Cardiopulmonary Bypass Surgery Clinical Trial
Official title:
Characterisation of the Haemostatic Changes In Patients Receiving Intravenous Heparin for Cardiopulmonary Bypass Surgery
This study is to understand the changes occurring in a blood clotting protein, von Willebrand
factor (VWF), in patients undergoing cardiac surgery who receive the blood thinner called
Heparin. These patients are given Heparin through their veins, to prevent blood clot
formation as it passes through the heart bypass machine. At the end of the operation, the
effect of Heparin is reversed by another drug, Protamine Sulphate.
Heparin prevents blood clots forming mainly by inactivating thrombin, a crucial protein
needed for blood clotting. This effect of Heparin is monitored through blood tests called the
'Anti Factor-Xa' and the 'APTT'.
Heparin has another effect on clotting: it can block the attachment of special blood cell
fragments called platelets to damaged blood vessels, but this effect is not usually measured.
Following blood vessel injury, the large VWF sticks to the damaged surface and captures
platelets to form a 'plug' which stops bleeding. The platelet plug is then stabilised by
other clotting proteins. This stops blood loss and allows vessel repair underneath.
Heparin blocks the ability of VWF to capture platelets at the site of blood vessel injury.
The higher the dose of Heparin, the greater this blocking effect is. This secondary effect of
Heparin cannot be readily monitored and may explain why bleeding complications occur in
patients receiving Heparin despite the monitoring with blood tests used.
This study will look at the blood levels of Heparin, VWF and platelets before, during and
after surgery and how well VWF functions in the presence of heparin, including its ability to
attach to platelets.
The investigators will determine if all of the heparin related changes in blood clotting can
be detected using a method that looks at all of the different steps in forming a blood clot.
Von Willebrand factor (VWF) is a large plasma glycoprotein involved in thrombosis,
haemostasis and vascular biology. Its principal role is to capture platelets at sites of
blood vessel endothelial injury allowing the formation of an unstable platelet plug, an
initial step in haemorrhage control. Following this, blood coagulation at the site of injury,
results in the formation of fibrin strands, which enmesh and stabilise the platelet plug,
until vessel repair is complete.
Following endothelial cell (EC) injury or activation, VWF becomes tethered, either to EC or
to the now exposed subendothelial matrix (SEM). The shear stress generated by blood flow
causes the tethered VWF to unravel, exposing its multiple platelet binding sites, resulting
in platelet capture.
One of the most important domains of VWF is the A1 domain, which contains binding sites for
the platelet receptor glycoprotein Ib (GPIb) as well as for collagen and heparin.
Heparin is the major component of mast cell secretory granules. Its precise physiological
role is unknown but it has been proposed that it plays a role in host defense mechanisms. The
anticoagulant properties of heparin, however, have been exploited pharmaceutically and
exogenous heparin has been a clinically useful anticoagulant since 1935.4 It is known to
potentiate the effects of antithrombin in the inactivation of Factor Xa and thrombin.
Unfractionated heparin therapy can be monitored using the plasma activated partial
thromboplastin time (APTT), anti -factor Xa activity or, if very high doses are used, the
activated clotting time (ACT). The APTT is most commonly used to monitor UFH therapy as it is
cost effective and readily available. However, it is subject to several pre-analytical and
analytical variables and therefore may not provide an accurate measure of the anticoagulant
effect of UFH. The anti-factor Xa activity is less susceptible to confounding factors and
makes this the assay of choice but it is less widely available.
Studies have shown that heparin also competitively inhibits the binding of VWF to platelet
receptor GPIb, an anti-thrombotic effect distinct from its anticoagulant role via
Antithrombin. This may in part explain why the bleeding complications that occur during
heparin therapy are unpredictable, despite using current techniques for monitoring its
anticoagulant effect. This additional activity of heparin is likely to be of particular
importance during CPB when very high concentrations of heparin are used to maintain the
extracorporeal circuit and which have to be reversed to restore haemostasis at the end of the
procedure. The currently available literature remains incomplete in the characterisation of
the changes that occur in VWF-dependent platelet function and do not explain the observed
recovery of VWF function above baseline levels, after reversal of heparin with protamine
sulphate. The aim of this study is to fully characterise the changes in VWF concentration,
function and platelet interaction, that occur in patients undergoing cardiac surgery and
receiving intravenous unfractionated heparin, intra- and post-operatively. This is a
prospective, single centre cohort study involving the analysis of haemostatic assays in
patients receiving IV heparin during cardiopulmonary bypass surgery. The study aims to
recruit 30 eligible adult patients (>18 years) undergoing first time cardiac surgery for the
correction of atrial septal defects or undergoing tissue mitral valve replacement and
receiving IV unfractionated heparin intra-operatively at Royal Brompton Hospital. The study
aims to recruit a uniform population of 30 patients which should be achieved within 6 months.
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