Novel Insights from Clinical Practice Received: May 12, 2010 Accepted after revision: June 13, 2010 Published online: November 9, 2010
Neonatology 2011;99:247–249 DOI: 10.1159/000316934
Severe Hemorrhage after Low-Molecular-Weight Heparin Treatment in a Preterm Neonate H.A. van Elteren a A.B. te Pas a W.J. Kollen b F.J. Walther a E. Lopriore a
Divisions of a Neonatology and b Hemato-Oncology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
Established Facts • Thromboembolic events in preterm neonates are increasingly being diagnosed. • Knowledge about the efficacy and safety of treatment with low-molecular-weight heparin in neonates with thromboembolic events is very limited.
Novel Insights • Treatment with low-molecular-weight heparin in preterm neonates can lead to severe hemorrhage. • Randomized trials are urgently needed to determine the optimal management of thromboembolic events in neonates.
Key Words Thromboembolic event ⴢ Extremely low birth weight neonates ⴢ Low-molecular-weight heparin ⴢ Hemorrhage
Abstract Thromboembolic events in preterm neonates are increasingly being diagnosed due to the increasing use of umbilical catheters and central venous catheters. Whether thromboembolic events should be treated routinely with low-molecular-weight heparin (LMWH) is controversial and the optimal management is still not clear due to the lack of randomized controlled trials. Most importantly, knowledge about the safety of treatment with LMWH in neonates with thromboembolic events is very limited. We present a case of severe hemorrhage in a preterm neonate after LMWH treatment and summarize the scarce data reported in the literature.
Introduction
The use of low-molecular-weight heparin (LMWH) in neonates is increasingly advocated for numerous clinical indications [1, 2]. Recent guidelines recommend treatment with LMWH in various thromboembolic events such as deep venous thrombosis, cerebral sino-venous thrombosis and renal vein thrombosis [1, 2]. The majority of recommendations are based on uncontrolled studies, small case series, in vitro experiments or extrapolation of study data performed in the adult and pediatric population [1, 2]. Data on the safety and efficacy of LMWH in neonates, and in particular in extremely low birth weight (ELBW) neonates, is scarce and based just on a handful of case series [3–6]. Although adverse effects are reported to be rare, several major complications have recently been described [3–6]. To increase the awareness
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E. Lopriore, MD, PhD Division of Neonatology, Department of Pediatrics, J6-S Leiden University Medical Center, PO Box 9600 NL–2300 RC Leiden (The Netherlands) Tel. +31 71 526 2909, Fax +31 71 524 8198, E-Mail e.lopriore @ lumc.nl
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cm). There were no signs of aneurysma spurium (i.e. pulsating hematoma resulting from tear in vessel wall after puncture). Hemoglobin level had dropped from 14.6 to 10.7 g/dl within a few days. Platelet count and clotting factors were within the normal range for preterm neonates (platelet count: 194 ! 109/l, prothrombin time: 12 s, activated partial thromboplastin time: 39 s, fibrinogen: 3.2 g/dl). Anti-FXa level was 0.69 U/ml. An emergency surgical drainage was performed under local anesthesia after administration of 1 mg of protamine sulfate. Fifteen ml of blood was evacuated. Besides residual scarring, the leg healed without complications. Tinzaparin treatment was continued and administered for a total of 3 months. At discharge, ultrasound examination showed that the intracardiac thrombus had resolved.
Fig. 1. Large hematoma in the left thigh near the insertion site of
a previous indwelling catheter.
among neonatologists on the potential side effects of LMWH, we present an additional case of severe hemorrhage in an ELBW neonate and summarize the findings reported in the literature.
