In the fetus, the ductus arteriosus shunts blood from the placenta to the aorta, bypassing the nonventilated lungs. Following birth, the ductus arteriosus closes, enabling perfusion of the newly ventilated lungs. The ductus arteriosus is subsequently remodeled into a fibrous band by mechanisms that are incompletely understood. Working in the Massberg laboratory in Munich, Echtler et al. found histological evidence of platelet accumulation within the lumen of the ductus arteriosus of newborn mice evaluated directly after birth. Intravital microscopy of newborn pups 20 minutes after birth demonstrated substantial adhesion of platelets at the ductus arteriosus, but not in the adjacent aorta. Using closure angiography, they demonstrated that mice deficient in the platelet fibrinogen receptor integrin áIIb, mice infused with an antibody to the collagen receptor GPVI, or congenitally thrombocytopenic mice demonstrated a high incidence of persistent patency of the ductus arteriosus. The thrombocytopenic mice with persistent patency demonstrated pulmonary hypertension and right ventricular remodeling. To assess the relevance of their results to the human process, the investigators evaluated specimens from newborns undergoing cardiac surgery for congenital heart disease. They demonstrated exposure of the adhesion protein von Willebrand factor and fibrinogen as well as platelet accumulation in the lumen of the ductus arteriosus. They also performed a retrospective analysis of premature infants that demonstrated thrombocytopenia as a major risk factor for patency of the ductus arteriosus.
The Role of Platelets for Sealing of the Contracted DA. The scheme delineates the proposed sequence of events contributing to postnatal DA occlusion, which ultimately leads to permanent DA closure. As a result, the luminal aspect of the DA wall adopts a prothrombotic phenotype with endothelial activation, deposition of vWF and fibrin(ogen), and eventually endothelial cell detachment from the internal elastic lamina, leading to the collagen exposure. Together, this triggers the accumulation of platelets circulating in the residual DA lumen. The platelet plug that forms seals the residual lumen of the contracted DA and, together with other mechanisms, facilitates subsequent luminal remodeling.
The Role of Platelets for Sealing of the Contracted DA. The scheme delineates the proposed sequence of events contributing to postnatal DA occlusion, which ultimately leads to permanent DA closure. As a result, the luminal aspect of the DA wall adopts a prothrombotic phenotype with endothelial activation, deposition of vWF and fibrin(ogen), and eventually endothelial cell detachment from the internal elastic lamina, leading to the collagen exposure. Together, this triggers the accumulation of platelets circulating in the residual DA lumen. The platelet plug that forms seals the residual lumen of the contracted DA and, together with other mechanisms, facilitates subsequent luminal remodeling.
In Brief
Persistence of a patent ductus arteriosus is a major cause of morbidity and mortality in preterm infants. The incidence is approximately 0.2 percent. However, in babies < 1,500 g, the incidence is > 30 percent. The model presented in this paper suggests that an initial contraction of the ductus arteriosus and subsequent platelet-mediated sealing are required for permanent closure. This model accounts for the observation that thrombocytopenia is associated with failed closure of patent ductus arteriosus by indomethacin, which stimulates constriction of the vessel but not sealing. These observations provide substantial evidence for platelet closure of the ductus arteriosus in mice and premature infants. The role of platelets in closure of the ductus arteriosus in mature newborns remains less clear, as hypoxia alone may stimulate sufficient remodeling. Nonetheless, these studies provide an important and unexpected role of platelets in the development of the heart.
