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Monitoring Warfarin Therapy in Patients with Lupus Anticoagulants

Stephan Moll, MD; and Thomas L. Ortel, MD, PhD
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For author affiliations and current author addresses, see end of text. For definitions of terms used in the article, see the glossary at end of text. Acknowledgments: The authors thank the staff of the Duke Clinical Coagulation Laboratory for technical assistance; Gerold Bepler, MD, Stephen Kantrow, MD, and Charles Greenberg, MD, for critical review of the manuscript; and Victor Hasselblad, PhD, for statistical analysis. Grant Support: In part by an Institutional Research Grant (ACS-IRG 158K) from the American Cancer Society; a Clinician-Scientist Award Initiation Grant (91-149) from the American Heart Association and Genentech, Inc.; and a grant (MO1-RR-30) from the National Center for Research Resources, General Clinical Research Centers Program, National Institutes of Health. Dr. Ortel is a Pew Scholar in the Biomedical Sciences. Requests for Reprints: Thomas L. Ortel, MD, PhD, Box 3422, Department of Medicine, Division of Hematology, Duke University Medical Center, Durham, NC 27710. Current Author Addresses: Dr. Moll: Franz-Volhard-Klinik, Virchowklinikum, Medizinische Fakultat Charite der Humboldt-Universitt zu Berlin, 13122 Berlin, Germany.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1997;127(3):177-185. doi:10.7326/0003-4819-127-3-199708010-00001
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Background: Recommended therapeutic international normalized ratios (INRs) for oral anticoagulation in patients with lupus anticoagulants who sustain a thromboembolic event are controversial. Patients with lupus anticoagulants often have a prolonged prothrombin time, which may complicate management of anticoagulant therapy.

Objectives: To determine the validity of the INR as a monitor for warfarin therapy in patients with lupus anticoagulants and to investigate alternate approaches to monitoring warfarin therapy in these patients.

Design: Prospective case series.

Setting: Tertiary care hospital.

Patients: 34 patients with lupus anticoagulants.

Measurements: Prothrombin times were determined by using several thromboplastins, and INRs were calculated for the patients receiving warfarin. Factor II levels, chromogenic factor X levels, and prothrombin-proconvertin times were determined for patients receiving warfarin.

Results: For patients with lupus anticoagulants who were not receiving warfarin, prothrombin times were often elevated and varied significantly with different thromboplastins. Individual thromboplastins differed in sensitivity to the presence of a lupus anticoagulant. For patients receiving warfarin, INRs obtained by using different thromboplastins greatly varied and often overestimated the extent of anticoagulation. Chromogenic factor X levels and prothrombin-proconvertin times correlated well with each other and with established therapeutic ranges.

Conclusions: Lupus anticoagulants can influence prothrombin times and lead to INRs that do not accurately reflect the true level of anticoagulation. Use of the INR to standardize prothrombin times is invalid for some patients with lupus anticoagulants. To prevent supratherapeutic or subtherapeutic anticoagulation, these patients must be individually monitored with a test that is insensitive to lupus anticoagulants.


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Figure 1.
Coagulation cascade showing the coagulation reactions of the activated partial thromboplastin time, the dilute Russell viper venom time, the prothrombin time, and the prothrombin-proconvertin time.[15, 16]

Phospholipid-dependent reactions (PL) include activation of factor X to factor Xa by factor VIIa-tissue factor (extrinsic factor X-ase complex), the activation of factor X by factor IXa in the presence of factor VIIIa and calcium ions (intrinsic factor X-ase complex), and the activation of prothrombin by factor Xa in the presence of factor Va and calcium ions (prothrombinase complex). Antiphospholipid antibodies have been shown to interfere in vitro with the activation of factor X by the intrinsic factor X-ase complex and the activation of prothrombin by the prothrombinase complex .

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Figure 2.
International normalized ratios of 16 patients (designated by L) who had lupus anticoagulants and were receiving warfarin and 10 patients (designated by N) who did not have lupus anticoagulants and were receiving warfarin.

The ratios were obtained by using eight different thromboplastins (white square = Dade Innovin, black square = Simplastin Excel, white triangle = Dade Thromboplastin C Plus, black triangle = Simplastin Excel S, white circle = Dade Thromboplastin IS, black circle = Simplastin, white diamond = MDA Simplastin L, and black diamond = Sigma thromboplastin).

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Figure 3.
Therapeutic and nontherapeutic results obtained by using the prothrombin-proconvertin time, chromogenic factor X, and factor II assays and by using international normalized ratios.white circle

Values are for 16 patients who had lupus anticoagulants and were receiving warfarin. The results of the prothrombin-proconvertin time and chromogenic factor X assays are compared in the left panel, results of the factor II and chromogenic factor X assays are compared in the middle panel, and the international normalized ratios obtained by using Simplastin Excel S (black square) and Dade Thromboplastin IS ( ) and results of the chromogenic factor X assay are compared in the right panel. The horizontal and vertical lines mark the following therapeutic ranges for the individual assays: prothrombin-proconvertin time, 9% to 27%; chromogenic factor X, 11% to 42%; factor II, 5% to 35%; and international normalized ratio, 2 to 3.5. Values for the factor II, chromogenic factor X, and the prothrombin-proconvertin time assays are the percentage of control pooled plasma activity.

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