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Antiphospholipid Syndrome
Authors

Jean G. Bustamante1; Amandeep Goyal2; Mayank Singhal3.

Affiliations
1 Einstein Medical Center
2 University of Kansas Medical Center
3 Cape Fear Valley, Methodist University

Last Update: July 4, 2022.

Continuing Education Activity

Antiphospholipid antibodies are autoantibodies that are directed against phospholipid-binding proteins.
Antiphospholipid syndrome (APLS) is characterized by the presence of antiphospholipid antibodies in the setting of
thrombosis and/or pregnancy loss. The most common sites of venous and arterial thrombosis are the lower limbs and
the cerebral arterial circulation, respectively. However, thrombosis can occur in any organ. This activity examines
when antiphospholipid syndrome should be considered in differential diagnosis and how to evaluate it properly. This
activity highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

Identify the clinical criteria required to make a diagnosis of antiphospholipid syndrome.

Review the workup of a patient with antiphospholipid syndrome.

Summarize the treatment and management options available for antiphospholipid syndrome.

Describe interprofessional team strategies for improving care and outcomes in patients with antiphospholipid
syndrome.

Access free multiple choice questions on this topic.

Introduction
Antiphospholipid antibodies are autoantibodies that are directed against phospholipid-binding proteins.
Antiphospholipid syndrome (APLS) is a multisystemic autoimmune disorder. The hallmark of APLS comprises the
presence of persistent antiphospholipid antibodies (APLA) in the setting of arterial and venous thrombus and/or
pregnancy loss. The most common sites of venous and arterial thrombosis are the lower limbs and the cerebral arterial
circulation, respectively. However, thrombosis can occur in any organ.

To identify APLA, the laboratory tests include enzyme-linked immunosorbent assay (ELISA), and functional assays.
The three known APLA are:

1. Anticardiolipin antibodies IgG or IgM (ELISA)

2. Anti-beta-2-glycoprotein-I antibodies IgG or IgM (ELISA)

3. Lupus anticoagulants (Functional assays)

Etiology
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Antiphospholipid syndrome can be primary when there is no evidence of autoimmune disease, or it can be secondary
to autoimmune processes like systemic lupus erythematosus (SLE) in 40% of the cases.[1] Genetic risk factors
heighten the risk of antiphospholipid antibody-associated thrombosis, such as coagulation factor mutations. HLA-
DR7, DR4, DRw53, DQw7, and C4 null alleles have been reported to be associated with APLS. Infections such as
borrelia burgdorferi, treponema, HIV, and leptospira have been implicated in the induction of antiphospholipid
antibody (APLA) formation.[2] Many drugs, including chlorpromazine, procainamide, quinidine, and phenytoin, can
induce APLA production. Low levels of APLA may also be normally present.

Epidemiology
Low titer anticardiolipin antibodies can be seen in up to 10% of healthy individuals, and the prevalence of a positive
APLA test increases with age. High titers and persistent positivity is rare among healthy individuals (less than 1%).
Patients with SLE are at high risk of having a positive APLA test, as well as an APLA related clinical outcome
(thrombosis or pregnancy-related morbidity). 50% to 70% of the patients with SLE with positive APLA progress to
APLS.[3][1] APLA positivity has also been demonstrated in up to 20% of patients with rheumatoid arthritis.[4] A
study of 197 couples with habitual abortions identified 20% of them having APLA.[5] Another study identified the
presence of APLA (lupus anticoagulant or anticardiolipin antibodies) in 14% of patients with recurrent venous
thromboembolism. [6]

Pathophysiology
While not all patients with APLA develop APLS, there is a strong association between the presence of APLA and
venous thrombosis, myocardial infarction, and ischemic stroke. [7] Antibody profile, including type and titer and
underlying comorbidities, may determine the likelihood of developing clinical APLS. Tripple positivity with positive
lupus anticoagulant and high titers of anticardiolipin and anti-beta-2-glycoprotein I antibodies pose a high risk for the
development of APLS. In contrast, isolated or intermittent positivity or low titers of anticardiolipin or anti-beta-2-
glycoprotein I antibodies pose a low risk. [8][9] Patients with SLE, coexisting cardiovascular risk factors, history of
recurrent thrombotic events despite anticoagulation therapy, and history of arterial thrombosis are also at high risk for
recurrent thrombosis.

