Role of Microparticles in the Coagulopathy of Acute Promyelocytic Leukemia

Related Clinical Trial
Effectiveness and Safety of Therapy Based on Attenuated ATO Plus Low-Dose ATRA in Patients With APL. A Study for Oral SY-2101 for Participants With Acute Promyelocytic Leukemia Treatment Study for Children and Adolescents With Acute Promyelocytic Leukemia Frontline Oral Arsenic Trioxide for APL A Study of CG-806 in Patients With Relapsed or Refractory Acute Myeloid Leukemia Total Marrow Irradiation for Refractory Acute Leukemia Phase I Combination of Midostaurin, Bortezomib, and Chemo in Relapsed/Refractory Acute Myeloid Leukemia Therapeutic Allogeneic Lymphocytes and Aldesleukin in Treating Patients With High-Risk or Recurrent Myeloid Leukemia After Undergoing Donor Stem Cell Transplant MEK Inhibitor MEK162, Idarubicin, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Organ-Sparing Marrow-Targeted Irradiation Before Stem Cell Transplant in Treating Patients With High-Risk Hematologic Malignancies Decitabine and Total-Body Irradiation Followed By Donor Bone Marrow Transplant and Cyclophosphamide in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Symptom-Adapted Physical Activity Intervention in Minimizing Physical Function Decline in Older Patients With Acute Myeloid Leukemia Undergoing Chemotherapy A Phase II Study Of The Farnesyltransferase Inhibitor ZANESTRA (R115777, NSC #702818, IND #58,359) In Complete Remission Following Induction And/Or Consolidation Chemotherapy In Adults With Poor-Risk Acute Myelogenous Leukemia (AML) And High-Risk Myelodysplasia (MDS) Radiolabeled BC8 Antibody, Busulfan, Cyclophosphamide Followed by Donor Stem Cell Transplant in Treating Patients With Acute Myelogenous Leukemia in First Remission 3-AP and High-Dose Cytarabine in Treating Patients With Advanced Hematologic Malignancies Busulfan and Etoposide Followed by Peripheral Blood Stem Cell Transplant and Low-Dose Aldesleukin in Treating Patients With Acute Myeloid Leukemia Vaccine Therapy and Basiliximab in Treating Patients With Acute Myeloid Leukemia in Complete Remission Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia GTI-2040 in Treating Patients With Relapsed, Refractory, or High-Risk Acute Leukemia, High-Grade Myelodysplastic Syndromes, or Refractory or Blastic Phase Chronic Myelogenous Leukemia PXD101 in Treating Patients With Acute Myeloid Leukemia Decitabine and Valproic Acid in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia or Previously Treated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Rasburicase and Allopurinol in Treating Patients With Hematologic Malignancies Lenalidomide and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Bendamustine and Idarubicin in Treating Older Patients With Previously Untreated AML or MDS Clofarabine and Cytarabine in Treating Patients With Acute Myeloid Leukemia With Minimal Residual Disease Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Lymphocytic or Myelogenous Leukemia Dasatinib, Cytarabine, and Idarubicin in Treating Patients With High-Risk Acute Myeloid Leukemia Sirolimus and Azacitidine in Treating Patients With High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia That is Recurrent or Not Eligible for Intensive Chemotherapy AR-42 and Decitabine in Treating Patients With Acute Myeloid Leukemia CPI-613, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Tosedostat in Combination With Cytarabine or Decitabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome Decitabine, Donor Natural Killer Cells, and Aldesleukin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Selinexor and Chemotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia Cediranib Maleate in Treating Patients With Relapsed, Refractory, or Untreated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome SJG-136 in Treating Patients With Relapsed or Refractory Acute Leukemia, Myelodysplastic Syndromes, Blastic Phase Chronic Myelogenous Leukemia, or Chronic Lymphocytic Leukemia Daunorubicin Hydrochloride, Cytarabine and Oblimersen Sodium in Treating Patients With Previously Untreated Acute Myeloid Leukemia GTI-2040 and High-Dose Cytarabine in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia Lenalidomide, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia Connect® MDS/AML Disease Registry Combined PD1 Inhibitor and Decitabine in Elderly Patients With Relapse and Refractory Acute Myeloid Leukemia Vorinostat in Treating Patients With Acute Myeloid Leukemia Clofarabine, Cytarabine, and G-CSF in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Romidepsin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia Bortezomib in Treating Patients With High-Risk