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Which lab test is best to monitor heparin therapy? What the evidence says. CNE SERIES. (Nursing Pharmacology).

Heparin has been an effective treatment to prevent blood clots. The partial thromboplastin time has been the gold standard for monitoring. However, anti-Xa testing has demonstrated faster achievement of therapeutic range and fewer dosage changes.

Many hospitalized patients require anticoagulation therapy to prevent fatal complications from blood clots. Heparin is prescribed commonly to decrease morbidity and mortality by preventing formation or extension of clots in patients with thrombotic conditions, such as atrial fibrillation, unstable angina, non-ST elevation myocardial infarction, venous thromboembolism, and embolic stroke, and for prophylaxis in many postoperative patients (Fruge & Lee, 2015). However, heparin is a high-risk medication. Three major risks of heparin therapy are bleeding secondary to unintentional overdose, clot formation secondary to unintentional under dosage, and heparin-induced thrombocytopenia (HIT) secondary to an immune response. Monitoring for all three risks is crucial for positive patient outcomes. In particular, monitoring for correct dosage now can be accomplished through use of the anti-Xa assay or Xa factor (Paluri, Darapu, Koya, & Marques, 2014).

Heparin Therapy:

An Overview

Heparin comes in two forms: low-molecular-weight (LMWH) and unfractionated (UFH). LMWH (e.g., enoxaparin [Lovenox[R]]) has a fraction of the polysaccharide chains, yielding a much lower molecular weight. Fractionated heparin has been split into several smaller pieces with various chemicals, which produces a more stable pharmacologic response. Fractionation makes the pharmacodynamics of heparin more predictable. LMWH is administered as a subcutaneous injection, carries a slight risk for HIT, has little risk of bleeding, and in most patients, requires relatively little laboratory monitoring (Izadpanah, Hossein, Simin, & Mohammadi, 2015).

UFH has a high molecular weight up to 30,000 Dalton, a clinically irrelevant unit. Use of the term unfractionated means the large polysaccharide molecule remains intact. UFH can be administered by subcutaneous injection or intravenous infusion. Similar to LMWH, subcutaneous administration of UFH carries little risk of dosage error and, except in special circumstances, the medication requires little monitoring. An IV infusion of weight-based

UFH carries a high risk of overmedication leading to bleeding; undertreatment can contribute to clot formation or extension. Use of IV UFH requires extensive laboratory monitoring and dosage adjustment, often every 6 hours (John, Lisi, Greenfield, & George, 2015). IV UFH dosing has been adjusted historically based on the activated partial thrombopastin time (aPTT) (Vandiver & Vondracek, 2012). Today, many hospitals are monitoring heparin through use of the antiXa assay (Paluri et al., 2014).

HIT Risk

HIT is an immunologic disorder that occurs in 0.2%-5% of hospitalized patients (Bilen & Teruya, 2012). The risk is greatest in persons who receive UFH for 7-10 days; HIT may not develop until days after the heparin is stopped. The disorder seldom causes bleeding, but it can cause a sudden, severe drop in platelets by 50% or more (Greinacher, 2015). With such an extreme drop in platelets, HIT frequently leads to a paradoxical arterial and venous thrombus formation. Limb loss and death may result. All patients receiving any type of heparin should have platelets monitored routinely. Additional testing is prompted by decreased platelets, clinical presentation of thrombus, and clinical suspicion (Warkentin, 2016). Although no laboratory value can screen routinely for this disorder, HIT antibodies may be present in a small number of patients (Greinacher, 2015).

Bleeding or Clotting Risk

Heparin can cause bleeding because it interferes with several steps of the clotting cascade (Samuel et al., 2016). It inhibits anti-thrombin III, which prevents the conversion of prothrombin to thrombin. All heparins activate antithrombin, which inactivates thrombin. The slow anticoagulant effect of antithrombin is magnified when interacting with heparin. LMWH mainly inhibits factor Xa. UFH inhibits Xa and VII as well as fibrin formation. The result is the decreased ability of the body to produce a clot.

