The relationship between hemostatic markers and heparin during cardiopulmonary bypass surgery is complex, and bleeding may not be predicted by these markers, according to research in the British Journal of Haematology.

Bleeding is a risk for patients undergoing cardiopulmonary bypass surgery. Patients receive heparin for patency of the bypass circuit, which is known to inhibit the von Willebrand factor-platelet glycoprotein Ib alpha (VWF-GPIbα) interaction. This causes heparin to have an antithrombotic effect, as well as an anticoagulant effect.

The authors hypothesized that the inhibitory effect of heparin on the VWF-GPIbα interaction, which is not typically monitored during surgery, is important in patients receiving the highest doses of heparin during cardiopulmonary bypass.

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Patients are typically assessed by activated clotting time throughout the procedure; therefore, the investigators measured VWF antigen, VWF collagen-binding assays, and VWF ristocetin cofactor to determine the changes in VWF concentrations during surgery, and whether the VWF-GPIbα interaction could be detected with currently available tests.

The prospective, single-center observational study examined 30 adult patients in a cardiothoracic center in the United Kingdom. All patients underwent cardiopulmonary bypass and received intravenous heparin intra-operatively over 6 months.

The VWF antigen increased significantly during surgery and continued for 24 hours after surgery. The ratio of VWF collagen-binding to VWF antigen decreased after heparin was administered, but this result was not significant. The investigators noted the possibility that heparin caused a direct effect on collagen-binding and ristocetin cofactor.

Overall, 7 patients required a blood transfusion, but all 7 had VWF ristocetin cofactor measurements in normal range. Some patients continued to bleed after cardiopulmonary bypass despite heparin reversal with protamine sulfate.

The maximum amplitude fell after heparin was administered and rose after protamine was administered, even though platelet counts fell during surgery and were still reduced 24 hours after surgery.

Measuring the effect of heparin reversal on VWF is complicated, as protamine has a direct effect on VWF. The authors found that standard measures of coagulant activity, such as the activated clotting time, did not correlate with heparin activity measured by anti-Xa assay.

There is a complex relationship between hemostatic markers and drug effects during cardiopulmonary bypass.

“The off-target effects of both heparin and protamine [sulfate] make it difficult to confidently isolate the individual effects of each drug, as well as the biological variables in the stress response induced by surgery, which affect the [hemostatic] system, such as the release of inflammatory cytokines,” the authors noted.

“It is therefore not possible to use these data to create a predictor of bleeding due to the heparin-induced inhibition of the platelet [VWF-GPIbα] interaction. There was no relationship between the [hemostatic] parameters analyzed in this study and intraoperative blood loss or requirement for blood product replacement,” the investigators concluded.


Ranger A, Gaspar M, Elkhatteb A, et al. The heparin-von Willebrand factor interaction and conventional tests of haemostasis – the challenges in predicting bleeding in cardiopulmonary bypass. Br J Haematol. Published online December 5, 2020. doi:10.1111/bjh.17263