Inherited Platelet Disorders Research Articles

Immune or inherited thrombocytopenia? A population-based cohort study on children and adolescents presenting with a low platelet count.

Thrombocytopenia is a common hematologic finding in children and adolescents. Immune thrombocytopenia (ITP) is the most common cause of this finding, but the differential diagnosis includes a growing list of genetic disorders. We aimed to report differences in phenotypes of patients with ITP, inherited platelet disorder (IPD)/primary immunodeficiency disorder (PID), and other causes, with a focus on differentiating ITP from inherited thrombocytopenia. This retrospective, population-based observational cohort from 2006 to 2020 involved 506 Finnish children under 16years of age presenting with isolated thrombocytopenia. Of the 506 participants, 79.7% had ITP, 6.7% had IPD/PID, and 13.6% had other causes of thrombocytopenia. A platelet count of ≤12 × 109/L best distinguished between ITP and other reasons with a sensitivity of 60% and a specificity of 80%. Among patients with the lowest platelet count of less than 10 × 109/L, 95.9% had ITP, 3.3% had IPD/PID, and 0.8% had other causes. Severe bleeding events were reported in 20 patients (4.0%), but there were no cases of intracranial or fatal bleeding due to thrombocytopenia. Up to 50% of patients with a high suspicion of inherited thrombocytopenia remained without a specific diagnosis despite genetic testing. ITP remains the most common cause of thrombocytopenia. A platelet count of ≤12 × 109/L often leads to an ITP diagnosis. Genetic disorders are rare but should be suspected in patients with persisting thrombocytopenia, especially with platelet counts constantly above 12 × 109/L, a positive family history, or atypical clinical features.

Phenotypic and genotypic evaluation of bleeding diagnostic dilemmas: Two case studies

Inherited platelet disorders (IPDs) are a heterogeneous group of conditions that present significant challenges in diagnosis and management. Here, we report two cases of patients presenting with clinically significant bleeding but with unclear etiologies by conventional clinical laboratory testing. Further evaluation, utilizing a combination of high-dimensional multiplexed mass cytometry and genetic sequencing, revealed the underlying causes of bleeding in both cases, leading to definitive diagnoses. These cases underscore the potential utility of combined multimodal approaches in evaluating patients with bleeding disorders. Moreover, these high-parameter methods can offer substantial mechanistic insights and can enhance our understanding of the molecular pathogenesis of IPDs. Future studies involving larger patient cohorts are needed to further validate this strategy, directly comparing its diagnostic yield and accuracy with current clinical laboratory testing approaches, which can ultimately improve patient care.

MPN/MDS Overlap Syndrome Anticipated by a Severe Bleeding Diathesis: Hypothesis of a Preexisting Platelet Disorder.

We report the case of a patient with a conclusive diagnosis of “MDS/MPN” Overlap Syndrome preceded by platelet disorder and hemorrhagic phenotype. We want to induce a reflection about diagnosis of oncohematological disorders in patient with a documented personal history of bleeding and/or platelet disorder, considering all the possible differential diagnosis: 1) Bleeding as the epiphenomenon of a still undiagnosed Myeloid Neoplasm or 2) Myeloid Neoplasm with germline predisposition and pre-existing platelet disorder; 3) Inherited platelet disorder successively developing MPN/MDS Overlap Syndrome. This case report underlines the importance of genetic testing in case of patient with documented platelet function disorder, including both mutations associated with inherited platelet disorders and germline mutations more strictly predisposing to Myeloid Neoplasms.

