Role of Microparticles in the Coagulopathy of Acute Promyelocytic Leukemia

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Brief Title

Role of Microparticles in the Coagulopathy of Acute Promyelocytic Leukemia

Official Title

Role of Microparticles in the Coagulopathy of Acute Promyelocytic Leukemia

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.
    

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.
    


Study Type

Observational


Primary Outcome

Change From Baseline in the Levels and Cellular Origin of MPs at 5 Weeks


Condition

Acute Promyelocytic Leukemia


Study Arms / Comparison Groups

 Patients
Description:  patients with de novo acute promyelocytic leukemia with hemorrhage.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

20

Start Date

October 2014

Completion Date

December 2020

Primary Completion Date

December 2019

Eligibility 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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Jin Zhou, MD, PhD, 008645185555951, [email protected]

Location Countries

China

Location Countries

China

Administrative Informations


NCT ID

NCT02991066

Organization ID

1309


Responsible Party

Sponsor

Study Sponsor

First Affiliated Hospital of Harbin Medical University


Study Sponsor

Jin Zhou, MD, PhD, Study Chair, First Affiliated Hospital of Harbin Medical University


Verification Date

April 2018