OC 39.3 - Mapping hemorrhagic stroke in the fetal and neonatal period as a consequence of thrombocytopenia.

Background: Severe thrombocytopenia is a major clinical problem, it affects 1 in 2000 live births, 30 % of babies admitted to neonatal intensive care units, and 70% of babies with extremely low birth weight. Severe thrombocytopenia is most commonly caused by fetal and neonatal alloimmune thrombocytopenia (FNAIT). The main complication of FNAIT is intra-cerebral hemorrhage (ICH) which carries significant risk of life-long morbidities and death but a causative role of thrombocytopenia leading to ICH was unknown.

Aims: To demonstrate that platelets are required throughout development to maintain cerebral vasculature integrity and to prevent ICH. To understand the level of thrombocytopenia that would lead to ICH and to define the platelet count required to prevent/minimise ICH.

Methods: We have used two models of severe thrombocytopenia, the Nfe2 knock out mouse line which are deficient in platelets and secondly, a clinically relevant model of FNAIT. In both models we have determined the extent of thrombocytopenia by analysis of the peripheral blood and we used image analysis to determine brain bleeds and location.

Results: In the absence of platelets, brain bleeds occur as early at E11.5-E12 and persist through development. That the first bleeds always occur in the ganglionic eminence region of the brain. We demonstate that bleeds occur in different regions of the brain depending on when thrombocytopenia occurs and by controlling the level of thrombocytopenia we can determine the platelet count required to reduce the risk of ICH

Conclusion(s): We demonstrate that platelets are required throughout development for maintaining cerebral vasculature integrity and that ICH occurs in regions of the brain which in humans, can lead to neurologic damage. By tuning platelet counts in utero we have defined levels of thrombocytopenia that have differential risk of developing ICH and additionally, by the second week after birth the cerebral vasculature has developed a resilience to severe thrombocytopenia.