Antiphospholipid antibodies are considered pathogenic as they play an important role in thrombosis, and they are not
just a serological marker of APLS.

A “two-hit” thrombosis model is proposed to explain thrombus formation in patients with antiphospholipid syndrome.
A “first hit” injury to the endothelium needs to happen to have a “second hit” that potentiates the thrombus formation.
Beta-2 glycoprotein I do not bind unstimulated endothelium in vivo. One of the postulates, when causes of endothelial
injury are not identified, is a redox balance disturbance in the vascular beds that may prime the endothelium. Patients
with antiphospholipid syndrome have lower levels of the reduced, protective, and non-immunogenic beta-2
glycoprotein I. Annexin A2, an endothelial cell surface receptor, is upregulated with oxidative stress. Smoking can
lead to endothelial injury and increase the pro-thrombotic susceptibilities in patients with lupus anticoagulant.

Plasma nitrite levels are decreased in patients with APLS when compared with healthy controls. The
decreased expression and activity of endothelial nitric oxide synthase results in the generation of peroxynitrite and
superoxide. Preclinical models have shown how the domain I of beta-2 glycoprotein I autoantibodies antagonize the
activity of endothelial nitric oxide synthase with resultant monocyte adhesion and inhibition of nitric oxide-dependent
arterial relaxation. 

Tissue factor expression is upregulated by antiphospholipid antibodies through some intracellular signaling pathways
after binding the anti-beta 2 glycoprotein I autoantibodies to the monocytes' surface and endothelial cells' multiprotein
complexes. Autoantibodies from patients with APLS disrupt the mitochondrial function of neutrophils and monocytes

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and increase the production of reactive species of oxygen, resulting in the subsequent expression of tissue factor.[3]
[1] Complement activation and inhibition of fibrinolysis by the APLA has been established.

Intraplacental thrombosis, complement pathway activation, interference with trophoblast growth and differentiation
and impaired trophoblastic invasion, and hormone production are considered to play a role in APLS associated
pregnancy loss.

Histopathology
Kidney biopsy of patients with APLS having renal involvement demonstrated thrombotic microangiopathy. 

Skin biopsy from sites of non-healing ulcerations is usually non-specific and not always performed, but may show
occlusive vasculopathy without significant vasculitis.

History and Physical

The clinical features vary significantly and can be as mild as asymptomatic APLA positivity, or as severe as
catastrophic APLS. Arterial and venous thrombosis and pregnancy-related complications are the hallmarks of the
disease. However, several other organ systems may be involved (non-criteria manifestations).

Vascular Thrombosis

APLS can cause arterial and/or venous thrombosis involving any organ system. APLS related thrombotic events can
occur without preceding risk of thrombosis. They can be recurrent and can involve vessels unusual for other-cause-
thrombosis (such as upper extremity thrombosis, Budd-Chiari syndrome, and sagittal sinus thrombosis). Venous
thrombosis involving the deep veins of lower extremities is the most common venous involvement and may lead to
pulmonary embolism resulting in pulmonary hypertension. Any other site may be involved in venous thrombosis,
including pelvic, renal, mesenteric, hepatic, portal, axillary, ocular, sagittal, and inferior vena cava.

Arterial thrombosis may involve any sized arteries (aorta to small capillaries). The most common arterial
manifestation of APLS is transient ischemic events (TIAs) or ischemic stroke, and the occurrence of TIA or ischemic
stroke in young patients without other risk factors for atherosclerosis shall raise suspicion for APLS. Other sites for
arterial thrombosis may include retinal, brachial, coronary, mesenteric, and peripheral arteries. The occurrence of
arterial thrombosis carries a poor prognostic value, given the high risk of recurrence in these cases. 

