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Antiphospholipid Syndrome
CHAPTER 104
Antiphospholipid Syndrome Wendy Lim, MD, MSc Antiphospholipid syndrome (APS) is an acquired prothrombotic disorder characterized by the presence of antiphospholipid antibodies (aPL) in patients with venous and/or arterial thromboembolic complications or recurrent pregnancy morbidity. Patients with APS may have other clinical findings including thrombocytopenia and livedo reticularis. Antiphospholipid antibodies are autoantibodies that target phospholipid-binding proteins, and may cause prolongation of phospholipid-dependent coagulation assays such as the activated partial thromboplastin time (PTT). Despite this possible laboratory finding, aPL is associated with thrombotic rather than bleeding complications. There are many different types of aPL, but the aPL that are most strongly correlated with pathologic thrombosis are lupus anticoagulants (LA), anticardiolipin antibodies (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies. The target for most aPL appears to be β2-glycoprotein I (β2GPI), a plasma protein involved in the coagulation pathway although its exact physiologic function is unclear. APS can be primary (idiopathic) or secondary to autoimmune conditions (e.g. systemic lupus erythematosis [SLE]), drugs (e.g. chlorpromazine, procainamide, phenytoin) or infections (e.g. syphilis). Antiphospholipid antibodies that are infection- or drug-associated are often transient, and frequently lack anti-β2GPI activity, which may account for the lack of thrombotic complications in these patients.
Diagnosis: The diagnosis of APS is based on expert consensus criteria and has a clinical and laboratory component. Preliminary criteria for ‘definite APS’ were first published in 1999 and are known as the Sapporo criteria. These criteria were updated in 2005 and are currently used to diagnose APS (Table 104.1). The clinical criteria for APS include objectively confirmed arterial, venous or small vessel thrombosis, or pregnancy morbidity consisting of recurrent (three or more) fetal losses before the 10th week of gestation unexplained by maternal or paternal chromosomal abnormalities or by maternal anatomic or hormonal causes, one or more unexplained fetal deaths at or beyond the 10th week of gestation, or premature birth before the 34th week of gestation due to placental insufficiency, eclampsia or pre-eclampsia. The laboratory aspect of the diagnosis of APS is based on demonstrating the presence of aPL in a patient plasma or serum sample. aCL and anti-β2GPI antibodies are detected using enzyme-linked immunosorbent assays (ELISA) and LA is detected using screening and confirmatory clotting assays that have limited and excess phospholipid, respectively (see Chapter 129). Assays for other aPL, including antibodies against prothrombin, phosphatidylserine or phosphatidylinositol are currently not included in the diagnostic criteria as they are not standardized, and the clinical significance of these tests is uncertain. The presence of LA, medium or high titer IgG and/or IgM aCL (defined as greater than 40 GPL or MPL, or greater than the 99th percentile), and/or medium or high titer Transfusion Medicine and Hemostasis. http://dx.doi.org/10.1016/B978-0-12-397164-7.00104-X Copyright © 2013 Elsevier Inc. All rights reserved.
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TABLE 104.1 Revised Classification Criteria for Definite APS* APS is present if one or more clinical criteria and one laboratory criteria are met: Clinical criteria 1. Vascular thrombosis – arterial, venous or small vessel thrombosis. Thrombosis must be confirmed by objective testing or histopathology (no evidence of inflammation in the vessel wall) 2. Pregnancy morbidity a. One or more unexplained deaths of a morphologically normal fetus ≥10 weeks gestation (documented by ultrasound or direct examination) b. One or more premature births of a morphologically normal neonate <34 weeks gestation due to eclampsia, severe pre-eclampsia or placental insufficiency c. Three or more unexplained consecutive spontaneous abortions ≤10 weeks gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded Laboratory criteria All measurements must be documented on two or more occasions at least 12 weeks apart 1. LA present in plasma detected according to specific guidelines (a,b) 2. Anticardiolipin antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (>40 GPL or MPL or >99th percentile) measured by a standardized ELISA (c,d,e) 3. Anti-β2-glycoprotein-1 antibody of IgG and/or IgM isotype in serum or plasma (titer >99th percentile), measured by standardized ELISA according to recommended procedures (f) a. Brandt JT, Triplett DA, Alving B, Scharrer I. (1995). Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost 74, 1185–1190. b. Wisloff F, Jacobsen EM, Liestol S. (2002). Laboratory diagnosis of the antiphospholipid syndrome. Thromb Res 108, 263–271. c. Tincani A, Allegri F, Sanmarco M, Cinquini M, Taglietti M, Balestrieri G et al. (2001). Anticardiolipin antibody assay: a methodological analysis for a better consensus in routine determinations–a cooperative project of the European Antiphospholipid Forum. Thrombo Haemost 86, 575–583. d. Harris EN, Pierangeli SS. (2002). Revisiting the anticardiolipin test and its standardization. Lupus 11, 269–275. e. Wong RC, Gillis D, Adelstein S et al. (2004). Consensus guidelines on anti-cardiolipin antibody testing and reporting. Pathology 36, 63–68. f. Reber G, Tincani A, Sanmarco M, de Moerloose P, Boffa MC. (2004). Proposals for the measurement of anti-beta2glycoprotein I antibodies. Standardization group of the European Forum on Antiphospholipid Antibodies. J Thromb Haemost 2,1860–1862. *Adapted from Miyakis S, Lockshin MD, Atsumi T et al. (2006). International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4, 295–306.
IgG and/or IgM anti-β2GPI (defined as titers greater than the 99th percentile) meet the laboratory criteria. Notably, the aPL must be present on two or more occasions measured at least 12 weeks apart and no more than 5 years prior to clinical manifestations. Although there are no data to support the recommended time interval of 12 weeks, this concept of persistent aPL addresses the concern that transient aPL may result in misclassification of patients with APS. However, the significance of transient aPL is unclear and studies evaluating this, as well as the time interval, are required. There are patients who appear to have APS but do not meet the revised Sapporo criteria. It is important to note that the criteria were primarily designed to define a homogeneous population of patients for APS-related research studies. As a result, there are limitations in diagnosing APS when applying the criteria to individual patients, particularly in those who have ‘non-criteria’ manifestations. Clinical judgment, individual assessment and ongoing clinical and laboratory reassessment are recommended in these patients.
