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Antiphospholipid Syndrome
CHAPTER 108
Antiphospholipid Syndrome Lucia R. Wolgast, MD
Introduction: The antiphospholipid (aPL) syndrome (APS) is an autoimmune thrombophilic condition that is defined by a combination of clinical and laboratory criteria. In general terms, APS patients have developed circulating antibodies against plasma proteins that bind to phospholipids (i.e., aPL antibodies) with subsequent clinical morbidity of thrombosis and/or pregnancy complications. The investigational criteria for APS (often referred to as the Sydney Investigational Criteria) are detailed in Table 108.1 and require that patients have documented evidence for vascular thrombosis and/or obstetric complications, such as unexplained recurrent miscarriages, intrauterine growth restriction, intrauterine fetal demise, preeclampsia/toxemia, placental abruption, and preterm labor. The laboratory criteria require identifying the persistent aPL antibodies (i.e., at least two abnormal measurements at least 12 weeks apart), including elevated medium to high tiers of anticardiolipin (aCL) IgG or IgM antibodies, anti-β2-glycoprotein I (anti-β2GPI) IgG or IgM antibodies, and/or positive lupus anticoagulant (LA). The laboratory diagnosis of APS is discussed in Chapter 158. It is important for the reader to understand that these criteria were not designed to be requirements for the clinical diagnosis of APS. Rather, they were intended to provide TABLE 108.1 Sydney Investigational Criteria for the Diagnosis of the Antiphospholipid Syndromea Clinical • Vascular thrombosis (one or more episodes of arterial, venous, or small vessel thrombosis). For histopathologic diagnosis, there should be no evidence of inflammation in the vessel wall. • Pregnancy morbidities attributable to placental insufficiency, including (a) three or more otherwise unexplained recurrent spontaneous miscarriages, before 10 weeks of gestation, (b) one or more fetal losses after the 10th week of gestation, (c) stillbirth, and (d) episode of preeclampsia, preterm labor, placental abruption, intrauterine growth restriction, or oligohydramnios that are otherwise unexplained.
Laboratory • Medium- or high-titer aCL or anti-β2GPI IgG and/or IgM antibody present on two or more occasions, at least 12 weeks apart, measured by standard ELISAs. • Lupus anticoagulant in plasma, on two or more occasions, at least 12 weeks apart, detected according to the guidelines of the ISTH SSC Subcommittee on Lupus Anticoagulants and Phospholipid-Dependent Antibodies. β2GPI, β2-glycoprotein I; aCL, anticardiolipin; aPL, antiphospholipid; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulin. a“Definite APS” is considered to be present if at least one of the clinical criteria and one of the laboratory criteria are met. Modified from Miyakis, S., Lockshin, M. D., 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. Transfusion Medicine and Hemostasis. https://doi.org/10.1016/B978-0-12-813726-0.00108-2 Copyright © 2019 Elsevier Inc. All rights reserved.
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TABLE 108.2 Proposed Criteria for the Classification of Catastrophic Antiphospholipid Syndrome (APS) 1. Evidence of involvement of three or more organs, systems, and/or tissuesa 2. Development of manifestations simultaneously or in less than a week 3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissueb 4. Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies)c
Definite Catastrophic APS • All four criteria
Probable Catastrophic APS • All four criteria, except for only two organs, systems and/or tissues involvement • All four criteria, except for the absence of laboratory confirmation at least 6 weeks apart due to the early death of a patient never previously tested for aPL before the catastrophic APS event • Criteria 1, 2, and 4 • Criteria 1, 3, and 4 and the development of a third event in more than a week but less than a month, despite anticoagulation aUsually, clinical
evidence of vessel occlusions, confirmed by imaging techniques when appropriate. Renal involvement is defined by a 50% rise in serum creatinine, severe systemic hypertension (N180/100 mm Hg), and/or proteinuria (N500 mg/24 hours). bFor histopathological confirmation, significant evidence of thrombosis must be present, although, in contrast to Sydney criteria, vasculitis may coexist occasionally. cIf the patient had not been previously diagnosed as having an APS, the laboratory confirmation requires that the presence of antiphospholipid antibodies must be detected on two or more occasions at least 6 weeks apart (not necessarily at the time of the event), according to the proposed preliminary criteria for the classification of definite APS. Modified from Asherson, R. A., Cevera, R., de Groot, P. G., et al. (2003). Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus, 12, 530–534.
a uniformly rigorous definition of APS for the purpose of standardizing research on the disorder. In “real-world” clinical practice, some patients may be appropriately diagnosed for presumptive APS without meeting the strict investigational criteria. Some APS patients may be positive for other “noncriteria” clinical laboratory tests—see Chapter 158—that have not been included by consensus panels as diagnostic criteria for the disorder, but these positive noncriteria laboratory tests may indicate a clinical risk and warrant treatment. Furthermore, APS patients may have positive APS criteria assays but not the typical criteria manifestations. These “noncriteria manifestations” include thrombocytopenia, livedo reticularis, skin ulcers, nephropathy, migraine, cognitive defects, diffuse alveolar hemorrhage, and valvular heart disease (Libman–Sacks endocarditis), and these clinical manifestations may need to be managed differently. Occasional patients may even test entirely negative for the APS criteria assays but have typical clinical manifestations of the disorder—a situation referred to as seronegative APS (termed SNAPS). At present, APS may be divided into the following subcategories: (1) Primary APS is the “stand alone” disorder, in the absence of systemic lupus erythematosus (SLE), (2) secondary APS occurs in the presence of APS, (3) catastrophic APS (CAPS) manifests as disseminated thrombosis in large and small vessels with resulting multiorgan failure (Table 108.2), and (4) SNAPS includes patients whose diagnostic tests are entirely negative but who, on clinical grounds, are still suspected to have the disorder.
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Antigenic Specificities and Pathophysiology of Antiphospholipid Antibodies β2-glycoprotein I: β2-glycoprotein I (β2GPI), a 50-kd glycoprotein member of the
complement control protein superfamily 5, is a major antigenic target for aPL antibodies. It is a scavenger protein that binds and clears apoptotic cells, microparticles, and other subcellular elements in circulating blood, including von Willebrand factor (VWF). Thromboprotective roles include binding and clearance of low-density lipoprotein (oxLDL), binding to VWF to reduce platelet adhesion to collagen, acting as a cofactor for tissue-type plasminogen activator (t-PA), and annexin A2 allowing increased fibrinolytic activity. β2GPI contains five homologous complement control domains, with a fifth domain that contains a phospholipid binding site (Fig. 108.1). This binding site has cationic residues with an affinity for anionic phospholipids and a hydrophobic loop, which can insert into the lipid bilayer. All five domains of β2GPI have been reported to be recognized by anti-β2GPI antibodies derived from patients. However, the most significant correlation is IgG antibodies against an epitope on domain I (Gly40-Arg43), which has a strong association with thrombosis. The antibodies against the domain I recognize an epitope, which is cryptic in the soluble, unbound protein, but becomes exposed after β2GPI binds to phospholipid bilayers. Transmission electron microscopy and X-ray scattering studies of stained β2GPI molecules indicate that the free unbound protein has a circular confirmation, whereas β2GPI bound to phospholipid has either a “J” or “S” shape conformation, exposing hidden domains to the immune system. Direct injury to endothelial surfaces causes β2GPI to bind to exposed phospholipids. Complexes of β2GPI bound to exposed aPLs, such as cardiolipin, create antigenic targets for aPL antibodies. These aPL antibodies then bind to the β2GPI/phospholipid complexes and interfere with anticoagulant and fibrinolytic pathways. Through cellular signaling pathways, the bound aPL antibodies create a prothrombotic state—upregulating tissue factor expression and adhesion molecules. aPL antibodies can also interfere with β2GPI cofactor functions for t-PA and annexin A2 inhibiting fibrinolytic activity. aPL antibodies reduce the effectiveness of β2GPI in clearing atherogenic proteins such as oxLDL and procoagulant microparticles. aPL antibodies can reduce the effectiveness of β2GPI in regulating VWF-mediated platelet adhesion. In the placenta, aPL antibodies cause placental insufficiency by activating trophoblasts and endometrial cells, resulting in abnormal trophoblast proliferation, increased trophoblast apoptosis, disruption in differentiation of decidual endometrial cells, and interference in maternal spiral artery maturation. The presence of aPL antibodies can also disrupt protective anticoagulant mechanisms to endothelial and trophoblastic injury, such as the binding of the anticoagulant annexin A5 to exposed phospholipids. aPL antibodies have been shown to activate platelets and monocytes and interfere with β2GPI’s role as a regulator of the complement cascade. β2GPI complexed with HLA-DR7 on cell surfaces can trigger complement-mediated cytotoxicity, which has been shown to play a significant role in obstetric APS.
