<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03795649</url>
  </required_header>
  <id_info>
    <org_study_id>EP-12939/18-1</org_study_id>
    <nct_id>NCT03795649</nct_id>
  </id_info>
  <brief_title>The Immunomodulatory Effect of Antrifibrinolytic (Tranexamic Acid) in Total Knee Arthroplasty</brief_title>
  <official_title>The Immunomodulatory Effect of Antrifibrinolytic (Tranexamic Acid) in Total Knee Arthroplasty</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sisters of Mercy University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Clinical Hospital Centre Zagreb</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Sisters of Mercy University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The administration of the tranexamic acid (TRAXA), an antifibrinolytic, blocks primary&#xD;
      fibrinolysis, and thus the haemorrhage, in the early postoperative period. Significant&#xD;
      surgical operations, as well as trauma, initiate a similar dynamic homeostatic mechanism&#xD;
      between the creation of a clot (primary and secondary haemostasis) and its dissolution&#xD;
      (fibrinolysis). Antifibrinolytics have been proven effective in reducing haemorrhage in&#xD;
      patients who have undergone significant surgical operations with normal fibrinolysis, with&#xD;
      the use of an appropriate surgical technique.&#xD;
&#xD;
      A pharmacokinetic study has shown that peak fibrinolytic activity is present for 6 hours&#xD;
      after the incision and it persists for 18 hours in total knee and hip arthroplasty. The&#xD;
      administration of the tranexamic acid in optional orthopaedic surgery of total hip (THA) and&#xD;
      knee (TKA) arthroplasty reduces the postoperative haemorrhage, as well as the number and&#xD;
      volume of the postoperative autologous blood.&#xD;
&#xD;
      A trauma in the organism triggers the immunologic response. New term has been introduced -&#xD;
      the post-traumatic immunosuppression (PTI), characterised by: a change on the immunologic&#xD;
      cells (neutrophilia, monocytosis, increased number of mesenchymal stromal cells, reduced&#xD;
      expression of HLA-DR on monocytes, reduced function of natural killer (NK) cells, increased&#xD;
      lymphocyte apoptosis, a shift in homoeostasis towards the Th2 phenotype facilitated by Treg&#xD;
      lymphocytes - CD4+CD25+CD127-); a change in production levels of various cytokines&#xD;
      (anti-inflammatory cytokines): IL-10, IL-4; anti- and pro-inflammatory cytokine: IL-6;&#xD;
      pro-inflammatory cytokines IL-2, TNF-α, IFN-γ); the activation of the complement system (C5a&#xD;
      and C3a via factor VII - tissue factor system, activated by cell damage).&#xD;
&#xD;
      Post-traumatic immunosuppression can be made worse by transfusion, haemorrhage, stress,&#xD;
      significant surgical operation and immunosuppressive drugs.&#xD;
&#xD;
      The research has shown that Treg lymphocytes CD4+CD25+CD127- have an important role in&#xD;
      controlling the acquired and innate immunity (comprising 6-8% of all CD4+ lymphocytes).&#xD;
&#xD;
      Stopping haemorrhage prevents the occurrence of anaemia, as well as the need for transfusion&#xD;
      of blood products, which lead to developing the post-traumatic immunosuppression (PTI).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The administration of the tranexamic acid (TRAXA), an antifibrinolytic, blocks primary&#xD;
      fibrinolysis, and thus the haemorrhage, in the early postoperative period. Significant&#xD;
      surgical operations, as well as trauma, initiate a similar dynamic homeostatic mechanism&#xD;
      between the creation of a clot (primary and secondary haemostasis) and its dissolution&#xD;
      (fibrinolysis). Antifibrinolytics are initially used in patients with an accelerated&#xD;
      fibrinolysis of different pathogeneses. However, they have been proven effective in reducing&#xD;
      haemorrhage in patients who have undergone significant surgical operations with normal&#xD;
      fibrinolysis, with the use of an appropriate surgical technique.&#xD;
&#xD;
      A pharmacokinetic study has shown that peak fibrinolytic activity is present for 6 hours&#xD;
      after the incision and it persists for 18 hours in total knee and hip arthroplasty. The&#xD;
      administration of the tranexamic acid in optional orthopaedic surgery of total hip (THA) and&#xD;
      knee (TKA) arthroplasty reduces the postoperative haemorrhage, as well as the number and&#xD;
      volume of the postoperative autologous blood.&#xD;
&#xD;
      A randomized, placebo-controlled trial CRAS-2 has validated that the early post-traumatic&#xD;
      administration of the tranexamic acid, within 8 hours after the injury, in adult patients&#xD;
      with traumas or in patients with the risk of significant haemorrhage, reduces the fatality&#xD;
      rate.&#xD;
&#xD;
      The tranexamic acid is a synthetic derivative of lysine, an amino acid which blocks lysine&#xD;
      binding sites of the plasminogen molecule which are essential for its biding to fibrin. This&#xD;
      mechanism inhibits the plasminogen activation via a plasminogen activator which also binds to&#xD;
      fibrin. Thus, it prevents the conversion of plasminogen into plasmin, which is essential for&#xD;
      fibrin dissolution, the integral element of a stable clot. The second important&#xD;
      antifibrinolytic effect is blocking the lysine binding sites on the free plasmin molecule&#xD;
      which has already been formed through the conversion from the plasminogen. This inhibits its&#xD;
      binding to fibrin, and the TRAXA-plasmin complex is rapidly inactivated with the&#xD;
      α-2-antiplasmin and α-2-macroglobulin. Biological half-life is approximately 2-3 hours.&#xD;
&#xD;
      A trauma in the organism triggers the immunologic response. The initial immunologic reaction&#xD;
      occurs at the location of the injury, and it is called an inflammation. The inflammatory&#xD;
      response is characterized by a complex interaction of macrophages (a type of leukocytes which&#xD;
      develop from monocytes and are a part of the mononuclear phagocyte system, the main task of&#xD;
      which are phagocytosis, i.e. the clearance of foreign materiel from the organism, performing&#xD;
      the immunologic function - the defence against foreign materiel - antigens, and the&#xD;
      regulation of the inflammation via interleukins which they secrete - IL1, IL-2,TNF) and&#xD;
      dendritic cells (antigen-presenting cells), the consequence of which is the release of&#xD;
      cytokines (interleukins - glycoproteins which regulate interactions among cells) and&#xD;
      chemokine (small proteins from the cytokine group - able to induce chemotaxis, cell&#xD;
      migration), and the activation of the neutrophils, monocytes and mesenchymal stem cells&#xD;
      (cells not containing any information, located in the adipose tissue, cartilage and muscle&#xD;
      tissue).&#xD;
&#xD;
      If the initial inflammatory response at the location of the injury is strong enough, it will&#xD;
