Anticoagulation Monitoring and Targets: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference

Abstract

OBJECTIVES:

To derive systematic-review informed, modified Delphi consensus regarding anticoagulation monitoring assays and target levels in pediatric extracorporeal membrane oxygenation (ECMO) for the Pediatric ECMO Anticoagulation CollaborativE.

DATA SOURCES:

A structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2021.

STUDY SELECTION:

Anticoagulation monitoring of pediatric patients on ECMO.

DATA EXTRACTION:

Two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. Evidence tables were constructed using a standardized data extraction form.

DATA SYNTHESIS:

Risk of bias was assessed using the Quality in Prognosis Studies tool or the revised Cochrane risk of bias for randomized trials, as appropriate and the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. Forty-eight experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements for clinical recommendations focused on anticoagulation monitoring and targets, using a web-based modified Delphi process to build consensus (defined as > 80% agreement). One weak recommendation, two consensus statements, and three good practice statements were developed and, in all, agreement greater than 80% was reached. We also derived some resources for anticoagulation monitoring for ECMO clinician use at the bedside.

CONCLUSIONS:

There is insufficient evidence to formulate optimal anticoagulation monitoring during pediatric ECMO, but we propose one recommendation, two consensus and three good practice statements. Overall, the available pediatric evidence is poor and significant gaps exist in the literature.

During extracorporeal membrane oxygenation (ECMO), blood is in contact with the foreign surface of the ECMO circuit leading to activation of hemostasis, which can lead to patient thrombosis and/or ECMO circuit thrombosis and failure. Systemic anticoagulation mitigates this response but may contribute to life-threatening bleeding in the patient, especially when combined with the alterations in the hemostatic system associated with critical illness, platelet and clotting factor consumption due to the ECMO circuit and/or underlying critical illness, and age-related differences in hemostatic regulation across the pediatric age range (1–3). Because of the risk of bleeding, it is important to closely monitor systemic anticoagulation while on ECMO. However, small numbers of patients and variability in both clinical pathology and physical circuit component combinations make it difficult to design studies to determine best monitoring practices, and practice variation is high (4, 5). The objective of this subgroup of the Pediatric ECMO Anticoagulation CollaborativE (PEACE) was to derive systematic-review informed, modified Delphi consensus recommendations on anticoagulation monitoring in pediatric ECMO patients.

MATERIALS AND METHODS

Detailed methods and definitions of clinically relevant bleeding are described in the PEACE executive summary (6). Briefly, a structured literature search was performed using PubMed, EMBASE, and Cochrane Library (CENTRAL) databases from January 1988 to May 2020, with an update in May 2021, using a combination of medical subject heading terms and text words to evaluate anticoagulation monitoring (Supplemental Methods 1, http://links.lww.com/PCC/C496). Two authors reviewed all citations independently, with a third independent reviewer resolving any conflicts. Evidence tables were constructed using a standardized data extraction form (6). Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool or the revised Cochrane risk of bias for randomized trials, as appropriate (7–9), and the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system (10, 11). A panel of 48 experts met over the course of 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements or good practice statements for anticoagulation monitoring. The supporting literature was reviewed, and statements were developed using the Evidence to Decision framework, emphasizing the panel’s assessment of risks versus benefits of each proposed statement and a prioritized list of patient outcomes that had been created by a web-based survey of expert panel members (12–14). A web-based modified Delphi process was used to build consensus via the Research and Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. Additional references, not included in the structured literature search, were included in rationale statements to provide context but were not used to derive recommendations, consensus or good practice statements.

RESULTS

The structured literature search identified 4319 abstracts. Of these, 3822 references were excluded based on the abstract. An additional 446 references were excluded based on full article review, leaving 51 references that were used for consensus statement creation (Fig. 1). The included references are detailed in Supplemental Table 1 (http://links.lww.com/PCC/C496). A summary of risk of bias assessments are presented in Supplemental Figure 1 (http://links.lww.com/PCC/C496). One weak recommendation, two consensus statements, and three good practice statements met preset criteria for agreement (i.e., > 80%) were developed and are presented here.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram of studies screened and included in the anticoagulation monitoring subgroup.

Assays to Monitor UFH Anticoagulation

Clinical Recommendation

3.1 When monitoring unfractionated heparin-based anticoagulation, it is reasonable to consider a combination of anticoagulation monitoring assays including one or more “time to clot” assays (activated clotting time [ACT], activated partial thromboplastin time [aPTT], and/or viscoelastic tests) in combination with anti-factor Xa (anti-Xa) assay, where available. Consensus panel expertise with weak agreement, 89% agreement (n = 44), median 8, interquartile range [IQR] 7–9.