Other Antigenic Targets of Antibodies Associated With Antiphospholipid Syndrome: Targets other than β2GPI that have been identified for aPL antibodies
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(SAXS) of β2GPI in solution revealed an S-shape conformation, with a carbohydrate chain on top of the interface between domains I and II. In contrast to the SAXS structure, transmission electron microscopy (TEM) of negatively stained unbound β2GPI mounted on grids showed a circular conformation, but a “J” shape for β2GPI bound to phospholipid. The arginine 39-arginine 43 epitope on domain I that is recognized by thrombogenic aPL antibodies is cryptic in the free-β2GPI proposed conformations. This epitope then becomes exposed and available for antibody recognition after the protein is bound to phospholipid. (Reprinted From de Laat, B., & de Groot, P. G. (February 2011). Autoantibodies directed against domain I of β2-glycoprotein I Curr Rheumatol Rep 13(1), 70–76.)
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include other anionic phospholipids, including phosphatidylserine, phosphatidylethanolamine, and phosphatidylinositol, which have all been associated with increased thrombosis and pregnancy morbidity. Other antibodies associated with APS clinical manifestations include prothrombin (coagulation factor II), coagulation factor V, protein C, protein S, annexin A2, annexin A5, high- and low-molecular-weight kininogens, heparin, factor VII/VIIa, plasmin, vimentin, VWF, thrombospondin, and P-selectin.
Clinical Manifestations of the Antiphospholipid Syndrome: The clinical symptoms of APS can be categorized into “criteria manifestations” and “noncriteria manifestations.” The “criteria manifestations” include vascular thrombotic events found in thrombotic APS, pregnancy complications found in obstetric APS, and multiorgan damage found in CAPS. The “noncriteria manifestations” include other pathologic conditions that have been found in APS patients but have not been included in the definition of “definite APS” by the expert consensus groups. These noncriteria manifestation in conjunction with positive laboratory criteria findings may warrant patient management and treatment.
Criteria Manifestations of Thrombotic and Obstetric Antiphospholipid Syndrome Venous and Arterial Thromboembolism: Criteria manifestations of thrombotic APS include both venous and arterial thrombosis with 60% of APS patient presenting with venous thrombosis, 30% presenting with arterial thrombosis, and 10% presenting with both venous and arterial thrombosis. The most common manifestations are deep vein thrombosis of the lower extremity, pulmonary embolism, and stroke/transient ischemic attacks. Other venous manifestations include thrombosis of thoracic, abdominal, pelvic, renal and/or retinal veins. Other arterial manifestations include myocardial infarction, nonatherosclerotic coronary artery occlusion, pulmonary hypertension attributed to thrombotic occlusion, and occlusions of abdominal, renal, and retinal arteries. The diagnosis of APS should be considered in patients spontaneously presenting with thrombosis particularly in the absence of other risk factors. The diagnosis of thrombotic APS is especially suspected when transient ischemic attacks or strokes occur in younger patients, particularly those without the usual risk factors for cerebrovascular disease—e.g., cigarette smoking, hypertension, and diabetes mellitus. In addition, thrombotic APS may manifest in the presence of a predisposing provocative factors such as estrogen hormone replacement therapy, oral contraceptives, pregnancy, the postpartum state, vascular stasis, surgery, or trauma. Some patients with venous thrombosis may also have a concurrent genetic thrombophilic conditions such as factor V-Leiden polymorphism. Pregnancy Complications: Criteria manifestations of obstetric APS include recurrent fetal loss, preeclampsia, placental abruption, prematurity, intrauterine fetal demise, intrauterine growth restriction, and oligohydramnios. Women with obstetric APS generally present with a history of recurrent (i.e., three or more) miscarriages. In approximately half of patients, the pregnancy losses occur in the first trimester; other patients present with later losses, most in the second trimester, but some even later, including stillbirth. The specific pregnancy complications that define obstetric APS include
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the absence of another explanation for the complications, three or more recurrent spontaneous first trimester miscarriages, or one mid-trimester loss, stillbirth, episode of preeclampsia, preterm labor, placental abruption, intrauterine growth restriction, or oligohydramnios. Pregnant patients with APS are also more prone to develop deep vein thrombosis during pregnancy or the puerperium. Interestingly, early reproductive failure (i.e., infertility) is not associated with APS.
Noncriteria Clinical Manifestations Associated With Antiphospholipid Syndrome: The most common noncriteria clinical manifestations include cardiac, neurological, dermatological, and hematological symptoms, including coronary artery disease in the absence of thrombotic occlusion, peripheral vascular disease, valvular abnormalities, migraines, seizures, livedo reticularis (Fig. 108.2), skin ulcerations/ necrosis, thrombocytopenia, and immune thrombocytopenic purpura. Many of the noncriteria manifestations occur in patients with SLE or other autoimmune disorders and may warrant additional management to prevent APS-associated thrombosis and/or pregnancy complications. One or two early spontaneous miscarriages (less than 10 weeks gestation) with a low positive aCL or anti-β2GPI are also considered a noncriteria manifestation that may warrant additional management. Other rarer noncriteria manifestations include glomerulonephritis, APS nephropathy, primary biliary cirrhosis, pancreatitis, acute sensorineural hearing loss, osteonecrosis, and bleeding due to acquired factor deficiencies or von Willebrand disease.
Catastrophic Antiphospholipid Syndrome: Rare patients present with a cata-
strophic form of APS, which is characterized by severe widespread vascular occlusions, and a high mortality. The formal diagnostic criteria include evidence of involvement of at least three organs, systems and/or tissues, development of manifestations simultaneously or within 1 week, histopathologic confirmation of small vessel occlusion, and laboratory confirmation of the presence of aPL antibodies (Table 108.2).
FIGURE 108.2 Livedo Reticularis in a woman with antiphospholipid syndrome. (Reprinted with permission from Elsevier, Ruiz-Irastorza, G., Crowther, M., Branch, W., & Khamashta, M. A. (October 30, 2010). Antiphospholipid syndrome. Lancet 376(9751),1498–1509.)
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In contrast to the diagnostic criteria for APS, which exclude the diagnosis when histopathology shows evidence for vasculitis, the diagnostic criteria for CAPS do permit the presence of histological evidence for vasculitis together with thrombosis. These patients present with evidence for severe multiorgan ischemia/infarction, usually with concurrent microvascular thrombosis. Patients with CAPS can present with massive venous thromboembolism, along with respiratory failure, stroke, abnormal liver enzymes, renal impairment, adrenal insufficiency, and areas of cutaneous infarction. The respiratory failure is usually due to acute respiratory distress syndrome and diffuse alveolar hemorrhage. Laboratory evidence for disseminated intravascular coagulation is frequently present. According to the CAPS Registry, a web-based database of 433 patients with CAPS (https://ontocrf.costaisa.com/en/web/caps/), the majority of CAPS patients are female (69%), in their late thirties (mean age of 38.5 years), but patients can be present at any age (range 0–85 years). In half of the CAPS cases, the patients’ catastrophic event was their first APS manifestation. Precipitating factors of CAPS include infections, drugs (sulfur-containing diuretics, captopril, and oral contraceptives), surgical procedures, and cessation of prior anticoagulant therapy. In 26.9% of cases, the patients also had SLE. The most frequently affected organ was the kidney (73% of episodes), followed by lungs (58.9%), the brain (55.9%), the heart (49.7%), and the skin (45.4%). Other organs were also affected, including the peripheral vessels, intestines, spleen, adrenal glands, pancreas, retina, and bone marrow. Improved aggressive treatment has reduced mortality from ∼50% to ∼20% and relapse is rare in survivors.
