EDUCATIONAL COMMENTARY: UNFRACTIONATED HEPARIN … · 2019-03-21 · Unfractionated heparin(UFH) is...

$: EDUCATIONAL COMMENTARY: UNFRACTIONATED HEPARIN … · 2019-03-21 · Unfractionated heparin(UFH) is an antithrombotic medication that is still widely used to prevent and treat venous$
Commentary provided by: Wayne L. Chandler, MD

Department of Laboratories Seattle Children’s Hospital

Seattle, WA

EDUCATIONAL COMMENTARY: UNFRACTIONATED HEPARIN MONITORING: LIMITATIONS AND INTERFERENCE Educational commentary is provided through our affiliation with the American Society for Clinical

Pathology (ASCP). To obtain FREE CME/CMLE credits, click on Earn CE Credits under Continuing

Education on the left side of our web page.

Learning Objectives

On completion of this exercise, the participant should be able to

• describe the optimum sample collection and preparation for heparin monitoring;

• describe the 3 main assay types used for monitoring heparin; and

• explain the causes of discordant partial thromboplastin time results during heparin monitoring.

Introduction

Unfractionated heparin (UFH) is an antithrombotic medication that is still widely used to prevent and treat

venous and arterial thrombosis, particularly in the acute inpatient setting, owing to its rapid onset of

action, rapid clearance, and ability to be neutralized with protamine.1 It has largely been replaced by low-

molecular-weight heparin and direct oral anticoagulants for outpatient treatment of venous thrombosis.

Dosages of heparin for different indications vary widely: 3.0 to 5.0 U/mL during cardiopulmonary bypass,

0.3 to 0.7 U/mL for treatment of thrombosis, and 0.2 to 0.4 U/mL for prevention of thrombosis in

extracorporeal life support (ECLS) circuits.

The relationship between heparin dosage and heparin activity in blood is not simple. Heparin activity has

been reported to be affected by age, sex, ethnicity, pregnancy, circadian rhythms, variations in the

heparin clearance rate as a function of dosage, and binding of heparin to antithrombin and other cellular

and plasma proteins, all leading to substantial differences in the heparin dosage required to achieve the

same heparin activity.1,2 Monitoring heparin is not simple. Heparin is not a direct anticoagulant. It works

by binding to antithrombin and accelerating antithrombin’s inhibition of activated coagulation factors

including thrombin, factor Xa, and factor IXa. When antithrombin levels are low, heparin is less active.

What is really being monitored is the concentration of heparin-antithrombin complex, which is affected by

levels of both heparin and antithrombin in blood.

There are two critical assumptions when monitoring heparin: first, that the optimal level of the drug is

known for each treatment use; and second, that the assay used to measure the heparin level is accurate

and associated with improved outcome. As discussed below, these assumptions may not be true in all

cases. Current UFH monitoring is based on functional assays designed to measure heparin activity. A

EDUCATIONAL COMMENTARY: UNFRACTIONATED HEPARIN MONITORING: LIMITATIONS AND INTERFERENCE (cont.)

American Proficiency Institute – 2019 3rd Test Event 2

variety of heparin monitoring assays are available that use different methodologies (e.g. whole blood

versus plasma, clot-based versus chromogenic, anti-IIa versus anti-Xa) with varying degrees of precision,

accuracy, and standardization. No current UFH monitoring assay has a range that can accurately and

precisely measure heparin activity from 0.1 to 10.0 U/mL, levels that can be seen across the clinical

spectrum in situations from ECLS to cardiopulmonary bypass. Major assays used to monitor UFH and the

limitations and interferences for each type of assay are discussed below.

Preanalytical Issues Related to Heparin Monitoring

Preanalytical errors are one of the most common sources of heparin monitoring problems.1 The optimum

sample for heparin monitoring is peripheral blood drawn away from the site of heparin infusion and into a

properly filled citrate tube. The tube is then centrifuged to prepare platelet-free plasma, with the plasma

removed from the cells within 1 hour after centrifugation.3 Although a peripheral sample is optimal, in

some patients only samples from catheters are readily available. When the sample is drawn through a

catheter, there is always the possibility of dilution and contamination with the fluid in the catheter, with the

worst-case scenario being that the same catheter is used to infuse heparin and to draw the sample. No

single recommendation for catheter flushing is possible because the volume of blood needed to flush the

catheter completely varies, depending on the catheter material, length, diameter, and fluid in the catheter.

