PDF herunterladen
Hamostaseologie
DOI: 10.1055/a-2330-9112
Review Article

Utility of Global Hemostatic Assays in Patients with Bleeding Disorders of Unknown Cause

Dino Mehic
1   Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
,
Alice Assinger
2   Institute of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
,
Johanna Gebhart
1   Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
› Institutsangaben Funding The Vienna Bleeding Biobank is supported by an unrestricted grant of CSL Behring, the Medical-Scientific Fund of the Mayor of the Federal Capital Vienna (grant number 20023) and the Anniversary Fund of the Austrian National Bank (grant number 18500). D.M. received the Physician Pathway Scholarship from the Medical University of Vienna for protected research time.
› Weitere Informationen
Auch verfügbar auf
   Lizenzen und Reprints

Abstract

Bleeding disorder of unknown cause (BDUC) is a diagnosis of exclusion after exhaustive evaluation of plasmatic coagulation and platelet function. This review explores the utility of global hemostatic assays as confirmatory tests and in elucidating the pathophysiology of BDUC. Unlike traditional hemostatic tests that focus on coagulation factors, global assays are conducted both in plasma and also whole blood. These assays provide a more comprehensive understanding of the cell-based model of coagulation, aid in the identification of plasmatic factor abnormalities that may reduce hemostatic capacity, and allow for the assessment of impaired platelet–endothelial interactions under shear stress, as well as hyperfibrinolytic states. While clinical tests such as skin bleeding time and global assays such as PFA-100 exhibit limited diagnostic capacity, the role of viscoelastic testing in identifying hemostatic dysfunction in patients with BDUC remains unclear. Thrombin generation assays have shown variable results in BDUC patients; some studies demonstrate differences compared with healthy controls or reference values, whereas others question its clinical utility. Fibrinolysis assessment in vitro remains challenging, with studies employing euglobulin clot lysis time, plasma clot lysis time, and fluorogenic plasmin generation yielding inconclusive or conflicting results. Notably, recent studies suggest that microfluidic analysis unveils shear-dependent platelet function defects in BDUC patients, undetected by conventional platelet function assays. Overall, global assays might be helpful for exploring underlying hemostatic impairments, when conventional hemostatic laboratory tests yield no results. However, due to limited data and/or discrepant results, further research is needed to evaluate the utility of global assays as screening tools.

Keywords

global assays - von Willebrand disease - platelet function defects - hemophilia A/B - BDUC


Publikationsverlauf

Eingereicht: 29. Januar 2024

Angenommen: 17. Mai 2024

Artikel online veröffentlicht:
01. Juli 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Gebhart J, Hofer S, Panzer S. et al. High proportion of patients with bleeding of unknown cause in persons with a mild-to-moderate bleeding tendency: results from the Vienna Bleeding Biobank (VIBB). Haemophilia 2018; 24 (03) 405-413
    CrossrefPubMedGoogle Scholar
  • 2 Mezzano D, Quiroga T. Diagnostic challenges of inherited mild bleeding disorders: a bait for poorly explored clinical and basic research. J Thromb Haemost 2019; 17 (02) 257-270
    CrossrefPubMedGoogle Scholar
  • 3 Baker RI, Choi P, Curry N. et al; ISTH SSC Von Willebrand Factor, Platelet Physiology, and Women's Health Issues in Thrombosis and Haemostasis. Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH. J Thromb Haemost 2024; DOI: 10.1016/j.jtha.2024.03.005.
