Hamostaseologie最新文献

Inherited platelet disorders (IPD) are a heterogeneous group of diseases causing bleeding, which are often challenging to diagnose. To improve the diagnostic process for these disorders, the ThromKidplus study group of the Permanent Pediatric Commission of the Society for Thrombosis and Haemostasis Research (GTH) has updated the AWMF Guideline for the "Diagnosis of Inherited Platelet Disorders" (AWMF Registry Number 086-003).Key updates in the guideline include a detailed diagnostic algorithm, emphasizing the use of standardized questionnaires, thorough patient history, and specific laboratory tests such as light transmission aggregometry (LTA), flow cytometry, and genetic testing. Updated guidelines for pre-analytics standardize sample preparation and handling to ensure reliable test results. Updated protocols for aggregometry and flow cytometry aim to enhance diagnostic accuracy. The integration of next-generation sequencing (NGS) provides comprehensive genetic analysis, and a new chapter on future developments highlights emerging technologies and research fields.This guideline supports the diagnosis of IPD close to the patient's residence, limits the diagnostic process to essential steps, and assists in counseling affected individuals and their families, ensuring that the diagnosis provides especially quality of life benefits to the patient.

Congenital fibrinogen deficiencies (CFDs), traditionally considered rare monogenic disorders, are now recognized as more prevalent and genetically complex than previously thought. Indeed, the symptoms manifested in CFD patients, such as bleeding and thrombosis, are likely to result from variation in several genes rather than solely driven by variants in one of the three fibrinogen genes, FGB, FGA, and FGG. This review highlights recent advances in understanding the genetic causes of CFD and their variability, facilitated by the growing use and availability of next-generation sequencing data. Using gnomAD v4.1.0. data, which includes more than 800,000 individuals, we provide updated global prevalence estimates for CFDs based on frequencies of predicted deleterious variants in FGB, FGA, and FGG. Recessively inherited fibrinogen deficiencies (homozygous genotypes) could be present in around 29 individuals per million, while dominantly inherited deficiencies (heterozygous genotypes) may be present in up to 15,000 per million. These increased estimates can be attributed to the inclusion of broader, more diverse genetic datasets in the new version of gnomAD, thus capturing a greater range of rare variants and homozygous cases.

Hyperfibrinolysis is rarely investigated as an underlying mechanism in patients with mild-to-moderate bleeding disorders (MBDs) and bleeding disorders of unknown cause (BDUC). Hereditary hyperfibrinolytic disorders, including α2-antiplasmin (α2-AP) deficiency, plasminogen activator inhibitor type 1 (PAI-1) deficiency, Quebec platelet disorder, and tissue plasminogen activator (tPA) excess, present with mild-to-moderate bleeding symptoms that are common in patients with MBD or BDUC, but may also manifest as life-threatening bleeding. This review summarizes the available data on hyperfibrinolysis in MBD and BDUC patients, and its assessment by various methods such as measurement of fibrinolytic factors, global hemostatic assays (e.g., viscoelastic testing, turbidity-based plasma clot lysis), and fluorogenic plasmin generation (PG). However, evidence on the relationship between hyperfibrinolytic profiles and bleeding severity is inconsistent, and, although found in some coagulation factor deficiencies, has not been universally observed. In BDUC, increased tPA activity and paradoxical increases in thrombin-activatable fibrinolysis inhibitor and α2-AP have been reported. Some studies reported no change in PAI-1 levels, while others observed reduced PAI-1 levels in a significant subset of patients. The tPA-ROTEM (tPA-rotational thromboelastometry) assay identified a hyperfibrinolytic profile in up to 20% of BDUC patients. PG analysis revealed a paradoxically reduced peak plasmin, but showed strong predictive power in differentiating BDUC patients from healthy controls. Although global fibrinolytic assays may help identify hyperfibrinolytic profiles as a potential cause of increased bleeding in some MBD or BDUC patients, the utility of measuring fibrinolytic factors requires further investigation. Tranexamic acid is commonly used to treat hereditary hyperfibrinolysis and is also recommended in MBD/BDUC patients prior to hemostatic challenges.

Haemophilia is a rare genetic bleeding disorder that primarily affects males and results in the deficiency of clotting factors VIII (haemophilia A) or IX (haemophilia B). One of the most debilitating long-term complications of haemophilia is chronic joint damage with pain, and reduced mobility, due to bleeding into the joints. As the primary cause of morbidity in people with haemophilia (PwH), joint health assessment is critical for disease management and optimizing patient outcomes. Among the tools developed to monitor joint health in PwH, the Haemophilia Joint Health Score (HJHS) has emerged as the most widely used and validated clinical tool. There is evidence supporting the use of the HJHS in both children and adults. In contrast to scoring methods that incorporate imaging techniques, which primarily describe the morphology of the joints, the HJHS allows for the assessment and monitoring of joint functionality.

