Enoxaparin-Associated Skin Necrosis in an Older Patient: A Rare Side Effect

Key words: Deep venous thrombosis, enoxaparin, heparin-induced thrombocytopenia, low-molecular-weight heparin, skin necrosis, thrombosis.
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Enoxaparin is a low-molecular-weight heparin used to treat and prevent deep venous thrombosis (DVT).¹ Use of the drug has increased because of its ease of administration and its lower risk of bleeding compared with unfractionated heparin.² This agent, however, is not without side effects, some of which can prove fatal. The frequent use of enoxaparin, especially with protocol-driven orders to reduce DVT, makes it imperative that hospital staff promptly recognize possible side effects, including skin reactions.^3,4 We report a case of skin necrosis that developed in a frail, hospitalized, elderly woman after administration of enoxaparin and discuss the implications of this adverse reaction.

Case Presentation

A 91-year-old white woman with a medical history of hypertension, chronic kidney disease, and osteoporosis was admitted to our hospital for submandibular and parotid adenitis that rapidly evolved over the 2 days preceding her admission. The submandibular swelling quickly increased and compressed her airway, necessitating intubation. She was treated with cefepime, gentamicin, and clindamycin for the adenitis, and enoxaparin 30 mg subcutaneously per day for DVT prophylaxis was initiated. Laboratory test results at the time of admission were as follows: white blood cell count, 11.6 µL (normal, 4500-11,000 µL); hemoglobin, 11.8 g/dL (normal, 12.5-16.0 g/dL); hematocrit, 35% (normal, 41%-50%); platelet count, 449 x 10³/µL (normal, 150-350 x 10³ µL); blood urea nitrogen level, 47 mg/dL (normal in women, 6-21 mg/dL); and creatinine level, 3.4 mg/dL (normal, 0.6-1.1 mg/dL). The results of her blood cultures were negative, and her electrolyte level was normal.

Four days after admission, erythematous skin lesions started to appear on the patient’s face, arms, thighs, and abdominal wall (Figure 1). She had no hives or petechiae. She had received heparin within the past 90 days, but antiheparin antibodies were not checked. Her lowest platelet count during this hospitalization was 211 x 10³/µL, which represented a 53% reduction from the admission value. After we reviewed the medication list, enoxaparin was stopped, and biopsy samples were taken from the lesions. The results of these biopsies showed ulcerations with neutrophilic dermatitis without any microorganisms (Figure 2). Gram, periodic acid-Schiff, and acid-fast bacillus stains were negative for microorganisms. Immunofluorescence stains did not detect immunoglobulin G, immunoglobulin A, immunoglobulin M, or complement C3. The patient did not develop any new skin lesions after stopping enoxaparin, and the old lesions started to heal. After 7 days in the intensive care unit, the patient’s family requested withdrawal of care, and the patient died. An autopsy was not performed per her family’s wishes; however, the findings were consistent with low-molecular-weight heparin–induced skin necrosis, which was a likely variant of heparin-induced thrombocytopenia (HIT) with thrombosis.

Discussion

Heparin can cause several skin reactions, ranging from simple bruising to skin necrosis (Table 1).^5-13 Heparin therapy necessitates the injection of concentrated solutions of drug into the skin; thus, its side effects could represent a direct drug effect (ie, anticoagulation, toxicity), be attributed to nonspecific mediator release, or be an immune response. Immune-mediated skin reactions, including necrosis, can occur with enoxaparin. Rarely, heparin causes an urticarial rash from either local histamine release or from an IgE-mediated release of histamine and other mediators from mast cells and basophils; this is considered a type 1 hypersensitivity reaction (immediate hypersensitivity reaction) according to the traditional classification of these reactions (Table 2).^14,15 Immune skin reactions can also cause erythematous, well-circumscribed plaque formation at injection sites secondary to type IV reactions.¹⁵ 

Skin necrosis after administration of enoxaparin is rare, and the pathogenesis of this complication is not well understood. Heparin can induce antibody formation to heparin-platelet factor 4 complexes, which has been reported to cause thrombocytopenia and thrombocytopenia with thrombosis in approximately 1% and 0.2% of cases, respectively.¹⁶ These antibodies cause platelet aggregation, which can plug small vessels.¹⁷ Small dermal vessel thrombosis is apparent in some histopathologic specimens from patients with heparin-induced necrosis.¹⁸ The other proposed mechanisms in the development of skin necrosis include vasculitis, which is induced by type III hypersensitivity reactions; local trauma (ie, bleeding and capillary compression) at the injection site; and reduced absorption from adipose tissue resulting in high local concentrations of the drug.¹⁶ The skin necrosis observed with heparin is similar to the necrosis seen with warfarin, but the patient characteristics are different. Patients with enoxaparin-induced necrosis have low platelet counts, whereas those with warfarin-induced necrosis have normal platelet counts, but often show low levels of anticoagulant factors C and S.

