By Reem Alsultan, Pharm.D, BCPS
Clinical Toxicology Fellow
Poison and Drug Information Center
Intravenous unfractionated heparin (UFH) is widely used in the clinical setting including neurocritical care patients.1,2 Pharmacokinetic properties of UFH including its short half-life, ranging from 0.5 to 2 hours in a dose dependent manner, a rapid onset of action after administration, and the availability of a reliable reversal agent in the event of an emergent or life-threatening bleeding increase many practitioners comfort level in using it.3
A lack of adequate therapeutic effect of heparin within the first 24 to 48 hours of therapy has been associated with a 5 to 20-fold increase in thromboembolic events. 4 Although accurate therapeutic monitoring of heparin is necessary, patient response can vary for several reasons. First, heparin may have unpredictable pharmacokinetic properties given that its biological activity and bioavailability is limited by its ability to bind to plasma protein, platelet factor-4, macrophages, fibrinogen, lipoproteins, and endothelial cells.1 Age, hepatic or renal disease and altered production of heparin-binding proteins can also affect the bioavailability of UFH and increase the therapeutic variability.1,5 Pregnancy for instance, is associated with increased clotting factors such as factor VIII and fibrinogen which may shorten the aPTT, while congenital or acquired deficiency (from warfarin use) of factor XII might prolong aPTT. Finally, the narrow therapeutic index of UFH and the risk of bleeding make the therapeutic monitoring of UFH crucial.1,2,6
Two commonly utilized methods to monitor the therapeutic level of UFH are the activated partial thromboplastin time (aPTT) and the antifactor-Xa (anti-Xa).2,5 Activated partial thromboplastin time is a general assessment of the intrinsic and common pathways of the coagulation cascade.5 Conversely, the anti-Xa is a chromogenic assay that measures the inhibition of clotting factor Xa which is reflective of the plasma concentration of UFH.
aPTT vs Anti-Xa monitoring: pros and cons
The major advantages of aPTT are its familiarity with most practitioners and that it is automated and relatively inexpensive.5 However, aPTT lacks standardization, and sensitivity of reagents to heparin and coagulation factors varies among manufacturers. Activated partial thromboplastin time, unlike the prothrombin time, lacks the equivalent of the international normalized ratio, which corrects for reagent variation. Also, aPTT can be altered by some preanalytical variables such as time and site of blood sampling and the number of clotting factors. Patient’s specific reduction or elevation of these factor can either over- or underestimate the heparin response. Some conditions can prolong aPTT at baseline such as lupus anticoagulant. The anti-Xa assay is more specific by measuring only one enzyme and it is less likely to be affected by preanalytical and analytical variables such as the reagent variability compared to aPTT.5 Similar to aPTT, it can be automated and readily available. The major disadvantages of anti-Xa assay are that it is relatively expensive, not available in many laboratories and it needs to be calibrated for different agents, such as UFH, fondaparinux or direct oral anticoagulants. Although anti-Xa has demonstrated less variability it is more likely to be affected by recent use of low molecular weight heparin, fondaparinux and direct factor Xa inhibitors, as well as hyperbilirubinemia and hypertriglyceridemia.8
Therapeutic monitoring strategy of UFH
There is still uncertainty as to which therapeutic monitoring strategy, the aPTT or the anti-Xa, should be used to monitor UFH. The target range for aPTT is 1.5 to 2.5 times greater than the upper limit of the institutional reference range.7 The therapeutic range for anti-Xa, as cited by both American college of Chest Physician and College of American Pathologist guidelines is 0.3-0.7 IU/mL for UFH infusion, although this remains controversial.2 Several studies compared using aPTT to anti-Xa in monitoring therapeutic UFH in patients diagnosed with venous thromboembolism and acute coronary syndrome.8,9 These studies showed that using anti-Xa resulted in shorter time to therapeutic range with fewer dose adjustment compared to using aPTT. It is important to note that critically ill patients with high bleeding risk were not excluded in these studies. The study by Whitman-purves et al implemented a specific protocol for each indication with different aPTT and anti-Xa goals.9 For example, in patients with stroke or high bleeding risk the anti-Xa goal was 0.25-0.35 U/mL and the aPTT goal was 59-72 sec. They found no difference in bleeding or mortality events between the two methods.8,9
A recent study was conducted at Brigham and Women’s Hospital that included eighty patients to assess the correlation between aPTT and anti-Xa for UFH infusion.2 The UFH therapeutic value for aPTT was between 60 to 80 seconds (for atrial fibrillation and venous thromboembolism) while therapeutic anti-Xa was between 0.3-0.7 IU/mL. Most of the patients included in the study (83.8%) were admitted to non-intensive care units, and the most common indications for UFH were venous thromboembolic, atrial fibrillation and acute coronary syndrome. A moderate correlation between aPTT and anti-Xa with a concordant rate of 45.71% was demonstrated.2 Half of the patients (51.43%) had therapeutic aPTT and subtherapeutic anti-Xa, while only one patient had a therapeutic aPTT and a supratherapeutic anti-Xa. However, no thromboembolic events were reported in the study and there was only one episode of major bleeding. One patient had a retroperitoneal bleed, which occurred while the aPTT was supratherapeutic (125.7 seconds) and the anti-Xa was therapeutic (0.55 U/mL). However, there were 13 other patients with anti-Xa ≥0.55 U/mL who did not have any bleeding events. Based on these findings, the authors concluded that there is uncertainty about the therapeutic level of these assays, given the number of variables and patient-specific factors that can affect them.