In Germany, hemophilia patients with a severe bleeding phenotype receive lifelong prophylactic treatment with intravenous concentrated factor VIII (FVIII) or IX (FIX) to prevent bleeding events. To assess the economic value of emerging treatment options, studies describing the economic burden of hemophilia under the current standard of care in Germany are needed.This study classified hemophilia A (HA) and B (HB) patients by treatment regimen in administrative claims data to examine the real-world economic burden of Hemophilia in Germany from 2016 to 2021.Hemophilia patients were identified in InGef statutory health insurance claims data via ICD-10 codes D66 (HA) and D67 (HB) in combination with one or more claims for hemophilia-related medication.Each patient's factor regimen was classified as either indicative of a severe phenotype needing prophylaxis or a non-severe phenotype treated on demand using a classification threshold of 100,000 International Units (IU) FVIII/year (HA) and 80,000 IU FIX/year (HB). Health care resource utilization and cost outcomes were captured for each study year.Male prevalence per 100,000 ranged from 6.39 to 7.81 (HA) and 1.26 to 1.89 (HB), with 43 to 53% (HA) and 40 to 56% (HB) categorized as severe. In 2021, mean (standard deviation [SD]) per-patient medication costs were €321,987 (€157,915) in the severe treatment group versus €43,487 (€92,821) in the non-severe group for HA and €289,411 (€132,400) versus €19,253 (€23,655) for HB.The results demonstrate the high economic burden of severe HA and HB in Germany, driven by the need for continuous factor replacement therapy, and give an estimate of treatment costs based on a real-world therapy mix.

There is strong evidence that platelets significantly contribute to cancer progression. Numerous studies have shown that microRNAs in platelet microvesicles play an important role in different stages of cancer and can serve as new diagnostic and prognostic biomarkers. Since platelet microRNAs have opposing purposes, it is challenging to make clear-cut judgements regarding their involvement in carcinogenesis. However, it is well known that the processes regulated by microRNAs in cancer include cell proliferation, cell death, epithelial-mesenchymal transition, cancer metastasis, and angiogenesis. This review focusses on and summarizes current research in the field of platelet-cancer interactions and discusses the role of platelet microRNAs in cancer development, which is a promising area for future research and therapeutic development.

This study, involving a cohort of 980 patients with arterial and/or venous events, evaluated the relative importance of genetic and traditional risk factors using a machine learning model approach. The analysis revealed that conventional risk factors-such as age, gender, tobacco use, obesity-and acquired thrombophilia (most prominently antiphospholipid syndrome [APS]) outperformed any genetic risk variants analyzed. Of note, the presence of heterozygous FVL mutations was associated with a reduced arterial risk, whereas carriers of heterozygous factor VII activation protease (FSAP) mutations had a lower risk of venous events.Thus, by employing diverse statistical approaches, the study showed that acquired risk factors exert the most substantial impact on the development of thrombotic events, except for the well-known role of FVL mutations in venous events.

In this article, our goal is to offer an introduction and overview of the diagnostic approach to inherited platelet function defects (iPFDs) for clinicians and laboratory personnel who are beginning to engage in the field. We describe the most commonly used laboratory methods and propose a diagnostic four-step approach, wherein each stage requires a higher level of expertise and more specialized methods. It should be noted that our proposed approach differs from the ISTH Guidance on this topic in some points. The first step in the diagnostic approach of iPFD should be a thorough medical history and clinical examination. We strongly advocate for the use of a validated bleeding score like the ISTH-BAT (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool). External factors like diet and medication have to be considered. The second step should rule out plasmatic bleeding disorders and von Willebrand disease. Once this has been accomplished, the third step consists of a thorough platelet investigation of platelet phenotype and function. Established methods consist of blood smear analysis by light microscopy, light transmission aggregometry, and flow cytometry. Additional techniques such as lumiaggregometry, immune fluorescence microscopy, and platelet-dependent thrombin generation help confirm and specify the diagnosis of iPFD. In the fourth and last step, genetic testing can confirm a diagnosis, reveal novel mutations, and allow to compare unclear genetics with lab results. If diagnosis cannot be established through this process, experimental methods such as electron microscopy can give insight into the underlying disease.