Clinical manifestations of antiphospholipid syndrome

INTRODUCTION — Antiphospholipid syndrome (APS) is an autoimmune multisystem disorder characterized by arterial, venous, or small vessel thromboembolic events and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL) [1]. aPLs are a heterogenous group of autoantibodies which are directed against phospholipid-binding proteins.

APS occurs as a primary condition or in the setting of an underlying systemic autoimmune disease, particularly systemic lupus erythematosus (SLE).

The clinical manifestations of APS will be reviewed here. Pathogenesis, diagnosis, and treatment of APS are presented separately. (See "Pathogenesis of antiphospholipid syndrome" and "Diagnosis of antiphospholipid syndrome" and "Management of antiphospholipid syndrome".)

Catastrophic APS (CAPS) and kidney manifestations of APS are discussed separately. (See "Catastrophic antiphospholipid syndrome (CAPS)" and "Antiphospholipid syndrome and the kidney".)

EPIDEMIOLOGY — In a large retrospective analysis including patients without known autoimmune diseases, antiphospholipid antibodies (aPL) were present in approximately 9 percent of patients with pregnancy losses, 14 percent with stroke, 11 percent with myocardial infarction (MI), and 10 percent with deep vein thrombosis (DVT) [2].

Estimates in the United States suggest that aPL are associated with approximately 50,000 pregnancy losses, 110,000 strokes, 100,000 MIs, and 30,000 DVTs annually [2-8]. Epidemiologic studies done in the general population from the United States and Italy determined a prevalence of antiphospholipid syndrome (APS) ranging from 17 to 50 patients per 100,000 [9,10].

PRIMARY APS VERSUS APS WITH SLE — Approximately half of patients with antiphospholipid syndrome (APS) have primary disease, while the other half have a concomitant systemic autoimmune disease. Systemic lupus erythematosus (SLE) is the disease most commonly associated with APS, which is present in approximately 35 percent of cases [11].

Although many of the clinical manifestations of primary APS and APS associated with SLE are similar [12], patients with SLE-associated APS are more likely to have arthritis, livedo reticularis, heart valve disease, thrombocytopenia, and leukopenia than patients with primary APS [13-15]. Another study found that the frequencies of arterial thrombosis, venous thrombosis, and fetal loss were greater in patients with APS and SLE than in those with primary APS [16]. However, traditional cardiovascular risk factors and markers of early atherosclerosis are similar between patients with primary and SLE-associated APS [17,18].

A separate issue regarding the relationship of APS and SLE is the frequency of evolution of APS into SLE or lupus-like disease. Three studies involving 70 to 128 patients with APS found a variable rate of development of SLE over time:

●0 percent at 5 years [19]

●4 percent at 6.5 years [20]

●13 to 23 percent at 9 years [21,22]

CLINICAL MANIFESTATIONS — In addition to the hallmark features of venous, arterial, and/or small vessel thrombosis as well as specific pregnancy complications, other relatively common clinical features of antiphospholipid syndrome (APS) include livedo reticularis, thrombocytopenia, or transient ischemic attack [23].

Rarely, patients with APS can develop catastrophic APS (CAPS), with widespread thrombotic disease and multiorgan failure (table 1). CAPS can also rarely be the initial presentation of APS. (See "Catastrophic antiphospholipid syndrome (CAPS)".)

In a series of 1000 patients with either primary or autoimmune disease-associated APS, the various disease features were [24]:

●Deep vein thrombosis (DVT) – 32 percent

●Thrombocytopenia – 22 percent

●Livedo reticularis – 20 percent

●Stroke – 13 percent

●Superficial thrombophlebitis – 9 percent

●Pulmonary embolism – 9 percent

●Fetal loss – 8 percent

●Transient ischemic attack – 7 percent

Several studies have identified that particular combinations of features are seen more often together or in a given patient over time (eg, stroke and valvular heart disease, livedo and arterial thrombosis, thrombocytopenia and small vessel thrombosis). A cluster analysis demonstrated that small vessel thrombosis and pregnancy morbidity manifestations were found in patients with non-criteria manifestations [25]. (See "Diagnosis of antiphospholipid syndrome", section on 'Classification criteria'.)