      develop into a systemic inflammatory response, called systemic inflammatory response syndrome&#xD;
      (SIRS), which implies an inflammatory response of the entire body without a proven source of&#xD;
      infection. The criteria for the diagnosis of the SIRS are: heart rate higher than 90 bpm;&#xD;
      body temperature lower than 36°C or higher than 38°C; tachypnoea, respiratory rate higher&#xD;
      than 20 breaths per minute or the partial pressure of carbon dioxide in the blood lower than&#xD;
      4.3 kPa (32 mm Hg); the number of white blood cells, leukocytes, lower than 4.000 cells in 1&#xD;
      mm³ or higher than 12.000 cells in 1 mm³; or the presence of more than 10% of immature&#xD;
      neutrophils. A destructive immunologic inflammatory cascade can prevent or delay healing.&#xD;
&#xD;
      At the same time the compensatory anti-inflammatory response syndrome (CARS) is initiated,&#xD;
      which includes the immunologic response with the aim of re-establishing the immunologic&#xD;
      homeostasis. It is characterized by: a reduced cytokine response of monocytes to the&#xD;
      stimulation; a reduced number of antigen-presenting receptors (human leukocyte antigens or&#xD;
      HLA) on monocytes; an increased level of IL-10, an anti-inflammatory cytokine; lymphocyte&#xD;
      apoptosis (T-cells); lymphocyte dysfunction, i.e. reduced proliferation; reduced Th1&#xD;
      proinflammatory cytokine production (a shift in homoeostasis towards the Th2 phenotype&#xD;
      facilitated by the regulatory T lymphocytes). It clinically manifests as skin allergy,&#xD;
      hypothermia and leukopenia. Additional criteria include elevated levels of C-reactive&#xD;
      proteins, lactates and hyperglycaemia. If the immunosuppressive response persists, it may&#xD;
      increase the possibility of an infection occurring, and the inability to defend against the&#xD;
      infection, which may result in the development of sepsis, multiple organ failure and death.&#xD;
&#xD;
      Due to the wide clinical and laboratory criteria which both the SIRS and CARS terms include,&#xD;
      they are not the best terms for describing the immunologic response to a trauma, and a new&#xD;
      term has been introduced - the post-traumatic immunosuppression (PTI), characterised by: a&#xD;
      change on the immunologic cells (neutrophilia, monocytosis, increased number of mesenchymal&#xD;
      stromal cells, reduced expression of HLA-DR on monocytes, reduced function of natural killer&#xD;
      (NK) cells, increased lymphocyte apoptosis, a shift in homoeostasis towards the Th2 phenotype&#xD;
      facilitated by Treg lymphocytes - CD4+CD25+CD127-); a change in production levels of various&#xD;
      cytokines (anti-inflammatory cytokines): IL-10, IL-4; anti- and pro-inflammatory cytokine:&#xD;
      IL-6; pro-inflammatory cytokines IL-2, TNF-α, IFN-γ); the activation of the complement system&#xD;
      (C5a and C3a via factor VII - tissue factor system, activated by cell damage).&#xD;
&#xD;
      Post-traumatic immunosuppression can be made worse by transfusion, haemorrhage, stress,&#xD;
      significant surgical operation and immunosuppressive drugs.&#xD;
&#xD;
      The research has shown that Treg lymphocytes CD4+CD25+CD127- have an important role in&#xD;
      controlling the acquired and innate immunity (comprising 6-8% of all CD4+ lymphocytes).&#xD;
&#xD;
      The normal function of Treg lymphocytes is the suppression of the T-cell response against its&#xD;
      own antigens.&#xD;
&#xD;
      Stopping haemorrhage prevents the occurrence of anaemia, as well as the need for transfusion&#xD;
      of blood products, which lead to developing the post-traumatic immunosuppression (PTI).&#xD;
&#xD;
      Monitoring the immunologic status of patients with the understanding of the PTI mechanism can&#xD;
      enable timely and individual modulation of the immunologic status with pre-planned procedures&#xD;
      (preventing haemorrhage, anaemia, avoiding transfusion) and/or immunotherapy (drugs and&#xD;
      nutrients), and thereby prevent the occurrence of complications, such as infections.&#xD;
      Infections may result in sepsis and multiple-organ failure, and eventually be lethal for the&#xD;
      patient.&#xD;
&#xD;
      The research has proved that Treg lymphocytes CD4+CD25+CD127- have an important role in&#xD;
      controlling the acquired and innate immunity (comprising 6-8% of all CD4+ lymphocytes).&#xD;
&#xD;
      The normal function of Treg lymphocytes is the suppression of the T-cell response against its&#xD;
      own antigens.&#xD;
&#xD;
      There are two main types of regulatory lymphocytes: natural Treg, which are mostly developed&#xD;
      in the thymus, and inducible Treg, which arise in the periphery after being exposed to&#xD;
      cytokines, antigen-presenting cells or immunosuppressive drugs. It may be difficult to&#xD;
      differentiate these two lymphocyte Treg populations in vivo. Nevertheless, it is known that&#xD;
      different stages of the infection require different regulations. Acute infection, tissue&#xD;
      damage, inflammation caused by the innate immunologic response is limited, i.e. locally&#xD;
      controlled via natural Treg lymphocytes. This mechanism triggers the activation of inducible&#xD;
      Treg lymphocytes.&#xD;
&#xD;
      For the first time, in 1995, it was described that the suppression of CD4+ T-lymphocytes is&#xD;
      caused by a low T-cell population with the CD4+ CD25+ expression. Natural Treg lymphocytes,&#xD;
      apart from belonging to CD4+ T-cell population, have a CD25+ receptor, an α-receptor chain&#xD;
      for IL-2, and a receptor for the cytotoxic T-lymphocytic antigen 4 (CTLA 4), the tumour&#xD;
      necrosis factor receptor (TNF), but it differs from the activated T-cells by the expression&#xD;
      of the transcription factor FoxP3 (transcription factor encoded with the FoxP3 gene). The&#xD;
      expression of CD 127lo, an α-chain receptor for the interleukin 7 enables us to differentiate&#xD;
      Treg lymphocytes from the activated T-lymphocytes via flow cytometry. The number of&#xD;
      CD25+CD127lo cells correlates to the number of CD25+FoxP3+ cells in the peripheral blood.&#xD;
&#xD;
      Different studies show that the application of the 3-colour flow cytometry shows small&#xD;
      variation in the percentage of Treg lymphocytes in the peripheral blood from 6.35% to 8.34%.&#xD;
&#xD;
      There is a number of different mechanisms which achieve regulation by using the Treg&#xD;
      lymphocytes: the long-term interaction with dendritic cells (DC), thereby modulating the&#xD;
      function of antigen-presenting cells (APC), the production of the anti-inflammatory cytokine,&#xD;
      IL-10 and the CTLA4 expression on Treg cells which induces the enzyme indoleamine&#xD;
      2,3-dioxygenase (IDO) in APC which degrade the amino acid tryptophan, the lack of which&#xD;
      inhibits the activation of T-cells and induces T-cell apoptosis. Treg lymphocytes also induce&#xD;