Pregnancy Morbidity

Pregnancy loss in patients with APLS is common, especially in the second or third trimester. While genetic and
chromosomal defects are the most common cause of early (less than 10-week gestation) pregnancy loss, they may
also occur in patients with APLS. Tripple positivity (lupus anticoagulant, anticardiolipin and anti-beta-2-glycoprotein-
I antibodies), previous pregnancy loss, history of thrombosis, and SLE are risk factors for adverse pregnancy-related
outcomes and pregnancy losses in APLS. Besides pregnancy losses, other pregnancy-related complications in APLS
include pre-eclampsia, fetal distress, premature birth, intrauterine growth retardation, placental insufficiency, abruptio
placentae, and HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelet count).

Cutaneous Involvement

Several cutaneous manifestations have been reported, although all are non-specific for APLS. Livedo reticularis is the
most common cutaneous manifestation seen in APLS. However, it can also be seen in the healthy population and in
other disorders such as SLE, other connective tissue diseases, vasculitides, sepsis, multiple cholesterol emboli, and
Sneddon syndrome. Skin ulcerations, especially in lower extremities ranging from small ulcers to large ulcers
resembling pyoderma gangrenosum, have been reported in APLS. Other cutaneous manifestations include nail-fold
infarcts, digital gangrene, superficial thrombophlebitis, and necrotizing purpura.

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Valvular Involvement

Cardiac valve involvement is very common in APLS, with some studies noting a prevalence as high as
80%. [10] Mitral and aortic valves are most commonly involved with thickening, nodules, and vegetations evident on
echocardiography. This may lead to regurgitation and/or stenosis. 

Hematological Involvement

Thrombocytopenia has been seen in more than 15% of APLS cases.[11] Severe thrombocytopenia leading to
hemorrhage is rare. Positive Coomb test is frequently seen in APLS, although hemolytic anemia is rare. 

Neurological Involvement

The most common neurological complication of APLS includes TIAs and ischemic stroke, which may be recurrent,
leading to cognitive dysfunction, seizures, and multi-infarct dementia. Blindness secondary to the retinal artery or
vein occlusion can occur. Sudden deafness secondary to sensorineural hearing loss has been reported. 

Pulmonary Involvement

Pulmonary artery thromboembolism from deep vein thrombosis is common and may lead to pulmonary hypertension.
Diffuse pulmonary hemorrhage resulting from pulmonary capillaritis has been reported.

Renal Involvement

Hypertension, proteinuria, and renal failure secondary to thrombotic microangiopathy is the classic renal
manifestation of APLS, although this is not specific to APLS. Other renal manifestations reported include renal artery
thrombosis leading to refractory hypertension, fibrous intimal hyperplasia with organized thrombi with or without
recanalization, and focal cortical atrophy.

Catastrophic Anti-Phospholipid Syndrome (CAPS)

CAPS is a rare but life-threatening complication of APLS, with less than 1% of patients with APLS developing
CAPS. Mortality is very high (48%), especially in patients with SLE and those with cardiac, pulmonary, renal, and
splenic involvement. It is characterized by thrombosis in multiple organs over a short period of time (a few days).
Small and medium-sized arteries are most frequently involved. Clinical presentation varies depending on the organ
involved and may include peripheral thrombosis (deep vein, femoral artery or radial artery), pulmonary (acute
respiratory distress syndrome, pulmonary embolism, pulmonary hemorrhage), renal (thrombotic microangiopathy,
renal failure), cutaneous (livedo reticularis, digital ischemia, gangrene, skin ulcerations), cerebral (ischemic stroke,
encephalopathy), cardiac (valve lesions, myocardial infarction, heart failure), hematological (thrombocytopenia), and
gastrointestinal (bowel infarction) involvement.[12] 

Preliminary criteria for the classification of CAPS were published in 2003. [13] The four criteria are:

1. Involvement of three or more organs/systems/tissues

2. Manifestations developing simultaneously or within less than one week

3. Histopathological confirmation of small vessel occlusion in at least one organ/tissue

4. Laboratory confirmation of the presence of APLA

Definite CAPS can be classified by the presence of all four criteria, while probable CAPS can be classified if 3
criteria are present and the fourth is incompletely fulfilled.