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Laboratory Measurement of aPL: Consensus guidelines describing the optimal laboratory techniques for measuring LA and aCL, and recommended procedures for measuring anti-β2-GPI antibodies have been proposed (see Chapter 129).
Lupus Anticoagulants: LA (non-specific inhibitors) are antibodies that block phospholipid surfaces and reduce the coagulant potential of plasma, thus prolonging in vitro clotting assays such as the PTT, the dilute Russell viper venom time (dRVVT) and the kaolin clotting time. Failure to correct the prolonged clotting time after a 1:1 mix with normal platelet-free plasma and correction after addition of excess phospholipids confirms the presence of LA. Consensus guidelines recommend screening for LA with at least two phospholipid-dependent coagulation tests. LA detection can be problematic in patients receiving anticoagulant therapy because clotting times will be prolonged. In patients receiving warfarin anticoagulation, the sample can be diluted with normal plasma prior to LA measurement. Treatment with unfractionated heparin or low molecular weight heparin can also cause false positive results.
Anticardiolipin Antibodies: aCL do not prolong coagulation assays and because they are detected using ELISA techniques are reported as a titer. These antibodies may be IgG, IgM and IgA isotypes, although only IgG and IgM are recognized in the revised Sapporo criteria, and the IgG isotype has the strongest association with thrombosis. The ELISA tests for aCL are not well standardized and aCL testing has shown poor concordance among laboratories. aCL are reported as a titer specific to the isotype (GPL or MPL units) but because the accuracy and reliability of assays are limited, consensus guidelines recommend semi-quantitative reporting of results as low, medium or high titer.
Anti-β2-GPI Antibodies: Anti-β2-GPI antibodies may be IgG, IgM or IgA isotypes but only IgG and IgM are recognized in the revised Sapporo criteria. These antibodies similarly do not prolong coagulation assays and are reported as a titer. Laboratory testing for these antibodies is not yet standardized. Association between Different APL and Thrombosis: β2GP1 appears to be
the main target for aPL and antibodies to β2GP1 appear to correlate with the development of APS better than aCL or LA alone. However, standardization of the assay remains an issue. The association between aPL and thrombosis is stronger with LA than aCL. Some, but not all, aCL bind β2GP1. Patients with positive aCL testing by ELISA but no anti-β2GP1 activity may have a lower risk of thrombosis but further study is required. Studies evaluating aCL and thrombotic risk have been complicated by the inclusion of patients with low titer aCL – which is likely of little clinical significance – making interpretation of these studies challenging.
Pathogenesis: The pathogenesis of APS is incompletely elucidated but data supports the role of endothelial cells, monocytes, platelets and the complement system. Binding of aPL to β2GPI activates endothelial cells with upregulation of adhesion molecule expression and tissue factor production, and activates platelets resulting in
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increased glycoprotein IIb/IIIa expression and thromboxane A2 production, actions that result in procoagulant effects on the coagulation pathway. Fibrinolysis may be impaired by aPL interactions with protein C and plasmin, proteins involved in regulation of the coagulation cascade. Disruption of the annexin A5 shield (which normally covers anionic thrombogenic surfaces), defective placentation and more recently, complement activation have been implicated in the pathogenesis of fetal loss in patients with APS. A two-hit hypothesis has been proposed, in which patients with aPL require a ‘second hit’ that results in the development of the syndrome. Because many patients with APS who develop thrombosis do so in the setting of an additional risk factor, it is thought that the second hit may be a condition that precipitates venous thromboembolism (e.g. immobilization, estrogen use, pregnancy or postpartum states, or malignancy) or the presence of one or more cardiovascular risk factors (e.g. hypertension, hyperlipidemia or smoking).
Clinical Features: Thrombosis: The most common presenting finding among patients with APS is deep vein thrombosis, found in 30% of patients. Pulmonary embolism occurs in 10%, as does superficial thrombophlebitis. Thrombosis involving the upper extremity veins, cerebral sinuses, renal, hepatic and mesenteric veins can also occur. The most common arterial thrombotic complication is ischemic stroke, occurring in approximately 13% of patients. Transient ischemic attack, myocardial infarction and thrombosis of the peripheral arterial system or arterial bypass grafts have also been reported.
Recurrent Fetal Loss and Pregnancy-Related Complications: Recurrent fetal loss occurs in approximately 8% of patients with APS. Fetal loss can be early or late, and pregnancy complications such as eclampsia, pre-eclampsia and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome can also occur. Patients with APS may also present with ‘non-criteria’ findings. These include those described in the following sections.
Hematologic Manifestations: Thrombocytopenia (platelets <100,000/μl) is one of the most common findings, present in approximately 20% of patients with APS. The degree of thrombocytopenia is usually mild to moderate. The presence of thrombocytopenia does not appear to reduce thrombotic risk in patients with APS, nor does it appear to be associated with bleeding. Less commonly, patients can present with hemolytic anemia that is microangiopathic or autoimmune. In patients with thrombotic microangiopathy and aPL, thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), catastrophic APS (CAPS), acute renal failure, malignant hypertension and HELLP syndrome need to be considered. Although APS is associated with thrombosis, it can rarely be associated with bleeding complications if the aPL are directed against prothrombin. Most case reports of this occurrence are in patients with SLE or who have a transient viral infection who present with cutaneous purpura or epistaxis. These patients generally have LA that bind prothrombin and result in clearance of prothrombin.
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Skin Manifestations: The classic rash in APS is livedo reticularis, a red rash with a lacy, net-like pattern, present in approximately 20% of patients with APS. Sneddon’s syndrome is diagnosed in patients with livedo reticularis and stroke. Patients with livedo reticularis typically have arterial rather than venous thrombosis. Other skin manifestations include digital gangrene or necrosis, splinter hemorrhages, skin ulcers and pseudovasculitic skin lesions.
