Enoxaparin-induced retroperitoneal haematoma in patients with renal insufficiency.

Abstract

MarioFernandez-Ruiz,JuanManuelGuerra-ValesDepartment of Internal Medicine,University Hospital “12 de Octubre”,Madrid, SpainWe have read with particular interestthe recent article by Schmid and colleagues[1] on the use and safety of low-molecular-weight heparins (LMWH) in patients withrenal insufficiency (RI). As the authorspointed out, the risk of haemorrhagic eventsis increased in subjects with impaired renalfunction, independently of the type of anti-coagulant used. Low-molecular-weight he-parins have been shown to cause fewerbleeding complications than unfractionatedheparin (UFH) in most animal and clinicalstudies, although this benefitis less clear inthe presence of a decreased glomerular filtra-tion rate (GFR) [1, 2]. Parallel to its growingclinical use there has been an increased inci-dence of major bleeding episodes duringLMWH administration in recent years,mainly at the injection or instrumentationsites (including abdominal wall or epiduralhaematomas) [3]. Although it is well de-scribed in the context of UFH or cumarinicanticoagulant-based therapies, only a few ex-amples of LMWH-associated spontaneousretroperitoneal haematoma (SRH) have beendescribed in the literature, chieflyon thebasis of single case reports [3–9]. Hence wewould like to take this opportunity to reviewour 5-year experience in the managementand outcome of this complication, highlight-ing the role of RI in its incidence. We retro-spectively analysed all consecutive patientswith the diagnosis “non-traumatic retroperi-toneal haematoma” (identifiedby ICD-10code K66.1) seen between January 2005 andMay 2009 at the University Hospital “12 deOctubre”, a 1,300-bed tertiary care centre inSpain. Of a total of 109 patients we selectedby chart review those undergoing LMWHtherapy at the time of diagnosis. Patientswith a recent history of surgical or invasiveprocedures were specificallyexcluded. GFRat the time of diagnosis of SRH was esti-mated according to the 4-variable Modifica-tion of Diet in Renal Disease (MDRD) studyequation.Ta ble 1 summarises the clinical and ana-lytical features of the 8 patients (6 males;mean age 75.5 ± 4.5 years [range: 69–83]) di-agnosed with SRH in the course of LMWHtherapy during the study period. Enoxaparinwas the LMWH involved in all cases. It wasadministered at prophylactic dosage (40 mgsubcutaneously every 24 hours) in one pa-tient, the remaining receiving enoxaparin inconventional therapeutic doses (1 mg/kgbody weight SC every 12 hours). Concomi-tant use of oral anticoagulant (acenocumarol)or antiplatelet therapy (aspirin or clopido-grel) was recorded in 4 cases. Four of the pa-tients analysed had moderate renal impair-ment (GFR 30–59 ml/min) at the time whenSRH was diagnosed, and 2 had severe renalimpairment (GFR <30 ml/min). The meantotal GFR was 44.5 ± 26.7 ml/min. Theanti-factor Xa activity was not measured inany of the patients during the course ofLMWH therapy.The therapeutic approachwas exclusively based on supportive measures(including volume resuscitation and adminis-tration of fresh frozen plasma, platelets orpacked red blood cells) in 6 cases. A singledose (100 mg/kg body weight intravenously)of recombinant activated factor VII was ad-ministered in 2 patients. In addition, one ofthem underwent selective embolisation ofthe obturator branch of the right internaliliac artery. Four of the patients died duringthe hospital stay, amounting to a mortality of50%. The remaining patients recovered un-eventfully.In the absence of apparent trauma,retroperitoneal haemorrhage most fre-quently results from a ruptured abdominalaortic aneurysm or bleeding from an under-lying renal or adrenal condition [3]. SRHrepresents an infrequent but potentially fatalcomplication of LMWH therapy, with awide spectrum of clinical presentations(ranging from leg pain or paraesthesias tocatastrophic haemorrhagic shock), and re-quires a high level of suspicion for diagnosis[3, 7]. In spite of aggressive management theassociated mortality remains high, as ourcase series exemplifies.Analysis of previouscase reports of enoxaparin-induced SRH re-veals certain common predisposing risk fac-tors, such as age over 70 years, concomitantadministration of oral anticoagulant or an-tiplatelet agents and, specifically, the pres-ence of RI [6, 9]. Is a well-known fact thatrenal function impairment causes a delay inthe clearance of enoxaparin, resulting in in-appropriately elevated levels of anti-factorXa activity [8, 9]. Some pharmacokineticanalyses of anti-Xa activity suggest dose al-terations even in mild to moderate RI (thatis, a GFR between 30 and 59 ml/min) [10].As Schmid and colleagues comment, the effi-cacy and safety of enoxaparin in the settingof renal function impairment has been suffi-ciently studied and empirical dose reductionis usually recommended according to estab-lished guidelines [1]. On the other hand,both age-related sarcopenia and decline increatinine clearance may contribute to mis-diagnosis of RI in interpretation of serumcreatinine levels alone. Our experiencetherefore illustrates the crucial role of RI inthe aetiopathogenesis of enoxaparin-associ-ated SRH, and underpins the need to makeregular use of GFR prediction equationswhen evaluating renal function in elderly pa-tients, before as well as during treatmentwith LMWH. Although prospective studiesare needed to assess the reliability and cost-effectiveness of monitoring anti-factor Xaactivity in patients with RI, it seems to be areasonable measure in preventing such a po-tentially ominous complication.