    CrossrefPubMedGoogle Scholar
  • 4 Thomas W, Downes K, Desborough MJR. Bleeding of unknown cause and unclassified bleeding disorders; diagnosis, pathophysiology and management. Haemophilia 2020; 26 (06) 946-957
    CrossrefPubMedGoogle Scholar
  • 5 Mehic D, Pabinger I, Gebhart J. Investigating patients for bleeding disorders when most of the “usual” ones have been ruled out. Res Pract Thromb Haemost 2023; 7 (08) 102242
    CrossrefPubMedGoogle Scholar
  • 6 Gebhart J, Hofer S, Kaider A, Rejtö J, Ay C, Pabinger I. The discriminatory power of bleeding assessment tools in adult patients with a mild to moderate bleeding tendency. Eur J Intern Med 2020; 78: 34-40
    CrossrefPubMedGoogle Scholar
  • 7 Quiroga T, Goycoolea M, Panes O. et al. High prevalence of bleeders of unknown cause among patients with inherited mucocutaneous bleeding. A prospective study of 280 patients and 299 controls. Haematologica 2007; 92 (03) 357-365
    CrossrefPubMedGoogle Scholar
  • 8 Thomas W, Downes K, Evans G. et al. Current practice and registration patterns among United Kingdom Haemophilia Centre Doctors' Organisation centers for patients with unclassified bleeding disorders. J Thromb Haemost 2021; 19 (11) 2738-2743
    CrossrefPubMedGoogle Scholar
  • 9 Mehic D, Schwarz S, Shulym I, Ay C, Pabinger I, Gebhart J. Health-related quality of life is impaired in bleeding disorders of unknown cause: results from the Vienna Bleeding Biobank. Res Pract Thromb Haemost 2023; 7 (06) 102176
    CrossrefPubMedGoogle Scholar
  • 10 Rodeghiero F, Pabinger I, Ragni M. et al. Fundamentals for a systematic approach to mild and moderate inherited bleeding disorders: an EHA consensus report. HemaSphere 2019; 3 (04) e286-e286
    CrossrefPubMedGoogle Scholar
  • 11 Baker RI, O'Donnell JS. How I treat bleeding disorder of unknown cause. Blood 2021; 138 (19) 1795-1804
    CrossrefPubMedGoogle Scholar
  • 12 van Geffen M, van Heerde WL. Global haemostasis assays, from bench to bedside. Thromb Res 2012; 129 (06) 681-687
    CrossrefPubMedGoogle Scholar
  • 13 van Geffen M, Loof A, Lap P. et al. A novel hemostasis assay for the simultaneous measurement of coagulation and fibrinolysis. Hematology 2011; 16 (06) 327-336
    CrossrefPubMedGoogle Scholar
  • 14 Brummel-Ziedins KE, Wolberg AS. Global assays of hemostasis. Curr Opin Hematol 2014; 21 (05) 395-403
    CrossrefPubMedGoogle Scholar
  • 15 Lipets EN, Ataullakhanov FI. Global assays of hemostasis in the diagnostics of hypercoagulation and evaluation of thrombosis risk. Thromb J 2015; 13 (01) 4
    CrossrefPubMedGoogle Scholar
  • 16 Rejtő J, Königsbrügge O, Grilz E. et al. Influence of blood group, von Willebrand factor levels, and age on factor VIII levels in non-severe haemophilia A. J Thromb Haemost 2020; 18 (05) 1081-1086
    CrossrefPubMedGoogle Scholar
  • 17 Park CH, Seo JY, Kim HJ, Jang JH, Kim SH. A diagnostic challenge: mild hemophilia B with normal activated partial thromboplastin time. Blood Coagul Fibrinolysis 2010; 21 (04) 368-371
    CrossrefPubMedGoogle Scholar
  • 18 Mansouritorghabeh H. Clinical and laboratory approaches to hemophilia a. Iran J Med Sci 2015; 40 (03) 194-205
    PubMedGoogle Scholar
  • 19 Mehic D, Colling M, Pabinger I, Gebhart J. Natural anticoagulants: a missing link in mild to moderate bleeding tendencies. Haemophilia 2021; 27 (05) 701-709
    CrossrefPubMedGoogle Scholar
  • 20 Langdown J, Luddington RJ, Huntington JA, Baglin TP. A hereditary bleeding disorder resulting from a premature stop codon in thrombomodulin (p.Cys537Stop). Blood 2014; 124 (12) 1951-1956