Evaluation

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In addition to clinical criteria, the diagnosis of APLS requires the presence of lupus anticoagulant or moderate-high
titers of IgG or IgM anticardiolipin or anti-beta-2-glycoprotein I antibodies. The criteria also require a repeat APLA
test to be positive 12 weeks after the initial positive test to exclude clinically unimportant or transient antibody. If that
duration is less than 12 weeks, or the gap between two separate clinical manifestations and positive laboratory tests is
more than 5 years, the diagnosis of APLS is questionable. [14]

Lupus Anticoagulant Test

Lupus anticoagulant test is the strongest predictor for adverse pregnancy-related events. It is more specific but less
sensitive than anticardiolipin antibodies in predicting thrombosis. A positive lupus anticoagulant test is seen in 20% of
patients with anticardiolipin antibodies, and anticardiolipin antibodies are seen in 80% of patients with a positive
lupus anticoagulant test.  A false-positive syphilis test does not fulfill the criteria for a diagnosis of APLS, but one
should always check APLA in patients with previous thrombotic or adverse pregnancy-related events. The presence
of a lupus anticoagulant indicates the presence of a coagulation inhibitor of phospholipid-dependent coagulation
reactions. It does not react directly with coagulation factors and is not associated with bleeding complications. False-
positive and false-negative results can be seen in patients on heparin or warfarin.

It is a four-step test:

1. Prolonged phospholipid-dependent coagulation screening test (activated partial thromboplastin time or dilute

Russell viper venom time)

2. Inability to correct the prolonged screening test despite mixing the patient’s plasma with normal platelet-poor
plasma. This indicates the presence of an inhibitor

3. Correction or improvement in the prolonged screening test after the addition of excess phospholipid. This
indicates phospholipid dependency

4. Exclusion of other inhibitors. 

Anticardiolipin and Anti-beta-2-glycoprotein I Antibodies

Anticardiolipin antibodies and anti-beta-2-glycoprotein I antibodies are assessed by enzyme liked immunosorbent

assay (ELISA), and common assays include tests for IgG and IgM isotypes. IgG antibodies correlate better with
clinical manifestations than IgM or IgA. Titers more than 40 GPL units are associated with thrombotic events, while
lower titers have a less proven association with thrombotic events.

Other Laboratory Findings

Thrombocytopenia or anemia can be seen in APLS frequently. Renal failure and proteinuria may indicate renal
involvement with thrombotic microangiopathy. Erythrocyte sedimentation rate may be high during the acute
thrombotic event. However, markers of inflammation are usually normal otherwise. Patients with SLE may have
positive serologies specific for SLE, such as ANA, anti-Ds-DNA, Anti-smith, etc. Hypocomplementemia is not
usually seen in APLS, and when present with renal involvement, it indicates lupus nephritis. Notably, positive ANA
and even anti-Ds-DNA is frequently seen in primary APLS without associated SLE, and the presence of these
antibodies alone does not imply a diagnosis of SLE in patients without any clinical features of SLE. It may also be
important to test a patient with multiple thrombotic events or pregnancy losses for other hypercoagulable states
(hyperhomocysteinemia, Factor V Leiden and prothrombin mutations, deficiency of protein C, protein S, or
antithrombin III) when indicated.

Classification Criteria

The initial classification criteria, known as the Sapporo criteria, was published in 1999, which was updated in
2006. [14] The revised Sapporo classification criteria for APLS require at least one laboratory and one clinical
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criterion to be met.

Clinical Criteria

One of the following clinical findings should be confirmed to diagnose antiphospholipid antibody syndrome.

Vascular Thrombosis

One or more events of arterial, venous, or small-vessel thrombosis of any organ. Thrombosis must be
objectively confirmed with appropriate imaging or histopathology. For histopathology, thrombosis shall be
present without significant vessel wall inflammation.

A thrombotic episode in the past can be included as a criterion as long as it was appropriately confirmed
by appropriate diagnostic means, and there was no other cause of thrombosis.

