Clinical manifestations of antiphospholipid síndrome

Uptodate

Authors:
Doruk Erkan, MD, MPH
Stéphane Zuily, MD, MPH, PhD
Section Editor:
David S Pisetsky, MD, PhD
Deputy Editors:
Monica Ramirez Curtis, MD, MPH
Jennifer S Tirnauer, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jun 2017. | This topic last updated: Jun 03, 2016.

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. The pathogenesis, diagnosis, and
treatment of this disorder are presented separately. (See "Pathogenesis of antiphospholipid
syndrome" and "Diagnosis of antiphospholipid syndrome" and "Treatment of
antiphospholipid syndrome".)

BACKGROUND

The three major antiphospholipid antibody (aPL) tests that are recognized by international
classification criteria for antiphospholipid syndrome (APS) (table 1) are as follows:

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

immunosorbent assay (ELISA)
●Anti-beta2-glycoprotein-I (anti-beta2GPI) 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 described below (see 'Clinical manifestations' below), may be
at risk of developing APS. A detailed discussion on the diagnosis of APS is presented
elsewhere. (See "Diagnosis of antiphospholipid syndrome".)

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].

PRIMARY APS VERSUS APS WITH SLE — Although many of the clinical manifestations
of primary antiphospholipid syndrome (APS) and APS associated with systemic lupus
erythematosus (SLE) are similar [9], patients with SLE-associated APS are more likely to
have arthritis, livedo reticularis, heart valve disease, thrombocytopenia, and leukopenia than
patients with primary APS [10,11]. 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 [12]. However, traditional cardiovascular risk factors and
markers of early atherosclerosis are similar between patients with primary and SLE-
associated APS [13,14].

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 [15]

●4 percent at 6.5 years [16]
●13 to 23 percent at 9 years [17,18]

CLINICAL MANIFESTATIONS — In addition to venous, arterial, and/or small vessel

thrombosis as well as specific pregnancy complications, other more common clinical
features of antiphospholipid syndrome (APS) include livedo reticularis, thrombocytopenia,
or transient ischemic attack [19]. In rare cases, APS results in multiorgan failure due to small-
vessel thromboses, a condition referred to as "catastrophic antiphospholipid syndrome."
(See 'Catastrophic APS' below.)
In a series of 1000 patients with either primary or autoimmune disease-associated APS, the
various disease features were [20]:

●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

In addition to those manifestations mentioned above, other possible antiphospholipid

antibody (aPL)-related clinical manifestations include cardiac valve disease, pulmonary
hypertension, avascular necrosis, cutaneous ulcers that resemble pyoderma gangrenosum,
adrenal insufficiency due to hemorrhagic infarction, and cognitive deficits [19-24].

Thrombotic events — Thromboses are the hallmark of APS, and venous thromboses are
more common than arterial thromboses [20]. 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) [25]. The risk of recurrent thrombosis or
thromboembolism may be further enhanced in those with positivity to three aPL activities
(LA, aCL, and anti-beta-2-glycoprotein-I [anti-beta2GPI] antibodies) upon repeated testing
[26].

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 [20,27]. 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.

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 [20]. Occlusions in
the retinal, coronary, renal, and mesenteric arteries can also occur. Stroke in patients with
APS is discussed in further detail below. (See 'Neurological 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 [26,28-32]. The presence of LA or triple aPL positivity is the main risk
factors for recurrence [26,31,33,34].

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 [35-37]. 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 [37]. The
factors that determine the predilection for the venous or arterial circulation are not known.

Pregnancy complications — Pregnancy complications are the other hallmark of 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 "Pregnancy in women with antiphospholipid syndrome"
and "Evaluation of couples with recurrent pregnancy loss".)

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 must be considered, particularly in patients with histories of
thrombosis or spontaneous abortions [38,39]. (See 'Catastrophic APS' below and "HELLP
syndrome".)

Neurological 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 [40]. 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 APS [41,42]. In almost half of
all cases, Sneddon syndrome is associated with detectable aPL [41].

Cognitive deficits and/or white matter lesions have been associated with APS [43,44]. 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 [21]. 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 the presence of
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 [21]. These lesions may be difficult to distinguish from those
in multiple sclerosis [45,46].

Other less common neurologic disorders which have been associated with the presence of
aPL include epilepsy, psychosis, chorea and hemiballismus, transverse myelopathy,
sensorineural hearing loss, orthostatic hypotension, and migraine [20,21,47-57].

Hematologic abnormalities — Thrombocytopenia is frequently observed in APS patients,

with an incidence ranging from 22 to 42 percent [58]. 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 does not preclude the
occurrence of thrombotic complications of APS.