    CrossrefPubMedGoogle Scholar
  • 21 Quick AJ, Stanley-Brown M, Bancroft FW. A study of the coagulation defect in hemophilia and in jaundice. Thromb Haemost 1980; 44 (01) 2-5
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 22 Langdell RD, Wagner RH, Brinkhous KM. Effect of antihemophilic factor on one-stage clotting tests; a presumptive test for hemophilia and a simple one-stage antihemophilic factor assay procedure. J Lab Clin Med 1953; 41 (04) 637-647
    PubMedGoogle Scholar
  • 23 Burns ER, Lawrence C. Bleeding time. A guide to its diagnostic and clinical utility. Arch Pathol Lab Med 1989; 113 (11) 1219-1224
    PubMedGoogle Scholar
  • 24 Favaloro EJ. Clinical utility of closure times using the Platelet Function Analyzer-100/200. Am J Hematol 2017; 92 (04) 398-404
    CrossrefPubMedGoogle Scholar
  • 25 Ay C, Haselböck J, Laczkovics C, Koder S, Pabinger I. Thrombin generation in patients with a bleeding tendency of unknown origin. Ann Hematol 2011; 90 (09) 1099-1104
    CrossrefPubMedGoogle Scholar
  • 26 Hofer S, Ay C, Rejtö J. et al. Thrombin-generating potential, plasma clot formation, and clot lysis are impaired in patients with bleeding of unknown cause. J Thromb Haemost 2019; 17 (09) 1478-1488
    CrossrefPubMedGoogle Scholar
  • 27 Gebhart J, Laczkovics C, Posch F. et al. Plasma clot properties in patients with a mild-to-moderate bleeding tendency of unknown cause. Ann Hematol 2015; 94 (08) 1301-1310
    CrossrefPubMedGoogle Scholar
  • 28 Abdelfattah K, Cripps MW. Thromboelastography and rotational thromboelastometry use in trauma. Int J Surg 2016; 33 (Pt B): 196-201
    CrossrefPubMedGoogle Scholar
  • 29 Hartmann J, Hermelin D, Levy JH. Viscoelastic testing: an illustrated review of technology and clinical applications. Res Pract Thromb Haemost 2022; 7 (01) 100031
    CrossrefPubMedGoogle Scholar
  • 30 Miszta A, Huskens D, Donkervoort D, Roberts MJM, Wolberg AS, de Laat B. Assessing plasmin generation in health and disease. Int J Mol Sci 2021; 22 (05) 2758
    CrossrefPubMedGoogle Scholar
  • 31 Mangin PH, Gardiner EE, Nesbitt WS. et al; Subcommittee on Biorheology. In vitro flow based systems to study platelet function and thrombus formation: recommendations for standardization: communication from the SSC on Biorheology of the ISTH. J Thromb Haemost 2020; 18 (03) 748-752
    CrossrefPubMedGoogle Scholar
  • 32 Heubel-Moenen FCJI, Brouns SLN, Herfs L. et al. Multiparameter platelet function analysis of bleeding patients with a prolonged platelet function analyser closure time. Br J Haematol 2022; 196 (06) 1388-1400
    CrossrefPubMedGoogle Scholar
  • 33 Rodgers RP, Levin J. A critical reappraisal of the bleeding time. Semin Thromb Hemost 1990; 16 (01) 1-20
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 34 Lind SE. The bleeding time does not predict surgical bleeding. Blood 1991; 77 (12) 2547-2552
    CrossrefPubMedGoogle Scholar
  • 35 Quiroga T, Goycoolea M, Muñoz B. et al. Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study in 148 patients. J Thromb Haemost 2004; 2 (06) 892-898
    CrossrefPubMedGoogle Scholar
  • 36 Miller CH. Platelet Function Analyzer. In: Transfusion Medicine and Hemostasis. Elsevier; 2019: 817-818
    Google Scholar
  • 37 de Witt SM, Swieringa F, Cavill R. et al. Identification of platelet function defects by multi-parameter assessment of thrombus formation. Nat Commun 2014; 5: 4257
    CrossrefPubMedGoogle Scholar