Routine nursing care of the patient receiving heparin includes surveillance for changes in mental or neurological condition as well as pulse and blood pressure, or any unusual bleeding (stool, urine, emesis, needle sites, gums or mucous membranes, sputum, increased blood volume during menses). The patient should be taught safety measures to prevent injury, including care with ambulation, use of a soft bristle toothbrush, and use of an electric razor (Hoffman & Sullivan, 2017). Specific care of the patient receiving high doses of weight-based UFH requires laboratory monitoring with the aPTT or anti-Xa. Heparin in high doses has a narrow therapeutic index with inter-patient variability. This inter-patient variability also accounts for unwanted clot formation. A dose for one patient may be insufficient for another even though traditional monitoring values indicate otherwise. Careful, regular monitoring of therapy is essential.

Activated Partial Thromboplastin Time (aPTT)

The aPTT has been considered the gold standard of heparin monitoring since the 1970s (Vandiver & Vondracek, 2012). It measures the number of seconds needed for a clot to form in a blood sample after a reagent has been added. Partial refers to the use of a partial thromboplastin agent. In addition, an activator is added to hasten the time to clot formation. This test is familiar to most personnel; it is inexpensive and used commonly by many hospitals.

The aPTT has several disadvantages. It does not measure specifically the effect of heparin and does not correlate well with its antithrombotic effect. Testing is defined within each laboratory based on available reagents and equipment. Each reagent results in a variable response. Many other variables also can influence aPTT results. For example, an inappropriately prolonged aPTT can occur due to liver disease, use of vitamin K antagonists, disseminated intravascular coagulation, clotting factor anomalies, and warfarin (Coumadin[R]) use. This can result in under-coagulation of the patient. Acutely ill patients may have an antithrombin deficiency, resulting in an inaccurately low aPTT and undue coagulation (Zehnder, Price, & Jin, 2012).

Once anticoagulation therapy has been initiated, the goal is to prolong the patient's aPTT result to prevent further clot development. A therapeutic range of 1.5-2.5 times the control was determined by Basu, Gallus, Hirsh, and Cade (1972) using a sample of 237 patients. This range is now considered unsafe because therapeutic levels can vary between laboratories. Several studies have found an aPTT 1.5 times the control was subtherapeutic; an adequate aPTT often had to be 2.0-2.6 times the control depending on the reagent used (Byun, Jang, Kim, & Koh, 2016). Price and co-authors (2013) found 30-day mortality was significantly higher in patients with supratherapeutic aPTT values.

A normalized ratio does not exist for the aPTT (Marlar & Gausman, 2012). The current recommendation is that a corresponding heparin concentration of 0.2-0.4 units per milliliter by protamine titration should be used (Samuel et al., 2016). Using a conventional aPTT range may lead to inappropriate heparin dosing. Overdosing increases the risk for bleeding, and underdosing can contribute to clot formation or extension.

Anti-Factor Xa Assay

Anti-Xa, a more specific test than the aPTT, directly assesses the functional activity of heparin and its inhibition of clotting factors by measuring the inhibition of only one enzyme (Xa). The enzyme is inhibited by complexes found in the UFH. According to Vandiver and Vondracek (2012), the Xa assay has been recommended as the preferred laboratory test to monitor UFH since the 1990s but was cost prohibitive. The American College of Chest Physicians approved use of the anti-Xa assay (Garcia, Baglin, Weitz, & Sanama, 2012). The College of American Pathologists also recommended using the antiXa (Olson et al., 1998).

Advantages of the anti-Xa assay include achievement of therapeutic goal within 24 hours or less, fewer dosage adjustments and laboratory tests reducing the potential for titration errors, and saved nursing time (Fruge & Lee, 2015). Anti-Xa is not affected by factor VIII deficiency or other conditions that affect coagulation factors (e.g., liver disease); less blood is needed for the sample; and the patient may experience a decreased hospital length of stay. Fruge and Lee also noted it is critical for the aPTT to be therapeutic within 24 hours; the longer the level is subtherapeutic, the higher the risk for thrombosis. An adult therapeutic range for the anti-Xa assay is 0.3 0.7 units/ML for UFH. In some instances (e.g., younger age, pregnancy, obesity, renal failure), the anti-Xa may be used to monitor therapeutic ranges of LMW heparin; anti-Xa results in patients receiving LMW heparin should be 0.5-1.2 units/ML (Gehrie & Laposata, 2012).

