Laboratory Methods of Heparin Monitoring, Part 1

Unfractionated heparin remains to be widely used in clinical medicine for the treatment and prevention of thrombosis. Traditionally, the Activated Partial Thromboplastin Time (APTT) has been used to monitor and adjust the dose regimen of unfractionated heparin. Even with its widespread availability and inexpensive cost, APTT is a poorly standardized test. Furthermore, it is associated with a significant intra- and inter- laboratory variability. Because of these limitations and more, laboratories have been looking for an alternative monitoring method that will aid in providing optimal patient care. Recently, chromogenic anti-factor Xa assay otherwise known as Heparin Xa Assay has been gaining momentum because of its numerous advantages over APTT. This study aims to review pertinent published literature on the use of APTT and anti-Factor Xa assay with regards to monitoring unfractionated heparin. Likewise, compare and contrast the advantages and disadvantages of the two laboratory methods.

Review of the results of the different clinical studies and articles showed that there is no explicit recommendation on what is the most appropriate laboratory assay to monitor unfractionated heparin. Nevertheless, the anti-factor Xa assay proves to be a very promising alternative to APTT.

Anticoagulant therapy is used in the treatment and prevention of thrombosis. Commonly called a “conventional anticoagulant,” heparin is a negatively charged glycosaminoglycan composed of repeating sulfated disaccharides.1 The key to heparin anticoagulation is its binding properties to antithrombin.1,15 It may be used as unfractionated heparin or its low molecular weight derivatives.2

Unfractionated heparin (UFH) has been widely used in clinical medicine since 1970 to treat thromboembolitic disorders and acute coronary syndrome.3,4 It is the mainstay of intravenous anticoagulant therapy in acute patients, and not just in adult patients but also in the pediatric patient setting.5,6 Its advantages include: rapid onset of action, short half-life, ease of reversal, and extensively studied.5,15 Despite its popularity, it is significantly limited by its variable biochemical composition and unpredictable pharmacokinetics which pose a challenge to clinicians.4 Furthermore, it is highly antigenic and carries a significant risk to causing heparin-induced thrombocytopenia(HIT). Hence, laboratory monitoring is needed whenever an initial infusion or dose adjustment is done. Moreover, testing is imperative until such time that a stable therapeutic response is achieved. A stable therapeutic response is defined as a level of anticoagulation that provides optimal protection from further thromboembolytic events.

Activated partial thromboplastin time (APTT) is the most well-known general screening test of the intrinsic and common coagulation system, and in monitoring unfractionated heparin.5-8 The major advantages of APTT include: clinicians familiarity with the assay, its widespread availability, and inexpensive cost.4,8,10,20 However, the test is poorly standardized and is affected by a number of preanalytic, analytic and biologic variables; therefore, the relationship between APTT and clinical outcome remains an issue.9 This was highlighted in a meta-analysis done by Vardi et al.11 The authors reviewed medical literature on venous thromboembolism regarding the correlation between APTT and clinical outcomes. It lead them to conclude that there was no correlation between anticoagulation level and major clinical outcomes, except for initial coagulation measurement and the total number of mortality after three months.

In recent years, a newer method for monitoring UFH has been gaining momentum, chromogenic anti-factor Xa assay otherwise known as Heparin Assay. It specifically measures heparin by quantifying the amount of residual factor Xa in the sample. In contrast to APTT, this test demonstrates less variability. Guervil et al. concluded that monitoring UFH with Anti-Xa assay is a more superior test to APTT because it achieves a stable therapeutic anticoagulation level more rapidly; therefore, requires less dosage changes and fewer monitoring tests.14 However, this assay has limited availability and is more costly to perform. 13

Which is the better test? Why switch testing? This study aims to review related literature on the advantages and disadvantages of APTT and anti-Xa assay with regards to monitoring unfractionated heparin. A solid working knowledge of these assays with a focus on indications and clinical implications is necessary in order to provide optimal patient care and management. Choosing the right monitoring method would reduce the likelihood of harm associated with anticoagulant therapy.

Heparin: unfractionated and low molecular weight
Hemostasis is vital to survival. A balance of naturally occurring procoagulants and anticoagulants must be maintained to avoid clinical aberration. There are two major classes of anticoagulant that have been extensively studied: Vitamin K antagonists (ie warfarin) and heparin.1 These studies thereby provide a great deal of evidence that aid therapy.

Heparin, in its unfractionated form, is one of the most commonly administered parenteral drugs.16 Moreover, it is an indirect anticoagulant requiring antithrombin (AT) as a plasma cofactor.1,15,18Only about one third of a heparin dose binds to AT; consequently, this fraction of heparin/antithrombin interaction is responsible for the major anticoagulant effect of heparin.18 The rapid onset of reaction coupled with ease of total reversal by protamine contributes to the attractiveness of UFH.5.15 Likewise, clinicians are very familiar with it. However, one cannot ignore the drawbacks of heparin: (1) its pharmacokinetics is complicated by the ability of heparin to bind to endothelial cells, macrophages, and a number of plasma proteins; (2) its ability to induce immune-mediated platelet activation that could lead to heparin induced thrombocytopenia; and (3) its capability to bind to osteoblasts causing osteopenia.1,4,15,18 Adding heterogeneity to heparin is the way it is cleared from the body, which is influenced by the chain length of the molecule. Larger molecules are cleared more rapidly than smaller ones. In short, UFH is cleared faster than LMWH.

LMWH is an example of an anticoagulant that has replaced UFH in most clinical indications.18 It is a further refinement of UFH prepared by different methods of chemical or enzymatic depolymerization.18 It is composed of shorter chain lengths. It exhibits less non-specific binding as compared to UFH. Consequently, its anticoagulant effect is more predictable.

The use of heparin has declined since the advent of newer anticoagulants that have more predictable pharmacokinetics and pharmadynamics. As a result, unfractionated heparin still remains an important therapeutic agent in inpatient settings- especially when there is a need for a rapid anticoagulant effect.5,6

Bernadette V. Enderez, SBB(ASCP)CMMT(ASCP) is a clinical laboratory scientist at Hazel Hawkins Memorial Hospital and an MS student at Rush University in clinical lab management.


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5. Liveris, A., Bello, R. A., Friedmann, P., Duffy, M. A., Manwani, D., Killinger, J. S., . . . Weinstein, S. (2014). Anti-factor xa assay is a superior correlate of heparin dose than activated partial thromboplastin time or activated clotting time in pediatric extracorporeal membrane oxygenation*. Pediatric Critical Care Medicine : A Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies, 15(2), e72-9. doi:10.1097/PCC.0000000000000028 [doi]

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