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Table 131–4 summarizes the clinical features of APS. Patients generally present with thrombotic manifestations, that is, evidence for vasoocclusion or end-organ ischemia or infarction, and/or pregnancy losses and complications attributable to placental insufficiency. The usual age at presentation with thrombosis is approximately 35 to 45 years. Except for patients with SLE, men and women are equally susceptible to thrombotic manifestations. No differences have been observed between the arterial and venous distributions of thromboses of primary and secondary APS patients.134
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SYSTEMIC VASCULAR THROMBOSIS
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Patients can present with spontaneous venous and/or arterial thrombosis or embolism in any site; however, about half of all patients have deep vein thrombosis of the lower extremities.135,136 Other sites of venous thromboembolic events include pulmonary embolism, thoracic veins (superior vena cava, subclavian vein, or jugular vein), and abdominal or pelvic veins.136 Approximately one-fourth of patients present with arterial thromboses; the remainder present with concurrent arterial and venous thrombosis.136 Patients may also present with stroke, cerebral venous thrombosis, upper-extremity venous thrombosis,135 myocardial infarction, adrenal infarction, acalculous gallbladder infarction, aortic thrombosis with renal infarction,120 and mesenteric artery thrombosis.137,138 Thrombosis may occur spontaneously or in the presence of some other risk factor such as estrogen replacement therapy, oral contraceptives,134,139 vascular stasis, surgery, or trauma. Women are at particularly high risk for venous thrombosis during pregnancy and in the postpartum period.134 Some APS patients with venous thrombosis have concurrent genetic thrombophilic conditions such as the factor V Leiden variant, and it has been postulated that this may increase the risk of thrombosis.140,141,142,143 Concurrent positivity for all three aPL antibody assays—that is, the aCL antibody assay, anti-β2GPI antibody assay, and the LA assay—appears to be a highly significant risk factor for having an initial thrombotic event (Fig. 131–5).144 If this finding is confirmed, it could identify a group of patients who might warrant consideration for prophylactic treatment. A history of having had a thromboembolic event is probably the most significant risk factor for recurrence of venous thromboembolism in APS, with a reported frequency that reached approximately 30 percent in patients followed for 4 years after the first episode.145 The risk of recurrent thromboembolism correlates with the titer of antibodies,145,146 and with the presence of LA. In addition, it appears that the presence of anti-β2GPI domain I antibodies significantly increase the risk of thrombosis, compared to patients who have antibodies that are not domain I dependent and LA that is not domain I dependent.51
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SYSTEMIC LUPUS ERYTHEMATOSUS AND OTHER AUTOIMMUNE CONDITIONS
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APS patients frequently present with other autoimmune conditions. A significant proportion of SLE patients have elevated aPL antibodies, with estimates ranging between 12 and 30 percent for aCL antibodies and 15 and 34 percent for LA antibodies.147 APS has been associated with the concurrence of other autoimmune conditions including, but not limited to, rheumatoid arthritis,148 Sjögren syndrome,149 myasthenia gravis,150 Budd-Chiari syndrome in the setting of SLE,151 Graves disease,152 autoimmune hemolytic anemia, progressive systemic sclerosis,153 Evans syndrome,154 Takayasu arteritis,155 polyarteritis nodosa,156 and immune thrombocytopenia (see section Thrombocytopenia below and also Chap. 117).
