Warfarin therapy is used in lupus anticoagulant patients with thrombosis and yet the prothrombin time (PT)/international normalized ratio (INR) in these patients can sometimes be falsely elevated. Both a PT-based factor II (FII) assay and a chromogenic, enzymatic factor X (CFX) assay have been used for monitoring when the INR may be artifactual. This study compared FII and CFX assays in lupus anticoagulant-positive and lupus anticoagulant-negative warfarin-treated patients in a cross-sectional study of samples from 21 lupus anticoagulant-positive and 19 lupus anticoagulant-negative outpatients. Plasma samples were simultaneously measured for FII and CFX and the ratio of FII/CFX was used to measure concordance. Compared with lupus anticoagulant-negative patients 14 of the 21 lupus anticoagulant-positive patients had lower FII/CFX ratios (P < 0.01). Three of the patients had ratios less than 0.6 indicating strong disagreement (P < 0.0001). The patient with the lowest FII/CFX ratio had evidence suggesting a specific antibody to FII. Another patient showed that the discordance between FII and CFX varied over time. The CFX assay in the laboratory was technically superior, more precise, and less costly. The CFX assay is preferred for warfarin therapy monitoring in lupus anticoagulant patients when INR artifacts are suspected.

TO THE EDITOR: Current treatment of heparin-induced thrombocytopenia (HIT) is replacement of heparin with a direct thrombin-inhibitor (DTI) such as argatroban. 1 The argatroban package insert recommends that initial dosage be based on patient weight. However, this may be suboptimal, since argatroban is distributed predominantly in blood and extracellular fluid and not in lean tissue and/or adipose. 2 Additionally, monitoring argatroban therapy is challenging because the gold standard assays are not routinely available. Therefore, the activated partial thromboplastin time (aPTT) is used as a surrogate; a target of 1.5-3 times the baseline aPTT value, not to exceed 100 seconds, is recommended in the package insert. At our institution, this target would be approximately 40-100 seconds. However, studies have shown that the aPTT is not linearly related to DTI concentration, there are interlaboratory differences in aPTT assays, and there is significant interpatient variability. 3, 4 We developed a pharmacist-managed, computerized argatroban dosage protocol based on estimated patient blood volume 5 and monitored with a routine enzymatic anti-factor IIa argatroban concentration assay (developed in-house). Based on information provided in Figure 1 (Relationship at Steady State Between Argatroban Dose, Plasma Argatroban Concentration and Anticoagulant Effect) of the package insert, 2 we chose a conservative target therapeutic concentration of 0.5 µg/mL which, in the figure, corresponds to an approximate aPTT of 55 seconds, or about 1.7 times baseline.Initial argatroban dosage, based on estimated patient blood volume and creatinine clearance, was calculated with a network-deployed Microsoft Excel dosing tool. Although not recommended in the package insert, we administered a loading dose to achieve a therapeutic argatroban concentration as quickly as possible. Subsequent infusion rate adjustments were based on the enzymatic drug concentration and pharmacokinetic principles for continuous drug infusion.Initially, consistent with current package insert recommendation, the protocol did not account for renal function, although the drug is known to be partially renally eliminated. 2 However, experience with our first 17 patients demonstrated that reductions in starting infusion rates were necessary in patients with renal dysfunction to avoid elevated argatroban concentrations. Patients with significant hepatic dysfunction were treated with empirically reduced doses but were excluded from the data analysis.The final version of the protocol was implemented in March 2007. Data were collected from 44 subsequent patients. The median initial argatroban infusion rate was 35% (range 12-59%) of that recommended by the package insert. The first argatroban concentration was drawn per protocol approximately 8 hours after administration of the loading dose and initiation of infusion. The median initial argatroban concentration was 0.47 µg/mL (target 0.5 µg/mL), with the middle 80% of values between 0.27 and 0.85 µg/mL. The first infusion r...

Chromogenic factor X (CFX) monitoring is necessary in patients with potential international normalized ratio (INR) artifacts during warfarin therapy. The relationship of CFX with the INR needs to be quantitated to have warfarin protocols that are equivalent with either test as a monitoring parameter. This study investigated whether the CFX/INR relationship is different during warfarin initiation compared with that during chronic warfarin therapy. Outpatients (N = 164) taking chronic doses of warfarin and inpatients (N = 137) initiating warfarin therapy had plasma samples tested for CFX and INR. The best fit mathematical relationship of CFX and INR was determined for both groups. A six hundred and twenty-five bed, adult-only, private, tertiary care teaching hospital was the setting of the study. The best fit equation for chronic warfarin patients was quadratic using a reciprocal transformation of the INR. The best fit equation for the warfarin initiation patients was linear using logarithmic transformation of CFX and INR. The predicted CFX from INRs over the range of 1.4-2.2 was 7-18% higher in the warfarin initiation patients than in the chronic warfarin patients. Translation of CFX values into equivalent INRs for use in warfarin initiation and maintenance protocols is improved when using equations specific to the patient situation.