Catheter-drawn samples carry the risk of falsely low and falsely high heparin levels.

Citrate tubes, when properly filled, contain 1 part citrate and 9 parts whole blood. Underfilling citrate tubes

can result in blood being diluted by the citrate and an inappropriate citrate level in the plasma sample,

leading to falsely low heparin activity results, when using anti-Xa, assays and falsely prolonged clotting

times when clot-based tests are used. If the sample is inadequately centrifuged or the plasma is left in

contact with the cells for too long before removal, platelets can release proteins that neutralize part of the

heparin in the sample, resulting in falsely low heparin activity results.

Anti-Xa Heparin Activity Assay

In anti-Xa heparin activity assays, plasma containing heparin is added to purified factor Xa. Heparin-

antithrombin complex in the plasma binds to and inhibits factor Xa. The amount of residual factor Xa

measured using a factor Xa–sensitive chromogenic substrate is inversely proportional to the heparin

activity. Anti-Xa assays are sensitive to both the heparin and antithrombin levels in plasma (Figure 1). In

the United States, more than 95% of laboratories use anti-Xa assays that do not include supplemental

antithrombin. Anti-Xa assays that supplement with antithrombin can increase antithrombin and heparin-

antithrombin complex levels in samples from patients with low in vivo antithrombin concentrations,

resulting in an overestimation of heparin activity in the patient.4,5



Figure 1. Anti-Xa heparin activity versus unfractionated heparin and antithrombin levels.6

A) Anti-Xa versus unfractionated heparin level. B) Anti-Xa versus antithrombin level.

Anti-Xa assays are not affected by changes in coagulation factor levels, contact system levels, or lupus

inhibitors. They are more specific for heparin activity than clot-based assays such as the partial

thromboplastin time (PTT) or activated clotting time (ACT), both measured in seconds.6 Compared with

the PTT, when heparin is monitored with anti-Xa assays, it takes less time to reach therapeutic levels, the

time in the therapeutic range is greater, there are fewer heparin dosage changes, and fewer transfusions

are needed.7-10 Most therapeutic range recommendations are based on anti-Xa measurements.11 Anti-Xa

heparin activity assays have become the standard of care for UFH monitoring and should be available on

demand.

Limitations of anti-Xa assays include high levels of hemolysis or icterus, which can interfere with the

chromogenic measurement of residual factor Xa activity, resulting in falsely low heparin activity results.12-

14 If other anti-Xa inhibitors, such as low-molecular-weight heparin or direct oral anticoagulants, are

present in plasma, they can interfere with the anti-Xa assay, producing falsely high heparin activity

values.15 For samples that are above the linear range of the anti-Xa assay or where hemolysis/icterus is a

problem, sample dilution has been suggested as a possible solution. However, dilution can result in



heparin activity results above or below the level in the patient due to differences in antithrombin and other

heparin-binding protein levels in the diluent versus patient plasma.

Partial Thromboplastin Time

In the PTT, partial thromboplastin (anionic phospholipids) and a contact system activator are added to

plasma and incubated at 37°C to allow maximum activation of factor XII. These steps are followed by the

addition of calcium and measurement of the clotting time. The PTT was originally developed for

measuring factors VIII, IX, and XI.16 The PTT is sensitive to coagulation factor levels and inhibitors,

contact system levels, multiple anticoagulants, and lupus inhibitors.6,17-19 The PTT assay works best when

only one cause of prolongation is present (e.g. in heparin monitoring with normal coagulation factor levels

and no lupus inhibitor). When only a single factor is changing, the PTT shows a predictable response, but

when multiple causes of PTT prolongation are present at the same time, interpretation becomes complex