Our literature review identified several reported cases of enoxaparin-induced skin necrosis (Table 3).^18-29 Most patients were adult women with an age range of 18 to 89 years, with 43% being older than 55 years. These patients were often overweight, had diabetes, and were receiving broad-spectrum antibiotics. Approximately 50% had a history of recent heparin exposure. The skin reaction began between 1 and 25 days after these patients received the drug, and they typically presented with areas of erythema and tenderness at the injection site, which evolved into plaques and then skin necrosis. In the series reviewed by Handschin and colleagues³⁰ antiheparin–platelet factor 4 antibodies were present in nine of the 10 patients tested, and nine of 19 patients had thrombocytopenia. Treatment varied significantly in these patients, but five received unfractionated heparin after the low-molecular-weight heparin was stopped. Outcomes were generally good. One patient developed DVT, and two required debridement and skin grafting of their wounds.

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Our patient had extensive skin necrosis at multiple sites induced by enoxaparin administration. She had a 53% reduction in platelet count and a history of heparin treatment. Her risk for HIT syndrome was high, with a “4 Ts” score of 8 (2 points for a drop in platelet count of at least 50%, 2 points for onset, 2 points for skin necrosis, and 2 points for no other cause to explain this thrombocytopenia).³¹ In addition, her Naranjo score³² was 5, which is consistent with a probable adverse reaction. No new skin lesions occurred after the enoxaparin was stopped, and the old necrotic areas started to heal.

The true incidence of skin necrosis in critically ill patients is unknown and is probably underreported¹⁶; however, these patients are often older with complex presentations and important management questions. HIT should be considered in these patients when they have skin necrosis, a drop in platelet count, or both. HIT is defined as a fall in the platelet count of 50% or more.³³ The time of onset of thrombocytopenia is 5 to 10 days after starting heparin, but it can occur in less than 24 hours or within several days after discontinuing heparin.³³ Between 20% and 50% of patients develop vascular thrombi, usually in the veins. In HIT patients, 10% have skin lesions, and these lesions usually occur at the sites of heparin injection.³³ There are two classes of assays that can be used to detect HIT antibodies: platelet activation assays (including the serotonin release assay) and antiheparin–platelet factor 4 complex assays. The serotonin release assay has a high sensitivity (>90%) and specificity (>90%), but it is not readily available.³³ According to the American College of Chest Physicians evidence-based clinical practice guidelines,³⁴ patients with a HIT diagnosis should not receive heparin products or warfarin. The guidelines recommend using danaparoid, lepirudin, argatroban, fondaparinux, or bivalirudin for anticoagulation.Patients who have skin lesions and a high probability of having HIT need to be evaluated for the location of these skin lesions (remote or local), changes in platelet count, antibodies to heparin-platelet factor 4 complexes, and DVT.³⁴ Consultation with an expert may be required.

Conclusion

Hospitalized patients frequently receive low-molecular-weight heparin for DVT prophylaxis. These drugs can cause thrombocytopenia and thrombosis. They can also cause multiple skin reactions, including type IV delayed hypersensitivity skin necrosis. This reaction likely reflects a small vessel thrombosis and is operationally equivalent to HIT syndrome. Therefore, heparin-induced skin necrosis potentially has important clinical implications and could precede the development of large vessel thrombosis. The overall incidence of these skin reactions in hospitalized patients is uncertain, and they may be overlooked during the care of complicated patients. Prospective longitudinal studies are needed to determine the frequency of heparin-associated skin reactions and the clinical outcomes associated with the various types of these reactions. n

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Disclosures:

The authors report no relevant financial relationships.

Address correspondence to:

Khaled Sherif, MD

3601 4th Street

Lubbock, TX 79430

khaled.sherif@ttuhsc.edu