Therapeutic monitoring of UFH in critically ill patients:
Owing to complexities of their clinical status, monitoring of therapeutic anticoagulation can be challenging in the setting of critical illness.10 These patients can have a high risk of thrombosis due to several factors including indwelling central venous catheters, prolonged immobilization and acquired coagulation disorders. 10, 11At the same time, they may also be at a higher risk of bleeding due to drug-drug interactions, recent surgery or invasive procedures, and liver or kidney failure. In addition, critically ill patients might have a large burden of inflammatory response that could prolong aPTT that further misrepresents the clinical picture.2 Therefore, the accuracy of aPTT in monitoring UFH in critically ill patients is controversial.
Data investigating the correlation between aPTT and anti-Xa in critically ill patients, particularly neurocritical care population are limited. The table below summarize two studies that demonstrated the accuracy of aPTT monitoring of UFH in critically ill and neurocritical care patients.10, 12 (table 1).
Roessel et al evaluated the accuracy of aPTT in UFH therapeutic monitoring in critically ill patients by comparing aPTT therapeutic range (45-60 second) to anti-Xa goal of (0.3-0.7 IU/ml) as it was considered the gold standard in the study. 10 It was concluded that the sensitivity of aPTT to detect UFH underdosing and overdosing is low (0.63 and 0.37, respectively), because of that aPTT is not accurate enough to monitor UFH in critically ill patients.10 Most bleeding events were hematomas and one patient experienced gastrointestinal bleeding.
The other study by Samuel et al compared the performance of an aPTT protocol versus an anti-Xa protocol in adult patients as defined by the time to reach therapeutic range, the percentage of time the values were within the goal range and the number of times laboratory monitoring was conducted. Also, they analyzed the discordance between aPTT and anti-Xa. In this study
neurocritical care patients with various conditions that required continuous UFH were included. 12 This study concluded that using anti-Xa protocol resulted in more favorable results compared to using aPTT protocol. There was no significant difference in the bleeding events between the two methods and only 2 patients had major bleeding where 1 required blood transfusion and the other required discontinuation of the study protocol. There was discordance between anti-Xa and aPTT values 57% of the time, where the most common discordant pattern was a disproportionate prolongation of aPTT to anti-Xa values.
Anti-Xa monitoring in neurocritical care
Patients in neurocritical care unit are challenging, because they often have high risk of thrombosis and bleeding at the same time, which complicates the therapeutic monitoring of UFH.
In addition, there are clinical situations where aPTT might be over- or underestimating the therapeutic level of UFH.5 Some patients in neurocritical care units might have an elevated aPTT at baseline without an obvious reason. Therefore, patients’ specific factors and comorbidities can significantly affect UFH monitoring with aPTT and using anti-Xa at these situations alone or in addition to aPTT might be warranted.
Unfortunately, there is not enough data available to endorse which assay or therapeutic goal range for aPTT or anti-Xa for heparin use in neurocritical care patients. Caution should be advised while using UFH in neurocritical care patients until further prospective studies are available that aid in determining the optimum and safest therapeutic ranges and monitoring methods.