(e.g. trying to monitor heparin with a lupus inhibitor present).6

The PTT therapeutic range of 1.5 to 2.5 times normal was originally described for heparin monitoring in

relatively uncomplicated patients with deep venous thrombosis.2 This range is not consistent as it varies

with different instruments and reagents.2,20-22 The best approach for determining the UFH PTT

therapeutic range is to correlate the PTT versus anti-Xa heparin activities between 0.3 and 0.7 U/mL

(Figure 2).11 Using this type of correlation, the PTT ratio is typically 2.5 to 3.5 times the mean normal PTT

rather than 1.5 to 2.5 as originally described.21 The optimal method is to collect samples from 20 to 30

patients receiving heparin, with less than 10% of samples from the same patient and less than 50% of

samples with a prolonged prothrombin time (PT).23 Spiking plasma with heparin is not an acceptable

method for determining the UFH PTT therapeutic range and it can result in more patients receiving

inadequate heparin.24

In hospitalized patients receiving heparin, the most common cause of discordance between the PTT and

anti-Xa activity is a prolonged baseline PTT, often owing to coagulation factor or contact system

deficiencies or lupus inhibitors.17,25,26 In hospitalized patients, 33% to 43% had a prolonged PT, indicating

factor deficiency, and 13% to 25% of samples showed a prolonged PTT with normal PT, most often owing

to lupus inhibitors.17,27,28 In one study, transient lupus inhibitors were seen in 53% of intensive care unit

patients during admission. Most resolved spontaneously by the time of discharge and they were not

associated with thrombosis or bleeding.29 In contrast to the common transient lupus inhibitors present in

many hospitalized patients, antiphospholipid antibody syndrome is relatively rare and is characterized by

the development of persistent, sometimes high–titer, lupus inhibitors that are associated with platelet

activation and thrombosis (Table).30-32



Table. Prolonged PTT due to Lupus Inhibitors.

Duration Incidence Titer Thrombosis Bleeding

Persistent Uncommon Often high Common Rare

Transient 10%-25% of hospitalized patients

Often low Rare Rare

A shortened baseline PTT, often resulting from an acute-phase increase in factor VIII activity, is

associated with discordant low PTT values, resulting in an apparent subtherapeutic PTT despite high

doses of heparin given to the patient.33,34 The heparin responsiveness of different PTT reagents varies

and the PTT is sensitive to multiple different factors in addition to UFH. Therefore, it is not surprising that

PTT monitoring of UFH therapy has a limited ability to predict outcome in patients with thrombosis.2

Using the PTT to balance the risk of bleeding versus the risk of thrombosis is problematic.2,26,35 Without

further testing, it is difficult to separate baseline prolongation of the PTT resulting from factor deficiency

from prolongation caused by lupus inhibitor. In hospitalized patients, both may be present. When the

baseline PTT is prolonged, the usual therapeutic range for the PTT may provide insufficient

anticoagulation (low anti-Xa levels), particularly when there is a prothrombotic stimulus present, such as

extracorporeal circulation or a circulatory assist device.25,35

One approach to mitigating the discordance between the PTT and anti-Xa is correcting the heparinized

PTT for baseline PTT variations. The baseline PTT is determined after heparin is neutralized with

polybrene, protamine, or heparinase.17,36 Baseline PTTs can vary during hospitalization; therefore, a

single baseline PTT is inadequate. Separate baseline PTT measurements are required for each heparin

monitoring sample. To adjust the heparinized PTT for baseline PTT variation, a baseline-corrected PTT

was developed (Figure 2).17 This correction reduced the number of discordant samples by 64% and

improved the correlation between PTT and anti-Xa activity. This correction is effective for samples with

long or short baseline PTT values. Further work is needed to assess whether baseline-corrected PTTs

show improved clinical effectiveness.

Hemolysis, icterus, and lipemia have variable effects on the PTT that are instrument and reagent

dependent. In two studies, hemolysis resulted in shorter PTTs, potentially resulting in falsely low

estimates of heparin effect.12,37 In some older optical instruments, hemolysis, icterus, and lipemia could

interfere with clotting time detection. Mechanical clot detection and optical instruments that use

wavelengths that are less affected by hemolysis or icterus show less interference.



