Clinical and Laboratory Presentation and Underlying Mechanism in Patients with Low VWF

Abstract

Background Low von Willebrand factor (VWF) refers to subjects with plasma levels of 30 to 50 IU/dL. The mechanism of low VWF is poorly understood. We chose to determine the clinical presentation, laboratory phenotype, and underlying mechanisms of low VWF.

Material and Methods We included 250 patients characterized with low VWF. The International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) was used to assess clinical symptoms. To determine the underlying mechanisms of low VWF, we used as markers the VWF propeptide (VWFpp) assay and FVIII:C/VWF:Ag ratio for VWF synthesis and the VWFpp/VWF:Ag ratio for VWF clearance. Results were compared with those of 120 healthy controls. Cases with abnormal screening tests were further evaluated for coagulation factor levels and platelet disorders.

Results The median age of the cohort was 35 years (range 3–85), 21% were children (n = 53), 34% were adult males (n = 85), and 45% (n = 112) were adult females. According to the ISTH-BAT, abnormal bleeding was found in 35% of children, 47% of males, and 49% of females. No association was found between VWF activity levels and ISTH-BAT. Patients showed an overall decreased VWF synthesis/secretion and an enhanced VWF clearance was identified in 33% of them. In 89 patients (36%), there were other hemostasis-related defects, but there was no difference in the ISTH-BAT between the two groups.

Conclusion Our findings indicate that reduced VWF synthesis/secretion and enhanced VWF clearance are major mechanisms of low VWF levels. Patients with low VWF have significant bleeding manifestations. While other hemostasis defects occurred together with low VWF, this combination did not exacerbate clinical symptoms.

Keywords

VWD - VWF - low VWF - ISTH-BAT

Data Availability Statement

Contact the corresponding author for other data sharing: [e-mail].

Authors' Contribution

O.S. and F.P. conceptualized the study. O.S. collected and analyzed data and wrote the manuscript. P.C., G.C., M.T.P., and C.N. performed the phenotypic tests; S.M.S., A.C., F.B., and F.P. were involved in the patient's evaluation. L.B. and F.P. critically revised the manuscript. All authors have approved the final manuscript.

