Monitoring Unfractionated Heparin In Adult Patients Undergoing Extracorporeal Membrane Oxygenation (ECMO): ACT, APTT or Anti-Xa?

doi:10.21203/rs.3.rs-150951/v1

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Monitoring Unfractionated Heparin In Adult Patients Undergoing Extracorporeal Membrane Oxygenation (ECMO): ACT, APTT or Anti-Xa?

https://doi.org/10.21203/rs.3.rs-150951/v1

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posted 21 Jan, 2021

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Background: During ECMO, anticoagulant, particularly unfractionated heparin (UFH) is commonly used and monitored by laboratory tests, including ACT, APTT, and anti-Xa level.

Method: A single-center retrospective observational study was conducted on adult patients undergoing ECMO between January 2019 and January 2020 at a tertiary hospital. The correlations between ACT, APTT, anti-Xa, antithrombin, and UFH dose were assessed.

Results: 129 sets of measurements from 37 patients were obtained including ACT, APTT, anti-Xa, antithrombin, and UFH dose measured simultaneously. 102 out of 129 sets of values were interpreted as antithrombin deficiencies. The correlation coefficient between APTT and anti-Xa; ACT and anti-Xa are 0.72 and 0.33, respectively, p <0.001. The patients with normal antithrombin levels exhibited a significant correlation between APTT and anti-Xa (r = 0.80, p <0.001). ACT, on the other hand, was poorly correlated with UFH dose. Anti-Xa and APTT are only moderately correlated with UFH dose in the group without antithrombin deficiency, with correlation coefficients of 0.62 and 0.57 respectively, p <0.05.

Conclusion: APTT value is strongly correlated with anti-Xa value, particularly in patients with normal antithrombin levels. However, the ACT value was poorly correlated with anti-Xa and not with UFH dose. In groups without antithrombin deficiency, APTT and anti-Xa values only moderately correlated with UFH dose.

Critical Care & Emergency Medicine

Extracorporeal membrane oxygenation

Critically ill patients

Anticoagulation

correlation

ACT

APTT

anti-Xa

antithrombin.

Extracorporeal membrane oxygenation (ECMO) has been widely accepted as a treatment for life-threatening cardiac and pulmonary failure.^{1, 2} As with any other artificial system, hemostatic dysfunction during ECMO occurs as a consequence of shear stress and exposure of blood to the non-biologic surfaces of the ECMO circuit.^3–6 Heparin indirectly inhibits thrombin activity by binding to a specific active site of the enzyme inhibitor antithrombin (antithrombin III, AT), causing a conformational change that results in increasing its anticoagulant activity 1000- to 4000-fold.⁷ Heparin resistance in patients undergoing ECMO is often a multifactorial phenomenon in which acquired AT deficiency is partly attributed.⁴ Nevertheless, a proportion of anticoagulantly-active heparin is reversibly bound and neutralized by plasma protein, so-called heparin-binding proteins are acute phase reactants in critically ill patients.^{8, 9}

The efficacy of UFH is monitored by ACT, APTT, and anti-Xa tests. The ACT is a whole-blood-based point-of-care test (POCT) that measures the rate of clot formation. Therefore, an ACT result can be prolonged by multiple factors independent of UFH dose, such as anemia, hypofibrinogenemia, thrombocytopenia, other coagulation factor deficiencies, hypothermia, and hemodilution.^{5, 10} Since its first description in 1953, Activated Partial Thromboplastin Time (APTT) is frequently used to titrate heparin dose outside of the operating room.¹¹ APTT test, using platelet-poor plasma from centrifuged whole blood, is measured by photo-optical method or magnetic steel ball method (each has different strengths and weaknesses). The APTT target range is varied, depending on the method utilized and the reagent used. Also, its value is influenced by comorbidities such as vitamin K deficiency, liver disease or hemodilution, etc..¹² In 1973, Denson and colleagues introduced anti-Xa – which does not measure the heparin concentration in blood but estimates the anticoagulant effect of heparin by measuring the concentration of antithrombin-heparin complex. This complex reflects the exact concentration, as well as the effectiveness of heparin in normal antithrombin patients.^{4, 11, 13} Anti-Xa, is considered as better monitoring compared with the other two tests and can be performed cross-sectional between centers.⁵ However, an anti-Xa value is also affected by technical errors from the photo-optical method, such as hyperbilirubinemia, hemolysis, antithrombin deficiency.^{4, 13}

Until now there is no complete consensus on anticoagulation strategy and its monitoring during ECMO support.^{4, 5} Anti-Xa assay is not clinically feasible since it is not widely available and difficult to perform several times a day. Therefore, we conducted an observational study to assess the correlations between ACT, aPTT, anti-Xa, and administered UFH dose on adult ECMO patients.