Figure 2. Partial thromboplastin time (PTT) heparin therapeutic range and baseline-corrected PTT.6,17

A) Example of PTT response to unfractionated heparin spiked into pooled normal plasma. B) Heparin therapeutic range, correlation of PTT versus anti-Xa heparin activity from pediatric patients with normal prothrombin time and PTT (30 samples from 26 patients, r2 = 0.61). Solid lines represent the upper and lower limits of the 99% prediction interval. Results outside of these limits are considered discordant. C) PTT versus anti-Xa heparin activity in 182 pediatric patients. D) Baseline-corrected PTT versus anti-Xa heparin activity.

Activated Clotting Time

The ACT is a point-of-care whole-blood clotting time that uses a contact system activator, typically celite

or kaolin, which activates factor XII which, in turn, activates the coagulation system. The ACT has been

used during open heart surgery to monitor UFH levels during cardiopulmonary bypass.38 The levels of

heparin used during cardiopulmonary bypass are approximately ten times higher (3.0 to 5.0 U/mL) than

the typical levels used for standard heparin therapy (0.3 to 0.7 U/mL), resulting in ACT values greater

than 400 s after bypass heparinization. Activated clotting time has primarily been used as a threshold

method to maintain adequate levels of heparin during bypass, not as a true measure of heparin activity.



During bypass, ACT is poorly correlated with heparin activity (r2, 0.00-0.28).38-40 A modified ACT

protamine titration method developed for estimating heparin activity shows concordance of 0.3 to 0.67

U/mL with anti-Xa assays.39 Although little data is available, use of ACT-based protamine titration assays

would at least allow measurement of heparin activity, paving the way for studies of optimal heparin levels

during bypass.

The ACT has also been used to monitor lower levels of heparin during angioplasty and ECLS.41 Recent

studies have indicated that the ACT correlates poorly with anti-Xa heparin activity and heparin dosage

during ECLS, and that ACT was not predictive of bleeding, need for circuit change, or survival.42-50 Under

optimal conditions, the ACT is insensitive to UFH levels below 0.5 U/mL (Figure 3).6,51 The ACT is

sensitive to changes in platelet count (the source of procoagulant phospholipid in the assay), coagulation

factor levels, contact system levels, and lupus inhibitors. The ACT is highly variable, showing imprecision

that is greater than the therapeutic range.6,38,52,53 Activated clotting times also show high variability

between methods and are not interchangeable.38-40 Owing to inherent variability, low sensitivity to heparin

activity, and sensitivity to multiple other factors, at lower heparin doses there is little or no correlation

between the ACT value and heparin activity (Figure 3).6,38-40,42-48 Although useful for documenting

adequate heparinization during high-dose UFH therapy associated with cardiopulmonary bypass, ACT is

less useful for monitoring lower-dose heparin. There is little data to indicate the effect of hemolysis,

icterus, or lipemia on the ACT. Because it is a whole-blood point-of-care test, these potential

interferences are seldom, if ever, checked in the sample.

Viscoelastic testing has occasionally been used for heparin monitoring. It is essentially a whole-blood,

contact-activated clotting time, similar to the ACT, and has all the ACTs limitations. In one study, there

was no correlation between clotting times measured using viscoelastic testing and either bleeding or

thrombosis, whereas both were predicted by anti-Xa levels.48

Summary

Heparin activity primarily measures heparin-antithrombin complex levels, which are affected by age, sex,

ethnicity, pregnancy, circadian rhythms, heparin clearance, and heparin-protein binding, making the

relationship between heparin dosage and heparin level complex. To reduce preanalytical errors, blood

should be drawn peripherally, away from heparin infusion sites, and the plasma removed from cells within

1 hour. Anti-Xa assays are the most specific because they are unaffected by coagulation or contact factor



Figure 3. Activated clotting time (ACT) monitoring of low dose unfractionated heparin (UFH).6

A) ACT versus UFH spiked into normal whole blood. B) Daily quality control results for ACT, horizontal lines indicated the heparin therapeutic range for the ACT. C) ACT versus anti-Xa heparin activity in pediatric extracorporeal life support patients.

levels or lupus inhibitors but they are limited by interference from hemolysis and icterus. The PTT is

nonspecific for heparin and it is sensitive to coagulation and contact factor levels, multiple anticoagulants,

and lupus inhibitors. Unfractionated heparin PTT therapeutic ranges are best determined by correlating

the PTT versus anti-Xa heparin activity in patient samples. The ACT is used to maintain adequate high-

dose heparin levels during cardiopulmonary bypass but is poorly correlated with heparin activity. Because



of its inherent variability, low sensitivity to heparin activity, and sensitivity to multiple other factors, the

ACT shows little or no correlation with heparin levels at lower heparin dosages.