      the apoptosis of monocytes and affect the lower expression of HLA-DR on monocytes whereby&#xD;
      they directly affect the innate immunological response.&#xD;
&#xD;
      Elevated, suppressive activity of Treg cells in traumas prevents the protective Th1 response&#xD;
      for up to 7 days in comparison with the healthy population.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">December 18, 2018</start_date>
  <completion_date type="Anticipated">December 2019</completion_date>
  <primary_completion_date type="Anticipated">December 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The immunomodulation effect of Tranexamic Acid (IM)</measure>
    <time_frame>two years</time_frame>
    <description>Trial will include approximately 100 patients in total, which will be divided into four groups of 25 patients. The immunomodulation effect is monitored through the analysis of the lymphocyte subpopulation in the peripheral blood through flow cytometry.&#xD;
The result of each lymphocyte subpopulation will be registered as a percentage of all helper cells (CD4+) and all lymphocytes, as well as their absolute number in the peripheral blood.&#xD;
These parameters will be monitored dynamically in the chronological order as shown below:&#xD;
Day 1 - Preoperatively; Day 1 - Postoperatively T1 (IM) K - 6 hrs postoperatively T1 (IM) A - 6 hrs after the first TRAXA dose, and two hours before LMWH T1 (IM) B - 6 hrs postoperatively (after the transfusion of the autologous blood by means of the autotransfusion system); Day 3 - Postoperatively; Day 5 - Postoperatively; Day 7 - Postoperatively; For immunologic testing of each patient's blood 25 ml (5 ml x 5) during 7 days will be sampled.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The effect of the Tranexamic Acid on the primary fibrinolysis (F)</measure>
    <time_frame>two years</time_frame>
    <description>The fibrinolytic activity of plasma will be examined through euglobulin lysis time testing Blood sampling follows the same time intervals of blood sampling for determining Treg lymphocytes. Fibrinolysis is monitored until the third postoperative day.&#xD;
In total per patient for analysis of the fibrinolytic activity 15 mL (5 mL x 3) of blood will be sampled during a 3-day period.&#xD;
Day 1 - Preoperatively; Day 3 - Postoperatively T1 (F) K - 6 hrs postoperatively T1 (F) A - 6 hrs after the first TRAXA dose, and two hours before LMWH T1 (F) B - 6 hrs postoperatively (after the transfusion of the autologous blood by means of the autotransfusion system); Day 3 - Postoperatively;</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Hemorrhage</condition>
  <arm_group>
    <arm_group_label>The control group (Group K)</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>The control group (Group K) is comprised of surgical patients who will not receive blood transfusion, and who have contraindications for Tranexamic Acid.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group A, Tranexamic acid</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The treatment group (Group A) is comprised of the patients who will receive Tranexamic acid 1g intravenous 15 min. before releasing the pneumatic tourniquet and the repeating dose 3 hours later</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B, autologous transfusion</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>The treatment group (Group B) will be comprised of the patients who in the second selection have one or more contraindications for Tranexamic Acid administration and transfusion of autologous blood will be performed.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group C, alogenous transfusion</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>The treatment group (Group C) contraindications for Tranexamic Acid administration and the transfusion of alogenous blood will be performed in the case of acute haemorrhage followed by patient's hemodynamic instability.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tranexamic Acid</intervention_name>
    <description>Imunomodulatory effect</description>
    <arm_group_label>Group A, Tranexamic acid</arm_group_label>
    <arm_group_label>Group B, autologous transfusion</arm_group_label>
    <arm_group_label>Group C, alogenous transfusion</arm_group_label>
    <other_name>Medsamic</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ASA I/II status&#xD;
&#xD;
          -  scheduled for endoprosthetic total knee arthroplasty.&#xD;
&#xD;
          -  laboratory results suitable for elective endoprosthetic surgery: blood panel,&#xD;
             coagulation, liver enzymes, kidney function parameters, urine sediment;&#xD;
&#xD;
          -  patient voluntarily, in accordance with the KBCSM form on the administration of&#xD;
             Tranexamic Acid in endoprosthetic total knee arthroplasty, give their consent for its&#xD;
             administration.&#xD;
&#xD;
          -  signed informed consent for transfusion&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  general anaesthesia&#xD;
&#xD;
          -  revision arthroplasty&#xD;
&#xD;
          -  previous blood transfusions&#xD;
&#xD;
          -  known allergic reaction to TRAXA&#xD;
&#xD;
          -  presence of an infection and/or acutization of a chronic disease&#xD;
&#xD;
          -  existing malignant disease&#xD;
&#xD;
          -  autoimmune disease&#xD;
&#xD;
          -  hematologic disease&#xD;
&#xD;
          -  diabetes&#xD;
&#xD;
          -  renal failure&#xD;
&#xD;
          -  liver cirrhosis&#xD;
&#xD;
          -  chronic anticoagulant therapy&#xD;
&#xD;
          -  analgesia by non-steroidal anti-inflammatory drugs&#xD;
&#xD;
          -  combined use of the autologous and allogeneic blood postoperatively when the recovery&#xD;
             of the autologous blood is insufficient in relation to the haemorrhage.&#xD;
&#xD;
        Exclusion Criteria refers to the patients for whom Tranexamic Acid was contraindicated:&#xD;
        ----thromboembolic events (IM, CVI, DVT)&#xD;
&#xD;
          -  known risk of thrombosis or thromboembolic events (thrombogenic valve disease,&#xD;
             thrombogenic rhythm disorder, coagulation-hypercoagulation disorder)&#xD;
&#xD;
          -  epilepsy&#xD;
&#xD;
          -  patients who use oral contraceptives&#xD;
&#xD;
          -  known retinal arterial or venous occlusions.&#xD;
&#xD;
        To patients who fulfil the participation criteria for the trial in the first selection, and&#xD;
        for whom TRAXA is contraindicated in the second selection, blood transfusion will be&#xD;
        administered in accordance with the indication.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Renata Letica-Brnadić</last_name>
    <role>Study Chair</role>
    <affiliation>Clinical Hospital Centre &quot;Sisters of Mercy&quot;</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Renata Letica-Brnadić</last_name>
    <phone>+38598340722</phone>
    <email>rlbrnadic@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Klinički Bolnički Centar Sestre Milosrdnice</name>
