Clinical Manifestations of Antiphospholipid Syndrome

12/3/2020 Clinical manifestations of antiphospholipid syndrome - UpToDate
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Clinical manifestations of antiphospholipid syndrome

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
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2020. | This topic last updated: Jan 21, 2019.
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 diagnosis and treatment of this
disorder are presented separately. (See "Diagnosis of antiphospholipid syndrome" and
"Treatment 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
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Approximately half of patients with APS have primary disease, while the other half have a
concomitant systemic autoimmune disease. SLE is the disease most commonly associated
with APS, which is present in approximately 35 percent of cases [9].
Although many of the clinical manifestations of primary antiphospholipid syndrome (APS)

and APS associated with systemic lupus erythematosus (SLE) are similar [10], patients with
SLE-associated APS are more likely to have arthritis, livedo reticularis, heart valve disease,
thrombocytopenia, and leukopenia than patients with primary APS [11-13]. 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 [14]. However,
traditional cardiovascular risk factors and markers of early atherosclerosis are similar
between patients with primary and SLE-associated APS [15,16].
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 [17]

● 4 percent at 6.5 years [18]
● 13 to 23 percent at 9 years [19,20]
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 [21]. 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 [22]:
● 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, 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 [21-26].
Thrombotic events — Thromboses are the hallmark of APS, and venous thromboses are
more common than arterial thromboses [22]. 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) [27]. The risk of recurrent thrombosis or
thromboembolism may be further enhanced in those with positivity to three aPL activities,
also known as "triple positivity," (LA, aCL, and anti-beta-2-glycoprotein-I [aB2GPI] antibodies)
upon repeated testing [28].
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 [22,29]. 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 [30].
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 [22]. 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 [9,28,30-33]. 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 [34]. The presence of LA or
triple aPL positivity is the main risk factors for recurrence [28,33,35,36].
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 [37-39]. 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 [39].
The factors that determine the predilection for the venous or arterial circulation are not
known.
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 aPL [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 [23]. 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 [23]. 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 [22,23,47-57].
Hematologic abnormalities — Thrombocytopenia is commonly observed in APS patients

and is discussed further below (see 'Thrombocytopenia' below). 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 '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 [59]), pulmonary arterial
thrombosis, pulmonary microthrombosis, acute respiratory distress syndrome, and diffuse
alveolar hemorrhage [22,60-65]. (See "The diffuse alveolar hemorrhage syndromes" and
"Clinical features and diagnosis of pulmonary hypertension of unclear etiology 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) [22,66-71]. The mitral valve is most frequently
involved, followed by the aortic valve [72]. Involvement of the mitral and aortic valves can
lead to valvular regurgitation and, rarely, to stenosis [69-71]. Valve lesions, especially aortic
nodules, are highly associated with the risk of stroke [73,74]. 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) [75].
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 [66]. One study found that the presence of aPL was
associated with a twofold increased risk of myocardial infarction [76].
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) [1,22,77-79] (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 [1,80].
Livedo reticularis is the most common cutaneous manifestation of APS, and can be
associated with arterial lesions and multiple thromboses in APS [81]. In a series of 200
patients with APS, livedo reticularis was associated with cerebral or ocular ischemic events
(OR 10.8) [78]. 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" [82]. 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 [83]. Livedo racemosa, named by Ehrmann in 1907 [84], is a more striking
cutaneous finding than livedo reticularis [82]. In addition, livedo reticularis often occurs in
physiologic settings rather than in disease states [85]. 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 [83]. 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
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 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 [86]. Splenic or pancreatic infarction may also occur
[22]. 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 [86,87].
Ocular involvement — Amaurosis fugax, retinal venous [88] and arterial occlusion, and
anterior ischemic optic neuropathy have occurred in patients with aPL [22,89,90]. 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, especially
catastrophic APS [91,92]. 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 [93]. (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 [94].
Thus, the true nature of the association between osteonecrosis and the presence of APS is
not clear. (See "Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the
femoral head) in adults".)
PREGNANCY COMPLICATIONS
In addition to thrombotic events, 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 "Antiphospholipid syndrome: Pregnancy implications and
management in pregnant women" 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 must be considered, particularly in patients with histories of
thrombosis or spontaneous abortions [95,96]. (See 'Catastrophic APS' below and "HELLP
syndrome (hemolysis, elevated liver enzymes, and low platelets)".)
LABORATORY FINDINGS
In addition to the presence of antiphospholipid antibodies (aPLs), some of the more

common 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 1) are as
follows:
● Anticardiolipin antibodies (aCL) immunoglobulin G (IgG) and/or IgM enzyme-linked