References 1. Baluwala I, Favaloro EJ, Pasalic L. Therapeutic monitoring of unfractionated heparin: trials and

tribulations. Expert Rev Hematol. 2017;10(7):595-605. 2. Eikelboom JW, Hirsh J. Monitoring unfractionated heparin with the aPTT: time for a fresh look.

Thromb Haemost. 2006;96(5):547-552. 3. Johnston M. Monitoring heparin therapy. In: Kitchen S, Olson JD, Preston FE, eds. Quality in

Laboratory Hemostasis and Thrombosis. 2nd ed. Oxford, UK: Wiley-Blackwell; 2013:244-252. 4. Hanslik A, Kitzmuller E, Tran US, et al. Monitoring unfractionated heparin in children: a parallel-

cohort randomized controlled trial comparing 2 dose protocols. Blood. 2015;126(18):2091-2097. 5. Ignjatovic V, Summerhayes R, Gan A, et al. Monitoring unfractionated heparin (UFH) therapy:

which anti-factor Xa assay is appropriate? Thromb Res. 2007;120(3):347-351. 6. Saifee NH, Brogan TV, McMullan DM, et al. Monitoring hemostasis during extracorporeal life

support [published online March 21, 2019]. ASAIO J. doi:10.1097/MAT.0000000000000993 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):861-868.

8. Trucco M, Lehmann CU, Mollenkopf N, Streiff MB, Takemoto CM. Retrospective cohort study

comparing activated partial thromboplastin time versus anti-factor Xa activity nomograms for therapeutic unfractionated heparin monitoring in pediatrics. J Thromb Haemost. 2015;13(5):788-794.

9. Vandiver JW, Vondracek TG. A comparative trial of anti-factor Xa levels versus the activated

partial thromboplastin time for heparin monitoring. Hosp Pract (1995). 2013;41(2):16-24. 10. Belk KW, Laposata M, Craver C. A comparison of red blood cell transfusion utilization between

anti-activated factor X and activated partial thromboplastin monitoring in patients receiving unfractionated heparin. J Thromb Haemost. 2016;14(11):2148-2157.

11. Monagle P, Chan AKC, Goldenberg NA, et al. Antithrombotic therapy in neonates and children:

Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e737S-e801S.

12. Kostousov V, Nguyen K, Hundalani SG, Teruya J. The influence of free hemoglobin and bilirubin

on heparin monitoring by activated partial thromboplastin time and anti-Xa assay. Arch Pathol Lab Med. 2014;138(11):1503-1506.



13. Khan J, Chandler WL. Interference in the anti-Xa heparin activity assay due to hemolysis and icterus during pediatric extracorporeal life support. Artif Organs. 2019;43(9):880-887.

14. Vera-Aguilera J, Yousef H, Beltran-Melgarejo D, et al. Clinical scenarios for discordant anti-Xa.

Adv Hematol. 2016;2016:4054806. 15. Faust AC, Kanyer D, Wittkowsky AK. Managing transitions from oral factor Xa inhibitors to

unfractionated heparin infusions. Am J Health Syst Pharm. 2016;73(24):2037-2041. 16. Owens CA. A History of Blood Coagulation. Rochester, MN: Mayo Foundation; 2001. 17. Khan J, Chandler WL. Discordant partial thromboplastin time (PTT) vs anti-Xa heparin activity.

Am J Clin Pathol. 2019;151(4):424-432. 18. Chen J, Phillips B, Chandler WL. Evaluation of prothrombin time and activated partial

thromboplastin time mixing studies using an estimated factor correction method. Blood Coagul Fibrinolysis. 2016;27(1):90-96.

