Limited value of testing for factor XIII and α2-antiplasmin deficiency in patients with a bleeding disorder of unknown cause.

INTRODUCTION: In patients with an increased bleeding tendency, extensive diagnostic blood testing is often performed. When results of tier 1 assays of primary haemostasis are normal, protocols recommend additional testing to rule out rare disorders including coagulation factor XIII (FXIII) and α2-antiplasmin (α2AP) deficiency. AIM: To evaluate the added diagnostic value of FXIII and α2AP levels in patients with a bleeding disorder of unknown cause (BDUC). METHODS: A retrospective monocentre cohort study between August 2011 and August 2023 was conducted. In all patients with bleeding tendencies and normal diagnostic tests for von Willebrand disease and platelet function, FXIII and α2AP were measured. RESULTS: We included 158 consecutive patients; mean ISTH-BAT scores were 8.2 (SD ± 3.7) in children, 6.2 (SD ± 2.1) in men and 10.6 (SD ± 3.3) in women. Median age was 37 (range 5-79) years, 88.6% of patients were female. Patients displayed median FXIII activity of 111% (IQR = 97-131) and median α2AP activity of 112% (IQR = 103-119). Three (1.9%) patients had FXIII levels < 50%, respectively 43%, 45% and 46%. Corresponding ISTH-BAT scores were 7, 12 and 14. No α2AP levels < 60% was observed. No significant association was found between FXIII levels and ISTH-BAT scores. CONCLUSION: In our cohort of BDUC patients, no clinical relevant FXIII deficiencies were detected; absolute values were well above the 30% cutoff considered adequate for normal haemostasis. No α2AP deficiencies were detected. These data suggest that in BDUC patients, measuring FXIII or AP activity is of limited value.

Does the VWF:CB Assay Help to Diagnose von Willebrand Factor Deficiency in Patients With a Bleeding Disorder of Unknown Cause?

INTRODUCTION: The entity entitled bleeding disorder of unknown cause (BDUC) qualifies individuals displaying a mild haemorrhagic profile but normal routine coagulation tests. This study was designed to evaluate whether collagen-binding assay for von Willebrand Factor (VWF) measurement (VWF:CB) could allow to diagnose VW disease in such patients. METHODS: A large screening was conducted prospectively in two University Hospitals, using the bleeding assessment tool (BAT) recommended by the International Society of Thrombosis and Hemostasis. Patients with an abnormal BAT were confirmed to have a normal complete hemostatic evaluation. A large range of VWF assays was then carried out on a new blood sample for the 68 individuals (91% women) thus identified. Of note, five VWF:CB using different types of collagen were performed, as well as a comprehensive sequencing of the VWF gene. RESULTS: Of this cohort, only 3 individuals (all blood group O), had a VWF:CB between 40 and 50 IU/dL. No unknown anomaly of the VWF gene was disclosed. Of note, 54% of these patients had unexplained abnormal occlusion times on PFA-200. CONCLUSION: This study identified 68 cases of BDUC, after screening of a large population, indicating a low incidence. Only 3 cases were potentially confirmed as displaying moderate von Willebrand disease. VWF:CB tests were globally normal in the 65 other patients of the cohort. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT0279220.

Activated protein C and free protein S in patients with mild to moderate bleeding disorders.

