Antiphospholipid Syndrome: Avoiding Thrombotic and Obstetric Issues
Knowledge gaps regarding antiphospholipid syndrome pose challenges.
Knowledge gaps regarding antiphospholipid syndrome pose challenges.
Antiphospholipid syndrome (APS) is an autoimmune disorder that causes coagulation problems. It occurs in 2 forms. The first, vascular APS, primarily causes vascular thrombosis. The second form, obstetric APS, is similar but occurs in pregnant women and can cause harm to the woman and her unborn child (Table 1). With both conditions, patients develop persistent circulating antiphospholipid antibodies (aPLs), which include anticardiolipin antibodies, anti-beta2-glycoprotein I antibodies, and/or lupus anticoagulant (LA).1,2
Clinical thrombosis occurs when aPLs mediate the activation of platelets, monocytes, and endothelial cells. Subsequently, an inflammatory process disrupts the natural anticoagulant and fibrinolytic systems.3 Although all of the antibodies are significant, patients may not have all of them. The presence of LA is associated with the highest risk for causing both arterial thrombosis and venous thromboembolism. Patients deemed “triple positive” (possessing all 3 antibodies) are at highest risk for thrombosis and recurrent thrombosis.4
APS affects roughly 0.5% of the population, with approximately 80% of cases developing in women. Only 12% of cases are diagnosed after 50 years of age, making this primarily a disease of the young.8,9 APS may be idiopathic (also called primary) or may occur secondary to other related disease states such as systemic lupus erythematosus and a lupus-like syndrome.9 Approximately 13% of patients with stroke, 11% with myocardial infarction, 9.5% with deep vein thrombosis, and 6% with pregnancy morbidity are positive for aPLs. Despite adequate anticoagulation, 50% to 60% of patients with APS experience a thrombotic event within 6 years. Clearly, APS causes serious health consequences.10,11
Clinical management plans should focus on avoiding thrombotic and/or obstetric recurrences. Patients with vascular APS usually require long-term anticoagulants—management follows the process used to manage thrombotic events in the general population. If thrombosis occurs, patients receive unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for at least 5 days. They are then switched to oral anticoagulant agents, mainly vitamin K antagonists (VKAs). Among the VKAs, warfarin is used almost exclusively.1,2
In obstetric patients with APS, several strategies have been proposed to improve pregnancy outcomes, including combinations of low-dose aspirin and UFH or LMWH, with study results documenting improved pregnancy and live birth rates in patients managed this way. Thrombosis cannot explain all the aPL-mediated complications in obstetric APS.12 Unlike LMWH, heparin seems to prevent an aPL-related pathogenic action on the fetal side of the placenta (trophoblast cells) and also on maternal endometrial endothelial cells. Some experts prefer heparin for this reason. Among women who are treated adequately with aspirin and anticoagulants, 75% to 80% have successful pregnancies.13,14 Women who do not respond to aspirin and anticoagulants have limited options. Some clinicians prescribe prednisolone or intravenous immunoglobulin.5,15
The Drug Dilemma
Although VKAs remain the cornerstone of long-term APS treatment, their limits— narrow therapeutic window, food and drug interactions, and highly variable patient response—are well known. VKA management in APS patients requires close monitoring of international normalized ratio (INR). Frequent blood draws and rigid food rules may affect patients’ quality of life. Additionally, some patients with APS experience INR inaccuracy; they may need a higher INR therapeutic target of 3.0 to 4.0. APS patients with LA tend to have more problems with INR than others.1,2,16 LA interferes with INR and can prolong INR at baseline (before warfarin therapy starts). For these patients, experts still cannot agree on a standard INR target range.
