Rising von Willebrand factor levels in later life blur diagnostic lines and reshape bleeding and thrombotic risk for older patients.
Von Willebrand factor, a protein essential to normal clotting, rises steadily with age, complicating the diagnosis and management of von Willebrand disease and potentially driving thrombotic risk in older adults, a sweeping review spanning more than 30 years of research has found.
Reduced or dysfunctional VWF causes von Willebrand disease (VWD), which is the most common inherited bleeding disorder.
VWD is estimated to affect approximately 1% of the general population globally. It is classified into three main types – type 1 (partial quantitative deficiency), type 2 (qualitative defects, with subtypes 2A, 2B, 2M, and 2N) and type 3 (a virtually complete absence of VWF), each of which vary in severity and clinical presentation.
The analysis, published in The Lancet Haematology, integrates cross-sectional and longitudinal studies from cohorts spanning healthy donors to patients with genetically confirmed VWD, revealing a clear biological gradient that shows VWF levels increase by about 10–15 IU/dL every decade after age 40 years.
Population-based data underpin this shift. In an Italian cohort of 74 centenarians compared with 110 younger adults, VWF concentrations were significantly higher even after excluding those with chronic illness, the researchers found.
A larger donor study involving more than 5000 participants showed little change before age 40 years but a marked 15 IU/dL rise between ages 50 and 70. ABO blood group remained a strong modifier – individuals with non-O blood types experienced nearly twice the increment seen in those with group O, amplifying the prothrombotic tendency with age.
In patients with type 1 VWD or “low VWF” (30–50 IU/dL), longitudinal follow-up revealed that roughly half experience a clinically meaningful rise in plasma VWF with ageing, and about one in four achieve normal-range concentrations (>50 IU/dL).
In these cases, von Willebrand factor antigen and activity often increased linearly with age after 40 years, accompanied by parallel rises in factor VIII.
However, those with rapid VWF clearance variants, such as the Vicenza mutation, show no such recovery, underscoring the role of molecular subtype in age-dependent trajectories.
The methodology across studies combined serial antigen and activity measurements, bleeding assessment scores and genetic characterisation of VWF variants.
Some included repeated intra-individual testing spanning more than 20 years. Functional assays demonstrated that VWF collagen-binding capacity and platelet-dependent activity also rise with age, while high-molecular-weight multimers become more abundant as the protease ADAMTS13 activity declines.
Together, these shifts paint a molecular picture of the ageing vasculature becoming more adhesive and thrombosis-prone, the researchers said.
“Although age-related increases in VWF have long been recognised, their underlying mechanisms and clinical implications remain poorly understood,” the authors wrote.
“Current evidence suggests that both genetic and environmental factors are contributors and that these changes play a potential role in cardiovascular and other age-related diseases.
“There is already some evidence that genomic variants in the regulatory region of the VWF locus play a role in the age-dependent increment in VWF, but a more comprehensive evaluation of other regulatory elements adjacent to and within the VWF locus is merited.”
The researchers noted the clinical consequences were twofold. In older adults with type 1 VWD, rising VWF may mask laboratory evidence of disease, leading to underdiagnosis or reclassification. Cumulative bleeding assessment tool (BAT) scores still rise with age, reflecting the contribution of vascular fragility, comorbidities and procedures rather than VWF deficiency alone.
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Conversely, the same biochemical rise could push some patients into a hypercoagulable state. VWF or factor VIII activity above 150 IU/dL correlates with increased rates of venous thromboembolism, myocardial infarction and stroke in population cohorts.
They urged clinicians to recalibrate their approach. For surgical planning, older patients with baseline VWF levels near or above 50 IU/dL may need less replacement therapy to avoid overshooting into thrombotic territory.
Desmopressin, long a mainstay in younger patients, may pose cardiovascular risks in older adults, required cautious use, while standard thromboprophylaxis should not be withheld in those with normalised VWF but persistent thrombotic risk factors, the researchers said.
The review identifies key knowledge gaps notably the molecular pathways linking ageing, endothelial activation and VWF synthesis, which remained incompletely defined.
Inflammaging, oxidative stress, and changes in clearance receptor expression were likely contributors, while genomic studies also suggest that promoter variants in the VWF gene may have age-dependent effects on expression and that post-translational glycosylation and glycation could prolong VWF’s plasma half-life.
“Longitudinal studies are warranted to assess how these age-related changes influence bleeding risk, treatment needs, and diagnostic accuracy over time,” the authors concluded.
“In addition, the effects of age-related increases in VWF on thrombosis risk modulation in patients with von Willebrand disease remains poorly understood.
“Further studies on the clinical and biochemical evolution of von Willebrand disease in older patients are needed to guide treatment and establish if diagnoses should be revised, reclassified, or maintained despite normalisation, with the aim of ultimately improving long-term care.”
