Clinical trial NCT02649660: Lipidomics and Functional Analyses of Platelets in Fabry Disease
Official title: Lipidomics and Functional Analyses of Platelets in Fabry Disease
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Fabry Disease
Keywords: Fabry Disease
Platelets
Lipidomics
Sphingolipids
α-Galactosidase A
Globotriaosylceramide
Gb3
GL-3
CD77
Alpha-galactosidase
Platelet activation
Lysosomal storage disease
LysoGb3
Spingosine-1-Phosphate
Platelet function
CD62P
P-selectin
Lead sponsor: Spital Linth
Sponsor class: OTHER_GOV
Collaborators: name: University of Zurich
name: National University of Singapore
First posted: 2016-01-07
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with Fabry Disease and healthy volunteers

Brief summary: This study aims to evaluate whether platelets are biochemically and functionally altered in Fabry disease (FD) and therefore possibly implicated in FD manifestations such as cerebrovascular events. To test this hypothesis the investigators aim to compare platelet and plasma lipid profiles, as well as platelet function and coagulation parameters of FD patients and healthy controls.

Detailed description: Fabry disease (FD) is a severe X-linked inborn error of the lysosomal glycosphingolipid metabolism. FD patients have significantly increased risks for cardiac and cerebrovascular events, which can also occur early and in absence of the typical FD symptoms. However, the pathophysiological mechanisms leading to vascular occlusion and ischemia in FD are largely unclear. Prevention of recurrent cerebrovascular events is usually based on empirical anti-platelet therapy.

Prothrombotic states and partially activated platelets have been reported for FD patients. Platelets contain glycosphingolipids, including globotriaosylceramide (Gb3), and have lysosomal α-galactosidase activity. To investigate whether the lack of or the reduced α-galactosidase enzyme activity present in Fabry disease affects platelet lipid metabolism the investigators plan to perform LC-MS-based lipidomics analyses of platelets and plasma in FD patients and healthy controls. To assess whether platelets are functionally altered in FD, the investigators aim to determine the activation status, activability, aggregability and other parameters along with plasma markers of coagulation using flow cytometry, aggregometry and immunoassays.

Eligibility criteria: Inclusion Criteria:

* Healthy Volunteers: without any known cardiovascular, cerebrovascular and renal diseases and without any known conditions affecting platelet function, blood coagulation and lipid metabolism.
* Patients: Genetically confirmed Fabry Disease
* Adult persons (18-65 years old), both female and male
* Informed written consent

Exclusion Criteria:

* Failure to meet inclusion criteria
* Pregnancy (as declared by the study participant, no pregnancy test will be performed)

Primary outcomes:
measure: Differences in sphingolipid profiles of platelets and plasma between Fabry disease patients and healthy subjects
timeFrame: Baseline
measure: Differences in platelet function assessed by aggregometry
timeFrame: Baseline
Secondary outcomes:
measure: Differences in expression of the platelet activation marker P-selectin (CD62P) between Fabry disease patients and healthy subjects at baseline and after agonist stimulation
timeFrame: Baseline
measure: Differences in expression of the platelet activation marker CD63 between Fabry disease patients and healthy subjects at baseline and after agonist stimulation
timeFrame: Baseline
measure: Differences in plasma levels of the platelet activation marker soluble P-selectin between Fabry disease patients and healthy subjects
timeFrame: Baseline
measure: Differences in plasma levels of the platelet activation marker sCD40L between Fabry disease patients and healthy subjects
timeFrame: Baseline
measure: Differences in presence of platelet aggregates between Fabry disease patients and healthy subjects
timeFrame: Baseline
measure: Differences of alpha-galactosidase A enzyme activity in plasma and isolated platelets between Fabry disease patients and healthy subjects
timeFrame: Baseline
measure: Differences in phospholipid profiles in platelets and plasma between Fabry disease patients and healthy subjects
timeFrame: Baseline
Other outcomes:
Locations:
city: Uznach
country: Switzerland
facility: Spital Linth
state: SG
city: Zürich
country: Switzerland
facility: University Hospital, Zürich
state: ZH
Study officials:
affiliation: Spital Linth
name: Pierre-Alexandre Krayenbühl, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Feldt-Rasmussen U. Fabry disease and early stroke. Stroke Res Treat. 2011;2011:615218. doi: 10.4061/2011/615218. Epub 2011 Jun 23.
citation: Tao RV, Sweeley CC, Jamieson GA. Sphingolipid composition of human platelets. J Lipid Res. 1973 Jan;14(1):16-25.
citation: Beutler E, Kuhl W, Matsumoto F, Pangalis G. Acid hydrolases in leukocytes and platelets of normal subjects and in patients with Gaucher's and Fabry's disease. J Exp Med. 1976 Apr 1;143(4):975-80. doi: 10.1084/jem.143.4.975.
citation: Sims K, Politei J, Banikazemi M, Lee P. Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry. Stroke. 2009 Mar;40(3):788-94. doi: 10.1161/STROKEAHA.108.526293. Epub 2009 Jan 15.
citation: Igarashi T, Sakuraba H, Suzuki Y. Activation of platelet function in Fabry's disease. Am J Hematol. 1986 May;22(1):63-7. doi: 10.1002/ajh.2830220110.
citation: DeGraba T, Azhar S, Dignat-George F, Brown E, Boutiere B, Altarescu G, McCarron R, Schiffmann R. Profile of endothelial and leukocyte activation in Fabry patients. Ann Neurol. 2000 Feb;47(2):229-33.
citation: Vedder AC, Biro E, Aerts JM, Nieuwland R, Sturk G, Hollak CE. Plasma markers of coagulation and endothelial activation in Fabry disease: impact of renal impairment. Nephrol Dial Transplant. 2009 Oct;24(10):3074-81. doi: 10.1093/ndt/gfp263. Epub 2009 Jun 10.