  • 38 Belkacemi M, Merad Y. Variables that influence Platelet Function Analyzer-100™ closure times in healthy Algerian adults. Int J Appl Basic Med Res 2021; 11 (03) 154-159
    CrossrefPubMedGoogle Scholar
  • 39 Pujol-Moix N, Martinez-Perez A, Sabater-Lleal M. et al. Influence of ABO locus on PFA-100 collagen-ADP closure time is not totally dependent on the von Willebrand factor. Results of a GWAS on GAIT-2 project phenotypes. Int J Mol Sci 2019; 20 (13) 3221-3221
    CrossrefPubMedGoogle Scholar
  • 40 Hayward CP, Harrison P, Cattaneo M, Ortel TL, Rao AK. Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Platelet Function Analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function. J Thromb Haemost 2006; 4 (02) 312-319
    CrossrefPubMedGoogle Scholar
  • 41 Favaloro EJ. Clinical utility of the PFA-100. Semin Thromb Hemost 2008; 34 (08) 709-733
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 42 Fressinaud E, Veyradier A, Truchaud F. et al. Screening for von Willebrand disease with a new analyzer using high shear stress: a study of 60 cases. Blood 1998; 91 (04) 1325-1331
    CrossrefPubMedGoogle Scholar
  • 43 Ardillon L, Ternisien C, Fouassier M. et al. Platelet Function Analyser (PFA-100) results and von Willebrand factor deficiency: a 16-year ‘real-world’ experience. Haemophilia 2015; 21 (05) 646-652
    CrossrefPubMedGoogle Scholar
  • 44 Favaloro EJ. Utility of the Platelet Function Analyser (PFA-100/200) for exclusion or detection of von Willebrand disease: a study 22 years in the making. Thromb Res 2020; 188: 17-24
    CrossrefPubMedGoogle Scholar
  • 45 Favaloro EJ, Pasalic L, Curnow J. Monitoring therapy during treatment of von Willebrand disease. Semin Thromb Hemost 2017; 43 (03) 338-354
    PubMedGoogle Scholar
  • 46 James PD, Connell NT, Ameer B. et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv 2021; 5 (01) 280-300
    CrossrefPubMedGoogle Scholar
  • 47 Mammen EF, Comp PC, Gosselin R. et al. PFA-100 system: a new method for assessment of platelet dysfunction. Semin Thromb Hemost 1998; 24 (02) 195-202
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 48 Baccolo A, Falcinelli E, Mezzasoma AM. et al. Usefulness of global tests of primary hemostasis in the initial screening of mild/moderate bleeding disorders for orienting towards von Willebrand disease or inherited platelet functions disorders. Thromb Res 2023; 221: 79-82
    CrossrefPubMedGoogle Scholar
  • 49 Kaufmann J, Adler M, Alberio L, Nagler M. Utility of the platelet function analyzer in patients with suspected platelet function disorders: diagnostic accuracy study. TH Open 2020; 4 (04) e427-e436
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 50 Norman JE, Westbury SK, Jones ML, Mumford AD. How should we test for nonsevere heritable platelet function disorders?. Int J Lab Hematol 2014; 36 (03) 326-333
    CrossrefPubMedGoogle Scholar
  • 51 Harrison P, Robinson M, Liesner R. et al. The PFA-100: a potential rapid screening tool for the assessment of platelet dysfunction. Clin Lab Haematol 2002; 24 (04) 225-232
    CrossrefPubMedGoogle Scholar
  • 52 Mehic D, Rast JS, Fuchs M. et al. Utility of the Platelet Function Analyzer (PFA-100) in patients with bleeding disorder of unknown cause. Blood 2023; 142 (Suppl. 01) 3965
    CrossrefPubMedGoogle Scholar
  • 53 Kwaan HC, Walsh M, Lindholm PF, Othman M. Emerging use of viscoelastography in thrombosis and hemostasis: a challenge to conventional coagulation tests? Part I: The use of thromboelastography and thromboelastometry in the assessment of hemostatic function. Semin Thromb Hemost 2022; 48 (07) 767-768
