Lipidomics and Functional Analyses of Platelets in Fabry Disease

Fabry Disease Clinical Trial

Official title:

Lipidomics and Functional Analyses of Platelets in Fabry Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02649660
• Other study ID #: FabryPlatelets
• Status: Recruiting
• Phase: N/A
• First received: December 6, 2015
• Last updated: May 5, 2017
• Start date: October 2015
• Est. completion date: December 31, 2017

Study information

• Verified date: May 2017
• Source: Spital Linth
• Contact: Pierre-Alexandre Krayenbühl, MD
• Phone: +41 55 285 40 62
• Email: Pierre-Alexandre.Krayenbuehl[@]spital-linth.ch
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 32
• Est. completion date: December 31, 2017
• Est. primary completion date: December 31, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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)

Related Conditions & MeSH terms

• Fabry Disease

Locations

Country	Name	City	State
Switzerland	Spital Linth	Uznach	SG
Switzerland	University Hospital, Zürich	Zürich	ZH

Sponsors (3)

Lead Sponsor	Collaborator
Spital Linth	National University, Singapore, University of Zurich

Country where clinical trial is conducted

Switzerland, 

References & Publications (7)

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. — View Citation

DeGraba T, Azhar S, Dignat-George F, Brown E, Boutière B, Altarescu G, McCarron R, Schiffmann R. Profile of endothelial and leukocyte activation in Fabry patients. Ann Neurol. 2000 Feb;47(2):229-33. — View Citation

Feldt-Rasmussen U. Fabry disease and early stroke. Stroke Res Treat. 2011;2011:615218. doi: 10.4061/2011/615218. Epub 2011 Jun 23. — View Citation

Igarashi T, Sakuraba H, Suzuki Y. Activation of platelet function in Fabry's disease. Am J Hematol. 1986 May;22(1):63-7. — View 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. — View Citation

Tao RV, Sweeley CC, Jamieson GA. Sphingolipid composition of human platelets. J Lipid Res. 1973 Jan;14(1):16-25. — View Citation

Vedder AC, Biró 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 1 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Differences in sphingolipid profiles of platelets and plasma between Fabry disease patients and healthy subjects	Determination of sphingolipid concentrations in isolated platelets and plasma by targeted LC-MS (liquid chromatography mass spectrometry)-based lipidomics analysis of globotriaosylceramides (Gb3), globotriaosylspingosines (Lyso-Gb3), globotetraosylceramides (Gb4), lactosylceramides (LacCer), glucosylceramides, ceramides, sphingomyelins, sphingosines and sphingosine-1-phosphates.	Baseline
Primary	Differences in platelet function assessed by aggregometry	Determination of platelet aggregation after agonist stimulation with TRAP (thrombin receptor activator peptide), ADP (adenosine disphosphate) and arachidonic acid by light transmission aggregometry.	Baseline
Secondary	Differences in expression of the platelet activation marker P-selectin (CD62P) between Fabry disease patients and healthy subjects at baseline and after agonist stimulation	Flow cytometric analysis of platelet surface expression of CD62P in whole blood determined at baseline and after platelet activation with the agonists TRAP (thrombin receptor activator peptide), ADP, and arachidonic acid.	Baseline
Secondary	Differences in expression of the platelet activation marker CD63 between Fabry disease patients and healthy subjects at baseline and after agonist stimulation	Flow cytometric analysis of platelet surface expression of CD63 in whole blood determined at baseline and after platelet activation with the agonists TRAP (thrombin receptor activator peptide), ADP, and arachidonic acid.	Baseline
Secondary	Differences in plasma levels of the platelet activation marker soluble P-selectin between Fabry disease patients and healthy subjects	Plasma concentrations of soluble P-selectin (soluble CD62P) are determined by ELISA (enzyme-linked immunosorbent assay)	Baseline
Secondary	Differences in plasma levels of the platelet activation marker sCD40L between Fabry disease patients and healthy subjects	Plasma concentrations of sCD40L (soluble CD40 ligand) are determined by ELISA (enzyme-linked immunosorbent assay)	Baseline
Secondary	Differences in presence of platelet aggregates between Fabry disease patients and healthy subjects	Flow cytometric assessment of platelet-platelet and platelet-leukocyte aggregates	Baseline
Secondary	Differences of alpha-galactosidase A enzyme activity in plasma and isolated platelets between Fabry disease patients and healthy subjects	Analysis of the alpha-galactosidase A enzyme activity using a fluorometric enzyme assay with 4-methylumbelliferyl-a-D-galactopyranoside as substrate.	Baseline
Secondary	Differences in phospholipid profiles in platelets and plasma between Fabry disease patients and healthy subjects	Determination of phospholipid concentrations in isolated platelets and plasma by targeted LC-MS-based lipidomics analysis of phosphatidylcholines, phosphatidylserines, phosphatidylinositols, and phosphatidylethanolamines.	Baseline