A Retrospective Evaluation of Children Who Have Suffered a Grade III or IV Intraventricular Hemorrhage and Their Parents for Platelet Dysfunction.

Abstract 1440

This study is intended to evaluate children that have survived a grade III or IV intraventricular head bleed and their parents for a potential autosomal dominant inherited platelet dysfunction due to platelet dense granule deficiency (δ-SPD). Intraventricular hemorrhage (IVH) poses a significant risk in premature neonates less than 32 weeks gestation. Infants suffering from high grade (III-IV) periventricular or intraventicular bleeding have mortality rates approaching 50%. In addition, survivors of high grade IVH may suffer severe brain damage or a multitude of other long term neurological sequelae. Thus, we believe that investigation into the pathogenesis of neonatal IVH is not only crucial for the survival of these infants, but also for their quality of life in the future.

Current data suggest that the pathogenesis of IVH in the premature infant is related to a loss of ability to regulate cerebral blood flow. Changes in local blood pressure, which would otherwise be autoregulated, remain unrestrained and result in capillary bleeding. Previous prospective studies from our lab have shown that full term neonates have a transient platelet dysfunction at the time of birth (Blood, 100(11), 691a, 2002), which appears to be related to a platelet dense granule storage pool deficiency (δ-SPD). We have also found that 1 day old, full term neonates have mature platelets similar to adults. Our prospective data suggests that at day 3–5 after birth, premature infants of gestational age 26–33 weeks (n=29) have a δ-SPD similar to that observed in full-term umbilical cord blood platelets suggesting a delay in platelet maturation. Only one preemie included in the study had suffered an IVH (grade I); all preemies who suffered Grade III/IV IVH during our study died before we could obtain blood (Blood 108(11):1113, 2006). Parents evaluated had normal platelet storage pools.

Our current and on-going retrospective study of children that have survived a grade III/IV IVH and their parents supports our hypothesis that platelet dysfunction may play a significant role in the etiology of IVH. Survivors were identified from a database and parents sent a letter requesting their participation in the study. For those agreeing to participate, informed consent was obtained for this Institutional Review Board approved project. A vial of peripheral blood was obtained from both the IVH surviving child and their parent(s) to determine the platelet dense granule storage pool using the electron microscopy whole mount technique. Parents completed a vetted bleeding questionnaire for assessment of bleeding history/tendencies. Our preliminary data from 6 families reveals that all children surviving a grade III/IV IVH have a δ-SPD with an average of 2.64 ± 0.14 dense granules per platelet (DG/PL) whereas normal = 4–6 DG/PL. Their mothers also have a tendency for δ-SPD (5/6 δ-SPD and 1 within normal limits) with an overall average of 2.93 ± 0.35 DG/PL. Data collected from the questionnaires substantiate the laboratory results with a history of menorrhagia (determined by an established numerical pictorial method) the most significant correlation in 4/6 mothers. The fathers (4/5) tend to have normal numbers of DG/PL (4.06 ± 0.61; 1 had δ-SPD at 1.72 DG/PL). Interestingly, for the one mother with a normal number of DG/PL, the father had δ-SPD. Thus, all children evaluated to date in this study have δ-SPD and a parent who also has δ-SPD. The implication of these preliminary data suggest that potential identification of platelet dysfunction in women at risk for premature delivery could allow for prophylactic intervention for the premature neonate to reduce the morbidity and mortality related to IVH. As this study is currently ongoing, it is anticipated that additional data will be available for presentation.