Among its disadvantages, anti-Xa assay does not reflect all the anticoagulant properties of UFH, including prothrombin, factors IX and VIII, and antithrombin activity (Price et al., 2013; Takemoto et al., 2013). Patients with severe antithrombin deficiency have abnormal values. Other anticoagulant medications such as LMWH and fondaparinux (Arixtra[R]) can increase antiXa levels. The anti-Xa blood test must be processed rapidly within 1 hour of being drawn to prevent heparin neutralization from platelet factor IV (Byun et al., 2016). Also, the cost for the anti-Xa reagent has been mentioned as a disadvantage. Vandiver and Vondracek (2012) found the cost of the anti-Xa reagent to be an additional $1.15 for each test compared to the aPTT reagent.

Converting a Healthcare System to Anti-Xa

The University of Pittsburgh Medical Center is a collection of 20 hospitals and 60,000 employees located in western Pennsylvania. In 2015, a pilot study was conducted at one of the hospitals comparing aPTT and anti-Xa use. Results indicated all patients monitored with the anti-Xa assay were within therapeutic range 8 hours faster and required 0.3 fewer dosage adjustments than patients monitored with aPTT (Donahue, Schmidhofer, & Smith, 2016). On June 1, 2016, the health system began using the anti-Xa assay rather than aPTT to monitor IV heparin therapy. All medical, nursing, and laboratory staff were educated before this transition via a computer software program. Users also completed a quiz to assess knowledge. A command center staffed with nurse educators, patient safety officers, and pharmacists was available to answer questions during implementation. See Table 1 for adopted therapeutic ranges; see Table 2 for a sample weight-based protocol.

Since implementation of the anti-Xa protocol, two of the authors used it multiple times. They did not find the transition between tests to be difficult. Nurses who participated in the study noticed use of the anti-Xa protocol saved time, and fewer titrations were needed. The patients also reached a therapeutic range sooner.

Conclusion

Monitoring for risks of heparin therapy remains crucial for positive patient outcomes. Even though aPTT has a variety of possible results based on the reagent and laboratory equipment, it continues to be the most ordered test in the United States (Vandiver & Vondracek, 2012). The test to monitor heparin therapy continues to be the choice of clinicians and institutions. With better outcomes from the anti-Xa assay (Paluri et al., 2014), its use may become more common. Nurses must assess each patient carefully and individually, including review of the history, risk factors, and indications for anticoagulant therapy, and compare factors to the best evidence. Only then can the highest quality, most cost-effective care be provided.

Instructions For Continuing Nursing Education Contact Hours

Which Lab Test Is Best to Monitor Heparin Therapy? What the Evidence Says

Deadline for Submission: June 30, 2019 MSNJ 1709

To Obtain CNE Contact Hours

1. For those wishing to obtain CNE contact hours, you must read the article and complete the evaluation through the AMSN Online Library. Complete your evaluation online and print your CNE certificate immediately, or later. Simply go to www.amsn.org/library

2. Evaluations must be completed online by June 30, 2019. Upon completion of the evaluation, a certificate for 1.2 contact hours, which includes 1.2 hours of pharmacology credit, may be printed.

Learning Outcome

After completing this learning activity, the learner will be able to compare and contrast optimal tests for monitoring heparin therapy.

Learning Engagement Activity

Examine the heparin protocol/guidelines used in your organization. Is there anything you could do differently in your organization?

The author(s), editor, editorial board, content reviewers, and education director reported no actual or potential conflict of interest in relation to this continuing nursing education article.

This educational activity is jointly provided by Anthony J. Jannetti, Inc. and the Academy of Medical-Surgical Nurses (AMSN).

Anthony J. Jannetti, Inc. is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.