Publication History

Received: 14 July 2023

Accepted: 04 October 2023

Accepted Manuscript online:
05 October 2023

Article published online:
02 November 2023

• References

• 1 Lenting PJ, Casari C, Christophe OD, Denis CV. von Willebrand factor: the old, the new and the unknown. J Thromb Haemost 2012; 10 (12) 2428-2437
• 2 Springer TA. von Willebrand factor, Jedi knight of the bloodstream. Blood 2014; 124 (09) 1412-1425
• 3 Lillicrap D. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy. Blood 2013; 122 (23) 3735-3740
• 4 Sadler JE, Budde U, Eikenboom JC. et al; Working Party on von Willebrand Disease Classification. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost 2006; 4 (10) 2103-2114
• 5 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
• 6 O'Donnell JS. Low VWF: insights into pathogenesis, diagnosis, and clinical management. Blood Adv 2020; 4 (13) 3191-3199
• 7 Bowman ML, James PD. Controversies in the diagnosis of Type 1 von Willebrand disease. Int J Lab Hematol 2017; 39 (Suppl. 01) 61-68
• 8 Flood VH, Christopherson PA, Gill JC. et al. Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States. Blood 2016; 127 (20) 2481-2488
• 9 Lavin M, Aguila S, Schneppenheim S. et al. Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels. Blood 2017; 130 (21) 2344-2353
• 10 Aguila S, Lavin M, Dalton N. et al. Increased galactose expression and enhanced clearance in patients with low von Willebrand factor. Blood 2019; 133 (14) 1585-1596
• 11 Gallinaro L, Cattini MG, Sztukowska M. et al. A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor. Blood 2008; 111 (07) 3540-3545
• 12 Federici AB, Canciani MT, Forza I. et al. A sensitive ristocetin co-factor activity assay with recombinant glycoprotein Ibalpha for the diagnosis of patients with low von Willebrand factor levels. Haematologica 2004; 89 (01) 77-85
• 13 Seidizadeh O, Baronciani L, Pagliari MT. et al. Genetic determinants of enhanced von Willebrand factor clearance from plasma. J Thromb Haemost 2023; 21 (05) 1112-1122
• 14 Stufano F, Boscarino M, Bucciarelli P. et al. Evaluation of the utility of von Willebrand factor propeptide in the differential diagnosis of von Willebrand disease and acquired von Willebrand syndrome. Semin Thromb Hemost 2019; 45 (01) 36-42
• 15 Elbatarny M, Mollah S, Grabell J. et al; Zimmerman Program Investigators. Normal range of bleeding scores for the ISTH-BAT: adult and pediatric data from the merging project. Haemophilia 2014; 20 (06) 831-835
• 16 Nichols WL, Hultin MB, James AH. et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008; 14 (02) 171-232
• 17 Laffan MA, Lester W, O'Donnell JS. et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (04) 453-465
• 18 Sadler JE. Von Willebrand disease type 1: a diagnosis in search of a disease. Blood 2003; 101 (06) 2089-2093
• 19 Atiq F, Boender J, van Heerde WL. et al. Importance of genotyping in von Willebrand disease to elucidate pathogenic mechanisms and variability in phenotype. HemaSphere 2022; 6 (06) e718
• 20 Veyradier A, Boisseau P, Fressinaud E. et al; French Reference Center for von Willebrand disease. A laboratory phenotype/genotype correlation of 1167 French patients from 670 families with von Willebrand disease: a new epidemiologic picture. Medicine (Baltimore) 2016; 95 (11) e3038
• 21 Goodeve A, Eikenboom J, Castaman G. et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood 2007; 109 (01) 112-121
• 22 James PD, Notley C, Hegadorn C. et al. The mutational spectrum of type 1 von Willebrand disease: results from a Canadian cohort study. Blood 2007; 109 (01) 145-154
• 23 Atiq F, Wuijster E, de Maat MPM, Kruip MJHA, Cnossen MH, Leebeek FWG. Criteria for low von Willebrand factor diagnosis and risk score to predict future bleeding. J Thromb Haemost 2021; 19 (03) 719-731
• 24 Lavin M, Aguila S, Dalton N. et al. Significant gynecological bleeding in women with low von Willebrand factor levels. Blood Adv 2018; 2 (14) 1784-1791
• 25 Seidizadeh O, Ahmadinejad M, Homayoun S, Mannucci PM, Peyvandi F. Von Willebrand disease combined with coagulation defects in Iran. Blood Transfus 2021; 19 (05) 428-434
• 26 Doherty D, Michelle Lavin, Byrne M. et al. Enhanced VWF clearance in low VWF pathogenesis: limitations of the VWFpp/VWF:Ag ratio and clinical significance. Blood Adv 2023; 7 (03) 302-308
• 27 Ng CJ, Liu A, Venkataraman S. et al. Single-cell transcriptional analysis of human endothelial colony-forming cells from patients with low VWF levels. Blood 2022; 139 (14) 2240-2251
• 28 Lillicrap D. Low von Willebrand factor phenotype: the enigma continues. Blood 2022; 139 (14) 2102-2103
• 29 Eikenboom J, Federici AB, Dirven RJ. et al; MCMDM-1VWD Study Group. VWF propeptide and ratios between VWF, VWF propeptide, and FVIII in the characterization of type 1 von Willebrand disease. Blood 2013; 121 (12) 2336-2339
• 30 Sanders YV, Groeneveld D, Meijer K. et al; WiN study group. von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease. Blood 2015; 125 (19) 3006-3013
• 31 Pagliari MT, Rosendaal FR, Ahmadinejad M. et al. Von Willebrand factor propeptide and pathophysiological mechanisms in European and Iranian patients with type 3 von Willebrand disease enrolled in the 3WINTERS-IPS study. J Thromb Haemost 2022; 20 (05) 1106-1114