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STROKE AND OTHER NEUROLOGIC CONDITIONS
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The most common neurologic manifestations of APS are stroke or transient ischemic attacks (TIAs), which were the initial presentation of up to 30 percent of adults with APS in a large European cohort.157 In the European Catastrophic Antiphospholipid Antibody Syndrome (CAPS) Registry, cerebral manifestations occurred in 62 percent of patients and caused 13 percent of deaths.158 Recurrent strokes are more likely in patients with APS and other risk factors for cerebrovascular disease, such as cigarette smoking, hypertension hyperlipidemia, oral contraceptive use, and SLE.159,160
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Most APS patients with stroke have arterial thromboembolic occlusive events that are clinically indistinguishable from the more common arteriosclerotic strokes. APS should be suspected in young patients with TIAs or stroke, particularly when the more typical risk factors for cerebrovascular disease are absent.161 Cerebral venous thrombosis is less common in APS patients and presents at a younger age, and is more extensive than in non-APS patients with the disorder.162 In one series of 40 cases of cerebral venous thrombosis, three patients (8 percent) had elevated aPL antibody levels.163 Superior sagittal sinus thrombosis has been reported with primary APS.164
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There is controversy about whether migraines in patients with aPL antibodies should be regarded as thromboocclusive events.165 Other neurologic abnormalities reported to be associated with aPL antibodies include seizures/epilepsy,166 chorea, Guillain-Barré syndrome, transient global amnesia, dementia, diabetic peripheral neuropathy, and orthostatic hypotension.167 Recurrent acute transverse myelopathy has been described with APS.168,169,170,171,172 However, in one study of 315 SLE patients, including 10 with a history of transverse myelopathy, that disorder was not associated with aPL antibodies.173 Multiple sclerosis patients have a high incidence of elevated aCL antibody levels (in one series, 9 percent had IgG antibodies and 44 percent had IgM antibodies),174 however, no clinical distinctions were found between aPL-positive and aPL-negative patients and the antibodies do not appear to be associated with thrombosis. Patients with psychotic disorders have an increased prevalence of LA and aCL antibodies, even in the absence of treatment with antipsychotic drugs.175
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CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME
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CAPS is a relatively infrequent but devastating presentation of APS, is characterized by severe widespread vascular occlusions.176 Diagnostic criteria for CAPS include evidence of involvement of at least three organs, systems, and/or tissues; development of manifestations simultaneously or in less than 1 week; histopathologic confirmation of small-vessel occlusion; and laboratory confirmation of the presence of aPL antibodies.177 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 percent), in their late thirties (mean age of 38.5 years), but the condition can present at any age (range: 0 to 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 percent of cases, the patients also had SLE. The most frequently affected organ was the kidney (73 percent of episodes), followed by lungs (58.9 percent), the brain (55.9 percent), the heart (49.7 percent), and the skin (45.4 percent). Other organs were also affected, including the peripheral vessels, intestines, spleen, adrenal glands, pancreas, retina, and marrow. Patients present with evidence for severe multiorgan ischemia/infarction, often with concurrent disseminated microvascular thrombosis. Patients with CAPS can present with renal insufficiency, respiratory failure resulting from acute respiratory distress syndrome (ARDS) and pulmonary emboli, cerebral manifestations such as encephalopathy, stroke and seizures, cardiac problems such as heart failure, myocardial infarction and valvular defects, and skin complications such as livedo reticularis and skin necrosis.178 Most patients show histologic evidence of microangiopathy mainly affecting small vessels of the kidneys, lungs, brain, heart, and liver. Only a minority of patients experience large-vessel occlusions. Laboratory evidence for disseminated intravascular coagulation is frequently present. An LA is present in 81.7 percent of patients, and the aCL IgG is the most common positive aPL antibody.178 Improved treatment has reduced mortality from approximately 50 percent to approximately 20 percent.176 Relapse is rare in survivors. The only identified predictive factor for adverse outcome is underlying SLE.179
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PREGNANCY LOSSES, OBSTETRIC COMPLICATIONS, AND INFERTILITY
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At this time, aPL screening of otherwise asymptomatic with no history of prior complications obstetrical patients is not warranted because of the high frequency of false-positive tests; most studies have estimated the prevalence of aPL antibodies among general obstetric populations to be approximately 5 percent or less and most of these aPL-positive patients are not clinically affected.180
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Among obstetric patients with recurrent fetal losses, approximately 16 to 38 percent have aPL antibodies. In addition, pregnant women with elevated aPL antibodies had significantly more obstetric complications, including preeclampsia, abruption placentae, miscarriage, prematurity, intrauterine fetal demise, intrauterine growth restriction, and oligohydraminos, than aPL antibody-negative pregnant women.181,182,183 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. Pregnancy complications attributable to APS include three or more recurrent spontaneous first trimester miscarriages, one or more fetal losses during the second trimester, stillbirth, episode of preeclampsia, preterm labor, placental abruption, intrauterine growth restriction, and oligohydramnion.184,185,186 Pregnant patients with APS are also more prone to developing deep vein thrombosis during pregnancy or the puerperium. Rarely, pregnant patients develop CAPS.187,188 The best predictor for pregnancy loss in a patient who tests positive for aPL antibodies has been demonstrated to simply be a previous history of pregnancy loss, complications, or thrombosis.146,189 A recent study reported that any aPL antibody-positive women with an unexplained early loss prior to 10 weeks have a higher risk of complications in their second pregnancy190 but the degree of laboratory abnormalities were not associated with increased risk. Positivity by more than one assay appears to correlate with increased pregnancy morbidities.182,191 Histologic abnormalities were found in many, but not all, placentas of aPL patients.192 Studies of placental pathology in patients with aPL antibodies, but without a prior history of fetal loss, showed that approximately half had evidence of uteroplacental vascular pathology, approximately half had evidence of thrombotic occlusion, and approximately one-third had chronic villitis and/or decidual plasma cell infiltrates.193,194
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Overall, it appears that the presence of aPL antibodies does not affect the success rate of implantation. Although one group has reported data that indicated that women with recurrent implantation failure were more likely to have positive assays for aPL antibodies compared to fertile negative controls,195 a review of 29 studies showed mixed results.196 Many of the studies were noted to have limitations, including problems with study design and statistical power. The current consensus is that aPL antibodies are not a cause of infertility.197 Recently, the14th International Congress on Antiphospholipid Antibodies Task Force also concluded that “there are no data to support the inclusion of infertility as criteria for APS and investigation of APS in patients with infertility should not be done in routine clinical practice, being reserved only for research purposes.”196
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CUTANEOUS MANIFESTATIONS
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The cutaneous manifestations of APS may comprise the first signs of APS in some patients.198,199 Livedo reticularis is relatively common, occurring in 24 percent of a series of 1000 aPL patients,200 and occasionally presents in a necrosing form.201 Noninflammatory vascular thrombosis is the most frequent histopathologic feature. Necrotizing vasculitis, livedoid vasculitis, thrombophlebitis, cutaneous ulceration and necrosis, erythematous macules, purpura, ecchymoses, painful skin nodules, and subungual splinter hemorrhages, anetoderma (macular atrophy), discoid lupus erythematosus, and cutaneous T-cell lymphoma have all been reported.
