February, 1999 - Laboratory Monitoring Of Anticoagulant Therapy

LABORATORY MONITORING OF ANTICOAGULANT THERAPY

Andrea Cortese Hassett, Ph.D.
Scientific Director
Coagulation and Molecular Immunodiagnostics Laboratory

INTRODUCTION

Heparin and warfarin have been used in the treatment of venous thromboembolism for nearly 50 years. Since their introduction, considerable progress has been made in our understanding of the pharmacology of these agents that has led to new insights into laboratory monitoring of these agents. In addition there has been agents such as danaparoid, hirudin and argatroban that have been or are expected to be approved for clinical use in the near future. Many of these reagents require some type of monitoring to maximize safety and effectiveness. The laboratory’s role is changing rapidly and it is clear that it plays a critical role in the clinical care of patients with thromboembolic disease. Our objective is to discuss the laboratory monitoring of these agents including the recent recommendations from the College of American Pathologists to improve monitoring.

ORAL ANTICOAGULANT THERAPY (oat)

The prothrombin time (PT) although one of the oldest forms of therapeutic drug monitoring remains the test of choice for monitoring changes in patients on oral anticoagulants. Thromboplastin reagents whether recombinant or derived from a natural source vary widely with regard to their responsiveness or sensitivity. All thromboplastins are assigned an International Sensitivity Index (ISI) so their sensitivities can be compared. The INR normalizes the PT ratio and is calculated by raising the PT ratio (ratio of patient PT to the mean normal PT) to the power of the ISI as follows: INR= (PT ratio)ISI. During the initiation phase of OAT, the patient’s status should be monitored 4-5 times per week. The frequency of testing once the patient is stabilized should be determined on an individual patient basis. There is general agreement of the target range INR of 2.0 to 3.0 for patient management. For patients with a mechanical heart valve, a target range INR of 2.5 to 3.5 is recommended and for patients with lupus anticoagulant, the target INR of 3.0 to 3.5.

The INR was intended to improve the management of anticoagulated patients. It is not known how well the INR correlates with the diagnosis or outcome in

clinical settings such as liver disease, drug induced coagulopathies, and hereditary or acquired coagulopathies, hence its use in these situations should be restricted. Lupus anticoagulants can alter the PT and give rise to INR values that can result in incorrect dosing. Alternative tests such as the factor X chromogenic assay is recommended in monitoring these patients.

UNFRACTIONATED HEPARIN (UFH)

Heparin accelerates the inactivation of thrombin and Factor Xa by antithrombin III. Currently the activated partial thromboplastin time (aPTT) is the most common test used to monitor heparin therapy. Laboratories must determine the appropriate therapeutic range for their own aPTT system used to monitor heparin therapy. This is most effectively done by regression analysis of patient dose response curves, corresponding the aPTT range to a heparin concentration of 0.3 to 0.7 anti-Xa U/mL (UFH therapeutic range). Patients receiving heparin but demonstrating an inadequate aPTT response can be evaluated using the anti-Xa assay. A quantitative anti-Xa assay is necessary for monitoring heparin in patients with a prolonged aPTT that may be related to lupus anticoagulants or deficiencies of factor XII and the contact factors (prekallikrein and high molecular weight kininogen). Upon administration of heparin samples should be obtained every 6 hours until the patient is within the target therapeutic range (0.3 - 0.7 anti-Xa U/mL); samples should be obtained daily thereafter.

LOW MOLECULAR WEIGHT HEPARIN (LMWH)

Low molecular weight heparin’s are fragments of unfractionated heparin produced by either chemical or enzymatic depolymerization. The pharmacokinetics of LMWH heparin’s differ from unfractionated heparin and allows for highly predictable anticoagulant effects of a given dose, decreasing the need for monitoring. Monitoring is, however recommended in the following clinical settings: renal insufficiency, obesity, pediatric patients and patients on prolonged therapy for pregnancy, malignancy or antiphospholipid antibody syndrome.

The chromogenic anti-factor Xa method is recommended for determining the plasma concentration of LMW heparin since the aPTT in most cases is not prolonged. The laboratory needs to be informed of the LMWH type used for patient therapy for appropriate calibration to ensure accurate measurements. Currently there are three FDA approved LMWHs; enoxaparin (Lovenox), dalteparin (Fragmin) and ardeparin (Normiflo). Samples for testing should be obtained four hours after administration. For twice-a-day dosing in the treatment of venous thromboembolism, an acceptable target range is 0.6 to 1.0 U/mL for each individual LMW heparin.

DANAPAROID (Orgaran)

Danaparoid is a heparin-like substance with anticoagulant activity, exhibiting predominantly anti-Xa activity. The half-life of danaparoid is much longer than heparin (24 hours) and no antidote for reversal is known. Danaparoid has been used for hemodialysis, acute ischemic stroke, disseminated intravascular coagulation and in patients with HIT (Heparin Induced Thrombocytopenia). Caution is advised, since cross-reactivity to heparin has been reported in 10% of patients. Additionally cardiopulmonary bypass has been successful with danaparoid.

Drug monitoring is achieved with the anti-Xa assay. Although anti-Xa monitoring is advised, since bleeding complicatons are uncommon, it has been suggested that dosing can be done without monitoring if renal function is normal. Samples for testing should be obtained 6 hours after administration and a target therapeutic range of 0.5 - 0.8 U/mL has been reported.

HIRUDIN (Lepirudin)

Lepirudin is a recombinant hirudin product isolated from leeches. This product exhibits an anticoagulant effect by direct thrombin inhibition. This mechanism differs significantly from heparin, which requires the presence of antithrombin III for physiological effect. Since Lepirudin is not activated nor crossreacts with antiheparin proteins, it is the recommended for use in patients with HIT who require continued anticoagulation.

In spite of the predicable target levels of anticoagulation by lepirudin, some studies indicate that monitoring and appropriate dosage adjustments may be indicated. The test most often used for laboratory monitoring is the aPTT. A commonly accepted therapeutic range of aPTT ratio (aPTT of the patient divided by the aPTT of the control) prolongation is 1.5 to 3.0 x baseline. Recent studies have found that the aPTT varies depending on the reagent and may not adequately reflect an accurate anticoagulant response. The ecarin clotting time (ECT) has been gaining greater acceptance as a more accurate and sensitive assay for monitoring particularly in cardiac patients.

SUMMARY

This report reviews the accepted general guidelines for monitoring anticoagulant agents. Detailed discussions of these recommendations can be found in Arch. Pathol. Lab Med., 122 , 1998, pp. 768-807.