An unusual case of massive subcutaneous chest wall haemorrhage with enoxaparin

Abstract

Enoxaparin is used in the treatment of acute coronary syndromes and offers improved outcome in the composite endpoint of death, myocardial infarction and major bleeding when compared with unfractionated heparin (UFH). Our report describes a rare case of massive life-threatening subcutaneous chest wall haemorrhage, distant to the injection site. Clinicians should be aware of atypical presentations of haemorrhage when using combination antiplatelet and antithrombotic therapy.

Keywords::

• Enoxaparin
• clexane
• bleeding
• subcutaneous
• haemorrhage
• haematoma
• acute coronary syndrome, atypical, low-molecular weight heparin

Case

A 65-year-old man with previous coronary artery bypass grafting (CABG) was admitted following a non-ST-elevation myocardial infarction (NSTEMI) and treated with aspirin and clopidogrel (loading dose 300 mg, maintenance 75 mg once daily) and enoxaparin 1mg/kg twice daily. Coronary angiography performed two weeks previously had demonstrated occluded grafts and he was under consideration for redo-CABG. Clopidogrel was stopped 48 h after admission on the advice of the surgical team with aspirin and enoxaparin continuing whilst awaiting transfer to the Cardiothoracic Centre.

On day 10 after admission the patient complained of backache and was seen overnight by the on-call team, who noted simply a small bruise inferior to the left scapula. By morning he became tachycardic and hypotensive. His ECG showed new right bundle branch block. The bruise had enlarged, covering most of his back (Figure 1). A provisional diagnosis of a retroperitoneal bleed was made.

Figure 1. Photographs demonstrating large subcutaneous haematoma extending from left axillary region to thigh.

Blood tests demonstrated significant haemorrhage; the haemoglobin had dropped from 12.6 g/dl to 4.3 g/dl. The platelet count also dropped from 155 × 10⁹/l to 94 × 10⁹/l. The clotting screen and renal function were within normal parameters. He was resuscitated with a six-unit red cell and a single-pool platelet transfusion to counteract aspirin-induced platelet dysfunction as well as recombinant factor VIIa concentrate (NovoSeven™) on the advice of the haematologists. It was felt by them that protamine sulphate would not be of benefit as enoxaparin had been given 14 h earlier. Urgent contrast-enhanced computed tomography scan demonstrated massive left chest wall subcutaneous haematoma but no retroperitoneal or intrathoracic bleed (Figure 2). Arterial and venous-enhanced phases did not demonstrate any underlying vascular abnormality or an active bleeding point.

Figure 2. Computed-tomography scan demonstrating the haematoma (arrowed) just under the level of the axilla with fat stranding and cystic appearances within the mass, consistent with a massive left chest wall haematoma.

Aspirin and enoxaparin were withheld and pressure bandaging applied, in agreement with a consultant vascular surgical review. The patient required a further four-unit blood transfusion but the bruising receded and he was discharged home on aspirin (recommenced 10 days following the initial haemorrhage) and subsequently reviewed in clinic, where he has remained stable. The visible bruising has resolved with no palpable subcutaneous haematoma. He has proceeded to successful, uncomplicated redo-CABG.

Discussion

Low-molecular weight heparins (LMWH) have been advocated for use in acute coronary syndrome (ACS), with significant reductions in hospital mortality, re-infarction, development of congestive cardiac failure and overall major adverse cardiac event rate (MACE) when combined with aspirin. LMWH has increased bioavailability, longer subcutaneous half-life, a better anti-Xa effect via antithrombin and reduced frequency of heparin-induced thrombocytopenia and osteoporosis when compared with unfractionated heparin (UFH).

Enoxaparin has been compared to UFH in several trials. A meta-analysis by Petersen et al. (1) demonstrated a significant reduction in composite endpoint of death or non-fatal myocardial infarction (MI) (10.1% versus 11.0%; OR: 0.91; 95% CI: 0.83–0.99). A more recent meta-analysis by Murphy et al. (2), however, demonstrated this decrease to be driven largely through a reduction in MI (5.5% versus 6.9%, OR: 0.75, 95% CI: 0.65–0.86, P = 0.001). Superiority to UFH is not demonstrated consistently when individual endpoints are examined, resulting in the European Society of Cardiology to recommend enoxaparin in ACS as ‘at least as effective as UFH’ (3).

