Rare bleeding disorders (RBDs), defined as hereditary coagulation factor deficits other than haemophilia, are characterized by a heterogenous clinical phenotype ranging from life-threatening bleeding to thrombosis. There are uncertainties concerning treatment intensity and levels needed to achieve haemostasis, and epidemiological data from Germany, Austria, and Switzerland (GTH region) are scarce.We performed a narrative literature review, focusing on bleeding phenotype and thrombotic risk. Epidemiologic data, including adults and children, and general treatment approaches have been collected via an online survey among GTH haemophilia centres (all categories) and the general information service of the German national registry (Deutsches Hämophilieregister, DHR).We provided an overview on RBDs, revealing that especially in FV, FVII, and FXI deficiencies, the correlation between factor levels and bleeding phenotype is poor. A thrombotic risk needs to be considered in FVII deficiency and afibrinogenaemia or dysfibrinogenaemia. The survey was completed by 34 centres from Germany, Austria, and Switzerland, and compared with 137 centres reporting data to the DHR. FVII deficiency was confirmed to be the most frequent, and FII deficiency was the rarest RBD in this region. For treatment, single factor concentrates were preferred over multifactor concentrates or plasma, and tranexamic acid was often part of the treatment. Approximately 30, 40, and <10% of patients with severe FV, FVII, and FXI deficiency (defined as factor level <10%), respectively, were receiving prophylactic treatment, suggesting an overall milder bleeding phenotype.More detailed registry data could give insights into the treatment landscape of RBDs, considering the challenge of clinical trials in rare diseases.

Inherited deficiencies of coagulation factors are rare and exhibit variable associations with severe bleeding phenotypes. Although conventional hemostatic assays serve as useful screening tools, they often fail to accurately predict clinical bleeding severity. Disease management is further complicated by poor correlation between residual factor levels and the overall symptom severity in affected patients and limited clinical experience. In this review, we evaluate the utility of global coagulation tests, such as the thrombin generation assay, plasmin generation assay (PGA), and rotational thromboelastometry (ROTEM), in assessing the severity of rare coagulation factor deficiencies and their clinical manifestations.Overall, thrombin generation, plasmin generation, and ROTEM were impaired in most rare coagulation factor deficiencies. Furthermore, significantly reduced coagulation factor activity and consequently decreased thrombin generation potential correlated with the clinical bleeding severity in deficiencies of prothrombin and factors V, VII, X, and XI. PGA was significantly impaired in fibrinogen and prothrombin deficiency and variably reduced in FV- and FX-deficient patients, but did not correlate with the presence or severity of bleeding manifestations. Lastly, ROTEM parameters were able to discriminate between asymptomatic FX-, FXI-, and fibrinogen-deficient patients and those with a history of bleeding.Although these studies are mostly limited to small sample sizes and prospective data are lacking, the available literature suggests that TGA, PGA, and ROTEM may be useful in stratifying patients according to their overall bleeding severity, as well as their risk of major bleeding complications in some of the rare coagulation factor deficiencies.

Factor XI (FXI) deficiency is an autosomal bleeding disorder characterized by low FXI levels, resulting in bleeding after trauma or surgery. Genetic variants affecting FXI structure and function often result in bleeding diatheses.This study aimed to estimate the variant detection rate (VDR), and assess its correlation with FXI activity (FXI:C) in a large cohort of FXI-deficient patients.Genetic defects in the gene were analyzed in 316 index patients (IPs) using Sanger or next-generation sequencing. Multiplex ligation-dependent probe amplification or copy number variation analysis was used to detect duplications and deletions.Genetic defects were identified in 249 IPs (VDR of 79%). A strong negative correlation (Pearson coefficient: -0.891) was found between FXI:C levels and VDRs: higher FXI:C levels corresponded to a lower likelihood of detecting genetic alterations, with a significant decline in VDR beyond 60 IU/dL. A total of 286 genetic variants were identified in gene: 56% missense, 24% nonsense, 11% small deletions/insertions, and 6% splice-site variants. Large deletions were rare (3%). A total of 48 novel variants were detected. Ashkenazi Jewish founder variants were the most frequent (14.3%). Variants p.Gln134Ter, p.Ile215_Asp216del, and p.Glu315Lys (27% of cases) were recurrent. In four cases, large deletions extended beyond the gene and included the neighboring gene, encoding prekallikrein.This study demonstrated a significant negative correlation between FXI:C levels and VDRs, underscoring the importance of genetic testing. Findings included combined deficiencies in FXI and prekallikrein due to large deletions affecting both and genes.

