I got a little too little and a lot too much

That's enough of that stuff

Marcia Ball

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, Ruiz-Irastorza 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 half-life. 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 adverse events, as well as the INR at the time of an adverse event.

Another caveat regarding the interpretation of the INR in APS involves aPL. In patients with APS, particularly those with a lupus anticoagulant (LAC), aPL may interfere with the prothrombin time assay, leading to an unreliable INR. This phenomenon has been reported to occur in 6.5–10% of patients with an LAC (6–8). It occurs most often in the subset of patients that have a prolonged INR prior to initiation of anticoagulant therapy. Simple reliance on the INR may not always provide an accurate assessment of the level of anticoagulation in patients with APS.

Given these concerns, as well as the available clinical data, we favor a more individualized approach to the management of anticoagulant therapy. Once a patient has been started on warfarin and a stable INR in the 2.0–3.0 range has been achieved, we recommend checking the INR and a factor II (prothrombin) activity assay simultaneously. If the patient is adequately anticoagulated, i.e., the factor II level is in the therapeutic range (15–25%) (3), there is no reason to increase the INR target. In such a patient, a higher INR target range would significantly increase the risk of bleeding and probably offer little additional protection against thrombosis. In contrast, if a patient with an INR in the 2.0–3.0 range has a factor II level >30% and is therefore not adequately anticoagulated, the dose of warfarin needs to be increased to achieve a therapeutic factor II level (9). For subsequent monitoring of such a patient, an INR range corresponding to a therapeutic factor II level could be established or the INR may be abandoned in favor of the factor II assay. Chromogenic factor X assays have also been used as an alternative approach to check the level and adequacy of anticoagulation in patients with an LAC. Although this individualized approach is rational and based on sound pharmacologic principles, it is important to note that it has not been studied in any randomized clinical trials.

The optimal degree of anticoagulation for patients with arterial thrombosis as the initial event remains unclear. As Ruiz-Irastorza et al (1) point out, only 1 observational study attempts to specifically address this issue (10). Therefore, it may be premature to advocate high-intensity anticoagulation (target INR range 3.0–4.0) for all patients with APS with arterial thrombosis in the absence of randomized controlled trials. One treatment approach that may be beneficial in this subset of patients is the combined use of vitamin K antagonists and antiplatelet agents. Such combination therapy has been shown to be beneficial only in specific situations such as mechanical heart valves (11), and is associated with a more than 2-fold increase in bleeding risk (12). Despite this risk, a recent study showed that the use of such combination therapy is common among patients with cardiac diseases in the community (13). This approach in patients with APS needs to be appropriately studied. The literature provides very little guidance for the treatment of APS patients with arterial events and high-risk patients. Randomized controlled trials and cohort studies focusing on patients with APS in these subgroups are greatly needed.


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  • 1
    Ruiz-Irastorza G, Hunt BJ, Khamashta MA. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum 2007; 57: 14871495.
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    Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy [published erratum appears in Chest 2005;127:416]. Chest 2004; 126(3 Suppl ): 401S28S.
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    Sise HS, Lavelle SM, Adamis D, Becker R. Relation of hemorrhage and thrombosis to prothrombin during treatment with coumarin-type anticoagulants. N Engl J Med 1958; 259: 26671.
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    Zivelin A, Rao LV, Rapaport SI. Mechanism of the anticoagulant effect of warfarin as evaluated in rabbits by selective depression of individual procoagulant vitamin K-dependent clotting factors. J Clin Invest 1993; 92: 213140.
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    Salem DN, Stein PD, Al-Ahmad A, Bussey HI, Horstkotte D, Miller N, et al. Antithrombotic therapy in valvular heart disease-native and prosthetic: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl ): 457S82S.
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    Douketis JD, Arneklev K, Goldhaber SZ, Spandorfer J, Halperin F, Horrow J. Comparison of bleeding in patients with nonvalvular atrial fibrillation treated with ximelagatran or warfarin: assessment of incidence, case-fatality rate, time course and sites of bleeding, and risk factors for bleeding. Arch Intern Med 2006; 166: 8539.
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    Johnson SG, Witt DM, Eddy TR, Delate T. Warfarin and antiplatelet combination use among commercially insured patients enrolled in an anticoagulation management service. Chest 2007; 131: 15007.