Other hematologic abnormalities reported in patients with APS include autoimmune

hemolytic anemia; bone marrow necrosis, especially if there is widespread thrombosis; and
various thrombotic microangiopathic syndromes including thrombotic thrombocytopenic
purpura (TTP) and hemolytic uremic syndrome (HUS) [58]. (See "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), pulmonary arterial thrombosis,
pulmonary microthrombosis, acute respiratory distress syndrome, and diffuse alveolar
hemorrhage [20,59-64]. (See "The diffuse alveolar hemorrhage syndromes" and "Clinical
features and diagnosis of pulmonary hypertension in adults" and "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) [20,65-70]. The mitral valve is most frequently
involved, followed by the aortic valve [71]. Involvement of the mitral and aortic valves can
lead to valvular regurgitation and, rarely, to stenosis [68-70]. Valve lesions, especially aortic
nodules, are highly associated with the risk of stroke [72,73]. 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) [74].

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 [65].

Cutaneous manifestations — APS has been associated with many cutaneous

abnormalities including splinter hemorrhages, livedo reticularis (picture 2), cutaneous
necrosis and infarction, superficial vein thrombosis [29], digital gangrene, skin ulcerations,
lesions resembling vasculitis (“pseudovasculitic” nodules, macules), and livedoid
vasculopathy (atrophie blanche) [1,20,75-77] (see "Livedoid vasculopathy"). A loss of
normal elastic tissue known as anetoderma (picture 3), which presents as localized areas
of wrinkled or flaccid skin, has also been noted in patients with SLE and APS [1,78].

Livedo reticularis is the most common cutaneous manifestation of APS, and can be
associated with arterial lesions and multiple thromboses in APS [79]. In a series of 200
patients with APS, livedo reticularis was associated with cerebral or ocular ischemic events
(OR 10.8) [76]. In 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" [80]. 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 [81]. Livedo racemosa, named by Ehrmann in 1907 [82], is a more striking
cutaneous finding than livedo reticularis [80]. In addition, livedo reticularis often occurs in
physiologic settings rather than in disease states [83]. 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 [81]. 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 "Clinical manifestations and diagnosis of
the Raynaud phenomenon", section on 'Livedo reticularis' and "Overview of cutaneous lupus
erythematosus", section on 'Vascular abnormalities'.)

As mentioned above, livedo reticularis in association with stroke is known as Sneddon

syndrome, and typically occurs in the presence of aPL. (See 'Neurological involvement'
above.)

Renal disease — Renal 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 renal failure with
proteinuria. 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 [84]. Splenic or pancreatic infarction may also occur
[20]. 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 [84,85].
Ocular involvement — Amaurosis fugax, retinal venous [86] and arterial occlusion, and
anterior ischemic optic neuropathy have occurred in patients with aPL [20,87,88]. The
presence of such antibodies may be a risk factor for occlusive vascular disorders of the eye.

Adrenal disease — Loss of adrenal function due to bilateral adrenal vein thrombosis,
resulting in hemorrhagic infarction, may occur in association with APS [89,90]. 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. Adrenal involvement has been
reported in 13 percent of cases of catastrophic APS [91]. (See "Causes of primary adrenal
insufficiency (Addison's disease)", section on 'Hemorrhagic infarction' and 'Catastrophic
APS' below.)

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 [92]. Thus, the true nature of the association between osteonecrosis and the presence
of APS is not clear. (See "Osteonecrosis (avascular necrosis of bone)", section on 'Systemic
lupus erythematosus'.)

OTHER ASSOCIATIONS — Various antiphospholipid antibodies (aPL) may be present in

some people who are otherwise healthy, who have 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 aPL'.)

CATASTROPHIC APS — A small subset of patients with antiphospholipid syndrome (APS)

has widespread thrombotic disease with multiorgan failure, which is called "catastrophic
APS." Thromboses in this setting typically involve multiple small blood vessels in various
organs rather than a large vessel deep vein thrombosis or stroke, although the latter can
occur. Preliminary criteria proposed for classification purposes have been published and
validated (table 2). Additional diagnostic algorithms have been proposed to facilitate early
recognition of catastrophic APS [93]. The important steps in the proposed algorithms
include:

●History of APS and/or antiphospholipid antibodies (aPL)

 ●Three or more new organ thromboses within a week
●Biopsy confirmation of a microthrombus
●Exclusion of other causes of multiple organ thromboses or microthromboses

Among 1000 patients with the APS followed for a mean of seven years, only eight (0.8
percent) developed catastrophic APS [20]. In the majority of these patients, multiorgan
involvement was present at the time of diagnosis of APS.