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CORONARY ARTERY DISEASE
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aPL antibodies are associated with increased susceptibility to coronary artery disease,202 particularly premature atherosclerosis.203,204 APS should be considered in patients who lack the usual risk factors for coronary artery disease and in patients with evidence for thrombotic or embolic coronary artery occlusion that lack angiographic evidence of atherosclerotic disease. aPL antibodies appear to be a risk factor for adverse outcomes following all coronary revascularization procedures,202 and for restenosis after percutaneous transluminal coronary angioplasty.205,206 An ultrasound study of carotid arteries provided evidence supporting an association of aPL antibodies with premature atherosclerosis; relatively young primary APS patients (mean age: 37 ± 11 years) had significantly increased intimal medial thickness compared to control non-APS groups.207
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VALVULAR HEART DISEASE
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Approximately 35 percent of patients with primary APS have cardiac valvular abnormalities detected by echocardiography.208 In one study, approximately 20 percent of cardiac patients with valvular heart disease had evidence for aPL antibodies compared with approximately 10 percent of matched control subjects.209 Valvulopathy includes leaflet thickening, vegetations, regurgitation, and stenosis.210 The mitral valve is mainly affected, followed by the aortic valve.211 Histologically, APS valvular lesions consist mainly of superficial or intravalvular fibrin deposits in association with variable degrees of vascular proliferation, fibroblast influx, fibrosis, and calcification. These can result in valve thickening, fusion, and rigidity, and lead to functional abnormalities.212 Deposits of immunoglobulins, including aCL antibodies, and of complement components are commonly found in the affected valves.213
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PERIPHERAL VASCULAR DISEASE
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Approximately one-third of patients with peripheral arterial disease undergoing bypass grafting procedures had elevated aPL antibody levels (mostly aCL antibodies).214 Intraarterial thromboembolic events are common at presentation of these patients and may complicate surgical management. However, these patients did not have an increased risk for reocclusion, a finding that was attributable to the use of anticoagulant therapy.
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PULMONARY MANIFESTATIONS
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Patients with APS may present with in situ thrombosis in pulmonary vessels. aPL antibodies are associated with pulmonary hypertension.215 In one prospective trial of 38 consecutive patients with precapillary pulmonary hypertension, approximately 30 percent had aPL antibodies with various phospholipid specificities.216 An interinstitutional study of 687 patients with chronic thromboembolic pulmonary hypertension reported that aPL antibodies were a significant risk factor.217 The majority of patients with CAPS (see “Catastrophic Antiphospholipid Syndrome” above) have dyspnea, and most of these individuals have ARDS.218
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ABDOMINAL MANIFESTATIONS
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The liver is the most frequently affected abdominal organ in APS, with occlusion of hepatic vessels, including those supplying the biliary tree.219 aPL antibody levels frequently are elevated in patients with chronic liver disease of various causes. In one prospective study of patients with liver disease, approximately half of patients with alcoholic liver disease and one-third of patients with chronic hepatitis C virus had elevated aPL antibody levels. The frequency was even higher in patients with more severe cirrhosis.220 A review reported that approximately 20 percent of patients with chronic hepatitis B and hepatitis C had aPL antibodies, most of which were cofactor independent.221 Some patients with hepatitis C present with true autoimmune aPL antibodies, the most common features reported being intraabdominal thrombosis and myocardial infarction.222
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Reported gastrointestinal manifestations of APS also include esophageal necrosis with perforation, intestinal ischemia and infarction, pancreatitis, and colonic ulceration. Primary biliary cirrhosis,223 acute acalculous cholecystitis with gallbladder necrosis,224,225 and giant gastric ulceration are associated with APS.226 APS has been reported in patients with mesenteric inflammatory venoocclusive disease227 and in patients with mesenteric and portal venous obstruction.228
