Discordant aPTT and Anti-Xa Values and Outcomes in Hospitalized Patients Treated With Intravenous Unfractionated Heparin

Elizabeth A Price MD MPH; Jing Jin MD; Huong (Marie) Nguyen MD: Gomathi Krishnan PhD; Raffick Bowen PhD; James L Zehnder MD


The Annals of Pharmacotherapy. 2013;47(2):151-158. 

In This Article

Abstract and Introduction


Background: Both the activated partial thromboplastin time (aPTT) and anti-Xa assay can be used to monitor unfractionated heparin (UFH). Following implementation of an anti-Xa method for heparin dosing protocols in our hospital, we became aware of many patients with discordant aPTT and anti-Xa values.

Objective: To determine the frequency of discordant aPTT and anti-Xa values in a large cohort of hospitalized patients treated with UFH, as well as the demographics, coagulation status, indication for UFH, and clinical outcomes in this population.

Methods: All aPTT and anti-Xa values from adults hospitalized between February and August 2009 at Stanford Hospital who were treated with UFH were analyzed. All samples were drawn simultaneously. A polynomial fit correlating aPTT and anti-Xa with a 99% confidence limit was designed. Paired aPTT/anti- Xa values were grouped according to whether the paired values fell within or outside of the concordant area. Patients were placed into groups based on concordance status, and clinical outcomes were assessed.

Results: A total of 2321 paired values from 539 patients were studied; 42% of data pairs had a high aPTT value relative to the anti-Xa value. Patients with elevated baseline prothrombin time/international normalized ratio or aPTT frequently demonstrated disproportionate relative prolongation of the aPTT. Patients with at least 2 consecutive high aPTT to anti-Xa values had increased 21-day major bleeding (9% vs 3%; p = 0.0316) and 30-day mortality (14% dead vs 5% dead at 30 days; p = 0.0202) compared with patients with consistently concordant values.

Conclusions: aPTT and anti-Xa values are frequently discordant when used to measure UFH in hospitalized patients. A disproportionate prolongation of the aPTT relative to the anti-Xa was the most common discordant pattern in our study. Patients with relatively high aPTT to anti-Xa values appear to be at increased risk of adverse outcomes. Monitoring both aPTT and Xa values may have utility in managing such patients.


Historically, unfractionated heparin (UFH) has been monitored using the activated partial thromboplastin time (aPTT), a global measurement of the ability of the heparin-antithrombin complex to inactivate the relevant clotting factors. Many factors can interfere with aPTT assessment of heparin. The aPTT will be prolonged when the patient has low coagulation factor levels and a compromised hemostatic system and shortened in the presence of elevated factor VIII or fibrinogen levels.[1] The concomitant use of warfarin can lengthen the aPTT.[2] Additionally, the aPTT may be prolonged in circumstances where no bleeding risk is present, such as in a patient with factor XII deficiency, or in the presence of lupus anticoagulants. Perhaps the biggest problem associated with using the aPTT to measure heparin effect, independent of patient variables, is the lack of standardization of methods. Thus, different reagent-instrument combinations may lead to significant differences in the aPTT time in seconds for a given heparin concentration.[3–5]

To address this issue, consensus panels have recommended that laboratories calibrate their aPTT assays by measuring the anti-Xa level based on the ability of heparin to neutralize fixed amounts of factor Xa added to plasma or by protamine titration.[6–8] However, the validity of this approach has recently been questioned, as such calibration methods may not enhance interlaboratory agreement in UFH monitoring.[9] An alternative is to use the anti-Xa assay to directly measure the functional activity of heparin in inhibiting coagulation factors.[10] This method has the advantage of less interference from several patient and preanalytic variables. There is little to no effect on the anti-Xa assay by such patient variables as decreased coagulation factors secondary to liver disease, consumptive coagulopathy, the presence of a lupus anticoagulant, or preanalytic variables such as timing of sampling and adequate filling of sample tubes.[11] However, standardization is also an issue with anti-Xa assays.[5,12] In addition, the precision of anti-Xa assays is lower than that of aPTT assays.[5] Anti-Xa measurements also do not give an overall assessment of hemostasis. In general, there is a lack of data correlating these methods of measuring heparin effect in patients and outcome data validating any particular approach.

In response to the limitations inherent in the use of aPTT alone, the use of the anti-Xa assay to monitor UFH was instituted in 2007 at Stanford Hospital and Clinics as the primary method for monitoring UFH; however, concomitant aPTT values were also obtained in all patients per coagulation laboratory protocol. Anecdotally, we have observed that aPTT and anti-Xa values have been frequently discordant in clinical practice. Thus, this study was designed to formally evaluate the concordance of aPTT and anti-Xa measurements in hospitalized adults treated with UFH, and more importantly, to assess the impact of discordant aPTT/anti-Xa measurements on patient outcomes in this population.