Pediatric Antiphospholipid Syndrome: APS has become increasingly recognized to be a significant cause of thrombosis in the pediatric population. A European registry report of an initial 121 cases described thrombotic manifestations similar to those seen with adults with APS. However, there was a significant and interesting difference between children with primary APS and the secondary APS, who had other autoimmune disease. The patients with primary APS tended to be younger and had a higher frequency of arterial thrombotic events, whereas the secondary APS patients were older and had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations. The catastrophic form of the syndrome has been reported in children but occurs more rarely than in adults. Thrombosis is rare in newborns delivered from mothers with APS, and only a few cases are reported, mostly associated with other prothrombotic factors. aPL antibodies have been found in up to 30% of offspring of mothers with APS. Other complications in neonates born to APS mothers include prematurity, neurodevelopment abnormalities, and learning disabilities.
Treatment of Patients With Antiphospholipid Syndrome: There is general agreement that patients with spontaneous and/or recurrent thrombosis require longterm anticoagulant therapy and that pregnant patients with a history of recurrent spontaneous pregnancy losses require antithrombotic therapy for most of the gestational period and for the puerperium. There have been uncertain approaches to treatment of patients with single thrombotic events, patients with provoked thrombotic events (i.e., trauma, surgery, stasis, airplane travel, pregnancy, or estrogens), patients with 1–2 early miscarriages, patients with noncriteria clinical manifestations, and patients with low-titer laboratory results. In addition, asymptomatic patients with multipositivity
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for criteria laboratory tests may be at increased risk for a clinical event and may warrant preventative treatment. Table 108.3 provides a summary of current recommended guidelines and treatment considerations.
Thrombotic Antiphospholipid Syndrome Treatment: In general, patients with thrombotic APS based on the diagnostic criteria should be treated with warfarin for the long term, at a therapeutic INR of 2.0–3.0. This is regardless of single or multiple positivity for aPL antibodies. In addition, patients with an arterial thrombotic event (i.e., stroke and/or myocardial infarction) should either be placed on a higher warfarin dose with INR 3.0–4.0 or be placed on long-term warfarin at a therapeutic INR of 2.0–3.0 and 100 mg daily dose of aspirin. APS patients with myocardial infarction and a stent placement should also be treated with clopidogrel (75 mg per day). Direct-acting oral anticoagulants (DOACs), either direct factor-Xa or thrombin inhibitors, have been proven effective for treatment of venous thromboembolism. However, their use specifically in APS patients has not been thoroughly evaluated. A recent randomized, open-label trial with 54 patients receiving rivaroxaban and 56 patients on warfarin showed the same safety profiles with no recurrent thrombosis or bleeding. Clinical trials are currently underway to confirm the safety and efficacy of DOACs in APS patients. DOACs can be considered in patients with poor anticoagulant compliance with warfarin or vitamin K antagonist allergy. DOACs are not recommended for APS patients with arterial thrombosis or with recurrent thrombosis while on therapeutic warfarin anticoagulation.
Obstetric Antiphospholipid Syndrome Treatment: The current approach to treating pregnant women with obstetric APS includes daily low-dose aspirin (75–81 mg per day) and either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Although clinical studies have shown efficacy with UFH, most clinicians treat with LMWH because it has a better pharmacokinetic profile and lower risk of heparin-induced thrombocytopenia and osteopenia. Heparin is then withheld when labor begins or 24 hours before a cesarean section. Anticoagulation is then resumed 6 weeks postpartum because of the increased risk of venous thromboembolism (VTE) in this period. With this management, the likelihood of a good pregnancy outcome in women with APS has been estimated to be about 75%–80%
Management of Noncriteria Clinical Manifestations: Treatment for noncriteria clinical manifestations of APS includes rituximab, glucocorticoids, vitamin D supplementation, and hydroxychloroquine. Rituximab may be effective in controlling noncriteria manifestations of APS such as persistent thrombocytopenia, autoimmune hemolytic anemia, cardiac valve disease, chronic skin ulcers, aPL-nephropathy, and/or cognitive dysfunction. Because low vitamin D levels correlated with noncriteria APS manifestations, it is recommended that vitamin D deficiency (<10–20 ng/mL) and insufficiency (<30 ng/mL) be corrected as a preventative strategy.
Catastrophic Antiphospholipid Syndrome Treatment: Patients with CAPS require aggressive treatment because of the high mortality. Treatment for CAPS is directed toward the thrombotic events and suppression of the cytokine cascade.
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TABLE 108.3 Antiphospholipid Syndrome (APS) Treatment Strategy Clinical Manifestation Laboratory Resulta
Treatment
Thrombotic APS Venous thromboembolism
Positive aCL and/or anti-β2GPI (IgG and/or IgM) immunoassays with medium or high titersb or Positive LA (confirm positive using two different assays)
Long-term vitamin K antagonist, INR 2.0–3.0
Low-titer positivity for aCL (IgG or IgM < 40 PL) or anti-β2GPI (IgG or IgM < 99th percentile)
Anticoagulation treatment and duration determined by additional risk factors at time of thrombosis.
Positive aCL and/or anti-β2GPI (IgG and/or IgM) immunoassays with medium or high titersb or Positive LA (confirm positive using two different assays)
Long-term vitamin K antagonist, INR 2.0–3.0 plus aspirin 100 mg per day or Long-term vitamin K antagonist, INR 3.0–4.0 Myocardial Infarction with percutaneous coronary interventions and stent placement: Long-term vitamin K antagonist, INR 2.0–3.0, aspirin 100 mg per day, and clopidogrel 75 mg per day.
Low-titer positivity for aCL (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile)
Anticoagulation treatment and duration determined by additional risk factors at time of thrombosis.
Noncriteria manifestations
Positive aCL and/or anti-β2GPI (IgG and/or IgM) immunoassays with medium or high titersb or Positive LA (confirm positive using two different assays)
Consider rituximab and/or vitamin D supplementation
Noncriteria manifestations
Low-titer positivity for aCL (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile)
Consider rituximab and/or vitamin D supplementation
Arterial thromboembolism (including stroke and myocardial infarction)
Refractory thrombotic APS (recurrent thrombosis despite treatment)
Higher intensity vitamin K antagonist, INR 3.0–4.0. First line add-on treatments: Antiplatelet agents or low-molecular-weight (LMW) heparin Second line add-on treatments: Glucocorticoids, hydroxychloroquine, statins, and/or rituximab
Obstetric APS Pregnant women with history of criteria pregnancy complicationsc or thrombotic events
Positive aCL and/or anti-β2GPI (IgG and/or IgM) immunoassays with medium or high titersb or Positive LA (confirm positive using two different assays)
Unfractionated or LMW heparin plus low-dose aspirin
Continued
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TABLE 108.3 Antiphospholipid Syndrome (APS) Treatment Strategy—cont’d Clinical Manifestation Laboratory Resulta
Treatment
Pregnant women with history of criteria pregnancy complicationsc or thrombotic events
Low-titer positivity for aCL (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile)
Unfractionated or LMW heparin plus low-dose aspirind
Noncriteria manifestation—one or two early miscarriage (<10 weeks of gestation)
Positive aCL and/or anti-β2GPI (IgG and/or IgM) immunoassays with medium or high titersb or Positive LA (confirm positive using two different assays)
Unfractionated or LMW heparin plus low-dose aspirind
Noncriteria manifestation—one or two early miscarriage (<10 weeks gestation)
Low-titer positivity for aCL (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile)
No treatment recommendation, however, assess pregnant patients for treatment due to additional risk factors.
