Severe Congenital Hemostatic Defects, Cerebral MIcrobleeds and COGnition

Cerebral Microbleeds in Severe Congenital Hemostatic Defects: Prevalence and Impact on Cognition

Cerebral microbleeds (CMBs) are haemosiderin deposits, resulting from the leakage of erythrocytes from small cerebral vessels, which can be detected noninvasively using susceptibility-sensitive magnetic resonance imaging (MRI) techniques. CMBs are commonly observed in daily practice: their prevalence range from five percent in healthy individuals over 65 years old to 50% in patients with a history of stroke. CMBs are associated with intracerebral hemorrhage (ICH) and also cognitive impairment and dementia.

The pathophysiology of CMBs is thought to primarily involve damage to brain microvasculature but the exact underlying cascade of events, including a potential role for haemostasis, has yet to be elucidated. Haemostatic defects (congenital or acquired) may contribute to an increased number and importance of CMBs. Congenital bleeding disorders such as haemophilia or von Willebrand disease (vWD), populations at high risk of ICH, are unique conditions that may give us further insights into a potential role of haemostatic defects in the pathophysiology of CMBs. CMBs might be the missing link between severe haemostatic defects, ICH risk and cognitive function.

We hypothesized that severe congenital haemostatic defects could contribute to an increased prevalence and number of CMBs, with an impact on cognition in adulthood.

Inclusion Criteria:

• Male or female, older than 18 years old, no upper age limit

• Adult patients with a severe congenital haemostatic defect

  • Severe or moderate congenital haemophilia A (or B) defined as <5 IU/dL (<5%) endogenous FVIII (FIX) activity at screening
  • Severe von Willebrand disease defined as VWF: Act ≤15IU/dL (<15%) at screening

• Ability of the participant to provide signed and dated informed consent

Exclusion Criteria:

• Contraindication for brain MRI
• HIV infection to avoid a bias towards severe multifactorial neurological complications
• Other known coagulation disorder(s) in addition to haemophilia or von Willebrand disease
• Lack of informed consent