Utility of thromboelastography with platelet mapping for monitoring platelet transfusion in qualitative platelet disorders

BackgroundPatients with pathogenic variants in RASGRP2 (inherited platelet disorder (IPD)-18) exhibit normal platelet counts but impaired platelet aggregation and αIIbβ3 activation. Moderate-to-severe bleeding episodes require patients to be transfused with platelets and/or pro-hemostatic agents. We recently demonstrated that hemostatic efficacy of transfused platelets is limited by dysfunctional endogenous platelets in a mouse model of IPD-18 (Rasgrp2−/− mice), as dysfunctional platelets were recruited to the forming hemostatic plug but did not participate in clot contraction. Thus, higher amounts of transfused platelets were required to outcompete these dysfunctional cells and to reverse bleeding. ObjectiveWe here studied the usefulness of thromboelastography with platelet mapping (TEG-PM) for ex vivo monitoring of the hemostatic potential in Rasgrp2−/− mice transfused with various amounts of wild-type (WT) platelets. MethodsWhole blood (WB) samples from WT and Rasgrp2−/− mice were tested in TEG-PM and parameters for clot formation and contraction (K time, α-angle, maximum amplitude [MA]) were measured. ResultsRasgrp2−/− WB samples did not contract in TEG-PM, consistent with a critical role of this protein in αIIbβ3 activation. Addition of WT platelets improved TEG parameters in a ratio-dependent manner, consistent with our recent in vivo studies showing impaired hemostasis at a 5:1, but not at a 2:1 ratio of mutant to WT platelets. K and α values were identified as better predictors of transfusion efficacy than MA, the most platelet-dependent TEG parameter. ConclusionThis proof-of-concept study supports the use of TEG-PM to monitor platelet transfusion ratios and hemostatic potential in IPD-18 and potentially other platelet disorders.

Understanding and Managing Inherited Platelet Disorders: A Case Study of Storage Pool Disease

Understanding and Managing Inherited Platelet Disorders: A Case Study of Storage Pool Disease

Illustrated State-of-the-Art Capsules of the ISTH 2024 Congress

Here, we present a series of illustrated capsules from the State of the Art (SOA) speakers at the 2024 International Society on Thrombosis and Haemostasis Congress in Bangkok, Thailand. This year’s Congress marks the first time that the International Society on Thrombosis and Haemostasis has held its flagship scientific meeting in Southeast Asia and is the first to be organized by an international Planning Committee. The Bangkok program will feature innovative science and clinical updates from around the world, reflecting the diversity and multidisciplinary growth of our field. In these illustrated SOA capsules, you will find an exploration of novel models of thrombosis and bleeding and biomaterial discoveries that can trigger or block coagulation. Thromboinflammation is now understood to drive many disease states, and the SOA speakers cover cellular and coagulation responses to COVID-19 and other infections. The theme of crosstalk between coagulation and inflammation expands with capsules on protein S signaling, complement, and fibrinolytic inhibitors. Novel agents for hemophilia and thrombosis prevention are introduced. Challenging clinical conditions are also covered, such as inherited platelet disorders and antiphospholipid antibody syndrome. The scientific program in Bangkok will also showcase the work of clinicians and scientists from all parts of the world and chronicle real-world challenges. For example, 2 SOA capsules address the diagnosis and management of von Willebrand disease in low-income settings. Take some time to browse through these short illustrated reviews; we’re sure that you’ll be entertained, educated, and inspired to further explore the world of thrombosis and hemostasis.

Bioprinting Soft 3D Models of Hematopoiesis using Natural Silk Fibroin-Based Bioink Efficiently Supports Platelet Differentiation.

Hematopoietic stem and progenitor cells (HSPCs) continuously generate platelets throughout one's life. Inherited Platelet Disorders affect ≈ 3 million individuals worldwide and are characterized by defects in platelet formation or function. A critical challenge in the identification of these diseases lies in the absence of models that facilitate the study of hematopoiesis ex vivo. Here, a silk fibroin-based bioink is developed and designed for 3D bioprinting. This bioink replicates a soft and biomimetic environment, enabling the controlled differentiation of HSPCs into platelets. The formulation consisting of silk fibroin, gelatin, and alginate is fine-tuned to obtain a viscoelastic, shear-thinning, thixotropic bioink with the remarkable ability to rapidly recover after bioprinting and provide structural integrity and mechanical stability over long-term culture. Optical transparency allowed for high-resolution imaging of platelet generation, while the incorporation of enzymatic sensors allowed quantitative analysis of glycolytic metabolism during differentiation that is represented through measurable color changes. Bioprinting patient samples revealed a decrease in metabolic activity and platelet production in Inherited Platelet Disorders. These discoveries are instrumental in establishing reference ranges for classification and automating the assessment of treatment responses. This model has far-reaching implications for application in the research of blood-related diseases, prioritizing drug development strategies, and tailoring personalized therapies.