Refractory obstetric APS
Consider add-on treatment with glucocorticoids, intravenous IgG (IVIG), and/or hydroxychloroquine
Asymptomatic Antiphospholipid Positive Carriers None
Triple positive for LA, aCL, and anti-β2GPI with medium or high titersb
Long-term prophylaxis with lowdose aspirin. Consider anticoagulant prophylaxis for high-risk situations—e.g., immobilization, surgery, air travel, etc. Consider unfractionated or LMW heparin for pregnant patients
Double positive for LA, aCL, or anti- Long-term prophylaxis with lowβ2GPI with medium or high titers dose aspirin. or Consider anticoagulant prophylaxis Persistently positive for isolated for high-risk situations—e.g., aCL IgG or IgM with medium or immobilization, surgery, air travel, high titers etc. or Consider unfractionated or LMW Single positive for LA heparin for pregnant patients
Patients with SLE or autoimmune disease
aLaboratory
Low-titer positivity for aCL (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile) and/or transiently positive.
No treatment, however, considers prophylaxis treatment with LMW heparin in situations with increased risk—surgery, prolonged immobilization, pre-/peripartum, ovarian stimulation, thalidomide therapy, and the patient is currently positived
Single positive LA or persistently positive aCL with medium or high titers
Low-dose aspirin and hydroxychloroquine
tests should be deferred until at least 12 weeks after the clinical event to avoid interferences of the acute phase of the disease. Earlier testing may yield false positive results. LA, aCL, and anti-β2GPI tests must be positive on two or more occasions at least 12 weeks apart to be considered “Positive.” bMedium or high titers include aCL IgG, or IgM > 40 GPL and/or anti-β2GPI IgG or IgM > 99th percentile. cSydney Investigational Criteria pregnancy complications include (a) >3 unexplained recurrent spontaneous miscarriages at <10 weeks of gestation, (b) one or more fetal losses after the 10th week of gestation, (c) stillbirth, and (d) episode of preeclampsia, preterm labor, placental abruption, intrauterine growth restriction, or oligohydramnios. dFrom recent recommendations by international consensus in Autoimmunity Reviews 16 (2017) 911–924 and 1103–1108.
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A triple-therapy strategy of anticoagulation with heparin, high-dose glucocorticoids, and either intravenous immunoglobulin (IVIG) or plasma exchange or both has improved outcomes. This triple-therapy strategy has resulted in the significant reduction in mortality rate to 30% in CAPS. Cyclophosphamide is recommended for patients with CAPS and inflammatory features of SLE or high-titer aPL antibodies. Rituximab may be useful in refractory or relapsing cases of CAPS.
Refractory Antiphospholipid Syndrome Treatment: For thrombotic APS patients who are refractory to standard warfarin anticoagulant therapy, an increase in warfarin intensity is recommended with an INR 3.0–4.0. If APS patients have a recurrence on high-intensity warfarin, then add-on treatment with an antiplatelet agent (i.e., clopidogrel) or LMWH may be considered, as well as a DOAC for recurrent venous thromboembolism. If anticoagulation fails, combinations of anticoagulation with glucocorticoids, hydroxychloroquine, statins, and/or rituximab may be considered. In patients with refractory obstetric APS, glucocorticoids, IVIG, and hydroxychloroquine have been shown to be effective. In addition, glucocorticoids should be considered in obstetric APS patients who have a severe immune thrombocytopenia or a significant contraindication to heparin therapy.
Management of Patients With Clinical Manifestations and Low-Titer Antiphospholipid Antibody Positivity: Currently there are no treatment recommendations for patients with low-titer positivity for aCL (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile) or transiently positive aPL antibodies. For patients with venous or arterial thromboembolism, anticoagulation treatment and duration should be determined by additional risk factors at time of thrombosis. In pregnant patients with history of greater than three early spontaneous miscarriages, one or more late miscarriages, stillbirth, an episode of preeclampsia, preterm labor, placental abruption, intrauterine growth restriction or oligohydramnios, and unfractionated or LMW heparin plus low-dose aspirin is recommended. No treatment is recommended in patients with low-titer antibodies and one or two miscarriages; however, they should be assessed for other risk factors.
Management of Asymptomatic Antiphospholipid Antibody-Positive Patients: Asymptomatic patients with no previous thrombosis but a high-risk aPL antibody profile (i.e., triple positive for APS criteria assays, persistently positive medium to high titers of aCL antibodies, or persistent LA positive) be given longterm prophylaxis with low-dose aspirin, especially if there are other thrombotic risk factors. Furthermore, aPL antibody carriers should receive thromboprophylaxis with usual doses of low-molecular-weight heparin in high-risk situations, such as surgery, prolonged immobilization, and the puerperium. In addition to low-dose aspirin, aPL-antibody carriers with SLE should receive hydroxychloroquine as primary prophylaxis. In patients with low-titer positivity for (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile) or transiently positive aPL antibodies, no treatment is recommended. However, if a patient is found to be currently positive during situations with increased risk—i.e., surgery, prolonged immobilization, pre-/peripartum, ovarian stimulation, thalidomide therapy—consider prophylaxis treatment with LMW
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heparin. No prophylaxis treatment is recommended in pregnant women with elevated low titer or transient aPL antibodies and without any history of spontaneous pregnancy losses, other attributable pregnancy complications, thrombosis, or embolism.
Antiphospholipid Syndrome Treatment Duration and Monitoring: Current treatment for APS involves long-term, indefinite management with anticoagulation. It is important to note that when treating APS patients, anticoagulation may interfere with LA testing and cause false positive results. Therefore diagnosing APS and monitoring for persistently positive criteria assays can be a challenge. In addition, it is uncertain how to manage APS patients whose aPL antibody tests become persistently negative. At this point, it is unclear if the prothrombotic state induced by aPL antibodies fully disappears when patients are negative on aPL antibody tests. Because of inadequate data, there are no current recommendations on ceasing anticoagulant therapy in APS patients who become seronegative.
Future Management of Antiphospholipid Syndrome: APS is a heterogenous disorder requiring future efforts in improving the diagnosis through additional novel assays and evolving guidelines to identify patients with a propensity for thrombosis and/or pregnancy complications. Future targeted therapies for APS are still experimental and include tissue factor inhibitors, complement inhibitors, intracellular signaling inhibitors, and antagonists to platelet GP receptors and β2GPI receptors such as annexin A2, TLR4, and ApoE2. These potential treatments will require evaluation in well-designed prospective clinical trials.
Further Reading Arnaud, L., Conti, F., Massaro, L., et al. (2017). Primary thromboprophylaxis with lowdose aspirin an antiphospholipid antibodies: Pros and cons. Autoimmun Rev, 16, 1103–1108. Asherson, R. A., Cevera, R., de Groot, P. G., et al. (2003). Catastrophic antiphospholipid syndrome: International consensus statement on classification criteria and treatment guidelines. Lupus, 12, 530–534. Breen, K. A., Sanchez, K., Kirkman, N., et al. (2015). Endothelial and platelet microparticles in patients with antiphospholipid antibodies. Thromb Res, 135, 368–374. Cervera, R. (2017). Antiphospholipid syndrome. Thromb Res, 151, S43–S47. Cervera, R., Rodriguez-Pinto, I., Colafrancesco, S., et al. (2014). 14th international congress on antiphospholipid antibodies task force report on catastrophic antiphospholipid syndrome. Autoimmun Rev, 13, 699–707. de Laat, B., & de Groot, P. G. (2011). Autoantibodies directed against domain I of β2-glycoprotein I. Curr Rheumatol Rep, 13, 70–76. Erkan, D., Aguiar, C. L., Andrade, D., et al. (2014). 14th international congress on antiphospholipid antibodies: Task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev, 13, 685–696. Miyakis, S., Lockshin, M. D., 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.
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Ruiz-Iraastorza, G., Cuadrado, M. J., 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 syndrome. Lupus, 20, 206–218. Sciascia, S., Coloma-Bazan, E., Radin, M., et al. (2017). Can we withdraw anticoagulation in patients with antiphospholipid syndrome. Autoimmun Rev, 16, 1109–1114.