Research design

We retrospectively conducted an observational study of adult patients (age ≥ 18 years) who received peripheral ECMO in the Intensive Care Unit (ICU) of Cho Ray Hospital (a tertiary hospital) between January 2019 and January 2020. This study was approved by the Research Ethics Committee, University of Medicine and Pharmacy, Ho Chi Minh City and by the Research Ethics Committee of Cho Ray Hospital.

Patient Selection

Inclusion criteria: All adult patients (age ≥ 18 years) received ECMO in the Intensive Care Unit (ICU) of Cho Ray hospital between January 2019 and January 2020 with laboratory results of ACT, APTT, anti-Xa, antithrombin tests, and simultaneous UFH dosage were recorded.

Exclusion criteria: Patients who underwent ECMO for less than 24 hours, patients with pulmonary embolism who were treated with fibrinolytic therapy before or during ECMO.

Clinical data

Baseline characteristics included patients’ demographics (age, gender), diagnosis at ICU admission, ECMO indication and ECMO types. Major bleeding complications were defined by ELSO Anticoagulation guideline⁵ and hospital mortality was also recorded.

To accurately examine the correlation of UFH monitoring tests, only patients who had ACT, APTT, anti-Xa and antithrombin tests performed simultaneously on the same blood sample were recorded. UFH dosage (units per hour) at the time of obtaining blood sample was also recorded. Any case with missing or incorrectly recorded results was eliminated from the research. Patients undergoing ECMO for more than 14 days had data recorded up to 14 days to be representative of the study population. Antithrombin activity level of less than 80 percent of the reference range in our laboratory was defined as antithrombin deficiency.

ECMO anticoagulation protocol

In our center, the anticoagulation protocol was implemented based on the ELSO guideline. Patients received an initial UFH bolus dose of 50–100 units per kilogram of body weight at the time of cannulation for ECMO, and then the dose was maintained as a continuous infusion during ECMO course. The UFH dose was adjusted based on clinical factors such as the risk of hemorrhage and thrombosis, including current evidence of hemorrhage, coagulation tests and underlying diseases. The UFH infusion was initiated at a dose of 7.5–20 UI/kg per hour. Assessment of the activity of UFH would likely rely on three therapeutic monitoring blood tests: ACT and APTT at every 6 hours and anti-Xa at every 24 hours. Anti-Xa was only available on weekdays. Therapeutic goals were defined as an ACT of 180–220 seconds, an APTT of 45–80 seconds, and an anti-Xa level of 0.3–0.7 UI/mL. Since there is no specific UFH monitoring protocol, the physician will decide to adjust the UFH dose according to the risk of bleeding and the risk of thrombosis at that time. Plasma was infused in the case of severe antithrombin deficiency (antithrombin < 50%) and/or heparin resistance.

Laboratory measurement

ACT assay was conducted by Medtronic Activated Clotting Time Cartridges device, including 2 kits which are LR-ACT (ACT low range) and HR-ACT (ACT high range).

APTT assay was performed on 3 devices: STA-R Evolution (kaolin as activator, magnetic method); ACL TOP 750 (SynthAsil reagent, photo-optical method); SYSMEX 2500 (ACTIN FSL reagent, photo-optical method). In case of hyperbilirubinemia or hemolysis, the magnetic method was preferred.

Anti-Xa was performed on ACL TOP 750 device, photo-optical method, without exogenous antithrombin.

Statistical analysis

Data was expressed as percentages, median (interquartile range, IQR), or mean ± standard deviation (SD). Student’s t-test was used for quantitative variables with normal distribution or Wilcoxon rank-sum test in case of nonnormal distribution in 2 groups: reduction in antithrombin and non-reduction in antithrombin. Pearson/Spearman correlation coefficients and scatter plots were used to examined and presented for visual assessment of the association. A p-value of less than 0.05 was considered statistically significant.

During the study period, 37 patients were enrolled and 129 tests of measurement (including ACT, APTT, anti-Xa, antithrombin and UFH dose) were obtained.

The average age of these patients was 40 (IQR 32–50), and there were no statistically significant differences in gender. The most common indications for ECMO were acute myocarditis (54.0%), ARDS (35.1%), myocardial infarction (8.1%), and severe anaphylaxis (2.7%). There were 23 VA-ECMO (62.1%), 13 VV-ECMO (35.1%), and 1 VAV-ECMO. The median ECMO duration was 7 days (IQR 4–12 days).

The incidence of antithrombin deficiency was 79% (102/129 kits). In comparison with the group without antithrombin deficiency, the antithrombin deficiency group displayed higher ACT results as well as UFH dose, but not anti-Xa value.

