Ignite Creation Date:
2024-05-05 @ 11:21 PM
Last Modification Date:
2024-10-26 @ 10:32 AM
Study NCT ID:
NCT01314560
Status:
COMPLETED
Last Update Posted:
2011-09-19
First Post:
2011-03-11
Brief Title:
Study of the Pathophysiological Mechanisms Involved in Bleeding Events
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Assistance Publique - Hôpitaux de Paris
Study Overview
Official Title:
Study of the Pathophysiological Mechanisms Involved in Bleeding Events Observed in Patients With Lowe Syndrome
Status:
COMPLETED
Status Verified Date:
2011-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
LOWE
Brief Summary:
Lowe syndrome is associated with mutations in the OCRL1 gene which encodes OCRL1 a phosphatidylinositol-4 5-bisphosphate PtdIns4 5P 25-phosphatase PtdIns4 5P2 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
The main objective of the study is to confirm the presence of platelet dysfunction in Lowe syndrome and to characterize this abnormality
Detailed Description:
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-45-bisphosphate PtdIns45P2 OCRL also contains a Rho GTPase-activating proteinGAP-like domain that participates in the regulation of Rho proteins Rho Rac Cdc42 as GTPase-activating proteins or by mediating in protein-protein interactions PtdIns45P2 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 PtdIns45P2 levels andor 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 comprehension of the physiopathology implicated in the abnormal hemorrhagic risk is of major interest in term of prevention and clinical management in Lowe patients who requires frequent surgical care
Objectives
The main objective of the study is to confirm the presence of platelet dysfunction in Lowe syndrome and to characterize this abnormality The secondary aims are to settle a functional test allowing the detection of patients with increasing hemorrhagic risk Moreover we could determinate whether platelet is an interesting cellular model easily available for further OCRL1 studies in Lowe patients
Methods
We will investigate platelet activation response in 15 Lowe cases and 15 normal cases The evaluation criteria will include the PFA100 THROMBOELASTOMETRY ROTEM aggregation secretion adhesion in a flux system and clot retraction We will also compare molecular phospho-proteins phospholipid and structural modifications of the non activated platelet and of activating platelet
Conclusion
The characterization of a platelet activation abnormality in Lowe patients could lead to major benefit for the patients with systematic homeostasis screening and special precautions rules before surgery often required in this multisystemic condition Moreover this study could contribute to go further into PI45P2 signaling pathways and may provide clues to the interrelationship between these processes in normal metabolism and diseases states
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 comprehension of the physiopathology implicated in the abnormal hemorrhagic risk is of major interest in term of prevention and clinical management in Lowe patients who requires frequent surgical care
Objectives
The main objective of the study is to confirm the presence of platelet dysfunction in Lowe syndrome and to characterize this abnormality The secondary aims are to settle a functional test allowing the detection of patients with increasing hemorrhagic risk Moreover we could determinate whether platelet is an interesting cellular model easily available for further OCRL1 studies in Lowe patients
Methods
We will investigate platelet activation response in 15 Lowe cases and 15 normal cases The evaluation criteria will include the PFA100 THROMBOELASTOMETRY ROTEM aggregation secretion adhesion in a flux system and clot retraction We will also compare molecular phospho-proteins phospholipid and structural modifications of the non activated platelet and of activating platelet
Conclusion
The characterization of a platelet activation abnormality in Lowe patients could lead to major benefit for the patients with systematic homeostasis screening and special precautions rules before surgery often required in this multisystemic condition Moreover this study could contribute to go further into PI45P2 signaling pathways and may provide clues to the interrelationship between these processes in normal metabolism and diseases states
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None