The primary objective of this study is to investigate the role of vascular cells, with focus on pulmonary arterial endothelial cells (PAEC), in the development and pathogenesis of extensive thromboembolisms as observed in CTEPH.
ID
Source
Brief title
Condition
- Coagulopathies and bleeding diatheses (excl thrombocytopenic)
- Pulmonary vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main objective of this study is to investigate the role of the CTEPH
endothelium in platelet adhesion and clot formation. Pulmonary arterial
endothelial cells (ECs) will be characterized before and after interaction with
peripheral blood under shear stress. Cellular phenotypes of PAECs from CTEPH
patients are compared to PAECs from control subjects, and possible underlying
mechanisms will be investigated based on gained results.
Secondary outcome
1. Characterize PAECs coagulation factors expression profile. We will compare
control and CTEPH-PAECs to identify differences.
2. Study endothelial-blood interaction under high levels of fluid shear stress
to investigate how the diseased endothelium influences coagulation under
conditions resembling human hemodynamics. We will compare control, CTEPH and
PAH-PAECs to identify differences.
3. Characterize plasma from PH patients on soluble protein markers that
influences cellular behavior to express pro-thromboembolic proteins. We will
compare plasma from control, CTEPH and PAH-PAECs to identify differences.
4. Confirm if increased thrombosis found in CTEPH is a vascular problem rather
than a hemostatic problem. We will do this by studying endothelial-blood
interaction where control, CTEPH and PAH blood will be perfused over control
PAECs to compare and identify differences.
5. Investigate potential drug treatments that could act on the coagulation
pathway to prevent recurrent or to treat CTEPH.
Background summary
Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary
hypertension (PH), a group of deadly lung disorders, that is characterized by
obstruction or occlusion of the pulmonary arteries by thrombotic material and
occlusive vascular remodelling. The mechanisms driving the disease remain
unclear. Recurrent thromboembolisms as a result from a pulmonary embolism (PE)
or inadequate fibrinolysis are thought to be the two major contributors to the
development of CTEPH. Moreover, many patients have pre-existing CTEPH when a PE
is diagnosed, therefore in situ thrombosis should be considered as a potential
third factor.
Thrombosis and haemostasis are tightly regulated processes that includes timely
controlled interactions of endothelial cells, platelets, red and white blood
cells, and fibrin. Injury to vascular beds activate the formation of a
thrombus, while healthy vascular beds will prevent coagulation or regulate
lysis of a thrombus. This indicates the importance of the endothelium to play
an important role in the progression the disease.
CTEPH can be considered as a dual vascular disorder with obstructions in the
major vessels and secondary pulmonary arteriopathy in the microvasculature,
similar as in pulmonary arterial hypertension (PAH). PAH is a different form
of PH and has been well characterized by endothelial hyperproliferation with
microvascular dysfunction. Although classified in a different group, CTEPH and
PAH show similar hemodynamic and pathological features, and therefore some of
the patients share drug treatment, although robust scientific evidence is
lacking.
Study objective
The primary objective of this study is to investigate the role of vascular
cells, with focus on pulmonary arterial endothelial cells (PAEC), in the
development and pathogenesis of extensive thromboembolisms as observed in
CTEPH.
Study design
This is an experimental in vitro study using cells from surgical material from
CTEPH patients and, healthy control and patient derived blood samples. This
makes it possible to study endothelial-blood interaction involved in
coagulation in a functional assay.
Study burden and risks
The pulmonary endarterectomy surgery will not be performed for the purpose of
this study. Therefore, tissue sample collection from surgical material, that is
removed to clear the pulmonary vasculature, will not have an additional risk
for the patient. Drawing venous blood is a regular diagnostic technique and the
volume of 50 mL will have a minimal risk on the healthy subject or patient. The
blood collection is performed during the regular hospital visits and blood
sampling for diagnostic purposes.
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
PH patients diagnosed with pulmonary hypertension older than 18 years can be
included in this study. Cells will be only isolated from chronic thromboembolic
pulmonary hypertension (CTEPH) patients undergoing a pulmonary endarterectomy.
Blood will be drawn from CTEPH as wel as pulmonary arterial hypertension
patients and healthy controls
Exclusion criteria
PH patients who are categorized in group 2, 3 and 5 of the WHO classes
pulmonary hypertension (PH), are excluded from this study. Blood from control
subjects are only considered as controls if they do not have PH and/or do not
do have any bleeding disorders or take any medication that acts on the
coagulation cascade.
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 | NL69167.029.19 |