      <address>
        <city>Zagreb</city>
        <zip>10000</zip>
        <country>Croatia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Renata Letica-Brnadić</last_name>
      <phone>+38598340722</phone>
      <email>rlbrnadic@gmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>Croatia</country>
  </location_countries>
  <reference>
    <citation>Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, McClelland B, Laupacis A, Fergusson D. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD001886. doi: 10.1002/14651858.CD001886.pub2.</citation>
    <PMID>17943760</PMID>
  </reference>
  <reference>
    <citation>Astedt B. Clinical pharmacology of tranexamic acid. Scand J Gastroenterol Suppl. 1987;137:22-5.</citation>
    <PMID>3321402</PMID>
  </reference>
  <reference>
    <citation>Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, Cook L, Kawahara T, Perel P, Prieto-Merino D, Ramos M, Cairns J, Guerriero C. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. 2013 Mar;17(10):1-79. doi: 10.3310/hta17100.</citation>
    <PMID>23477634</PMID>
  </reference>
  <reference>
    <citation>Oremus K, Sostaric S, Trkulja V, Haspl M. Influence of tranexamic acid on postoperative autologous blood retransfusion in primary total hip and knee arthroplasty: a randomized controlled trial. Transfusion. 2014 Jan;54(1):31-41. doi: 10.1111/trf.12224. Epub 2013 Apr 25.</citation>
    <PMID>23614539</PMID>
  </reference>
  <reference>
    <citation>Raveendran R, Wong J. Tranexamic acid: more evidence for its use in joint replacement surgery. Transfusion. 2014 Jan;54(1):2-3. doi: 10.1111/trf.12494. No abstract available.</citation>
    <PMID>24405302</PMID>
  </reference>
  <reference>
    <citation>Parkin J, Cohen B. An overview of the immune system. Lancet. 2001 Jun 2;357(9270):1777-89. doi: 10.1016/S0140-6736(00)04904-7.</citation>
    <PMID>11403834</PMID>
  </reference>
  <reference>
    <citation>Islam MN, Bradley BA, Ceredig R. Sterile post-traumatic immunosuppression. Clin Transl Immunology. 2016 Apr 29;5(4):e77. doi: 10.1038/cti.2016.13. eCollection 2016 Apr.</citation>
    <PMID>27195120</PMID>
  </reference>
  <reference>
    <citation>Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55. doi: 10.1378/chest.101.6.1644.</citation>
    <PMID>1303622</PMID>
  </reference>
  <reference>
    <citation>Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med. 1996 Oct 15;125(8):680-7. doi: 10.7326/0003-4819-125-8-199610150-00009.</citation>
    <PMID>8849154</PMID>
  </reference>
  <reference>
    <citation>Ward NS, Casserly B, Ayala A. The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients. Clin Chest Med. 2008 Dec;29(4):617-25, viii. doi: 10.1016/j.ccm.2008.06.010.</citation>
    <PMID>18954697</PMID>
  </reference>
  <reference>
    <citation>Osuka A, Ogura H, Ueyama M, Shimazu T, Lederer JA. Immune response to traumatic injury: harmony and discordance of immune system homeostasis. Acute Med Surg. 2014 Jan 28;1(2):63-69. doi: 10.1002/ams2.17. eCollection 2014 Apr.</citation>
    <PMID>29930824</PMID>
  </reference>
  <reference>
    <citation>Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, Kelleher A, Fazekas de St Groth B. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006 Jul 10;203(7):1693-700. doi: 10.1084/jem.20060468. Epub 2006 Jul 3.</citation>
    <PMID>16818676</PMID>
  </reference>
  <reference>
    <citation>Venet F, Chung CS, Kherouf H, Geeraert A, Malcus C, Poitevin F, Bohe J, Lepape A, Ayala A, Monneret G. Increased circulating regulatory T cells (CD4(+)CD25 (+)CD127 (-)) contribute to lymphocyte anergy in septic shock patients. Intensive Care Med. 2009 Apr;35(4):678-86. doi: 10.1007/s00134-008-1337-8. Epub 2008 Oct 23.</citation>
    <PMID>18946659</PMID>
  </reference>
  <reference>
    <citation>Venet F, Chung CS, Monneret G, Huang X, Horner B, Garber M, Ayala A. Regulatory T cell populations in sepsis and trauma. J Leukoc Biol. 2008 Mar;83(3):523-35. doi: 10.1189/jlb.0607371. Epub 2007 Oct 3.</citation>
    <PMID>17913974</PMID>
  </reference>
  <reference>
    <citation>Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol. 2007 Nov;7(11):875-88. doi: 10.1038/nri2189.</citation>
    <PMID>17948021</PMID>
  </reference>
  <reference>
    <citation>Shevach EM, DiPaolo RA, Andersson J, Zhao DM, Stephens GL, Thornton AM. The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol Rev. 2006 Aug;212:60-73. doi: 10.1111/j.0105-2896.2006.00415.x.</citation>
    <PMID>16903906</PMID>
  </reference>
  <reference>
    <citation>Hartigan-O'Connor DJ, Poon C, Sinclair E, McCune JM. Human CD4+ regulatory T cells express lower levels of the IL-7 receptor alpha chain (CD127), allowing consistent identification and sorting of live cells. J Immunol Methods. 2007 Jan 30;319(1-2):41-52. doi: 10.1016/j.jim.2006.10.008. Epub 2006 Nov 3.</citation>
    <PMID>17173927</PMID>
  </reference>
  <reference>
    <citation>Fragkou PC, Torrance HD, Pearse RM, Ackland GL, Prowle JR, Owen HC, Hinds CJ, O'Dwyer MJ. Perioperative blood transfusion is associated with a gene transcription profile characteristic of immunosuppression: a prospective cohort study. Crit Care. 2014 Oct 1;18(5):541. doi: 10.1186/s13054-014-0541-x.</citation>
    <PMID>25270110</PMID>
  </reference>
  <results_reference>
    <citation>Blanie A, Bellamy L, Rhayem Y, Flaujac C, Samama CM, Fontenay M, Rosencher N. Duration of postoperative fibrinolysis after total hip or knee replacement: a laboratory follow-up study. Thromb Res. 2013 Jan;131(1):e6-e11. doi: 10.1016/j.thromres.2012.11.006. Epub 2012 Nov 26.</citation>
    <PMID>23195143</PMID>
  </results_reference>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>December 30, 2018</study_first_submitted>
  <study_first_submitted_qc>January 3, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 8, 2019</study_first_posted>
  <last_update_submitted>January 3, 2019</last_update_submitted>
  <last_update_submitted_qc>January 3, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 8, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sisters of Mercy University Hospital</investigator_affiliation>
    <investigator_full_name>Renata Letica-Brnadić</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemorrhage</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tranexamic Acid</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03795649
org study id: EP-12939/18-1
nct id: NCT03795649
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The administration of the tranexamic acid (TRAXA), an antifibrinolytic, blocks primary
      fibrinolysis, and thus the haemorrhage, in the early postoperative period. Significant
      surgical operations, as well as trauma, initiate a similar dynamic homeostatic mechanism
      between the creation of a clot (primary and secondary haemostasis) and its dissolution
      (fibrinolysis). Antifibrinolytics have been proven effective in reducing haemorrhage in
      patients who have undergone significant surgical operations with normal fibrinolysis, with
      the use of an appropriate surgical technique.