Use of crushed tranexamic acid tablets in water for paediatric patients with bleeding disorders.

Ε-Aminocaproic acid oral solution (EACA OS) is the only commercially available antifibrinolytic for patients who cannot swallow tablets. Insurance denials and high costs remain barriers to its use. To determine the safety and efficacy of crushed tranexamic acid tablets in water (cTXAw) for children with bleeding disorders. We retrospectively reviewed records of children (<10 years) with bleeding disorders who received cTXAw or EACA OS from 1 December 2018, through 31 July 2022, at Mayo Clinic (Rochester, Minnesota). Bleeding outcomes were defined according to ISTH criteria. Thirty-two patients were included (median age, 3 years; male, n=23). Diagnoses were VWD (n=17), haemophilia (n=5), FVII deficiency (n=3), inherited platelet disorder (n=4), ITP (n=2), and combined FV and FVII deficiencies (n=1). Thirty-two courses of cTXAw (monotherapy 24/32; mean duration 6 days) and fifteen courses of EACA (monotherapy 12/15; mean duration 5 days) were administered. No surgical procedures (n=28) were complicated by bleeding. Of the 19 bleeding events, 16 had effective haemostasis, two had no reported outcome, and one had no response. cTXAw and EACA were equally effective in preventing and treating bleeding (p value>.1). No patients had adverse effects. Eight of 19 patients (42%) who were initially prescribed EACA OS did not receive it because of cost or insurance denial. The estimated average wholesale price of one treatment was $94 for cTXAw and $905 for EACA OS. CTXAw appears to be an effective, safe, and low-cost alternative option to EACA OS for young children with bleeding disorders.

Glanzmann Thrombasthenia 10 Years Later: Progress Made and Future Directions.

Glanzmann thrombasthenia (GT) is the most common inherited platelet disorder (IPD) with mucocutaneous bleeding and a failure of platelets to aggregate when stimulated. The molecular cause is insufficient or defective αIIbβ3, an integrin encoded by the ITGA2B and ITGB3 genes. On activation αIIbβ3 undergoes conformational changes and binds fibrinogen (Fg) and other proteins to join platelets in the aggregate. The application of next-generation sequencing (NGS) to patients with IPDs has accelerated genotyping for GT; progress accompanied by improved mutation curation. The evaluation by NGS of variants in other hemostasis and vascular genes is a major step toward understanding why bleeding varies so much between patients. The recently discovered role for glycoprotein VI in thrombus formation, through its binding to fibrin and surface-bound Fg, may offer a mechanosensitive back-up for αIIbβ3, especially at sites of inflammation. The setting up of national networks for IPDs and GT is improving patient care. Hematopoietic stem cell therapy provides a long-term cure for severe cases; however, prophylaxis by monoclonal antibodies designed to accelerate fibrin formation at injured sites in the vasculature is a promising development. Gene therapy using lentil-virus vectors remains a future option with CRISPR/Cas9 technologies offering a promising alternative route.

Living, Caring, Learning – Setting boundaries for the wellbeing of everyone in bleeding disorders care

Abstract Cathy, a haemophilia nurse specialist in the UK, reflects on a challenging patient with a rare inherited platelet disorder. The patient did not attend regular clinic appointments, and when presenting at clinic due to severe bleeding or feeling unwell was often aggressive and abusive towards staff. The care team were concerned that he was putting his health at risk and followed protocols for vulnerable adults to try and ensure he was accessing the care he needed. This involved bringing in expertise outside of the multidisciplinary team (MDT), including non-medical services. Steps were also taken to ensure staff safety and wellbeing through in-house psychological support and the agreement of strategies for dealing with difficult behaviour. Ultimately, it was necessary to find an alternative care pathway for the patient. While acknowledging her disappointment in this outcome, Cathy reflects on how the processes followed have reinforced the development of individualised care plans for all patients with complex needs, and the importance of access to specialist services beyond the MDT. She also highlights considerations around the safety and wellbeing of the care team, the role of discussion and ‘debriefing’, and the value of staff access to psychological support.