Neurologic Manifestations: Symptoms other than stroke include cognitive deficits, headache or migraine. Unusual presentations include seizure, and mood or movement disorders. Neuroimaging may reveal white matter lesions in patients with cognitive deficits suggestive of a vasculopathy.
Cardiovascular Disease: In addition to coronary artery disease and thrombosis, patients with APS can have valvular heart disease, with thickening of the valve leaflets, nodules or vegetations. The mitral valve is more commonly affected than the aortic valve. There have also been reports of intracardiac thrombi, pericardial effusion and cardiomyopathy. Peripheral arterial disease with thrombosis can also occur. Pulmonary Disease: Pulmonary hypertension can develop independent or secondary to chronic thromboembolic disease. Other pulmonary conditions including alveolar hemorrhage, fibrosing alveolitis and adult respiratory distress syndrome have been reported. Gastrointestinal Disease: Thrombosis resulting in ischemia of the bowel, colon, or esophagus with resultant gastrointestinal bleeding, as well as splenic and pancreatic infarction has been reported. Thrombosis of the hepatic or portal veins can result in Budd-Chiari syndrome, an unusual complication of APS.
Management of Patients with APS: The mainstay of APS treatment is antithrombotic therapy. Other treatments may have a role in the management of APS but are supported by little evidence. These include hydroxychloroquine for patients who have APS and SLE, and plasma exchange in patients who have CAPS. Antithrombotic Therapy: Appropriate use of antithrombotic agents requires an assessment of the bleeding risk balanced against the risk of thrombosis. In the following section, the evidence supporting the optimal antithrombotic management for different scenarios involving patients with aPL is outlined.
Bleeding Risk: The risk of major bleeding in patients with APS is estimated at 2–3% per year, based on studies evaluating the efficacy of warfarin in patients with APS. This is comparable to the bleeding rates observed in anticoagulated patients without APS. This risk may be higher in selected patients who have severe thrombocytopenia or patients with aPL directed against prothrombin. However for the vast majority of patients with APS, this bleeding rate is exceeded by the risk of recurrent thrombosis.
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Antithrombotic Management of Patients with aPL Without Prior Thrombosis: The role of antithrombotic prophylaxis in asymptomatic patients with aPL is controversial. Observational studies suggest aspirin may be effective in reducing thromboembolic complications in patients with aPL and no prior thrombosis. However, a small randomized trial and parallel observational study demonstrated no benefit. In this trial, 98 asymptomatic patients who were persistently aPL-positive were randomized to placebo or aspirin 81 mg/day. After a mean of 2.3 years, there was no difference in the rates of thrombosis between the groups (aspirin 2.75 per 100 patient years, placebo 0 per 100 patient years). The parallel observational study in 74 asymptomatic persistently aPLpositive patients who were already taking aspirin or declined randomization into the trial showed similar results. Most patients who developed thrombosis had additional risk factors for this (e.g. hypertension, smoking, obesity, or use of estrogen). Taken together, it appears that the risk of thrombosis in asymptomatic persistently aPL-positive patients is low, and aspirin does not appear to reduce thrombotic events. However, given that the trial was relatively small and there are observational data that support aspirin – particularly in patients who have SLE – some experts recommend aspirin for these patients. This is reflected in recommendations from an expert panel, who recommend that asymptomatic patients with aPL who have SLE receive aspirin and hydroxychloroquine. These experts also recommend strict control of cardiovascular risk factors and use of thromboprophylaxis in high risk situations for all asymptomatic patients with aPL. Antithrombotic Management of Patients with aPL and Venous Thromboembolism: Initial Treatment: Treatment of venous thromboembolism in patients with APS is identical to patients without APS, consisting of initial parenteral therapy with unfractionated heparin, low molecular weight heparin or fondaparinux usually overlapped with vitamin K antagonists. The parenteral therapy is continued for a minimum of 5 days and until the international normalized ratio (INR) is above 2.0 for at least 24 hours. Alternately, oral therapy with rivaroxaban can be used, although rivaroxaban has not been specifically studied in patients with APS. Long-Term Treatment: Retrospective studies suggest that high intensity warfarin (INR greater than 3.0) is more effective than either aspirin or warfarin administered with a target INR less than 3.0. However, two randomized trials have shown that high intensity warfarin is not superior to moderate intensity warfarin (INR 2.0–3.0) in preventing recurrent thrombosis. These trials enrolled 114 and 109 APS patients respectively, and found that the incidence of recurrent thrombosis was approximately 11% among patients who received high intensity warfarin and was 3.5–5.5% among patients who received moderate intensity warfarin. Major bleeding rates were comparable between both groups. When the results of both trials were combined in a meta-analysis, a significant excess of minor bleeding was evident in patients allocated to high intensity warfarin. These trials demonstrate that if warfarin is used for patients with venous thromboembolism and APS, it should be administered at moderate intensity with a target INR of 2.0–3.0. Duration of Treatment: The optimal duration of anticoagulation to prevent recurrent venous thromboembolism in patients with aPL is unknown. The best estimates of the risk of recurrent venous thromboembolism among patients with aPL and prior venous
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thromboembolism is based on retrospective studies of untreated patients or studies of patients followed prospectively after their anticoagulants have been discontinued. Prospective studies suggest there is an increased risk of recurrence, ranging from 10–67% per year. In the largest prospective study, 412 patients with a first episode of venous thromboembolism were tested for aCL 6 months following their initial event, and followed prospectively after their anticoagulants were discontinued. Over 4 years, 29% of patients with elevated aCL had recurrent thrombosis, compared with 14% of patients without aCL (risk ratio [RR] 2.1, 95% CI 1.3–3.3). Notably, the patients included in these prospective studies had aPL testing performed once which would not meet the revised Sapporo criteria for definite APS. The risk of recurrence appears to be highest during the first 6 months following warfarin discontinuation, with an event rate of 1.30 events per year of follow-up. Based on these data, the general consensus is to treat patients with APS and venous thromboembolism for at least 3 months, although many of these patients receive indefinite duration anticoagulation given the high risks of recurrence.