Patients with LA-positive APS may benefit from use of an alternative test for warfarin monitoring: the chromogenic factor X (CFX) assay. CFX is a phospholipid- independent test unaffected by the LA clotting artifact. CFX results, reported as a percentage of normal activity, are inversely related to INR values. Normal target CFX ranges from 20% to 40%, where 40% equals an INR of 2.0 and 20% equals an INR of 3.0. The drawbacks with the CFX assay are its cost, which can exceed $400 per test, and the fact that many facilities send the test to an outside laboratory, creating a 24- to 72-hour delay. LA patients who have prolonged prothrombin time values at baseline and those who test positive for LA more than once not only benefit from this test, but they absolutely need it. Patients who experience recurrent venous thromboembolism may also benefit from more accurate monitoring with CFX. Some sites use CFX with INR monitoring when initiating anticoagulation. Once the patient stabilizes, the CFX is used intermittently (eg, once for every 4 to 6 INR draws) to ensure that the CFX and INR still correlate and the originally CFX-calibrated INR goal is still therapeutic.17
Newer Agents, Limited Role
The newer, direct oral anticoagulants inhibit a single enzyme of the coagulation cascade. Compared with VKA, they are more pharmacokinetically and pharmacodynamically stable profiles. Prescribed as fixed doses, they have few food or drug interactions, require no laboratory monitoring, and predictably address coagulation. To date, no large phase 3 clinical trials have been completed in APS patients, but they are under way. The role of anticoagulants in APS management remains uncertain. The 14th International Congress on Antiphospholipid Antibodies Task Force Report on Catastrophic Antiphospholipid Syndrome recommends using the directacting anticoagulant only in patients with proven VKA allergy or intolerance or poor anticoagulant control.18
Information is needed to fill our APS knowledge gaps. Despite decades of research, our understanding of how this condition develops remains elusive. The research community is forging ahead: The AntiPhospholipid Syndrome Alliance for Clinical Trials and International Networking group (APS ACTION) has been formed to promote research and to educate prescribers and patients. APS ACTION encourages persistently aPL-positive patients to enroll in largescale clinical trials.11 Other patient resources are listed in Table 2. As we learn and apply better information, perhaps patients with APS will be more likely to deliver healthy children and suffer fewer clot-related medical problems.
Ms. Bartok is a retired pharmacist and a professional writer. Her primary practice was in indigent care, and she currently manages a small caseload of elderly patients with chronic disease.
1. Moll S, Ortel T. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med. 1997;127:177-185.
2. Robert A, Le Querrec A, Delahousse B, et al. Control of oral anticoagulation in patients with the antiphospholipid syndrome: influence of the lupus anticoagulant on international normalized ratio. Thromb Haemost. 1998;80:99-103.
3. Willis R, Harris E, Pierangeli S. Pathogenesis of the antiphospholipid syndrome. Semin Thromb Hemost. 2012;38:305-321.
4. Galli M. The antiphospholipid triangle. J Thromb Haemost. 2010;8:234-236.
5. D'Ippolito S, Meroni PL, Koike T, Veglia M, Scambia G, Di Simone N. Obstetric antiphospholipid syndrome: a recent classification for an old defined disorder. Autoimmun Rev. 2014;13:901-908. 6. Meroni PL, Raschi E, Grossi E, et al. Obstetric and vascular APS: same autoantibodies but different diseases? Lupus. 2012;21:708-710.
7. Galarza-Maldonado C, Kourilovitch MR, Perez-Fernandez OM, et al. Obstetric antiphospholipid syndrome. Autoimmun Rev. 2012;11:288-295.
8. Cohen D, Berger S, Steup-Beekman G, Bloemenkamp K, Bajema I. Diagnosis and management of the antiphospholipid syndrome. Br Med J. 2010;340:c2541.
9. Cervera R, Piette J, Font J, et al. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002;46:1019-1027.
10. Gómez-Puerta JA, Cervera R. Diagnosis and classification of the antiphospholipid syndrome. J Autoimmun. 2014;48-49:20-25.
11. Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, Ramire de Jesus G, Erkan D. Estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature. Arthritis Care Res (Hoboken). 2013;65:1869-1873.
12. Girardi G, Redecha P, Salmon JE. Heparin prevents antiphospholipid antibody-induced fetal loss by inhibiting complement activation. Nat Med. 2004;10:1222-1226.
13. Ziakas PD, Pavlou M, Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol. 2010;115:1256-1262.
14. Ruffatti A, Tonello M, Visentin MS, et al. Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case-control study. Rheumatology. 2011;50:1684-1689.
15. Branch W; Obstetric Task Force. Report of the Obstetric APS Task Force: 13th International Congress on Antiphospholipid Antibodies, 13th April 2010. Lupus. 2011;20:158-164.
16. Adcock D, Duff S. Enhanced standardization of the international normalized ratio through the use of plasma calibrants: a concise review. Blood Coagul Fibrinolysis. 2000;11:583-590.
17. Crowl A, Schullo-Feulner A, Moon JY. Warfarin monitoring in antiphospholipid syndrome and lupus anticoagulant. Ann Pharmacother. 2014;48:1479-1483.
18. Cervera R, Rodríguez-Pintó I, Colafrancesco S, et al. 14th International Congress on Antiphospholipid Antibodies Task Force Report on Catastrophic Antiphospholipid Syndrome. Autoimmun Rev. 2014;13:699-707.