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Trial record 5 of 144 for:    "Acute promyelocytic leukemia"

Role of Microparticles in the Coagulopathy of Acute Promyelocytic Leukemia

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ClinicalTrials.gov Identifier: NCT02991066
Recruitment Status : Recruiting
First Posted : December 13, 2016
Last Update Posted : April 24, 2018
Sponsor:
Information provided by (Responsible Party):
First Affiliated Hospital of Harbin Medical University

Brief Summary:
Although the clinical application of differentiation therapy has made great success in the treatment of acute promyelocytic leukemia (APL), early fatal bleeding remains an unsolved problem which accounts for the main reason of induction failure in APL patients. The clinical manifestation of both serious bleeding and thrombosis illustrate the complexity of the pathogenesis of coagulopathy in APL. Despite extensive research, the pathogenesis of coagulopathy in APL is still unclear. Microparticles, 0.11μm in diameter, are small membrane vesicles released to circulation by blood cells and vascular endothelial cells during activation or apoptosis. Microparticles (MPs) derived from different cells types all exert procoagulant activity mediated by phosphatidylserine (PS) and carry some basic substances derived from their origin cells. Also, the biological activity of microparticles is often significantly higher than that of the cells they come from. According to these problems and background knowledge, our project aims to observe the roles of microparticles derived from APL cells and the procoagulant or profibrinolytic activating factors resided on these microparticles in the pathogenesis of coagulopathy in APL, and the effects of different induction therapies, chemotherapeutic drugs or differentiation agents on these microparticles and their procoagulant or profibrinolytic activating factors. To carry out this study, microparticles are obtained from patients who undergo different induction therapies at different time points or from primary bone marrow APL cells which are treated by different drugs in vitro at different time points, the expressions and activities of five procoagulant or profibrinolytic activating factors, which are highly expressed in APL cells, PS exposure and the functional state of these microparticles, will be dynamically monitored. Further study of the pathogenesis of coagulopathy in APL can provide clues and help for deep understanding of clinical manifestations, guiding clinical treatment as well as judging prognosis, and establishing theoretical basis for exploring new treatment.

Condition or disease
Acute Promyelocytic Leukemia

Detailed Description:

The investigators plan to measure routine laboratory parameters of coagulation and fibrinolysis, the procoagulant or profibrinolytic activity of microparticles (MPs), and explore the role of the procoagulant and profibrinolytic activating factor of MPs in the pathogenesis of coagulopathy in patients with APL.

i. Dynamic turbidimetry of plasma clot formation. The effects of MPs on the kinetics of fibrin formation and on the optical properties of clots are studied using dynamic turbidimetry of re-calcified plasma samples (platelet-free plasma and microparticle-depleted plasma) without adding any clotting activator. Clotting of plasma samples induced by Ca2+ is followed by monitoring the optical density at λ = 405 nm at 37 °C.

ii. Thrombin generation assay. The amount of thrombin formed in plasma upon re-calcification is measured directly using a modified thrombin generation test . Because fibrin interferes with colorimetric measurements, plasma samples are first defibrinated by adding reptilase followed by incubation at 37 °C. The clots are removed. Then a chromogenic substrate for thrombin is added to the plasma samples. Thrombin generation is started by adding CaCl2 with simultaneous recording of the absorbance at λ = 405 nm.

iii. Thrombin generating capacity of the MPs. MPs are reconstituted in defibrinated (reptilase treated), normal pooled microparticle-depleted plasma. Then a chromogenic substrate for thrombin is added to the samples. Thrombin generation is started by adding CaCl2 with simultaneous recording of the absorbance at λ = 405 nm.

iv. Thrombin generation inhibitory experiments. The following inhibitors are pre-incubated with the microparticles: Annexin V, anti-human tissue factor (TF) and irrelevant control immunoglobulin G (IgG). Then repeats the experiment iii.