In addition to those manifestations mentioned above, some of the other possible antiphospholipid antibody (aPL)-related clinical manifestations include cardiac valve disease, pulmonary hypertension, thrombocytopenia, cutaneous ulcers and adrenal insufficiency due to hemorrhagic infarction, and cognitive deficits [23,24,26-29].

Thrombotic events — Thromboses are the hallmark of APS, and venous thromboses are more common than arterial thromboses [24]. The risk of both venous and arterial thrombosis and/or thromboembolism is increased in individuals with positive tests for lupus anticoagulant (LA) activity (odds ratio [OR] 11) or with medium or high levels of anticardiolipin antibodies (aCL; OR 1.6) [30]. The risk of recurrent thrombosis or thromboembolism may be further enhanced in those with positivity to three aPL, also known as "triple positivity," (LA, aCL, and anti-beta2 glycoprotein [GP] I antibodies) upon repeated testing [31].

Venous thrombosis — The deep veins of the lower extremities are the most common sites of thrombosis, with estimates from large cohort studies ranging from 20 to 30 percent of patients with APS [24,32]. Other sites of venous thrombosis include the pelvic, renal, pulmonary, hepatic, portal, axillary, subclavian, ocular, and cerebral sinuses, as well as the inferior vena cava. Superficial vein thrombosis can also occur [33].

Arterial thrombosis — The most common site of arterial thrombosis is in the cerebral vasculature, usually in the form of a stroke or transient ischemic attack [24]. Occlusions in the retinal, coronary, renal, and mesenteric arteries can also occur. Stroke in patients with APS is discussed in further detail below. (See 'Neurologic involvement' below.)

Recurrent thrombotic events — The recurrence rate of thrombotic events among patients with APS is highly variable among studies, with an annual recurrent thrombosis risk ranging from 5 to 12 percent [11,31,33-36]. In patients after a first unprovoked venous thromboembolism (VTE) for which the anticoagulation was stopped, the annual risk of recurrent VTE can be much higher, ranging from 10 to 20 percent [37]. The presence of LA or triple aPL positivity is the main risk factors for recurrence [31,36,38,39].

Most, but not all, studies have indicated that an initial arterial thrombosis tends to be followed by an arterial event and that an initial venous thrombosis is usually followed by a venous event [40-42]. In a report in which 186 recurrences occurred in 101 patients, the site of recurrence was arterial in 93 percent of those with an initial arterial thrombosis, and the site of recurrence was venous in 76 percent of those with an initial venous thrombosis [42]. The factors that determine the predilection for the venous or arterial circulation are not known.

Neurologic involvement — Central nervous system abnormalities are a common feature of APS that have been attributed to both vascular thrombosis as well as direct injury to neuronal tissue by aPL [43]. Stroke and transient ischemic attack are the most common neurologic manifestations of APS. A thrombotic stroke occurring in a young patient with no overt risk factors for cerebrovascular disease is a classic setting in which to suspect APS [2].

Ischemic stroke may be a manifestation in situ thrombosis or due to embolism arising from valvular heart disease. If routine transthoracic echocardiography is normal, transesophageal echocardiography may be indicated to assess for vegetations due to nonbacterial endocarditis. (See 'Cardiac involvement' below.)

Sneddon syndrome, which is characterized by widespread livedo reticularis in association with a stroke, has also been described among patients with aPL [44,45]. In almost half of all cases, Sneddon syndrome is associated with detectable aPL [44].

Cognitive deficits independent of stroke and/or white matter lesions have been associated with APS [46,47]. The degree of reported cognitive deficits ranges from subtle findings to transient global amnesia to permanent and profound cognitive functioning. The cognitive deficits reported in APS are sometimes but not always associated with white matter lesions. As an example, cognitive deficits were evaluated in a study of 60 patients with primary or secondary APS who underwent comprehensive neuropsychological testing [26]. The APS patients were compared with 60 healthy controls, matched for age, sex, and education, and 25 disease controls (systemic lupus erythematosus [SLE] and rheumatoid arthritis patients who did not have APS). The following observations were made:

●Cognitive deficits were significantly more frequent in the patients with APS (42 versus 18 and 16 percent of the healthy and disease controls, respectively).

