A Case of an Allergic Contact Dermatitis Following the Administration of Enoxaparin: A Case Report and Review of the Literature

Introduction

Allergic contact dermatitis (ACD) is a delayed-type hypersensitivity reaction that develops upon skin contact with specific allergens, leading to localized inflammation. This inflammatory response is mediated by T-cells that recognize the allergen as foreign, resulting in erythema, itching and vesiculation at the contact site. ¹ Though ACD is commonly triggered by allergens such as metals, preservatives, and fragrances, certain medications can also provoke these responses. Among these, injectable medications like enoxaparin, a low-molecular-weight heparin (LMWH) used widely for its anticoagulant properties, have occasionally been associated with localized allergic skin reactions.^{2 -4} Enoxaparin is frequently prescribed to prevent venous thromboembolism (VTE) in high-risk patients, especially post-operatively. ² However, adverse reactions such as ACD remain underrecognized due to their rarity and the often-mild nature of symptoms, which may go undiagnosed.

While ACD is generally common, cases specifically involving enoxaparin are rarely documented. A 2023 case report of Saraiva et al, identified a limited number of reported instances of ACD triggered by these agents, with systemic hypersensitivity reactions like urticaria, angioedema, and anaphylaxis more commonly reported. ³ The nonspecific and subtle nature of localized allergic reactions can lead to misdiagnosis, often as a simple irritant contact dermatitis rather than a true allergic response. The actual frequency of ACD due to enoxaparin injections may thus be underestimated in clinical practice. ⁴

The limited literature on enoxaparin-related ACD cases suggests that these reactions may manifest days to weeks after the initiation of therapy, typically confined to the injection sites. ⁵ Enoxaparin itself contains additional compounds, such as preservatives and stabilizers, that can contribute to sensitization in some patients. ⁶ However, recent research focuses on severe hypersensitivity reactions to LMWHs, and data on ACD specifically is sparse. Few studies explored the underlying mechanisms that could make certain patients more susceptible to developing ACD upon enoxaparin exposure. As a result, there remains a need for thorough documentation of these cases, which could improve understanding of risk factors, symptoms, and management options. ⁷

Current gaps in knowledge about ACD related to LMWHs are significant, as reactions of this type can interfere with patient adherence to necessary anticoagulant therapy. ⁸ Patch testing plays a role in diagnosing allergic contact dermatitis but has limited applicability in routine clinical practice for LMWH-related reactions, often requiring alternative methods like intradermal or provocation testing for accurate diagnosis. ⁹ As a result, cases like these may not only remain undetected but also untreated, with potential consequences for patient outcomes, especially when anticoagulant therapy is needed for extended periods. To address these issues, in this case report, we discuss a unique case of enoxaparin-induced ACD in a young woman with a history of polycystic ovarian syndrome (PCOS) and hidradenitis suppurativa, who was undergoing VTE prophylaxis following sleeve gastrectomy.

Case Presentation

This is a case of a 27-year-old Saudi woman with a history of PCOS and hidradenitis suppurativa, who recently underwent sleeve gastrectomy and was on a 21-day prophylactic enoxaparin 40 mg/day subcutaneous injection for venous thromboembolism. She presented to our dermatology outpatient clinic with a 1-month history of itchy skin lesions on her lower thighs and left upper shoulder, corresponding to the sites of enoxaparin injections. These skin lesions developed on the sixth-day after starting enoxaparin therapy. Her medication history included doxycycline 100 mg/day, which was discontinued post-surgery. Skin examination revealed localized ill-defined erythematous edematous plaques with fine scales on bilateral lower thighs (Figure 1A) and the left upper shoulder (Figure 1B). A 4 mm skin punch biopsy for hematoxylin and eosin (H&E) staining to further evaluate the skin lesions and revealed spongiotic dermatitis with eosinophils (Figures 2 and 3). Considering the clinical findings in addition to the histopathology results, a diagnosis of allergic contact dermatitis was established. The patient was informed about the nature of the skin allergy and was advised to discontinue enoxaparin, with arrangements for an alternative to be made by her primary team if needed. She was prescribed topical mometasone ointment twice daily for 2 weeks. On 4-weeks follow-up, the patient had no active lesions.

