To determine whether serum soluble VEGFR1 is also reduced in HHT2 patients and might be used as marker of disease severity.
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
- Vascular haemorrhagic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Level of sFLT1 in correlation to symptom severity.
Secondary outcome
geen
Background summary
Hereditary haemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber
syndrome, is an autosomal dominant inherited disease affecting approximately
1:5000 people. Most cases of HHT are the result of a pathogenic DNA sequence
variant in ENG (type 1), ACVLR1 (type 2) or SMAD4 gene leading to
multi-systemic vascular dysplasia. Affected individuals often suffer from
epistaxis and bleeding in the gastrointestinal tract due to mucosal
telangiectasia, frequently leading to iron deficiency anaemia. Pulmonary
(pAVM), cerebral (cAVM) and hepatic vascular malformations (hVM) can cause
major morbidity and mortality. Penetrance of symptoms vary greatly between
disease causing mutations, within families and with age.
Angiogenesis is tightly controlled by pro- and anti-angiogenic factors. An
imbalance in this process can lead to excessive or insufficient angiogenic
responses, which has been associated with different diseases including HHT.
Studies in humans and animal models have demonstrated that for transforming
growth factor-β (TGF-β) and VEGF signalling play crucial roles in maintaining
physiological vascular homeostasis by modulating endothelial cell function.
Flt1 is a receptor for vascular endothelial growth factor receptor [VEGF],
whereas endoglin [ENG] is an auxiliary receptor TGF-β super-family members.
Both signalling pathways modulate angiogenesis and are involved in vascular
homeostasis. Increased levels of soluble Flt1 and soluble ENG dysregulate VEGF
and TGF-β signalling respectively, resulting in endothelial dysfunction of
maternal blood vessels.
Recently, we have investigated the mechanisms underlying vessel malformations
in Acvrl1+/- mutant mice, a model of HHT2 and have found that excessive
angiogenesis in HHT2 is attributed to reduced expression levels of soluble
VEGFR1 (sFLT1), providing scientific evidence supporting the use of anti-VEGF
therapies in HHT. Serum soluble VEGFR1 has been suggested to be a biomarker for
the development of preeclampsia, neovascular age-related macular degeneration
and response to anti-angiogenic therapies. Here our aim is to determine whether
serum soluble VEGFR1 is also reduced in HHT2 patients and might be used as
marker of disease severity.
Study objective
To determine whether serum soluble VEGFR1 is also reduced in HHT2 patients and
might be used as marker of disease severity.
Study design
Patients with HHT type 2 routinely visiting the pulmonary outpatient clinics
will be informed about the study during a regular visit. Patients will be given
information about the study and given 2 weeks to think about participation.
After 2 weeks dr AE Hosman will contact the patient to give them additional
information or answer any questions and ask them whether they want to
participate. If they would like to participate patients will get an appointment
following another regular check-up at the pulmonary outpatient clinics. Any
questions may be answered and additional information may be given if the
participant wishes so. Informed consent will be signed when participants want
to participate and blood will be drawn at a moment when blood needs to be drawn
using venepuncture for general diagnostics. The venepuncture is already part
of the routine laboratory diagnostic care, this is not considered an additional
intervention. 30 patients will be included.
To study the role of soluble FLT1 in the severity of clinical features of HHT
type 2 the levels of soluble FLT1 will be measured in patient material. To be
able to correlate this data to clinical severity we will use the epistaxis
severity score (ESS, appendix I) and the HHT severity score (appendix II). The
ESS is a validated questionnaire consisting of 6 multiple choice questions. The
HHT severity score has not yet been validated but has been used in previous
research and consists of a score based on clinical features, this information
will be extracted from medical charts.
Study procedures will be performed at the St. Antonius Hospital Nieuwegein and
do not interfere with other procedures or protocols. Due to the use of two
extra tubes of blood taken during routine sampling, this is not an additional
procedure to disease treatment. The venepuncture is already part of the routine
laboratory diagnostic care, this is not considered an additional intervention.
The blood material will be transferred to the clinical chemistry lab, were the
blood will be prepared for transport to the LUMC, Leiden, following the next
steps:
1-Collect whole blood into commercially available anticoagulant-treated tubes
e.g., EDTA-treated
2-Cells are removed from plasma by centrifugation for 15 minutes at 1,000-2,000
x g using a refrigerated centrifuge (it removes platelets as well). The
resulting supernatant is designated plasma.
3-Following centrifugation, it is important to immediately transfer the liquid
component (plasma) into a clean polypropylene tube using a Pasteur pipette. The
samples should be apportioned into 0.5 ml aliquots, stored, and transported at -
20°C or lower. It is important to avoid freeze-thaw cycles.
Residual blood will be discarded safely according to laboratory protocol.
All medical charts will be reviewed and documented in the digital and secured
HHT database, that is used for both clinical care and research purposes.
To determine patient characteristics we will use the the epistaxis severity
score and the HHT severity score . The ESS is a validated questionnaire
consisting of 6 multiple choice questions. The HHT severity score is based on
clinical features, this information will be extracted from medical charts.
Study burden and risks
There are no risks or benefits for patients included in this study. There is no
compensation. The blood sample is taken during routing venepuncture, does not
put the patient in any extra action or risk and standard patient care is
followed. Data will only be accessible to HHT-researchers of the St. Antonius
Hospital and researchers of the department of nefrology in the LUMC. Data will
be filed into a database, where a study number will be assigned to all
patients
Koekoekslaan 1
Nieuwegein 3435CM
NL
Koekoekslaan 1
Nieuwegein 3435CM
NL
Listed location countries
Age
Inclusion criteria
Patients with (I) hereditary hemorrhagic telangiectasia type 2 (ACVRL1 mutation) who have been screened previously by the st antonius hospital, HHT centre of exellence, (II) 18 years or older and (III) mentally competent.
Exclusion criteria
None
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
CCMO | NL59720.100.16 |