The Timed Up and Go (TUG) test is frequently used to assess patients' functional mobility. However, its psychometric characteristics in patients with haemophilia (PwH) are unknown. This study's primary aim was to determine the validity, reliability, standard error of measurement (SEM), and minimal detectable change (MDC) of the TUG in PwH. The secondary aim was to determine predictors for the TUG time.A total of 40 PwH were included. Test-retest reliability was assessed by the same rater at two time points and inter-rater reliability was assessed by two raters. Construct validity was tested via correlation analyses between the TUG and the haemophilia joint health score (HJHS), the short physical performance battery (SPPB), the HEP-Test-questionnaire, and the Haemophilia Activity List (HAL). SEM and MDC were calculated. Multiple linear regression analyses with several patient-specific predictors were performed.Test-retest and inter-rater reliability analyses revealed excellent ICCs of 0.990 (95% CI: 0.972-0.995) and 0.929 (95% CI: 0.870-0.962), respectively. The SEM and MDC of the TUG were 0.34 and 1.52 seconds, respectively. Large correlations ( > 0.5) were observed between the TUG and the HJHS, SPPB, HEP-Test-Q, and HAL. Regression analysis revealed the HJHS as the sole significant predictor, with the full model explaining 37.0% of the variance in TUG performance.In PwH, the TUG is a reliable test possessing an excellent test-retest and inter-rater reliability, while showing a high validity. TUG times can mainly be predicted by HJHS. The TUG can therefore be considered a suitable tool to evaluate mobility in adult PwH.

Emicizumab is a bispecific monoclonal antibody that mimics the cofactor function of activated factor VIII (FVIIIa). It is approved for routine prophylaxis in patients with severe or moderate congenital hemophilia A (HA), both with and without FVIII inhibitors, and is increasingly used as a first-line treatment in acquired HA (AHA). Owing to its predictable pharmacokinetic profile, emicizumab monitoring is generally limited to cases with suspected reduced efficacy, such as due to poor adherence or the development of anti-drug antibodies (ADAs). However, emicizumab interferes with standard clotting assays, particularly by shortening activated partial thromboplastin times (APTT). To address this, modified FVIII one-stage clotting assays (mOSA), which use higher sample pre-dilution and emicizumab-specific calibration, are commonly employed to estimate plasma levels, although other assay formats like emicizumab-calibrated chromogenic substrate assays based on human factors or liquid chromatography tandem mass spectrometry are also available. Additionally, global assays such as in vitro thrombin generation testing are being explored to better reflect clinical hemostatic efficacy. This review summarizes current knowledge on assay interferences caused by emicizumab, challenges in functional measurement of plasma levels, and strategies to ensure reliable laboratory assessment. We also discuss the relevance and methods for ADA detection and provide an overview of current and emerging strategies for thrombin generation measurement as a global indicator of treatment effectiveness.

