Comparison of a single dose fibrinogen with placebo and the number of blood transfusions after ascending aorta surgery (FIBTEG study)

Cardiothoracic surgery (CTC) is associated with blood loss and an increased
risk for impaired coagulation by the use of a CBP. Coagulation is a process of
primary hemostasis by adhesion of trombocytes and aggregation, followed by
secondary coagulation and fibrin formation. During CTC fibrinogen is the first
coagulation factor which reaches critical concentration necessary for clotting.
Point of Care clotting assay with thromboelastography (TEG) provides
qualitative information on coagulation factors and clot strength. Specific
coagulation factor correction of impaired clotting improves clot strength and
may reduces the number of perioperative allogeneic blood transfusions,
resulting in possible reduction of postoperative blood loss and reduction of
the risk of re-operation in the short and long term.
The hypothesis of this study is that a single dose fibrinogen concentrate
immediately after CTC leads to a decrease in the number of allogenic blood
transfusions in patients with clinically impaired clotting, verified by TEG.

The purpose of this study is to answer the following question: Leads a primary
coagulation corrected with a single dose of fibrinogen concentrate after
ascending aorta-arc reconstruction to a decrease in the number of allogenic
blood transfusions, compared to placebo?

Mono Center, prospective, double-blind, randomized, placebo-controlled study

During the operation, clotting is measured with point of care with TEG, and the
usual intra-operative hemostasis protocol was followed (transfusion of blood
products in the form of blood plasma (FFP), thrombocytes (5ET) and erythrocytes
(PRBC) based on TEG and laboratory results. After disconnection of the HLM
patients receive a single dose of fibrinogen concentrate (FC) or placebo
intravenously and they will be assigned randomly to FC (4,6 or 8 grams,
depending on weight) dissolved in water or an equivalent volume of 0.9% NaCl.

General anesthesia and monitoring
Elective ascending aorta-arch reconstruction is done under general anesthesia.
Prior to induction, a patient routinely receives a venous cannula in the hand
and an arterial cannula in the a right radial. After induction, an endotracheal
tube is placed in the arterial cannula in the left radial, a central venous
line in the right jugular vein and esophageal ultrasound probe. The anesthesia
policy for a study patient does not differ from a patient who does not
participate in the study.

TEG
During surgery the TEG will monitor clotting, executed by the anesthesiologist.
Per patient, 20 ml of blood spread over 4 times, 6 ml routine bloodsample and
14 ml extra bloodsample for this study. Blood samples will be taken from the
arterial cannula or from the circuit of the HLM. There is no additional
venipuncture or arterial puncture site. TEG measurements have been established
in the intraoperative hemostaseprotocol and are identical for all patients.
This protocol is the basis of the study protocol. Transfusion products are
ordered (or 5ET FFP). Based on TEG measurements. A study patient receives a
dose study medication immediately after disconnenction of the CPB. Three blood
samples are taken during surgery for the TEG determiniation and also for
determination of plasma fibrinogen concentration at the same time for all study
patients.

Study Medication
After discontinuation of the CBP a study patient receives a single dose of FC
(4,6 or 8 grams, depending on weight) administered, or the same volume of 0.9%
NaCl. Fibrinogen Concentrate (brand name; Haemocomplettan P) is a normal
constituent of human plasma and acts like endogenous fibrinogen. It is since
registration in 1997 used for therapy and prophylaxis of hemorrhagic diathesis.
In the Netherlands it is used to include major perioperative bleeding and has a
permanent place in transfusion protocols to massive blood loss. Administration
of fibrinogen has a low allergy risk and low risk of thrombotic complications.
This is supported by the registrations in the farmacosurveillance program
Haemocomplettan P, which mentioned only 9 reports of thrombotic side effects in
250,000 doses of 4 grams in 21 countries.
The study group who receive fibrinogen after discontinuation of the CBP will
expected to require less blood products have improved coagulation. This may
lead to a more favorable postoperative situation.

Intensive Care and postoperative phase
The postoperative care in the ICU takes routine bloodsamples for measurements.
In the context of the study 24 hours after the gift FC / placebo a 3ml of blood
was taken for the determination of plasma fibrinogen concentration. The blood
sampling was taken from the artery of the patient. There is no additional
venipuncture or arterial puncture necessary. Twenty-four hours after the
operation, the total number of transfused blood products and total blood loss
was monitored in study patients. For this, a researcher will visit the patient.
In an uneventful course patients stay after elective ascending aorta-arch
reconstruction normally for 48 hours in the ICU. After that the patient will be
resigned to another department. During the hospitalization patients are
monitored remotely. The required postoperative data is collected by the
researchers from the electronic patient file and Meta Vision (OK and IC patient
data management system). The study is terminated after discharge from the
hospital. Patients will be after discharge not approached again by the
researchers, in any form whatsoever.

Substudies.
Three substudies involve comparative and observational research.
(1) Routine TEG and FF-TEG are compared at the end of the study with the von
Clauss fibrinogen test, the gold standard .
(2) Fibrinogen is the first coagulation factor in need of supplementation. This
together with thrombin generation is essential in the clotting cascade. This
substudy investigates the height of the trombinepeak after discontinuation of
HLM. Therefore it compares the TEG and FF-TEG data with the thrombin level and
coagulation factor assays ( preoperatively , t = 0 , t = 10 , postoperative and
in case of allogeneic blood transfusion also t = 15 ) . This includes a total
of 36 ml ( 4x 9 mL ) of blood samples which are processed and stored until all
measurements are performed.
( 3 ) Erythrocytes supply in addition to platelets and coagulation factors also
contribute to thrombus formation because they are incorporated into the clot .
To understand the relationship between clot strength and the effect of
hematocrit ( Ht ) this is measured at two timepoints. At induction and after
discontinuation of the HLM are Hb , Ht and platelets measured (2x3 ml) , this
are routine assays to which timing is specified for the study. The study will
show the impact of reduced Ht and platelet number on the clot strength after
discontinuation of HLM.