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 54 Carll T, Wool GD. Basic principles of viscoelastic testing. Transfusion 2020; 60 (Suppl. 06) S1-S9
    PubMedGoogle Scholar
  • 55 Volod O, Bunch CM, Zackariya N. et al. Viscoelastic hemostatic assays: a primer on legacy and new generation devices. J Clin Med 2022; 11 (03) 860
    CrossrefPubMedGoogle Scholar
  • 56 Nogami K. The utility of thromboelastography in inherited and acquired bleeding disorders. Br J Haematol 2016; 174 (04) 503-514
    CrossrefPubMedGoogle Scholar
  • 57 de Moreuil C, Mehic D, Nopp S. et al. Hemostatic biomarkers associated with postpartum hemorrhage: a systematic review and meta-analysis. Blood Adv 2023; 7 (19) 5954-5967
    CrossrefPubMedGoogle Scholar
  • 58 Moore HB, Moore EE, Gonzalez E. et al. Hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown: the spectrum of postinjury fibrinolysis and relevance to antifibrinolytic therapy. J Trauma Acute Care Surg 2014; 77 (06) 811-817 , discussion 817
    CrossrefPubMedGoogle Scholar
  • 59 Schmidt DE, Majeed A, Bruzelius M, Odeberg J, Holmström M, Ågren A. A prospective diagnostic accuracy study evaluating rotational thromboelastometry and thromboelastography in 100 patients with von Willebrand disease. Haemophilia 2017; 23 (02) 309-318
    CrossrefPubMedGoogle Scholar
  • 60 Topf HG, Strasser ER, Breuer G, Rascher W, Rauh M, Fahlbusch FB. Closing the gap - detection of clinically relevant von Willebrand disease in emergency settings through an improved algorithm based on rotational Thromboelastometry. BMC Anesthesiol 2019; 19 (01) 10
    CrossrefPubMedGoogle Scholar
  • 61 Ghosh K, Shetty S, Kulkarni B. Correlation of thromboelastographic patterns with clinical presentation and rationale for use of antifibrinolytics in severe haemophilia patients. Haemophilia 2007; 13 (06) 734-739
    CrossrefPubMedGoogle Scholar
  • 62 Veen CSB, Huisman EJ, Cnossen MH. et al. Evaluation of thromboelastometry, thrombin generation and plasma clot lysis time in patients with bleeding of unknown cause: a prospective cohort study. Haemophilia 2020; 26 (03) e106-e115
    PubMedGoogle Scholar
  • 63 Wieland Greguare-Sander A, Wuillemin WA, Nagler M. Thromboelastometry as a diagnostic tool in mild bleeding disorders: a prospective cohort study. Eur J Anaesthesiol 2019; 36 (06) 457-465
    CrossrefPubMedGoogle Scholar
  • 64 MacDonald S, Wright A, Beuche F. et al. Characterization of a large cohort of patients with unclassified bleeding disorder; clinical features, management of haemostatic challenges and use of global haemostatic assessment with proposed recommendations for diagnosis and treatment. Int J Lab Hematol 2020; 42 (02) 116-125
    CrossrefPubMedGoogle Scholar
  • 65 Mehic D, Jilma B, Schörgenhofer C. et al. Rotational thromboelastometry (ROTEM) in patients with bleeding of unknown cause: evidence for hemostatic imbalance [abstract]. Accessed November 1, 2023 at: https://abstracts.isth.org/abstract/rotational-thromboelastometry-rotem-in-patients-with-bleeding-of-unknown-cause-evidence-for-hemostatic-imbalance/
    PubMedGoogle Scholar
  • 66 de Laat-Kremers RMW, Ninivaggi M, Devreese KMJ, de Laat B. Towards standardization of thrombin generation assays: inventory of thrombin generation methods based on results of an International Society of Thrombosis and Haemostasis Scientific Standardization Committee survey. J Thromb Haemost 2020; 18 (08) 1893-1899
