von Willebrand disease and aging: an evolving phenotype

Abstract

Summary. Background: Because the number of elderly von Willebrand disease (VWD) patients is increasing, the pathophysiology of aging in VWD has become increasingly relevant. Objectives: To assess age-related changes in von Willebrand factor (VWF) and factor VIII (FVIII) levels and to compare age-related differences in bleeding phenotype between elderly VWD patients and those < 65 years. We also studied co-morbidity in elderly patients. Patients/ Methods: We included VWD patients with VWF levels ≤ 30 U dL À1 in the nationwide cross-sectional 'Willebrand in the Netherlands' (WiN-) study. Patients reported bleeding episodes and treatment of VWD in the year preceding inclusion and during life. This was compared between VWD patients older (n = 71) and younger (16-64 years, n = 593) than 65 years. In elderly patients, agerelated changes in VWF and FVIII levels were studied longitudinally by including all historically measured levels. All medical records were examined for co-morbidity. Results: In elderly type 1 patients, a decade age increase was associated with a 3.5 U dL À1 (95% CI, À0.6 to 7.6) VWF:Ag increase and 7.1 U dL À1 (95% CI, 0.7 to 13.4) FVIII:C increase. This increase was not observed in elderly type 2 patients. Elderly type 2 patients reported significantly more bleeding symptoms in the year preceding inclusion than younger patients (16/27, 59% vs. 87/ 221, 39%; P = 0.048), which was not observed in type 1 VWD. Conclusions: von Willebrand factor parameters and bleeding phenotype evolve with increasing age in VWD. VWF and FVIII levels increase with age in type 1 patients with no mitigation in bleeding phenotype. In type 2 patients VWF parameters do not increase with age and in these patients aging is accompanied by increased bleeding.

Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States

“…There are a number of possible reasons for this lack of diagnostic fidelity. VWF levels increase with age, such that patients diagnosed many years prior to study entry may have "outgrown" their diagnosis [30][31][32] ; furthermore, the appropriate reference interval for an older adult is not well defined. Assays for VWF function may not be ideal, resulting in potential false positive or false negative laboratory results.…”

How I treat type 2 variant forms of von Willebrand disease

“…A reduction of at least one VWF functional test (below 30 IU/dL) discrepant from VWF:Ag is highly suggestive of type 2 VWD. At variance with type 1 VWD, the laboratory phenotype of type 2 VWD does not improve over age, 31 and is therefore, consistent among family members. Since VWF:CBA has been shown to be reduced in all type 2 variants (with the exception of type 2N), it could be theoretically proposed as a sensitive screening tool for types 1 and 2 VWD.…”

A 1½ year old girl with excessive bleeding following accidental trauma to the upper labial frenum during playing

“…Risk of joint bleeding depends on the level of residual Von Willebrand factor in plasma, severity of the disease and patients with type 3 Von Willebrand disease who has reduced FVIII level. 68 Von Willebrand factor rise physiologically throughout life but such age-dependant increase in Von Willebrand factor does not provide protection to alleviate bleeding symptoms. 69 However, patients with Von Willebrand disease are at reduced risk of developing cardiovascular disease and ischemic stroke.…”