The study showed a strong correlation between APTT and anti-Xa value with the correlation coefficient of 0.72. This correlation was stronger when the patients were in the group with antithrombin deficiency, which was shown in Table 1A: the linear regression line of the scatter plot went up following the direction of the short axis of the eclipse. While ACT value had a weak positive correlation with anti-Xa value in both groups with and without antithrombin deficiency, the trend line, illustrated on the 1B plot, went up but still had wide fluctuation, and the 2 axes of the eclipse almost had the same length. For UFH dose at that time, the only anti-Xa value had a moderate positive correlation with UFH dose, while APTT value had a moderate positive correlation with UFH dosing and ACT had no correlation with UFH dosing of patients in both groups with and without antithrombin deficiency. All the correlation is shown in Table 2 as well as demonstrated in plot 2.

Table 1

ACT, APTT, anti-Xa, and UFH dose values
	Total (N = 129)	Group without antithrombin deficiency (n = 27)	Group with antithrombin deficiency (n = 102)	p-value
ACT (second)	184 [175; 196]	178 [168; 189]	185 [175;200]	0.033
APTT (second)	49 [40; 59]	47 [42; 54]	50 [40 ; 60]	0.300
Anti-Xa (IU/ml)	0,28 [0.21; 0.41]	0,28 [0.24; 0.37]	0.28 [0.19; 0.42]	0.812
Heparin dose (IU/h)	800 [600; 1000]	600 [600; 800]	800 [600; 1075]	0.110
Data presented as median [interquartile range]

Table 2

Correlation between ACT, APTT, anti-Xa values, and concurrent heparin dosing.
Correlation coefficient Spearman	All	Normal antithrombin level
APTT vs. anti-Xa	0.72 (p < 0.001)	0.80 (p < 0.001)
ACT vs. anti-Xa	0.33 (p < 0.001)	0.40 (p = 0.038)
APTT vs. UFH dose	0.14 (p < 0.100)	0.62 (p < 0.001)
ACT vs. UFH dose	-0.03 (p < 0.740)	0.16 (p = 0.420)
Anti-Xa vs. UFH dose	0.39 (p < 0.001)	0.57 (p = 0.001)

UFH is monitored by ACT, APTT, and anti-Xa. Of the three tests above, anti-Xa is considered to be more reliable than the other two,⁵ however, anti-Xa is not as commonly ordered or as often (many times a day) due to its high cost and complicating techniques. ACT is considered as the most common test being a fast and inexpensive method despite its limited reliability.^{3, 5} The value of the APTT test in monitoring UFH in ECMO has recently gained more attention. In recent studies, APTT moderately correlated with anti-Xa, UFH dose, and UFH concentration, while ACT poorly correlated with anti-Xa, UFH dosing, and UFH concentration.^{11, 14–17} These researches were mainly done in pediatric ECMO patients. Most of the reagents for the anti-Xa assay require a patient’s endogenous antithrombin instead of adding exogenous antithrombin because the prevalence of antithrombin deficiency in the general population is very low. However, acquired antithrombin deficiency has been associated with patients on ECMO, which results in a lower value of anti-Xa than heparin concentration. Therefore, we investigated the subgroup of patients without antithrombin deficiency, when the anti-Xa value correlates better with heparin concentration in order to reappraise the value of ACT and APTT tests.

In our study, there was a strong positive relationship between the value of APTT and the value of anti-Xa (r = 0.72, p < 0.001), especially in normal antithrombin level group (r = 0.80, p < 0.001). Meanwhile, ACT value correlated poorly with anti-Xa, even in the subgroup of patients with normal antithrombin level. Khaja et al. also found that APTT value correlated closer with anti-Xa than ACT value (r = 0.364 vs 0.125, respectively). However, this study was conducted on infants with a small sample size (21 patients) and no analysis on the role of antithrombin. In another study by Liveris et al., 17 pediatric and neonatal ECMO patients had shown similar results; the correlation of coagulation monitoring assay with UFH dose was poor with ACT assay, moderate with APTT assay, and strong with anti-Xa assay.¹¹ There have been few studies to evaluate the correlation of ACT, APTT, anti-Xa, and heparin dose in adult ECMO patients. One research by Atallah et al. on 46 patients receiving ECMO found a Pearson correlation of APTT and heparin dose from 0.43 to 0.54; meanwhile, the Pearson correlation of ACT was only 0.11–0.14.¹⁴ However, the UFH dose cannot represent efficacy or concentration of UFH in adult patients, especially in critically ill patients and ECMO patients.