    CrossrefPubMedGoogle Scholar
  • 67 Dargaud Y, Wolberg AS, Luddington R. et al. Evaluation of a standardized protocol for thrombin generation measurement using the calibrated automated thrombogram: an international multicentre study. Thromb Res 2012; 130 (06) 929-934
    CrossrefPubMedGoogle Scholar
  • 68 Wu Y, Lu Y, Zhang J. Thrombin generation assay: the present and the future. Blood Coagul Fibrinolysis 2023; 34 (01) 1-7
    CrossrefPubMedGoogle Scholar
  • 69 Tripodi A, Legnani C, Chantarangkul V, Cosmi B, Palareti G, Mannucci PM. High thrombin generation measured in the presence of thrombomodulin is associated with an increased risk of recurrent venous thromboembolism. J Thromb Haemost 2008; 6 (08) 1327-1333
    CrossrefPubMedGoogle Scholar
  • 70 Eichinger S, Hron G, Kollars M, Kyrle PA. Prediction of recurrent venous thromboembolism by endogenous thrombin potential and D-dimer. Clin Chem 2008; 54 (12) 2042-2048
    CrossrefPubMedGoogle Scholar
  • 71 Königsbrügge O, Scheiner B, Simbrunner B. et al. Characterization of a prothrombotic phenotype using thrombin generation and thrombin activity in cirrhosis and portal hypertension. Thromb Res 2023; 222: 124-130
    CrossrefPubMedGoogle Scholar
  • 72 Verhagen MJA, Valke LLFG, Schols SEM. Thrombin generation for monitoring hemostatic therapy in hemophilia A: a narrative review. J Thromb Haemost 2022; 20 (04) 794-805
    CrossrefPubMedGoogle Scholar
  • 73 Verhagen MJA, van Heerde WL, van der Bom JG. et al. In patients with hemophilia, a decreased thrombin generation profile is associated with a severe bleeding phenotype. Res Pract Thromb Haemost 2023; 7 (02) 100062
    CrossrefPubMedGoogle Scholar
  • 74 Pike GN, Cumming AM, Hay CRM, Bolton-Maggs PHB, Burthem J. Sample conditions determine the ability of thrombin generation parameters to identify bleeding phenotype in FXI deficiency. Blood 2015; 126 (03) 397-405
    CrossrefPubMedGoogle Scholar
  • 75 Rugeri L, Quélin F, Chatard B, De Mazancourt P, Negrier C, Dargaud Y. Thrombin generation in patients with factor XI deficiency and clinical bleeding risk. Haemophilia 2010; 16 (05) 771-777
    CrossrefPubMedGoogle Scholar
  • 76 Livnat T, Shenkman B, Martinowitz U. et al. The impact of thrombin generation and rotation thromboelastometry on assessment of severity of factor XI deficiency. Thromb Res 2015; 136 (02) 465-473
    CrossrefPubMedGoogle Scholar
  • 77 Keularts IM, Hamulyak K, Hemker HC, Béguin S. The effect of DDAVP infusion on thrombin generation in platelet-rich plasma of von Willebrand type 1 and in mild haemophilia A patients. Thromb Haemost 2000; 84 (04) 638-642
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 78 Thomas W, White D, MacDonald S. Thrombin generation measured by two platforms in patients with a bleeding tendency: comment. J Thromb Haemost 2021; 19 (11) 2896-2899
    CrossrefPubMedGoogle Scholar
  • 79 Vincent LM, Tran S, Livaja R, Bensend TA, Milewicz DM, Dahlbäck B. Coagulation factor V (A2440G) causes East Texas bleeding disorder via TFPIα. J Clin Invest 2013; 123 (09) 3777-3787
    CrossrefPubMedGoogle Scholar
  • 80 Dargaud Y, Scoazec JY, Wielders SJH. et al. Characterization of an autosomal dominant bleeding disorder caused by a thrombomodulin mutation. Blood 2015; 125 (09) 1497-1501
    CrossrefPubMedGoogle Scholar
  • 81 Cunha MLR, Bakhtiari K, Peter J, Marquart JA, Meijers JCM, Middeldorp S. A novel mutation in the F5 gene (factor V Amsterdam) associated with bleeding independent of factor V procoagulant function. Blood 2015; 125 (11) 1822-1825
