Study of the Pathophysiological Mechanisms Involved in Bleeding Events (LOWE)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01314560
First received: March 11, 2011
Last updated: September 16, 2011
Last verified: March 2011
  Purpose

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.


Condition Intervention
Oculocerebrorenal Syndrome
Other: Blood sample

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Study of the Pathophysiological Mechanisms Involved in Bleeding Events Observed in Patients With Lowe Syndrome

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • The platelet function will be evaluated by comparing the intensity of platelet responses obtained in patient and controls [ Time Frame: 18 months ] [ Designated as safety issue: No ]

    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


Secondary Outcome Measures:
  • Characterization of abnormalities in platelet-signalling pathways [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    Characterization of abnormalities in platelet-signalling pathways


Enrollment: 30
Study Start Date: February 2009
Study Completion Date: December 2010
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
experimental
Other: Blood sample
Blood sample
Other Name: Blood sample

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-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 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 PI(4,5)P2 signaling pathways and may provide clues to the interrelationship between these processes in normal metabolism and diseases states.

  Eligibility

Ages Eligible for Study:   6 Years to 45 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Patient with a clinical syndrome of Lowe (congenital cataracts, renal tubular dysfunction and neuromuscular damage) with a molecular defect in the gene known OCRL1.
  • For the centre of Necker, patients should have a weight> 10 kg. For the centre of Toulouse site, patients should have a weight> 40 kg.
  • No alteration of glomerular function (creatinine clearance> 30 ml/min/1.73m ²)
  • No significant anemia (hematocrit> 25%, hemoglobin> 8 g / L)
  • Every patient should have included a signed informed consent. For minor patients, the consent of parents or legal guardian must be obtained.
  • Patients may be included only if they receive social security coverage or CMU

Exclusion Criteria:

  • Weight less than 10 kg for the centre of Necker
  • Weight less than 40 kg for the centre of Toulouse
  • Major renal insufficiency (creatinine clearance <30 ml/min/1.73m ²)
  • Profound anemia (hematocrit <25%, Hb <8g/dl)
  • Patients taking drugs interfering with hemostasis in the eight days before the survey
  • Patients with major behavior disorder making it difficult to achieve the blood sample, despite the nitrous oxide
  • Patients with a other pathology of hemostasis (hemophilia, thrombotic disease)
  • Participation in another clinical study requiring a blood sample within 4 weeks
  • Contraindication to EMLA patch: confers Summary of Product Characteristics.
  • Contraindication to KALINOX: confers Summary of Product Characteristics.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01314560

Locations
France
Necker Enfants Malades Hospital, Genetic
Paris, France, 75015
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: Geneviève Baujat, MD, PhD Hôpital Necker Enfants Malades, Paris
  More Information

No publications provided

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01314560     History of Changes
Other Study ID Numbers: P071008
Study First Received: March 11, 2011
Last Updated: September 16, 2011
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Lowe syndrome
OCRL
Haemostasis
Bleeding Disorders
Platelet Function Tests

Additional relevant MeSH terms:
WAGR Syndrome
Chromosome Deletion
Oculocerebrorenal Syndrome
Syndrome
46, XY Disorders of Sex Development
Abnormalities, Multiple
Amino Acid Transport Disorders, Inborn
Aneuploidy
Aniridia
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Chromosome Aberrations
Chromosome Disorders
Congenital Abnormalities
Disease
Disorders of Sex Development
Endocrine System Diseases
Eye Abnormalities
Eye Diseases
Eye Diseases, Hereditary
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Gonadal Disorders
Intellectual Disability
Iris Diseases
Kidney Diseases
Kidney Neoplasms
Metabolic Diseases

ClinicalTrials.gov processed this record on October 21, 2014