immunosorbent assay (ELISA)
● Anti-beta2-glycoprotein-I antibodies (anti-B2GPI) 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".)
Antiphospholipid antibodies (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 aPL'.)
Thrombocytopenia — 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; however, a decrease in platelet count
frequently preceded an episode of catastrophic APS [97].
Hypocomplementemia — Hypocomplementemia can be observed in primary APS, similar

to what is observed in patients with SLE [98,99]. As an example, in an observational cohort
that included 70 patients with primary APS, nearly half presented with low complement
levels [98]. 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 [100], or a history of a false-positive serologic test for
syphilis. (See "Diagnosis of antiphospholipid syndrome", section on 'When to suspect the
diagnosis'.)
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 [101]. 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 [22]. In the majority of these patients, multiorgan
involvement was present at the time of diagnosis of APS.
It is often difficult to distinguish catastrophic APS from other conditions which can lead to
multiple organ thrombosis due to overlapping features [102]. While a comprehensive
differential diagnosis for catastrophic APS 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 "Disseminated intravascular coagulation (DIC) in adults: Evaluation
and management".)
● 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 [91]. The treatment of the
catastrophic APS is presented elsewhere. (See "Treatment of antiphospholipid syndrome",
section on 'Treatment of 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 [9]. 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 [103]. 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) [104].
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.
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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".)
INFORMATION FOR PATIENTS
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Basics." The Basics patient education pieces are written in plain language at the 5th to 6th
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and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
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
● 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 antibodies
(aB2GPI) IgG and/or IgM ELISA, and the lupus anticoagulant (LA) test. (See
'Antiphospholipid antibodies' 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 "Antiphospholipid syndrome: Pregnancy implications and
management in pregnant women".)
● 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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REFERENCES
1. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an
update of the classification criteria for definite antiphospholipid syndrome (APS). J
Thromb Haemost 2006; 4:295.
2. Andreoli L, Chighizola CB, Banzato A, et al. Estimated frequency of antiphospholipid

antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and
deep vein thrombosis: a critical review of the literature. Arthritis Care Res (Hoboken)
2013; 65:1869.
3. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the 'black box'
of early pregnancy loss. Hum Reprod Update 2002; 8:333.
4. Stephenson MD. Frequency of factors associated with habitual abortion in 197 couples.
Fertil Steril 1996; 66:24.
5. Martin JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2009. Natl Vital Stat Rep
2011; 60:1.
6. Roger VL, Go AS, Lloyd-Jones DM, et al. Executive summary: heart disease and stroke
statistics--2012 update: a report from the American Heart Association. Circulation 2012;
125:188.
7. White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107:I4.
8. www.census.gov/population/www/cen2010/glance/index.html (Accessed on October 1

9, 2015).

9. Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the

antiphospholipid syndrome during a 10-year period: a multicentre prospective study of
1000 patients. Ann Rheum Dis 2015; 74:1011.
10. Vianna JL, Khamashta MA, Ordi-Ros J, et al. Comparison of the primary and secondary
antiphospholipid syndrome: a European Multicenter Study of 114 patients. Am J Med
1994; 96:3.
11. Djokovic A, Stojanovich L, Kontic M, et al. Association between cardiac manifestations

and antiphospholipid antibody type and level in a cohort of Serbian patients with
primary and secondary antiphospholipid syndrome. Isr Med Assoc J 2014; 16:162.
12. Cervera R, Boffa MC, Khamashta MA, Hughes GR. The Euro-Phospholipid project:
epidemiology of the antiphospholipid syndrome in Europe. Lupus 2009; 18:889.
13. Unlu O, Erkan D, Barbhaiya M, et al. The Impact of Systemic Lupus Erythematosus on
the Clinical Phenotype of Antiphospholipid Antibody-Positive Patients: Results From the
AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Clinical
Database and Repository. Arthritis Care Res (Hoboken) 2019; 71:134.
14. Danowski A, de Azevedo MN, de Souza Papi JA, Petri M. Determinants of risk for venous
and arterial thrombosis in primary antiphospholipid syndrome and in antiphospholipid
syndrome with systemic lupus erythematosus. J Rheumatol 2009; 36:1195.
15. Ribeiro AR, Carvalho JF. [Traditional risk factors for cardiovascular disease in primary
antiphospholipid syndrome (APS) when compared with secondary APS: a study with 96
patients]. Acta Reumatol Port 2010; 35:36.
16. Belizna CC, Richard V, Primard E, et al. Early atheroma in primary and secondary
antiphospholipid syndrome: an intrinsic finding. Semin Arthritis Rheum 2008; 37:373.
17. Roubey RA. Autoantibodies to phospholipid-binding plasma proteins: a new view of

lupus anticoagulants and other "antiphospholipid" autoantibodies. Blood 1994;
84:2854.
18. Mujic F, Cuadrado MJ, Lloyd M, et al. Primary antiphospholipid syndrome evolving into
systemic lupus erythematosus. J Rheumatol 1995; 22:1589.
19. Gómez-Puerta JA, Martín H, Amigo MC, et al. Long-term follow-up in 128 patients with
primary antiphospholipid syndrome: do they develop lupus? Medicine (Baltimore) 2005;
84:225.
20. Veres K, Szodoray P, Szekanecz Z, et al. Clinical and immunoserological characteristics

of the transition from primary to overlap antiphospholipid syndrome. Lupus 2010;