    CrossrefPubMedGoogle Scholar
  • 82 Holm E, Zetterberg E, Lövdahl S, Berntorp E. Patients referred for bleeding symptoms of unknown cause: does evaluation of thrombin generation contribute to diagnosis?. Mediterr J Hematol Infect Dis 2016; 8 (01) e2016014
    CrossrefPubMedGoogle Scholar
  • 83 Alves GSA, Orsi FA, Santiago-Bassora FD. et al. Laboratory evaluation of patients with undiagnosed bleeding disorders. Blood Coagul Fibrinolysis 2016; 27 (05) 500-505
    CrossrefPubMedGoogle Scholar
  • 84 MacDonald S, White D, Langdown J, Downes K, Thomas W. Investigation of patients with unclassified bleeding disorder and abnormal thrombin generation for physiological coagulation inhibitors reveals multiple abnormalities and a subset of patients with increased tissue factor pathway inhibitor activity. Int J Lab Hematol 2020; 42 (03) 246-255
    CrossrefPubMedGoogle Scholar
  • 85 Cornette M, Monteyne T, De Kesel PM, Devreese KMJ. Thrombin generation measured by two platforms in patients with a bleeding tendency. J Thromb Haemost 2021; 19 (06) 1460-1471
    CrossrefPubMedGoogle Scholar
  • 86 Undas A, Slowik A, Wolkow P, Szczudlik A, Tracz W. Fibrin clot properties in acute ischemic stroke: relation to neurological deficit. Thromb Res 2010; 125 (04) 357-361
    CrossrefPubMedGoogle Scholar
  • 87 Undas A, Nowakowski T, Cieśla-Dul M, Sadowski J. Abnormal plasma fibrin clot characteristics are associated with worse clinical outcome in patients with peripheral arterial disease and thromboangiitis obliterans. Atherosclerosis 2011; 215 (02) 481-486
    CrossrefPubMedGoogle Scholar
  • 88 Undas A, Zawilska K, Ciesla-Dul M. et al. Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives. Blood 2009; 114 (19) 4272-4278
    CrossrefPubMedGoogle Scholar
  • 89 Okraska-Bylica A, Wilkosz T, Słowik L, Bazanek M, Konieczyńska M, Undas A. Altered fibrin clot properties in patients with premature peripheral artery disease. Pol Arch Med Wewn 2012; 122 (12) 608-615
    PubMedGoogle Scholar
  • 90 Antovic A, Mikovic D, Elezovic I, Zabczyk M, Hutenby K, Antovic JP. Improvement of fibrin clot structure after factor VIII injection in haemophilia A patients treated on demand. Thromb Haemost 2014; 111 (04) 656-661
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 91 Brummel-Ziedins KE, Branda RF, Butenas S, Mann KG. Discordant fibrin formation in hemophilia. J Thromb Haemost 2009; 7 (05) 825-832
    CrossrefPubMedGoogle Scholar
  • 92 Gray LD, Hussey MA, Larson BM. et al. Recombinant factor VIIa analog NN1731 (V158D/E296V/M298Q-FVIIa) enhances fibrin formation, structure and stability in lipidated hemophilic plasma. Thromb Res 2011; 128 (06) 570-576
    CrossrefPubMedGoogle Scholar
  • 93 Szczepaniak P, Zabczyk M, Undas A. Increased plasma clot permeability and susceptibility to lysis are associated with heavy menstrual bleeding of unknown cause: a case-control study. PLoS One 2015; 10 (04) e0125069
    CrossrefPubMedGoogle Scholar
  • 94 Wiewel-Verschueren S, Knol HM, Lisman T. et al. No increased systemic fibrinolysis in women with heavy menstrual bleeding. J Thromb Haemost 2014; 12 (09) 1488-1493
    CrossrefPubMedGoogle Scholar
  • 95 Longstaff C. Measuring fibrinolysis: from research to routine diagnostic assays. J Thromb Haemost 2018; 16 (04) 652-662
    CrossrefPubMedGoogle Scholar
  • 96 Miszta A, Kopec AK, Pant A. et al. A high-fat diet delays plasmin generation in a thrombomodulin-dependent manner in mice. Blood 2020; 135 (19) 1704-1717