The ACT is a whole blood test, therefore it is influenced by all of the properties in the hemostasis system rather than only being effective to UFH. ACT is also prone to technical errors. Within the results of this study, we showed that when taking antithrombin level into consideration, ACT in the group without antithrombin deficiency was statistically higher. Unlike ACT, the APTT value correlated strongly with anti-Xa at the same time. Beside the fact that APTT is a more reliable tool to monitor anticoagulatory activity, APTT assay in our study was also done by both photo-optical and magnetic measurement methods. This helped to minimize the weaknesses of the test in cases of increased bilirubin or hemolysis, and increased the sensitivity of the test.

In regards to the UFH dose, it is usually only maintained within the therapeutic range so no outlier value was observed. In patients without antithrombin deficiency, APTT and anti-Xa values were strongly and positively correlated with each other and with UFH dose. Therefore, the UFH dose was lower and less fluctuating. For patients with antithrombin deficiency, ACT, APTT, and anti-Xa values were lower and did not correlate well with each other, causing a higher and unsteady UFH dose.

The results of this study have shown that APTT is more reliable than ACT in monitoring the efficacy and titrating UFH dose in adult patients on ECMO. We also found that the value of APTT in monitoring UFH was no less than anti-Xa level for the following reasons: (1) In patients without antithrombin deficiency, APTT strong correlation with anti-Xa; (2) In patients with antithrombin deficiency, both APTT and anti-Xa did not correlate well with UFH dose; (3) APTT is common and can be performed several times a day for monitoring UFH. In the future, APTT should be reaccessed in parallel with a more precise measuring method than the traditional quantitative anti-Xa method, such as measurement of anti-Xa by adding exogenous antithrombin in patients with antithrombin deficiency.

Strengths and limitations

To our knowledge, this is the first study that was conducted on adult ECMO patients to assess ACT, APTT, anti-Xa, and UFH dose in regarding to antithrombin level, through which to determine the relationship of these tests in different perspective.

Several limitations might be taken into account when considering our results. Firstly, this is a single-center study, so our results might have limitations when trying to generalize for other ICUs or other settings. Secondly, our sample was small, yet still sufficient to achieve the study goal.

In adult patients undergoing ECMO using UFH anticoagulants, there was a strong positive correlation between the value of APTT and the value of anti-Xa, with an especially strong correlation in patients with normal antithrombin level. However, the ACT value was poorly correlated with anti-Xa and does not correlate with UFH dose. Values such as APTT and anti-Xa only correlate moderately with heparin dose in groups without antithrombin deficiency.

Ethics approval and consent to participate

This study was approved by the Research Ethics Committee, University of Medicine and Pharmacy, Ho Chi Minh City and by the Research Ethics Committee of Cho Ray Hospital. “No.122/HĐĐĐ v/v chấp thuận các vấn đề đạo đức NCYSH”. Approval date: 26/02/2020.

Consent for publication:

Not applicable

Availability of data and materials:

Data are available on request to the authors. A summary of relevant information will be published with the manuscript.

Competing interests

The authors declare that they have no competing interests

Funding

Not applicable

Authors' contributions

Tung Phi Nguyen, Xuan Thi Phan, Dai Quang Huynh, Hai Ngoc Truong, Thao Thi Ngoc Pham conceived and planned the study.

Xuan Thi Phan, Tung Phi Nguyen, Dai Quang Huynh, Ha Thi Viet Truong, Yen Nguyen Hai Le, Tuan Manh Nguyen, Thi Thi Ho, Thao Thi Ngoc Pham analysed data and contributed to the interpretation of the results.

Tung Phi Nguyen, Xuan Thi Phan, Dai Quang Huynh, Quan Quoc Minh Du, Thao Phuong Le wrote the manuscript with input from all authors.

All authors read and approved the final manuscript.

Acknowledgements

We thank Dr. Linh Thanh Tran, Dr. Huy Minh Pham, Dr. Hien Thi Thu Huynh, Dr.Viet Anh Ngo, Dr.Duy Ba Nguyen, Dr.An Hoang Tran, Dr.Hung Qui Nguyen, Dr.Bach Xuan Nguyen, Dr.Ngan Hoang Kim Trieu, Dr. Yen Hai Le and other members of ICU department, Cho Ray hospital for collecting samples in this study

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posted 21 Jan, 2021

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Monitoring Unfractionated Heparin In Adult Patients Undergoing Extracorporeal Membrane Oxygenation (ECMO): ACT, APTT or Anti-Xa?

Status:

Version 1

Abstract

Figures

Background

Methods

Research design

Patient Selection

Clinical data

ECMO anticoagulation protocol

Laboratory measurement

Statistical analysis

Results

Discussion

Strengths and limitations

Conclusion

Declarations

References

Status:

Version 1