●Cognitive dysfunction in the APS patients was associated with livedo reticularis on physical examination and with the finding of white matter lesions on brain magnetic resonance imaging (MRI).

●No relationship was detected between cognitive dysfunction and previous central nervous system disease (eg, stroke).

Multifocal white matter lesions on MRI that are suggestive of a vasculopathy are a common finding on MRI in APS patients [26]. These lesions may be difficult to distinguish from those in multiple sclerosis [48,49].

Other less common neurologic disorders that have been reported in aPL-positive patients include epilepsy, psychosis, chorea, and hemiballismus, transverse myelopathy, sensorineural hearing loss, and migraine [24,26,50-60]. However, no strong association has been established between these manifestations and aPL.

Hematologic abnormalities — Thrombocytopenia can be observed in APS patients and is discussed further below (see 'Thrombocytopenia' below). Other hematologic abnormalities reported in patients with APS include autoimmune hemolytic anemia, especially if there is widespread thrombosis; and various thrombotic microangiopathic syndromes including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) [61]. (See 'Other' below and "Evaluation of bone marrow aspirate smears", section on 'Bone marrow necrosis'.)

Pulmonary involvement — Patients with APS may develop various lung manifestations including pulmonary thromboembolic disease, thromboembolic and non-thromboembolic pulmonary hypertension (pulmonary arterial hypertension [62,63]), pulmonary arterial thrombosis, pulmonary microthrombosis, acute respiratory distress syndrome, and diffuse alveolar hemorrhage [24,64-69]. (See "The diffuse alveolar hemorrhage syndromes" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)

Cardiac involvement — Cardiac manifestations of APS most commonly involve the valves, including valvular thickening and valve nodules (also referred to as nonbacterial vegetations or Libman-Sacks endocarditis) (picture 1) [24,70-75]. The mitral valve is most frequently involved, followed by the aortic valve [76]. Involvement of the mitral and aortic valves can lead to valvular regurgitation and, rarely, to stenosis [73-75]. Valve lesions, especially aortic nodules, are highly associated with the risk of stroke [77,78]. The risk of heart valve disease is higher in patients with LA or immunoglobulin G (IgG) aCL (OR 6) than those with IgM aCL (OR 3) [79].

Patients with APS also have an increased risk for developing coronary artery disease. Myocardial infarction may be due to coronary thromboembolism, accelerated atherosclerosis leading to a plaque rupture, or microvascular thrombosis (detected by MRI) with a normal coronary vascular bed [70]. One study found that aPL (including lupus anticoagulant and anticardiolipin anti-beta 2 glycoprotein (GP) 1 antibodies) was associated with a twofold increased risk of myocardial infarction [80].

Cutaneous manifestations — APS has been associated with many cutaneous abnormalities including splinter hemorrhages, livedo reticularis and racemosa (picture 2), cutaneous necrosis and infarction, digital gangrene, skin ulcerations, lesions resembling vasculitis ("pseudovasculitic" nodules, macules), and livedoid vasculopathy (with/without atrophie blanche) [1,24,81-84]. (See "Livedoid vasculopathy".)

Livedo is the most common cutaneous manifestation of APS. Although livedo reticularis is nonspecific, livedo racemosa can be associated with arterial lesions and multiple thromboses in APS [85]. Livedo is present in more than 20 percent of SLE patients with aPL compared with 10 percent in SLE patients without aPL. In the general population, prevalence of livedo is lower than in patients with SLE [86]. In a series of 200 patients with APS, livedo reticularis was associated with cerebral or ocular ischemic events (OR 10.8) [82]. By contrast, livedo reticularis was observed with decreased frequency in patients who experienced only venous thromboses (OR 0.2).

There is considerable ambiguity in the literature with regard to the terms "livedo reticularis" and "livedo racemosa" [87]. Livedo racemosa is characterized by a violaceous net-like pattern on the skin with irregular and/or broken circles; livedo reticularis is characterized by unbroken circles [88]. Livedo racemosa, named by Ehrmann in 1907 [89], is a more striking cutaneous finding than livedo reticularis [87]. In addition, livedo reticularis often occurs in physiologic settings rather than in disease states [90]. The clinical significance of differentiating between livedo racemosa and livedo reticularis was illustrated in a study of 111 patients with livedo racemosa and 32 patients with livedo reticularis [88]. The former were more likely to have biopsy-proven cutaneous vasculitis; to be younger and male; and to have arthralgia, higher levels of C-reactive protein (CRP), and antibodies to phosphatidylserine prothrombin complexes. (See "Overview of cutaneous lupus erythematosus", section on 'Vascular abnormalities' and "Clinical manifestations and diagnosis of Raynaud phenomenon", section on 'Signs and symptoms of Raynaud phenomenon'.)

