Review
Thromboembolism and anticoagulation management in the preterm infant

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Summary

The incidence of preterm thromboembolism has been increasing due to advances in diagnostic imaging which allow better detection of thrombi in sick preterm infants. At the same time, improvement in neonatal intensive care unit supportive care has increased the number of surviving and living preterm infants with thromboembolic risk factors. Disruption in the fine balance of hemostasis with potential risk factors, specifically septicemia and indwelling catheters, increase the occurrence of thromboembolic events. Treatment strategies in preterm infants are challenging due to limited data.

Introduction

Preterm infants (PIs) are at greater risk than older children for thrombosis and thromboembolic complications [1]. Their hemostatic system is very dynamic and different from children and adults [2], [3]. Whereas some have reported that the evolution of hemostatic cascade in utero places PIs in a relative pro-thrombotic state, they in fact appear to be in relative hemostatic balance as they rarely suffer spontaneous thrombosis (Fig. 1) [2], [4], [5]. When the balance is disrupted, in particular with vascular access devices and septicemia, the risk of developing thromboembolism increases significantly [4]. Dehydration, polycythemia, fluctuations in blood pressure and maternal risks such as pre-eclampsia, diabetes mellitus (DM), autoimmune disorders, chorioamnionitis are other potential contributors to the development of thrombosis in PIs [1], [3]. Postnatally, the coagulation proteins in PIs continue to change substantially over the subsequent six months of age [1], [2], [6], [7].

The Canadian and German registries have reported incidences of thromboembolism in 2.4 per 1000 and 5.1 per 100,000 live births respectively [1], [2], [3], [8], [9]. A review of 4734 neonates in The Netherlands (January 2004 to July 2010) recorded an incidence of 6.8 per 1000 neonatal intensive care unit (NICU) admissions with 63% of the neonates at <32 weeks of gestation. This rate is higher than the previous reported incidences [10]. The distribution of events and imaging techniques in these three neonatal registries were similar. All symptomatic venous and arterial thrombotic episodes were included but central nervous system (CNS) events were excluded in the Canadian registry [1], [2].

The lack of clinical data related to preterm thromboembolism forces extrapolation of treatment strategies from adult data [2]. Furthermore, heterogeneity in gestational age of PIs with different maturational stages of coagulation system poses a challenge to develop a “one-size-fits-all” treatment strategy. This review article focuses on hemostasis, types of thrombosis, risk factors, diagnosis, management, and outcome of thrombosis in PIs.

Section snippets

Evolution of fetal and neonatal hemostasis

Components of hemostasis change throughout fetal life and these components do not cross the placenta [11]. The development of the hemostasis system is incomplete at birth [2], [11]. Platelets are the first component that appears in fetuses at five weeks of conception and reaches the normal adult range of 150 to 450×109/L by 22 weeks of gestation [12]. Platelet aggregation in PIs has been reported to be hypo-reactive and impaired due to deficiency of α-adrenergic receptors on the platelet

Hemostastic dysregulation in septic preterm infants

Sepsis continues to be a significant cause of mortality and morbidity in PIs. Activation of procoagulant pathways, consumption of clotting factors, alterations in fibrinolysis and reduced anticoagulant activity are factors that contribute to dysfunction of the coagulation cascade in sepsis [15]. Initiation of coagulation is triggered by pro-inflammatory cytokines with amplification of thrombin generation and inhibition of the fibrinolytic system. This mechanism causes fibrin deposition in the

Overview and incidence

Vascular access is a major challenge in PIs [11]. Umbilical venous catheter (UVC) is necessary to provide vascular access for hemodynamic monitoring, intravenous fluids, medication and frequent blood sampling. However, it carries an additional risk for thrombosis and is the commonest cause of thrombosis in PIs. Incidence of UVC thromboembolic event varies between 21% and 71% in different studies [2]. The discordant results between studies are due to differences in research methodology, the

General principles of management

Treatment of thromboembolism in PIs is still based on expert opinion [17]. The major challenge in the management of preterm thromboembolism is the paucity of evidence-based guidelines on optimal duration, dose, safety, and efficacy of anticoagulation [2]. Each individual risk/benefit ratio has to be considered carefully before commencing anticoagulation. Withholding anticoagulation therapy in PIs with high risk of hemorrhage is also equally an active decision [1], [2], [10].

UFH has been the

Perspective

All PIs with thromboembolic event warrant a long-term follow-up with an emphasis on PTS, PHT, renal impairment, neurological deficit, discrepancy in limb growth and claudication. Large cohort studies to determine the natural history of thrombosis in PI would be beneficial.

Practice points

  • Most thromboses in premature infants are secondary to vascular access devices: thus judicious use; careful placement; and early removal of vascular access is appropriate.

  • There appears to be no benefit to routine

Conflict of interest statement

None declared.

Funding sources

None.

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