In the case of familial thrombocytopenia, a congenital defect should be considered; however, in particular older patients who have had thrombocytopenia for a long time have often not yet been genetically analyzed using modern sequencing methods. Remarkably, sometimes they are still suspected of suffering from chronic immune thrombocytopenia until genetic testing reveals a congenital defect. We report on elderly Finnish siblings (both older than 60 years) with lifelong thrombocytopenia. The lifelong bleeding tendency in both the siblings was usually treated with tranexamic acid and platelet transfusions when necessary. In 2022, the older brother presented at the University Hospital in Helsinki because he had recently been suffering from gastrointestinal bleeding and also had mild pancytopenia. Because his sister lived abroad, the Finnish colleagues recommended that the sister should present to the University Hospital in Freiburg. Independent genetic testing of both the siblings using NGS identified the diagnosis of -associated gray platelet syndrome. The disease comprises macrothrombocytopenia and a reduction of α-granules in platelets, resulting in a grayish appearance of platelets on the blood smear. Patients usually suffer from a mild to moderate bleeding diathesis. Interestingly, during the last years a more syndromic character of the disease has been described: besides the platelet phenotype, the immune system can also be affected. In the course of the disease patients may develop pancytopenia, splenomegaly, and bone marrow fibrosis. Comprehensive diagnostics including molecular genetic analyses are particularly important to provide these patients with adequate care and treatment.

Venous thromboembolism (VTE) is an increasingly frequent complication of solid tumors and hematological malignancies, significantly contributing to morbidity and mortality. In patients with acute cancer-associated VTE, therapeutic anticoagulation with direct oral factor Xa inhibitors (DXIs) or low-molecular-weight heparin (LMWH) for 3 to 6 months is recommended by clinical practice guidelines based on randomized controlled trials. Although extended secondary VTE prophylaxis should be considered in patients with persisting active cancer, the type, intensity, and duration of continued anticoagulation have not been rigorously studied until recently. In non-cancer patients, low-dose DXIs (apixaban 2.5 mg BID or rivaroxaban 10 mg OD) are the preferred options to prevent recurrent VTE beyond the first 6 months of treatment. The recently published API-CAT trial compared low-dose with full-dose apixaban for extended secondary VTE prophylaxis in 1,766 patients with active cancer. Over a 12-month period, low-dose apixaban was associated with similar efficacy, but significantly improved safety compared with full-dose apixaban, with cumulative incidence rates of recurrent VTE and major or clinically relevant non-major bleeding of 2.1% versus 2.8% (adjusted subhazard ratio [sHR]: 0.76; 95% confidence interval [CI]: 0.41-1.41;  < 0.001 for noninferiority) and 12.1% versus 15.6% (adjusted sHR: 0.75; 95% CI: 0.58-0.97;  = 003 for superiority), respectively. Based on these findings, extended secondary VTE prophylaxis with low-dose DXIs, preferably apixaban 2.5 mg BID, is proposed for most patients with persisting active cancer. To facilitate informed decision-making in clinical practice, we provide an expert consensus on criteria that either justify cessation of anticoagulation or require continued full-dose anticoagulation.

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 ThromKid 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.

Major bleeding (MB) is a serious complication in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). Although its association with long-term adverse outcomes is well documented, the impact of in-hospital MB on early cardiovascular prognosis remains incompletely characterized.To investigate the association between in-hospital MB and major adverse cardiovascular events (MACE) in patients with ACS treated with PCI.We conducted a retrospective cohort study on 829 consecutive ACS patients who underwent successful PCI between January 2021 and December 2023. MB was defined as Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding events. MACE was defined as a composite of all-cause mortality, recurrent myocardial infarction, ischemic stroke, urgent target vessel revascularization, or new-onset/decompensated heart failure with left ventricular ejection fraction (LVEF) <30%. Clinical data and outcomes were extracted from hospital records and independently adjudicated.MB occurred in 4.5% of patients ( = 37). The incidence of in-hospital MACE was significantly higher among patients with MB compared to those without (40.5% vs. 8.1%,  < 0.001). In multivariate logistic regression, MB was the strongest independent predictor of in-hospital MACE (OR: 12.43, 95% CI: 3.43-44.98,  < 0.001), followed by reduced LVEF (OR per % increase: 0.794, 95% CI: 0.747-0.843,  < 0.001), age, and white blood cell count.In-hospital MB is a potent and independent predictor of early MACE in patients with ACS undergoing PCI. These findings emphasize the need for careful risk stratification, bleeding prevention strategies, and individualized antithrombotic management in this high-risk population.