Aggregates of nonmuscular myosin IIA in erythrocytes associate with GATA1- and GFI1B-related thrombocytopenia

BackgroundThe transcription factor GATA1 is an essential regulator of erythroid cell gene expression and maturation and is also relevant for platelet biogenesis. GATA1-related thrombocytopenia (GATA1-RT) is a rare X-linked inherited platelet disorder (IPD) characterized by macrothrombocytopenia and dyserythropoiesis. Enlarged platelet size, reduced platelet granularity, and noticeable red blood cell anisopoikilocytosis are characteristic but unspecific morphological findings in GATA1-RT. ObjectivesTo expand the investigation of platelet phenotype of patients with GATA1-RT by light- and immunofluorescence microscopy on a blood smear. MethodsWe assessed blood smears by light- and immunofluorescence microscopy after May-Grünwald Giemsa staining using a set of 13 primary antibodies against markers belonging to different platelet structures. Antibody binding was visualized by fluorescently labeled secondary antibodies. ResultsWe investigated 12 individuals with genetically confirmed GATA1-RT from 8 unrelated families. While confirming the already known characteristic of platelet morphology (platelet macrocytosis and reduced expression of markers for α-granules), we also found aggregates of nonmuscular myosin heavy chain II A (NMMIIA) in the erythrocytes in all individuals (1-3 aggregates/cell, 1-3 μm diameter). By systematically reanalyzing blood smears from a cohort of patients with 19 different forms of IPD, we found similar NMMIIA aggregates in the red blood cells only in subjects with GFI1B-related thrombocytopenia (GFI1B-RT), the other major IPD featured by dyserythropoiesis. ConclusionAggregates of NMMIIA in the erythrocytes associate with GATA1-RT and GFI1B-RT and can facilitate their diagnosis on blood smears. This previously unreported finding might represent a novel marker of dyserythropoiesis assessable in peripheral blood.

Classic Light Transmission Platelet Aggregometry: Do We Still Need it?

For more than 50 years, light transmission aggregometry has been accepted as the gold standard test for diagnosing inherited platelet disorders in platelet-rich plasma, although there are other functional approaches performed in whole blood. In this article, several advantages and disadvantages of this technique over other laboratory approaches are discussed in the view of recent guidelines, and the necessity of functional assays, such as light transmission aggregometry in the era of molecular genetic testing, is highlighted.

Inherited Thrombocytopenias Predisposing to Hematologic Neoplasms. Experience of the Spanish Group for Inherited Platelet Disorders (GEAPC)

