Antithrombin as a Predictor of Heparin Resistance in Cardiac Surgery With Cardiopulmonary Bypass

This study aims to investigate whether the level of antithrombin (AT) in the blood before cardiac surgery can predict how well patients respond to heparin, a medication used to prevent blood clotting during surgery with a heart-lung machine (cardiopulmonary bypass).

Heparin requires antithrombin to work effectively. Some patients have lower levels of antithrombin, which may result in reduced response to heparin, a condition known as heparin resistance. This can lead to difficulties achieving adequate anticoagulation during surgery and may require additional medication or adjustments in treatment.

In this study, an additional blood sample will be taken after anesthesia induction but before the administration of heparin. No changes will be made to the patient's treatment or care. Clinical data, including laboratory values, heparin dosing, and surgical outcomes, will be collected from routine medical records.

The goal is to identify a clinically useful antithrombin threshold that can help detect patients at risk of heparin resistance. This may improve patient safety, optimize treatment strategies, and reduce unnecessary use of antithrombin therapy in the future.

Study Overview

• Status: Not yet recruiting
• Conditions: Cardiac Surgery; Cardiopulmonary Bypass; Heparin Resistance
• Intervention / Treatment: Other: No intervention (observational study)

Detailed Description

This prospective observational cohort study aims to evaluate whether preoperative antithrombin (AT) levels can predict heparin resistance in adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) at Sahlgrenska University Hospital, Sweden.

Heparin is routinely administered during CPB to prevent thrombus formation in the extracorporeal circuit. Its anticoagulant effect depends on the presence of antithrombin, a key endogenous inhibitor of coagulation. Reduced levels of antithrombin are known to impair the anticoagulant response to heparin and may result in heparin resistance. Clinically, this can lead to repeated heparin dosing, delays in achieving adequate anticoagulation, and increased use of antithrombin supplementation. However, there is currently no well-established threshold for antithrombin levels that can reliably identify patients at risk prior to heparin administration.

The study is designed as a non-interventional investigation in which all patients are managed according to standard clinical practice. A single additional blood sample for measurement of antithrombin will be obtained after induction of anesthesia and prior to administration of heparin. This timing is chosen to ensure standardized conditions and to minimize the influence of hemodilution and perioperative physiological changes.

Clinical and perioperative data will be collected from routine medical records, including anesthesia records, perfusion protocols, and laboratory systems. These data will be used to assess the relationship between preoperative antithrombin levels and the anticoagulant response to heparin during CPB, as well as associated perioperative outcomes.

The primary objective is to determine whether antithrombin levels can serve as a clinically useful predictor of heparin resistance. The analysis will focus on evaluating the discriminative ability of antithrombin and identifying a threshold value that may be useful for clinical decision-making. Secondary analyses will explore the association between antithrombin levels, heparin dosing requirements, and perioperative outcomes.

As an observational study, no changes are made to patient management. The study is expected to provide clinically relevant information that may support more individualized anticoagulation strategies and reduce unnecessary use of antithrombin supplementation in the future.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Anna Corderfeldt Keiller, PhD; Phone Number: +46313427737; Email: anna.corderfeldt@gu.se
• Study Contact Backup: Name: Daniel Bengtsson, MSc; Phone Number: +313427730; Email: daniel.bengtsson@vgregion.se

Study Locations

• Sweden
  • Västra Götalandsregionen
    • Gothenburg, Västra Götalandsregionen, Sweden, 41345
      • Sahlgrenska University Hospital
      • Contact: Daniel Bengtsson, MSc; Phone Number: +313427730; Email: daniel.bengtsson@vgregion.se
      • Contact: Anna Corderfeldt Keiller, PhD; Phone Number: +313427737; Email: anna.corderfeldt@gu.se
      • Principal Investigator: Anna Corderfeldt Keiller, PhD
      • Sub-Investigator: Daniel Bengtsson, MSc
      • Sub-Investigator: Nina Alves Martins, BSc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients undergoing elective or sub-acute cardiac surgery with cardiopulmonary bypass at Sahlgrenska University Hospital, Sweden. Patients are consecutively included to reflect routine clinical practice and minimize selection bias.

Description

Inclusion Criteria:

• Age ≥18 years
• Planned cardiac surgery with cardiopulmonary bypass
• Ability to provide informed consent

Exclusion Criteria:

• Emergency cardiac surgery
• Ongoing antithrombin supplementation prior to surgery
• Known severe congenital coagulation disorder affecting interpretation of outcomes
• Severe liver failure
• Missing key data required to define heparin resistance (e.g., missing heparin dose or ACT values)

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Patients undergoing cardiac surgery with cardiopulmonary bypass; Adult patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) at Sahlgrenska University Hospital, Sweden. All patients are managed according to standard clinical practice. A preoperative blood sample is collected to measure antithrombin levels, and clinical data are collected to assess the relationship between antithrombin levels and heparin resistance. No study-specific intervention is performed.

