Anti-Xa assays: What is their role today in antithrombotic therapy?

Cleveland Clinic Journal of Medicine. 2019 June;86(6):417-425 | 10.3949/ccjm.86a.18029
June 3, 2019|Cleveland Clinic Journal of Medicine
Erika Hutt Centeno, MD;Michael Militello, PharmD, RPh, BCPS;Marcelo P. Gomes, MD
Author and Disclosure Information

Erika Hutt Centeno, MD
Department of Internal Medicine, Cleveland Clinic; Clinical Instructor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Michael Militello, PharmD, RPh, BCPS
Medical Operations, Inpatient Pharmacy, Cleveland Clinic

Marcelo P. Gomes, MD
Department of Vascular Medicine, Cleveland Clinic; Clinical Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Erika Hutt Centeno, MD, Department of Internal Medicine, G10, Cleveland Clinic; 9500 Euclid Avenue, Cleveland, OH, 44195; huttcee@ccf.org

Release date: June 1, 2019
Expiration date: May 31, 2020
Estimated time of completion: 1 hour

Click here to start this CME/MOC activity.

ABSTRACT

Although some suggest anti-Xa assays should be the preferred method for monitoring intravenous unfractionated heparin therapy, which method is best is unknown owing to the lack of large randomized controlled trials correlating different assays with clinical outcomes. This article provides an overview of heparin monitoring and the pros, cons, and clinical applications of anti-Xa assays.

KEY POINTS

  • Intravenous unfractionated heparin treatment is typically monitored by the activated partial thromboplastin time (aPTT), with a therapeutic target defined as the range that corresponds to an anti-Xa level of 0.3 to 0.7 U/mL.
  • Monitoring unfractionated heparin is important to achieve a therapeutic target within the first 24 hours and to maintain therapeutic levels thereafter.
  • The heparin anti-Xa assay is unreliable for unfractionated heparin monitoring when switching from oral factor Xa inhibitor therapy to intravenous unfractionated heparin. In such cases, the aPTT is preferred.
  • Most patients receiving low-molecular-weight heparin do not need monitoring, but monitoring should be considered for pregnant women with prosthetic heart valves, using an anti-Xa assay specific for low-molecular-weight heparin.

MONITORING UNFRACTIONATED HEPARIN IMPROVES OUTCOMES

In 1960, Barritt and Jordan10 conducted a small but landmark trial that established the clinical importance of unfractionated heparin for treating venous thromboembolism. None of the patients who received unfractionated heparin for acute pulmonary embolism developed a recurrence during the subsequent 2 weeks, while 50% of those who did not receive it had recurrent pulmonary embolism, fatal in half of the cases.

The importance of achieving a specific aPTT therapeutic target was not demonstrated until a 1972 study by Basu et al,11 in which 162 patients with venous thromboembolism were treated with heparin with a target aPTT of 1.5 to 2.5 times the control value. Patients who suffered recurrent events had subtherapeutic aPTT values on 71% of treatment days, while the rest of the patients, with no recurrences, had subtherapeutic aPTT values only 28% of treatment days. The different outcomes could not be explained by the average daily dose of unfractionated heparin, which was similar in the patients regardless of recurrence.

Subsequent studies showed that the best outcomes occur when unfractionated heparin is given in doses high enough to rapidly achieve a therapeutic prolongation of the aPTT,12–14 and that the total daily dose is also important in preventing recurrences.15,16 Failure to achieve a target aPTT within 24 hours of starting unfractionated heparin is associated with increased risk of recurrent venous thromboembolism.13,17

,

Raschke et al17 found that patients prospectively randomized to weight-based doses of intravenous unfractionated heparin (bolus plus infusion) achieved significantly higher rates of therapeutic aPTT within 6 hours and 24 hours after starting the infusion, and had significantly lower rates of recurrent venous thromboembolism than those randomized to a fixed unfractionated heparin protocol, without an increase in major bleeding.

Smith et al,18 in a study of 400 consecutive patients with acute pulmonary embolism treated with unfractionated heparin, found that patients who achieved a therapeutic aPTT within 24 hours had lower in-hospital and 30-day mortality rates than those who did not achieve the first therapeutic aPTT until more than 24 hours after starting unfractionated heparin infusion.

Such data lend support to the widely accepted practice and current guideline recommendation8 of using laboratory assays to adjust the dose of unfractionated heparin to achieve and maintain a therapeutic target. The use of dosing nomograms significantly reduces the time to achieve a therapeutic aPTT while minimizing subtherapeutic and supratherapeutic unfractionated heparin levels.19,20

THE aPTT REFLECTS THROMBIN INHIBITION

The aPTT has a log-linear relationship with plasma concentrations of unfractionated heparin,21 but it was not developed specifically for monitoring unfractionated heparin therapy. Originally described in 1953 as a screening tool for hemophilia,22–24 the aPTT is prolonged in the setting of factor deficiencies (typically with levels < 45%, except for factors VII and XIII), as well as lupus anticoagulants and therapy with parenteral direct thrombin inhibitors.8,25,26

Because thrombin (factor IIa) is 10 times more sensitive than factor Xa to inhibition by the heparin-antithrombin complex,4,7 thrombin inhibition appears to be the most likely mechanism by which unfractionated heparin prolongs the aPTT. In contrast, aPTT is minimally or not at all prolonged by low-molecular-weight heparins, which are predominantly factor Xa inhibitors.7

HEPARIN ASSAYS MEASURE UNFRACTIONATED HEPARIN ACTIVITY

While the aPTT is a surrogate marker of unfractionated heparin activity in plasma, unfractionated heparin activity can be measured more precisely by so-called heparin assays, which are typically not direct measures of the plasma concentration of heparins, but rather functional assays that provide indirect estimates. They include protamine sulfate titration assays and anti-Xa assays.

Protamine sulfate titration assays measure the amount of protamine sulfate required to neutralize heparin: the more protamine required, the greater the estimated concentration of unfractionated heparin in plasma.8,27–29 Protamine titration assays are technically demanding, so they are rarely used clinically.

Anti-Xa assays provide a measure of the functional level of heparins in plasma.29–33 Chromogenic anti-Xa assays are available on automated analyzers with standardized kits29,33,34 and may be faster to perform than the aPTT.35

Experiments in rabbits show that unfractionated heparin inhibits thrombus formation and extension at concentrations of 0.2 to 0.4 U/mL as measured by the protamine titration assay,27 which correlated with an anti-Xa activity of 0.35 to 0.67 U/mL in a randomized controlled trial.32

Assays that directly measure the plasma concentration of heparin exist but are not clinically relevant because they also measure heparin molecules lacking the pentasaccharide sequence, which have no anticoagulant activity.36