Good Practice Statements.

3.2 A thorough understanding of anticoagulation assays is necessary for management of ECMO and includes: 1) Obtaining manufacturer package insert information, 2) using institutional experts in hemostasis to educate ECMO clinicians. 98% agreement (n = 44), median 8, IQR 7–9.

3.3 Use a multidisciplinary approach, which may include input from critical care, surgery, transfusion medicine, hematology and pharmacy, to develop an institutional anticoagulation protocol; also consider consulting these experts in ECMO hemostasis in cases not easily managed with the institutional protocol. 82% agreement (n = 44), median 8, IQR 7–9.

3.4 Investigate promptly any discrepancies in results of anticoagulation assays in ECMO to identify underlying causes for the discrepancy. 85% agreement (n = 46), median 9, IQR 7–9.

Summary of the evidence:

Heparin monitoring assays include measurements of time to conversion of fibrin to fibrinogen (colloquially “time to clot assays”) such as the ACT, the aPTT, thromboelastogram, rotational thromboelastometry (ROTEM), and the anti-Xa assay, a measure of heparin dose efficacy on exogenous factor Xa (15). aPTT has been considered more predictive of coagulation status than ACT both within and between neonatal ECMO patients (16). aPTT monitoring of heparin therapy for ECMO patients has been shown to be associated with decreased hemorrhagic complications when compared with ACT (17). Of note, however, there are many different aPTT reagents available, each with different sensitivities to age-related hemostatic changes, different linearity, and response to heparin dosing. ECMO clinicians need to understand the properties of their local laboratory test to interpret and manage patient care.

Assessment of coagulation status by viscoelastic assays such as thromboelastogram or ROTEM has become more common (5, 18). In a retrospective comparison of neonatal ECMO patients who experienced hemorrhage (> 2 mL/kg/ECMO hr) to those who did not, significant differences between thromboelastogram results were noted over time (19). Another study noted a reduction in hemothoraces in neonatal congenital diaphragmatic hernia patients on ECMO when thromboelastogram monitoring was added to their anticoagulation management algorithm (20). Although these studies suggest the assays may be useful decision support for prediction and choice of therapies for bleeding and clotting, other studies of neonatal ECMO patients have been less convincing (21). Although some studies have reported normative thromboelastogram and ROTEM data for well children, there is insufficient information to standardize the measurements of heparin effect in children or the critically ill (22). Indeed, in a retrospective single center study of children on ECMO, the proportion of variation in coagulation test results explained by heparin dose was 13.3% for anti-Xa, 11.9% for ratio thromboelastogram R time, and 9.9% for delta thromboelastogram R time, compared with less than 1% for ACT and aPTT (23).

Several studies have found poor correlation between ACT and aPTT and the anti-Xa assay in ECMO patients likely due to ongoing factor and platelet consumption (18, 24, 25). The anti-Xa assay more closely correlates to heparin dosing than the time to clot assays (26, 27). Studies comparing pediatric ECMO patients managed with anti-Xa monitoring strategy with prior practice noted fewer heparin boluses, less frequent blood draws and changes in heparin infusion dosing, fewer circuit changes and hemorrhagic complications, and improved survival (28, 29). Unfortunately, studies are confounded by technology changes in addition to changes in anticoagulation monitoring strategy and management. One small study appeared to suggest that anti-Xa was more closely associated with circuit thrombotic complications, with decreased anti-Xa measurements associated with increased odds of subsequent circuit change, while there was no difference in ACT measurement between the groups (30).

There are several studies that support using multiple anticoagulation monitoring assays in combination (31–35). These approaches have been associated with decreased blood product transfusion, decreased bleeding complications, and increased circuit duration (34, 35). Frequency of anticoagulation monitoring was assessed in an observational cohort study which compared anticoagulation monitoring using a “simple” strategy (every 2-hr ACT measurement; daily anti-Xa and aPTT) at one center versus an “intensive” strategy (every 2 hr ACT; every 12 hr aPTT, international normalized ratio [INR], anti-Xa, and daily antithrombin) at another center and found no difference in outcomes including bleeding and thrombotic complications and survival (36). There is, additionally, no evidence that pediatric ECMO patients anticoagulated using a lower compared with higher anticoagulation targets have improved survival or decreased bleeding and thrombotic events. In one study of 604 patients supported with venoarterial ECMO for cardiac and respiratory indications, higher heparin dose, but not ACT level, was associated with improved survival (37). Finally, there is no current evidence to support that time to target therapeutic anticoagulation test or longer duration in the therapeutic range is associated with improved survival or lower bleeding and thrombotic events in children supported with ECMO (38, 39). In one study, inability to achieve anticoagulation target and frequent heparin dose changes were associated with increased intracranial events (40). Finally, several studies have concluded that current laboratory assays may not be sufficient to predict bleeding and clotting complications in pediatric patients managed with ECMO, despite different combinations of assays (41, 42).