BACKGROUND: Underlying mechanisms for bleeding and impaired thrombin generation (TG) and plasma clot formation (PCF) in patients with mild to moderate bleeding disorders (MBDs) are still to be elucidated, especially in bleeding disorder of unknown cause (BDUC). The role of the natural anticoagulants activated protein C (APC) and free protein S (PS) has not yet been investigated in this patient population. AIMS: To analyze antigen levels of APC and PS in patients with MBDs and BDUC and investigate associations to clinical bleeding phenotype and severity as well as and hemostatic capacity. METHODS: Antigen levels of APC and free PS were measured in 262 patients from the Vienna Bleeding Biobank (VIBB), a single-center cohort study, by ELISA and compared to 61 healthy controls (HC). RESULTS: Antigen levels of APC were higher in MBD patients than in HC when adjusted for age, sex and BMI (median (IQR) 33.1 (20.6-52.6) and 28.6 (16.4-47.2) ng/mL). This was most pronounced in patients with BDUC (35.3 (21.7-54.3) ng/mL). No differences in PS antigen levels between patients and HC were seen overall, or according to specific diagnoses. Further, no association between APC or PS and bleeding severity or global tests of hemostasis or TG were identified, while paradoxically APC weakly correlated with shorter lag time and time to peak of PCF in BDUC. CONCLUSION: Our data demonstrate increased antigen levels of APC in BDUC, which might contribute to the bleeding tendency in some patients and could be a future therapeutic target in BDUC.

Investigating patients for bleeding disorders when most of the "usual" ones have been ruled out.

A State of the Art lecture titled "Investigating Patients for Bleeding Disorders When Most of the Usual Ones Have Been Ruled Out" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. Mild to moderate bleeding disorders (MBDs) in patients in whom no diagnosis of an established disorder, such as platelet function defect, von Willebrand disease, or a coagulation factor deficiency, can be identified are classified as bleeding disorders of unknown cause (BDUCs). Prospective data from the Vienna Bleeding Biobank and other studies have revealed a high proportion of BDUCs of up to 70% among patients with MBD who have a similar bleeding phenotype as other MBDs. As BDUC is a diagnosis of exclusion, the accuracy of the diagnostic workup is essential. For example, repeated testing for von Willebrand disease should be considered if von Willebrand factor values are <80 IU/dL. Current evidence does not support the clinical use of global assays such as thromboelastography, platelet function analyzer, or thrombin generation potential. Rare and novel bleeding disorders due to genetic variants in fibrinolytic factors or natural anticoagulants are rare and should only be analyzed in patients with specific phenotypes and a clear family history. In BDUC, blood group O was identified as a risk factor for increased bleeding severity and bleeding risk after hemostatic challenges. Future studies should improve the phenotypical characterization and ideally identify novel risk factors in BDUC, as a multifactorial pathogenesis is suspected. Finally, we summarize relevant new data on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress.

Health-related quality of life is impaired in bleeding disorders of unknown cause: results from the Vienna Bleeding Biobank.

Background: Bleeding disorder of unknown cause (BDUC) is a diagnosis of exclusion after extensive investigation of coagulation and platelet function and is commonly seen among patients with mild-to-moderate bleeding disorders. Despite increasing awareness among treating physicians, little is known about the health-related quality of life (HrQoL) in BDUC. Objectives: To investigate HrQoL in patients with BDUC in comparison to the general population and patients diagnosed with other established bleeding disorders. Methods: Patients with mild-to-moderate bleeding disorders from the Vienna Bleeding Biobank, a prospective cohort study, were contacted via mail and phone to complete the 36-Item Health Survey Questionnaire form. Results: In total, 333/657 (50.7%) patients completed the 36-Item Health Survey Questionnaire. Patients with BDUC (n = 207, 62%) had significantly impaired HrQoL both in physical (47.8 vs 49.2) and mental health parameters (42.9 vs 51.0) compared to the general population (n = 2914, 56% females), which remained after adjustment for sex and age in multivariable linear regression. The impairment in HrQoL, compared to patients with von Willebrand disease, platelet function defects, or mild clotting factor deficiencies, did not prevail after adjustment for age and sex. In patients with BDUC, age and the presence of at least 1 comorbidity were associated with impaired physical health but not sex or bleeding severity. Of all analyzed bleeding symptoms, only joint bleeding was associated with impaired physical health and gastrointestinal bleeding with mental health in BDUC. Conclusion: The impairments in HrQoL in patients with BDUC emphasize the burden of BDUC on mental and physical well-being, encouraging early recognition and better counseling of patients with BDUC.