Clinical Trial: Study of the Pathophysiological Mechanisms Involved in Bleeding Events
Study Status: Completed
Recruit Status: Completed
Study Type: Interventional
Official Title: Study of the Pathophysiological Mechanisms Involved in Bleeding Events Observed in Patients With Lowe Syndrome
Brief Summary:
Lowe syndrome is associated with mutations in the OCRL1 gene, which encodes OCRL1, a phosphatidylinositol-4, 5-bisphosphate (PtdIns(4, 5)P (2))5-phosphatase. PtdIns(4, 5)P2, a substrate of OCRL1, is an important signaling molecule within the cell. An abnormal rate of hemorrhagic events was found in a retrospective clinical survey, suggesting platelet dysfunction.
The main objective of the study is to confirm the presence of platelet dysfunction in Lowe syndrome and to characterize this abnormality.
Detailed Summary:
Introduction: Lowe syndrome (LS), also known as oculocerebrorenal syndrome of Lowe (OCRL), is a rare X-linked condition characterized by congenital cataracts, defective renal tubule cell function, muscular hypotonia and variable degrees of mental retardation. Patients with LS require frequent surgery, some of which are associated with a severe haemorrhagic risk, such as scoliosis reduction, hip surgery, or eye surgery. In a recent retrospective clinical survey of French LS patients, we observed an abnormal rate of haemorrhagic events, some of which had dramatic outcomes. LS is caused BYMUTATIONS in the OCRL gene, which encodes OCRL, an inositol polyphosphate 5-phosphatase. The preferred OCRLsubstrate is the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2). OCRL also contains a Rho GTPase-activating protein(GAP)-like domain that participates in the regulation of Rho proteins (Rho, Rac, Cdc42), as GTPase-activating proteins or by mediating in protein-protein interactions. PtdIns(4,5)P2 and Rho-dependent signalling play a central role in many important cellular processes, including vesicular trafficking and cytoskeletal organization both of which are very important for platelet function. Thus, modulation of PtdIns(4,5)P2 levels and/or Rho-dependent signalling would be expected to impact platelet function.
Based on the clinical observation, we tested whether hemorrhagic symptom of 6 Lowe patients could be related to homeostasis abnormalities and we found that all the six patients had a prolonged closure time tested by PFA100 analyzer (Platelet Function Analyzer). These results were measured in absence of interfering factor such anemia, thrombopenia, or von Willebrand factor deficiency, thus suggesting platelet dysfunction.
Study justification:
The com
Sponsor: Assistance Publique - Hôpitaux de Paris
Current Primary Outcome: The platelet function will be evaluated by comparing the intensity of platelet responses obtained in patient and controls [ Time Frame: 18 months ]
The platelet function will be evaluated by comparing the intensity of platelet responses obtained in patient and controls. Various platelet responses will be studied:
- The measurement of platelet closure time by PFA100
- Aggregation, retraction, secretion and adhesion
Original Primary Outcome: Same as current
Current Secondary Outcome: Characterization of abnormalities in platelet-signalling pathways [ Time Frame: 18 months ]
Original Secondary Outcome: Same as current
Information By: Assistance Publique - Hôpitaux de Paris
Dates:
Date Received: March 11, 2011
Date Started: February 2009
Date Completion:
Last Updated: September 16, 2011
Last Verified: March 2011