Other: No intervention (observational study); This is a prospective observational study. No intervention is assigned as part of the study protocol. All patients receive standard clinical care. A preoperative blood sample is collected for measurement of antithrombin levels, and clinical data are recorded to assess the relationship between antithrombin levels and heparin resistance without influencing treatment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heparin resistance	Heparin resistance defined as failure to achieve an activated clotting time (ACT) ≥480 seconds after administration of an initial heparin dose of 350 IU/kg, according to standard clinical practice.	Intraoperative (immediately after initial heparin administration)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Activated clotting time after initial heparin dose	Activated clotting time (ACT) measured after administration of the initial heparin dose.	Intraoperative (after initial heparin administration)
Total heparin dose	Total cumulative heparin dose administered until activated clotting time (ACT) ≥480 seconds is achieved.	Intraoperative
Antithrombin supplementation	Administration of antithrombin concentrate due to insufficient anticoagulation.	Intraoperative

Collaborators and Investigators

• Sponsor: Sahlgrenska University Hospital
• Investigators: Principal Investigator: Anna Corderfeldt Keiller, PhD, Sahlgrenska University Hospital and University of Gothenburg, Department of Clinical Sciences, Gothenburg, Sweden

Publications and helpful links

General Publications

• Chen Y, Phoon PHY, Hwang NC. Heparin Resistance During Cardiopulmonary Bypass in Adult Cardiac Surgery. J Cardiothorac Vasc Anesth. 2022 Nov;36(11):4150-4160. doi: 10.1053/j.jvca.2022.06.021. Epub 2022 Jun 24.
• Levy JH, Sniecinski RM, Maier CL, Despotis GJ, Ghadimi K, Helms J, Ranucci M, Steiner ME, Tanaka KA, Connors JM. Finding a common definition of heparin resistance in adult cardiac surgery: communication from the ISTH SSC subcommittee on perioperative and critical care thrombosis and hemostasis. J Thromb Haemost. 2024 Apr;22(4):1249-1257. doi: 10.1016/j.jtha.2024.01.001. Epub 2024 Jan 11.
• Rivera Jimenez KE, Mamani Ticona YM, Gutierrez-Chavez G, Astudillo CO, Calle E, Heredia GAT, Lopez Delgado DS, Rivera-Lozada O, Barboza JJ. Heparin Resistance in Cardiac Surgery with Cardiopulmonary Bypass: Mechanisms, Clinical Implications, and Evidence-Based Management. Medicina (Kaunas). 2025 Nov 23;61(12):2088. doi: 10.3390/medicina61122088.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: April 16, 2026
• First Submitted That Met QC Criteria: April 16, 2026
• First Posted (Actual): April 24, 2026

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Anticoagulation; Cardiac surgery; Cardiopulmonary bypass; ACT; Antithrombin III; Activated clotting time; Predictive biomarker; Heparin resistance; Antithrombin; Heparin response
• Additional Relevant MeSH Terms: Investigative Techniques; Methods; Observation
• Other Study ID Numbers: ANTITHROMBIN-HLM-2026

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

De-identified individual participant data underlying the results reported in this study (including demographic, clinical, laboratory, and perioperative variables) will be made available. Data will be stored and managed through DORIS, a secure research data repository at the University of Gothenburg, in accordance with Swedish data protection legislation and the General Data Protection Regulation (GDPR, EU 2016/679).

Access to data will be provided upon reasonable request from qualified researchers, subject to ethical approval and data access agreements. A persistent digital object identifier (DOI) will be assigned to the dataset. Data access will be granted following review and approval of a methodologically sound research proposal, ensuring compliance with applicable legal and ethical requirements.

• IPD Sharing Time Frame: Data will be available beginning 6 months following publication of the primary results and will remain available for at least 5 years thereafter.

IPD Sharing Access Criteria

Access to de-identified individual participant data and supporting documentation (study protocol, statistical analysis plan, and analytic code) will be granted to qualified researchers upon reasonable request. Requests must include a methodologically sound research proposal and, where applicable, approval from a relevant ethics committee.

Data will be made available following approval of a data access agreement, in compliance with applicable legal and ethical requirements, including the General Data Protection Regulation (GDPR, EU 2016/679) and Swedish data protection legislation.

Data and analytic code will be accessed through DORIS, a secure research data repository at the University of Gothenburg, and will not be publicly downloadable.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

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