Antiphospholipid Syndrome Lucia R. Wolgast, MD
Introduction: The antiphospholipid (aPL) syndrome (APS) is an autoimmune thrombophilic condition that is defined by a combination of clinical and laboratory criteria. In general terms, APS patients have developed circulating antibodies against plasma proteins that bind to phospholipids (i.e., aPL antibodies) with subsequent clinical morbidity of thrombosis and/or pregnancy complications. The investigational criteria for APS (often referred to as the Sydney Investigational Criteria) are detailed in Table 108.1 and require that patients have documented evidence for vascular thrombosis and/or obstetric complications, such as unexplained recurrent miscarriages, intrauterine growth restriction, intrauterine fetal demise, preeclampsia/toxemia, placental abruption, and preterm labor. The laboratory criteria require identifying the persistent aPL antibodies (i.e., at least two abnormal measurements at least 12 weeks apart), including elevated medium to high tiers of anticardiolipin (aCL) IgG or IgM antibodies, anti-β2-glycoprotein I (anti-β2GPI) IgG or IgM antibodies, and/or positive lupus anticoagulant (LA). The laboratory diagnosis of APS is discussed in Chapter 158. It is important for the reader to understand that these criteria were not designed to be requirements for the clinical diagnosis of APS. Rather, they were intended to provide TABLE 108.1 Sydney Investigational Criteria for the Diagnosis of the Antiphospholipid Syndromea Clinical • Vascular thrombosis (one or more episodes of arterial, venous, or small vessel thrombosis). For histopathologic diagnosis, there should be no evidence of inflammation in the vessel wall. • Pregnancy morbidities attributable to placental insufficiency, including (a) three or more otherwise unexplained recurrent spontaneous miscarriages, before 10 weeks of gestation, (b) one or more fetal losses after the 10th week of gestation, (c) stillbirth, and (d) episode of preeclampsia, preterm labor, placental abruption, intrauterine growth restriction, or oligohydramnios that are otherwise unexplained.
Laboratory • Medium- or high-titer aCL or anti-β2GPI IgG and/or IgM antibody present on two or more occasions, at least 12 weeks apart, measured by standard ELISAs. • Lupus anticoagulant in plasma, on two or more occasions, at least 12 weeks apart, detected according to the guidelines of the ISTH SSC Subcommittee on Lupus Anticoagulants and Phospholipid-Dependent Antibodies. β2GPI, β2-glycoprotein I; aCL, anticardiolipin; aPL, antiphospholipid; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulin. a“Definite APS” is considered to be present if at least one of the clinical criteria and one of the laboratory criteria are met. Modified from Miyakis, S., Lockshin, M. D., 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. Transfusion Medicine and Hemostasis. https://doi.org/10.1016/B978-0-12-813726-0.00108-2 Copyright © 2019 Elsevier Inc. All rights reserved.
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TABLE 108.2 Proposed Criteria for the Classification of Catastrophic Antiphospholipid Syndrome (APS) 1. Evidence of involvement of three or more organs, systems, and/or tissuesa 2. Development of manifestations simultaneously or in less than a week 3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissueb 4. Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies)c
Definite Catastrophic APS • All four criteria
Probable Catastrophic APS • All four criteria, except for only two organs, systems and/or tissues involvement • All four criteria, except for the absence of laboratory confirmation at least 6 weeks apart due to the early death of a patient never previously tested for aPL before the catastrophic APS event • Criteria 1, 2, and 4 • Criteria 1, 3, and 4 and the development of a third event in more than a week but less than a month, despite anticoagulation aUsually, clinical
evidence of vessel occlusions, confirmed by imaging techniques when appropriate. Renal involvement is defined by a 50% rise in serum creatinine, severe systemic hypertension (N180/100 mm Hg), and/or proteinuria (N500 mg/24 hours). bFor histopathological confirmation, significant evidence of thrombosis must be present, although, in contrast to Sydney criteria, vasculitis may coexist occasionally. cIf the patient had not been previously diagnosed as having an APS, the laboratory confirmation requires that the presence of antiphospholipid antibodies must be detected on two or more occasions at least 6 weeks apart (not necessarily at the time of the event), according to the proposed preliminary criteria for the classification of definite APS. Modified from Asherson, R. A., Cevera, R., de Groot, P. G., et al. (2003). Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus, 12, 530–534.
a uniformly rigorous definition of APS for the purpose of standardizing research on the disorder. In “real-world” clinical practice, some patients may be appropriately diagnosed for presumptive APS without meeting the strict investigational criteria. Some APS patients may be positive for other “noncriteria” clinical laboratory tests—see Chapter 158—that have not been included by consensus panels as diagnostic criteria for the disorder, but these positive noncriteria laboratory tests may indicate a clinical risk and warrant treatment. Furthermore, APS patients may have positive APS criteria assays but not the typical criteria manifestations. These “noncriteria manifestations” include thrombocytopenia, livedo reticularis, skin ulcers, nephropathy, migraine, cognitive defects, diffuse alveolar hemorrhage, and valvular heart disease (Libman–Sacks endocarditis), and these clinical manifestations may need to be managed differently. Occasional patients may even test entirely negative for the APS criteria assays but have typical clinical manifestations of the disorder—a situation referred to as seronegative APS (termed SNAPS). At present, APS may be divided into the following subcategories: (1) Primary APS is the “stand alone” disorder, in the absence of systemic lupus erythematosus (SLE), (2) secondary APS occurs in the presence of APS, (3) catastrophic APS (CAPS) manifests as disseminated thrombosis in large and small vessels with resulting multiorgan failure (Table 108.2), and (4) SNAPS includes patients whose diagnostic tests are entirely negative but who, on clinical grounds, are still suspected to have the disorder.
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Antigenic Specificities and Pathophysiology of Antiphospholipid Antibodies β2-glycoprotein I: β2-glycoprotein I (β2GPI), a 50-kd glycoprotein member of the
complement control protein superfamily 5, is a major antigenic target for aPL antibodies. It is a scavenger protein that binds and clears apoptotic cells, microparticles, and other subcellular elements in circulating blood, including von Willebrand factor (VWF). Thromboprotective roles include binding and clearance of low-density lipoprotein (oxLDL), binding to VWF to reduce platelet adhesion to collagen, acting as a cofactor for tissue-type plasminogen activator (t-PA), and annexin A2 allowing increased fibrinolytic activity. β2GPI contains five homologous complement control domains, with a fifth domain that contains a phospholipid binding site (Fig. 108.1). This binding site has cationic residues with an affinity for anionic phospholipids and a hydrophobic loop, which can insert into the lipid bilayer. All five domains of β2GPI have been reported to be recognized by anti-β2GPI antibodies derived from patients. However, the most significant correlation is IgG antibodies against an epitope on domain I (Gly40-Arg43), which has a strong association with thrombosis. The antibodies against the domain I recognize an epitope, which is cryptic in the soluble, unbound protein, but becomes exposed after β2GPI binds to phospholipid bilayers. Transmission electron microscopy and X-ray scattering studies of stained β2GPI molecules indicate that the free unbound protein has a circular confirmation, whereas β2GPI bound to phospholipid has either a “J” or “S” shape conformation, exposing hidden domains to the immune system. Direct injury to endothelial surfaces causes β2GPI to bind to exposed phospholipids. Complexes of β2GPI bound to exposed aPLs, such as cardiolipin, create antigenic targets for aPL antibodies. These aPL antibodies then bind to the β2GPI/phospholipid complexes and interfere with anticoagulant and fibrinolytic pathways. Through cellular signaling pathways, the bound aPL antibodies create a prothrombotic state—upregulating tissue factor expression and adhesion molecules. aPL antibodies can also interfere with β2GPI cofactor functions for t-PA and annexin A2 inhibiting fibrinolytic activity. aPL antibodies reduce the effectiveness of β2GPI in clearing atherogenic proteins such as oxLDL and procoagulant microparticles. aPL antibodies can reduce the effectiveness of β2GPI in regulating VWF-mediated platelet adhesion. In the placenta, aPL antibodies cause placental insufficiency by activating trophoblasts and endometrial cells, resulting in abnormal trophoblast proliferation, increased trophoblast apoptosis, disruption in differentiation of decidual endometrial cells, and interference in maternal spiral artery maturation. The presence of aPL antibodies can also disrupt protective anticoagulant mechanisms to endothelial and trophoblastic injury, such as the binding of the anticoagulant annexin A5 to exposed phospholipids. aPL antibodies have been shown to activate platelets and monocytes and interfere with β2GPI’s role as a regulator of the complement cascade. β2GPI complexed with HLA-DR7 on cell surfaces can trigger complement-mediated cytotoxicity, which has been shown to play a significant role in obstetric APS.
