PB0570 - Report of variable bleeding tendency due to congenital PAI-1 deficiency and discussion of possible new deficiency without genomic sequence abnormality

Background: Various and fatal bleeding tendencies are observed in humans with congenital PAI-1 deficiency. However, these symptoms are completely absent in PAI-1 knockout mice. Therefore, detailed analysis of bleeding symptoms in human PAI-1 deficiency is important for analyzing PAI-1 function in humans.

Aims: At present, there are three families with genetically confirmed PAI-1 deficiency, of which we have reported on two of them. Since the initial report of these cases, a number of previously unrecognized bleeding events have been observed. Therefore, we are reporting here for the first time on the details of these new bleeding events.

Methods: We are using an ECLT assay system with Ca ions to screen for PAI-1 deficiency, followed by genetic analysis. Although the two previous cases were detected by this method, there are several cases with no abnormalities at all in the coding region of the SERPINE1 gene, and a definitive diagnosis cannot be made at this time. Recent advances in next generation sequencing technology have revealed the presence of 12 different splice variants in the SERPINE1 gene. Therefore, the new variants were subjected to an in silico structural analysis.

Results: Our reported G397R mutation in SERPINE1 was found to cause Serpinopaty due to B-sheet instability, and it was clear that some of these new variants could alter the structure of the region.

Conclusion(s): This suggests that PAI-1 deficiency may be caused in the absence of abnormalities in the SERPINE1 gene and that new methods are needed for genetic analysis of PAI-1 deficiency.