Primary Hemostasis Pathology in Patients on ECMO During Lung Transplantation
Condition: ECMO Primary Hemostasis Pathology
Study type: Observational

Summary: 
      Lung transplantation is a very long and difficult procedure accompanied by a number of
      possible complications. In the vast majority of cases, the operation itself is performed
      using the ECMO support, which can negatively affect blood clotting, especially the formation
      of a platelet blood clot, i.e. primary hemostasis. Thus, the procedure may be accompanied by
      considerable blood loss, which amount can subsequently negatively affect the postoperative
      period. It can be assumed, that precise diagnosis of primary hemostasis disorders and
      subsequent targeted therapy can reduce blood loss and improve outcome of the patient.
      However, the role of primary hemostasis has not yet been sufficiently specified in this area.
      Usually, coagulation functions during surgery, are at our department monitored by using ROTEM
      tests (assesses clot strength), PFA 200 (assesses primary haemostasis under high shear stress
      conditions and is very sensitive to vWF deficiency) and ROTEM / platelet (assesses primary
      haemostasis under "low shear stress" conditions and is very susceptible to platelet
      dysfunction). Targeted therapy by administering necessary clotting factors is used, if any
      pathology in these tests is detected. However, it is not known, whether the targeted therapy
      administered is effective enough in patients during the support of extracorporeal
      circulation. In our monocentric, prospective, observational study, data from the tests
      mentioned above will be analyzed, and their correlation with a laboratory examination of VWF
      levels and activity will be monitored. Based on these data, we will try to determine whether
      perioperative examination of primary hemostasis during lung transplantation (PFA examination,
      Rotem / platelet-aggregometry and von Willebrand factor-vWF level) is of clinical
      significance and whether the diagnosis of hemostasis disorder at this level and subsequent
      targeted therapy may reduce perioperative blood loss.
    

Detailed description: 
      ECMO is a type of extracorporeal circulation that has experienced a significant increase in
      use in the last decade as a substitute for lung or heart functions in patients, both
      perioperatively - especially extensive thoracic surgery procedures such as lung
      transplantation, or in resuscitation care - in life-threatening conditions associated with
      heart or lung failure. It uses the classical principle of extracorporeal circulation
      technology to create continuous, non-pulsating blood flow and, at the same time, its
      extracorporeal oxygenation. In its two basic configurations, it can only be used to provide
      respiratory support (veno-venous configuration, VV ECMO), or also cardiac support
      (veno-arterial configuration, VA ECMO).

      Due to the fact that ECMO circuit is an artificial system consisting of cannulas, blood pump
      and oxygenator itself, the blood is exposed to a huge surface that is not covered by
      endothelium, thus stimulates the activation of proinflammatory and procoagulant systems. This
      exposure results in a prothrombotic condition that is associated with a high risk of
      thrombotic complications. At the same time, however, with this continuous activation of the
      coagulation cascade, platelets and coagulation factors are depleted, this may lead to an
      increased risk of bleeding. Pathological shear stress may result in direct binding of VWF
      (von Willebrand factor) and the platelet GPIIb / IIIa receptor, resulting in their activation
      and thrombotic complications, however, the effect of non-physiological shear stress may also
      lead to loss of GPIbα and GPVI platelet receptors, which, in the opposite, causes a disorder
      of their adhesion and aggregation to VWF and collagen and increases risk of bleeding. Another
      important factor is loss and fragmentation of the large VWF multimers, a condition known as
      acquired von Willebrand's syndrome, which causes platelet adhesion to be impaired and thus
      contributes to bleeding complications.

      Both of these situations, definitely, increase morbidity and mortality in patients, so it is
      necessary to find an optimal and reliable options for the coagulation system functions
      monitoration, based on which it is possible to immediately perform a targeted therapeutic
      intervention.

      Results of several studies suggest, that increased platelet activation or decreased function
      results in both thrombotic and bleeding complications in patients requiring extracorporeal
      support, and these changes cannot be detected by tests, which are usually performed (ROTEM or
      other common coagulation tests).

      Hypothesis:

      ECMO causes an early disorder of primary hemostasis, which is detectable by point of care
      (POC) testing methods PFA 200 and ROTEM / platelet, according to their results, targeted and
      effective therapy can be applied.

      Objectives:

      Primary objective is to find out:

        -  whether ECMO implantation leads to an early failure of primary hemostasis, which can be
           diagnosed by POC examination - PFA 200, Rotem / platelet-aggregometry and von Willebrand
           factor levels.

        -  whether targeted therapy of primary hemostasis disorders (based on the results of POC
           tests) leads to normalization of these tests results and cessation of bleeding

      Secondary objectives:

        -  to determine the extent of correlation of POC tests of primary hemostasis and laboratory
           examination of VWF function and quantity

        -  to clarify the correlation between possible pathological values of these tests and
           clinically significant bleeding in the patient

        -  identification of the most reliable method for the assessment of primary hemostasis

      Methods:

      The group of patients will be represented by patients indicated for implantation of ECMO
      support during the lung transplantation procedure. ROTEM, PFA 200 and ROTEM / platelet POCs
      will be used for the perioperative detection of primary and secondary hemostasis disorders-
      this is a standard approach in Motol University Hospital. In addition to these standard
      tests, an analysis of the blood sample will also be performed in cooperation with the
      Institute of hematology and blood transfusion. These tests are represented by quantification
      of vFW (using quantification of vWF antigen), vFW function test - Ristocetin Cofactor Assay
      (ex vivo examination of patient's blood plasma, which is depleted of platelets but contains
      vWF) and Colagen Binding Assay (measures the ability of VWF, especially its large multimers,
      to bind to collagen).

      Blood samples will be taken:

        1. after induction into general anesthesia

        2. shortly (15-60 minutes) after ECMO initiation

        3. shortly (10 minutes) after administration of aimed therapy (vWF or platelets)

        4. shortly after ECMO explantation (during admission to the ICU, approximatelly 60 minutes
           after explantation) An informed consent will be signed with the patient prior to lung
           transplantation.

      Time schedule: 1 year (i.e. 40 patients, on average, about 35 patients undergo lung
      transplantation per year at our department).
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients on waiting list for planned lung transplantation procedure. Patients with COPD,
        cystic fibrosis, interstitial pulmonary fibrosis, primary pulmonary hypertension
      
Keywords: ECMO; PFA 200; ROTEMplatelets; bleeding