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Antiphospholipid Syndrome

Editor: Mayank Singhal Updated: 2/26/2024 1:31:56 AM

Introduction

Antiphospholipid antibodies are autoantibodies that are directed against phospholipid-binding proteins. Antiphospholipid syndrome (APLS) is a multisystemic autoimmune disorder.[1] The hallmark of APLS comprises the presence of persistent antiphospholipid antibodies (APLA) in the setting of arterial and venous thrombus and/or pregnancy loss.[2]

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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Etiology

Antiphospholipid syndrome can be primary when there is no evidence of autoimmune disease or secondary to autoimmune processes like systemic lupus erythematosus (SLE) in 40% of cases.[3]

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.[4]

Many drugs, including chlorpromazine, procainamide, quinidine, and phenytoin, can induce APLA production. Low levels of APLA may also be normally present.

APS can be further classified according to the clinical manifestations (obstetric or thrombotic; in some cases, both) and whether it involves life-threatening multiorgan involvement:

  • Thrombotic APS: Patients are diagnosed with APS based on arterial or venous thrombosis and persistent laboratory criteria for APLA.
  • Obstetric APS: Patients are diagnosed based on APS-defining pregnancy morbidity (including premature birth due to severe preeclampsia, fetal death after 10 weeks gestation, placental insufficiency, or multiple embryonic losses within 10 weeks gestation) and persistent laboratory criteria for APLA. Patients with both thromboembolic complications and APS-defining pregnancy morbidity are recognized as having both thrombotic and obstetric APS.
  • Catastrophic APS: It is a rare and life-threatening form of APS defined as thrombotic complications (microvascular or macrovascular) affecting multiple organs.[5]

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 and an APLA-related clinical outcome (thrombosis or pregnancy-related morbidity). About 50% to 70% of the patients with SLE with positive APLA progress to APLS.[6][3] 

APLA positivity has also been demonstrated in up to 20% of patients with rheumatoid arthritis.[7] A study of 197 couples with habitual abortions identified 20% having APLA.[8] Another study identified the presence of APLA (lupus anticoagulant or anticardiolipin antibodies) in 14% of patients with recurrent venous thromboembolism.[9]

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.[10] 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.[11][12] Patients with SLE, coexisting cardiovascular risk factors, a history of recurrent thrombotic events despite anticoagulation therapy, and a 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 are not just a serological marker of APLS.

A "2-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 compared to healthy controls. The reduced 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. 

Antiphospholipid antibodies upregulate tissue factor expression 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 and increase the production of reactive oxygen species, resulting in the subsequent expression of tissue factor.[6][3] Complement activation and inhibition of fibrinolysis by the APLA have been established.

Intraplacental thrombosis, complement pathway activation, interference with trophoblast growth and differentiation, 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 the risk of thrombosis. They can be recurrent and 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 the lower extremities is the most common venous involvement and may lead to pulmonary embolism, resulting in pulmonary hypertension. Any other site may involve 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. 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 weeks 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 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 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.[13]

Valvular Involvement

Cardiac valve involvement is very common in APLS, with some studies noting a prevalence as high as 80%.[14] Mitral and aortic valves are most commonly involved with thickening, nodules, and vegetation, evident on echocardiography. This may lead to regurgitation or stenosis. 

Hematological Involvement

Thrombocytopenia has been seen in more than 15% of APLS cases.[15] 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.[16] Diffuse pulmonary hemorrhage resulting from pulmonary capillaritis has been reported.

Renal Involvement

Hypertension, proteinuria, and renal failure secondary to thrombotic microangiopathy are the classic renal manifestations 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 Antiphospholipid Syndrome 

Catastrophic antiphospholipid syndrome (CAPS) is a rare but life-threatening complication of APLS, with less than 1% of patients with APLS developing CAPS. Mortality is 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 (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.[17]

Preliminary criteria for the classification of CAPS were published in 2003.[18] The 4 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

The presence of all 4 criteria can classify definite CAPS, while probable CAPS can be classified if 3 criteria are present and the fourth is incompletely fulfilled.

Evaluation

In addition to clinical criteria, diagnosing APLS requires 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 antibodies. If that duration is less than 12 weeks, or the gap between two separate clinical manifestations and positive laboratory tests is more than five years, the diagnosis of APLS is questionable.[19]

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 diagnosing 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-linked 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 of 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. The 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 are 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, were published in 1999 and updated in 2006.[19] The revised Sapporo classification criteria for APLS require at least one laboratory and one clinical 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 the morphologically normal fetuses (normal fetal morphology confirmed by ultrasound or direct examination) at or beyond 10 weeks of gestation.
  • One or more premature births of morphologically normal neonates 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