Introduction In inherited thrombocytopenic disorders (IT) associated with germline genetic variants in the transcription factors RUNX1 (RUNX1-RT) and ETV6 (ETV6-RT) or ankyrin 26 (ANKRD26-RT), bleeding is usually not clinically relevant. However, patients have a high risk (10-45%) of developing hematologic malignancies (HM). Genetic diagnosis at an early stage of life is essential for these patients and their families, as the underlying genotype determines the natural history of the disease and, consequently, its prognosis and clinical management. High-Throughput Sequencing (HTS) has greatly facilitated diagnosing and providing personalized medicine for these patients. Objective The aim of this study was to evaluate the frequency, clinical characteristics, platelet phenotype and molecular alterations of patients with IT predisposing to HM, within the series of IT patients recruited by the Spanish Group of Inherited Platelet Disorders (GEAPC). Methods Since 2008, we have enrolled 296 patients (174 families) suspected of having any type of IT. They were selected according to their clinical and biological background. Bleeding (bleeding score (BS); ISTH-BAT), complete blood count and smear, and in many patients platelet phenotyping (platelet aggregation (LTA), cytometry, microscopy, etc.) were performed. Sanger sequencing of candidate genes (until 2014) or HTS was used for genetic diagnosis of patients. Candidate genetic variants were classified in accordance with the ACMG/AMP criteria, also taking into account the adapted specifications for RUNX1. Results Genetic diagnosis was obtained in 208 patients (76.3%) (135 families), identifying 26 different types of IT. Thirty patients (17 families) had RUNX1-RT (14.4%), 16 (5 families) had ANKRD26-RT (7.7%) and 7 cases (4 families) had ETV6-RT (3.4%). In patients with RUNX1-RT, the median age at identification of cytopenia and at genetic diagnosis was 17 (0-56) and 27 (1-71) years, respectively. Mild-to-moderate thrombocytopenia (95x109 pl/L (15-142)) and mild bleeding (BS=2(0-12)) was observed in 89% of these patients. Of the 13 patients evaluated, 83.3% had a reduced LTA at 2µg/ml collagen and 80% had low levels of glycoprotein Ia (collagen receptor). We identified 15 different variants in RUNX1 (8 novel); 47% missense, 30% nonsense, 12% large deletions, 6% splicing and 6% frameshift. Sixty-five percent of the variants were classified as pathogenic (PV), 6% as likely pathogenic (LPV), and 29% of uncertain significance (VUS). In 7 cases the variant was de novo. Ten patients (33.3%) developed HM (median age 49 years) (Table 1). Of these, 53% had at least one family member with HM (AML, 53.5%; MDS, 10.7%; CML, 7.1%; AML-post-MDS, 3.6%) or solid tumor (breast cancer, 14.2% [50% BRCA2+]; prostate, 7.1%; stomach, 3.6%). In 16 cases with ANKRD26-RT, thrombocytopenia was identified at age 16 (0-60 years), while the genetic diagnosis was made at age 36 (0-79 years). In all cases the thrombocytopenia was moderate [median: 53.5x109 pl/L (8-119)], mostly asymptomatic (BS=1.5(0-12)) and not associated with platelet dysfunction (5 cases studied). We detected 3 different variants in the 5'UTR of ANKRD26 (1 LPV, 2 VUS). One patient had a de novo variant. Twenty-five percent developed neoplasia (3 HM cases; 1 breast cancer) at 42 years of age (median). Two of 5 families had a history of HM (MDS or AML) (Table 1). The ETV6-RT patients were genetically diagnosed at the age of 30 (3-59) years, while thrombocytopenia, moderate [97 x 109 cells/L (8-119)] and not associated with a bleeding diathesis (BS=0 (0-4)), was detected at the age of 12 (2-33) years. In one case, a defect in LTA, activation and platelet dense granule number was detected in platelet function studies. In this group we identified 4 different ETV6 missense variants (2 PV and 2 LPV/VUS). One patient developed B-ALL at the age of 12 years (Table 1). Conclusions Inherited thrombocytopenia that predisposes to HM is the most common form of IT in this Spanish cohort (25.5% of cases [19% of families]). We found an excessive delay (10-20 years) in the genetic diagnosis of patients with respect to the age of identification of the cytopenia. The high rate of development of HM of 28% reinforces the critical importance of early genetic diagnosis of these IT in order to apply optimal surveillance and clinical management aimed at early detection of their evolution to neoplasm.

Targeted long-read sequencing identifies and characterizes structural variants in cases of inherited platelet disorders

