Searching for the cause of bleeding disorders of unknown cause (BDUC)

Sanquin researcher Tirsa van Duijl has been awarded a Veni grant for her research into haemostasis. She aims to better understand why, in the majority of people with an increased bleeding tendency or heavy menstrual bleeding, no underlying cause can be identified. The Veni grant supports innovative scientific research and enables talented early-career researchers to further develop their independent research careers. This grant is awarded by NWO, the Dutch Research Council

In more than half of people with an increased bleeding tendency, the underlying biological cause remains unknown. These individuals experience bleeding symptoms, yet extensive laboratory testing fails to reveal an explanation. This is particularly relevant for women, who are at risk of chronic anemia due to heavy menstrual bleeding and severe postpartum hemorrhage. Because the underlying cause is unknown, it remains difficult to provide targeted treatment.

Proteolysis

Haemostasis, and the subsequent breakdown of a blood clot, relies on a complex network of proteins that activate and inactivate one another. This process depends on the precise and timely cleavage of proteins. These cleavage events generate smaller protein fragments known as peptides. Although these peptides are often regarded merely as degradation products, they may in fact play active roles in hemostasis.

Interplay between proteins

Genetic variation can lead to differences in blood proteins and affect the efficiency of proteolysis. The combined effect of these variations influences both clot formation and clot breakdown. Through her research, Van Duijl aims to map these mechanisms in greater detail, helping to identify diagnoses and ultimately personalized treatment strategies for more people with bleeding disorders.

Many more proteins are cleaved than previously known

For her research project, The right cut, at the right time: discovering proteolytic mechanisms that control bleeding, Van Duijl uses mass spectrometry to uncover hidden molecular interactions. By triggering coagulation and measuring cleavage products over time, thousands of peptides can be monitored simultaneously. This time-resolved peptidomics approach provides a unique perspective on the full hemostatic process without losing amino acid-level detail. Early findings indicate that far more proteins undergo proteolytic cleavage during coagulation and fibrinolysis than previously recognized.

Comparing proteolytic profiles with BDUC and healthy individuals

The research has two main objectives. First, Van Duijl will investigate how proteolytic profiles differ between healthy individuals and people with bleeding disorders of unknown cause (BDUC). By comparing these profiles, she hopes to identify abnormalities that may explain why some individuals bleed more easily than others. The study will also examine genetic variants located within or near protease-recognition motifs, which may alter cleavage efficiency and thereby affect hemostatic function.

The role of blood cells

Second, she will investigate how blood cells, including platelets and white blood cells, influence proteolytic processes. In addition, she will search for novel bioactive peptides that play active roles in hemostasis or wound healing. In the future, such peptides may provide new opportunities for diagnostics and treatment for people with bleeding disorders of unknown cause.