The FIBRINOGEN study; to evaluate and compare the ex vivo effects of recombinant human fibrinogen (rhFGN) , variants rhFbgAα610 and Aα847, and Haemocomplettan supplementation on blood coagulation

Excessive blood loss (>2L/24 hours or >200mL/hour) is one of the most common
complications of cardiac surgery, and a risk factor for prolonged mechanical
ventilation, pneumonia, wound infection, sepsis, and mortality. Fibrinogen is a
key protein in the coagulation cascade and thus a potential biomarker for
bleeding. It has been suggested that a fibrinogen plasma level of higher than
1.0 g per L is sufficient to ensure that the coagulation is not limited by
fibrinogen concentration. However, cardiac surgery can result in a significant
reduction of the fibrinogen levels in blood due to blood loss and hemodilution.
Therefore, fibrinogen levels in the lower normal range may be too low to ensure
an appropriate coagulation during and after cardiac surgery. Measurement of
fibrinogen before, during, and after cardiac surgery may clarify its
distribution patron, and might be relevant for the safety assessment of
fibrinogen concentrate administration.
Fibrinogen suppletion could function as a first-line therapy to restore normal
fibrinogen levels, normalize the coagulation profile of the blood, and might
provide a new strategy to reduce blood transfusion requirements during and
after cardiac surgery.
The only currently available source of human fibrinogen is plasma transfusion
or plasma derived fibrinogen suppletion (Haemocomplettan, CSL Behring) from
human donor blood. The development of a recombinant human fibrinogen (rhFGN)
might decrease the need of plasma transfusions, and provide substantial safety
advantages over fibrinogen purified from human donor blood. However, it remains
unclear how supplement of fibrinogen/rhFGN may affect the dynamic features of
fibrinogen metabolism and to which extent coagulation is influenced after
suppletion.

Hypothesis
A low/normal preoperative fibrinogen level might cause an increase in blood
loss and blood transfusion requirements after cardiac surgery. Fibrinogen
supplementation with Haemocomplettan, rhFGN variant Aα610 or Aα847 might reduce
transfusion requirements after cardiac surgery. rhFGN variant Aα847 might be
more resistant to fibrinolysis than Haemocomplettan or rhFGN variant Aα610.

The aim of this study is to evaluate fibrinogen concentrations, coagulation and
fibrinolysis during and after CABG, to characterize the ex vivo effects of
rhFGN variant Aα610 (wild type) and Aα847 when added to blood samples collected
after CABG, and to compare the ex vivo effects of the rhFGN variants and plasma
derived fibrinogen (Haemocomplettan) supplementation on blood coagulation
profiles as measured by ROTEM (rotation thormboelastometry) in blood samples
collected from patients after isolated CABG surgery with low/normal fibrinogen
levels preoperative.

Observational ex vivo suppletion study without invasive measurements, performed
in the LUMC in Leiden, the Netherlands.

Blood will be drawn at seven time points perioperative, with a total of 81 mL.
The blood will then be analysed with a rotational thromboelastograph (ROTEM) to
asses global hemostasis and dynamic changes in clot formation. The remaining
blood will be stored for coagulation and fibrinolytic assays. At arrival of the
patient at the intensive care unit the collected blood will also be used for ex
vivo rhFGNs and Haemocomplettan suppletion and ROTEM analysis for coagulation
measurements.

The measurements necessary to asses the defined study endpoints are not
expected to negatively influence the result of treatment or patient condition.