BackgroundGenetic diagnosis of inherited platelet disorders (IPDs) is mainly performed by high-throughput sequencing (HTS). These short-read–based sequencing methods sometimes fail to characterize the genetics of the disease. ObjectivesTo evaluate nanopore long-read DNA sequencing for characterization of structural variants (SVs) in patients with IPDs. MethodsFour patients with a clinical and laboratory diagnosis of Glanzmann thrombasthenia (GT) (P1 and P2) and Hermansky–Pudlak syndrome (HPS) (P3 and P4) in whom HTS missed the underlying molecular cause were included. DNA was analyzed by both standard HTS and nanopore sequencing on a MinION device (Oxford Nanopore Technologies) after enrichment of DNA spanning regions covering GT and HPS genes. ResultsIn patients with GT, HTS identified only 1 heterozygous ITGB3 splice variant c.2301+1G>C in P2. In patients with HPS, a homozygous deletion in HPS5 was suspected in P3, and 2 heterozygous HPS3 variants, c.2464C>T (p.Arg822∗) and a deletion affecting 2 exons, were reported in P4. Nanopore sequencing revealed a complex SV affecting exons 2 to 6 in ITGB3 (deletion-inversion-duplication) in homozygosity in P1 and compound heterozygosity with the splice variant in P2. In the 2 patients with HPS, nanopore defined the length of the SVs, which were characterized at nucleotide resolution. This allowed the identification of repetitive Alu elements at the breakpoints and the design of specific polymerase chain reactions for family screening. ConclusionThe nanopore technology overcomes the limitations of standard short-read sequencing techniques in SV characterization. Using nanopore, we characterized novel defects in ITGB3, HPS5, and HPS3, highlighting the utility of long-read sequencing as an additional diagnostic tool in IPDs.

To Determine the Incidence of Various Subtypes of VWD with Specified VWF:RCof/ VWF:Ag Ratio’s In Pediatric Patients

Background: VWD is the most common inherited bleeding disorder characterized by defects in the concentration, structure, or function VWF. There are three main types of VWD that differ according to the degree of disease severity and inheritance pattern (Type 1, Type 2A, 2B, 2M, 2N and Type 3). Methodology: This is 05 years study (Feb 2016–Jan 2021) conducted in hematology section. In present study, amongst total inherited bleeding disorders, Incidence of VWD is 27%, Hemophilia (50%), inherited platelet disorders (14%) and remainder are undiagnosed. Amongst VWD, Type 1 VWD is the most common subtype studied, comprising 66% of total cases. Type 2 &amp; 3 VWD comprised 23% and 10% of total cases showing good correlation with the literature and other studies. Discussion: The European cross-sectional study yielded a population-based estimate of 0.05 per 100,000 for type 3 VWD. Estimates by VWD type from Europe and Western Pacific reported higher prevalence estimates for type 1 disease than type 2 or type 3: 2.7–7.2 per 100,000 for type 1 VWD, 0.8–2.5 per 100,000 for type 2, and 0.1–0.3 per 100,000 for type 3. Conclusion: VWD usually presents with mild bleeding symptoms (except in type 3 VWD) the diagnosis is often delayed. Prompt diagnosis and management can help to avoid potentially life-threatening bleeding events and unnecessary exposure to blood products.

Multiplexed Functional Assessment of Glanzmann Thrombasthenia Variants

High throughput genome and exome sequencing tests are used to identify disease-causing genetic variants, including those that cause inherited platelet disorders (IPDs) like Glanzmann Thrombasthenia (GT). However, most variants identified in clinical tests are classified as variants of unknown significance (VUS), lacking sufficient evidence to guide informed clinical decision-making. This frequent result of a VUS complicates clinical diagnosis and can be a source of uncertainty, distress, and inequity for patients. Functional studies that demonstrate a damaging effect of variants are considered strong evidence of pathogenicity but are missing for most variants. However, individually testing the function of all possible missense changes in IPD genes is impractical. Multiplexed assays of variant effect (MAVEs) have been developed for select diseases to simultaneously measure the functional effect of all possible nucleotides in a specific genomic region. However, MAVEs have typically been employed in cell lines, and often utilize over-expression systems, which don't account for the proper cellular and genomic context needed to assess variants in IPDs. In this study, we use CRISPR/CAS9 mediated homology directed repair (HDR) in CD34+ cells to create MKs with GT mutations in the gene ITGA2B and show that they model GT patient platelet phenotypes. We then implement a MAVE in CD34+ derived MKs to evaluate the impact on αIIb expression of a library of all possible single nucleotide changes for 12 nucleotides surrounding a type I GT variant. This was done by introducing a pooled library of HDR donors containing a mixture of test variants into CD34+ cells. This resulted in a pool of endogenously edited MKs, each containing one of 32 different nucleotide changes. These MKs were sorted into CD42+ and CD41+ or CD41- populations and analyzed using high throughput sequencing to assess variant enrichment. Analysis of sequencing reads indicated distribution of variant containing reads across all 12 nucleotides and incorporation of all 48 different HDR donors (32 changes, 12 identity replacements). Numerous indels were also identified. Our results identified two distinct clusters of variants: those supporting a damaging effect on expression, and those likely having no effect on expression. Notably, we observed that all nonsense variants and indels resulting in a stop codon clustered in the CD41- enriched population, whereas all silent variants clustered in the CD41+ enriched population. To classify variants more precisely, we used an expectation-maximization (EM) algorithm based on the distribution of read counts between the CD41+ and CD41- populations. This identified 12 missense, 3 nonsense, and 30 indel variants as abnormal, compared to 24 missense and 10 silent variants as normal with respect to CD41 expression. Agreement of our results with computational assessments of variant effects supported the findings. In conclusion, we developed an approach for the multiplexed assessment of GT variants, enabling the simultaneous evaluation of the functional effect of at least 32 different variants within a specific region of ITGA2B. This opens the door to assessing the functional impact of all possible nucleotide changes across the entire ITGA2B coding region and lays the foundation for similar investigations in other IPD genes.