19:1520.
21. Ruiz-Irastorza G, Crowther M, Branch W, Khamashta MA. Antiphospholipid syndrome.

Lancet 2010; 376:1498.
22. Cervera R, Piette JC, Font J, et al. Antiphospholipid syndrome: clinical and immunologic
manifestations and patterns of disease expression in a cohort of 1,000 patients.
Arthritis Rheum 2002; 46:1019.
23. Tektonidou MG, Varsou N, Kotoulas G, et al. Cognitive deficits in patients with
antiphospholipid syndrome: association with clinical, laboratory, and brain magnetic
resonance imaging findings. Arch Intern Med 2006; 166:2278.
24. Sanna G, Bertolaccini ML, Khamashta MA. Unusual clinical manifestations of the
antiphospholipid syndrome. Current Rheumatology Reviews 2006; 2:387.
25. Abreu MM, Danowski A, Wahl DG, et al. The relevance of "non-criteria" clinical
manifestations of antiphospholipid syndrome: 14th International Congress on
Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid
Syndrome Clinical Features. Autoimmun Rev 2015; 14:401.
26. Meroni PL, Chighizola CB, Rovelli F, Gerosa M. Antiphospholipid syndrome in 2014:
more clinical manifestations, novel pathogenic players and emerging biomarkers.
Arthritis Res Ther 2014; 16:209.
27. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors
for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a
systematic review of the literature. Blood 2003; 101:1827.
28. Pengo V, Ruffatti A, Legnani C, et al. Clinical course of high-risk patients diagnosed with
antiphospholipid syndrome. J Thromb Haemost 2010; 8:237.
29. Cervera R, Khamashta MA, Shoenfeld Y, et al. Morbidity and mortality in the
antiphospholipid syndrome during a 5-year period: a multicentre prospective study of
1000 patients. Ann Rheum Dis 2009; 68:1428.
30. Zuily S, Regnault V, Guillemin F, et al. Superficial vein thrombosis, thrombin generation
and activated protein C resistance as predictors of thromboembolic events in lupus and
antiphospholipid patients. A prospective cohort study. Thromb Res 2013; 132:e1.
31. Schmidt-Tanguy A, Voswinkel J, Henrion D, et al. Antithrombotic effects of

hydroxychloroquine in primary antiphospholipid syndrome patients. J Thromb Haemost
2013; 11:1927.

32. Wittkowsky AK, Downing J, Blackburn J, Nutescu E. Warfarin-related outcomes in

patients with antiphospholipid antibody syndrome managed in an anticoagulation
clinic. Thromb Haemost 2006; 96:137.
33. Forastiero R, Martinuzzo M, Pombo G, et al. A prospective study of antibodies to beta2-

glycoprotein I and prothrombin, and risk of thrombosis. J Thromb Haemost 2005;
3:1231.
34. Kearon C, Parpia S, Spencer FA, et al. Antiphospholipid antibodies and recurrent
thrombosis after a first unprovoked venous thromboembolism. Blood 2018; 131:2151.
35. Pengo V, Biasiolo A, Pegoraro C, et al. Antibody profiles for the diagnosis of
antiphospholipid syndrome. Thromb Haemost 2005; 93:1147.
36. Ruffatti A, Tonello M, Del Ross T, et al. Antibody profile and clinical course in primary
antiphospholipid syndrome with pregnancy morbidity. Thromb Haemost 2006; 96:337.
37. Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical course after the first
thrombotic event in 70 patients. Ann Intern Med 1992; 117:303.
38. Finazzi G, Brancaccio V, Moia M, et al. Natural history and risk factors for thrombosis in
360 patients with antiphospholipid antibodies: a four-year prospective study from the
Italian Registry. Am J Med 1996; 100:530.
39. Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the
antiphospholipid-antibody syndrome. N Engl J Med 1995; 332:993.
40. Arnson Y, Shoenfeld Y, Alon E, Amital H. The antiphospholipid syndrome as a

neurological disease. Semin Arthritis Rheum 2010; 40:97.
41. Francès C, Piette JC. The mystery of Sneddon syndrome: relationship with
antiphospholipid syndrome and systemic lupus erythematosus. J Autoimmun 2000;
15:139.
42. Hilton DA, Footitt D. Neuropathological findings in Sneddon's syndrome. Neurology

