Urticarial reaction to low molecular weight heparin injections

Introduction

Cutaneous reactions are a common side effect of various medical pharmaceuticals. In the context of low molecular weight heparin (LMWH), cutaneous reactions are thought to occur at an incidence of 7.5%, ¹ hypersensitivity and skin necrosis appear the most common.^1–3 A study looking at the incidence of cutaneous reactions to heparin-identified women, body mass index over 25 kg/m² and a medication course of more than 9 days were significant factors associated to patients who had been diagnosed with a delayed-type hypersensitivity reaction to heparin. ²

LMWH is frequently used in pregnancy for venous thromboembolism (VTE) prophylaxis, it has additional roles in preventing recurrent pregnancy loss, ⁴ in vitro fertilisation and those with a history of gestational vascular complications. ⁵ This signifies the importance of understanding its side effect profile within the obstetric population.

This case discusses a woman with prior uncomplicated subcutaneous heparin exposure presenting in her third pregnancy having developed an urticarial drug hypersensitivity reaction at LMWH administration sites. This raises the question, does pregnancy physiology have an effect on dermatological adverse effects to medications?

Case report

History

A 30-year-old woman presented to obstetric antenatal triage in her third pregnancy at 30 weeks of gestation with painful bruising and redness across her abdomen and thighs at subcutaneous LMWH injection sites. She initially received enoxaparin (Inhixa^®); this was later switched to Clexane^® 40 mg daily. She was admitted for observation, and over subsequent days, the rash became more oedematous and urticated (Figure 1), associated with itching and soreness. She remained otherwise clinically well.

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Figure 1.

Day 1: Erythematous plaques at sites of subcutaneous low molecular weight heparin injections on abdomen and thighs with associated bruising. Day 3: Expanding urticated erythematous plaques with worsening bruising at similar sites.

She was diagnosed with Crohn's disease at 29 years of age between her second and third pregnancies. Further past medical history included renal calculi and iron deficiency anaemia. Her Crohn's disease had been stable on ustekinumab for 2 years prior to conception of her third pregnancy.

Regarding her obstetric history, her first pregnancy at age 26 was complicated by obstetric cholestasis and preeclampsia. She consequently underwent induction of labour (IOL) at 36 weeks and 2 days of gestation requiring a ventouse-assisted birth. Of note, she was discharged postnatally on 10 days of LMWH (enoxaparin) following postnatal risk assessment for VTE prophylaxis. She had no adverse reactions to this course of treatment. Following a 1 year interpregnancy interval, she conceived her second pregnancy which proceeded without complication and had a spontaneous vaginal birth at 39 weeks following spontaneous onset of labour. She received aspirin 150 mg nightly from 12 to 36 weeks of gestation for preeclampsia prophylaxis.

Her current third pregnancy was unremarkable until the third trimester when she developed a skin reaction to LMWH. She continued on ustekinumab 90 mg subcutaneously every 6 weeks throughout this pregnancy. As in her second pregnancy, she took aspirin for preeclampsia prophylaxis between 12 and 36 weeks. Following an obstetric review at 28 weeks, she was commenced on LMWH for VTE prophylaxis after a risk assessment was completed. She presented at 30 weeks with a progressive rash as described above, she was investigated and managed as follows.

Investigations

Initial admission blood results demonstrated a C-reactive protein of 10 mg/L (normal range = 30 ng/mL ⁶ ). Bile acids were 4, liver function tests were within normal limits and a full blood count was reassuring. Autoimmune blood tests revealed a positive p-ANCA (MPO/PR3 were within normal limits), anti-nuclear antibodies, complement and anti-skin antibodies were all normal. A urine dip for protein and blood was negative. She was normotensive and asymptomatic of preeclampsia.

A 4 mm skin punch biopsy from the left thigh demonstrated intraepidermal vesicle formation with the presence of macrophages; papillary dermis oedema; perivascular lymphocytic inflammation at the mid dermis; while the deeper dermis shows chronic inflammation (Figure 2). Clinicopathological correlation confirmed the diagnosis of urticarial drug hypersensitivity reaction.

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Figure 2.

Photomicrograph from abdominal skin punch biopsy showing intraepidermal vesicle formation with the presence of macrophages; papillary dermis oedema; perivascular lymphocytic inflammation at the mid dermis (stain: haematoxylin and eosin, magnification 100×).

Discussion

We present the case of a 30-year-old woman with a localised urticarial drug reaction to LMWH at multiple injection sites. LMWH is frequently used in pregnancy, most often for VTE risk factors. ⁸ The true incidence of skin reactions to all medications is likely underappreciated due to underreporting.

A published case series reports localised and generalised urticarial reactions to nadroparin calcium LMWH injections in six pregnant women, all subsiding on drug cessation. ⁹ Acute localised exanthematous pustulosis reaction has also been reported to enoxaparin given after caesarean section. ¹⁰ A 2009 study ² of 320 patients included pregnant women in their investigation of heparin-induced skin lesions, the small number of pregnant women in the study limited their ability to conclude if pregnancy can be considered an absolute risk factor of a cutaneous reaction. While limited of note, their raw data identified pregnancy as a statistically significant variable to the development of a cutaneous reaction, however, when this was statistically tested through multiple linear regression analysis, pregnancy was not found to be a risk factor. Our case would support this on the basis this patient previously tolerated LMWH postnatally after her first child. While it remains a possibility that the immunological changes during pregnancy contributed to this reaction, the immediate postnatal tolerance would suggest this is unlikely. The immunological physiology of pregnancy is complex and still not fully understood. In the context of a delayed hypersensitivity reaction, the pathogenesis may be linked to the shift from T helper (Th) 1 to Th2 immune response in the first and second trimesters. ¹¹ Fujisaki et al. ¹² found T-lymphocyte activity is reduced during pregnancy and quickly restored several days after delivery.

There must therefore be consideration around the influence the immunomodulator (ustekinumab) has had on the development of these lesions in this pregnancy, when previous tolerance to LMWH postpartum has been demonstrated. Currently, there are no documented cases linking LMWH and ustekinumab and a cutaneous reaction. However, as a monoclonal antibody interleukin inhibitor, it is known to cause side effects of hypersensitivity vasculitis and cutaneous lesions ¹³ as do many immunomodulators. Another possibility is the period of exposure required before the development of a cutaneous reaction.

Current data suggests there is limited evidence of cross-reactivity between different heparin formulations, fondaparinux is the favoured second-line agent for subcutaneous anticoagulation if someone has experienced a cutaneous reaction to LMWH.^1,2

Conclusion

The immunological changes that occur during pregnancy do not fully account for a cutaneous reaction to LMWH. Although cases are rare and prior literature inconclusive, further research in this area would be recommended. There is little in the literature on the interactions of LMWH and ustekinumab or other immunomodulators. Over the last 10 years, clinicians have observed a massive upscale in the use of these drugs across a variety of inflammatory and autoimmune conditions; this is likely to continue. Highlighting a need to further research this potential interaction.

Finally, this case importantly serves as a reminder to report drug reactions, particularly in pregnancy to assist in building available evidence and literature as women are so often excluded from studies when pregnant.