      A pharmacokinetic study has shown that peak fibrinolytic activity is present for 6 hours
      after the incision and it persists for 18 hours in total knee and hip arthroplasty. The
      administration of the tranexamic acid in optional orthopaedic surgery of total hip (THA) and
      knee (TKA) arthroplasty reduces the postoperative haemorrhage, as well as the number and
      volume of the postoperative autologous blood.

      A trauma in the organism triggers the immunologic response. New term has been introduced -
      the post-traumatic immunosuppression (PTI), characterised by: a change on the immunologic
      cells (neutrophilia, monocytosis, increased number of mesenchymal stromal cells, reduced
      expression of HLA-DR on monocytes, reduced function of natural killer (NK) cells, increased
      lymphocyte apoptosis, a shift in homoeostasis towards the Th2 phenotype facilitated by Treg
      lymphocytes - CD4+CD25+CD127-); a change in production levels of various cytokines
      (anti-inflammatory cytokines): IL-10, IL-4; anti- and pro-inflammatory cytokine: IL-6;
      pro-inflammatory cytokines IL-2, TNF-α, IFN-γ); the activation of the complement system (C5a
      and C3a via factor VII - tissue factor system, activated by cell damage).

      Post-traumatic immunosuppression can be made worse by transfusion, haemorrhage, stress,
      significant surgical operation and immunosuppressive drugs.

