Mathematical model of platelet turnover in thrombocytopenic and nonthrombocytopenic preterm neonates

Abstract

Kulshrestha M, Sola-Visner M, Widness JA, Veng-Pedersen P, Mager DE. Mathematical model of platelet turnover in thrombocytopenic and nonthrombocytopenic preterm neonates. Am J Physiol Heart Circ Physiol 308: H68 -H73, 2015. First published October 31, 2014 doi:10.1152/ajpheart.00528.2013.-Neonatal thrombocytopenia affects 22-35% of all neonates admitted to neonatal intensive care units. The purpose of this study was to develop a mathematical model for characterizing platelet (PLT) kinetics in thrombocytopenic preterm neonates. Immature PLT fraction (IPF) and PLT counts were measured for up to 35 days after birth in 27 very low birth weight preterm neonates. PLT transfusions were administered to 8 of the 27 (24%) subjects. The final model included a series of four transit compartments to mimic the production and survival of IPF and PLT. Model parameters were estimated using nonlinear mixed effects modeling with the maximum likelihood expectation maximization algorithm. The model adequately captured the diverse phenotypes expressed by individual subject profiles. Typical population survival values for IPF and PLT life spans in nonthrombocytopenic patients were estimated at 0.912 and 10.7 days, respectively. These values were significantly shorter in thrombocytopenic subjects, 0.429 and 2.56 days, respectively. The model was also used to evaluate the influence of growth and laboratory phlebotomy loss on the time course of IPF and PLT counts. Whereas incorporating body weight was essential to correct for expanding blood volume due to growth, phlebotomy loss, a possible covariate, did not significantly influence PLT kinetics. This study provides a platform for identifying potential covariates that influence the interindividual variability in model parameters regulating IPF and PLT kinetics and for evaluating future pharmacological therapies for treating thrombocytopenic neonates. neonatal thrombocytopenia; immature platelet fraction; platelets; transit compartment model NEONATAL THROMBOCYTOPENIA is a common hematological disorder, and ϳ22-35% of all neonates admitted to the neonatal intensive care unit suffer from this condition (22,27). Premature very low birth weight (VLBW, Ͻ1,500 g at birth) neonates are more often affected, as the incidence of thrombocytopenia is inversely proportional to gestational age. Traditionally, the definition of thrombocytopenia in neonates of all gestational ages is the same as in adults, namely a platelet (PLT) count of Ͻ150 ϫ 10 3 /l based on fetuses in the second trimester having PLT counts within the normal adult range (13).The underlying general mechanisms responsible for neonatal thrombocytopenia are similar to adults, namely, increased PLT destruction, decreased PLT production, PLT sequestration, or a combination of these processes (27). However, it is more difficult to identify causes of neonatal thrombocytopenia as the diagnosis can be challenging owing to the dynamic nature of newborn development and technical difficulties associated with performing certain diagnostic tests i...

Thrombocytopenia and platelet transfusion in the neonate

“…In VLBW infants with severe thrombocytopenia associated with NEC or sepsis, IPF# is decreased by~50% (IPF# 4.7 Â 10 9 /L) [38]. This suggests that a decreased megakaryopoietic activity contributes to the development of severe thrombocytopenia [40]. In summary, the percentage of IPF (IPF%) is higher compared to controls in the case of platelet consumption, and normal in the case of bone marrow failure.…”

“…Chronic platelet consumption, inadequate thrombopoietin production due to liver dysfunction, or rare congenital disorders in platelet production should be considered. The analysis of platelet counts in a small case series of very low birth weight infants demonstrated that the platelet life span is shortened from 10 to 2.5 days in thrombocytopenic infants [40]. Chronic liver dysfunction, particularly after prolonged parental nutrition or surgery for NEC with cholestasis, aggravates thrombocytopenia.…”

Time course of immature platelet count and its relation to thrombocytopenia and mortality in patients with sepsis

“…In contrast, AIPC is considered to specifically reflect the daily platelet production [ 23 ]. The role of AIPC in thrombocytopenia is similar to that of the reticulocyte production index in evaluating anemia: correction for mature platelets is not required because the lifespan of an immature platelet is less than 24 h [ 24 , 25 ]. Therefore, a low AIPC in thrombocytopenia suggests decreased thrombopoiesis, such as in aplastic conditions, or an inadequate megakaryocytic response [ 19 , 21 ].…”

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

“…It has recently been shown that a lower number of mature platelets during the latter half of the 1st week of life was associated with PDA in preterm infants, while immature platelets were not independently associated with PDA ( 55 ). Importantly, a mathematical model of platelet turnover in preterm infants demonstrated significantly shorter population survival values for immature platelets and shorter platelet life spans in thrombocytopenic vs. non-thrombocytopenic neonates, indicating a preferential depletion of older, more mature platelets in thrombocytopenic infants ( 56 ).…”