19. Moore GW. Commonalities and contrasts in recent guidelines for lupus anticoagulant detection.

Int J Lab Hematol. 2014;36(3):364-373. 20. Rozen L, Copette F, Noubouossie DF, Demulder A. Evaluation of three APTT reagents in a

routine laboratory: toward a compromise. Clin Lab. 2013;59(7-8):921-924. 21. Bates SM, Weitz JI, Johnston M, Hirsh J, Ginsberg JS. Use of a fixed activated partial

thromboplastin time ratio to establish a therapeutic range for unfractionated heparin. Arch Intern Med. 2001;161(3):385-391.

22. Greaves M. Evaluation of antiphospholipid antibodies. In: Kitchen S, Olson JD, Preston FE, eds.

Quality in Laboratory Hemostasis and Thrombosis. Chichester, UK: Wiley-Blackwell; 2013. 23. Marlar RA, Gausman J. The optimum number and types of plasma samples necessary for an

accurate activated partial thromboplastin time-based heparin therapeutic range. Arch Pathol Lab Med. 2013;137(1):77-82.

24. Gausman JN, Marlar RA. Inaccuracy of a “spiked curve” for monitoring unfractionated heparin

therapy. Am J Clin Pathol. 2011;135(6):870-876. 25. Warkentin TE. Anticoagulant failure in coagulopathic patients: PTT confounding and other pitfalls.

Expert Opin Drug Saf. 2014;13(1):25-43. 26. Price EA, Jin J, Nguyen HM, Krishnan G, Bowen R, Zehnder JL. Discordant aPTT and anti-Xa

values and outcomes in hospitalized patients treated with intravenous unfractionated heparin. Ann Pharmacother. 2013;47(2):151-158.



27. Amukele TK, Baird GS, Chandler WL. Reducing the use of coagulation test panels. Blood Coagul Fibrinolysis. 2011;22(8):688-695.

28. Malbora B, Bilaloglu E. Lupus anticoagulant positivity in pediatric patients with prolonged

activated partial thromboplastin time: a single-center experience and review of literature. Pediatr Hematol Oncol. 2015;32(7):495-504.

29. Wenzel C, Stoiser B, Locker GJ, et al. Frequent development of lupus anticoagulants in critically

ill patients treated under intensive care conditions. Crit Care Med. 2002;30(4):763-770. 30. Devreese K, Peerlinck K, Hoylaerts MF. Thrombotic risk assessment in the antiphospholipid

syndrome requires more than the quantification of lupus anticoagulants. Blood. 2010;115(4):870-878.

31. Swadzba J, Iwaniec T, Pulka M, De Laat B, De Groot PG, Musial J. Lupus anticoagulant:

performance of the tests as recommended by the latest ISTH guidelines. J Thromb Haemost. 2011;9(9):1776-1783.

32. Gebhart J, Posch F, Koder S, et al. High risk of adverse pregnancy outcomes in women with a

persistent lupus anticoagulant. Blood Adv. 2019;3(5):769-776. 33. Levine MN, Hirsh J, Gent M, et al. A randomized trial comparing activated thromboplastin time

with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Arch Intern Med. 1994;154(1):49-56.

34. Takemoto CM, Streiff MB, Shermock KM, et al. Activated partial thromboplastin time and anti-xa

measurements in heparin monitoring: biochemical basis for discordance. Am J Clin Pathol. 2013;139(4):450-456.

35. Adatya S, Sunny R, Fitzpatrick MJ, et al. Coagulation factor abnormalities related to discordance

between anti-factor Xa and activated partial thromboplastin time in patients supported with continuous-flow left ventricular assist devices. J Heart Lung Transplant. 2016;35(11):1311-1320.

36. Tientadakul P, Kongkan C, Chinswangwatanakul W. Use of an automated coagulation analyzer

to perform heparin neutralization with polybrene in blood samples for routine coagulation testing: practical, rapid, and inexpensive. Arch Pathol Lab Med. 2013;137(11):1641-1647.