2003; 60:1181.
43. Muscal E, Brey RL. Neurologic manifestations of the antiphospholipid syndrome:

integrating molecular and clinical lessons. Curr Rheumatol Rep 2008; 10:67.
44. Sanna G, Bertolaccini ML, Cuadrado MJ, et al. Neuropsychiatric manifestations in

systemic lupus erythematosus: prevalence and association with antiphospholipid
antibodies. J Rheumatol 2003; 30:985.

45. Cuadrado MJ, Khamashta MA, Ballesteros A, et al. Can neurologic manifestations of
Hughes (antiphospholipid) syndrome be distinguished from multiple sclerosis? Analysis
of 27 patients and review of the literature. Medicine (Baltimore) 2000; 79:57.
46. Theodoridou A, Settas L. Demyelination in rheumatic diseases. J Neurol Neurosurg

Psychiatry 2006; 77:290.
47. Avcin T, Cimaz R, Meroni PL. Recent advances in antiphospholipid antibodies and
antiphospholipid syndromes in pediatric populations. Lupus 2002; 11:4.
48. Shoenfeld Y, Lev S, Blatt I, et al. Features associated with epilepsy in the
antiphospholipid syndrome. J Rheumatol 2004; 31:1344.
49. Sanna G, Bertolaccini ML, Cuadrado MJ, et al. Central nervous system involvement in
the antiphospholipid (Hughes) syndrome. Rheumatology (Oxford) 2003; 42:200.
50. Asherson RA, Mercey D, Phillips G, et al. Recurrent stroke and multi-infarct dementia in
systemic lupus erythematosus: association with antiphospholipid antibodies. Ann
Rheum Dis 1987; 46:605.
51. Levine SR, Salowich-Palm L, Sawaya KL, et al. IgG anticardiolipin antibody titer > 40 GPL
and the risk of subsequent thrombo-occlusive events and death. A prospective cohort
study. Stroke 1997; 28:1660.
52. Herranz MT, Rivier G, Khamashta MA, et al. Association between antiphospholipid
antibodies and epilepsy in patients with systemic lupus erythematosus. Arthritis Rheum
1994; 37:568.
53. Cervera R, Asherson RA, Font J, et al. Chorea in the antiphospholipid syndrome. Clinical,
radiologic, and immunologic characteristics of 50 patients from our clinics and the
recent literature. Medicine (Baltimore) 1997; 76:203.
54. Verrot D, San-Marco M, Dravet C, et al. Prevalence and signification of antinuclear and
anticardiolipin antibodies in patients with epilepsy. Am J Med 1997; 103:33.
55. Kandiah DA, Sali A, Sheng Y, et al. Current insights into the "antiphospholipid"
syndrome: clinical, immunological, and molecular aspects. Adv Immunol 1998; 70:507.
56. Mouadeb DA, Ruckenstein MJ. Antiphospholipid inner ear syndrome. Laryngoscope
2005; 115:879.
57. Chapman J, Rand JH, Brey RL, et al. Non-stroke neurological syndromes associated with
antiphospholipid antibodies: evaluation of clinical and experimental studies. Lupus
2003; 12:514.

58. Uthman I, Godeau B, Taher A, Khamashta M. The hematologic manifestations of the

antiphospholipid syndrome. Blood Rev 2008; 22:187.
59. Zuily S, Domingues V, Suty-Selton C, et al. Antiphospholipid antibodies can identify

lupus patients at risk of pulmonary hypertension: A systematic review and meta-
analysis. Autoimmun Rev 2017; 16:576.
60. Espinosa G, Cervera R, Font J, Asherson RA. The lung in the antiphospholipid syndrome.
Ann Rheum Dis 2002; 61:195.
61. Asherson RA, Higenbottam TW, Dinh Xuan AT, et al. Pulmonary hypertension in a lupus
clinic: experience with twenty-four patients. J Rheumatol 1990; 17:1292.
62. Deane KD, West SG. Antiphospholipid antibodies as a cause of pulmonary capillaritis
and diffuse alveolar hemorrhage: a case series and literature review. Semin Arthritis
Rheum 2005; 35:154.
63. Asherson RA, Cervera R. Review: antiphospholipid antibodies and the lung. J Rheumatol
1995; 22:62.
64. Kanakis MA, Kapsimali V, Vaiopoulos AG, et al. The lung in the spectrum of
antiphospholipid syndrome. Clin Exp Rheumatol 2013; 31:452.
65. Zuily S, Wahl D. Pulmonary hypertension in antiphospholipid syndrome. Curr