Superficial venous thrombosis shall not be included as a criterion.

Pregnancy Morbidity 

One or more unexplained fetal deaths of morphologically normal fetus (normal fetal morphology confirmed by
ultrasound or direct examination) at or beyond 10 weeks of gestation.

One or more premature births of morphologically normal neonate before the 34th week of gestation.
Prematurity must be secondary to eclampsia, severe preeclampsia, or placental insufficiency.

Three or more consecutive spontaneous abortions before the 10th week of gestation after ruling out any
anatomic or hormonal abnormalities in the mother and parental chromosomal causes.

Laboratory Criteria

One of the following laboratory findings should be confirmed to diagnose antiphospholipid antibody syndrome.

Detection of lupus anticoagulant in plasma on two or more occasions, 12 or more weeks apart.

Detection of IgG or IgM anticardiolipin antibodies in serum or plasma in moderate to high titers (more than 40
GPL or more than 99th percentile) measured by standard ELISA on two or more occasions, twelve or more
weeks apart.

Detection of IgG or IgM anti-beta-2-glycoprotein I antibody in serum or plasma in moderate to high titers
(more than 99th percentile) measured by standard ELISA, on two or more occasions, 12 or more weeks apart.

Treatment / Management
Thrombosis Management

In patients with a positive blood test for APLA but no prior history of thrombotic events or pregnancy-related
outcomes, primary thromboprophylaxis is debatable. Patients with SLE with positive APLA are especially at higher
risk of developing thrombotic events, and hydroxychloroquine is recommended in these patients, which has been
shown to be thromboprotective. [15] Low dose aspirin may also be considered. Prophylaxis for other patients with
APLA who have high-risk APLA profile such as triple positivity with other thrombotic risk factors may be considered
for low dose aspirin.

In patients with a venous thrombotic event, warfarin with an INR goal of 2.0 to 3.0 is recommended for the longterm.
The INR goal for patients with arterial thrombosis is debatable with a goal of 2.0 to 3.0 mostly used, while some
recommend a higher goal of more than 3.0.[16] Low molecular weight heparin can be used in patients who are unable
to tolerate warfarin, or who show no response to warfarin. In patients who have recurrent thrombosis despite adequate
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warfarin, the addition of aspirin to warfarin, or high-intensity anticoagulation with warfarin with the INR goal of more
than 3.0 can be considered. 

There are no randomized controlled trials to demonstrate the efficacy of newer anticoagulant agents,
including clopidogrel, aspirin-dipyridamole, argatroban, fondaparinux, dabigatran, etc. These agents can only be used
in APLS with one venous thrombotic agent if there is allergy/intolerance to warfarin. They are not recommended in
APLS, where warfarin use is feasible or where there are recurrent events of venous or arterial thrombosis.

Pregnancy Management

All pregnant females with positive APLA should be kept under surveillance during their pregnancy to ensure the fetal
well being and to avoid maternal complications. Treatment for pregnant females is aimed at reducing the risk of
adverse fetal outcomes and is dictated by the clinical scenario. It must be noted that warfarin is teratogenic and shall
not be used in pregnancy. Low-molecular-weight heparin (LMWH) or unfractionated heparin both can be used;
however, LMWH is preferred because of better bioavailability, longer half-life, convenient once a day dosing and
lower risk of thrombocytopenia and osteoporosis.

For pregnant females with positive APLA but no history of arterial or venous thrombosis:

First pregnancy: No treatment is indicated

History of single pregnancy loss at gestation less than 10 weeks: No treatment is indicated

History of multiple pregnancy losses at gestation less than 10 weeks: Low dose aspirin in combination
with prophylactic dose unfractionated heparin or LMWH throughout pregnancy. 

History of one or more pregnancy losses at gestation more than 10 weeks: Low dose aspirin in
combination with therapeutic dose unfractionated heparin or LMWH throughout pregnancy. Aspirin
should be started before conception, and both aspirin and heparin/LMWH can be discontinued 6 to 12
weeks postpartum.

