Haemostatic Markers in Cardiopulmonary Bypass
Haemostatic Markers in Cardiopulmonary Bypass
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.
Inclusion Criteria:

 1. Patients undergoing first time cardiopulmonary bypass surgery for correction of atrial
 septal defects or tissue mitral valve repair

 2. Receiving intravenous Heparin for cardiopulmonary bypass

 Exclusion Criteria:

 -  Concomitant Aortic Stenosis which is associated with an acquired von Willebrand
 Syndrome (aVWS)

 -  Patients with a baseline platelet count of <100x109/L

 -  Patients with a known coagulation factor deficiency or platelet function disorder

 -  Patients receiving heparin therapy prior to CPB within last 7 days