Haemostatic Markers in Cardiopulmonary Bypass

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.

Study Overview

• Status: Completed
• Conditions: Cardiopulmonary Bypass Surgery; Unfractionated Heparin

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

This is a prospective cohort study, and patients undergoing cardiopulmonary bypass surgery will be recruited when they are assessed pre operatively at the Royal Brompton Hospital (RBH) Normal controls will be staff members from Imperial College London.

Patient recruitment:

Patients who meet the inclusion criteria will be identified by the anaesthetic team when they are assessed preoperatively. They will be provided with a Participant Information Sheet and have the opportunity to ask questions and discuss the study with the researchers before providing consent. The study aims to recruit 30 patients.

Description

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

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative & Qualitative VWF Assessment	VWF antigen level, Ristocetin Cofactor Assay	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global Test of Haemostasis	Thromboelastography	6 months

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: Royal Brompton & Harefield NHS Foundation Trust
• Investigators: Principal Investigator: Deepa Arachachillage, MBBS, Imperial College London

Publications and helpful links

General Publications

• Sobel M, McNeill PM, Carlson PL, Kermode JC, Adelman B, Conroy R, Marques D. Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo. J Clin Invest. 1991 May;87(5):1787-93. doi: 10.1172/JCI115198.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2019
• Primary Completion (Actual): July 18, 2019
• Study Completion (Actual): July 18, 2019

Study Registration Dates

• First Submitted: March 1, 2019
• First Submitted That Met QC Criteria: March 1, 2019
• First Posted (Actual): March 4, 2019

Study Record Updates

• Last Update Posted (Actual): September 25, 2019
• Last Update Submitted That Met QC Criteria: September 23, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Unfractionated Heparin; Cardiopulmonary Bypass Surgery
• Other Study ID Numbers: 248558

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No