A(nother) day in the life of neonatal platelets

In this issue of Blood, Liu et al demonstrate that neonatal platelets survive longer than their adult counterparts, which provides the rapidly growing fetus and neonate with a mechanism to expand platelet mass and maintain hemostasis during the transition from fetal to adult hematopoiesis.¹ 

Thrombocytopenia, which may contribute to intracranial hemorrhage in preterm neonates, is a major clinical problem encountered in the neonatal intensive care unit. Significant intracranial bleeding can lead to hydrocephalus, seizures, neurologic deficits, and death. The current treatment of thrombocytopenia in preterm neonates is platelet transfusions, but the risks of this therapy include viral infections, transfusion-related acute lung injury, and volume overload.²  New therapies are urgently needed, but first a basic understanding of neonatal thrombopoiesis is needed. In their article, Liu et al reveal a novel biological strategy for maintaining platelet homeostasis in neonates that is independent of the rate of platelet production.¹ 

Using a mouse model for neonatal thrombopoiesis, the authors found an approximate doubling of the platelet count during the newborn period despite a 5-fold increase in blood volume; however, the increase in blood volume was also accompanied by an ∼10-fold increase in platelet mass. How does the mouse achieve such a large increase in total platelets? During the first 14 days of life, the transition of murine hematopoiesis from the fetal liver to the postnatal adult marrow is nearly complete.¹  Using in vivo biotin-labeled platelets in newborn mice, the authors demonstrate that platelet production in neonatal mice during the first 2 weeks of life is similar to that of adult mice, which clearly does not account for the increase in platelet mass. Instead, platelet life span temporarily expands from 4 to 5 days during the murine newborn period. This increase in neonatal platelet life span is accounted for by cell-intrinsic factors, as exogenously injected adult platelets into murine pups have the same life span as those in injected into adult mice. This enhanced life span is only seen for the first 2 weeks of life, after which the murine platelets have a normal life span. These survival findings were confirmed in human cultured cord blood vs adult peripheral blood platelets, suggesting the murine findings also apply to humans.

Recent data have shown that the Bcl-2 family member Bcl-x_L, which inhibits the activity of the proapoptotic proteins Bak and Bax, is a critical prosurvival protein that regulates platelet senescence.³  In the current study, the prosurvival protein Bcl-2 was significantly higher in both cord blood platelets and murine neonatal platelets when compared with their respective adult counterparts. There were no differences in Bcl-x_L expression. However, the increased Bcl-2 expression did not account for the increased neonatal platelet life span, as Bcl-2-deficient murine pups had normal platelet counts. In contrast, neonatal platelets are more resistant to apoptosis when cultured with the Bcl-2/Bcl-x_L inhibitor ABT-737 when compared with adult platelets, which suggests the increased life span in newborn platelets involves the apoptosis program.

In summary, the authors have nicely demonstrated that the neonatal period is associated with a large increase in platelet mass, which is a result of an increase in platelet life span and not an increase in platelet production. Perhaps that would explain why, in sepsis and other states associated with enhanced platelet destruction in neonates, platelet drop can be precipitous and recovery is often sluggish.⁴  The biological mechanism underlying this increased life span is an opportunity for future investigation but likely involves Bcl-2 and Bcl-x_L, as well as other components of the apoptosis pathway. Understanding the regulation of platelet life span may provide new therapeutic opportunities to improve platelet survival, thereby avoiding thrombocytopenic states and their potential for hemorrhagic events in the preterm neonate.