Primary thromboprophylaxis is debatable in patients with a positive blood test for APLA but no prior history of thrombotic events or pregnancy-related outcomes. Confirmatory testing of APLA is required at least 12 weeks after the initial testing. Patients with SLE with positive APLA are especially at higher risk of developing thrombotic events, and hydroxychloroquine is recommended for these patients, which is thromboprotective.[20] Low-dose aspirin may also be considered. Prophylaxis for other patients with APLA with high-risk APLA profiles, 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 long term. However, a direct oral anticoagulant (DOAC) may reasonably be used in selected individuals. The INR goal for patients with arterial thrombosis is debatable, with a goal of 2.0 to 3.0 primarily used, while some suggest a higher goal of more than 3.0.[21] Low molecular weight heparin can be used in patients who cannot tolerate warfarin or show no response. In patients with recurrent thrombosis despite adequate warfarin, adding aspirin to warfarin or high-intensity anticoagulation with an INR goal of more than 3.0 can be considered.(B3)

No randomized controlled trials 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 an allergy/intolerance to warfarin. They are not recommended in APLS, where warfarin use is feasible or where there are recurrent venous or arterial thrombosis events.

Pregnancy Management

All pregnant females with positive APLA should be under surveillance during their pregnancy to ensure fetal well-being and 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 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
    • Account of single pregnancy loss at gestation less than ten weeks: No treatment is indicated
    • History of multiple pregnancy losses at gestation less than ten 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 ten weeks: Low-dose aspirin in combination with therapeutic dose unfractionated heparin or LMWH throughout pregnancy. Aspirin should be started before conception, and aspirin and heparin/LMWH can be discontinued 6 to 12 weeks postpartum, regardless of the route of delivery.
  • For pregnant females with positive APLA and a 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.
  • For pregnant females with APS based on laboratory criteria for APLA and APS-defining pregnancy morbidity of ≥1 preterm deliveries of a morphologically normal infant before 34 weeks of gestation due to placental insufficiency (e.g., severe eclampsia, preeclampsia) and NO history of venous or arterial thrombosis.
    • Low-dose aspirin during pregnancy in most cases. Prophylactic-dose LMWH with low-dose aspirin is recommended if there is extensive decidual inflammation and vasculopathy or thrombosis on placental examination.
    • Postpartum dose, according to the mode of delivery:
      • Vaginal delivery:
        • Low-dose aspirin and intermittent pneumatic compression while in the hospital. Low-dose aspirin and graduated compression stockings for six weeks.
      • Cesarean delivery:
        • Low-dose aspirin or prophylactic-dose LMWH for six weeks.

Anticoagulation can be resumed 6 to 12 hours after cesarean delivery or 4 to 6 hours after vaginal birth unless there is a significant risk for significant bleeding. Warfarin and heparin are not contraindicated during breastfeeding, and there is a low risk of hemorrhage.[22]

Catastrophic Antiphospholipid Syndrome Management

Early diagnosis is crucial in the management of catastrophic antiphospholipid syndrome (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 combined 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 a platelet count of 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 beneficial in some patients with severe refractory thrombocytopenia. 

Renal involvement with thrombotic microangiopathy shall be confirmed with a renal biopsy to rule out lupus nephritis, especially in patients with concomitant SLE. Anticoagulation and corticosteroids can be used for thrombotic microangiopathy. There is no known effective treatment for patients with cardiac valve nodules or deformities. However, anticoagulation is recommended if there is evidence of embolism or intracardiac thrombus.

Follow up

Patients who are otherwise tolerating anticoagulation and have no other systemic autoimmune diseases can be seen as an outpatient once or twice a year. Coagulation studies (performed prior to initiating anticoagulation and during therapy to guide dosing), a biochemistry panel including renal function tests, and a complete blood count (CBC) are used to monitor patients. Repeated APLA testing is not indicated unless required for future treatment decisions. Moreover, patients who have symptomatic organ-system involvement should have appropriate evaluations based on their symptoms.

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% developing severe disability at a 10-year follow-up.[23] 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 due to 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.

Consultations

The patients are seen by internists, rheumatologists, hematologists, and obstetricians.

Pearls and Other Issues

It is essential 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 involving multiple specialties. Primary care physicians play the most critical role in identifying patients with APLS. Hematologists and rheumatologists play a crucial role in diagnosing, managing, and follow-up. Involvement of other specialties, such as neurology, nephrology, cardiology, and 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.

Given the complexity and variety of underlying conditions leading to antiphospholipid antibody syndrome, all interprofessional team members must be able to provide input for both diagnosis and subsequent treatment, particularly in cases involving pregnancy, where obstetrics should also be consulted.

Pharmacists can assist in managing these patients, especially by identifying drug interactions because the metabolism of warfarin is affected by several medications; they can also work with clinicians to appropriately dose warfarin and determine if the INR is responding appropriately. Specialty-trained nurses can also assume this role. Managing these patients requires each team member to be able to voice their concerns if therapy is not producing the desired result so that changes in the patient's treatment regimen can be made without delay. Communication among the interprofessional team members and close patient monitoring is vital in managing APLS.

