Anticoagulation Monitoring

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This article reviews the commonly used anticoagulants (warfarin and heparin) and associated recommended laboratory testing. Emphasis is on the various modes of International Normalized Ratio testing and associated variability (clinical laboratory, point of care, patient self-testing). Unfractionated heparin and well-recognized coagulation testing issues are reviewed. The newer anticoagulants (heparin analogs, direct factor Xa inhibitors, and direct thrombin inhibitors) and various applied coagulation laboratory testing and related issues are also discussed.

Section snippets

Discovery of heparin and vitamin K antagonists

The discoveries of heparin and VKAs are fascinating glimpses into the scientific practices and larger cultural backdrops of the associated historical times. The discovery of heparin was steeped in controversy, with multiple scientists claiming credit.4, 5 Furthermore, reading the original description of its early crude preparations, made from autolyzing bovine liver, evokes vivid pungent and visceral reactions even today.5

The discovery of warfarin reads like a Horatio Alger success story.4, 5, 6

Warfarin–vitamin K antagonist therapy: use the international normalized ratio to monitor

Warfarin's mechanism of anticoagulation action is by inhibiting gamma carboxylation of the vitamin K–dependent coagulation factors. This results in a decreased level of active coagulation factors and an excess of precursor coagulation factors, or proteins induced by VKAs.

The demonstration of warfarin's effectiveness early in its development was hampered by highly variable laboratory assays. The development of the international normalized ratio (INR) system in the mid-1980s helped reduce

Point-of-care testing international normalized ratio accuracy and reproducibility

Significant INR variability has been demonstrated within the controlled environment of a clinical laboratory. With point-of-care testing (POCT), additional test reliability concerns arose, most notably related to personnel competency and test environment (ie, temperature, humidity).19, 20 In recognition of these additional concerns associated with POCT, two key questions were posed when POCT INR test devices became commercially available: how do INRs generated from POCT devices compare with

Heparins

Heparin is a negatively charged glycosaminoglycan comprised of repeating sulfated disaccharide units (Fig. 4) derived from animal or plant sources. Heparin has been used for treatment for almost a century; the reader is referred to the many excellent reviews on this subject for more detail.37, 38, 39, 40

Laboratory testing to monitor unfractionated heparin anticoagulant effect

Review of the intrinsic pathway of coagulation demonstrates the multiple points at which UFH blocks clotting, with corresponding prolongation of the activated PTT. The major UFH effect on PTT prolongation is, however, directly caused by inhibition of thrombin activity.

Early in its clinical use, PTT was advocated as the preferred laboratory test for establishing the patient had achieved the desired therapeutic range, and sequential PTT determinations to ensure the patient maintained the desired

Direct FXa inhibitors (xabans)

There is limited information on oral direct FXa inhibitors, because many are in the midst of clinical trials and no definitive statement can be made regarding their clinical applicability.67

Two xabans (rivaroxaban and apixaban) have received the most attention. Both have excellent bioavailability, predictable pharmacokinetics, are taken orally, bind reversibly to FXa, and have plasma half-lives of many hours. They differ in metabolism; rivaroxaban is excreted renally, whereas apixaban is

Direct thrombin inhibitors

Thrombin plays a central role in hemostasis, acting at multiple points in the clotting cascade.38, 39, 40 It has both prothrombotic (ie, cleavage of fibrinogen to fibrin to start clot formation, activation of FXIII, platelet activation, and inhibition of fibrinolysis by a thrombin-activatable fibrinolysis inhibitor) and anticoagulant (ie, protein C activation) effects, and effects on endothelium and vascular smooth muscle cells.38, 39, 40 Thrombin itself is inhibited by AT and this interaction

Summary

This is a dissatisfying end to an exciting time in clinical anticoagulant therapy. With the exception of the INR for monitoring patients on chronic warfarin therapy, any other coagulation test used to monitor any other anticoagulant suffers from a lack of standardization and the presence of significant variability of results depending on which reagent or test method is used.

For the laboratorian, caveat emptor. It is absolutely critical to know how the assay performs with the target patient

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