Other Antigenic Targets of Antibodies Associated With Antiphospholipid Syndrome: Targets other than β2GPI that have been identified for aPL antibodies
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(SAXS) of β2GPI in solution revealed an S-shape conformation, with a carbohydrate chain on top of the interface between domains I and II. In contrast to the SAXS structure, transmission electron microscopy (TEM) of negatively stained unbound β2GPI mounted on grids showed a circular conformation, but a “J” shape for β2GPI bound to phospholipid. The arginine 39-arginine 43 epitope on domain I that is recognized by thrombogenic aPL antibodies is cryptic in the free-β2GPI proposed conformations. This epitope then becomes exposed and available for antibody recognition after the protein is bound to phospholipid. (Reprinted From de Laat, B., & de Groot, P. G. (February 2011). Autoantibodies directed against domain I of β2-glycoprotein I Curr Rheumatol Rep 13(1), 70–76.)
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include other anionic phospholipids, including phosphatidylserine, phosphatidylethanolamine, and phosphatidylinositol, which have all been associated with increased thrombosis and pregnancy morbidity. Other antibodies associated with APS clinical manifestations include prothrombin (coagulation factor II), coagulation factor V, protein C, protein S, annexin A2, annexin A5, high- and low-molecular-weight kininogens, heparin, factor VII/VIIa, plasmin, vimentin, VWF, thrombospondin, and P-selectin.
Clinical Manifestations of the Antiphospholipid Syndrome: The clinical symptoms of APS can be categorized into “criteria manifestations” and “noncriteria manifestations.” The “criteria manifestations” include vascular thrombotic events found in thrombotic APS, pregnancy complications found in obstetric APS, and multiorgan damage found in CAPS. The “noncriteria manifestations” include other pathologic conditions that have been found in APS patients but have not been included in the definition of “definite APS” by the expert consensus groups. These noncriteria manifestation in conjunction with positive laboratory criteria findings may warrant patient management and treatment.
Criteria Manifestations of Thrombotic and Obstetric Antiphospholipid Syndrome Venous and Arterial Thromboembolism: Criteria manifestations of thrombotic APS include both venous and arterial thrombosis with 60% of APS patient presenting with venous thrombosis, 30% presenting with arterial thrombosis, and 10% presenting with both venous and arterial thrombosis. The most common manifestations are deep vein thrombosis of the lower extremity, pulmonary embolism, and stroke/transient ischemic attacks. Other venous manifestations include thrombosis of thoracic, abdominal, pelvic, renal and/or retinal veins. Other arterial manifestations include myocardial infarction, nonatherosclerotic coronary artery occlusion, pulmonary hypertension attributed to thrombotic occlusion, and occlusions of abdominal, renal, and retinal arteries. The diagnosis of APS should be considered in patients spontaneously presenting with thrombosis particularly in the absence of other risk factors. The diagnosis of thrombotic APS is especially suspected when transient ischemic attacks or strokes occur in younger patients, particularly those without the usual risk factors for cerebrovascular disease—e.g., cigarette smoking, hypertension, and diabetes mellitus. In addition, thrombotic APS may manifest in the presence of a predisposing provocative factors such as estrogen hormone replacement therapy, oral contraceptives, pregnancy, the postpartum state, vascular stasis, surgery, or trauma. Some patients with venous thrombosis may also have a concurrent genetic thrombophilic conditions such as factor V-Leiden polymorphism. Pregnancy Complications: Criteria manifestations of obstetric APS include recurrent fetal loss, preeclampsia, placental abruption, prematurity, intrauterine fetal demise, intrauterine growth restriction, and oligohydramnios. Women with obstetric APS generally present with a history of recurrent (i.e., three or more) miscarriages. In approximately half of patients, the pregnancy losses occur in the first trimester; other patients present with later losses, most in the second trimester, but some even later, including stillbirth. The specific pregnancy complications that define obstetric APS include
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the absence of another explanation for the complications, three or more recurrent spontaneous first trimester miscarriages, or one mid-trimester loss, stillbirth, episode of preeclampsia, preterm labor, placental abruption, intrauterine growth restriction, or oligohydramnios. Pregnant patients with APS are also more prone to develop deep vein thrombosis during pregnancy or the puerperium. Interestingly, early reproductive failure (i.e., infertility) is not associated with APS.
Noncriteria Clinical Manifestations Associated With Antiphospholipid Syndrome: The most common noncriteria clinical manifestations include cardiac, neurological, dermatological, and hematological symptoms, including coronary artery disease in the absence of thrombotic occlusion, peripheral vascular disease, valvular abnormalities, migraines, seizures, livedo reticularis (Fig. 108.2), skin ulcerations/ necrosis, thrombocytopenia, and immune thrombocytopenic purpura. Many of the noncriteria manifestations occur in patients with SLE or other autoimmune disorders and may warrant additional management to prevent APS-associated thrombosis and/or pregnancy complications. One or two early spontaneous miscarriages (less than 10 weeks gestation) with a low positive aCL or anti-β2GPI are also considered a noncriteria manifestation that may warrant additional management. Other rarer noncriteria manifestations include glomerulonephritis, APS nephropathy, primary biliary cirrhosis, pancreatitis, acute sensorineural hearing loss, osteonecrosis, and bleeding due to acquired factor deficiencies or von Willebrand disease.
Catastrophic Antiphospholipid Syndrome: Rare patients present with a cata-
strophic form of APS, which is characterized by severe widespread vascular occlusions, and a high mortality. The formal diagnostic criteria include evidence of involvement of at least three organs, systems and/or tissues, development of manifestations simultaneously or within 1 week, histopathologic confirmation of small vessel occlusion, and laboratory confirmation of the presence of aPL antibodies (Table 108.2).
FIGURE 108.2 Livedo Reticularis in a woman with antiphospholipid syndrome. (Reprinted with permission from Elsevier, Ruiz-Irastorza, G., Crowther, M., Branch, W., & Khamashta, M. A. (October 30, 2010). Antiphospholipid syndrome. Lancet 376(9751),1498–1509.)
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In contrast to the diagnostic criteria for APS, which exclude the diagnosis when histopathology shows evidence for vasculitis, the diagnostic criteria for CAPS do permit the presence of histological evidence for vasculitis together with thrombosis. These patients present with evidence for severe multiorgan ischemia/infarction, usually with concurrent microvascular thrombosis. Patients with CAPS can present with massive venous thromboembolism, along with respiratory failure, stroke, abnormal liver enzymes, renal impairment, adrenal insufficiency, and areas of cutaneous infarction. The respiratory failure is usually due to acute respiratory distress syndrome and diffuse alveolar hemorrhage. Laboratory evidence for disseminated intravascular coagulation is frequently present. According to the CAPS Registry, a web-based database of 433 patients with CAPS (https://ontocrf.costaisa.com/en/web/caps/), the majority of CAPS patients are female (69%), in their late thirties (mean age of 38.5 years), but patients can be present at any age (range 0–85 years). In half of the CAPS cases, the patients’ catastrophic event was their first APS manifestation. Precipitating factors of CAPS include infections, drugs (sulfur-containing diuretics, captopril, and oral contraceptives), surgical procedures, and cessation of prior anticoagulant therapy. In 26.9% of cases, the patients also had SLE. The most frequently affected organ was the kidney (73% of episodes), followed by lungs (58.9%), the brain (55.9%), the heart (49.7%), and the skin (45.4%). Other organs were also affected, including the peripheral vessels, intestines, spleen, adrenal glands, pancreas, retina, and bone marrow. Improved aggressive treatment has reduced mortality from ∼50% to ∼20% and relapse is rare in survivors.