      The research has shown that Treg lymphocytes CD4+CD25+CD127- have an important role in
      controlling the acquired and innate immunity (comprising 6-8% of all CD4+ lymphocytes).

      Stopping haemorrhage prevents the occurrence of anaemia, as well as the need for transfusion
      of blood products, which lead to developing the post-traumatic immunosuppression (PTI).
The administration of the tranexamic acid (TRAXA), an antifibrinolytic, blocks primary
      fibrinolysis, and thus the haemorrhage, in the early postoperative period. Significant
      surgical operations, as well as trauma, initiate a similar dynamic homeostatic mechanism
      between the creation of a clot (primary and secondary haemostasis) and its dissolution
      (fibrinolysis). Antifibrinolytics are initially used in patients with an accelerated
      fibrinolysis of different pathogeneses. However, they have been proven effective in reducing
      haemorrhage in patients who have undergone significant surgical operations with normal
      fibrinolysis, with the use of an appropriate surgical technique.

      A pharmacokinetic study has shown that peak fibrinolytic activity is present for 6 hours
      after the incision and it persists for 18 hours in total knee and hip arthroplasty. The
      administration of the tranexamic acid in optional orthopaedic surgery of total hip (THA) and
      knee (TKA) arthroplasty reduces the postoperative haemorrhage, as well as the number and
      volume of the postoperative autologous blood.

      A randomized, placebo-controlled trial CRAS-2 has validated that the early post-traumatic
      administration of the tranexamic acid, within 8 hours after the injury, in adult patients
      with traumas or in patients with the risk of significant haemorrhage, reduces the fatality
      rate.

      The tranexamic acid is a synthetic derivative of lysine, an amino acid which blocks lysine
      binding sites of the plasminogen molecule which are essential for its biding to fibrin. This
      mechanism inhibits the plasminogen activation via a plasminogen activator which also binds to
      fibrin. Thus, it prevents the conversion of plasminogen into plasmin, which is essential for
      fibrin dissolution, the integral element of a stable clot. The second important
      antifibrinolytic effect is blocking the lysine binding sites on the free plasmin molecule
      which has already been formed through the conversion from the plasminogen. This inhibits its
      binding to fibrin, and the TRAXA-plasmin complex is rapidly inactivated with the
      α-2-antiplasmin and α-2-macroglobulin. Biological half-life is approximately 2-3 hours.

      A trauma in the organism triggers the immunologic response. The initial immunologic reaction
      occurs at the location of the injury, and it is called an inflammation. The inflammatory
      response is characterized by a complex interaction of macrophages (a type of leukocytes which
      develop from monocytes and are a part of the mononuclear phagocyte system, the main task of
      which are phagocytosis, i.e. the clearance of foreign materiel from the organism, performing
      the immunologic function - the defence against foreign materiel - antigens, and the
      regulation of the inflammation via interleukins which they secrete - IL1, IL-2,TNF) and
      dendritic cells (antigen-presenting cells), the consequence of which is the release of
      cytokines (interleukins - glycoproteins which regulate interactions among cells) and
      chemokine (small proteins from the cytokine group - able to induce chemotaxis, cell
      migration), and the activation of the neutrophils, monocytes and mesenchymal stem cells
      (cells not containing any information, located in the adipose tissue, cartilage and muscle
      tissue).

      If the initial inflammatory response at the location of the injury is strong enough, it will
      develop into a systemic inflammatory response, called systemic inflammatory response syndrome
      (SIRS), which implies an inflammatory response of the entire body without a proven source of
      infection. The criteria for the diagnosis of the SIRS are: heart rate higher than 90 bpm;
      body temperature lower than 36°C or higher than 38°C; tachypnoea, respiratory rate higher
      than 20 breaths per minute or the partial pressure of carbon dioxide in the blood lower than
      4.3 kPa (32 mm Hg); the number of white blood cells, leukocytes, lower than 4.000 cells in 1
      mm³ or higher than 12.000 cells in 1 mm³; or the presence of more than 10% of immature
      neutrophils. A destructive immunologic inflammatory cascade can prevent or delay healing.

      At the same time the compensatory anti-inflammatory response syndrome (CARS) is initiated,
      which includes the immunologic response with the aim of re-establishing the immunologic
      homeostasis. It is characterized by: a reduced cytokine response of monocytes to the
      stimulation; a reduced number of antigen-presenting receptors (human leukocyte antigens or
      HLA) on monocytes; an increased level of IL-10, an anti-inflammatory cytokine; lymphocyte
      apoptosis (T-cells); lymphocyte dysfunction, i.e. reduced proliferation; reduced Th1
      proinflammatory cytokine production (a shift in homoeostasis towards the Th2 phenotype
      facilitated by the regulatory T lymphocytes). It clinically manifests as skin allergy,
      hypothermia and leukopenia. Additional criteria include elevated levels of C-reactive
      proteins, lactates and hyperglycaemia. If the immunosuppressive response persists, it may
      increase the possibility of an infection occurring, and the inability to defend against the
      infection, which may result in the development of sepsis, multiple organ failure and death.

      Due to the wide clinical and laboratory criteria which both the SIRS and CARS terms include,
      they are not the best terms for describing the immunologic response to a trauma, and a new
      term has been introduced - the post-traumatic immunosuppression (PTI), characterised by: a
      change on the immunologic cells (neutrophilia, monocytosis, increased number of mesenchymal
      stromal cells, reduced expression of HLA-DR on monocytes, reduced function of natural killer
      (NK) cells, increased lymphocyte apoptosis, a shift in homoeostasis towards the Th2 phenotype
      facilitated by Treg lymphocytes - CD4+CD25+CD127-); a change in production levels of various
      cytokines (anti-inflammatory cytokines): IL-10, IL-4; anti- and pro-inflammatory cytokine:
      IL-6; pro-inflammatory cytokines IL-2, TNF-α, IFN-γ); the activation of the complement system
      (C5a and C3a via factor VII - tissue factor system, activated by cell damage).

      Post-traumatic immunosuppression can be made worse by transfusion, haemorrhage, stress,
      significant surgical operation and immunosuppressive drugs.

      The research has shown that Treg lymphocytes CD4+CD25+CD127- have an important role in
      controlling the acquired and innate immunity (comprising 6-8% of all CD4+ lymphocytes).

      The normal function of Treg lymphocytes is the suppression of the T-cell response against its
      own antigens.

      Stopping haemorrhage prevents the occurrence of anaemia, as well as the need for transfusion
      of blood products, which lead to developing the post-traumatic immunosuppression (PTI).