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Figure 1.

Localized ill-defined erythematous edematous plaques with fine scales over the (A) shoulder and (B) thigh.

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Figure 2.

Photomicrograph of the skin punch biopsy exhibits parakeratosis, acanthosis and mild spongiosis (H/E stain, original magnification × 40).

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Figure 3.

High power view reveals superficial perivascular lymphocytes and scattered eosinophils (H/E stain, original magnification ×400).

Following the resolution of lesions, patch testing was conducted, which showed sensitivity to nickel. No reaction to enoxaparin was detected on patch testing.

Discussion

Allergic contact dermatitis (ACD) resulting from subcutaneous enoxaparin injections is an uncommon yet clinically significant condition that requires recognition, particularly in patients requiring long-term anticoagulation therapy. This case report describes a 27-year-old woman who developed pruritic, erythematous skin lesions localized to the injection sites after initiating enoxaparin for venous thromboembolism (VTE) prophylaxis. These findings contribute to the limited number of documented cases of enoxaparin-induced ACD, underscoring the need for increased awareness among healthcare providers about this rare but important adverse reaction.

The prevalence of hypersensitivity reactions to LMWHs varies across patient populations. One study reported rates of 1.9% in orthopedic patients, 7.5% in medical patients, and 19.8% in obstetric patients, indicating a higher risk in certain groups. ¹⁰ Additionally, hypersensitivity reactions to LMWHs are often underreported, with most cases focusing on systemic rather than localized reactions. ¹¹ This case emphasizes the importance of identifying localized reactions, as the dermatitis in our patient was confined to injection sites and lacked systemic involvement, supporting a diagnosis of ACD.

Histopathological examination in this patient revealed spongiotic dermatitis with perivascular lymphocytic infiltration and eosinophils, a hallmark feature of LMWH-induced ACD. ¹² The presence of eosinophils in spongiotic dermatitis has been suggested as a characteristic finding in LMWH-related ACD, distinguishing it from irritant contact dermatitis, which lacks immune-mediated changes.^12,13 This highlights the diagnostic value of histopathology in confirming ACD cases when clinical presentation is unclear.

Patch testing, commonly used to identify allergens in ACD, demonstrated limited utility in this case. While nickel was identified as a potential allergen, patch testing failed to confirm sensitivity to enoxaparin, a limitation consistent with earlier reports. ⁸ Negative patch test results are not uncommon in delayed-type hypersensitivity (DTH) to LMWHs, likely due to the test’s inability to fully replicate in vivo conditions. In such cases, intracutaneous testing or controlled challenge tests may provide greater diagnostic sensitivity and should be considered when clinical suspicion remains high. ⁸

Management of enoxaparin-induced ACD in this case was achieved using mometasone alone, with resolution of symptoms within 4 weeks. These findings align with previous reports recommending topical corticosteroids to alleviate symptoms and prevent progression. ¹⁴ However, recurrent or severe reactions may warrant transitioning to alternative anticoagulants. According to Kavut and Koca, patients with LMWH hypersensitivity may benefit from unfractionated heparin (UFH) or other anticoagulants, though these alternatives carry variable risks and require careful clinical management. ¹⁵ LMWHs are distinguished from Unfractionated Heparins (UFHs) by their molecular weight, which ranges from 4 to 6 kiloDaltons (kD), compared to 10 to 20 kD for UFHs. ¹⁶

Delayed-type hypersensitivity reactions often exhibit cross-reactivity among LMWHs, UFH, danaparoid, and fondaparinux, complicating the selection of alternative anticoagulants. Hirudins, which have a distinct chemical structure, are less likely to demonstrate cross-reactivity and represent a safer option. ¹⁷ Transitioning to a hirudin or fondaparinux can serve as an effective interim solution while awaiting the results of further allergological testing ¹⁷ (see Table 1).

