Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jun;23(6):1787-1799.
doi: 10.1016/j.jtha.2025.02.030. Epub 2025 Mar 6.

Bleeding symptoms in persons with rare bleeding disorders and a heterozygous genotype: data from the Rare Bleeding Disorders in the Netherlands study

Sterre P E Willems  1 , Marjon H Cnossen  2 , Nick van Es  3 , Paul L den Exter  4 , Ilmar C Kruis  5 , Dominique P M S M Maas  1 , Karina Meijer  6 , Laurens Nieuwenhuizen  7 , Sanna Rijpma  8 , Joline L Saes  9 , Annet Simons  10 , Roger E G Schutgens  9 , Marjan Weiss  10 , Nicole M A Blijlevens  11 , Waander L van Heerde  12 , Saskia E M Schols  13
Affiliations
Free article

Bleeding symptoms in persons with rare bleeding disorders and a heterozygous genotype: data from the Rare Bleeding Disorders in the Netherlands study

Sterre P E Willems et al. J Thromb Haemost. 2025 Jun.
Free article

Abstract

Background: Limited data exist on persons with rare bleeding disorders possessing a heterozygous genotype, as most studies focus on biallelic genotypes and more severe coagulation factor deficiencies. A growing body of evidence suggests that persons with a heterozygous genotype experience clinically relevant bleeding symptoms.

Objectives: This study aimed to explore the incidence of bleeding symptoms and postoperative bleeding in persons with a heterozygous genotype.

Methods: This cross-sectional substudy of the Rare Bleeding Disorders in the Netherlands study (2017-2019) included persons with rare coagulation factor deficiencies and disorders of fibrinolysis with a heterozygous or biallelic genotype. Clinical data and laboratory samples were collected during a single study visit along with questionnaires.

Results: In total, 86 persons with a heterozygous genotype and 55 with a biallelic genotype were included. Median factor activity levels in persons with a heterozygous genotype approached 50% with considerable heterogeneity (range, 11%-93%). In 75%, persons with a heterozygous genotype reported bleeding severity of grade II or III. Female-specific bleeding was common. In total, 425 surgical procedures were performed. Persons with a heterozygous genotype were less likely to receive periprocedural treatment, and omission of periprocedural treatment was associated with postoperative bleeding in procedures with intermediate-high bleeding risk. Postoperative bleeding was comparable for persons with a heterozygous genotype (35%; 59/171) and a biallelic genotype (35%; 86/247; P = .926).

Conclusion: In our population with rare bleeding disorders, the majority of persons possessing a heterozygous genotype exhibited spontaneous bleeding symptoms. Especially in intermediate-high risk procedures, a proactive approach to periprocedural hemostatic treatment in persons with a heterozygous genotype seems beneficial.

Keywords: blood coagulation disorders; fibrinolysis; genotype; hemostasis; heterozygote; inherited.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interests M.H.C. has received investigator-initiated research and travel grants as well as speaker fees over the years from the Netherlands Organisation for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Dutch “Innovatiefonds Zorgverzekeraars,” Baxter, Baxalta, Shire, Takeda, Pfizer, Bayer Schering Pharma, CSL Behring, Sobi Biogen, Novo Nordisk, Novartis, and Nordic Pharma and has served as a steering board member for Roche, Bayer, and Novartis. All grants, awards, and fees go to the Erasmus MC as an institution. W.L.v.H. reports financial support from Takeda, Bayer, Sobi, and CSL Behring and funding from Takeda and Bayer for Enzyre B.V. K.M. reports speaker fees from Bayer and Alexion, participation in a trial steering committee for Bayer, consulting fees from UniQure, participation in data monitoring, and end point adjudication committee for Octapharma. S.E.M.S. has received travel grants from Takeda and Bayer, an unrestricted educational grant from Takeda and has served as a steering board member for Roche and Novo Nordisk. R.E.G.S. reports grants from Bayer, Baxalta, Pfizer, and Novo Nordisk outside the submitted work. All other authors have no competing interest relevant to the contents of this manuscript.

MeSH terms

LinkOut - more resources