Balance of benefits versus harms:

We suggest that a “time to clot” assay (ACT, aPTT, prothrombin time [PT]/INR, and/or thromboelastogram/ROTEM) is used to assess patient coagulation status in combination with the anti-Xa assay to assess heparin efficacy. Additional assays that may be helpful include platelet and fibrinogen levels, platelet function assay, and antithrombin activity assay. Anticoagulation targets should be adjusted considering patient and circuit related factors and perceived risk of bleeding versus clotting. Table 1 includes the characteristics of commonly used anticoagulation monitoring assays and Table 2 outlines factors associated with variability in results. A suggested approach to interpreting discrepancies in unfractionated heparin (UFH) monitoring assays (i.e., scenarios in which simultaneous results of different assays would direct different clinician actions) is in Supplemental Table 2 (http://links.lww.com/PCC/C496).

TABLE 1.

Commonly Used Anticoagulation Monitoring Assays for Unfractionated Heparin and Bivalirudin

Test	Activated Clotting Time	Activated Partial Thromboplastin Time	Anti-Factor Xaa	Viscoelastic Testing (Thromboelastogram and ROTEM)	Dilute Thrombin Time	Prothrombin Time/International Normalized Ratiob
Agent monitored	Any	Unfractionated heparin and bivalirudin	Unfractionated heparin	Any	Unfractionated heparin and bivalirudin	Bivalirudin
Sample	Whole blood	Citrated plasma	Citrated plasma	Whole blood	Citrated plasma	Citrated plasma
Measures	Time to clot	Time to clot	Chromogenic	Time to clot	Time to clot	Time to clot
Clot detection method	Optical or electromechanical	Optical or electromechanical	Not applicable	Electromechanical	Optical or electromechanical	Optical or electromechanical
Testing location	POC	POC and laboratory	Laboratory	POC and laboratory	Laboratory	Laboratory
Therapeutic range	Varies by analyzer	Varies by analzer and reagent but should correlate to anti-factor Xa of 0.35–0.7 or protamine titration of 0.2–0.4 U/mL for heparin. Usually 60–90 s for bivalirudin	0.35–0.7 U/mLa	Varies by thromboelastogram/ROTEM	Varies by analyzer but 60–90 s commonly used	Varies by indication for treatment
Therapeutic ranges validation	Cardiopulmonary bypass	Treatment of venous thrombosis	Treatment of venous thrombosis	Not validated	Not validated	Not validated
Established pediatric ranges	No	No	No	No	No	No

POC = point of care, ROTEM = rotational thromboelastometry.

^aMultiple assay configurations (exogenous antithrombin/dextran sulphate [DS] stabilizer/neither antithrombin nor DS) will all lead to markedly different results on same sample.

^bInternational normalized ratio traditionally used to monitor vitamin K antagonists, however, this table only refers to its role in the monitoring of bivalirudin.

“Time to clot” assays measure formation of a fibrin “clot” as determined by a threshold mass of fibrin.

TABLE 2.

Commonly Used Anticoagulation Monitoring Assays and Factors Associated With Variability in Results

