Our study explores the relationship between TTR during UFH therapy and prognosis in patients with acute PE admitted to a tertiary care center ICCU. Given the clinical challenge of balancing therapeutic aPTT levels, the findings contribute valuable insights into optimizing anticoagulation management in acute high-risk PE cases. Our main findings are: a) Therapeutic Range Achievement: Only 57% of patients achieved therapeutic aPTT at least once during their hospital stay, with a mean TTR of 24.6%. b) Gender differences in TTR: Men demonstrated higher mean and median TTR values than women. Conversely, women spent more time above the therapeutic range. c) Mortality and TTR Correlation: Lower TTR was significantly associated with increased 30-day and 1-year mortality rates. The mean TTR for patients who died within the first 30 days (9.5%) and 1 year (12.9%) was substantially lower than survivors. However, TTR did not emerge as an independent predictor of mortality in multivariate analysis, suggesting its role may be secondary to other factors, such as age, albumin levels, and malignancy.

Only 57% of patients achieved therapeutic aPTT levels at least once during hospitalization, with a mean TTR for this group of 43%. Nevertheless, total patients mean TTR was only 24.6%. The low overall TTR suggests a substantial gap in maintaining effective anticoagulation within the therapeutic window which is supported by previous studies suggests that a significant proportion of patients fail to achieve therapeutic aPTT within the critical 48 h, with only 26.3–33.1% of patients reaching the range during this period [6]. Similarly, another research reported that 60% of patients did not achieve therapeutic aPTT level within 24 h. [7].

These findings highlight the challenge of UFH titration in critical care settings, especially for acute PE patients with complex profiles such as renal impairment or obesity. [1].

Men demonstrated higher mean TTR compared to women (31.8 ± 30.9% vs. 19 ± 22.7%) while women spent more time above therapeutic range (22.5 ± 27.2% vs. 13.4 ± 19.1%). This is in line with previous studies that found that women had higher heparin levels and aPTT values than men after receiving the same heparin doses, indicating a heightened sensitivity to heparin in females [11]. Similarly, research on heparin administration during carotid endarterectomy reported that females reached significantly higher levels of anticoagulation compared to males [12]. These differences could stem from physiological variations or disparities in anticoagulation response, warranting further research to tailor UFH dosing more effectively based on sex-specific factors (Fig. 3).

ROC Curve analysis of TTR value and TTR

Lower TTR was significantly associated with increased 30-day and 1-year mortality rates. The mean TTR for patients who died within the first 30 days (9.5%) and 1 year (12.9%) was substantially lower than survivors. However, TTR did not emerge as a strong independent predictor of mortality in multivariate analysis, suggesting its role may be secondary to other factors, such as age, albumin levels, and malignancy. ROC curve analysis identified a TTR cutoff of 21.5% with high sensitivity (81.3%) and high negative predicting value (96.8%) but poor positive predictive value (12%) for 1-year mortality. TTR as a screening tool remains questionable because it does not consistently identify patients at high risk of death (low PPV).

Previous studies found that patients who achieved therapeutic aPTT within 24 h had improved mortality and fewer bleeding events, emphasizing the importance of timely therapeutic anticoagulation [9]. Nevertheless, this might be due to the fact that patients who achieved therapeutic aPTT were less complicated than patients who did not achieve sufficient therapeutic aPTT and had more comorbidities and more complicated PE. More complicated patients can find difficulties in achieving therapeutic aPTT due to heparin resistance that can be caused by antithrombin III (ATIII) deficiency or elevated levels of factor VIII and fibrinogen, which are common in critically ill patients [13]. Additionally, comorbid conditions can significantly affect anticoagulation therapy. For example, liver disease can alter the metabolism of anticoagulants, and conditions like vitamin K deficiency can impact coagulation pathways, making it more challenging to maintain therapeutic aPTT levels. [14].

This highlights TTR’s potential utility as a screening tool to identify high-risk patients while underscoring its limitations as a standalone predictor. Moreover, the multivariate mortality predictors such as age, albumin levels, and malignancy were significant independent predictors of 1-year mortality. These findings reinforce the multifactorial nature of outcomes in PE patients and the need for holistic risk stratification beyond TTR alone. [15].

Unlike earlier studies that focused on single or initial aPTT measurements, our study evaluates TTR over the first 72 h of hospitalization. By using a continuous assessment of aPTT levels, the study offers a more dynamic understanding of anticoagulation balance and its impact on patient outcomes. Moreover, previous research emphasized the percentage of patients achieving therapeutic aPTT but lacked detailed exploration of TTR’s correlation with mortality. This study bridges that gap, demonstrating significant differences in mean TTR between survivors and non-survivors at 30 days and 1 year. Finally, with a mean follow-up period of 35 months, the study extends its observations beyond short-term outcomes, providing valuable insights into the long-term prognosis of PE patients.

This study underscores the need for improved strategies to maintain therapeutic aPTT levels during UFH therapy. Potential approaches include: Enhanced monitoring protocols, such as more frequent aPTT assessments; Development of algorithms to personalize UFH dosing based on demographic and clinical factors; Consideration of alternative anticoagulants (e.g., LMWH or direct oral anticoagulant—DOACs) in eligible patients to overcome the challenges associated with UFH.

The concept of an aPTT"therapeutic range"for unfractionated heparin (UFH) is historical and was not validated specifically for pulmonary embolism (PE). The commonly used range of 1.5–2.5 times control was derived from early studies but has since been shown to be unreliable, with significant variation based on reagents and lab methods [16, 17]. aPTT is also influenced by biological and analytical variability—such as acute-phase reactants, liver dysfunction, and inter-laboratory differences—reducing its correlation with heparin activity and clinical outcomes [18,19,20]. These limitations undermine the utility of aPTT-based TTR as a prognostic tool in PE. Anti-factor Xa monitoring, though not without limitations, is considered a more direct and consistent measure of heparin effect [19, 20]. Given the lack of standardization and weak correlation with outcomes, caution is needed when interpreting aPTT-based TTR in this context.

Our study has several limitations, First, it was a single center study, which limits generalizability to other populations or settings. Second, the sample size was relatively small for mortality analysis with reduced power to detect subtle associations. Third, we did not include patients who initially received thrombolysis due to shock and had worse outcomes. Finally, Various physiological and pathological conditions, including liver dysfunction, disseminated intravascular coagulation (DIC), factor deficiencies, inflammation, and acute-phase reactants, affect aPTT. These confounders may impact TTR calculations and should be acknowledged when interpreting the results. These factors introduce variability that is independent of heparin dosing, potentially limiting the reliability of TTR as a surrogate marker for anticoagulation quality.