Interference in point-of-care international normalized ratio monitoring in patients with lupus anticoagulant is correlated with anti–β2-glycoprotein I antibody titers

Background: Patients with antiphospholipid syndrome (APS) receive anticoagulant therapy with vitamin K antagonists (VKAs) to prevent recurrent thrombosis. VKA treatment requires strict monitoring with an international normalized ratio (INR). It is known that lupus anticoagulants (LAs) can lead to elevated INR results with point-of-care-testing (POCT) devices, which could result in inadequate adaptation of anticoagulant therapy. Objective: To determine discrepancies between POCT-INR and laboratory-INR in patients who are LA-positive on VKA therapy. Methods: Paired INR testing was performed with 1 POCT device (CoaguChek XS) and 2 laboratory assays (Owren and Quick method) in 33 patients with LA-positive APS on VKA in a single-center cross-sectional study. Patients were tested for anti–β2-glycoprotein I, anticardiolipin, and antiphosphatidylserine/prothrombin immunoglobulin (Ig) G and IgM antibodies. Agreement between assays was evaluated with Spearman's correlation, Lin's correlation coefficient, and Bland–Altman plots. Agreement limits were considered satisfactory if differences were ≤20% as determined by the Clinical and Laboratory Standards Institute. Results: We found poor agreement between POCT-INR and laboratory-INR based on Lin's concordance correlation coefficient (ρc) of 0.42 (95% CI, 0.26-0.55) between POCT-INR and Owren-INR, a ρc of 0.64 (95% CI, 0.47-0.76) between POCT-INR and Quick-INR, and a ρc of 0.77 (95% CI, 0.64-0.85) between Quick-INR and Owren-INR. High anti-β2-glycoprotein I IgG antibody titers correlated with INR disagreement between POCT-INR and laboratory-INR. Conclusion: There is a disagreement between INR values measured with the CoaguChek XS and laboratory-INR in a proportion of patients with LA. Consequently, laboratory-INR monitoring should be preferred over POCT-INR monitoring in patients with LA-positive APS, especially in patients with high anti-β2-glycoprotein IgG antibody titers

Non-invasive method to obtain blood curves of 99mTc-mebrofenin

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In vivo visualization and quantification of (disturbed) Oatp-mediated hepatic uptake and Mrp2-mediated biliary excretion of 99mTc-mebrofenin in mice

Hepatic transport of Tc-99m-mebrofenin through organic anion transport protein 1a and 1b (Oatp1a/1b) and multidrug resistance protein 2 (Mrp2) was investigated by small-animal SPECT. On the basis of the results, a noninvasive method to visualize and quantify disturbances in hepatic transport is proposed. Methods: Friend virus B wild-type mice (untreated, bile duct-ligated, vehicle-or rifampicin-treated) and strain-matched knockout mice unable to express the uptake transporters Oatp1a/1b (Slco1a/1b(-/-)/(-/-)) or the efflux transporter Mrp2 (Abcc2(-/-)) were intravenously injected with Tc-99m-mebrofenin (n = 3 per group). After dynamic small-animal SPECT and short CT acquisitions, time-activity curves of the liver and of the gallbladder and intestines were obtained and correlated with direct blood samples. Results: Normal hepatobiliary clearance of Tc-99m-mebrofenin was severely impaired in the bile duct-ligated animal, as evidenced by elevated hepatic tracer levels. In Slco1a/1b2(-/-)/(-/-) mice, a lower area under the curve (AUC) for the liver (P = 0.014) was obtained and no activity was detected in the gallbladder and intestines. Renal rerouting was observed, along with an increase in the blood AUC (P = 0.01). Abcc2(-/-) mice had a higher liver AUC (P = 0.009), a delayed emergence time of Tc-99m-mebrofenin in the gallbladder (P = 0.009), and a lower AUC for the gallbladder and intestines (P = 0.001). The blood curve was similar to that of wild-type mice. Tc-99m-mebrofenin disposition was altered after rifampicin treatments. We observed a dose-dependent delayed time point at which tracer maximized in liver, an increased AUC for liver, and a lower AUC for gallbladder and intestines (P = 0.042, 0.034, and 0.001, respectively, highest dose). Emergence in the gallbladder occurred later (P = 0.009, highest dose), and blood AUC was higher (P = 0.006). Conclusion: The current study visualized and quantified hepatic uptake and biliary efflux of Tc-99m-mebrofenin. Our results demonstrated the possibility of discriminating, on a quantitative level, between lack of functional activity of sinusoidal uptake versus that of biliary efflux transporters

Optimisation of lupus anticoagulant tests: should test samples always be mixed with normal plasma?

Coagulation factor deficiencies are thought to interfere with the detection of the phospholipid-dependent coagulation inhibitor known as lupus anticoagulant (LA). Treatment with vitamin K antagonists (VKA) in particular, is thought to preclude accurate LA assessment. For this reason, the procedure to detect LA includes a mixing test, in which coagulation factor deficiencies are corrected by mixing samples with an equal volume of normal plasma. Despite these mixing tests, interpretation of LA test results is considered difficult in patients receiving high intensity VKA treatment. As a result, VKA treatment is often temporarily discontinued to allow LA assessment. However, whether coagulation factor deficiencies influence LA test results is unclear. We found that neither deficiency of a single coagulation factor, nor a functional coagulation factor deficiency due to high intensity VKA treatment, resulted in false positive dRVVT- or APTT-based (silica clotting time; SCT) LA test results. LA was readily detected in unmixed samples from VKA-treated LA-positive patients with both dRVVT and SCT reagents. VKA treatment caused an underestimation of the strength of the LA with SCT reagents, but did not lead to misclassification of LA status. Although mixing with normal plasma during both screen and confirm tests allowed more accurate assessment of the strength of the LA with SCT reagents in samples with an international normalised >2.5, the mixing procedure itself lead to misclassification of LA in weakly positive samples from patients not treated with VKA. Based on these findings, we conclude that mixing studies are not necessary during LA-assessmen