What medical authority citations support the unreliability of International Normalized Ratio (INR) for patients with lupus anticoagulants, necessitating the use of factor X chromogenic assay?

INR Unreliability in Lupus Anticoagulant Patients: Support for Chromogenic Factor X Assay

The International Society on Thrombosis and Haemostasis (ISTH) confirms that INR measurements in lupus anticoagulant (LA) positive patients show significantly higher between-thromboplastin variability compared to LA-negative patients, supporting the need for chromogenic factor X assay when INR results are unreliable. 1

Evidence for INR Unreliability in LA Patients

• The ISTH reports that between-thromboplastin variability of PT-INR in LA-positive patients has a coefficient of variation (CV) of 12.4%, compared to only 6.7% in controls without LA 1
• Different commercial thromboplastins have varying sensitivities to LA interference:
  • Recombinant thromboplastins (particularly human recombinant types) tend to be more sensitive to LA interference 1
  • One specific thromboplastin (Thromborel R, human recombinant) measured considerably greater INR values in LA patients but not in controls 2

Mechanisms of INR Interference

• LA can influence PT and lead to INR values that do not accurately reflect the true level of anticoagulation 3
• The baseline PT in patients with LA is rarely prolonged because phospholipid concentrations in PT reagents are much higher than those in APTT, which typically quenches LA activity 2
• However, phospholipid composition and concentrations vary among commercial thromboplastins, making this effect inconsistent across different laboratory systems 2

Evidence Supporting Chromogenic Factor X Assay

• When INR results are suspected to be unreliable, chromogenic factor X assay is recommended as an alternative monitoring method 1
• The chromogenic factor X assay is not sensitive to lupus anticoagulant interference 3
• The therapeutic range for factor X activity is 22-40% of normal when using chromogenic factor X assay 1
• Studies comparing chromogenic factor X with INR in LA patients show that factor X correlates negatively with INR in anticoagulated patients both with and without LA, supporting its reliability 4

Comparison with Other Alternative Methods

• Phospholipid-rich dilute Russell's viper venom time (prdRVVT) has been investigated but found unsuitable for monitoring warfarin therapy in LA patients 4
• Factor II (FII) activity has also been studied as an alternative:
  • While FII and chromogenic factor X (CFX) are generally well-correlated (r = 0.92) 5, some studies show discordance
  • In one study, 14 of 21 LA-positive patients had lower FII/CFX ratios compared to LA-negative patients, with 3 patients showing strong disagreement (ratios < 0.6) 6
  • The chromogenic factor X assay was found to be technically superior, more precise, and less costly than FII assays 6

Clinical Recommendations

• Use LA-insensitive thromboplastins with proper instrument-specific ISI calibration when monitoring LA patients on warfarin 1
• Avoid point-of-care INR devices in LA-positive patients 1
• Establish a baseline INR measurement before starting warfarin therapy to verify if the local thromboplastin is sensitive to the patient's LA 1
• When INR values remain erratic despite using LA-insensitive thromboplastins, switch to chromogenic factor X assay 1
• Consider direct oral anticoagulants (DOACs) as an alternative treatment option for LA patients with unreliable INR measurements 3

Caveats and Pitfalls

• The chromogenic factor X assay, while reliable, is expensive and not widely available in all laboratories 4
• Factors that can influence INR measurement accuracy include citrate concentration in blood collection tubes, underfilled collection tubes, and automated clot detectors 1
• Avoid frequent dose adjustments based solely on single INR values that seem inconsistent with the clinical picture or previous stable pattern 1
• Some studies suggest that LA interference on PT-INR with most commercial thromboplastins is not enough to cause concern for the majority of treated patients if LA-insensitive thromboplastins are used 2