Current Controversy on Platelets and Patent Ductus Arteriosus Closure in Preterm Infants

Abstract

Platelets are critically involved in murine patent ductus arteriosus (PDA) closure. To date, the clinical significance of these findings in human preterm infants with PDA is still controversial. We discuss the available study data on the role of platelets for PDA closure in preterm infants: Several mostly retrospective studies have yielded conflicting results on whether thrombocytopenia contributes to failed spontaneous ductal closure. The same applies to investigations on the role of thrombocytopenia as a risk factor for unsuccessful ductus arteriosus closure by pharmacological treatment with cyclooxygenase inhibitors. Nonetheless, recent meta-analyses have concluded that thrombocytopenia constitutes an independent risk factor for both failed spontaneous and pharmacological PDA closure in preterm infants. However, the available investigations differ in regard to patient characteristics, diagnostic strategies, and treatment protocols. Several studies suggest that impaired platelet function rather than platelet number is critically involved in failure of ductus arteriosus closure in the preterm infant. A recent randomized-controlled trial on platelet transfusions in preterm infants with PDA failed to show any benefit for liberal vs. restrictive transfusion thresholds on PDA closure rates. Importantly, liberal transfusions were associated with an increased rate of intraventricular hemorrhage, and thus should be avoided. In conclusion, the available evidence suggests that thrombocytopenia and platelet dysfunction contribute to failure of spontaneous and pharmacological PDA closure in preterm infants. However, these platelet effects on PDA seem to be of only moderate clinical significance. Furthermore, platelet transfusions in thrombocytopenic preterm infants in order to facilitate PDA closure appear to cause more harm than good.

Keywords: hemodynamics; patent ductus arteriosus; platelets; thrombocytopenia; very low birth weight.

Figure 1

Structural factors that play a role in ductus arteriosus closure. Illustrated are the structural features known to regulate ductus closure in mice, preterm infants, and term-gestation infants. Mice have mature smooth muscle cells (pink) that constrict robustly in response to oxygen but lack intimal cushions (yellow), which may explain why platelets (green) are required for vessel occlusion and remodeling. Term-gestation infants have a thick medial layer composed of mature smooth muscle cells that are very sensitive to oxygen-induced constriction. They also have prominent vasa vasorum (purple circles) which results in local ischemic areas and hypoxic signaling during closure. A platelet plug and mononuclear cells (blue circles) adhere to the lumen during closure and promote formation of a permanent seal and remodeling. In contrast, several structural factors contribute to failed ductal closure in preterm infants. The preterm ductus has an underdeveloped media containing immature smooth muscle cells and less vasa vasorum, making it less sensitive to oxygen/hypoxia signaling. Preterm vessels also lack prominent intimal cushions and have preterm platelets. Characteristics of preterm human platelets that are associated with an enhanced vulnerability to dysfunction, which in turn might contribute to higher rates of ductal patency in immature preterm infants are also listed. ADP, adenosine di-phosphate; GPIIb/IIIa, glycoprotein IIb/IIIa; PAC-1, procaspase activating compound 1 which detects activated GPIIb/IIIa.