesions have also been reported. Systemic complications include venous and/or arterial thrombosis.3,4 Histological findings show microvascular occlusion.7 Heparin skin necrosis has been associated in some cases with protein C and S deficiencies.3,8

Management of immune-mediated reactions

Various allergy tests are used to confirm diagnosis of these immune-mediated reactions, and to search for crossreactions between the different LMWHs and UFH. Prick tests are used if a type I reaction is suspected. Subcutaneous tests are the gold standard for type IV hypersensitivity, but as these tests can induce AEs (e.g. anaphylaxis), less sensitive tests such as prick and epicutaneous tests should be performed first and only if these are negative should subcutaneous tests be used. Allergy tests are contraindicated in cases of skin necrosis because they could lead to severe complications.3,4

As a general rule, based on revised studies, it can be said that when a skin lesion is suspected to be related to heparin use and suggestive of an immune-mediated reaction, heparin treatment should be stopped. The diagnostic tests described above should be performed to identify a valid alternative treatment. There is extensive crossreactivity between the different LMWHs, UFH, and even danaparinoid and fondaparinux. Hirudins have a different chemical structure, and there is no cross-reactivity to heparins. In cases of HIT, hirudins, fondaparinux and danaparinoid can be safely used (crossreactivity in vitro is not clinically relevant). For delayed-type reactions, a practical approach could be to change to a hirudin or fondaparinux until results of cutaneous testing are available.3–5,7

Bleeding diathesis

Development of bleeding complications such as large ecchymoses during heparin therapy is the most common reason for its discontinuation9 (Fig. 2). The rate of bleeding seems to be lower with LMWH than with UFH.3 In cases with severe bleeding, it is advisable to determine the APTT level for UFH and level of anti-Xa for LMWH. If urgent reversal of heparin effect is needed, protamine sulfate can be used.

Figure 2.

 Large haematomas at heparin injection sites.

Other less common cutaneous adverse events associated with heparin

There are reported cases of less common AEs associated with heparin.

  • 1 Skin lesions associated with hypereosinophilia, related to LMWH use: it has been suggested that eosinophilia, associated or not with skin lesions, is more common in patients treated with subcutaneous heparin for a long time, as prolonged antigen presentation activates CD4 cells, which stimulate activation of eosinophils. Cutaneous lesions develop as erythematous plaques at injection sites. This reaction can be managed as explained previously for delayed hypersensitivity.3,10
  • 2 Maculopapular exanthems, flexural exanthems, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms have been reported.1 We suggest the same management as for delayed-type reactions.
  • 3 Alopecia can develop as a complication associated with chronic use.8,9
  • 4 Calcinosis cutis and calcifying panniculitis are very rare reactions secondary to subcutaneous injections of calcium-containing heparins, usually in patients with predisposing underlying conditions such as osteomalacia or renal failure. The exact pathophysiological mechanisms are unknown, but may result from the combination of metastatic and dystrophic calcification, with local trauma being a probable promoting factor. There is no specific treatment, and lesions resolve with discontinuation of the drug.11–13
  • 5 One case of acute generalized exanthematous pustulosis related to dalteparin use has been reported.14 As this seems to be a cell-mediated reation, it should be managed as a delayed-type hypersensitivity reaction.
  • 6 A case of leucocytoclastic vasculitis15 and a case of IgA cutaneous vasculitis16 have also been published. As mentioned above, these conditions result from deposit of immune complexes on skin endothelial structures. Treatment with the suspected drug should be stopped, and diagnostic tests performed as for delayed-type reactions.
  • 7 Two cases of enoxaparin-induced bullous pemphigoid-like eruption (with negative direct immunofluorescence) have been described in the literature. Lesions resolved after discontinuation of enoxaparin.17
  • 8 Bullous haemorrhagic dermatosis is an infrequent idiosyncratic reaction.18 It usually resolves spontaneously without discontinuing heparin treatment.

Conclusion

Skin lesions related to heparin use are considered uncommon, but they are probably under-reported. They can be classified into allergic and nonallergic reactions, and various diagnostic tests are available. When a cutaneous lesion attributable to the use of heparin is detected, interruption of the treatment is normally required.

Learning points

  • • Cutaneous AEs associated with heparin are probably under-reported, with an incidence of 7.5% estimated in a recent prospective study.
  • • Type I immediate hypersensitivity reactions are now infrequent due to purification procedures. Prick test is the diagnostic tool used for these reactions.
  • • Type IV delayed hypersensitivity reactions appear as pruriginous erythematous plaques at injection sites or as maculopapular exanthems. Subcutaneous testing is the gold standard diagnostic test, but it is only performed if prick and epicutaneous tests are negative.
  • • Skin necrosis is thought to be mediated by heparin-dependent antibodies or by deposition of immune complexes. Allergy tests are contraindicated.
  • • When an immune-mediated reaction is suspected, heparin treatment should be discontinued. Fondaparinux or a hirudin can be used until results of diagnostic tests are available.
  • • Bleeding complications are the most common reason for heparin discontinuation. Other less common cutaneous AEs associated with heparin include exanthems, alopecia, calcinosis cutis, cutaneous vasculitis and bullous eruptions.

CPD questions

Learning objective

To demonstrate up-to-date knowledge about the cutaneous adverse events associated with heparin and their adequate management.

Question 1

Which of the following anticoagulants is a synthetic pentasaccharide (anti-Xa)?

a) Lepirudin

b) Rivaroxaban

c) Enoxaparin sodium

d) Fondaparinux sodium

e) Heparin calcium

Question 2

Which of these statements about allergic tests for heparin-induced skin reactions is false?

a) Allergy tests are used to confirm diagnosis and to identify a valid alternative treatment.

b) Epicutaneous tests are never used

c) Prick test is used for type I immediate hypersensitivity reactions

d) Subcutaneous test is the gold standard for the diagnosis of type IV delayed hypersensitivity reactions

e) Allergy tests should not be performed in cases of skin necrosis

Question 3

Which of these anticoagulants has no crossreactivity with low-molecular-weight heparins?

a) Heparin calcium

b) Heparin sodium

c) Fondaparinux

d) Danaparinoid sodium

e) Lepirudin

Question 4

Which of these sentences about the management of immune-mediated reactions related to heparin use is false?

a) In general it is advisable to stop heparin administration

b) Any other anticoagulant can be used, as cross-reactivity is never clinically relevant

c) A hirudin or fondaparinux can be used instead of heparin until the results of allergy tests are available

d) In cases of a type IV delayed hypersensitivity reaction, prick or epicutaneous tests should be performed before subcutaneous tests

e) Allergy tests are useful to identify an alternative anticoagulant

Question 5

Which of these statements about the cutaneous adverse effects of heparin is true?

a) Bleeding complications are the most common reason for discontinuation of heparin treatment

b) Hypereosinophilia is always associated with skin lesions

c) Acute generalized exanthematous pustulosis related to heparin use has never been reported

d) Alopecia has been described as a consequence of heparin overdose

e) Calcinosis cutis is always treated by surgical resection

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