Ignite Creation Date:
2024-05-06 @ 12:34 PM
Last Modification Date:
2024-10-26 @ 1:01 PM
Study NCT ID:
NCT03795649
Status:
UNKNOWN
Last Update Posted:
2019-01-08
First Post:
2018-12-30
Brief Title:
The Immunomodulatory Effect of Antrifibrinolytic Tranexamic Acid in Total Knee Arthroplasty
Sponsor:
Sisters of Mercy University Hospital
Organization:
Sisters of Mercy University Hospital
Study Overview
Official Title:
The Immunomodulatory Effect of Antrifibrinolytic Tranexamic Acid in Total Knee Arthroplasty
Status:
UNKNOWN
Status Verified Date:
2019-01
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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 - CD4CD25CD127- 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 CD4CD25CD127- 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
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 - CD4CD25CD127- 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 CD4CD25CD127- 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
Detailed Description:
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 ie 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-2TNF 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 36C or higher than 38C tachypnoea respiratory rate higher than 20 breaths per minute or the partial pressure of carbon dioxide in the blood lower than 43 kPa 32 mm Hg the number of white blood cells leukocytes lower than 4000 cells in 1 mm³ or higher than 12000 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 ie 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 - CD4CD25CD127- 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 CD4CD25CD127- 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 andor 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 CD4CD25CD127- 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 ie 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 CD25CD127lo cells correlates to the number of CD25FoxP3 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 635 to 834
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 23-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
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 ie 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-2TNF 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 36C or higher than 38C tachypnoea respiratory rate higher than 20 breaths per minute or the partial pressure of carbon dioxide in the blood lower than 43 kPa 32 mm Hg the number of white blood cells leukocytes lower than 4000 cells in 1 mm³ or higher than 12000 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 ie 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 - CD4CD25CD127- 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 CD4CD25CD127- 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 andor 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 CD4CD25CD127- 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 ie 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 CD25CD127lo cells correlates to the number of CD25FoxP3 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 635 to 834
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 23-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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None