Introduction:
Extracorporeal circulation known as "extracorporeal membrane oxygenation" (ECMO) is a
method of supportive therapy for terminal respiratory failure (1-3) or temporary
replacement of lung function in the perioperative period during lung transplantation (4).
In the former case, it is V-V ECMO (veno-venous ECMO), while in the latter case it is V-A
ECMO (veno-arterial ECMO). According to the EURO-ELSO recommendations, the use of
unfractionated heparin (UFH) is recommended as anticoagulation of the ECMO set (5).
However, 40-50% of patients on ECMO experience not only bleeding but also thrombotic
complications (6,7). Nowadays, there is an increasing number of case reports and small
studies showing that UFH is not used and instead only standard thrombosis prophylaxis
with low molecular weight heparin (LMWH) is administered without signs of thrombosis in
the ECMO set (8,9). ECMO has been shown to cause impaired primary hemostasis, which can
be detected by devices such as the PFA 200, ROTEM-Platelet, and Multiplate. The main
pathology involves platelets and to a lesser extent von Willebrand factor (vWF) (10-12).
The ECMO system is a high-flow "high shear stress" system that is comparable to the
arterial circulation in vivo. In this setting, the so-called "white thrombus" plays a
major role in thrombosis formation. Antiplatelet drugs are commonly used to prevent
thrombosis in such a system, for example in cardiology and neurology. Thus, it can be
assumed that ECMO-induced impairment of primary hemostasis, specifically impaired
platelet plug formation, could naturally serve as a prevention of white thrombus
formation and thrombosis of the ECMO set. However, prevention of thrombosis in the venous
system or on the surface of ECMO cannulae, i.e., prevention of "red thrombus formation",
is still necessary because of the existence of the Virchow triad. Since the main target
of action of LMWH is factor FXa and the main target of UFH is mainly factor FIIa, it can
be assumed that LMWH could be sufficient to prevent thrombosis, with minimal risk of
bleeding. It is important to emphasize that LMWH only minimally blocks thrombin
generation and affects the conversion of fibrinogen to fibrin only to a limited extent
(i.e., thrombin time - TT), unlike UFH. Moreover, ROTEM testing can be used to monitor
both UFH and LMWH (13-16). A recent study published by us supports this hypothesis and
suggests that the use of LMWH in patients on ECMO support may represent a safe
alternative to anticoagulation or thromboprophylaxis. The study shows that its use
resulted in a relatively low incidence of bleeding and thrombotic complications (17).
Thus, it can be assumed that LMWH will be suitable and effective for the prevention of
thrombus formation with minimal risk of bleeding, even in patients undergoing lung
transplantation with perioperative ECMO support. This hypothesis is supported by studies
that have found that UFH leads to higher platelet activation compared with LMWH (18-20).
On the other hand, the use of activated factor FVIIa at low doses of 12 µg/kg appears to
be safe (without increasing thrombotic events) and effective in reducing postoperative
bleeding in cardiac surgery. Since FVIIa acts at the site of damaged endothelium, it can
be assumed that relatively small doses of FVIIa will be sufficient to stop bleeding, but
not so high as to cause thrombosis. In addition, it can be assumed that isolated
administration of this factor may be less thrombogenic compared with other preparations
that also contain factors acting on the axes of the intrinsic clotting pathway, such as
prothrombin complex concentrate (PCC, contains FII, FVII, FIX, FX) or Haemate P (contains
vWF and FVIII). Therefore, early administration of low-dose FVIIa may represent an
effective way to minimize perioperative blood loss without increasing the risk of
thrombosis (21). Another property of recombinant activated FVIIa is its ability to
positively affect platelet adhesion and aggregation, which is present during ECMO support
(20,22).
Aim and nature of the study:
This is a pilot observational study to prospectively compare two groups of patients with
different types of anticoagulation (LMWH vs. UFH) undergoing bilateral lung
transplantation with perioperative V-A ECMO support.
Hypothesis:
The use of LMWH represents a safe alternative method of ECMO anticoagulation and
thromboprophylaxis that reduces the rate of bleeding and thrombotic complications
compared to the current method of anticoagulation with UFH.
Methodology:
The study was approved by the Ethics Committee of Motol University Hospital. All patients
enrolled in the study will sign an informed consent for participation in the study and
data collection. It will be explained to the patients that there are two types of
anticoagulation that are currently standardly used at Motol Hospital for patients with
ECMO support. The type of anticoagulation will be determined at the discretion of the
anaesthesiologist, with the aim of dividing patients as evenly as possible into different
groups. Two groups of patients with different types of anticoagulation (LMWH vs. UFH)
will be compared. As this is a pilot project, a total of 40 patients will be included in
the study, with each group comprising 20 patients.
In case of blood loss ≥ 500 ml and ongoing bleeding, i.e. "wet operating field", the
following Motol University bleeding management protocol will be initiated in both UFH and
LMWH group:
investigate PFA 200 (Col/EPI) and ROTEM (EXTEM, INTEM, FIBTEM and HEPTEM)
in case of pathology of PFA 200 and/or CT EXTEM/CT HEPTEM - administer Novoseven at
10-30 ug/kg (recombinant activated factor VIIa)
re-examine all ROTEM tests (EXTEM, FIBTEM, HEPTEM) and if needed normalize them:
CT-EXTEM > 80s by administering PCC at 10-30 ug/kg
normalise CT-HEPTEM > 240s by administering Haemate P at 10-30j/kg
for FIBTEM pathology - administer Exacyl at 10-30 mg/kg prior to Fibrinogen
administration and normalize FIBTEM MCF ≤10 mm by administering Hemocompletan at
10-30 mg/kg - or more precisely: desired MCF - current MCF x 6.25 mg/kg e.g. (10 -
- x (6.25 x 80 kg) = 3000 mg (add 0.5 g of fibrinogen per 1 mm)
administer platelets at EXTEM MCF ≤ 50mm and FIBTEM MCF ≥ 10mm administer 5-10 mL/kg
platelets (2 TU platelets from apheresis in an adult patient) or maintain platelets
≥ 50-100 x109/L
if bleeding continues give Factor XIII - Fibrogammin at 10-30j/kg
if PFA Col/EPI pathology persists and bleeding continues - give Haemate P at
20-40j/kg (if not already given to correct CT INTEM)
if bleeding continues, repeat Novoseven 10-30 ug/kg every 4 hours for a total of 3
times
if severe bleeding continues, give full dose of Novoseven 100 ug/kg
if bleeding does not stop - discontinue anticoagulation/thromboprophylaxis
Note:
for blood loss over 50% of blood volume, consider Octaplas or frozen plasma (in an
adult patient with blood loss over 2000-3000 ml)
maintain normal pH, calcium, magnesium, normothermia and haematocrit ≥0.3 (required
for normal primary haemostasis)
administer 5% albumin or transfusion products as above to maintain normovolemia (try
to minimise intake of other colloids or crystalloids)
Statistical analysis:
statistical program GraphPad will be used, paired t-test, p < 0.05