Pediatric Antiphospholipid Syndrome: APS has become increasingly recognized to be a significant cause of thrombosis in the pediatric population. A European registry report of an initial 121 cases described thrombotic manifestations similar to those seen with adults with APS. However, there was a significant and interesting difference between children with primary APS and the secondary APS, who had other autoimmune disease. The patients with primary APS tended to be younger and had a higher frequency of arterial thrombotic events, whereas the secondary APS patients were older and had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations. The catastrophic form of the syndrome has been reported in children but occurs more rarely than in adults. Thrombosis is rare in newborns delivered from mothers with APS, and only a few cases are reported, mostly associated with other prothrombotic factors. aPL antibodies have been found in up to 30% of offspring of mothers with APS. Other complications in neonates born to APS mothers include prematurity, neurodevelopment abnormalities, and learning disabilities.
Treatment of Patients With Antiphospholipid Syndrome: There is general agreement that patients with spontaneous and/or recurrent thrombosis require longterm anticoagulant therapy and that pregnant patients with a history of recurrent spontaneous pregnancy losses require antithrombotic therapy for most of the gestational period and for the puerperium. There have been uncertain approaches to treatment of patients with single thrombotic events, patients with provoked thrombotic events (i.e., trauma, surgery, stasis, airplane travel, pregnancy, or estrogens), patients with 1–2 early miscarriages, patients with noncriteria clinical manifestations, and patients with low-titer laboratory results. In addition, asymptomatic patients with multipositivity
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for criteria laboratory tests may be at increased risk for a clinical event and may warrant preventative treatment. Table 108.3 provides a summary of current recommended guidelines and treatment considerations.
Thrombotic Antiphospholipid Syndrome Treatment: In general, patients with thrombotic APS based on the diagnostic criteria should be treated with warfarin for the long term, at a therapeutic INR of 2.0–3.0. This is regardless of single or multiple positivity for aPL antibodies. In addition, patients with an arterial thrombotic event (i.e., stroke and/or myocardial infarction) should either be placed on a higher warfarin dose with INR 3.0–4.0 or be placed on long-term warfarin at a therapeutic INR of 2.0–3.0 and 100 mg daily dose of aspirin. APS patients with myocardial infarction and a stent placement should also be treated with clopidogrel (75 mg per day). Direct-acting oral anticoagulants (DOACs), either direct factor-Xa or thrombin inhibitors, have been proven effective for treatment of venous thromboembolism. However, their use specifically in APS patients has not been thoroughly evaluated. A recent randomized, open-label trial with 54 patients receiving rivaroxaban and 56 patients on warfarin showed the same safety profiles with no recurrent thrombosis or bleeding. Clinical trials are currently underway to confirm the safety and efficacy of DOACs in APS patients. DOACs can be considered in patients with poor anticoagulant compliance with warfarin or vitamin K antagonist allergy. DOACs are not recommended for APS patients with arterial thrombosis or with recurrent thrombosis while on therapeutic warfarin anticoagulation.
Obstetric Antiphospholipid Syndrome Treatment: The current approach to treating pregnant women with obstetric APS includes daily low-dose aspirin (75–81 mg per day) and either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Although clinical studies have shown efficacy with UFH, most clinicians treat with LMWH because it has a better pharmacokinetic profile and lower risk of heparin-induced thrombocytopenia and osteopenia. Heparin is then withheld when labor begins or 24 hours before a cesarean section. Anticoagulation is then resumed 6 weeks postpartum because of the increased risk of venous thromboembolism (VTE) in this period. With this management, the likelihood of a good pregnancy outcome in women with APS has been estimated to be about 75%–80%
Management of Noncriteria Clinical Manifestations: Treatment for noncriteria clinical manifestations of APS includes rituximab, glucocorticoids, vitamin D supplementation, and hydroxychloroquine. Rituximab may be effective in controlling noncriteria manifestations of APS such as persistent thrombocytopenia, autoimmune hemolytic anemia, cardiac valve disease, chronic skin ulcers, aPL-nephropathy, and/or cognitive dysfunction. Because low vitamin D levels correlated with noncriteria APS manifestations, it is recommended that vitamin D deficiency (<10–20 ng/mL) and insufficiency (<30 ng/mL) be corrected as a preventative strategy.
Catastrophic Antiphospholipid Syndrome Treatment: Patients with CAPS require aggressive treatment because of the high mortality. Treatment for CAPS is directed toward the thrombotic events and suppression of the cytokine cascade.
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TABLE 108.3 Antiphospholipid Syndrome (APS) Treatment Strategy Clinical Manifestation Laboratory Resulta
Treatment
Thrombotic APS Venous thromboembolism
Positive aCL and/or anti-β2GPI (IgG and/or IgM) immunoassays with medium or high titersb or Positive LA (confirm positive using two different assays)
Long-term vitamin K antagonist, INR 2.0–3.0
Low-titer positivity for aCL (IgG or IgM < 40 PL) or anti-β2GPI (IgG or IgM < 99th percentile)
Anticoagulation treatment and duration determined by additional risk factors at time of thrombosis.
Positive aCL and/or anti-β2GPI (IgG and/or IgM) immunoassays with medium or high titersb or Positive LA (confirm positive using two different assays)
Long-term vitamin K antagonist, INR 2.0–3.0 plus aspirin 100 mg per day or Long-term vitamin K antagonist, INR 3.0–4.0 Myocardial Infarction with percutaneous coronary interventions and stent placement: Long-term vitamin K antagonist, INR 2.0–3.0, aspirin 100 mg per day, and clopidogrel 75 mg per day.
Low-titer positivity for aCL (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile)
Anticoagulation treatment and duration determined by additional risk factors at time of thrombosis.
Noncriteria manifestations
Positive aCL and/or anti-β2GPI (IgG and/or IgM) immunoassays with medium or high titersb or Positive LA (confirm positive using two different assays)
Consider rituximab and/or vitamin D supplementation
Noncriteria manifestations
Low-titer positivity for aCL (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile)
Consider rituximab and/or vitamin D supplementation
Arterial thromboembolism (including stroke and myocardial infarction)
Refractory thrombotic APS (recurrent thrombosis despite treatment)
Higher intensity vitamin K antagonist, INR 3.0–4.0. First line add-on treatments: Antiplatelet agents or low-molecular-weight (LMW) heparin Second line add-on treatments: Glucocorticoids, hydroxychloroquine, statins, and/or rituximab
Obstetric APS Pregnant women with history of criteria pregnancy complicationsc or thrombotic events
Positive aCL and/or anti-β2GPI (IgG and/or IgM) immunoassays with medium or high titersb or Positive LA (confirm positive using two different assays)
Unfractionated or LMW heparin plus low-dose aspirin
Continued
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TABLE 108.3 Antiphospholipid Syndrome (APS) Treatment Strategy—cont’d Clinical Manifestation Laboratory Resulta
Treatment
Pregnant women with history of criteria pregnancy complicationsc or thrombotic events
Low-titer positivity for aCL (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile)
Unfractionated or LMW heparin plus low-dose aspirind
Noncriteria manifestation—one or two early miscarriage (<10 weeks of gestation)
Positive aCL and/or anti-β2GPI (IgG and/or IgM) immunoassays with medium or high titersb or Positive LA (confirm positive using two different assays)
Unfractionated or LMW heparin plus low-dose aspirind
Noncriteria manifestation—one or two early miscarriage (<10 weeks gestation)
Low-titer positivity for aCL (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile)
No treatment recommendation, however, assess pregnant patients for treatment due to additional risk factors.