As mentioned above, livedo reticularis in association with stroke is known as Sneddon syndrome, and half of the time occurs in the presence of aPL. (See 'Neurologic involvement' above.)

Kidney disease — Kidney disease occurs in a minority of patients with primary APS. Glomerular capillaries and other renal vessels, both arteries and veins of all sizes, can be affected. The disease may be silent or may produce acute or chronic kidney failure with proteinuria and hypertension. A detailed discussion of kidney involvement in patients with APS, including those with underlying SLE, is presented separately. (See "Antiphospholipid syndrome and the kidney".)

Gastrointestinal involvement — Patients with APS may have ischemia involving the esophagus, stomach, duodenum, jejunum, ileum, or colon resulting in gastrointestinal bleeding, abdominal pain, an acute abdomen, esophageal necrosis with perforation, or giant gastric or atypical duodenal ulceration [91]. Splenic or pancreatic infarction may also occur [24]. In addition, the liver may be involved; hepatic or portal venous thrombosis may result in the Budd-Chiari syndrome, hepatic-veno-occlusive disease, hepatic infarction, portal hypertension, and cirrhosis [91,92].

Ocular involvement — Amaurosis fugax, retinal venous [93] and arterial occlusion, and anterior ischemic optic neuropathy have occurred in patients with aPL [24,94,95].

Adrenal disease — Loss of adrenal function due to bilateral adrenal vein thrombosis, resulting in hemorrhagic infarction, may occur in association with APS, especially catastrophic APS [96,97]. An enlarged adrenal or an adjacent mass may be apparent on a computed tomography (CT) scan, but MRI is more effective in determining the age of adrenal hemorrhage and in differentiating bleeding from other causes of adrenal gland enlargement. Adrenal hemorrhagic infarction may present as abdominal, lumbar, pelvic, or thoracic pain. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Hemorrhagic infarction'.)

Adrenal involvement can also be seen in CAPS. (See "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Thrombosis and organ involvement'.)

Osteonecrosis — Asymptomatic changes in the appearance of the femoral heads of patients with primary APS have been noted on MRI. These findings have been interpreted to indicate osteonecrosis. However, of the 30 patients who were the subject of one report, none had changes on plain radiographs, and none had progressive changes on subsequent MRIs [98]. Thus, the true nature of the association between osteonecrosis and the presence of APS is not clear.

PREGNANCY COMPLICATIONS — In addition to thrombotic events, pregnancy complications are the other hallmark of antiphospholipid syndrome (APS). These complications include fetal death after 10 weeks gestation, premature birth due to severe preeclampsia or placental insufficiency, or embryonic losses (<10 weeks gestation). Fetal loss in patients with aPL and the approach to women with recurrent fetal loss are discussed in detail separately. (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy" and "Recurrent pregnancy loss: Evaluation".)

In aPL-positive patients with preeclampsia or the HELLP Syndrome (hemolysis, elevated liver enzymes, and low platelet count in association with pregnancy), the possibility of the evolving catastrophic APS (CAPS) must be considered, particularly in patients with histories of thrombosis or spontaneous abortions [99,100]. (See "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)" and "Catastrophic antiphospholipid syndrome (CAPS)", section on 'When to suspect'.)

LABORATORY FINDINGS — In addition to the presence of antiphospholipid antibodies (aPL), some of the other potential laboratory findings include thrombocytopenia, hemolytic anemia, prolonged activated partial thromboplastin time (aPTT), a history of a false-positive serologic test for syphilis, and low complement levels.