Acute Myeloid Leukemia in Remission Clofarabine, Cytarabine, and Filgrastim Followed by Infusion of Non-HLA Matched Ex Vivo Expanded Cord Blood Progenitors in Treating Patients With Acute Myeloid Leukemia Decitabine in Treating Children With Relapsed or Refractory Acute Myeloid Leukemia or Acute Lymphoblastic Leukemia Economic Analysis of Blood Product Transfusions According to the Treatment of Acute Myeloid Leukaemia in the Elderly Comparison of Diagnostic Yield Among M-FISH, FISH Probe Panel and Conventional Cytogenetic Analysis in AML Gemtuzumab Ozogamicin in Treating Patients With Acute Myeloid Leukemia Bortezomib in Treating Young Patients With Refractory or Recurrent Leukemia Red Cell Transfusion Goals in Patients With Acute Leukemias A PALG Prospective Multicenter Clinical Trial to Compare the Efficacy of Two Standard Induction Therapies (DA-90 vs DAC) and Two Standard Salvage Regimens (FLAG-IDA vs CLAG-M) in AML Patients ≤ 60 Years Old An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia Fludarabine and Cytarabine as Continuous Infusion Plus G-CSF Priming for Elderly Patients With Resistant AML Phase I/II Trial of ATRA and TCP in Patients With Relapsed or Refractory AML and no Intensive Treatment is Possible Prognostic Values of Next Generation Sequencing (NGS) in Acute Myeloid Leukemia Patients With Allo-HSCT PET/MRI, 18F-FDG PET/CT and Whole Body MRI in Finding Extramedullary Myeloid Leukemia in Patients With Newly Diagnosed Acute Myeloid Leukemia Pilot Clinical Trial of Pazopanib in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) or at Initial Diagnosis When no Intensive Treatment is Possible A Safety Study of SGN-CD33A in AML Patients FLAG+Ida With G-CSF Priming for Patients Younger Than 60 Years With Resistant AML Study on Number and Outcome of Pregnancy in Acute Promielocitic Leukaemia (APL) Patients Treated With Chemotherapy Biomarkers in Bone Marrow Samples From Patients With Acute Promyelocytic Leukemia Treatment Study for Children and Adolescents With Acute Promyelocitic Leukemia A Study for Improving the Outcome of Childhood Acute Promyeloid Leukemia ASCT for Relapsed APL After Molecular Remission Diagnostic Study of Patients With Acute Lymphoblastic Leukemia or Acute Promyelocytic Leukemia National Acute Promyelocytic Leukemia (APL) Observational Study NAPOLEON-Registry of the German AML Intergroup All-trans Retinoic Acid, and Arsenic +/- Idarubicin Safety, Efficacy, & Pharmacokinetic Study of Tamibarotene to Treat Patients With Relapsed or Refractory APL Randomized,International Multi-center Clinical Trial of RIF Plus RA for Non-high-risk APL Gemtuzumab Ozogamicin in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Acute Promyelocytic Leukemia AIDA 2000 Guidelines Tretinoin, Cytarabine, and Daunorubicin Hydrochloride With or Without Arsenic Trioxide Followed by Tretinoin With or Without Mercaptopurine and Methotrexate in Treating Patients With Acute Promyelocytic Leukemia The Acute Promyelocytic Leukaemia Asian Consortium (APL-AC) Project Combined Retinoic Acid,Arsenic Trioxide and Chemo for Newly-diagnosed APL French Registry of First-line Treatment of Acute Promyelocytic Leukemia New Retinoid Agent Combined With Arsenic Trioxide for Untreated Acute Promyelocytic Leukemia Combined Tretinoin and Arsenic Trioxide for Patients With Newly Diagnosed Acute Promyelocytic Leukemia Followed by Risk-Adapted Postremission Therapy Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Promyelocytic Leukemia Treatment of Relapsed Promyelocytic Leukemia With Arsenic Trioxide (ATO) Treatment of Newly Diagnosed Patients With Acute Promyelocytic Leukemia (PETHEMA LPA 2005) Long-Term Quality of Life in Patients With Acute Promyelocytic Leukemia Tamibarotene and Arsenic Trioxide for Relapsed Acute Promyelocytic Leukemia Long-term QoL in Acute Promyelocytic Leukemia Treated With ATO or Standard Chemotherapy Treatment of Non-high-risk Acute Promyelocytic Leukemia (APL) With Realgar-Indigo Naturalis Formula (RIF) Treatment of Acute Promyelocytic Leukemia With All-Trans Retinoic Acid (ATRA) and Idarubicin (AIDA) Single Agent Arsenic Trioxide in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia Study for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia Treatment Protocol for Relapsed Acute Promyelocytic Leukemia (APL) With Arsenic Study of NRX 195183 Therapy for Patients With Relapsed or Refractory Acute Promyelocytic Leukemia Oral Arsenic Trioxide for Newly Diagnosed Acute Promyelocytic Leukaemia Role of Microparticles in the Coagulopathy of Acute Promyelocytic Leukemia Proteasome Inhibition in Acute Promyelocytic Leukemia

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