Background Diagnosis of inherited platelet function disorders (IPFDs) is important for appropriate management and to improve epidemiologic and clinical knowledge. However, there remains a lack of consensus on the diagnostic approach. Objectives To gain knowledge on the current practices for the diagnosis of IPFD worldwide. Methods A 67‐item questionnaire was distributed to the ISTH members and to the members of several national hemostasis and thrombosis societies. Results A total of 202 laboratories from 37 countries participated in the survey. The most frequent criterion to define patients with a suspected IPFD was a history of mucocutaneous bleeding and no acquired cause, but heterogeneity on the identification criteria was evident. Only 64.5% of respondents performed a direct clinical interview. On average, each laboratory studied 72 patients per year. The most commonly used laboratory equipment were the light‐transmission aggregometer, the Platelet Function Analyzer‐100, and the flow cytometer. Screening tests were platelet count, peripheral blood smear, light‐transmission aggregometry, and Platelet Function Analyzer‐100. Second‐step tests were flow cytometry, molecular genetic analysis, and electron microscopy. Methodologies varied widely. In total, ~ 14 000 patients were investigated yearly and 60% turned out to not have a defect. Of the remaining 40%, only 8.7% received a diagnosis at a molecular level. Conclusions Many laboratories worldwide are involved in the diagnosis of IPFD. A large fraction of the patients studied remain without a diagnosis. A high variability in the diagnostic approaches is evident.

Key Points: Developed a targeted sequencing platform covering 63 genes linked to heritable bleeding, thrombotic, and platelet disorders. The ThromboGenomics platform provides a sensitive genetic test to obtain molecular diagnoses in patients with a suspected etiology.

Megakaryocytes transfer a diverse and functional transcriptome to platelets during the final stages of thrombopoiesis. In platelets, these transcripts reflect the expression of their corresponding proteins and, in some cases, serve as a template for translation. It is not known, however, if megakaryocytes differentially sort mRNAs into platelets. Given their critical role in vascular remodeling and inflammation, we determined whether megakaryocytes selectively dispense transcripts for matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) into platelets. Next-generation sequencing (RNA-Seq) revealed that megakaryocytes express mRNA for 10 of the 24 human MMP family members. mRNA for all of these MMPs are present in platelets with the exception of MMP-2, 14, and 15. Megakaryocytes and platelets also express mRNA for TIMPs 1-3, but not TIMP-4. mRNA expression patterns predicted the presence and, in most cases, the abundance of each corresponding protein. Nonetheless, exceptions were observed: MMP-2 protein is present in platelets but not its transcript. In contrast, quiescent platelets express TIMP-2 mRNA but only traces of TIMP-2 protein. In response to activating signals, however, platelets synthesize significant amounts of TIMP-2 protein. These results demonstrate that megakaryocytes differentially express mRNAs for MMPs and TIMPs and selectively transfer a subset of these into platelets. Among the platelet messages, TIMP-2 serves as a template for signal-dependent translation.

Excessive bleeding at surgery is a feared complication in patients with inherited platelet disorders. However, very few studies have evaluated the frequency of surgical bleeding in these hemorrhagic disorders. We performed a worldwide, multicentric, retrospective study to assess the bleeding complications of surgery, the preventive and therapeutic approaches adopted, and their efficacy in patients with inherited platelet disorders: the Surgery in Platelet disorders And Therapeutic Approach (SPATA) study. We rated the outcome of 829 surgical procedures carried out in 423 patients with well-defined forms of inherited platelet disorders: 238 inherited platelet function disorders and 185 inherited platelet number disorders. Frequency of surgical bleeding was high in patients with inherited platelet disorders (19.7%), with a significantly higher bleeding incidence in inherited platelet function disorders (24.8%) than in inherited platelet number disorders (13.4%). The frequency of bleeding varied according to the type of inherited platelet disorder, with biallelic Bernard Soulier syndrome having the highest occurrence (44.4%). Frequency of bleeding was predicted by a pre-operative World Health Organization bleeding score of 2 or higher. Some types of surgery were associated with a higher bleeding incidence, like cardiovascular and urological surgery. The use of pre-operative pro-hemostatic treatments was associated with a lower bleeding frequency in patients with inherited platelet function disorders but not in inherited platelet number disorders. Desmopressin, alone or with antifibrinolytic agents, was the preventive treatment associated with the lowest bleedings. Platelet transfusions were used more frequently in patients at higher bleeding risk. Surgical bleeding risk in inherited platelet disorders is substantial, especially in inherited platelet function disorders, and bleeding history, type of disorder, type of surgery and female sex are associated with higher bleeding frequency. Prophylactic pre-operative pro-hemostatic treatments appear to be required and are associated with a lower bleeding incidence.

Introduction Genetic testing for inherited bleeding, thrombotic and platelet disorders (BTPD) provides a significant opportunity to improve patient care. Gene panel tests have recently been implemented to diagnose BTPD patients, however, all differ in their gene content. While considering an exhaustive list of genes is desirable, best practice suggests genes should only be tested with appropriate evidence, to provide clinical actionable findings. Objective The Scientific and Standardization Subcommittee (SSC) on Genomics in Thrombosis and Hemostasis of the International Society on Thrombosis and Haemostasis (ISTH) aimed to generate a list of disease‐causing (TIER1) genes with conclusive evidence for causing BTPD. Methods Gene‐disease associations were curated based on literature evidence and expert discussions during yearly SSC meetings. Reference transcripts were assessed based on community input, transcript and protein length, and expression levels in the relevant tissues. Results We curated information for 91 gene‐disease associations using peer‐reviewed literature describing genotype and phenotype information from diagnostic and research laboratories, knowledge from specific functional hemostasis, platelet and molecular assays or phenotypes that support gene‐disease associations, and observations in mouse models recapitulating the human diseases. For each gene, we have assigned the OMIM reference and disease name, the mode of inheritance, mutational mechanism for the disease and the Locus Reference Genome (LRG)‐based main transcript. The list is available at https://www.isth.org/page/GinTh_GeneLists. Conclusion Evidence‐based curated BTPD genes ensure the best possible design for a diagnostic‐grade gene panel test and such gene‐disease pairs are essential to guide appropriate interpretation and reporting of variants.