Antiphospholipid antibodies — The three major aPL tests that are recognized by international classification criteria for antiphospholipid syndrome (APS) (table 2) are as follows:

●Anticardiolipin antibodies (aCL) immunoglobulin G (IgG) and/or IgM enzyme-linked immunosorbent assay (ELISA)

●Anti-beta2 glycoprotein (GP) I antibodies IgG and/or IgM ELISA

●Lupus anticoagulant (LA) test

Generally, the diagnosis of APS is made in the presence of one or more of the above aPL in the setting of a vascular thrombosis or a specific type of pregnancy morbidity. Individuals with one or more aPL, but without a history of thrombosis, pregnancy complications, or the other clinical manifestations (see 'Clinical manifestations' above), may be at risk of developing APS. A detailed discussion on diagnosis of APS is presented elsewhere. (See "Diagnosis of antiphospholipid syndrome".)

An aPL may be present in some people who do not have APS and are otherwise healthy, who have another autoimmune or rheumatic disease, or who have been exposed to certain drugs or infectious agents. These and other associations are discussed in more detail elsewhere. (See "Diagnosis of antiphospholipid syndrome", section on 'Other conditions associated with antiphospholipid antibodies'.)

The development of newer tests (antibodies directed against domain I of B2-glycoprotein I or antiphosphatidylserine-prothrombin antibodies) will be useful to identify high-risk APS patients for tailored management [101,102].

Thrombocytopenia — Thrombocytopenia can be observed in APS patients, with an incidence ranging from 22 to 42 percent [61]. The frequency of thrombocytopenia is higher in SLE-associated APS than in primary APS. The degree of thrombocytopenia is usually moderate, with a platelet count usually in the range of 100,000 to 140,000/microL, and is rarely associated with hemorrhagic events. Thrombocytopenia is a predictive factor of APS-related manifestations (thrombosis, pregnancy morbidity, hemolytic anemia, or death) [103,104], and a decrease in platelet count frequently preceded an episode of catastrophic APS [105].

Hypocomplementemia — Hypocomplementemia can be observed in primary APS, similar to what is observed in patients with SLE [106,107]. As an example, in an observational cohort that included 70 patients with primary APS, nearly half presented with low complement levels [106]. However, complement levels such as C3 and C4 are generally not used to trend disease activity as they are sometimes used in SLE. (See "Acquired disorders of the complement system", section on 'Increased consumption by immune complexes'.)

Other — Other laboratory abnormalities include the prolongation of a blood coagulation test (eg, aPTT), a hemolytic anemia [86], or a history of a false-positive serologic test for syphilis. (See "Diagnosis of antiphospholipid syndrome", section on 'When to suspect the diagnosis'.)

MORTALITY — Antiphospholipid syndrome (APS) is associated with increased morbidity and mortality. A large, multicenter, prospective study of 1,000 APS patients found a decreased survival rate of 90.7 percent at 10 years [11]. The main causes of death during the 10-year follow-up included thrombosis (31 percent), sepsis (27 percent), malignancy (14 percent), hemorrhage (11 percent), systemic lupus erythematosus (SLE) involvement (8 percent), and catastrophic APS (5 percent). The mean age at death was 59, with a standard deviation of 14 years. There were no differences in the mortality rates in the presence of underlying disease: 6.8 percent of patients with SLE-associated APS compared with 7.1 percent of patients with primary APS died. Note, however, that during the study period over 40 percent of patients were lost to follow-up.

The presence of antiphospholipid antibodies (aPL) in the serum of patients with SLE has been identified as an independent risk factor for premature death. This was illustrated in an observational study of 667 patients with SLE, 49 of whom died [108]. There was an increased risk of premature death in patients with aPL, thrombocytopenia, and arterial occlusion. Other factors associated with premature death were the intensity of anticoagulation treatment, renal involvement, pleuritis, and disease activity.

Although some of the risk of early death is due to the increased propensity to thromboembolic disease, in some settings, aPL may be a marker for a higher mortality rate that is not due to thrombophilia per se. As an example, in a study of 300 consecutive patients with a first ischemic stroke, stroke victims with elevated levels of aPL (immunoglobulin G [IgG] anticardiolipin antibodies [aCL] >20 units) had a higher mortality rate during approximately two years of follow-up than those with lower or absent aCL levels (33 versus 18 percent mortality, relative risk [RR] 1.94, 95% CI 1.05-3.67) [109]. However, the increased mortality was not due to recurrent stroke but was associated with other characteristics of those with aPL, including a higher rate of malignancy and more prevalent risk factors for coronary heart disease.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Antiphospholipid syndrome".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Antiphospholipid syndrome (Beyond the Basics)").