37. Woolley A, Golmard JL, Kitchen S. Effects of haemolysis, icterus and lipaemia on coagulation

tests as performed on Stago STA-Compact-Max analyser. Int J Lab Hematol. 2016;38(4):375-388.

38. Martindale SJ, Shayevitz JR, D’Errico C. The activated coagulation time: suitability for monitoring

heparin effect and neutralization during pediatric cardiac surgery. J Cardiothorac Vasc Anesth. 1996;10(4):458-463.



39. Guzzetta NA, Monitz HG, Fernandez JD, Fazlollah TM, Knezevic A, Miller BE. Correlations between activated clotting time values and heparin concentration measurements in young infants undergoing cardiopulmonary bypass. Anesth Analg. 2010;111(1):173-179.

40. Ichikawa J, Mori T, Kodaka M, Nishiyama K, Ozaki M, Komori M. Changes in heparin dose

response slope during cardiac surgery: possible result in inaccuracy in predicting heparin bolus dose requirement to achieve target ACT. Perfusion. 2017;32(6):474-480.

41. Bembea MM, Annich G, Rycus P, Oldenburg G, Berkowitz I, Pronovost P. Variability in

anticoagulation management of patients on extracorporeal membrane oxygenation: an international survey. Pediatr Crit Care Med. 2013;14(2):e77-e84.

42. Khaja WA, Bilen O, Lukner RB, Edwards R, Teruya J. Evaluation of heparin assay for coagulation

management in newborns undergoing ECMO. Am J Clin Pathol. 2010;134(6):950-954. 43. Nankervis CA, Preston TJ, Dysart KC, et al. Assessing heparin dosing in neonates on

venoarterial extracorporeal membrane oxygenation. ASAIO J. 2007;53(1):111-114. 44. Bembea MM, Schwartz JM, Shah N, et al. Anticoagulation monitoring during pediatric

extracorporeal membrane oxygenation. ASAIO J. 2013;59(1):63-68. 45. Panigada M, Artoni A, Passamonti SM, et al. Hemostasis changes during veno-venous

extracorporeal membrane oxygenation for respiratory support in adults. Minerva Anestesiol. 2016;82(2):170-179.

46. Sulkowski JP, Preston TJ, Cooper JN, et al. Comparison of routine laboratory measures of

heparin anticoagulation for neonates on extracorporeal membrane oxygenation. J Extra Corpor Technol. 2014;46(1):69-76.

47. Koerber JM, Smythe MA, Begle RL, Mattson JC, Kershaw BP, Westley SJ. Correlation of

activated clotting time and activated partial thromboplastin time to plasma heparin concentration. Pharmacotherapy. 1999;19(8):922-931.

48. Moynihan K, Johnson K, Straney L, et al. Coagulation monitoring correlation with heparin dose in

pediatric extracorporeal life support. Perfusion. 2017;32(8):675-685. 49. Baird CW, Zurakowski D, Robinson B, et al. Anticoagulation and pediatric extracorporeal

membrane oxygenation: impact of activated clotting time and heparin dose on survival. Ann Thorac Surg. 2007;83(3):912-919; discussion 919-920.

50. Irby K, Swearingen C, Byrnes J, Bryant J, Prodhan P, Fiser R. Unfractionated heparin activity

measured by anti-factor Xa levels is associated with the need for extracorporeal membrane oxygenation circuit/membrane oxygenator change: a retrospective pediatric study. Pediatr Crit Care Med. 2014;15(4):e175-182.



51. Maslow A, Chambers A, Cheves T, Sweeney J. Assessment of heparin anticoagulation measured using i-STAT and hemochron activated clotting time. J Cardiothorac Vasc Anesth. 2018;32(4):1603-1608.

52. Ojito JW, Hannan RL, Burgos MM, et al. Comparison of point-of-care activated clotting time

systems utilized in a single pediatric institution. J Extra Corpor Technol. 2012;44(1):15-20. 53. Doherty TM, Shavelle RM, French WJ. Reproducibility and variability of activated clotting time

measurements in the cardiac catheterization laboratory. Catheter Cardiovasc Interv. 2005;65(3):330-337.

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