Rheumatol Rep 2015; 17:478.
66. Denas G, Jose SP, Bracco A, et al. Antiphospholipid syndrome and the heart: a case
series and literature review. Autoimmun Rev 2015; 14:214.
67. Jouhikainen T, Pohjola-Sintonen S, Stephansson E. Lupus anticoagulant and cardiac

manifestations in systemic lupus erythematosus. Lupus 1994; 3:167.
68. Espínola-Zavaleta N, Vargas-Barrón J, Colmenares-Galvis T, et al. Echocardiographic

evaluation of patients with primary antiphospholipid syndrome. Am Heart J 1999;
137:973.
69. Hojnik M, George J, Ziporen L, Shoenfeld Y. Heart valve involvement (Libman-Sacks

endocarditis) in the antiphospholipid syndrome. Circulation 1996; 93:1579.
70. Turiel M, Sarzi-Puttini P, Peretti R, et al. Five-year follow-up by transesophageal

echocardiographic studies in primary antiphospholipid syndrome. Am J Cardiol 2005;
96:574.
71. Farzaneh-Far A, Roman MJ, Lockshin MD, et al. Relationship of antiphospholipid

antibodies to cardiovascular manifestations of systemic lupus erythematosus. Arthritis
Rheum 2006; 54:3918.
72. Zuily S, Huttin O, Mohamed S, et al. Valvular heart disease in antiphospholipid

syndrome. Curr Rheumatol Rep 2013; 15:320.
73. Roldan CA, Gelgand EA, Qualls CR, Sibbitt WL Jr. Valvular heart disease as a cause of
cerebrovascular disease in patients with systemic lupus erythematosus. Am J Cardiol
2005; 95:1441.
74. Roldan CA, Gelgand EA, Qualls CR, Sibbitt WL Jr. Valvular heart disease by transthoracic
echocardiography is associated with focal brain injury and central neuropsychiatric
systemic lupus erythematosus. Cardiology 2007; 108:331.
75. Zuily S, Regnault V, Selton-Suty C, et al. Increased risk for heart valve disease associated
with antiphospholipid antibodies in patients with systemic lupus erythematosus: meta-
analysis of echocardiographic studies. Circulation 2011; 124:215.
76. Chighizola CB, Andreoli L, de Jesus GR, et al. The association between antiphospholipid
antibodies and pregnancy morbidity, stroke, myocardial infarction, and deep vein
thrombosis: a critical review of the literature. Lupus 2015; 24:980.
77. Gibson GE, Su WP, Pittelkow MR. Antiphospholipid syndrome and the skin. J Am Acad
Dermatol 1997; 36:970.
78. Francès C, Niang S, Laffitte E, et al. Dermatologic manifestations of the

antiphospholipid syndrome: two hundred consecutive cases. Arthritis Rheum 2005;
52:1785.
79. Hairston BR, Davis MD, Pittelkow MR, Ahmed I. Livedoid vasculopathy: further evidence
for procoagulant pathogenesis. Arch Dermatol 2006; 142:1413.
80. Marzano A, Vanotti M, Alessi E. Anetodermic lupus panniculitis and antiphospholipid

antibodies: report of three cases. Acta Derm Venereol 2004; 84:385.
81. Toubi E, Krause I, Fraser A, et al. Livedo reticularis is a marker for predicting multi-
system thrombosis in antiphospholipid syndrome. Clin Exp Rheumatol 2005; 23:499.
82. Uthman IW, Khamashta MA. Livedo racemosa: a striking dermatological sign for the
antiphospholipid syndrome. J Rheumatol 2006; 33:2379.
83. Kawakami T, Yamazaki M, Mizoguchi M, Soma Y. Differences in anti-phosphatidylserine-

prothrombin complex antibodies and cutaneous vasculitis between regular livedo
reticularis and livedo racemosa. Rheumatology (Oxford) 2009; 48:508.
84. Ehrmann S. Ein Gefaessprozess Bei Lues. Wien Med Wochenschr 1907; 57:777.
85. Gibbs MB, English JC 3rd, Zirwas MJ. Livedo reticularis: an update. J Am Acad Dermatol
2005; 52:1009.
86. Uthman I, Khamashta M. The abdominal manifestations of the antiphospholipid

syndrome. Rheumatology (Oxford) 2007; 46:1641.
87. Qi X, De Stefano V, Su C, et al. Associations of antiphospholipid antibodies with