Antithrombotic Management of Patients with aPL and Ischemic Stroke: Antithrombotic recommendations for these patients are controversial. A nested prospective cohort study within a randomized trial evaluated the effect of warfarin (INR 1.4–2.8) and aspirin 325 mg/day in 1,770 patients with ischemic stroke where aPL were measured once prior to study entry. In patients who had positive testing for aPL, there was no difference in the risk of thrombotic events in the patients treated with warfarin (RR 0.99, 95% CI 0.75–1.31) compared with aspirin (RR 0.94, 95% CI 0.70–1.28). Based on this study, some experts recommend aspirin since no anticoagulant monitoring is required compared to warfarin. However, there are limitations in generalizing the results of this study, since only one aPL measurement was performed and it is unclear how many patients would meet the revised Sapporo criteria for definite APS. Consequently, other experts continue to recommend warfarin or combination warfarin and aspirin for patients with aPL and ischemic stroke, particularly for patients meeting the criteria for definite APS. Antithrombotic Management of Women with aPL and Pregnancy Loss: Systematic reviews which have evaluated heparin, aspirin and combination heparin and aspirin therapy suggest that for women who meet the revised Sapporo criteria for definite APS based on pregnancy morbidity and have no history of thrombosis and are pregnant, unfractionated heparin combined with aspirin appears to reduce the incidence of pregnancy loss. Expert recommendations based on these studies suggest using intermediate dose unfractionated heparin (e.g. 5,000–7,500 units subcutaneously every 12 hours) or low molecular weight heparin in standard prophylactic doses and low dose aspirin (75–100 mg/day).
Other Therapies: Hydroxychloroquine: There is some data to suggest that hydroxychloroquine may be useful for preventing thromboembolic complications in patients with APS, particularly in patients with SLE. However, hydroxychloroquine has not been studied prospectively in combination with aspirin and it is unclear if the effects are primarily on the SLE or on aPL.
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Plasma Exchange: Plasma exchange, with or without intravenous gamma globulin (IVIG), has been employed with success in patients with CAPS. Although plasma exchange for CAPS has not been formally evaluated in randomized studies, an assessment of 250 patients enrolled in the CAPS registry found that use of plasma exchange (in combination with other therapies) resulted in higher survival rates. The number of plasma exchange procedures required is unknown, but expert recommendations suggest at least five consecutive treatments.
Challenges in APS Management: There remain several scenarios where the antithrombotic management of patients with APS is uncertain, with no available clinical studies to guide their management. These include the management of patients with APS and recurrent thrombosis, and the management of patients with aPL and arterial thromboses other than ischemic stroke. Patients with aPL and Recurrent Thromboembolism: Patients who have recurrent thrombotic events despite adequate anticoagulation with warfarin have various options, based on expert opinion. These options include increasing the target INR from 2.0–3.0 to 3.1–4.0, adding low dose aspirin, low molecular weight heparin or hydroxychloroquine. Patients with aPL and Other Arterial Thromboses: There are no prospective studies evaluating optimal treatment of patients with aPL-associated arterial thrombosis outside of ischemic stroke. Many patients with myocardial infarction and aPL are treated empirically with long-term warfarin therapy administered to achieve an INR of 2.0–3.0 based on data extrapolated from venous thromboembolism studies.
Catastrophic APS: A subset of patients with APS have a malignant form of APS known as CAPS characterized by multi-organ thrombotic involvement. Preliminary criteria for CAPS include a history of APS and/or presence of aPL, thrombosis involving three or more organ systems within a week, histopathologic confirmation of microthrombosis and exclusion of other causes of multiple organ thromboses. The treatment of CAPS involves treating any identifiable causes (e.g. infection), anticoagulation (usually with heparin followed by long-term warfarin), high dose glucocorticoids (e.g. methylprednisolone 1 g IV daily for 3 days followed by prednisone 1–2 mg/kg/day) and plasma exchange with or without IVIG. The prognosis of CAPS is poor without treatment, and intensive treatment results in survival rates of 50–80%.
Future Directions: APS is a complex disorder with evolving diagnostic criteria. Insight into the pathophysiology of APS may lead to novel treatments for APS, which to date have focused on antithrombotic therapy. Complement activation may play an important role in fetal loss, and although there is currently no specific complement-targeted therapy approved for patients with APS, complement inhibition may prove to be a novel upstream treatment for APS. Other investigational treatments include the use of rituximab, other immunosuppressive agents and autologous stem cell transplantation, all of which require further study. Management of patients with aPL and APS can be challenging, as many patients with APS
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have risk factors for bleeding and have a high risk of recurrent thromboembolism. The clinical trials and observational studies performed to date have yielded valuable information on the management of patients with APS, but further research is required to address the ongoing controversies that exist in the management of these patients.
Recommended Reading APASS Writing Committee. (2004). Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA 291, 576–584. Bates SM, Greer IA, Middeldorp S et al. (2012). VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141(Suppl 2), e691S–e736S. Crowther MA, Ginsberg JS, Julian J et al. (2003). A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 349, 1133–1138. Erkan D, Harrison MJ, Levy R et al. (2007). Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebocontrolled trial in asymptomatic antiphospholipid antibody-positive individuals. Arthritis Rheum 56, 2382–2391. Finazzi G, Marchioli R, Brancaccio V et al. (2005). A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 3, 848–853. Mak A, Cheung MW, Cheak AA, Ho RC. (2010). Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology (Oxford) 49, 281–288. Miyakis S, Lockshin MD, Atsumi T et al. (2006). International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4, 295–306. Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I et al. (2011). Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus 20, 206–218. Schulman S, Svenungsson E, Granqvist S and the Duration of Anticoagulation Study Group. (1998). Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med 104, 332–338.