Nonacog beta pegol (N9-GP) is a glycoPEGylated FIX replacement product with extended half-life for treatment of haemophilia B patients. Monitoring of N9-GP with clotting-based one-stage FIX assays is complicated by high variations, mainly due to reagent-specific interference with polyethylene glycol.In 11 distinct specialized coagulation laboratories in Austria, N9-GP spiked samples were measured in replicates in two distinct surveys, 3 years apart, using five different one-stage assay reagents and one chromogenic FIX assay. Regression analysis was used to investigate if back-calculation of N9-GP levels is feasible.We could demonstrate a linear relationship between the spiked N9-GP concentration and measured FIX activity levels for all examined assays, suggesting that N9-GP activity may be back-calculated using reagent-/platform-specific conversion factors. Within-laboratory variation after 3 years was acceptable in most, but not all, laboratories.We demonstrate that back-calculation of N9-GP activity levels may be possible when using one-stage FIX assays. However, we recommend that every laboratory ascertain its own conversion factor. When measuring real patient samples, we encourage simultaneous measurement of N9-GP spiked control material with known concentrations to ensure the validity of the current back-calculation.

The prevention of intraoperative bleeding in patients with haemophilia is the key to a successful surgical procedure. Daily life of patients with haemophilia A and B significantly improved with prophylaxis with extended half-life factor concentrates (EHL-FVIII and EHL-FIX). The aim of this study was to investigate the efficacy and safety of EHL factor concentrates during surgery.In a retrospective chart review all surgical interventions in our hospital in patients with haemophilia A and B treated with EHL-FVIII or EHL-FIX undergoing surgery between 2016 and 2022 were included. Patients with inhibitors against FVIII or FIX were excluded.A total of 88 surgical interventions (41 minor, 47 major) in 52 patients with haemophilia were performed. The interventions consisted of 70 surgeries in 42 patients with haemophilia A and 18 surgeries in 10 patients with haemophilia B. The replacement therapy during the surgeries was performed with four different EHL FVIII and three different EHL FIX concentrates. Bolus injections were performed directly before surgery and continued after surgery with variable intervals ranging from 8 to 48 hours. The median dose before major surgery was 32.31 IU/kg FVIII and 47.06 IU/kg FIX and before minor surgery was 27.78 IU/kg FVIII and 33.78 IU/kg factor IX. There were 11 complications including 4 bleeding complications during/after surgery. No thromboembolic event and no inhibitor against FVIII or FIX were detected during follow-up.The replacement therapy with EHL factor concentrates in surgical interventions in patients with haemophilia A and B is safe and effective.

Hypofibrinogenemia is a congenital fibrinogen disorder characterized by a proportional decrease of functional and antigenic fibrinogen levels. Herein, we present a unique case illustrating the complex genotype-phenotype relationship in hypofibrinogenemia and the inability of low fibrinogen levels to counteract hypercoagulability.A 77-year-old male with factor V Leiden heterozygosity experienced surgery-related deep vein thrombosis at ages 65 and 71, along with poor wound healing and postoperative hematomas. Proportionally reduced functional and antigenic fibrinogen levels revealed hypofibrinogenemia. Whole exome sequencing identified a heterozygous fibrinogen gene cluster deletion and a hemizygous variant (p.Pro265Leu, rs6054) in the fibrinogen β () gene, both of which are associated with hypofibrinogenemia. The youngest son, who has noticeably higher fibrinogen levels, shares the deletion but does not carry the hemizygous variant. This suggests that the variant (p.Pro265Leu) contributes to a greater reduction in fibrinogen levels.This case suggests that the coexistence of thrombotic risk factors and potentially reduced thrombin clearance-resulting from low fibrinogen levels due to a fibrinogen gene cluster deletion and a hemizygous variant-may shift the hemostatic balance toward thrombosis in a patient with moderate hypofibrinogenemia.