splanchnic vein thrombosis: a systematic review with meta-analysis. Medicine
(Baltimore) 2015; 94:e496.
88. Zhu W, Wu Y, Xu M, et al. Antiphospholipid antibody and risk of retinal vein occlusion: a
systematic review and meta-analysis. PLoS One 2014; 10:e0122814.
89. Miserocchi E, Baltatzis S, Foster CS. Ocular features associated with anticardiolipin
antibodies: a descriptive study. Am J Ophthalmol 2001; 131:451.
90. Carbone J, Sánchez-Ramón S, Cobo-Soriano R, et al. Antiphospholipid antibodies: a risk

factor for occlusive retinal vascular disorders. Comparison with ocular inflammatory
diseases. J Rheumatol 2001; 28:2437.
91. Espinosa G, Santos E, Cervera R, et al. Adrenal involvement in the antiphospholipid

syndrome: clinical and immunologic characteristics of 86 patients. Medicine (Baltimore)
2003; 82:106.
92. Ramon I, Mathian A, Bachelot A, et al. Primary adrenal insufficiency due to bilateral
adrenal hemorrhage-adrenal infarction in the antiphospholipid syndrome: long-term
outcome of 16 patients. J Clin Endocrinol Metab 2013; 98:3179.
93. Cervera R, Bucciarelli S, Plasín MA, et al. Catastrophic antiphospholipid syndrome

(CAPS): descriptive analysis of a series of 280 patients from the "CAPS Registry". J
Autoimmun 2009; 32:240.
94. Tektonidou MG, Malagari K, Vlachoyiannopoulos PG, et al. Asymptomatic avascular

necrosis in patients with primary antiphospholipid syndrome in the absence of
corticosteroid use: a prospective study by magnetic resonance imaging. Arthritis
Rheum 2003; 48:732.
95. Gómez-Puerta JA, Cervera R, Espinosa G, et al. Catastrophic antiphospholipid syndrome

during pregnancy and puerperium: maternal and fetal characteristics of 15 cases. Ann
Rheum Dis 2007; 66:740.
96. Hanouna G, Morel N, Le Thi Huong D, et al. Catastrophic antiphospholipid syndrome

and pregnancy: an experience of 13 cases. Rheumatology (Oxford) 2013; 52:1635.

97. Pontara E, Banzato A, Bison E, et al. Thrombocytopenia in high-risk patients with

antiphospholipid syndrome. J Thromb Haemost 2018; 16:529.
98. Ramos-Casals M, Campoamor MT, Chamorro A, et al. Hypocomplementemia in

systemic lupus erythematosus and primary antiphospholipid syndrome: prevalence
and clinical significance in 667 patients. Lupus 2004; 13:777.
99. Oku K, Atsumi T, Bohgaki M, et al. Complement activation in patients with primary
antiphospholipid syndrome. Ann Rheum Dis 2009; 68:1030.
100. Ünlü O, Zuily S, Erkan D. The clinical significance of antiphospholipid antibodies in

systemic lupus erythematosus. Eur J Rheumatol 2016; 3:75.
101. Erkan D, Espinosa G, Cervera R. Catastrophic antiphospholipid syndrome: updated

diagnostic algorithms. Autoimmun Rev 2010; 10:74.
102. Ortel TL, Erkan D, Kitchens CS. How I treat catastrophic thrombotic syndromes. Blood
2015; 126:1285.
103. Drenkard C, Villa AR, Alarcón-Segovia D, Pérez-Vázquez ME. Influence of the

antiphospholipid syndrome in the survival of patients with systemic lupus
erythematosus. J Rheumatol 1994; 21:1067.
104. Tanne D, D'Olhaberriague L, Trivedi AM, et al. Anticardiolipin antibodies and mortality
in patients with ischemic stroke: a prospective follow-up study. Neuroepidemiology
2002; 21:93.
Topic 4667 Version 34.0

GRAPHICS
Libman-Sacks verrucous endocarditis
Verrucous endocarditis with valvular vegetations (arrows) in a 52-year-old woman with

systemic lupus erythematosus who died of pneumonia and chronic interstitial
pneumonitis. The vegetations had not been observed by echocardiography, although a
cardiac murmur had been heard by auscultation. A cerebrovascular accident was also
found at autopsy.
Courtesy of Peter H Schur, MD.
Graphic 79709 Version 2.0

Livedo reticularis
Patient with lupus and antiphospholipid antibodies with livedo reticularis (manifested
by a reddish-cyanotic, reticular pattern of the skin) which has resulted in ulcer
formation (arrows).
Courtesy of Samuel Moschella, MD.

Anetoderma
Multiple circumscribed, wrinkled lesions are present on the chest.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.

