Dino Mehic, Stéphanie E Reitsma, Claire de Moreuil, Helmuth Haslacher, Maximilian Christian Koeller, Bas de Laat, Cihan Ay, Ingrid Pabinger, Alisa Wolberg, Johanna Gebhart
{"title":"Plasmin Generation Analysis in Patients with Bleeding Disorder of Unknown Cause.","authors":"Dino Mehic, Stéphanie E Reitsma, Claire de Moreuil, Helmuth Haslacher, Maximilian Christian Koeller, Bas de Laat, Cihan Ay, Ingrid Pabinger, Alisa Wolberg, Johanna Gebhart","doi":"10.1182/bloodadvances.2024012855","DOIUrl":null,"url":null,"abstract":"<p><p>Bleeding disorder of unknown cause (BDUC) is a diagnosis of exclusion after evaluation of plasma coagulation and platelet function. The underlying mechanisms are unclear, but increased fibrinolysis and abnormal clot formation may play a role. All BDUC patients (n=375) from the Vienna bleeding biobank were analyzed in comparison to healthy controls (HC, n=100) in this case-control study. Plasmin generation (PG) parameters were analyzed using calibrated fluorescence detection in citrated-plasma samples. Turbidimetric plasma clot formation/ lysis of 293 (78%) BDUC patients and confocal microscopy of clots from representative BDUC patients (n=6) and HC (n=9) were assessed. Fibrinolytic factors were measured using commercially available ELISAs. In PG analysis, BDUC patients exhibited lower velocity and peak plasmin, but a higher endogenous plasmin potential compared to HC. Peak plasmin correlated with maximum clot absorbance, but not with clot lysis time. Clot absorbance is an indicator of clot fiber density. Confocal microscopy analysis revealed that BDUC patients' clots had a tendency towards thicker fibers, which negatively correlated with peak plasmin (r=-0.561, p=0.030). Peak plasmin correlated weakly with FXIII, but not with the other fibrinolytic factors (alpha2-antiplasmin, thrombin activatable fibrinolysis inhibitor or plasminogen activator inhibitor 1) or bleeding severity. A model comprising fibrinogen and parameters of PG yielded high predictive power in discriminating BDUC patients from HC during 5-fold stratified cross validation (80% of data, mean AUC: 0.847). The same model generalized well to unseen data (20% of data, AUC: 0.856). Overall, BDUC patients exhibited counterintuitively reduced peak plasmin, potentially related to altered clot structure.</p>","PeriodicalId":9228,"journal":{"name":"Blood advances","volume":null,"pages":null},"PeriodicalIF":7.4000,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood advances","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1182/bloodadvances.2024012855","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Bleeding disorder of unknown cause (BDUC) is a diagnosis of exclusion after evaluation of plasma coagulation and platelet function. The underlying mechanisms are unclear, but increased fibrinolysis and abnormal clot formation may play a role. All BDUC patients (n=375) from the Vienna bleeding biobank were analyzed in comparison to healthy controls (HC, n=100) in this case-control study. Plasmin generation (PG) parameters were analyzed using calibrated fluorescence detection in citrated-plasma samples. Turbidimetric plasma clot formation/ lysis of 293 (78%) BDUC patients and confocal microscopy of clots from representative BDUC patients (n=6) and HC (n=9) were assessed. Fibrinolytic factors were measured using commercially available ELISAs. In PG analysis, BDUC patients exhibited lower velocity and peak plasmin, but a higher endogenous plasmin potential compared to HC. Peak plasmin correlated with maximum clot absorbance, but not with clot lysis time. Clot absorbance is an indicator of clot fiber density. Confocal microscopy analysis revealed that BDUC patients' clots had a tendency towards thicker fibers, which negatively correlated with peak plasmin (r=-0.561, p=0.030). Peak plasmin correlated weakly with FXIII, but not with the other fibrinolytic factors (alpha2-antiplasmin, thrombin activatable fibrinolysis inhibitor or plasminogen activator inhibitor 1) or bleeding severity. A model comprising fibrinogen and parameters of PG yielded high predictive power in discriminating BDUC patients from HC during 5-fold stratified cross validation (80% of data, mean AUC: 0.847). The same model generalized well to unseen data (20% of data, AUC: 0.856). Overall, BDUC patients exhibited counterintuitively reduced peak plasmin, potentially related to altered clot structure.
期刊介绍:
Blood Advances, a semimonthly medical journal published by the American Society of Hematology, marks the first addition to the Blood family in 70 years. This peer-reviewed, online-only, open-access journal was launched under the leadership of founding editor-in-chief Robert Negrin, MD, from Stanford University Medical Center in Stanford, CA, with its inaugural issue released on November 29, 2016.
Blood Advances serves as an international platform for original articles detailing basic laboratory, translational, and clinical investigations in hematology. The journal comprehensively covers all aspects of hematology, including disorders of leukocytes (both benign and malignant), erythrocytes, platelets, hemostatic mechanisms, vascular biology, immunology, and hematologic oncology. Each article undergoes a rigorous peer-review process, with selection based on the originality of the findings, the high quality of the work presented, and the clarity of the presentation.