Warfarin and the antiphospholipid syndrome: does one size fit all?

The antiphospholipid syndrome (APS) is one of the most common causes of acquired thrombophilia, although it is almost unknown to the general public and often overlooked by primary care physicians. Among rheumatologists and other subspecialists that care for patients with this condition, APS is well known but remains perplexing. The clinical presentations are often dramatic and severe: stroke in young people, multiple and unexplained miscarriages in otherwise healthy women, and recurrent deep vein thrombosis in the absence of common risk factors. The interpretation of laboratory tests for antiphospholipid antibodies (aPL) can be difficult due to antibody heterogeneity, the variety of available assays, and interlaboratory variability. Treatment decisions may be surprisingly difficult. On one hand, the need for anticoagulation to prevent recurrent thrombotic events seems clear. On the other hand, many questions must be addressed for each patient. What anticoagulant is best? What level of anticoagulation is needed? How should anticoagulation be monitored in light of the fact that aPL may interfere with certain types of coagulation assays? For how long should patients be treated? Is it ever safe to reduce or discontinue treatment? Unfortunately, the medical literature provides only limited guidance to physicians trying to answer these questions. In this issue of Arthritis Care & Research, RuizIrastorza et al present a very useful, thorough, and scholarly review of the published data on secondary thromboprophylaxis in APS (1). They correctly point out that there are very few randomized controlled trials, and that even these have a number of shortcomings, e.g., exclusion of patients with more severe disease and patients with recurrent events. The authors have done an excellent job of assimilating data on high-risk APS patients (arterial and recurrent thromboses) from the published literature and have put forward recommendations for the management of this subset of patients. Given the paucity of randomized controlled studies addressing high-risk subsets, observational cohort studies and subgroup analyses from prospective studies were analyzed and included in the systematic review. The key question in the management of patients with APS and the topic of much debate and controversy is what constitutes adequate anticoagulation. Anticoagulation with vitamin K antagonists such as warfarin is routinely measured by the prothrombin time and expressed as the international normalized ratio (INR). In general, an INR of 2.0–3.0 (moderate-intensity anticoagulation) is the recommended goal for anticoagulant therapy for venous thromboembolism (2). In setting a target INR range for anticoagulation and managing warfarin dosage, it is important to understand the pharmacology of vitamin K antagonists. Not all vitamin K–dependent proteins (factors II, VII, IX, X, protein C, protein S, and protein Z) are affected equally by vitamin K antagonists, and not all have the same effect on the INR. The INR is affected primarily by levels of factor II (prothrombin), factor VII, and factor X. Among these, the level of factor VII has the greatest impact on the INR, whereas prothrombin has the least impact (3). In contrast, it is the level of prothrombin that most accurately reflects the capacity for thrombin generation and is thought to be the most important determinant of the therapeutic effect of warfarin (4,5). Thus, although the INR is the standard of care for monitoring warfarin therapy, it is not necessarily the best measure of therapeutic efficacy. Prothrombin is also the vitamin K–dependent factor with the longest halflife. This is important to bear in mind when anticoagulation is initiated and when dose alterations are made. Immediate changes in the INR are driven by changes in factor VII, not prothrombin. Therefore, an INR in the 2.0–3.0 range may or may not represent a therapeutically low level of prothrombin. For this reason, while evaluating the results of clinical studies, it is important to consider warfarin dose alterations and their temporal relationship to Raj S. Kasthuri, MB, BS, Robert A. S. Roubey, MD: University of North Carolina at Chapel Hill. Address correspondence to Robert A. S. Roubey, MD, Division of Rheumatology, Allergy, and Immunology, Thurston Arthritis Research Center, The University of North Carolina at Chapel Hill, CB #7280, Room 3330 Thurston Building, Chapel Hill, NC 27599-7280. E-mail: roubey@med. unc.edu. Submitted for publication July 23, 2007; accepted August 10, 2007. Arthritis & Rheumatism (Arthritis Care & Research) Vol. 57, No. 8, December 15, 2007, pp 1346–1347 DOI 10.1002/art.23111 © 2007, American College of Rheumatology