      Monitoring the immunologic status of patients with the understanding of the PTI mechanism can
      enable timely and individual modulation of the immunologic status with pre-planned procedures
      (preventing haemorrhage, anaemia, avoiding transfusion) and/or immunotherapy (drugs and
      nutrients), and thereby prevent the occurrence of complications, such as infections.
      Infections may result in sepsis and multiple-organ failure, and eventually be lethal for the
      patient.

      The research has proved that Treg lymphocytes CD4+CD25+CD127- have an important role in
      controlling the acquired and innate immunity (comprising 6-8% of all CD4+ lymphocytes).

      The normal function of Treg lymphocytes is the suppression of the T-cell response against its
      own antigens.

      There are two main types of regulatory lymphocytes: natural Treg, which are mostly developed
      in the thymus, and inducible Treg, which arise in the periphery after being exposed to
      cytokines, antigen-presenting cells or immunosuppressive drugs. It may be difficult to
      differentiate these two lymphocyte Treg populations in vivo. Nevertheless, it is known that
      different stages of the infection require different regulations. Acute infection, tissue
      damage, inflammation caused by the innate immunologic response is limited, i.e. locally
      controlled via natural Treg lymphocytes. This mechanism triggers the activation of inducible
      Treg lymphocytes.

      For the first time, in 1995, it was described that the suppression of CD4+ T-lymphocytes is
      caused by a low T-cell population with the CD4+ CD25+ expression. Natural Treg lymphocytes,
      apart from belonging to CD4+ T-cell population, have a CD25+ receptor, an α-receptor chain
      for IL-2, and a receptor for the cytotoxic T-lymphocytic antigen 4 (CTLA 4), the tumour
      necrosis factor receptor (TNF), but it differs from the activated T-cells by the expression
      of the transcription factor FoxP3 (transcription factor encoded with the FoxP3 gene). The
      expression of CD 127lo, an α-chain receptor for the interleukin 7 enables us to differentiate
      Treg lymphocytes from the activated T-lymphocytes via flow cytometry. The number of
      CD25+CD127lo cells correlates to the number of CD25+FoxP3+ cells in the peripheral blood.

      Different studies show that the application of the 3-colour flow cytometry shows small
      variation in the percentage of Treg lymphocytes in the peripheral blood from 6.35% to 8.34%.

      There is a number of different mechanisms which achieve regulation by using the Treg
      lymphocytes: the long-term interaction with dendritic cells (DC), thereby modulating the
      function of antigen-presenting cells (APC), the production of the anti-inflammatory cytokine,
      IL-10 and the CTLA4 expression on Treg cells which induces the enzyme indoleamine
      2,3-dioxygenase (IDO) in APC which degrade the amino acid tryptophan, the lack of which
      inhibits the activation of T-cells and induces T-cell apoptosis. Treg lymphocytes also induce
      the apoptosis of monocytes and affect the lower expression of HLA-DR on monocytes whereby
      they directly affect the innate immunological response.