Table 1: Comparing aPTT versus anti-Xa in UFH therapeutic monitoring in critically ill patients
Take home points
Roessel et al,
Retrospective observational study
To analyze the accuracy of the aPTT for the monitoring of UFH dosing in critically ill patients
N= 58 Critical ill patients admitted to the intensive and medium care unit and received UFH continuous infusion
Therapeutic reference range for aPTT (45-60 seconds), and anti-Xa (0.3-0.7 IU/ml), where anti -Xa is the gold standard reference
Detecting UFH underdosing:
- Sensitivity 63% and specificity 82% for aPTT
Detecting UFH overdosing:
- Sensitivity 37% and specificity 94% for aPTT
Detecting thrombotic events:
- Sensitivity 40% and specificity 81% for aPTT
- Sensitivity 60% and specificity 68% for anti-Xa
Detecting bleeding events:
- Sensitivity 33% and specificity 96% for aPTT
- Sensitivity 22% and specificity 96 % for anti-Xa
The sensitivity to detect UFH underdosing and overdosing
was low (0.63 and 0.37, respectively), therefore in critically ill patients, the aPTT is not accurate enough to
detect UFH underdosing and overdosing.
Samuel et al, Prospective observational study
To compare the performance of aPTT protocol versus anti-Xa protocol in adult patients as defined by the time to reach therapeutic range, the percentage of time the values were within
the goal range and the number of times laboratory monitoring
N= 85 patients with acute ischemic stroke, subarachnoid, intracranial, intraparenchymal and intraventricular hemorrhage, brain neoplasm, traumatic brain injury, spine surgery and traumatic spinal cord injury, where they were treated in neurosurgical intensive unit, intermediate care unit and all the floors received UFH continuous infusion
Therapeutic reference range for aPTT (60-80 seconds), and for anti-Xa (0.3-0.7 IU/ml); in this study they compared the 2 methods
Number of times checked in aPTT and anti-Xa (p=0.23)
- aPTT= 14 times
- anti-Xa= 7 times
Hours to reach therapeutic range in aPTT and anti-Xa (p=0.08)
- aPTT= 22 hours
- anti-Xa= 15 hours
Therapeutic range maintained above 50% (p<0.01)
- anti-Xa= 57%
Subtherapeutic range maintained above 50% (p<0.01)
- aPTT= 69%
- anti-Xa= 30%
Supratherapeutic range maintained above 50% (p<0.01)
- aPTT= 78%
- anti-Xa= 38%
Utilizing anti-Xa protocol to
monitor UFH showed favorable results compared with utilizing aPTT protocol by maintaining values within the therapeutic goal range.
Patients with discordant
values presenting with high aPTT to normal anti-Xa values may have an increased risk of bleeding complications.
- Tahir R. A review of unfractionated heparin and its monitoring. US pharmacist. 2007;32(7):26-36. http://www.uspharmacist.com/ index.asp? show1⁄4article&page1⁄48_2073.htm. Access April 11, 2020.
- Mclaughlin K, Rimsans J, Sylvester KW, et al. Evaluation of Antifactor-Xa Heparin Assay and Activated Partial Thromboplastin Time Values in Patients on Therapeutic Continuous Infusion Unfractionated Heparin Therapy. Clin Appl Thromb Hemost. 2019;25:1076029619876030
- Fresenius-Kabi. (2017). Heparin Sodium: HIGHLIGHTS OF PRESCRIBING INFORMATION. Lake Zurich, IL. Author.
- Bussey HI. Problems with monitoring heparin anticoagulation. 1999;19(1):2-5.
- Francis JL, Groce JB. Challenges in variation and responsiveness of unfractionated heparin. 2004;24(8 Pt 2):108S-119S.
- Cossette B, Pelletier ME, Carrier N, et al. Evaluation of bleeding risk in patients exposed to therapeutic unfractionated or low-molecular-weight heparin: a cohort study in the context of a quality improvement initiative. Ann Pharmacother. 2010;44(6):994‐1002. doi:10.1345/aph.1M615
- Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med .1972;287:324-7.
- Guervil DJ, Rosenberg AF, Winterstein AG, Harris NS, Johns TE, Zumberg MS. Activated partial thromboplastin time versus antifactor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion. Ann Pharmacother. 2011;45(7-8):861-8.
- Whitman-purves E, Coons JC, Miller T, et al. Performance of Anti-Factor Xa Versus Activated Partial Thromboplastin Time for Heparin Monitoring Using Multiple Nomograms. Clin Appl Thromb Hemost. 2018;24(2):310-316.
- Van roessel S, Middeldorp S, Cheung YW, Zwinderman AH, De pont AC. Accuracy of aPTT monitoring in critically ill patients treated with unfractionated heparin. Neth J Med. 2014;72(6):305-10.
- Hirsch DR, Ingenito EP, Goldhaber SZ. Prevalence of deep venous thrombosis among patients in medical intensive care. JAMA. 1995;274:335-7.
- Samuel S, Allison TA, Sharaf S, et al. Antifactor Xa levels vs. activated partial thromboplastin time for monitoring unfractionated heparin. A pilot study. J Clin Pharm Ther. 2016;41(5):499-502.