Case Report A female neonate was born after spontaneous delivery at 26+0 weeks’ gestation. Her birth weight was 798 g and Apgar scores were 9, 10 and 10 after 1, 5 and 10 min, respectively. She required continuous positive airway pressure due to respiratory distress syndrome and was treated with broad-spectrum antibiotics. Umbilical venous and arterial catheters were placed successfully on the first day. Three days after birth she became acutely ill and required intubation and mechanical ventilation. Blood, urine and liquor cultures were positive for Candida albicans, fulfilling the diagnostic criteria for disseminated candida sepsis. Echocardiography, primarily performed to exclude candida endocarditis, demonstrated the presence of a small thrombus (diameter: 3 mm) on the right atrium. In addition, severe thrombocytopenia was present (lowest platelet count 12 ! 109/l) and was treated with several platelet transfusions. Treatment with Tinzaparin (LMWH) was started by local protocol in a daily dosage of 275 IU/kg and administered subcutaneously through an indwelling catheter (Insuflon쏐). The place of injection (through the indwelling catheter) was changed routinely at least once a week to avoid local complications. The Tinzaparin dosage was chosen in accordance to Dutch guidelines [7]. Anti-FXa levels were measured regularly and were within the therapeutic range (0.5–1.0 U/ml). Thirteen days after Tinzaparin treatment was initiated, the clinical condition of the neonate deteriorated: she became pale, less reactive and had increasing episodes of apnea and cyanosis. On examination, a large and painful swelling (2.5 ! 2 cm diameter) was noted on the left upper-leg at the injection site of a previous indwelling catheter (fig. 1). Ultrasound examination showed a subcutaneous and intramuscular hematoma (3.2 ! 1.7 ! 3.5
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Discussion
We describe a major complication (severe hematoma) after Tinzaparin treatment in a ELBW neonate. Tinzaparin is a LMWH and acts as a potent co-inhibitor of several activated coagulation factors, especially factors Xa and IIa (thrombin). The primary inhibitory activity is mediated through the plasma protease inhibitor antithrombin. Benefits of LMWH over other antithrombotics are its superior bioavailability, minimal monitoring requirements, lack of interference by other drugs or diet, longer half-life, possibility of subcutaneous administration and dose-dependent clearance resulting in a more predictable anticoagulant response [8]. Although experience in the pediatric population is increasing, use of LMWH in ELBW neonates is still very limited and few studies have been performed to evaluate safety and dose requirement [3–6]. Whether the currently used therapeutic range is also applicable to ELBW neonates is not well known. Most importantly, no randomized controlled trials have been performed in ELBW neonates to determine the therapeutic effect of LMWH in neonates with thrombi. Recommendations in recent guidelines regarding LMWH therapy in neonates are thus considered to be weak and have low quality evidence [1]. Despite the various benefits, treatment with LMWH in neonates may also be harmful and is associated with minor and major hemorrhage. To date, three small case series of neonates treated with LMWH have reported on the potential side effects. In a prospective cohort study of 62 newborns (of whom 15 were preterm), Streif et al. [4] reported four (6%) major bleedings, including two major hematomas at the injection site and one small intracerebral hemorrhage 3 days after initiation of therapy. Four neonates (6%) developed minor bleeding including hematuria, bloody stool, and bleeding at the local enoxaparin administration site. van Elteren /te Pas /Kollen /Walther / Lopriore
In a retrospective study of 10 preterm neonates treated with LMWH due to venous and arterial thrombosis, Michaels et al. [3] reported bleeding complications in 3 patients (30%), including mild epistaxis (n = 1), small subependymal hemorrhage (n = 1) and oozing at an operative wound site (n = 1). In a retrospective study of 16 neonates (of whom 12 preterms) treated with LMWH, Malowany et al. [5] reported minor local adverse effects at the site of the indwelling subcutaneous catheter (induration, bruises, hematomas, or leakage) in 9 (56%) neonates but also major adverse events including scleral hemorrhage (n = 1), gastrointestinal tract bleeding (n = 3), infected hematoma (n = 1) and osteopenia (n = 1). In a recent case report with a similar clinical course as described in our patient, Obaid et al. [6] described an ELBW neonate with a severe hematoma after treatment with LMWH. The neonate developed rapidly progressive compartment syndrome at the site of enoxaparin administration with an indwelling catheter and necessitated surgical decompression. Caution should be used when interpreting these reports due to the small numbers of ELBW neonates and other methodological limitations. Moreover, the causative factor for the adverse event may not always be clear. ELBW neonates are known to be at greater risk of developing bleeding complications due to co-morbidity such as thrombocytopenia, immaturity of the vascular system and liver impairment. Nevertheless, these small case series and our case report raise important questions concerning patient safety in ELBW neonates and subcutaneous treatment with LMWH. While treatment with LMWH is reported to be
safe in adult patients, current studies suggest that preterm neonates could be more at risk to develop severe adverse effects. In addition, the mode of administration of the drug has not yet been studied in preterm neonates. Whether local complications would be less likely to occur if the injections were given each time on a different place is not known. Moreover, the intensity and duration of LMWH treatment may be different in children due to the lower thrombin generation compared to adults. The safety, intensity and duration of LMWH treatment in neonates and pediatric patients needs to be assessed in proper clinical studies, preferably in randomized clinical trials. Whether cardiac thrombi or line thrombi in neonates should be routinely treated with LMWH is controversial and the optimal management is still not clear due to the lack of randomized controlled trials. Complete or partial clot resolution after treatment with LMWH ranges from 59 to 80% with a mean time to resolution of 56 days [3, 4]. However, complete or partial resolution has also been reported to occur spontaneously, even in case of large cardiac thrombi [9]. In a recent study, Butler-O’Hara et al. [10] reported 24 preterm neonates with catheter-related thrombus. All thrombi resolved spontaneously without antithrombotic therapy. Given the potential severe complications, use of antithrombotic therapy in the neonatal population must be given only after a precise deliberation of risks and benefits. Neonatologists should be aware of the potentially severe side effects associated with LMWH treatment in neonates. Large multicenter randomized trials are urgently to determine the efficacy, safety and validity of medical treatment for thromboembolic events in preterm neonates.
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