v. Fibrinolytic activity. Incubate a fixed concentration of plasminogen with the plasma samples in the presence of a chromogenic substrate selective for plasmin. Plasmin formed from plasminogen bound at the surface of microparticles cleaves the chromogenic substrate and the released p-nitroaniline is detected by measuring A405nm as a function of time.

vi. Determination of fibrinolytic activity on microparticles. The capacity of microparticles to activate plasminogen is determined by incubating a fixed concentration of plasminogen (1mM) with the microparticles with or without t-PA and/or u-PA in the presence of a chromogenic substrate selective for plasmin. Plasmin formed from plasminogen bound at the surface of microparticles cleaves the chromogenic substrate and the released p-nitroaniline is detected by measuring A405nm.

vii. Fibrinolytic activity inhibitory experiments. The following inhibitors are pre-incubated with the microparticles: anti-human tissue type plasminogen activator (tPA) , anti-human urokinase type plasminogen activator (uPA), and respective irrelevant control IgGs; ε-aminocaproic acid and plasminogen activator inhibitor-1 (PAI-1).Then repeat the experiment vi.


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Study Type : Observational
Estimated Enrollment : 20 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Role of Microparticles in the Coagulopathy of Acute Promyelocytic Leukemia
Study Start Date : October 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020


Group/Cohort
Patients
patients with de novo acute promyelocytic leukemia with hemorrhage.
Control
healthy volunteers.



Primary Outcome Measures :
  1. Change From Baseline in the Levels and Cellular Origin of MPs at 5 Weeks [ Time Frame: 5 weeks ]
    Demonstration that the some procoagulant or profibrinolytic activating factors expressed on MP in APL patients' plasma associate with the thrombin generating capacity and fibrinolytic activity of patients' plasma.


Biospecimen Retention:   Samples Without DNA
Venous blood from patients with acute promyelocytic leukemia and from healthy volunteers is collected into 0.119M sodium citrate Vacuum tubes. platelet-free plasma is prepared within 4h using 2 serial centrifugations ( 15min at 1,500g, 2 min at 13,000g) and stored at -80℃ until use. A portion of PFP was filtered through a 0.1-um-pore size filter to collect microparticle-depleted plasma and stored at -80℃ until use. Experiments concerning procoagulant activity are detected immediately after blood collection.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
patients with acute promyelocytic leukemia
Criteria

Inclusion Criteria:

  • Patients with de novo APL accompanied by hemorrhage.
  • The diagnosis was confirmed by the presence of t(15;17) and/or the PML (promyelocytic leukemia)/RARa(retinoic acid receptor alpha) fusion gene.
  • Patients should receive single-agent arsenic trioxide (ATO) for induction therapy.

Exclusion Criteria:

  • Patients with relapsed acute promyelocytic leukemia.
  • Patients without evidence of bleeding.
  • Patients younger than 18 years.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02991066


Contacts
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Contact: Jin Zhou, MD, PhD 008645185555951 zhoujin1111@126.com

Locations
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China, Heilongjiang
the First Affiliated Hospital of Harbin Medical University Recruiting
Harbin, Heilongjiang, China, 150001
Contact: Jin Zhou, MD, PhD    008645185555951    zhoujin1111@126.com   
Sponsors and Collaborators
First Affiliated Hospital of Harbin Medical University
Investigators
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Study Chair: Jin Zhou, MD, PhD First Affiliated Hospital of Harbin Medical University

Publications:

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Responsible Party: First Affiliated Hospital of Harbin Medical University
ClinicalTrials.gov Identifier: NCT02991066     History of Changes
Other Study ID Numbers: 1309
First Posted: December 13, 2016    Key Record Dates
Last Update Posted: April 24, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Keywords provided by First Affiliated Hospital of Harbin Medical University:
Acute promyelocytic leukemia
Coagulopathy
Microparticles
Mechanism
Additional relevant MeSH terms:
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Leukemia
Leukemia, Promyelocytic, Acute
Hemostatic Disorders
Blood Coagulation Disorders
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Hematologic Diseases
Vascular Diseases
Cardiovascular Diseases
Hemorrhagic Disorders