Brain Vascular Malformations Research Network: Predictors of Phenotype and Clinical Course. Project 3: Cerebral Hemorrhage Risk in Hereditary Hemorrhagic Telangiectasia

Heriditary hemorrhagic telagiectasia (HHT) is a condition characterized by
blood vessel malformations, called telangiectasia and arteriovenous
malformations (AVMs), occurring in the brain, nose, lungs, stomach, bowels and
liver. Brain AVMs (BAVMs) in HHT are difficult to study because they are rare,
affecting approximately 10% of people with HHT. While other types of BAVMs have
been studied in depth, studies in the HHT population have been very small. This
will be the first large-scale collaboration achieved by joining with 16 HHT
Centers of Excellence to perform a large study of risk factors for bleeding
from BAVMs, called intracranial hemorrhage (ICH), in HHT patients.

Objective and Research Questions
To identify predictors of brain outcomes in HHT patients, we propose to
leverage our multicenter network of HHT Centers to characterize comprehensive
brain outcomes.

Study Aims:
Aim 1: We hypothesize that the presence of BAVMs (vs. HHT patients without
BAVMs) and multiplicity of BAVMs will be associated with worsening functional
outcome (modified Rankin Score (mRS)). We propose to further extend our cohorts
and longitudinal mRS measures and correlate BAVM and BAVM phenotypes (lesion
number, lesion type, initial presentation, etc.) with longitudinal mRS (primary
outcome), as well as with ICH. Furthermore, we propose to measure other
neurologic outcomes in HHT (stroke, seizure, migraine, mRS etc.) across all HHT
patients and in subgroups by organ phenotype (BAVM, pulmonary AVM, etc.) and
HHT gene (ENG vs. ACVRL1).

Aim 2: To define a severe bleeding phenotype in HHT for clinical trial
readiness. We hypothesize that weekly nasal bleeding duration (Patient-Reported
Outcome Cumulative nasal Bleeding duration, or PRO-CB) in HHT will predict the
need for invasive or life-sustaining therapies (surgery, urgent packing, blood
transfusions, iron infusions). We propose to measure PRO-CB longitudinally in
Cycle 3 HHT patients and correlate with the need for invasive or
life-sustaining therapies (primary outcome), as well as with ICH risk from
BAVMs and with bleeding in other HHT organ phenotypes (Pulmonary AVMs, GI
telangiectasia, etc).

Aim 3: To identify genetic predictors and circulating biomarkers of severe
bleeding and brain outcomes in HHT. We hypothesize that there are shared
predictors of severe bleeding from the nose and brain in HHT patients and that
identifying these predictors will allow for selection of *at-risk* patients for
clinical trials. Specifically, we will evaluate potential genetic, plasma
protein biomarker and circulating miRNA biomarker predictors of PRO-CB. Markers
associated with PRO-CB will then be tested for association with ICH, and with
other brain outcomes and HHT severity phenotypes.

This is an observational and multicenter study.

We will construct a relational database and web-based data collection
instrument. Data will include demographics, symptomology, cerebral
angioarchitecture, other organ involvement and HHT gene mutation results.

The database will be used to serve Aim 2 and Aim 3 but will also serve as a
platform to foster further HHT research. The recruitment of HHT BAVM cases will
be emphasized by use of a 3:1 ratio for enrolling non-BAVM to BAVM HHT cases,
i.e., for each brain AVM recruited, 3 patients without a brain AVM will be
recruited. When possible, these additional cases will be from patients in the
same family to facilitate exploratory or future studies. This will provide the
largest single sample available that will also have centralized expert
neuroradiological adjudication of the brain phenotype.

During blood draw, subjects may experience some discomfort or slight pain at
the site of needle entry into the vein. Small blood clot formation or bruising
may occur at the point of needle entry and there may be swelling in this area.
There is a remote risk of fainting. Infection could occur at the place where
the needle goes into the arm.