Abstract/Summary

Linking the genetic background of patients to a bleeding diathesis and altered platelet function is still challenging. We aimed to assess how the multiparameter microspot-based measurement of thrombus formation under flow can identify patients with a platelet bleeding disorder. For this purpose, we studied 16 patients, presenting with bleeding and/or albinism and a suspected platelet dysfunction, as well as 15 relatives. Genotyping of patients revealed a novel biallelic pathogenic variant in RASGRP2 (splice site c.240-1G>A), abrogating CalDAG-GEFI expression; a compound heterozygosity (c.537del, c.571A>T) in P2RY12, affecting P2Y12 signaling; and heterozygous variants of unknown significance in the P2RY12 and HPS3 genes. Other patients had confirmed Hermansky-Pudlak syndrome type 1 or 3. In 5 patients, no genetic variant was found. Platelet functions were assessed by routine laboratory measurements. Blood samples from all subjects and day controls were screened for blood cell counts and microfluidic outcome on six surfaces (48 parameters), in comparison to a reference cohort of healthy subjects. Differential analysis of the microfluidic data showed that key parameters of thrombus formation were compromised for the 16 index patients. Principal component analysis resulted in separate clusters of patients versus heterozygous family members plus control subjects. Clusters further segregated by inclusion of hematological values and laboratory measurements. Subject ranking indicated an overall impairment in thrombus formation for the patients carrying a (likely) pathogenic variant of the genes, but not for the asymptomatic relatives. Together, our results indicate the advantage of testing for multiparametric thrombus formation in this patient population.