Antiphospholipid Syndrome Wendy Lim, MD, MSc Antiphospholipid syndrome (APS) is an acquired prothrombotic disorder characterized by the presence of antiphospholipid antibodies (aPL) in patients with venous and/or arterial thromboembolic complications or recurrent pregnancy morbidity. Patients with APS may have other clinical findings including thrombocytopenia and livedo reticularis. Antiphospholipid antibodies are autoantibodies that target phospholipid-binding proteins, and may cause prolongation of phospholipid-dependent coagulation assays such as the activated partial thromboplastin time (PTT). Despite this possible laboratory finding, aPL is associated with thrombotic rather than bleeding complications. There are many different types of aPL, but the aPL that are most strongly correlated with pathologic thrombosis are lupus anticoagulants (LA), anticardiolipin antibodies (aCL) and anti-β2 glycoprotein I (anti-β2GPI) antibodies. The target for most aPL appears to be β2-glycoprotein I (β2GPI), a plasma protein involved in the coagulation pathway although its exact physiologic function is unclear. APS can be primary (idiopathic) or secondary to autoimmune conditions (e.g. systemic lupus erythematosis [SLE]), drugs (e.g. chlorpromazine, procainamide, phenytoin) or infections (e.g. syphilis). Antiphospholipid antibodies that are infection- or drug-associated are often transient, and frequently lack anti-β2GPI activity, which may account for the lack of thrombotic complications in these patients.
Diagnosis: The diagnosis of APS is based on expert consensus criteria and has a clinical and laboratory component. Preliminary criteria for ‘definite APS’ were first published in 1999 and are known as the Sapporo criteria. These criteria were updated in 2005 and are currently used to diagnose APS (Table 104.1). The clinical criteria for APS include objectively confirmed arterial, venous or small vessel thrombosis, or pregnancy morbidity consisting of recurrent (three or more) fetal losses before the 10th week of gestation unexplained by maternal or paternal chromosomal abnormalities or by maternal anatomic or hormonal causes, one or more unexplained fetal deaths at or beyond the 10th week of gestation, or premature birth before the 34th week of gestation due to placental insufficiency, eclampsia or pre-eclampsia. The laboratory aspect of the diagnosis of APS is based on demonstrating the presence of aPL in a patient plasma or serum sample. aCL and anti-β2GPI antibodies are detected using enzyme-linked immunosorbent assays (ELISA) and LA is detected using screening and confirmatory clotting assays that have limited and excess phospholipid, respectively (see Chapter 129). Assays for other aPL, including antibodies against prothrombin, phosphatidylserine or phosphatidylinositol are currently not included in the diagnostic criteria as they are not standardized, and the clinical significance of these tests is uncertain. The presence of LA, medium or high titer IgG and/or IgM aCL (defined as greater than 40 GPL or MPL, or greater than the 99th percentile), and/or medium or high titer Transfusion Medicine and Hemostasis. http://dx.doi.org/10.1016/B978-0-12-397164-7.00104-X Copyright © 2013 Elsevier Inc. All rights reserved.
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TABLE 104.1 Revised Classification Criteria for Definite APS* APS is present if one or more clinical criteria and one laboratory criteria are met: Clinical criteria 1. Vascular thrombosis – arterial, venous or small vessel thrombosis. Thrombosis must be confirmed by objective testing or histopathology (no evidence of inflammation in the vessel wall) 2. Pregnancy morbidity a. One or more unexplained deaths of a morphologically normal fetus ≥10 weeks gestation (documented by ultrasound or direct examination) b. One or more premature births of a morphologically normal neonate <34 weeks gestation due to eclampsia, severe pre-eclampsia or placental insufficiency c. Three or more unexplained consecutive spontaneous abortions ≤10 weeks gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded Laboratory criteria All measurements must be documented on two or more occasions at least 12 weeks apart 1. LA present in plasma detected according to specific guidelines (a,b) 2. Anticardiolipin antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (>40 GPL or MPL or >99th percentile) measured by a standardized ELISA (c,d,e) 3. Anti-β2-glycoprotein-1 antibody of IgG and/or IgM isotype in serum or plasma (titer >99th percentile), measured by standardized ELISA according to recommended procedures (f) a. Brandt JT, Triplett DA, Alving B, Scharrer I. (1995). Criteria for the diagnosis of lupus anticoagulants: an update. On behalf of the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH. Thromb Haemost 74, 1185–1190. b. Wisloff F, Jacobsen EM, Liestol S. (2002). Laboratory diagnosis of the antiphospholipid syndrome. Thromb Res 108, 263–271. c. Tincani A, Allegri F, Sanmarco M, Cinquini M, Taglietti M, Balestrieri G et al. (2001). Anticardiolipin antibody assay: a methodological analysis for a better consensus in routine determinations–a cooperative project of the European Antiphospholipid Forum. Thrombo Haemost 86, 575–583. d. Harris EN, Pierangeli SS. (2002). Revisiting the anticardiolipin test and its standardization. Lupus 11, 269–275. e. Wong RC, Gillis D, Adelstein S et al. (2004). Consensus guidelines on anti-cardiolipin antibody testing and reporting. Pathology 36, 63–68. f. Reber G, Tincani A, Sanmarco M, de Moerloose P, Boffa MC. (2004). Proposals for the measurement of anti-beta2glycoprotein I antibodies. Standardization group of the European Forum on Antiphospholipid Antibodies. J Thromb Haemost 2,1860–1862. *Adapted from Miyakis S, Lockshin MD, Atsumi T et al. (2006). International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4, 295–306.
IgG and/or IgM anti-β2GPI (defined as titers greater than the 99th percentile) meet the laboratory criteria. Notably, the aPL must be present on two or more occasions measured at least 12 weeks apart and no more than 5 years prior to clinical manifestations. Although there are no data to support the recommended time interval of 12 weeks, this concept of persistent aPL addresses the concern that transient aPL may result in misclassification of patients with APS. However, the significance of transient aPL is unclear and studies evaluating this, as well as the time interval, are required. There are patients who appear to have APS but do not meet the revised Sapporo criteria. It is important to note that the criteria were primarily designed to define a homogeneous population of patients for APS-related research studies. As a result, there are limitations in diagnosing APS when applying the criteria to individual patients, particularly in those who have ‘non-criteria’ manifestations. Clinical judgment, individual assessment and ongoing clinical and laboratory reassessment are recommended in these patients.