    CrossrefPubMedGoogle Scholar
  • 97 Valke LLFG, Bukkems LH, Barteling W. et al. Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: combining thrombin and plasmin generation. J Thromb Haemost 2020; 18 (12) 3222-3231
    CrossrefPubMedGoogle Scholar
  • 98 Van Geffen M, Menegatti M, Loof A. et al. Retrospective evaluation of bleeding tendency and simultaneous thrombin and plasmin generation in patients with rare bleeding disorders. Haemophilia 2012; 18 (04) 630-638
    CrossrefPubMedGoogle Scholar
  • 99 Saes JL, Schols SEM, Betbadal KF. et al. Thrombin and plasmin generation in patients with plasminogen or plasminogen activator inhibitor type 1 deficiency. Haemophilia 2019; 25 (06) 1073-1082
    CrossrefPubMedGoogle Scholar
  • 100 Mehic D, Reitsma S, Haslacher H. et al. PB1206 plasmin generation is impaired in patients with bleeding disorders of unknown cause. Res Pract Thromb Haemost 2023; 7: 101037
    CrossrefPubMedGoogle Scholar
  • 101 Gebhart J, Kepa S, Hofer S. et al. Fibrinolysis in patients with a mild-to-moderate bleeding tendency of unknown cause. Ann Hematol 2017; 96 (03) 489-495
    CrossrefPubMedGoogle Scholar
  • 102 Matus V, Willemse J, Quiroga T. et al. Procarboxypeptidase U (TAFI) and the Thr325Ile proCPU polymorphism in patients with hereditary mucocutaneous hemorrhages. Clin Chim Acta 2009; 401 (1–2): 158-161
    CrossrefPubMedGoogle Scholar
  • 103 Longstaff C, Thelwell C, Williams SC, Silva MMCG, Szabó L, Kolev K. The interplay between tissue plasminogen activator domains and fibrin structures in the regulation of fibrinolysis: kinetic and microscopic studies. Blood 2011; 117 (02) 661-668
    CrossrefPubMedGoogle Scholar
  • 104 Kowalski E, Kopec M. Niewiarowski. An evaluation of the euglobulin method for the determination of fibrinolysis. J Clin Pathol 1959; 12 (03) 215-218
    CrossrefPubMedGoogle Scholar
  • 105 Borawski J, Myśliwiec M. Plasma fibrinogen level is an important determinant of prolonged euglobulin clot lysis time in hemodialysis patients. Clin Appl Thromb Hemost 2001; 7 (04) 296-299
    CrossrefPubMedGoogle Scholar
  • 106 Smith AA, Jacobson LJ, Miller BI, Hathaway WE, Manco-Johnson MJ. A new euglobulin clot lysis assay for global fibrinolysis. Thromb Res 2003; 112 (5–6): 329-337
    CrossrefPubMedGoogle Scholar
  • 107 Ilich A, Kumar V, Ferrara MJ. et al. Euglobulin clot lysis time reveals a high frequency of fibrinolytic activation in trauma. Thromb Res 2021; 204: 22-28
    CrossrefPubMedGoogle Scholar
  • 108 Valke LLFG, Meijer D, Nieuwenhuizen L. et al. Fibrinolytic assays in bleeding of unknown cause: improvement in diagnostic yield. Res Pract Thromb Haemost 2022; 6 (02) e12681
    CrossrefPubMedGoogle Scholar
  • 109 Nagy M, Heemskerk JWM, Swieringa F. Use of microfluidics to assess the platelet-based control of coagulation. Platelets 2017; 28 (05) 441-448
    CrossrefPubMedGoogle Scholar
  • 110 Hathcock JJ. Flow effects on coagulation and thrombosis. Arterioscler Thromb Vasc Biol 2006; 26 (08) 1729-1737
    CrossrefPubMedGoogle Scholar
  • 111 Brouns SLN, van Geffen JP, Heemskerk JWM. High-throughput measurement of human platelet aggregation under flow: application in hemostasis and beyond. Platelets 2018; 29 (07) 662-669
    CrossrefPubMedGoogle Scholar
  • 112 Váradi K, Turecek PL, Schwarz HP. Thrombin generation assay and other universal tests for monitoring haemophilia therapy. Haemophilia 2004; Sep;10 Suppl 2: 17-21 DOI: 10.1111/j.1365-2516.2004.00936.x. . PMID: 15385042
    CrossrefPubMedGoogle Scholar