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Table 1.

Summary of Reported Cases of Delayed-Type Hypersensitivity Reactions to Enoxaparin.

Study	Authors	Year	Drug	Type of reaction	Population	Key findings
Study 1	Mirgh and Bhave 18	2016	Enoxaparin	Delayed-Type Hypersensitivity (DTH)	Pregnant woman with recurrent first trimester spontaneous abortions	Red patches and itching appeared at the injection sites, which later spread to distant areas after rechallenge. There was no evidence of necrosis or thrombosis. The lesions resolved after discontinuing enoxaparin and receiving symptomatic treatment.
Study 2	Santiago Sánchez-Mateos et al. 19	2010	Enoxaparin	Delayed-Type Hypersensitivity (DTH)	Elderly woman with paroxysmal atrial fibrillation and double aortic valve lesion	Itchy red papules appeared at the injection sites, merging into plaques, with dyshidrosiform lesions on the palms. The lesions spread after intravenous sodium heparin was administered. They resolved following the discontinuation of heparin and treatment with corticosteroids.
Study 3	Valdés et al 20	1998	Sodium Enoxaparin	Spongiotic Dermatitis	Adult woman patient	Red and swollen plaques appeared at the injection sites; recovery was achieved with the use of topical corticosteroids.
Study 4	Belhareth et al 21	2021	Enoxaparin	Eczematous eruptions	Adult woman patient	A widespread itchy rash, facial swelling, cheilitis, and eczematous lesions at the injection sites were observed. Blood tests revealed eosinophilia, elevated gamma GT, and increased lipase levels. Initially, carbamazepine-induced DRESS syndrome was suspected, but the final diagnosis was generalized eczema caused by heparin.

This case contributes to the limited but expanding body of literature on enoxaparin-induced allergic contact dermatitis (ACD). It underscores the importance of considering ACD in the differential diagnosis when patients present with localized eczematous eruptions at injection sites. Early recognition and appropriate management are critical, particularly in the context of the widespread use of low-molecular-weight heparins (LMWHs) in anticoagulation therapy.

In this case, patch testing was performed and yielded a negative result for enoxaparin. The patient did test positive for nickel sensitivity; however, this finding was considered clinically irrelevant due to the absence of any known exposure or correlation with the affected injection sites. It is important to recognize that negative patch tests do not definitively exclude the diagnosis of ACD, particularly with LMWHs such as enoxaparin. Also, the epicutaneous patch testing may have limited sensitivity in detecting LMWH-related hypersensitivity reactions.^22,23

Although the clinical features, temporal correlation with drug administration, and histopathological findings (notably spongiotic dermatitis with eosinophils) were suggestive of ACD, the lack of more specific confirmatory testing, such as intradermal testing or site-specific patch testing over previously affected areas, represents a significant limitation. Moreover, the histopathological findings, while supportive of a hypersensitivity reaction, are not pathognomonic and can be seen in a range of inflammatory dermatoses. Given these limitations, the diagnosis of ACD in this case remains plausible but not definitive. Nonetheless, documenting such presentations, even when diagnostic certainty is limited, can help raise awareness of rare cutaneous adverse reactions to enoxaparin and encourage more comprehensive diagnostic evaluation in future cases.

Conclusion

Enoxaparin-induced ACD, while rare, is an important adverse effect that clinicians should consider in patients presenting with localized skin reactions at injection sites. Histopathological analysis and appropriate diagnostic testing are essential to confirm the diagnosis and identify the causative agent. Early recognition and management, including the use of alternative anticoagulants when necessary, can prevent complications and improve patient outcomes. This case highlights the need for increased awareness and reporting of such reactions to enhance understanding and guide future management strategies.