For pregnant females with positive APLA and past history of arterial or venous thrombosis:

Low dose aspirin in combination with therapeutic dose unfractionated heparin or LMWH throughout
pregnancy. After delivery, these patients should be transitioned to warfarin, which should be continued
lifelong with the INR goal of 2.0 to 3.0.

Catastrophic Anti-Phospholipid Syndrome (CAPS) Management

Early diagnosis is crucial in the management of CAPS due to the high mortality associated with it. There are no
randomized controlled trials for the management of CAPS. Anticoagulation and high dose corticosteroids are used in
combination with IVIG, plasmapheresis, rituximab, cyclophosphamide, or eculizumab.

Management of Other Manifestations

The role of anticoagulation has not been established in other non-criteria manifestations of APLS. Thrombocytopenia
with platelet count more than 50,000/mm3 does not require any treatment; however, corticosteroids with or without
IVIG or rituximab can be used if platelet counts are less than 50,000/mm3. Splenectomy has also been proven to be
beneficial in some patients with severe refractory thrombocytopenia. Renal involvement with thrombotic
microangiopathy shall be confirmed with a renal biopsy, especially in patients with concomitant SLE to rule out lupus
nephritis. Anticoagulation and corticosteroids can be used for thrombotic microangiopathy. For patients with cardiac
valve nodules or deformity, there is no known effective treatment. However, if there is evidence of embolism or
intracardiac thrombus, anticoagulation is recommended.

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Differential Diagnosis
Thrombosis due to antiphospholipid antibody syndrome must be differentiated from other causes of thrombosis such
as hyperhomocysteinemia, factor V Leiden and prothrombin mutations, deficiency of protein C, protein S, or
antithrombin III.

APLS associated nephropathy has to be differentiated from thrombotic thrombocytopenic purpura (TTP), vasculitis,
hemolytic uremic syndrome (HUS), malignant hypertension, and lupus nephritis. A kidney biopsy is often needed to
make a diagnosis in these cases.

Prognosis
Some European studies have observed 90% to 94% survival over ten years. However, morbidity is high in APLS,
with more than 30% of patients developing permanent organ damage and more than 20% of patients developing
severe disability at a 10-year follow-up. [17] Poor prognostic features include CAPS, pulmonary hypertension,
nephropathy, CNS involvement, and gangrene of the extremities. 

Overall the prognosis of both primary and secondary APLS is similar, but in the latter, the morbidity may be increased
as a result of any underlying rheumatic or autoimmune disorder. Lupus patients with antiphospholipid
antibodies carry a higher risk of neuropsychiatric disorders.

Complications
Antiphospholipid antibody syndrome can lead to complications of the affected organs like fetal loss, stroke,
pulmonary embolism, pulmonary hypertension, valvular abnormality, acute coronary syndrome, mesenteric
thrombosis, or hepatic veno-occlusive disease.

Perioperative complications are common in APLS due to the added prothrombotic risk posed by the surgery. The
anticoagulation strategy should be clearly defined before any surgery in patients with APLS to prevent thrombosis.

Pearls and Other Issues

It is important to identify and manage other prothrombotic risk factors (such as hyperlipidemia, smoking,
hypertension, oral contraceptives, etc.) in patients with APLS.

Enhancing Healthcare Team Outcomes

Antiphospholipid antibody syndrome management requires an interprofessional team approach with the involvement
of multiple specialties. Primary care physicians play the most important role in identifying patients with APLS.
Hematologists and rheumatologist play a crucial role in the diagnosis, management, and follow up. Involvement of
other specialties such as neurology, nephrology, cardiology, dermatology may be needed if the specific organ system
is involved. Anticoagulation clinics can play a significant role in monitoring therapeutic warfarin levels, and INR with
close follow up. Pharmacists can assist in the management of these patients, especially by identifying drug
interactions because the metabolism of warfarin is affected by several medications. Close communication between the
interprofessional team with close monitoring of the patient is vital in the management of APLS.

Review Questions

Access free multiple choice questions on this topic.

Comment on this article.

References

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