Age-Dependent Control of Collagen-Dependent Platelet Responses by Thrombospondin-1—Comparative Analysis of Platelets from Neonates, Children, Adolescents, and Adults

Abstract

Platelet function is developmentally regulated. Healthy neonates do not spontaneously bleed, but their platelets are hypo-reactive to several agonists. The mechanisms underlying immature platelet function in neonates are incompletely understood. This critical issue remains challenging for the establishment of age-specific reference ranges. In this study, we evaluated platelet reactivity of five pediatric age categories, ranging from healthy full-term neonates up to adolescents (11–18 years) in comparison to healthy adults (>18 years) by flow cytometry. We confirmed that platelet hypo-reactivity detected by fibrinogen binding, P-selectin, and CD63 surface expression was most pronounced in neonates compared to other pediatric age groups. However, maturation of platelet responsiveness varied with age, agonist, and activation marker. In contrast to TRAP and ADP, collagen-induced platelet activation was nearly absent in neonates. Granule secretion markedly remained impaired at least up to 10 years of age compared to adults. We show for the first time that neonatal platelets are deficient in thrombospondin-1, and exogenous platelet-derived thrombospondin-1 allows platelet responsiveness to collagen. Platelets from all pediatric age groups normally responded to the C-terminal thrombospondin-1 peptide RFYVVMWK. Thus, thrombospondin-1 deficiency of neonatal platelets might contribute to the relatively impaired response to collagen, and platelet-derived thrombospondin-1 may control distinct collagen-induced platelet responses.

Platelets in the neonate: Not just a small adult

“…The neonatal platelet hyporeactivity is likely an integral part of this balanced system, but the specific cellular interactions and pathways involved need to be elucidated. Furthermore, while some studies have shown significant improvement in platelet reactivity in newborn infants by 10 to 14 days of life, 49,65 more recent studies assessing platelet activation in different age groups (from neonates to adolescents) have found that age‐dependent improvements in platelet reactivity follow highly variable patterns, depending on the platelet agonist and the platelet activation marker studied 66,67 . Interestingly, some studies have identified platelet functional deficiencies extending into adolescence 66,67 .…”

“…Furthermore, while some studies have shown significant improvement in platelet reactivity in newborn infants by 10 to 14 days of life, 49 , 65 more recent studies assessing platelet activation in different age groups (from neonates to adolescents) have found that age‐dependent improvements in platelet reactivity follow highly variable patterns, depending on the platelet agonist and the platelet activation marker studied. 66 , 67 Interestingly, some studies have identified platelet functional deficiencies extending into adolescence. 66 , 67 The mechanisms regulating the neonatal platelet hyporeactivity and the complex transition from a neonatal to an adult platelet are poorly understood, and should be the focus of future research.…”

“… 66 , 67 Interestingly, some studies have identified platelet functional deficiencies extending into adolescence. 66 , 67 The mechanisms regulating the neonatal platelet hyporeactivity and the complex transition from a neonatal to an adult platelet are poorly understood, and should be the focus of future research. Similarly, it will be important to determine whether and how platelets contribute to the rapid angiogenesis needed to support the growth of a fetus and neonate, and how adult platelet transfusions affect these processes.…”

Neonatal Platelets: Lower G12/13 Expression Contributes to Reduced Secretion of Dense Granules

“…In healthy individuals, coagulation is tightly regulated to maintain the hemostatic balance between bleeding and thrombosis. The developing hemostatic system matures in several phases from fetus to adult, gradually changing and adapting to the requirements of each developmental stage [ 1 , 2 , 3 ]. Consequently, neonatal hemostasis differs from that of adults and has several peculiarities [ 4 , 5 ].…”

“…Early studies of the functional structure of neonatal platelets showed lower surface expression of GPIbα (CD42b) and varying expression of P-selectin and integrin αIIbβ3 depending on gestational age [ 19 , 20 , 21 , 22 ]. Neonatal platelets exhibit reduced granule secretion upon stimulation, resulting in less shedding of bioactive molecules into circulation [ 3 , 14 ]. We showed that inorganic polyphosphate (PolyP), a prothrombotic substance accumulated in platelet dense granules, is shed to a lesser extent by neonatal platelets than adult platelets.…”