Incidence of heparin resistance and heparin failure in patients receiving extracorporeal membrane oxygenation: an exploratory retrospective analysis

Abstract

Background

Unfractionated heparin (UFH) is used in most centers for extracorporeal membrane oxygenation (ECMO) anticoagulation. When standard doses do not achieve desired target values, heparin resistance is reported, most commonly defined as doses of UFH > 35 000 IU/d.

Objectives

To study the incidence of heparin resistance and its association with thromboembolic complications in patients requiring ECMO support.

Methods

In this observational cohort study, we included adults who received venovenous, venoarterial ECMO and extracorporeal carbon dioxide removal between January 2010 and May 2022. Main risk factor was heparin resistance (UFH, > 35 000 IU/d or > 20 IU/kg/h); the outcome was thromboembolism. Multivariable Poisson regression was used to estimate the effects of heparin resistance, adjusted for several clinical variables on the thromboembolism rate per 100 ECMO patient-days.

Results

Of the 197 patients included, 33 (16.8%) required UFH > 35 000 IU/d and 14 (7.1%) required UFH > 20 IU/kg/h. Thromboembolic complications occurred at a rate of 5.89/100 ECMO d. Heparin resistance was not associated with thromboembolic events (incidence rate ratio [IRR], 0.93; 95% CI, 0.14-5.82), whereas COVID-19 (IRR, 2.33; 95% CI, 1.4-3.96; P < .001) and ECMO type (venoarterial ECMO: IRR, 2.29; 95% CI, 1.34-3.92; P = .002; extracorporeal carbon dioxide removal: IRR, 2.89; 95% CI, 1.46-5.59; P = .002; reference venovenous ECMO) were significantly associated with the risk of thromboembolic events.

Conclusion

A significant proportion of patients fulfilled the common definition of heparin resistance. However, this did not influence the occurrence of thromboembolic events.

Introduction

Extracorporeal membrane oxygenation (ECMO) has become an essential treatment for severe acute respiratory and/or circulatory failure [[1], [2], [3]]. The extracorporeal circuit requires effective anticoagulation, but the precarious balance between preventing clotting or thromboembolic events and bleeding complications remains a challenge in a critically ill and potentially coagulopathic patient [4,5].
Unfractionated heparin (UFH) is the most commonly used anticoagulant agent [6]. The complex pharmacokinetics and dynamics of UFH, due in part to its requirement for antithrombin III (AT) binding and acute-phase reactants, lead to marked inter- and intraindividual variability of its effect on coagulation monitoring, requiring frequent dose adjustments [7]. An inadequate/altered test response to heparin has in the past been incorrectly labeled as “heparin resistance.” In this context, a drug resistance would implicate that the drug (UFH) could not act on its target in coagulation (AT) [8]. However, although AT deficiency is frequent among critically ill patients, and ECMO patients in specific, it does not meet the criteria for true drug resistance at the molecular level [9].
A recent communication from the International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee (SSC) Subcommittee on Perioperative and Critical Care Thrombosis and Hemostasis highlighted the differences between the definition of “heparin resistance” used in the literature and the definition used by survey respondents [10]. In the literature, a requirement of UFH > 35 000 IU/d, regardless of the patient’s weight, to achieve the target values for anticoagulation is generally defined as “heparin resistance” [7,11]. This cutoff was first used in a randomized controlled trial in 1994, including noncritically ill patients with an acute thrombotic event who did not reach activated partial thromboplastin time (APTT) anticoagulation targets with a UFH dose of up to 35 000 IU/d. The authors acknowledged that the cutoff was arbitrarily chosen, expecting that 25% of patients with acute thromboembolic events would fall into this category [12]. Using an absolute cutoff for this definition obviously carries the limitation of overestimating alterations to heparin response in heavier or obese patients and underestimating alterations in patients with lower weight.
In contrast, only 17% of respondents used this definition but defined heparin resistance rather as a weight-adjusted heparin requirement of > 30 IU/kg/h [10]. In addition, it remains unclear whether a higher heparin requirement (ie, “heparin resistance”) is associated with an increased thromboembolic risk (ie, heparin failure) [13]. For these reasons, the ISTH communication recently recommended using the term “alterations in heparin response” instead of “heparin resistance” [10].
The aim of the current study was to investigate the rate of heparin resistance during ECMO and its association with thromboembolic events and to determine risk factors for the need for high doses of UFH to achieve anticoagulation targets.

Section snippets

Patients and study design

This exploratory observational cohort study included a population of adult recipients of venovenous (VV) and venoarterial (VA) ECMO and extracorporeal carbon dioxide removal (ECCO2R) anticoagulated with UFH, of whom we sampled all consecutive patients in a medical intensive care unit of a tertiary referral hospital (Vienna General Hospital, Medical University of Vienna) between January 2010 and May 2022. Data were collected from the local prospective ECMO registry and extracted from the

Baseline characteristics, anticoagulation targets, and mortality

A total of 197 patients with the following rates of heparin resistance according to different cutoffs of heparin requirement were included: 33 (16.8%) required > 35 000 IU/d, 14 (7.1%) required > 20 IU/kg/h, 1 (0.5%) required > 30 IU/kg/h, and 0 required > 40 IU/kg/h. Therefore, only the 2 cutoffs of UFH > 35 000 IU/d and UFH > 20 IU/kg/h were analyzed. One patient was switched to argatroban due to suspected heparin-induced thrombocytopenia. This patient was only observed until the

Discussion

In this retrospective study, we found high rates of heparin resistance in ECMO recipients defined by different cutoffs for heparin requirements. Platelet counts and fibrinogen levels were higher in patients with alterations in heparin response. After adjustment for COVID-19 status and ECMO type, alterations in heparin response had no effect on thromboembolism-free time during ECMO.

Conclusion

Alterations in drug response to UFH are common in ECMO patients but are not associated with an increased risk for thromboembolic events after adjustment for relevant covariates.

Author contributions

B.N., T.S., and N.B. were involved in study design, data collection, data analysis, data interpretation, and writing. P.S., P.K., R.B., and A.K. were involved in data collection, data analysis, data interpretation, and manuscript preparation. M.S., H.H., and J.H.L. were involved in data analysis, data interpretation, and manuscript preparation. All authors helped to revise the draft of the manuscript. All authors read and approved the final manuscript.

Declaration of competing interests

N.B. and T.S.: speaker fees: Mitsubishi Tanabe; investigator-initiated research grant: Mitsubishi Tanabe and CSL Behring.
J.H.L.: research steering committees and advisory committees for Merck, Octapharma, Takeda, and Werfen.
All other authors have no conflicts of interest to disclose.