Anomalies of Dense Platelet Granules

Completed

• Conditions: Spontaneous Induced Unexplained Haemorrhagic
• Interventions: Other: Haemostasis consultation; Biological: Standard management of patients suspected of thrombopathy

• Registration Number: NCT04095715
• Lead Sponsor: Assistance Publique - Hôpitaux de Paris

Brief Summary

The study aims to know the overall prevalence of granular deficits and their breakdown by type (anomaly of number, content or secretion) in a population of patients with hemorrhagic symptomatology after exclusion of other known causes.

This study consists also to evaluate the association between the presence of a deficit in dense granules and (1) the intensity of the hemorrhagic phenotype (hemorrhagic score) (2) the nature of hemorrhages (post-operative, spontaneous, atypical...)

-Evaluate the association between the type of deficit in dense granules and (1) the intensity of the hemorrhagic phenotype (hemorrhagic score) (2) the nature of hemorrhages (post-operative, spontaneous, atypical...)

Detailed Description

Patients will be recruited during the exploration visit (v0) or the confirmation/typing visit (v1) according to their follow-up.

* Exploration visit (v0): inclusion of patients without prior platelet exploration, and study of their dense platelet granules.

* Confirmation/typing visit (v1): verification of the persistence of anomalies detected in patients with an abnormality identified during v0 (no later than 6 months after v0) and in patients for whom a dense granules anomaly has already been identified during their standard management prior to the start of the study. Completion of complementary examinations to complement the typing of the granular anomaly and molecular analysis for family cases

Study Timeline

• Study First Submitted: 2019-06-18
• Study First Submitted QC: 2019-09-17
• Study First Posted: 2019-09-19
• Study Start: 2019-12-09
• Primary Completion: 2023-02-21
• Study Completion: 2023-02-21
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-27
• Last Update Posted: 2023-10-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 166

Inclusion Criteria

• Adult or child patient ≥ 2 years
• Having a hemorrhagic score ISTH > 3 for men, > 5 for women and > 2 for children.
• With no abnormal coagulation (defined by normal TP and TCK or activity ≥ 50% of FII, FV, FVII, FX, FVIII, FIX, FXI)
• no deficiency of Willebrand factor (defined by a cofactor activity with Ristoctin (VWF: RCo < 50%))
• no a known major thrombocytopenia/thrombopathy linked to a deficiency of one of the major platelet receptors
• Information of the patient and/or his legal representative present

Exclusion Criteria

• Inability or refusal of compliance with research requirements
• Thrombocytopenia < 100 G/L
• Treatments interfering with platelet functions within 10 days prior to inclusion
• Malignant hemopathy

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Children and adults with unexplained hemorrhagic syndrome	Haemostasis consultation	Patients with spontaneous or induced hemorrhagic manifestations who are present for a consultation to investigate a thrombopathy or during follow-up consultations as part of their usual care.
Children and adults with unexplained hemorrhagic syndrome	Standard management of patients suspected of thrombopathy	Patients with spontaneous or induced hemorrhagic manifestations who are present for a consultation to investigate a thrombopathy or during follow-up consultations as part of their usual care.

Primary Outcome Measures

Name	Time	Method
Platelet response to different agonists	At 6 months	Use of some low-dose agonists such as ADP, epinephrine or collagen, which are particularly susceptible to granular defects, on platelet-rich plasma (PRP) prepared from the patient's blood sample to be explored
Granular Delta content	Baseline (M0)	Dosage of platelet serotonin by measuring platelet serotonin by HPLC.
Measurement of ATP	At 6 months	The measurement is based on the principle of bioluminescence with a two-step transformation reaction of luciferin in the presence of luciferase, this reaction requiring the presence of ATP
Measurement of granules opacity	at 6 months	Delta granules contain calcium, which makes them naturally opaque to electrons and thus allows their direct visualization in electronic microscopy.

Secondary Outcome Measures

Name	Time	Method
Hemorrhagic risk assessment	Baseline (M0)	Evaluation using the ISTH score
Prothrombin consumption	at 6 months	Evaluated by% of residual Thrombin after plasma coagulation
Genetic anomalies of delta granules	At 6 months	Sequencing on a broad set of genes involved in platelet function. Bioinformatic analysis is carried out using BWA-MEM software (Alignment on the genome version HG19)
Typage of delta granules anomalies	At 6 months	Fib-SEM technic by focussed ion beam scanning which allows a 3D reconstitution of the platelets and thus to visualize any empty granules

Trial Locations

Locations (1)

Hôpital Necker Enfants Malades - AP-HP; 🇫🇷 Paris, France