Linking hemostasis to bone health in bleeding disorders

In this issue of Blood Advances, Citla-Sridhar et al¹ provide evidence that impaired bone health in hemophilia and von Willebrand disease may extend beyond reduced physical activity, implicating hemostatic pathways through associations between thrombin-plasmin dynamics and bone mineral density (BMD).

Reduced BMD is increasingly recognized as a clinically relevant comorbidity in individuals with inherited bleeding disorders. Persons with hemophilia have consistently been shown to have lower BMD,² an observation traditionally attributed to decreased physical activity related to joint disease and bleeding risk. However, this explanation likely does not fully account for the differences observed.³ In contrast, the impact of other bleeding disorders, including von Willebrand disease, on BMD remains less well characterized.⁴

Citla-Sridhar et al evaluated bone health in persons with hemophilia and von Willebrand disease compared with healthy controls using DEXA (Dual-Energy X-ray Absorptiometry) imaging alongside clinical and laboratory assessments. They found that persons with von Willebrand disease had significantly lower BMD, whereas a similar but nonsignificant trend was observed in hemophilia; both groups demonstrated reduced bone mineral content. Traditional markers of bone turnover were not associated with BMD, whereas higher levels of physical activity correlated with improved bone health.

In contrast, measures of global hemostatic function showed clear associations with bone outcomes. Models incorporating thrombin and plasmin generation explained more of the variability in BMD than clinical factors or bone remodeling markers alone. Thrombin generation was associated with higher BMD, whereas plasmin generation showed the opposite relationship, suggesting a possible link between hemostatic balance and bone health.

These findings push back on the idea that bone disease in bleeding disorders is primarily driven by reduced activity and joint disease. The relationship between thrombin and plasmin generation and BMD is consistent with previous preclinical work, suggesting that coagulation factors play a role in bone development and remodeling.5, 6, 7 Thrombin has been shown to influence osteoblast differentiation and bone formation, whereas plasmin-mediated pathways may contribute to bone resorption. Taken together, these observations suggest that differences in hemostatic balance may influence bone density, although this has not yet been demonstrated causally in patients. At the same time, physical activity remained an important correlate of bone outcomes in this cohort, reinforcing that more traditional explanations still matter.⁸ What stands out is that the hemostatic assays appeared more informative than the traditional bone turnover markers in this study, which raises the question of whether we are measuring the right biology when we assess bone health in this population. The signal observed in von Willebrand disease is also notable, particularly given that the cohort was largely composed of individuals with type 1 disease, where abnormalities in hemostasis are often considered mild. However, the differences in age and sex distribution between the hemophilia and von Willebrand disease groups, along with the cross-sectional design, make it difficult to draw firm conclusions and highlight the need for further study in larger and more comparable cohorts.

This study also leaves several practical questions unanswered. The lack of association between traditional bone turnover markers and BMD, compared with the signal seen with hemostatic assays, raises the possibility that current biomarkers may not fully reflect the processes driving bone changes in bleeding disorders. The findings in von Willebrand disease suggest that even relatively modest differences in hemostasis could have measurable effects on bone health, and that this risk may be underrecognized. It is also unclear how these findings should change clinical practice. For example, it remains uncertain whether hemostatic testing could help identify patients at higher risk for bone disease or whether current screening approaches are sufficient, particularly in populations such as those with von Willebrand disease, where data are limited. Longitudinal studies will be important to determine whether these associations reflect causal relationships and better understand how hemostatic balance, physical activity, and other clinical factors interact over time.

Together, these findings support a possible link between hemostatic balance and skeletal health in inherited bleeding disorders while also highlighting the remaining gaps in our understanding of bone health in these populations. Although the cross-sectional design and cohort differences limit interpretation, the results suggest that our current framework for understanding bone disease in these populations may be incomplete. As treatment strategies in hemophilia and von Willebrand disease continue to evolve, particularly with the use of mimetic and rebalancing therapies, it will be increasingly important to understand how these interventions may affect bone health. Further work is needed to determine whether these observations have direct clinical implications and whether they should influence how bone health is assessed and managed in patients with bleeding disorders.

Conflict-of-interest disclosure: N.M. receives honoraria from Star Therapeutics and Sanofi and research funding from Sanofi and Takeda to her university.