Anomalies of Dense Platelet Granules

Overview

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…)

Full Title of Study: “Diagnosis of Platelet Dense Granules Anomalies in Unexplained Hemorrhagic Syndromes”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: February 21, 2023

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

Interventions

  • Other: Haemostasis consultation
    • Haemostasis consultation
  • Biological: Standard management of patients suspected of thrombopathy
    • Standard management of patients suspected of thrombopathy

Arms, Groups and Cohorts

  • Children and adults with unexplained hemorrhagic syndrome
    • 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.

Clinical Trial Outcome Measures

Primary Measures

  • Platelet response to different agonists
    • Time Frame: Baseline (M0)
    • Us 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
  • Platelet response to different agonists
    • Time Frame: 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
    • Time Frame: Baseline (M0)
    • Dosage of platelet serotonin by measuring platelet serotonin by HPLC.
  • Measurement of ATP
    • Time Frame: Baseline (M0)
    • 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 ATP
    • Time Frame: 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
    • Time Frame: Baseline (M0)
    • Delta granules contain calcium, which makes them naturally opaque to electrons and thus allows their direct visualization in electronic microscopy.
  • Measurement of granules opacity
    • Time Frame: at 6 months
    • Delta granules contain calcium, which makes them naturally opaque to electrons and thus allows their direct visualization in electronic microscopy.

Secondary Measures

  • Hemorrhagic risk assessment
    • Time Frame: Baseline (M0)
    • Evaluation using the ISTH score
  • Typage of delta granules anomalies
    • Time Frame: 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
  • Genetic anomalies of delta granules
    • Time Frame: 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)
  • Prothrombin consumption
    • Time Frame: Baseline (M0)
    • Evaluated by% of residual Thrombin after plasma coagulation
  • Prothrombin consumption
    • Time Frame: at 6 months
    • Evaluated by% of residual Thrombin after plasma coagulation

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 2 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Assistance Publique – Hôpitaux de Paris
  • Collaborator
    • Assistance Publique Hopitaux De Marseille
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Delphine BORGEL, PhD, Principal Investigator, APHP

References

Gresele P, Harrison P, Bury L, Falcinelli E, Gachet C, Hayward CP, Kenny D, Mezzano D, Mumford AD, Nugent D, Nurden AT, Orsini S, Cattaneo M. Diagnosis of suspected inherited platelet function disorders: results of a worldwide survey. J Thromb Haemost. 2014 Sep;12(9):1562-9. doi: 10.1111/jth.12650. Epub 2014 Jul 25.

Quiroga T, Goycoolea M, Panes O, Aranda E, Martinez C, Belmont S, Munoz B, Zuniga P, Pereira J, Mezzano D. High prevalence of bleeders of unknown cause among patients with inherited mucocutaneous bleeding. A prospective study of 280 patients and 299 controls. Haematologica. 2007 Mar;92(3):357-65. doi: 10.3324/haematol.10816.

Fiore M, Garcia C, Sié P, et al. δ-storage pool disease: an underestimated cause of unexplained bleeding. Hématologie 2017-8; 243-254.

Gresele P; Subcommittee on Platelet Physiology of the International Society on Thrombosis and Hemostasis. Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. J Thromb Haemost. 2015 Feb;13(2):314-22. doi: 10.1111/jth.12792. Epub 2015 Jan 22. No abstract available.

Mumford AD, Frelinger AL 3rd, Gachet C, Gresele P, Noris P, Harrison P, Mezzano D. A review of platelet secretion assays for the diagnosis of inherited platelet secretion disorders. Thromb Haemost. 2015 Jul;114(1):14-25. doi: 10.1160/TH14-11-0999. Epub 2015 Apr 16.

Selle F, James C, Tuffigo M, Pillois X, Viallard JF, Alessi MC, Fiore M. Clinical and Laboratory Findings in Patients with delta-Storage Pool Disease: A Case Series. Semin Thromb Hemost. 2017 Feb;43(1):48-58. doi: 10.1055/s-0036-1584568. Epub 2016 Jun 15.

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