SUMMARY AND RECOMMENDATIONS

●Definition – Antiphospholipid syndrome (APS) is an autoimmune multisystem disorder characterized by arterial, venous, or small vessel thromboembolic events and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL). APS occurs as a primary condition or in the setting of an underlying systemic autoimmune disease, particularly systemic lupus erythematosus (SLE). (See 'Introduction' above.)

●Antiphospholipid antibodies – The three major aPL tests that are recognized by international classification criteria for APS (table 2) are anticardiolipin antibodies (aCL) immunoglobulin G (IgG) and/or IgM enzyme-linked immunosorbent assay (ELISA), anti-beta2 glycoprotein (GP) I antibodies IgG and/or IgM ELISA, and the lupus anticoagulant (LA) test. (See 'Antiphospholipid antibodies' above.)

●Clinical manifestations

•Thrombotic events – Thromboses are the hallmark of APS. The deep veins of the lower extremities are the most common sites of venous thrombosis, and the cerebral vasculature (stroke and transient ischemic attack) is the most common site for arterial thrombosis. Superficial vein thrombosis can also occur. (See 'Thrombotic events' above and 'Neurologic involvement' above.)

•Neurologic involvement – Stroke and transient ischemic attack are the most common neurologic manifestations of APS. Cognitive deficits independent of stroke and/or white matter lesions have also been associated with APS. (See 'Neurologic involvement' above.)

•Hematologic abnormalities – Thrombocytopenia can be observed in APS, but the degree is usually moderate and is rarely associated with hemorrhagic events. Other hematologic abnormalities reported with APS include various thrombotic microangiopathy (TMA) syndromes and autoimmune hemolytic anemia. (See 'Hematologic abnormalities' above.)

•Pulmonary involvement – Patients with APS may develop various lung manifestations including pulmonary thromboembolic disease, thromboembolic and non-thromboembolic pulmonary hypertension (pulmonary arterial hypertension), pulmonary arterial thrombosis, pulmonary microthrombosis, acute respiratory distress syndrome, and diffuse alveolar hemorrhage. (See 'Pulmonary involvement' above.)

•Cardiac involvement – Cardiac manifestations of APS most commonly involve the valves, including valvular thickening, and valve nodules (also referred to as nonbacterial vegetations or Libman-Sacks endocarditis), which can lead to valvular dysfunction. (See 'Cardiac involvement' above.)

•Cutaneous manifestations – Livedo (picture 2) is the most common cutaneous manifestation of APS; while livedo reticularis is also relatively common in the general population, livedo racemosa is more specific for APS. Other cutaneous abnormalities that can occur in APS patients include splinter hemorrhages, cutaneous necrosis and infarction, digital gangrene, skin ulcerations, lesions resembling vasculitis ("pseudovasculitic" nodules, macules), and livedoid vasculopathy. (See 'Cutaneous manifestations' above.)

•Other manifestations – Other less common manifestations of APS include ocular involvement, renal disease, adrenal insufficiency, and gastrointestinal involvement. (See 'Ocular involvement' above and 'Kidney disease' above and 'Adrenal disease' above and 'Gastrointestinal involvement' above.)

●Pregnancy complications – Pregnancy complications are another hallmark of APS. These complications include fetal death after 10 weeks gestation, premature birth due to severe preeclampsia or placental insufficiency, and/or multiple embryonic losses (<10 weeks gestation). (See 'Pregnancy complications' above and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

●Catastrophic APS – Rarely, patients with APS can develop catastrophic APS (CAPS), with widespread thrombotic disease and multiorgan failure (table 1). CAPS can also rarely be the initial presentation of APS. (See "Catastrophic antiphospholipid syndrome (CAPS)".)

●Prognosis – APS is associated with increased morbidity and mortality. Major causes of death include thrombosis, sepsis, malignancy, hemorrhage, SLE involvement, and catastrophic APS. (See 'Mortality' above.)