Studies have focused on enoxaparin-related bleeding (4–7) and have demonstrated a significant increase in overall haemorrhage. It is an important prognostic factor when treating ACS and confers nearly a four-fold increased risk of mortality and MACE (8). TIMI (thrombolysis in myocardial infarction) major bleeding was higher in the enoxaparin arm of a meta-analysis of 12 trials and nearly 50 000 patients across the entire ACS spectrum (4.3% versus 3.4%, OR: 1.25, 95% CI: 1.04–1.50, P = 0.019) and for the ST-elevation myocardial infarction (STEMI) cohort (2.6% versus 1.8%, OR: 1.45, 95% CI: 1.23–1.72, P < 0.001) but not the non-ST elevation ACS (NSTE-ACS) subgroup, where the finding was not statistically significant (6.3% versus 5.4% with UFH, OR: 1.13, 95% CI: 0.84–1.54, P = 0.419) (2). No difference in the primary endpoint (net clinical events defined as death, non-fatal MI, or non-fatal major bleeding by 30 days) was reported in NSTEMI patients. Recent changes to practice with an emphasis on early intervention and the use of potent antiplatelet agents such as glycoprotein IIb/IIIa inhibitors were assessed in the SYNERGY trial (9) and have also demonstrated increased TIMI major bleeding with enoxaparin compared to UFH (9.1% versus 7.6%, P = 0.008).

Critique over existing data supporting enoxaparin use suggests that large studies tend not to recruit ‘real world patients’. The trials referenced above excluded patients with significant renal impairment whilst average patient age varied between 60 and 68 years old with no age-adjusted assessment of bleeding risk made. Multivariate analysis in an observational study (10) revealed elevations of serum creatinine by increments of 20 μmol/l was predictive of major bleeding (OR: 1.44, 95% CI: 0.96–2.16, P = 0.079). Ten-year increments in age was found to be an independent risk factor for increased bleeding risk (OR: 1.57, 95% CI: 1.13–2.20, P = 0.008), a finding also supported by Lopes et al. (11). Additional risk factors such as obesity (weight > 100 kg) are not considered during these trials. Limited data exists to quantify adequately the bleeding risk in such populations. Co-administration of clopidogrel was the strongest predictor of bleeding (OR: 7.70, 95% CI: 1.16–51.9, P = 0.034) (10) but of all the trials reviewed, was only routinely used in SYNERGY in approximately two-thirds of the cohorts. These factors are seldom considered when recommendations are generated and the bleeding risks in patients treated with aspirin, clopidogrel and enoxaparin have not been adequately evaluated in these higher risk groups.

Why bleeding occurred at this site in our patient with a normal weight and renal function is unclear. There are very few similar cases to our knowledge. Ozpolat et al. (12) describe a haemorrhage in an 81-year-old man treated with enoxaparin for deep vein thrombosis, developing a large subpectoral haematoma, treated with surgical evacuation and switching to UFH treatment. Had bleeding not stemmed following conservative management, embolization could have been utilised, however it appears the use of activated factor VIIa concentrate and pressure-bandaging with supportive treatment in the way of red cell transfusion has on this occasion been successful.

The routine use of aspirin, clopidogrel and LMWH is established as an excellent treatment strategy for ACS, however, we would like this case to serve as a reminder that many patients have a real risk of bleeding associated with an overall poor prognosis. This bleeding rarely can occur in unusual sites and clinicians should, therefore, remain vigilant. Careful risk assessment must take place for all patients where this treatment strategy is adopted.

Acknowledgements

The authors thank the patient described in the case who provided full written consent for submission of the case report, the medical and cardiology teams involved in his care and Dr Qasim and Dr Soo as supervising Consultants.

Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.