Anthony J. Jannetti, Inc. is a provider approved by the California Board of Registered Nursing, provider number CEP 5387. Licensees in the state of California must retain this certificate for four years after the CNE activity is completed.

This article was reviewed and formatted for contact hour credit by Rosemarie Marmion, MSN, RN-BC, NE-BC, AMSN Education Director.

REFERENCES

Basu, D., Gallus, A., Hirsh, J., & Cade, J. (1972). A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. New England Journal of Medicine, 287(7), 324-327.

Bilen, O., & Teruya, J. (2012). Complications of anticoagulation. Disease Monthly, 58, 440-447.

Byun, J., Jang, I., Kim, J., & Koh, E. (2016). Establishing the heparin therapeutic range using aPTT and anti-Xa measurements for monitoring unfractionated heparin therapy. Blood Research, 51(3), 171-174.

Donahue, L., Schmidhofer, M., & Smith, R. (2016, April-May). Anti Xa is coming. Extra, 1.

Fruge, K., & Lee, Y (2015). Comparison of unfractionated heparin protocols using antifactor Xa monitoring or activated partial thrombin time monitoring. American Journal of Health Systems Pharmacology, 72(Suppl. 2), 590-597.

Garcia, D.A., Baglin, T.P., Weitz, J.I., & Samana, M.M. (2012). Parenteral anticoagulants: Antithrombotics therapy and prevention of thrombosis (9th ed.): American College of Chest Physicians evidence-based clinical practice guidelines. Chest, 141(2, Suppl.), e24s-e43s.

Gehrie, E., & Laposata, M. (2012). Test of the month: The chromogenic anti-factor Xa assay. American Journal of Hematology, 87(2), 194-196.

Greinacher, A. (2015). Heparin induced thrombocytopenia. The New England Journal of Medicine, 373(3), 252-261.

Hoffman, J., & Sullivan, N. (2017). Medical-surgical nursing: Making connections to practice. Philadelphia, PA: FA. Davis.

Izadpanah, M., Hossein, K., Simin, D.-K., & Mohammadi, M. (2015). Heparin & related drugs for venous thromboembolism prophylaxis: Subcutaneous or intravenous infusion. Journal of Comparative Effectiveness Research, 4(2), 167-184.

John, S.M., Lisi, D., Greenfield, N., & George, M.L. (2015). Anti-factor Xa monitoring in patients on unfractionated heparin. US Pharmacist, 40(3), HS26-HS32.

Marlar, R.A., & Gausman, J.N. (2012). The effect of instrumentation and laboratory site on the accuracy of the aPTT-based heparin therapeutic range. International Journal of Laboratory Hematology, 34(6), 614-620.

Olson, J.D., Arkin, C.F., Brandt, J.T., Cunningham, M.T., Giles, A., Koepke, J.A., & Witte, D.L. (1998). College of American Pathologists Conference XXXI on laboratory monitoring of anti-coagulant therapy: Laboratory monitoring of unfractionated heparin therapy. Archives of Pathology and Laboratory Medicine, 122(9), 782-798.

Paluri, R., Darapu, H., Koya, S., & Marques, S. (2014). Anti factor Xa assay for effective monitoring of heparin: A case report. International Journal of Medical and Health Sciences, 3(4), 328-329.

Price, E., Jing J., Huong, M., Krishnan, G., Bowen, R., & Zehnder, J. (2013). Discordant aPTT and anti-Xa values and outcomes in hospitalized patients treated with intravenous unfractionated heparin. The Annals of Pharmacotherapy, 47(2), 151-158.

Samuel, S., Allison, T., Sharaf, S., Yau, G., Ranjbar, G., Mckaig, N., ... Choi, H. (2016). Antifactor Xa levels vs. activated partial thromboplastin time for monitoring unfractionated heparin: A pilot study.

Journal of Clinical Pharmacy and Therapeutics, 41(5), 499-502.

Sheth, H. (2017, January). UPMC policy guidelines nomogram. Pittsburgh, PA: University of Pittsburgh Medical Center.