Influences on Coagulation Monitoring	Activated Clotting Time	Anti-Factor Xaa	aPTT When monitoring UFH	aPTT When Monitoring Bivalirudin	Thromboelastogram R-time or ROTEM INTEM Clotting Time	Thromboelastogram Maximum Amplitude or ROTEM INTEM Maximum Clot Firmness	Prothrombin Time/International Normalized Ratio When Monitoring Bivalirudin	Dilute Thrombin Time When Monitoring Bivalirudin
Sample factors
Heparin contamination	↑	↑	↑	↑	↑	↔/↓	↔/↑	↑
Dilution	↑	↓	↑	↑	↑	↔/↓	↑	↑
Under/over-filled sample tubes	Sample must be redrawn because results will be uninterpretable
Delay in sample analysis (beyond 2 hr)	Sample must be redrawn because results will be uninterpretable (optimal time to sampling for bivalirudin is unknown. Some current protocols restrict to 1 hr)
Gross hemolysis due to sampling	Sample must be redrawn because results will be uninterpretable
Patient factors
Hypothermia	↑	↔a	↔a	↔a	↔a	↔a	↔a	↔a
Elevated levels of inflammatory markers including: fibrinogen and factor VIII	↓	↔	↓	↓	↓	↔/↑	↔	↓
Increased heparin binding proteins in the presence of systemic inflammation, infection, malignancies	↓	↓	↓	↔	↓	↔/↑	↔	↔
Thrombocytopenia (generally < 50 × 109)	↑	↔	↔	↔	↔/↑	↓	↔	↔
Antithrombin deficiency	↓	↓b	↓		↓	↔
Consumptive coagulopathy (i.e., disseminated intravascular coagulation)	↑	↔/↓b	↑		↑	↓
Hepatic dysfunction (decreased coagulation factor production)	↑	↔/↓b	↑		↑	↓
Procoagulant factor deficiency(s)	↑	↔	↑	↑	↑	↔/↓	↑	↔
Presence of a lupus anticoagulant	↑	↔	↑	↑	↑	↔	↔	↔
Assay factors
Elevated triglyceride level	↔	↓c	↔/↑c	↔/↑c	↔	↔	↔/↑c	↔
Elevated total bilirubin level	↔	↓c	↔/↑c	↔/↑c	↔	↔	↔/↑c	↔
Elevated plasma-free hemoglobin	↔	↓c	↔/↑c	↔/↑c	↔	↔	↔/↑c	↔
Drug factors
Loss of linearity outside specific dose ranges	Low dose	N/A	Very high dose	High dose	Low and high dose	N/A	Therapeutic range	N/A
Impaired renal function (decreased UFH or bivalirudin elimination)	↑	↑	↑	↑	↑	↔/↓	↑	↑

aPTT = activated partial thromboplastin time, INTEM = intrinsically activated thromboelastometry, N/A = not applicable, ROTEM = rotational thromboelastometry, UFH = unfractionated heparin.

↑ = increase in laboratory result, ↓ = decrease in laboratory result, ↔ = no change in laboratory result status.

^aHypothermia does not alter results because test is performed at standard 37°C. Whether test result accurately reflects biological activity inpatient is unknown.

^bFor anti-factor Xa assay without added exogenous antithrombin.

^cThere is a threshold above which triglycerides, bilirubin, or hemoglobin will interfere with optical detection systems that is specific for each analyzer. See manufacturers notes for details.

Interference in Anticoagulation Monitoring Assays

Consensus Statement

3.5 In each center, we consider that ECMO clinicians and their laboratory define thresholds of bilirubin, plasma free hemoglobin and triglycerides above which chromogenic or optical clot detection-based anticoagulation monitoring assays should be considered unreliable. Consensus panel expertise with strong agreement, 98% agreement (n = 43), median 8, IQR 7–9.

Summary of the evidence:

Tests to assess coagulation may be affected by patient factors and specific aspects of laboratory tests used. Thus, the provider titrating anticoagulation must understand intrinsic test result variance and external factors that affect test results. We collated characteristics of commonly used anticoagulation monitoring assays and factors associated with variability in results (Tables 1 and 2).

Hemolysis and hyperbilirubinemia, commonly seen in ECMO patients may affect the results of the anti-Xa assay. Elevated levels of substances such as plasma-free hemoglobin and bilirubin may lead to an underestimation of anti-Xa activity. Optical assays of anti-Xa, aPTT, and PT may variably be impacted (43, 44). Thus, heparin titration in the presence of elevated plasma-free hemoglobin and serum bilirubin may result in erroneous evaluation of anticoagulation status and may lead increased risk of bleeding or clotting.

Monitoring Anticoagulation With Direct Thrombin Inhibitors

Clinical Recommendation

3.6 There is insufficient evidence to recommend a specific assay or therapeutic range for monitoring direct thrombin inhibitors (DTIs) in pediatric ECMO. Recommendation (no level), very low-quality pediatric evidence, 83% agreement (n = 46), median 7, IQR 7–9.

Summary of the evidence.

