Abstract
Introduction: Heparin resistance refers to the need for higher doses of unfractionated heparin to achieve therapeutic anticoagulation. A universal definition is lacking, with commonly used criteria including a total daily dose >35,000 units or a weight-based dose >25 units/kg/hr. In contrast, cardiac bypass protocols define resistance using activated clotting time (ACT), with at least one ACT <400 seconds after heparinization or the need for exogenous AT. Many institutions monitor heparin with PTT, though anti-factor Xa assays more accurately reflect anticoagulation. In settings without anti-Xa testing, heparin resistance may be misdiagnosed. We conducted a retrospective study to assess outcomes associated with various definitions of heparin resistance. If outcome differences exist, specific definitions may be more clinically useful and warrant earlier intervention.
Methods: We retrospectively reviewed patients receiving heparin drips at our institution from 2017 to 2025. Based on dosing, patients were classified into three groups:
Definition 1: >35,000 units/day
Definition 2: >25 units/kg/hr to reach therapeutic or subtherapeutic PTT (excluding loading dose)
Definition 3: Met both criteria above
We collected data on demographics, labs, indication for heparin, survival (overall, 30-day, and 1-year), hospital length of stay, bleeding-related ICD codes, and treatments. Categorical variables were reported as frequencies/percentages; continuous variables as means ± SD or medians with IQRs. We used Cox proportional hazards models for survival analysis. Wilcoxon rank-sum tests compared hospital stay lengths. Kruskal-Wallis or Fisher's exact tests compared complications. All tests were two-sided at a 5% significance level, conducted in R (v4.5.0, R Core Team, 2025).
Results: We reviewed 5,414 patients from our institution from the start of 2013 up until April 2025. There were 5041 patients who met definition 1, 60 patients who met definition 2, and 313 patients who met both definitions. Our study showed that the 30-day mortality was highest in subjects who met criteria for definition 2 (24.6%) compared to 13.4% for subjects under definition 1 and 21.4% for subjects meeting both definitions (p-value < 0.001). Similarly, one-year mortality was highest (47.2%) in subjects under definition 2 when compared to the definition 1 category (28.3%) and both definitions (42.2%) (p-value < 0.001). The median length of stay was highest in the category that met both definitions (5 days) when compared to subjects in definitions 2 and 1, where the median was 13.5 and 9 days, respectively (p-value <0.001).
However, the prevalence of major bleeding complications was highest for subjects in definition 1 (17%) when compared to 10.2% (both definitions) and 7.8% (definition 2) with a p-value of 0.002. Whereas, the rate of hemorrhagic shock was highest in subjects meeting both definitions (2.2%), followed by those under definition 1 (1.9%) and definition 2 (0%) (p-value 0.7). A hemoglobin drop of more than 2 g/dL was observed in 13.6% of subjects under definition 1, compared to 7.3% in those meeting both definitions and 5.9% in the definition 2 group (p-value 0.002).
Patients who met both Definition 1 and 2 had an increased risk of mortality of about 38% (HR 1.38; 95% CI: 1.17–1.63; p < 0.001). Patients meeting Definition 2 alone had an 85% increased risk of mortality (HR 1.85; 95% CI: 1.34–2.56; p < 0.001). Both 30-day and 1-year mortality were increased amongst all 3 groups (p<0.001). Patients who met both the criteria for heparin resistance had a statistically significant increase in length of stay, with the median being 15 days in patients who met criteria for both 1 and 2.
Conclusion: Our findings support that weight-adjusted definitions of heparin resistance are associated with substantially worse long-term outcomes, even when the analysis was adjusted for treatment variations in different definition groups, and may provide more prognostic utility than fixed-dose thresholds alone. It might be necessary to adopt those definitions to prompt early realization and early treatment to avoid adverse outcomes. These results highlight the importance of standardized definitions to better identify and manage heparin resistance in clinical practice.