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Laboratory Measurement of aPL: Consensus guidelines describing the optimal laboratory techniques for measuring LA and aCL, and recommended procedures for measuring anti-β2-GPI antibodies have been proposed (see Chapter 129).
Lupus Anticoagulants: LA (non-specific inhibitors) are antibodies that block phospholipid surfaces and reduce the coagulant potential of plasma, thus prolonging in vitro clotting assays such as the PTT, the dilute Russell viper venom time (dRVVT) and the kaolin clotting time. Failure to correct the prolonged clotting time after a 1:1 mix with normal platelet-free plasma and correction after addition of excess phospholipids confirms the presence of LA. Consensus guidelines recommend screening for LA with at least two phospholipid-dependent coagulation tests. LA detection can be problematic in patients receiving anticoagulant therapy because clotting times will be prolonged. In patients receiving warfarin anticoagulation, the sample can be diluted with normal plasma prior to LA measurement. Treatment with unfractionated heparin or low molecular weight heparin can also cause false positive results.
Anticardiolipin Antibodies: aCL do not prolong coagulation assays and because they are detected using ELISA techniques are reported as a titer. These antibodies may be IgG, IgM and IgA isotypes, although only IgG and IgM are recognized in the revised Sapporo criteria, and the IgG isotype has the strongest association with thrombosis. The ELISA tests for aCL are not well standardized and aCL testing has shown poor concordance among laboratories. aCL are reported as a titer specific to the isotype (GPL or MPL units) but because the accuracy and reliability of assays are limited, consensus guidelines recommend semi-quantitative reporting of results as low, medium or high titer.
Anti-β2-GPI Antibodies: Anti-β2-GPI antibodies may be IgG, IgM or IgA isotypes but only IgG and IgM are recognized in the revised Sapporo criteria. These antibodies similarly do not prolong coagulation assays and are reported as a titer. Laboratory testing for these antibodies is not yet standardized. Association between Different APL and Thrombosis: β2GP1 appears to be
the main target for aPL and antibodies to β2GP1 appear to correlate with the development of APS better than aCL or LA alone. However, standardization of the assay remains an issue. The association between aPL and thrombosis is stronger with LA than aCL. Some, but not all, aCL bind β2GP1. Patients with positive aCL testing by ELISA but no anti-β2GP1 activity may have a lower risk of thrombosis but further study is required. Studies evaluating aCL and thrombotic risk have been complicated by the inclusion of patients with low titer aCL – which is likely of little clinical significance – making interpretation of these studies challenging.
Pathogenesis: The pathogenesis of APS is incompletely elucidated but data supports the role of endothelial cells, monocytes, platelets and the complement system. Binding of aPL to β2GPI activates endothelial cells with upregulation of adhesion molecule expression and tissue factor production, and activates platelets resulting in
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increased glycoprotein IIb/IIIa expression and thromboxane A2 production, actions that result in procoagulant effects on the coagulation pathway. Fibrinolysis may be impaired by aPL interactions with protein C and plasmin, proteins involved in regulation of the coagulation cascade. Disruption of the annexin A5 shield (which normally covers anionic thrombogenic surfaces), defective placentation and more recently, complement activation have been implicated in the pathogenesis of fetal loss in patients with APS. A two-hit hypothesis has been proposed, in which patients with aPL require a ‘second hit’ that results in the development of the syndrome. Because many patients with APS who develop thrombosis do so in the setting of an additional risk factor, it is thought that the second hit may be a condition that precipitates venous thromboembolism (e.g. immobilization, estrogen use, pregnancy or postpartum states, or malignancy) or the presence of one or more cardiovascular risk factors (e.g. hypertension, hyperlipidemia or smoking).
Clinical Features: Thrombosis: The most common presenting finding among patients with APS is deep vein thrombosis, found in 30% of patients. Pulmonary embolism occurs in 10%, as does superficial thrombophlebitis. Thrombosis involving the upper extremity veins, cerebral sinuses, renal, hepatic and mesenteric veins can also occur. The most common arterial thrombotic complication is ischemic stroke, occurring in approximately 13% of patients. Transient ischemic attack, myocardial infarction and thrombosis of the peripheral arterial system or arterial bypass grafts have also been reported.
Recurrent Fetal Loss and Pregnancy-Related Complications: Recurrent fetal loss occurs in approximately 8% of patients with APS. Fetal loss can be early or late, and pregnancy complications such as eclampsia, pre-eclampsia and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome can also occur. Patients with APS may also present with ‘non-criteria’ findings. These include those described in the following sections.
Hematologic Manifestations: Thrombocytopenia (platelets <100,000/μl) is one of the most common findings, present in approximately 20% of patients with APS. The degree of thrombocytopenia is usually mild to moderate. The presence of thrombocytopenia does not appear to reduce thrombotic risk in patients with APS, nor does it appear to be associated with bleeding. Less commonly, patients can present with hemolytic anemia that is microangiopathic or autoimmune. In patients with thrombotic microangiopathy and aPL, thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), catastrophic APS (CAPS), acute renal failure, malignant hypertension and HELLP syndrome need to be considered. Although APS is associated with thrombosis, it can rarely be associated with bleeding complications if the aPL are directed against prothrombin. Most case reports of this occurrence are in patients with SLE or who have a transient viral infection who present with cutaneous purpura or epistaxis. These patients generally have LA that bind prothrombin and result in clearance of prothrombin.
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Skin Manifestations: The classic rash in APS is livedo reticularis, a red rash with a lacy, net-like pattern, present in approximately 20% of patients with APS. Sneddon’s syndrome is diagnosed in patients with livedo reticularis and stroke. Patients with livedo reticularis typically have arterial rather than venous thrombosis. Other skin manifestations include digital gangrene or necrosis, splinter hemorrhages, skin ulcers and pseudovasculitic skin lesions.