THROMKIDplus Patient Registry and Biomaterial Banking for Children with Inherited Platelet Disorders.

Inherited platelet disorders (IPDs) represent a heterogeneous group of disorders that include both quantitative (thrombocytopenia or thrombocytosis) and qualitative (thrombocytopathy) defects. To gain better knowledge about the prevalence, pathogenesis, and clinical consequences of specific diseases, to improve diagnosis and treatment of patients with IPD, and to support translational research on a genetic, molecular, and physiological basis, the THROMKIDplus study group currently comprising 24 sites in Germany, Austria, and Switzerland decided to establish a patient registry with associated biomaterial banking for children. This registry is designed as a retrospective-prospective, multicenter observational study and supposed to launch in the second half of 2023. Blood smears, plasma, platelet pellets, and DNA of patients will be stored in certified biomaterial banks for future translational research projects. The main inclusion criteria are (1) diagnosis of or highly suspected IPD after assessment of a THROMKIDplus competence center and (2) patients aged 0 to 17 years. Initial and follow-up data on patient history, laboratory parameters, standardized documentation of bleeding tendency, and congenital defects are collected according to good clinical practice and current data protection acts by using the MARVIN platform, a broadly used data management system supported by the German Society for Pediatric Oncology Hematology (GPOH). The THROMKIDplus study group intends to enroll ∼200 patients retrospectively and an annual amount of ∼50 patients prospectively.

PB0358 Hereditary Bleeding Disorders Web-Based Registry of Patients with Inherited Platelet Disorders

PB0358 Hereditary Bleeding Disorders Web-Based Registry of Patients with Inherited Platelet Disorders

PB1384 Survey on Functional and Molecular Characterization of Inherited Platelet Disorders in Spain

PB1384 Survey on Functional and Molecular Characterization of Inherited Platelet Disorders in Spain

Treatment of Inherited Platelet Disorders: Current Status and Future Options.

Inherited platelet disorders (IPDs) comprise a heterogeneous group of entities that manifest with variable bleeding tendencies. For successful treatment, the underlying platelet disorder, bleeding severity and location, age, and sex must be considered in the broader clinical context. Previous information from the AWMF S2K guideline #086-004 (www.awmf.org) is evaluated for validity and supplemented by information of new available and future treatment options and clinical scenarios that need specific measures. Special attention is given to the treatment of menorrhagia and risk management during pregnancy in women with IPDs. Established treatment options of IPDs include local hemostatic treatment, tranexamic acid, desmopressin, platelet concentrates, and recombinant activated factor VII. Hematopoietic stem cell therapy is a curative approach for selected patients. We also provide an outlook on promising new therapies. These include autologous hematopoietic stem cell gene therapy, artificial platelets and nanoparticles, and various other procoagulant treatments that are currently tested in clinical trials in the context of hemophilia.