Analytic response of monitoring assays for direct thrombin inhibitors (DTIs):

The analytic response of aPTT, plasma dilute thrombin time, ecarin clotting time, and PT/INR hemostasis assays have been evaluated for use in monitoring anticoagulation with bivalirudin. aPTT is the most commonly reported assay used to monitor bivalirudin during ECMO (45–50) and shows a curvilinear increase in clotting time as a function of bivalirudin concentration (51). Because the aPTT cannot be diluted, it can be difficult to assess the bivalirudin when levels are supratherapeutic. The aPTT is prolonged by low coagulation factor levels, sample contamination with heparin, and lupus inhibitors, which are common in hospitalized patients (33, 43, 52, 53) and does not correlate well with other tests used to monitor direct thrombin inhibitors (DTIs) or with DTI levels in many patient (51, 54–58).

Two different approaches to dilution of the thrombin time assay have been reported, including either dilution of the patient plasma sample (diluted thrombin time) (59) or the use of a standardized lower thrombin dose (i.e., 5 National Institutes of Health units in the dilute thrombin time) (55, 56). Both modified thrombin times have resulted in improved sensitivity in DTI monitoring. No studies have currently reported use of the plasma dilute thrombin time to monitor bivalirudin during pediatric ECMO, but its improved analytic response and reduced interference warrant further study.

The ecarin clotting time is a highly specific test for DTIs that correlates well with plasma diluted thrombin times (51, 54, 55). Its response is almost linear with DTI level and can be calibrated to report the level of drug (54). It has good sensitivity and specificity for DTIs, but availability is limited.

The PT/INR is also prolonged by DTIs, correlation between PT and DTI levels is similar to aPTT and ACT (54). Prolongation of the PT was weak compared with other assays, it was difficult to distinguish therapeutic doses of bivalirudin from over or under dosage (60). Further studies of PT/INR as a bivalirudin monitoring tool would be needed due to the small size of current studies.

Clinical monitoring of DTIs during ECMO:

Only limited data are available on the use of DTIs, mainly bivalirudin and to a lesser extent, argatroban, during ECMO (45–50). No validated therapeutic ranges are available. Four studies reported use of bivalirudin in pediatric patients on ECMO using aPTT monitoring (45, 47, 48, 50).

Recent studies evaluating aPTT to monitor bivalirudin have reported similar rates of thrombosis, bleeding, transfusion and mortality between pediatric ECMO patients anticoagulated with bivalirudin and heparin, while other studies have reported decreased circuit interventions and decreased transfusion, time to reach therapeutic targets and cost using bivalirudin versus heparin (45, 47, 48, 50). None of these studies were randomized trials.

Balance of benefits versus harms:

At this time, there is insufficient evidence to recommend a specific assay or therapeutic range for monitoring DTIs used in pediatric patients supported with ECMO. Multicenter quality improvement bundles and clinical studies using DTIs to prevent thrombosis in pediatric patients with ventricular assist devices typically use the aPTT to monitor DTIs, but there is no evidence that the aPTT is the optimal test or that the target range being used is the optimal therapeutic range during ECMO support (50). Adjunctive markers of optimal therapeutic effect for DTIs such as ecarin clotting time and dilute thrombin time warrant further investigation.

CONCLUSIONS

Data to guide frequency of monitoring and use of specific anticoagulation assay(s) during anticoagulation with UFH or DTIs in pediatric ECMO are scarce and, at times, contradictory. We suggest that an appropriate panel of assays combined with interpretation by experts in anticoagulation, ECMO, and pediatric intensive care medicine, may result in superior bleeding and clotting outcomes; however, research in this area is desperately needed. It is crucial for clinicians caring for ECMO patients to have a thorough understanding of the anticoagulation monitoring assays used in their institutions to effectively interpret assay results.

ACKNOWLEDGMENTS

The authors thank all members of Pediatric Extracorporeal Membrane Oxygenation (ECMO) Anticoagulation CollaborativE (PEACE) for their support, especially during the COVID-19 pandemic. The authors acknowledge the important contributions of Dr. M. Patricia Massicotte to the design and execution of the PEACE project. In addition, they thank AABB, the American Society of Extracorporeal Therapists, the American Pediatric Surgical Association, the Children’s Hospital Neonatal Consortium, the Collaborative Pediatric Critical Care Research Network, the European Society for Pediatric and Neonatal Intensive Care, the International Society of Blood Transfusion, Pediatric Cardiac Critical Care Consortium, Pediatric Cardiac Intensive Care Society, the Society for Critical Care Medicine (Pediatric Section and Clinical Pharmacy and Pharmacology Section), and the Society of Thoracic Surgeons for contribution through representation on the PEACE Expert Panel.

Supplementary Material

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