Revised classification criteria for the antiphospholipid syndrome
Antiphospholipid syndrome is present if at least one of the clinical criteria and one of the
laboratory criteria that follow are met*
Clinical criteria
1. Vascular thrombosis ¶
One or more clinical episodes Δ of arterial, venous, or small vessel thrombosis ◊, in any tissue or organ. Thrombosis must
be confirmed by objective validated criteria (ie, unequivocal findings of appropriate imaging studies or histopathology).
For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel
wall.
2. Pregnancy morbidity
a. One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with
normal fetal morphology documented by ultrasound or by direct examination of the fetus; or
b. One or more premature births of a morphologically normal neonate before the 34th week of gestation because of:
(i) eclampsia or severe preeclampsia defined according to standard definitions, or (ii) recognized features of placental
insufficiency §; or
c. Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal
anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.
In studies of populations of patients who have more than one type of pregnancy morbidity, investigators are strongly
encouraged to stratify groups of subjects according to a, b, or c above.
Laboratory criteria ¥
1. LA present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the
International Society on Thrombosis and Haemostasis (Scientific Subcommittee on LAs/phospholipid-dependent
antibodies).
2. aCL of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (ie, >40 GPL or MPL, or >the 99th
percentile), on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA.
3. Anti-beta-2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titer >the 99th percentile), present
on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA, according to recommended
procedures.
LA: lupus anticoagulant; aCL: anticardiolipin antibody; Ig: immunoglobulin; ELISA: enzyme-linked immunosorbent assay; APS:
antiphospholipid syndrome; aPL: antiphospholipid antibodies; LDL: low-density lipoprotein; HDL: high-density lipoprotein; GFR:
glomerular filtration rate.
* Classification of APS should be avoided if less than 12 weeks or more than five years separate the positive aPL test and the clinical
manifestation.
¶ Coexisting inherited or acquired factors for thrombosis are not reasons for excluding patients from APS trials. However, two
subgroups of APS patients should be recognized, according to: (a) the presence; and (b) the absence of additional risk factors for
thrombosis. Indicative (but not exhaustive) cases include: age (>55 in men and >65 in women) and the presence of any of the
established risk factors for cardiovascular disease (hypertension, diabetes mellitus, elevated LDL or low HDL cholesterol, cigarette
smoking, family history of premature cardiovascular disease, body mass index ≥30 kg m –2, microalbuminuria, estimated GFR <60
mL minute –1), inherited thrombophilias, oral contraceptives, nephrotic syndrome, malignancy, immobilization, and surgery. Thus,
patients who fulfill criteria should be stratified according to contributing causes of thrombosis.
Δ A thrombotic episode in the past could be considered as a clinical criterion, provided that thrombosis is proved by appropriate
diagnostic means and that no alternative diagnosis or cause of thrombosis is found.
◊ Superficial venous thrombosis is not included in the clinical criteria.
§ Generally accepted features of placental insufficiency include: (i) abnormal or non-reassuring fetal surveillance test(s), eg, a non-
reactive non-stress test, suggestive of fetal hypoxemia; (ii) abnormal Doppler flow velocimetry waveform analysis suggestive of fetal
hypoxemia, eg, absent end-diastolic flow in the umbilical artery; (iii) oligohydramnios, eg, an amniotic fluid index of 5 cm or less; or
(iv) a postnatal birth weight less than the 10th percentile for the gestational age.
¥ Investigators are strongly advised to classify APS patients in studies into one of the following categories: I, more than one
laboratory criteria present (any combination); IIa, LA present alone; IIb, aCL antibody present alone; IIc, anti-beta-2 glycoprotein-I
antibody present alone.
From: Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classiﬁcation criteria for deﬁnite
antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4:295. http://onlinelibrary.wiley.com/doi/10.1111/j.1538-
7836.2006.01753.x/abstract. Copyright © 2006 International Society on Thrombosis and Haemostasis. Reproduced with permission of John
Wiley & Sons, Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to
PowerPoint, printed, shared, or emailed. Please contact Wiley's Permissions Department either via email: permissions@wiley.com or use the
RightsLink service by clicking on the Request Permission link accompanying this article on Wiley Online Library
(www.onlinelibrary.wiley.com).

Classification criteria for catastrophic antiphospholipid antibody syndrome (CAPS)
Criteria
1. Evidence of involvement of three or more organs, systems, and/or tissues
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 tissue
4. Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies,
and/or anti-beta2-glycoprotein I antibodies)
Classification
Definite catastrophic APS
Requires all four criteria
Probable catastrophic APS
All four criteria, except for only two organs, systems, and/or sites of tissue involvement or
All four criteria, except for the laboratory confirmation at least six weeks apart due to the early death of a patient never
tested for aPL before the catastrophic APS or
Criteria 1, 2, and 4 above or
1, 3, and 4 and the development of a third event in more than a week but less than a month, despite anticoagulation
aPL: antiphospholipid antibodies.
Adapted from: Asherson, RA, Cervera, R, de Groot, PG, et al. Lupus 2003; 12:530.