Neurologic Manifestations: Symptoms other than stroke include cognitive deficits, headache or migraine. Unusual presentations include seizure, and mood or movement disorders. Neuroimaging may reveal white matter lesions in patients with cognitive deficits suggestive of a vasculopathy.
Cardiovascular Disease: In addition to coronary artery disease and thrombosis, patients with APS can have valvular heart disease, with thickening of the valve leaflets, nodules or vegetations. The mitral valve is more commonly affected than the aortic valve. There have also been reports of intracardiac thrombi, pericardial effusion and cardiomyopathy. Peripheral arterial disease with thrombosis can also occur. Pulmonary Disease: Pulmonary hypertension can develop independent or secondary to chronic thromboembolic disease. Other pulmonary conditions including alveolar hemorrhage, fibrosing alveolitis and adult respiratory distress syndrome have been reported. Gastrointestinal Disease: Thrombosis resulting in ischemia of the bowel, colon, or esophagus with resultant gastrointestinal bleeding, as well as splenic and pancreatic infarction has been reported. Thrombosis of the hepatic or portal veins can result in Budd-Chiari syndrome, an unusual complication of APS.
Management of Patients with APS: The mainstay of APS treatment is antithrombotic therapy. Other treatments may have a role in the management of APS but are supported by little evidence. These include hydroxychloroquine for patients who have APS and SLE, and plasma exchange in patients who have CAPS. Antithrombotic Therapy: Appropriate use of antithrombotic agents requires an assessment of the bleeding risk balanced against the risk of thrombosis. In the following section, the evidence supporting the optimal antithrombotic management for different scenarios involving patients with aPL is outlined.
Bleeding Risk: The risk of major bleeding in patients with APS is estimated at 2–3% per year, based on studies evaluating the efficacy of warfarin in patients with APS. This is comparable to the bleeding rates observed in anticoagulated patients without APS. This risk may be higher in selected patients who have severe thrombocytopenia or patients with aPL directed against prothrombin. However for the vast majority of patients with APS, this bleeding rate is exceeded by the risk of recurrent thrombosis.
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Antithrombotic Management of Patients with aPL Without Prior Thrombosis: The role of antithrombotic prophylaxis in asymptomatic patients with aPL is controversial. Observational studies suggest aspirin may be effective in reducing thromboembolic complications in patients with aPL and no prior thrombosis. However, a small randomized trial and parallel observational study demonstrated no benefit. In this trial, 98 asymptomatic patients who were persistently aPL-positive were randomized to placebo or aspirin 81 mg/day. After a mean of 2.3 years, there was no difference in the rates of thrombosis between the groups (aspirin 2.75 per 100 patient years, placebo 0 per 100 patient years). The parallel observational study in 74 asymptomatic persistently aPLpositive patients who were already taking aspirin or declined randomization into the trial showed similar results. Most patients who developed thrombosis had additional risk factors for this (e.g. hypertension, smoking, obesity, or use of estrogen). Taken together, it appears that the risk of thrombosis in asymptomatic persistently aPL-positive patients is low, and aspirin does not appear to reduce thrombotic events. However, given that the trial was relatively small and there are observational data that support aspirin – particularly in patients who have SLE – some experts recommend aspirin for these patients. This is reflected in recommendations from an expert panel, who recommend that asymptomatic patients with aPL who have SLE receive aspirin and hydroxychloroquine. These experts also recommend strict control of cardiovascular risk factors and use of thromboprophylaxis in high risk situations for all asymptomatic patients with aPL. Antithrombotic Management of Patients with aPL and Venous Thromboembolism: Initial Treatment: Treatment of venous thromboembolism in patients with APS is identical to patients without APS, consisting of initial parenteral therapy with unfractionated heparin, low molecular weight heparin or fondaparinux usually overlapped with vitamin K antagonists. The parenteral therapy is continued for a minimum of 5 days and until the international normalized ratio (INR) is above 2.0 for at least 24 hours. Alternately, oral therapy with rivaroxaban can be used, although rivaroxaban has not been specifically studied in patients with APS. Long-Term Treatment: Retrospective studies suggest that high intensity warfarin (INR greater than 3.0) is more effective than either aspirin or warfarin administered with a target INR less than 3.0. However, two randomized trials have shown that high intensity warfarin is not superior to moderate intensity warfarin (INR 2.0–3.0) in preventing recurrent thrombosis. These trials enrolled 114 and 109 APS patients respectively, and found that the incidence of recurrent thrombosis was approximately 11% among patients who received high intensity warfarin and was 3.5–5.5% among patients who received moderate intensity warfarin. Major bleeding rates were comparable between both groups. When the results of both trials were combined in a meta-analysis, a significant excess of minor bleeding was evident in patients allocated to high intensity warfarin. These trials demonstrate that if warfarin is used for patients with venous thromboembolism and APS, it should be administered at moderate intensity with a target INR of 2.0–3.0. Duration of Treatment: The optimal duration of anticoagulation to prevent recurrent venous thromboembolism in patients with aPL is unknown. The best estimates of the risk of recurrent venous thromboembolism among patients with aPL and prior venous
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thromboembolism is based on retrospective studies of untreated patients or studies of patients followed prospectively after their anticoagulants have been discontinued. Prospective studies suggest there is an increased risk of recurrence, ranging from 10–67% per year. In the largest prospective study, 412 patients with a first episode of venous thromboembolism were tested for aCL 6 months following their initial event, and followed prospectively after their anticoagulants were discontinued. Over 4 years, 29% of patients with elevated aCL had recurrent thrombosis, compared with 14% of patients without aCL (risk ratio [RR] 2.1, 95% CI 1.3–3.3). Notably, the patients included in these prospective studies had aPL testing performed once which would not meet the revised Sapporo criteria for definite APS. The risk of recurrence appears to be highest during the first 6 months following warfarin discontinuation, with an event rate of 1.30 events per year of follow-up. Based on these data, the general consensus is to treat patients with APS and venous thromboembolism for at least 3 months, although many of these patients receive indefinite duration anticoagulation given the high risks of recurrence.
