Severe Congenital Hemostatic Defects, Cerebral MIcrobleeds and COGnition (HEMICOG)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Cerebral Microbleeds, Congenital Haemophilia, Congenital Von Willebrand Disease
• Intervention / Treatment: Other: 3-Tesla brain MRI and a comprehensive neuropsychological assessment

• Study Type: Observational
• Enrollment (Estimated): 200

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Participation in this study (with the delivery of an information note) will be offered to all eligible patients during a follow-up visit related to haemophilia or Von Willebrand Disease within the Haemostasis-Transfusion Department of the Lille University Hospital.

Description

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

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The rate of patients with at least one CMB on 3-Tesla brain MRI (using specific sequences dedicated to the detection of CMBs).	Within 3 Months after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number and anatomical location (deep/lobar) of CMBs on 3-Tesla brain MRI		Within 3 Months after inclusion
Multi-domain cognitive performances assessed by standardized scales as follows	- MoCA	Within 3 Months after inclusion
Multi-domain cognitive performances assessed by standardized scales as follows	Memory: The free and cued selective reminding test (FCSRT, French version) ; The Wechsler digit span task will be used to examine verbal short term and working memory.	Within 3 Months after inclusion
Multi-domain cognitive performances assessed by standardized scales as follows	- Processing speed and attention: digit symbol coding subtest of WAIS 4; the Continuous Performance Test (third edition, CPT3).	Within 3 Months after inclusion
Multi-domain cognitive performances assessed by standardized scales as follows	- Executive function: The categorical and literal fluency test and the Trail-Making Test (TMT).	Within 3 Months after inclusion
Multi-domain cognitive performances assessed by standardized scales as follows	- Social cognition: MINI-SEA)	Within 3 Months after inclusion
Multi-domain cognitive performances assessed by standardized scales as follows	- Depression: CES-D	Within 3 Months after inclusion
Multi-domain cognitive performances assessed by standardized scales as follows	- Anxiety: HAM-A	Within 3 Months after inclusion
Multi-domain cognitive performances assessed by standardized scales as follows	- Fatigue: The Chalder Fatigue Scale	Within 3 Months after inclusion
Multi-domain cognitive performances assessed by standardized scales as follows	- Sleepiness and the impact of sleep disorders: The Epworth Sleepiness Scale	Within 3 Months after inclusion

Collaborators and Investigators

• Sponsor: University Hospital, Lille

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2023
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: October 5, 2023
• First Submitted That Met QC Criteria: October 18, 2023
• First Posted (Actual): October 19, 2023

Study Record Updates

• Last Update Posted (Actual): October 19, 2023
• Last Update Submitted That Met QC Criteria: October 18, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Cognition; Magnetic resonance imaging (MRI); Cerebral microbleeds (CMBs); Congenital haemophilia; Congenital von Willebrand disease (vWd); Cerebral small vessel disease (SVD)
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Blood Platelet Disorders; Hemophilia A; Von Willebrand Diseases
• Other Study ID Numbers: 2022_0601

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No