Coagulation monitoring to prevent hemostatic complications in kids on extracorporeal membrane oxygenation

Extracorporeal membrane oxygenation (ECMO) ECMO has become increasingly
important as supportive therapy for patients with life-threatening cardiac
and/or respiratory failure. Despite improvement in technology and increasing
clinical practice, the incidence of hemostatic complications remain high and
they are the primary causes of morbidity and mortality in patients treated with
ECMO worldwide. Bleeding and clotting complications occur in about 50% of the
pediatric ECMO patients, associated to a decrease in survival of about 40%.
The interaction between blood and the ECMO circuit generates a hypercoagulable
state, and unfractionated heparin is used to maintain patency of the circuit as
well as to reduce thrombotic events while minimizing bleedings. Worldwide, no
consensus exists about how to monitor this precarious hemostatic balance.
Current conventional tests (APTT, ACT, anti-FXa assay, platelets, d-dimer,
fibrinogen, antithrombin) assess only isolated parts of the coagulation
cascade, while alternative tests (TEG/ROTEM and TGA) assess the complete
coagulation cascade. In addition, acquired von Willebrand disease (AVWD) may
add to the bleeding problems in ECMO patients. The incidence and association
with bleeding complications in pediatric ECMO patients, however, is unknown.
We hypothese that the alternative coagulation tests better reflect the
thrombotic or haemorrhagic phenotype than the conventional tests, and as a
consequence will improve coagulation monitoring in ECMO patients, leading to
less hemostatic complications and improved survival. Furthermore, we hypothese
that AVWD contributes to the bleeding problems in children on ECMO.

The primary objectives of this study are:
1. to investigate the association between both conventional and alternative
coagulation tests, and hemostatic complications, including bleeding and
clotting complications in pediatric ECMO patients
2. to investigate the incidence and severity of AVWD and its association with
bleeding complications in pediatric ECMO patients

The secondary objectives of this study are :
1. to analyze the longitudinal hemostatic profile over time in ECMO children
2. to analyze the incidence of bleeding and clotting complications during the
first 14 days of ECMO therapy
3. to analyze the mortality associated with hemostatic complications during the
first 14 days of ECMO therapy
4. to analyze the longitudinal presence and severity of AVWD over time in ECMO
children

This is a prospective, multicenter, observational study of pediatric patients
(0-17 years old) on ECMO in the centers of the Phoenix consortium during three
years.

The Pediatric HematOlogy Extracorporeal circulation NetworX (PHOENiX)
consortium consists of ECMO centers of Rome (Bambino Gesù Hospital, Dr A
Rizza), London (Great Ormond Street, Dr A Hoskote, Dr A Karimova), Detroit
(Children*s Hospital of Michigan, Dr M Chitlur), Toronto (SickKids, Dr L
Brandao), Edmonton (Stollery Children*s Hospital, Prof. P. Massicotte),
Nijmegen (Radboudumc, Dr. A. van Heijst), Vienna (University Children*s
Hospital, Prof. C. Male) and Rotterdam (Sophia Children*s Hospital ErasmusMC,
Dr CH van Ommen, Dr E Wildschut).

Hemostatic complications, including bleeding and thrombotic complications,
occur in about 50% of the pediatric patients on ECMO. Death is associated with
these complications in more than one third of these patients. Therefore,
prevention of these complications is rather important. This study investigates
the association between conventional and/or alternative coagulation tests and
the hemostatic complications and the incidence of AVWD and its association with
bleeding in children on ECMO.
If one or a combination of the coagulation tests appear to have a good
association with hemostatic complications, the test(s) can be incorporated in a
new anticoagulation protocol, that might cause less hemostatic complications
and thus decreases mortality in this patient group. In addition, if AVWD may
cause bleeding in ECMO patients, treatment of AVWD, for example with VWF
concentrate, may be a prophylactic or treatment option.

The risk of this study is extra blood withdrawal. The extra blood needed varies
between 2.0 mL and 4.5 mL/day depending on age and the type of tests performed
on routine base. (TGA and VWF is always extra, ROTEM in some centers). Blood
will always be taken from a central line or ECMO circuit. It may be possible
that patients need a red cell transfusion earlier due to the withdrawal of
blood. Benefit: patients will be checked very thoroughly on hemostatic
complications due to the study and diagnosis of these complications may be made
earlier.

It is important to perform this study in pediatric patients as the hemostatic
system develops over time from neonatal to adult age. Although all components
of the hemostatic system are present at birth, important differences exist
among preterm and term neonates, older children and adults. This is called
*developmental hemostasis*. These differences have important consequences for
interpretation of laboratory results during ECMO among others. It is therefore
not possible to extrapolate from adult results.