      Elevated, suppressive activity of Treg cells in traumas prevents the protective Th1 response
      for up to 7 days in comparison with the healthy population.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Outcomes Assessor)
measure: The immunomodulation effect of Tranexamic Acid (IM)
time frame: two years
description: Trial will include approximately 100 patients in total, which will be divided into four groups of 25 patients. The immunomodulation effect is monitored through the analysis of the lymphocyte subpopulation in the peripheral blood through flow cytometry.
The result of each lymphocyte subpopulation will be registered as a percentage of all helper cells (CD4+) and all lymphocytes, as well as their absolute number in the peripheral blood.
These parameters will be monitored dynamically in the chronological order as shown below:
Day 1 - Preoperatively; Day 1 - Postoperatively T1 (IM) K - 6 hrs postoperatively T1 (IM) A - 6 hrs after the first TRAXA dose, and two hours before LMWH T1 (IM) B - 6 hrs postoperatively (after the transfusion of the autologous blood by means of the autotransfusion system); Day 3 - Postoperatively; Day 5 - Postoperatively; Day 7 - Postoperatively; For immunologic testing of each patient's blood 25 ml (5 ml x 5) during 7 days will be sampled.
measure: The effect of the Tranexamic Acid on the primary fibrinolysis (F)
time frame: two years
description: The fibrinolytic activity of plasma will be examined through euglobulin lysis time testing Blood sampling follows the same time intervals of blood sampling for determining Treg lymphocytes. Fibrinolysis is monitored until the third postoperative day.
In total per patient for analysis of the fibrinolytic activity 15 mL (5 mL x 3) of blood will be sampled during a 3-day period.
Day 1 - Preoperatively; Day 3 - Postoperatively T1 (F) K - 6 hrs postoperatively T1 (F) A - 6 hrs after the first TRAXA dose, and two hours before LMWH T1 (F) B - 6 hrs postoperatively (after the transfusion of the autologous blood by means of the autotransfusion system); Day 3 - Postoperatively;
arm group label: The control group (Group K)
arm group type: No Intervention
description: The control group (Group K) is comprised of surgical patients who will not receive blood transfusion, and who have contraindications for Tranexamic Acid.
arm group label: Group A, Tranexamic acid
arm group type: Active Comparator
description: The treatment group (Group A) is comprised of the patients who will receive Tranexamic acid 1g intravenous 15 min. before releasing the pneumatic tourniquet and the repeating dose 3 hours later
arm group label: Group B, autologous transfusion
arm group type: Other
description: The treatment group (Group B) will be comprised of the patients who in the second selection have one or more contraindications for Tranexamic Acid administration and transfusion of autologous blood will be performed.
arm group label: Group C, alogenous transfusion
arm group type: Other
description: The treatment group (Group C) contraindications for Tranexamic Acid administration and the transfusion of alogenous blood will be performed in the case of acute haemorrhage followed by patient's hemodynamic instability.
intervention type: Drug
intervention name: Tranexamic Acid
description: Imunomodulatory effect
arm group label: Group A, Tranexamic acid
arm group label: Group B, autologous transfusion
arm group label: Group C, alogenous transfusion
other name: Medsamic
criteria: 
gender: All
minimum age: 30 Years
maximum age: 80 Years
healthy volunteers: No
last name: Renata Letica-Brnadić
role: Study Chair
affiliation: Clinical Hospital Centre "Sisters of Mercy"
last name: Renata Letica-Brnadić
phone: +38598340722
email: rlbrnadic@gmail.com
facility: 
status: Recruiting
contact: 
country: Croatia
citation: Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, McClelland B, Laupacis A, Fergusson D. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD001886. doi: 10.1002/14651858.CD001886.pub2.
PMID: 17943760
citation: Astedt B. Clinical pharmacology of tranexamic acid. Scand J Gastroenterol Suppl. 1987;137:22-5.
PMID: 3321402
citation: Roberts I, Shakur H, Coats T, Hunt B, Balogun E, Barnetson L, Cook L, Kawahara T, Perel P, Prieto-Merino D, Ramos M, Cairns J, Guerriero C. The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients. Health Technol Assess. 2013 Mar;17(10):1-79. doi: 10.3310/hta17100.
PMID: 23477634
citation: Oremus K, Sostaric S, Trkulja V, Haspl M. Influence of tranexamic acid on postoperative autologous blood retransfusion in primary total hip and knee arthroplasty: a randomized controlled trial. Transfusion. 2014 Jan;54(1):31-41. doi: 10.1111/trf.12224. Epub 2013 Apr 25.
PMID: 23614539
citation: Raveendran R, Wong J. Tranexamic acid: more evidence for its use in joint replacement surgery. Transfusion. 2014 Jan;54(1):2-3. doi: 10.1111/trf.12494. No abstract available.
PMID: 24405302
citation: Parkin J, Cohen B. An overview of the immune system. Lancet. 2001 Jun 2;357(9270):1777-89. doi: 10.1016/S0140-6736(00)04904-7.
PMID: 11403834
citation: Islam MN, Bradley BA, Ceredig R. Sterile post-traumatic immunosuppression. Clin Transl Immunology. 2016 Apr 29;5(4):e77. doi: 10.1038/cti.2016.13. eCollection 2016 Apr.
PMID: 27195120
citation: Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992 Jun;101(6):1644-55. doi: 10.1378/chest.101.6.1644.
PMID: 1303622
citation: Bone RC. Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med. 1996 Oct 15;125(8):680-7. doi: 10.7326/0003-4819-125-8-199610150-00009.
PMID: 8849154
citation: Ward NS, Casserly B, Ayala A. The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients. Clin Chest Med. 2008 Dec;29(4):617-25, viii. doi: 10.1016/j.ccm.2008.06.010.
PMID: 18954697
citation: Osuka A, Ogura H, Ueyama M, Shimazu T, Lederer JA. Immune response to traumatic injury: harmony and discordance of immune system homeostasis. Acute Med Surg. 2014 Jan 28;1(2):63-69. doi: 10.1002/ams2.17. eCollection 2014 Apr.
PMID: 29930824
citation: Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, Kelleher A, Fazekas de St Groth B. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006 Jul 10;203(7):1693-700. doi: 10.1084/jem.20060468. Epub 2006 Jul 3.
PMID: 16818676
citation: Venet F, Chung CS, Kherouf H, Geeraert A, Malcus C, Poitevin F, Bohe J, Lepape A, Ayala A, Monneret G. Increased circulating regulatory T cells (CD4(+)CD25 (+)CD127 (-)) contribute to lymphocyte anergy in septic shock patients. Intensive Care Med. 2009 Apr;35(4):678-86. doi: 10.1007/s00134-008-1337-8. Epub 2008 Oct 23.
PMID: 18946659
citation: Venet F, Chung CS, Monneret G, Huang X, Horner B, Garber M, Ayala A. Regulatory T cell populations in sepsis and trauma. J Leukoc Biol. 2008 Mar;83(3):523-35. doi: 10.1189/jlb.0607371. Epub 2007 Oct 3.
PMID: 17913974
citation: Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol. 2007 Nov;7(11):875-88. doi: 10.1038/nri2189.
PMID: 17948021
citation: Shevach EM, DiPaolo RA, Andersson J, Zhao DM, Stephens GL, Thornton AM. The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol Rev. 2006 Aug;212:60-73. doi: 10.1111/j.0105-2896.2006.00415.x.
PMID: 16903906
citation: Hartigan-O'Connor DJ, Poon C, Sinclair E, McCune JM. Human CD4+ regulatory T cells express lower levels of the IL-7 receptor alpha chain (CD127), allowing consistent identification and sorting of live cells. J Immunol Methods. 2007 Jan 30;319(1-2):41-52. doi: 10.1016/j.jim.2006.10.008. Epub 2006 Nov 3.
PMID: 17173927
citation: Fragkou PC, Torrance HD, Pearse RM, Ackland GL, Prowle JR, Owen HC, Hinds CJ, O'Dwyer MJ. Perioperative blood transfusion is associated with a gene transcription profile characteristic of immunosuppression: a prospective cohort study. Crit Care. 2014 Oct 1;18(5):541. doi: 10.1186/s13054-014-0541-x.
PMID: 25270110
citation: Blanie A, Bellamy L, Rhayem Y, Flaujac C, Samama CM, Fontenay M, Rosencher N. Duration of postoperative fibrinolysis after total hip or knee replacement: a laboratory follow-up study. Thromb Res. 2013 Jan;131(1):e6-e11. doi: 10.1016/j.thromres.2012.11.006. Epub 2012 Nov 26.
PMID: 23195143
responsible party type: Principal Investigator
investigator affiliation: Sisters of Mercy University Hospital
investigator full name: Renata Letica-Brnadić
investigator title: Principal Investigator
mesh term: Hemorrhage
mesh term: Tranexamic Acid