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Approximately 20 to 40 percent of patients with APS have varying degrees of thrombocytopenia. The decrease in platelet count is generally mild or moderate and is rarely significant enough to cause bleeding complications or affect anticoagulant therapy.229,230 The majority of patients with APS and thrombocytopenia have antibodies against αIIbβ3 integrin and/or glycoprotein Ib-IX complex.231 Patients presenting with immune thrombocytopenic purpura frequently have elevated aPL antibodies, and these patients are more prone to thrombosis.232 aPL antibodies and antibodies against platelet membrane glycoprotein were present simultaneously in approximately 70 percent of patients with immune-mediated thrombocytopenia.233 Thrombocytopenia itself is not protective against thrombosis in these patients. In a prospective cohort study, 5-year thrombosis-free survival of aPL-positive and aPL-negative immune thrombocytopenic purpura patients were 39 percent and 98 percent, respectively.234
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The presence of a concurrent hemostasis defect needs to be considered when patients with APS exhibit a bleeding tendency (Table 131–5). Acquired hypoprothrombinemia with severe bleeding has been reported.235,236 This diagnosis may be missed when coagulation abnormalities are attributed only to the LA effect, so a specific assay for prothrombin should be performed when the prothrombin time is prolonged. Other causes of bleeding in APS include acquired thrombocytopathies, thrombocytopenia (see “Thrombocytopenia,” above), acquired inhibitors against specific coagulation factors, such as factor VIII, and the acquired von Willebrand syndrome (AVWS).
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RETINAL ABNORMALITIES
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The diagnosis of aPL antibody retinopathy should be suspected in patients with diffuse retinal vasoocclusion, particularly when characterized by involvement of arteries and veins, neovascularization at presentation, and symptoms of systemic rheumatologic disease.237 aPL antibodies were present in 5 to 33 percent of patients with retinal vein occlusion.238,239 Cilioretinal artery occlusion,240 optic neuropathy,241 and severe vasoocclusive retinopathy242 have been described with APS.
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APS may affect the renal system. Patients may present with renal artery stenosis and/or thrombosis, renal infarction, renal vein thrombosis, and glomerulonephritis that is distinct from vasoocclusive disease.200,243 An entity named “APS nephropathy” has been described, which consists of a vasoocclusive disease of small-size intrarenal vessels.244 This nephropathy features fibrous intimal hyperplasia, focal cortical atrophy, and thrombotic microangiopathy. A review of 29 consecutive renal biopsies from patients with primary APS, performed at two institutions over 22 years, described 20 cases of APS nephropathy and nine cases with other distinct pathologic features.243 These features included membranous nephropathy, minimal change disease/focal segmental glomerulonephritis, mesangial C3 nephropathy, and pauci-immune crescentic glomerulonephritis.
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ANTIPHOSPHOLIPID SYNDROME AND AIDS
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Although patients with HIV-1 infection frequently have elevated aPL antibody levels, they do not often have thrombotic manifestations. A review indicated that approximately 50 percent of HIV-1 patients test positive for aPL antibodies, most of which are not cofactor dependent.221 HIV-infected patients with manifestations of APS have also presented with avascular bone and cutaneous necrosis.222
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ANTIPHOSPHOLIPID SYNDROME IN CHILDREN
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Increasingly, APS has become recognized in children,245 in whom diverse clinical features are common. The results of a European registry have been reported.246 Review of 121 cases indicated that although the thrombotic manifestations were similar to adults with APS, there was a difference between children with primary APS and the secondary APS; the children with primary APS were younger and had a higher frequency of arterial thrombotic events, whereas the children with secondary APS patients had a higher frequency of venous thrombotic events associated with hematologic and skin manifestations. CAPS has been reported in children, but is rare.247,248
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Thrombosis is rare in newborns delivered from mothers with APS, and only a few cases are reported, mostly associated with other prothrombotic factors.249 aPL antibodies have been found in up to 30 percent of offspring of mothers with APS.250
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In a recent European prospective study, 17 percent of neonates born to APS mothers were premature; however, no specific complications were found during the 5-year followup.251 The study did show a higher rate of neurodevelopmental abnormalities with learning disabilities similar to two retrospective reports where learning disabilities without other neurodevelopmental abnormalities were present in 15 to 20 percent of cases.252,253
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Acute adrenal failure secondary to bilateral infarction of the adrenal glands has been reported as the first manifestation of primary APS.254 Adrenal hemorrhage has been reported.255 aPL antibodies have been associated with marrow necrosis.256