Takemoto, C., Streiff, M., Shernock, K., Kraus, P., Chen, J., Jani, J., & Kickler, T (2013). Activated partial thromboplastin time and anti-Xa measurements in heparin monitoring: Biochemical basis for discordance. American Journal of Clinical Pathology, 139(4), 450-456.

Vandiver, J., & Vondracek, T (2012). Anti-factor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin. Pharmacotherapy: The Journal of Pharmacology and Drug Therapy, 32(6), 546-558.

Warkentin, T. (2016). Clinical picture of heparin induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia. Thrombosis and Haemostasis, 116(5), 1-10.

Zehnder, J., Price, E., & Jin, J. (2012). Controversies in heparin monitoring. American Journal of Hematology, 87(5), S137-S140.

Joyce Heil, MSN, RN, CMSRN, is Nursing Instructor, University of Pittsburgh Medical Center, School of Nursing (Shadyside Campus), Pittsburgh, PA.

Alice Blazeck, DNSc, RN, is Assistant Professor, University of Pittsburgh School of Nursing, Pittsburgh, PA.

Jane Haines, DNP, RN, CMSRN, is Assistant Professor, University of Pittsburgh School of Nursing, Pittsburgh, PA.

Acknowledgment: Joyce Heil would like to acknowledge Dr. Linda Kmetz and Dr. Janey Roach for their guidance and support.
TABLE 1.
Therapeutic Ranges for aPTT and Anti-Xa Assay at UPMC

Heparin Order Set   Anti-Xa Therapeutic Ranges       aPTT (seconds)
                    (units/ML)

DVT/PE              0.3-0.7                          68-106
UA/NSTEMI           0.3-0.6                          68-96
Afib/post-op        0.3-0.45                         68-82
Stroke, EP, VAD,    0.25-0.35                        59-72
High risk for
bleeding
                    Anti Xa Supratherapeutic         aPTT (seconds)
                    Range (units/ML)
Stroke, EP, VAD,    0.25-0.35                        59-72
High risk for
bleeding
Notify MD if        [greater than or equal to] 0.7   > 106 (stroke, EP,
                                                     VAD, high risk
                                                     bleed)
                    > 1
                                                     > 125 (all others)

Notes: A-fib = atrial fibrillation postoperatively, DVT = deep vein
thrombosis, EP = electrophysiology, NSTEMI = non-ST elevation
myocardial infraction, PE = pulmonary embolus, UA = unstable angina,
VAD = ventricular assist device Reprinted with permission from Donahue
et al., 2016.

TABLE 2.
Sample Weight-Based Heparin Protocol for DVT/PE

Patient weight: 53.4 kilograms
Heparin infusion guidelines: Round infusion rate to the nearest tenth.
Concentration of heparin: 25,000 units in 250 ml (100 units per ml)

If Anti Xa is:   Change Heparin Rate   Next anti-Xa Due:

[less than or    Increase rate 214     STAT anti-Xa 6 hours after
equal to]0.20    units/hour            rate change
0.21-0.29        Increase rate 107     STAT anti-Xa 6
                 units/hour            hours after rate change
0.30-0.70        No change in          Repeat STAT anti-Xa every 6
                 infusion rate         hours for two consecutive
                                       results. After therapeutic
                                       range obtained (0.30.7) for
                                       two consecutive results, order
                                       anti-Xa for 4:00 a.m. daily
                                       for 5 days. Follow the
                                       protocol for each subsequent
                                       anti-Xa result.
0.71-0.80        Decrease rate 107     STAT anti-Xa 6 hours after
                 units/hour            rate change
0.81-0.99        Decrease rate 160     STAT anti-Xa 2 hours after
                 units/hour            rate change
[greater than    Hold heparin          STAT anti-Xa 2 hours after
or equal to]1    infusion for 2        rate change
                 hours. Restart
                 after decreasing
                 rate 214 units/hour

Reprinted with permission from Sheth, 2017.
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Author:Heil, Joyce; Blazeck, Alice; Haines, Jane
Publication:MedSurg Nursing
Article Type:Report
Date:May 1, 2017
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