Contributor Disclosures
Doruk Erkan, MD, MPH Grant/Research/Clinical Trial Support: Lupus Clinical Trials Consortium
[Lupus]; GlaxoSmithKline [Lupus]; American College of Rheumatology & European League Against
Rheumatism [Antiphospholipid syndrome]. Consultant/Advisory Boards: GlaxoSmithKline [Lupus];
Exagen [Lupus and antiphospholipid syndrome]; UCB[Antiphospholipid syndrome]. Speaker's Bureau:
GlaxoSmithKline [Lupus]. Stéphane Zuily, MD, MPH, PhD Nothing to disclose David S Pisetsky, MD,
PhD Consultant/Advisory Boards: Celgene [Lupus]; DILIsym [Drug-induced liver injury]; EMD Serono
[SLE]. Monica Ramirez Curtis, MD, MPH Nothing to disclose Jennifer S Tirnauer, MD Nothing to
disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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Antiphospholipid syndrome (APS) is an autoimmune multisystem disorder characterized by

APS occurs as a primary condition or in the setting of an underlying systemic autoimmune

In a large retrospective analysis including patients without known autoimmune diseases,

PRIMARY APS VERSUS APS WITH SLE

https://www.uptodate.com/contents/clinical-manifestations-of-antiphospholipid-syndrome/print?search=antiphospholipid syndrome&source=sear… 1/28

Although many of the clinical manifestations of primary antiphospholipid syndrome (APS)

● 0 percent at 5 years [17]

● Deep vein thrombosis (DVT) – 32 percent

https://www.uptodate.com/contents/clinical-manifestations-of-antiphospholipid-syndrome/print?search=antiphospholipid syndrome&source=sear… 2/28

In addition to those manifestations mentioned above, some of the other possible

Arterial thrombosis — The most common site of arterial thrombosis is in the cerebral

Recurrent thrombotic events — The recurrence rate of thrombotic events among

Neurological involvement — Central nervous system abnormalities are a common feature

https://www.uptodate.com/contents/clinical-manifestations-of-antiphospholipid-syndrome/print?search=antiphospholipid syndrome&source=sear… 3/28

Sneddon syndrome, which is characterized by widespread livedo reticularis in association

● No relationship was detected between cognitive dysfunction and previous central

Hematologic abnormalities — Thrombocytopenia is commonly observed in APS patients

marrow necrosis, especially if there is widespread thrombosis; and various thrombotic

Pulmonary involvement — Patients with APS may develop various lung manifestations

Cardiac involvement — Cardiac manifestations of APS most commonly involve the valves,

Cutaneous manifestations — APS has been associated with many cutaneous abnormalities

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

Renal disease — Renal disease occurs in a minority of patients with primary APS.

Gastrointestinal involvement — Patients with APS may have ischemia involving the

Adrenal disease — Loss of adrenal function due to bilateral adrenal vein thrombosis,

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enlargement. Adrenal hemorrhagic infarction may present as abdominal, lumbar, pelvic, or

Osteonecrosis — Asymptomatic changes in the appearance of the femoral heads of patients

In addition to the presence of antiphospholipid antibodies (aPLs), some of the more

Antiphospholipid antibodies — The three major aPL tests that are recognized by

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

● Anti-beta2-glycoprotein-I antibodies (anti-B2GPI) IgG and/or IgM ELISA

Thrombocytopenia — Thrombocytopenia is frequently observed in APS patients, with an

Hypocomplementemia — Hypocomplementemia can be observed in primary APS, similar

Other — Other laboratory abnormalities include the prolongation of a blood coagulation

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

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

● HIT – Heparin-induced thrombocytopenia (HIT) is an immune-mediated

● TMA – Thrombotic microangiopathies (TMA) are systemic syndromes (acquired or

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Antiphospholipid syndrome (APS) is associated with increased morbidity and mortality. A

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SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

● Antiphospholipid syndrome (APS) is an autoimmune multisystem disorder characterized

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● Thrombocytopenia is frequently observed in APS patients. The degree of

● Livedo reticularis ( picture 2) is the most common cutaneous manifestation of APS.

• History of APS and/or aPL

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• 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

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2. Andreoli L, Chighizola CB, Banzato A, et al. Estimated frequency of antiphospholipid

7. White RH. The epidemiology of venous thromboembolism. Circulation 2003; 107:I4.

8. www.census.gov/population/www/cen2010/glance/index.html (Accessed on October 1

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9. Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the