Antithrombotic Management of Patients with aPL and Ischemic Stroke: Antithrombotic recommendations for these patients are controversial. A nested prospective cohort study within a randomized trial evaluated the effect of warfarin (INR 1.4–2.8) and aspirin 325 mg/day in 1,770 patients with ischemic stroke where aPL were measured once prior to study entry. In patients who had positive testing for aPL, there was no difference in the risk of thrombotic events in the patients treated with warfarin (RR 0.99, 95% CI 0.75–1.31) compared with aspirin (RR 0.94, 95% CI 0.70–1.28). Based on this study, some experts recommend aspirin since no anticoagulant monitoring is required compared to warfarin. However, there are limitations in generalizing the results of this study, since only one aPL measurement was performed and it is unclear how many patients would meet the revised Sapporo criteria for definite APS. Consequently, other experts continue to recommend warfarin or combination warfarin and aspirin for patients with aPL and ischemic stroke, particularly for patients meeting the criteria for definite APS. Antithrombotic Management of Women with aPL and Pregnancy Loss: Systematic reviews which have evaluated heparin, aspirin and combination heparin and aspirin therapy suggest that for women who meet the revised Sapporo criteria for definite APS based on pregnancy morbidity and have no history of thrombosis and are pregnant, unfractionated heparin combined with aspirin appears to reduce the incidence of pregnancy loss. Expert recommendations based on these studies suggest using intermediate dose unfractionated heparin (e.g. 5,000–7,500 units subcutaneously every 12 hours) or low molecular weight heparin in standard prophylactic doses and low dose aspirin (75–100 mg/day).
Other Therapies: Hydroxychloroquine: There is some data to suggest that hydroxychloroquine may be useful for preventing thromboembolic complications in patients with APS, particularly in patients with SLE. However, hydroxychloroquine has not been studied prospectively in combination with aspirin and it is unclear if the effects are primarily on the SLE or on aPL.
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Plasma Exchange: Plasma exchange, with or without intravenous gamma globulin (IVIG), has been employed with success in patients with CAPS. Although plasma exchange for CAPS has not been formally evaluated in randomized studies, an assessment of 250 patients enrolled in the CAPS registry found that use of plasma exchange (in combination with other therapies) resulted in higher survival rates. The number of plasma exchange procedures required is unknown, but expert recommendations suggest at least five consecutive treatments.
Challenges in APS Management: There remain several scenarios where the antithrombotic management of patients with APS is uncertain, with no available clinical studies to guide their management. These include the management of patients with APS and recurrent thrombosis, and the management of patients with aPL and arterial thromboses other than ischemic stroke. Patients with aPL and Recurrent Thromboembolism: Patients who have recurrent thrombotic events despite adequate anticoagulation with warfarin have various options, based on expert opinion. These options include increasing the target INR from 2.0–3.0 to 3.1–4.0, adding low dose aspirin, low molecular weight heparin or hydroxychloroquine. Patients with aPL and Other Arterial Thromboses: There are no prospective studies evaluating optimal treatment of patients with aPL-associated arterial thrombosis outside of ischemic stroke. Many patients with myocardial infarction and aPL are treated empirically with long-term warfarin therapy administered to achieve an INR of 2.0–3.0 based on data extrapolated from venous thromboembolism studies.
Catastrophic APS: A subset of patients with APS have a malignant form of APS known as CAPS characterized by multi-organ thrombotic involvement. Preliminary criteria for CAPS include a history of APS and/or presence of aPL, thrombosis involving three or more organ systems within a week, histopathologic confirmation of microthrombosis and exclusion of other causes of multiple organ thromboses. The treatment of CAPS involves treating any identifiable causes (e.g. infection), anticoagulation (usually with heparin followed by long-term warfarin), high dose glucocorticoids (e.g. methylprednisolone 1 g IV daily for 3 days followed by prednisone 1–2 mg/kg/day) and plasma exchange with or without IVIG. The prognosis of CAPS is poor without treatment, and intensive treatment results in survival rates of 50–80%.
Future Directions: APS is a complex disorder with evolving diagnostic criteria. Insight into the pathophysiology of APS may lead to novel treatments for APS, which to date have focused on antithrombotic therapy. Complement activation may play an important role in fetal loss, and although there is currently no specific complement-targeted therapy approved for patients with APS, complement inhibition may prove to be a novel upstream treatment for APS. Other investigational treatments include the use of rituximab, other immunosuppressive agents and autologous stem cell transplantation, all of which require further study. Management of patients with aPL and APS can be challenging, as many patients with APS
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have risk factors for bleeding and have a high risk of recurrent thromboembolism. The clinical trials and observational studies performed to date have yielded valuable information on the management of patients with APS, but further research is required to address the ongoing controversies that exist in the management of these patients.
Recommended Reading APASS Writing Committee. (2004). Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA 291, 576–584. Bates SM, Greer IA, Middeldorp S et al. (2012). VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141(Suppl 2), e691S–e736S. Crowther MA, Ginsberg JS, Julian J et al. (2003). A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 349, 1133–1138. Erkan D, Harrison MJ, Levy R et al. (2007). Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: a randomized, double-blind, placebocontrolled trial in asymptomatic antiphospholipid antibody-positive individuals. Arthritis Rheum 56, 2382–2391. Finazzi G, Marchioli R, Brancaccio V et al. (2005). A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 3, 848–853. Mak A, Cheung MW, Cheak AA, Ho RC. (2010). Combination of heparin and aspirin is superior to aspirin alone in enhancing live births in patients with recurrent pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of randomized controlled trials and meta-regression. Rheumatology (Oxford) 49, 281–288. Miyakis S, Lockshin MD, Atsumi T et al. (2006). International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4, 295–306. Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I et al. (2011). Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus 20, 206–218. Schulman S, Svenungsson E, Granqvist S and the Duration of Anticoagulation Study Group. (1998). Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med 104, 332–338.