It is often difficult to distinguish CAPS from other conditions which can lead to multiple organ
thrombosis due to overlapping features. While a comprehensive differential diagnosis for
CAPS is beyond the scope of this topic, a few major causes of multiple organ thromboses
to consider include the following:

●DIC – Disseminated intravascular coagulation (DIC) is a systemic condition

involving widespread activation of coagulation and fibrinolysis that may occur in the
setting of sepsis or malignancy. Like catastrophic APS, DIC may be associated with
laboratory features such as elevated fibrin degradation products, depressed
fibrinogen levels, or elevated D-dimer concentrations. Unlike catastrophic APS, DIC
is always associated with an underlying systemic disorder, DIC is more likely to be
associated with bleeding, and in acute DIC the prothrombin time (PT) and activated
partial thromboplastin time (aPTT) are prolonged. (See "Clinical features, diagnosis,
and treatment of disseminated intravascular coagulation in adults".)
●HIT – Heparin-induced thrombocytopenia (HIT) is an immune-mediated
thrombocytopenia that occurs in the setting of heparin exposure. In HIT, heparin-
induced antibodies can cause platelet activation leading to potentially fatal arterial
and venous thromboses. Like catastrophic APS, HIT can cause moderate
thrombocytopenia and thromboses in various organs. Unlike catastrophic APS, HIT
almost always occurs in the setting of heparin exposure with a clear temporal
relationship, and HIT is not associated with aPL. (See "Clinical presentation and
diagnosis of heparin-induced thrombocytopenia".)
●TMA – Thrombotic microangiopathies (TMA) are systemic syndromes (acquired or
inherited) in which small vessel platelet microthrombi form in various vascular beds,
leading to thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and
organ injury that may be life-threatening. Like catastrophic APS, TMAs may present
with unexplained severe thrombocytopenia and organ involvement. Unlike
catastrophic APS, TMAs typically do not cause large vessel thromboses, and many
of the TMAs are associated with specific laboratory abnormalities related to their
 underlying pathophysiology. (See "Approach to the patient with suspected TTP,
HUS, or other thrombotic microangiopathy (TMA)".)

Catastrophic APS is frequently fatal, with a reported mortality rate approaching 50 percent
despite anticoagulant and immunosuppressive treatment [89]. The treatment of the
catastrophic APS is presented elsewhere. (See "Treatment of antiphospholipid syndrome",
section on 'Catastrophic antiphospholipid syndrome'.)

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 [32]. 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.

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 [94]. 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, the presence of 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) [95].
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
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●Beyond the Basics topic (see "Patient education: The antiphospholipid syndrome
(Beyond the Basics)").

SUMMARY AND RECOMMENDATIONS

●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.)
●The three major aPL tests that are recognized by international classification criteria
for APS (table 1) are anticardiolipin antibodies (aCL) immunoglobulin G (IgG) and/or
IgM enzyme-linked immunosorbent assay (ELISA), anti-beta2-glycoprotein-I (anti-
beta2GPI) antibodies IgG and/or IgM ELISA, and the lupus anticoagulant (LA) test.
(See 'Background' above.)
●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
'Neurological involvement' above.)
●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 "Pregnancy in women
with antiphospholipid syndrome".)
●Thrombocytopenia is frequently observed in APS patients. 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. Other
hematologic abnormalities reported with APS include bone marrow necrosis, various
thrombotic microangiopathy (TMA) syndromes, and autoimmune hemolytic anemia.
(See 'Hematologic abnormalities' above.)
●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 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.)
●Livedo reticularis (picture 2) is the most common cutaneous manifestation of APS.
Other cutaneous abnormalities include splinter hemorrhages, cutaneous necrosis
and infarction, superficial vein thrombosis, digital gangrene, skin ulcerations, lesions
resembling vasculitis (“pseudovasculitic” nodules, macules), and livedoid
vasculopathy (atrophie blanche). (See 'Cutaneous manifestations' above.)
●Other less common manifestations of APS include renal disease, adrenal
insufficiency, and gastrointestinal involvement. (See 'Renal disease' above and
'Adrenal disease' above and 'Gastrointestinal involvement' above.)
●A small subset of patients with APS has widespread thrombotic disease with
multiorgan failure, which is called catastrophic APS (table 2). The key features for
identifying patients with catastrophic APS include (see 'Catastrophic APS' above):
•History of APS and/or aPL
•Three or more new organ thromboses within a week
•Biopsy confirmation of a microthrombus
 •Exclusion of other causes of multiple organ thromboses or microthromboses
such as disseminated intravascular coagulation (DIC), heparin-induced
thrombocytopenia (HIT), or a thrombotic microangiopathy (TMA).
●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.)
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