Refractory obstetric APS
Consider add-on treatment with glucocorticoids, intravenous IgG (IVIG), and/or hydroxychloroquine
Asymptomatic Antiphospholipid Positive Carriers None
Triple positive for LA, aCL, and anti-β2GPI with medium or high titersb
Long-term prophylaxis with lowdose aspirin. Consider anticoagulant prophylaxis for high-risk situations—e.g., immobilization, surgery, air travel, etc. Consider unfractionated or LMW heparin for pregnant patients
Double positive for LA, aCL, or anti- Long-term prophylaxis with lowβ2GPI with medium or high titers dose aspirin. or Consider anticoagulant prophylaxis Persistently positive for isolated for high-risk situations—e.g., aCL IgG or IgM with medium or immobilization, surgery, air travel, high titers etc. or Consider unfractionated or LMW Single positive for LA heparin for pregnant patients
Patients with SLE or autoimmune disease
aLaboratory
Low-titer positivity for aCL (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile) and/or transiently positive.
No treatment, however, considers prophylaxis treatment with LMW heparin in situations with increased risk—surgery, prolonged immobilization, pre-/peripartum, ovarian stimulation, thalidomide therapy, and the patient is currently positived
Single positive LA or persistently positive aCL with medium or high titers
Low-dose aspirin and hydroxychloroquine
tests should be deferred until at least 12 weeks after the clinical event to avoid interferences of the acute phase of the disease. Earlier testing may yield false positive results. LA, aCL, and anti-β2GPI tests must be positive on two or more occasions at least 12 weeks apart to be considered “Positive.” bMedium or high titers include aCL IgG, or IgM > 40 GPL and/or anti-β2GPI IgG or IgM > 99th percentile. cSydney Investigational Criteria pregnancy complications include (a) >3 unexplained recurrent spontaneous miscarriages at <10 weeks of gestation, (b) one or more fetal losses after the 10th week of gestation, (c) stillbirth, and (d) episode of preeclampsia, preterm labor, placental abruption, intrauterine growth restriction, or oligohydramnios. dFrom recent recommendations by international consensus in Autoimmunity Reviews 16 (2017) 911–924 and 1103–1108.
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A triple-therapy strategy of anticoagulation with heparin, high-dose glucocorticoids, and either intravenous immunoglobulin (IVIG) or plasma exchange or both has improved outcomes. This triple-therapy strategy has resulted in the significant reduction in mortality rate to 30% in CAPS. Cyclophosphamide is recommended for patients with CAPS and inflammatory features of SLE or high-titer aPL antibodies. Rituximab may be useful in refractory or relapsing cases of CAPS.
Refractory Antiphospholipid Syndrome Treatment: For thrombotic APS patients who are refractory to standard warfarin anticoagulant therapy, an increase in warfarin intensity is recommended with an INR 3.0–4.0. If APS patients have a recurrence on high-intensity warfarin, then add-on treatment with an antiplatelet agent (i.e., clopidogrel) or LMWH may be considered, as well as a DOAC for recurrent venous thromboembolism. If anticoagulation fails, combinations of anticoagulation with glucocorticoids, hydroxychloroquine, statins, and/or rituximab may be considered. In patients with refractory obstetric APS, glucocorticoids, IVIG, and hydroxychloroquine have been shown to be effective. In addition, glucocorticoids should be considered in obstetric APS patients who have a severe immune thrombocytopenia or a significant contraindication to heparin therapy.
Management of Patients With Clinical Manifestations and Low-Titer Antiphospholipid Antibody Positivity: Currently there are no treatment recommendations for patients with low-titer positivity for aCL (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile) or transiently positive aPL antibodies. For patients with venous or arterial thromboembolism, anticoagulation treatment and duration should be determined by additional risk factors at time of thrombosis. In pregnant patients with history of greater than three early spontaneous miscarriages, one or more late miscarriages, stillbirth, an episode of preeclampsia, preterm labor, placental abruption, intrauterine growth restriction or oligohydramnios, and unfractionated or LMW heparin plus low-dose aspirin is recommended. No treatment is recommended in patients with low-titer antibodies and one or two miscarriages; however, they should be assessed for other risk factors.
Management of Asymptomatic Antiphospholipid Antibody-Positive Patients: Asymptomatic patients with no previous thrombosis but a high-risk aPL antibody profile (i.e., triple positive for APS criteria assays, persistently positive medium to high titers of aCL antibodies, or persistent LA positive) be given longterm prophylaxis with low-dose aspirin, especially if there are other thrombotic risk factors. Furthermore, aPL antibody carriers should receive thromboprophylaxis with usual doses of low-molecular-weight heparin in high-risk situations, such as surgery, prolonged immobilization, and the puerperium. In addition to low-dose aspirin, aPL-antibody carriers with SLE should receive hydroxychloroquine as primary prophylaxis. In patients with low-titer positivity for (IgG or IgM < 40 GPL) or anti-β2GPI (IgG or IgM < 99th percentile) or transiently positive aPL antibodies, no treatment is recommended. However, if a patient is found to be currently positive during situations with increased risk—i.e., surgery, prolonged immobilization, pre-/peripartum, ovarian stimulation, thalidomide therapy—consider prophylaxis treatment with LMW
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heparin. No prophylaxis treatment is recommended in pregnant women with elevated low titer or transient aPL antibodies and without any history of spontaneous pregnancy losses, other attributable pregnancy complications, thrombosis, or embolism.
Antiphospholipid Syndrome Treatment Duration and Monitoring: Current treatment for APS involves long-term, indefinite management with anticoagulation. It is important to note that when treating APS patients, anticoagulation may interfere with LA testing and cause false positive results. Therefore diagnosing APS and monitoring for persistently positive criteria assays can be a challenge. In addition, it is uncertain how to manage APS patients whose aPL antibody tests become persistently negative. At this point, it is unclear if the prothrombotic state induced by aPL antibodies fully disappears when patients are negative on aPL antibody tests. Because of inadequate data, there are no current recommendations on ceasing anticoagulant therapy in APS patients who become seronegative.
Future Management of Antiphospholipid Syndrome: APS is a heterogenous disorder requiring future efforts in improving the diagnosis through additional novel assays and evolving guidelines to identify patients with a propensity for thrombosis and/or pregnancy complications. Future targeted therapies for APS are still experimental and include tissue factor inhibitors, complement inhibitors, intracellular signaling inhibitors, and antagonists to platelet GP receptors and β2GPI receptors such as annexin A2, TLR4, and ApoE2. These potential treatments will require evaluation in well-designed prospective clinical trials.
Further Reading Arnaud, L., Conti, F., Massaro, L., et al. (2017). Primary thromboprophylaxis with lowdose aspirin an antiphospholipid antibodies: Pros and cons. Autoimmun Rev, 16, 1103–1108. Asherson, R. A., Cevera, R., de Groot, P. G., et al. (2003). Catastrophic antiphospholipid syndrome: International consensus statement on classification criteria and treatment guidelines. Lupus, 12, 530–534. Breen, K. A., Sanchez, K., Kirkman, N., et al. (2015). Endothelial and platelet microparticles in patients with antiphospholipid antibodies. Thromb Res, 135, 368–374. Cervera, R. (2017). Antiphospholipid syndrome. Thromb Res, 151, S43–S47. Cervera, R., Rodriguez-Pinto, I., Colafrancesco, S., et al. (2014). 14th international congress on antiphospholipid antibodies task force report on catastrophic antiphospholipid syndrome. Autoimmun Rev, 13, 699–707. de Laat, B., & de Groot, P. G. (2011). Autoantibodies directed against domain I of β2-glycoprotein I. Curr Rheumatol Rep, 13, 70–76. Erkan, D., Aguiar, C. L., Andrade, D., et al. (2014). 14th international congress on antiphospholipid antibodies: Task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev, 13, 685–696. Miyakis, S., Lockshin, M. D., 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.
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Ruiz-Iraastorza, G., Cuadrado, M. J., 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 syndrome. Lupus, 20, 206–218. Sciascia, S., Coloma-Bazan, E., Radin, M., et al. (2017). Can we withdraw anticoagulation in patients with antiphospholipid syndrome. Autoimmun Rev, 16, 1109–1114.