References


[1]

Knight JS, Branch DW, Ortel TL. Antiphospholipid syndrome: advances in diagnosis, pathogenesis, and management. BMJ (Clinical research ed.). 2023 Feb 27:380():e069717. doi: 10.1136/bmj-2021-069717. Epub 2023 Feb 27     [PubMed PMID: 36849186]

Level 3 (low-level) evidence

[2]

Garcia D, Erkan D. Diagnosis and Management of the Antiphospholipid Syndrome. The New England journal of medicine. 2018 Sep 27:379(13):1290. doi: 10.1056/NEJMc1808253. Epub     [PubMed PMID: 30257161]


[3]

Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. The New England journal of medicine. 2002 Mar 7:346(10):752-63     [PubMed PMID: 11882732]


[4]

Arvieux J, Renaudineau Y, Mane I, Perraut R, Krilis SA, Youinou P. Distinguishing features of anti-beta2 glycoprotein I antibodies between patients with leprosy and the antiphospholipid syndrome. Thrombosis and haemostasis. 2002 Apr:87(4):599-605     [PubMed PMID: 12008941]


[5]

Garra W, Carmi O, Kivity S, Levy Y. Catastrophic antiphospholipid syndrome in lupus-associated immune thrombocytopenia treated with eltrombopag A case series and literature review. Medicine. 2023 Feb 10:102(6):e32949. doi: 10.1097/MD.0000000000032949. Epub     [PubMed PMID: 36820549]

Level 2 (mid-level) evidence

[6]

Lim W. Antiphospholipid syndrome. Hematology. American Society of Hematology. Education Program. 2013:2013():675-80. doi: 10.1182/asheducation-2013.1.675. Epub     [PubMed PMID: 24319251]


[7]

Olech E, Merrill JT. The prevalence and clinical significance of antiphospholipid antibodies in rheumatoid arthritis. Current rheumatology reports. 2006 Apr:8(2):100-8     [PubMed PMID: 16569368]

Level 2 (mid-level) evidence

[8]

Stephenson MD. Frequency of factors associated with habitual abortion in 197 couples. Fertility and sterility. 1996 Jul:66(1):24-9     [PubMed PMID: 8752606]

Level 2 (mid-level) evidence

[9]

Ginsberg JS, Wells PS, Brill-Edwards P, Donovan D, Moffatt K, Johnston M, Stevens P, Hirsh J. Antiphospholipid antibodies and venous thromboembolism. Blood. 1995 Nov 15:86(10):3685-91     [PubMed PMID: 7579334]


[10]

Ginsburg KS, Liang MH, Newcomer L, Goldhaber SZ, Schur PH, Hennekens CH, Stampfer MJ. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Annals of internal medicine. 1992 Dec 15:117(12):997-1002     [PubMed PMID: 1443986]

Level 2 (mid-level) evidence

[11]

Pengo V, Biasiolo A, Pegoraro C, Cucchini U, Noventa F, Iliceto S. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thrombosis and haemostasis. 2005 Jun:93(6):1147-52     [PubMed PMID: 15968401]


[12]

Les I, Ruiz-Irastorza G, Khamashta MA. Intensity and duration of anticoagulation therapy in antiphospholipid syndrome. Seminars in thrombosis and hemostasis. 2012 Jun:38(4):339-47. doi: 10.1055/s-0032-1304720. Epub 2012 Mar 30     [PubMed PMID: 22467528]


[13]

Bouabdella S, Dikhaye S, Zizi N. [Extremity necrosis revealing antiphospholipid syndrome]. La Revue du praticien. 2023 Jan:73(1):64     [PubMed PMID: 36820458]


[14]

Espínola-Zavaleta N, Vargas-Barrón J, Colmenares-Galvis T, Cruz-Cruz F, Romero-Cárdenas A, Keirns C, Amigo MC. Echocardiographic evaluation of patients with primary antiphospholipid syndrome. American heart journal. 1999 May:137(5):973-8     [PubMed PMID: 10220649]

Level 2 (mid-level) evidence

[15]

Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps MT, Jacobsen S, Lakos G, Tincani A, Kontopoulou-Griva I, Galeazzi M, Meroni PL, Derksen RH, de Groot PG, Gromnica-Ihle E, Baleva M, Mosca M, Bombardieri S, Houssiau F, Gris JC, Quéré I, Hachulla E, Vasconcelos C, Roch B, Fernández-Nebro A, Boffa MC, Hughes GR, Ingelmo M, Euro-Phospholipid Project Group. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis and rheumatism. 2002 Apr:46(4):1019-27     [PubMed PMID: 11953980]

Level 2 (mid-level) evidence

[16]

Yao WC, Leong KH, Chiu LT, Chou PY, Wu LC, Chou CY, Kuo CF, Tsai SY. The trends in the incidence and thrombosis-related comorbidities of antiphospholipid syndrome: a 14-year nationwide population-based study. Thrombosis journal. 2022 Sep 1:20(1):50. doi: 10.1186/s12959-022-00409-8. Epub 2022 Sep 1     [PubMed PMID: 36050731]


[17]

Cervera R, Font J, Gómez-Puerta JA, Espinosa G, Cucho M, Bucciarelli S, Ramos-Casals M, Ingelmo M, Piette JC, Shoenfeld Y, Asherson RA, Catastrophic Antiphospholipid Syndrome Registry Project Group. Validation of the preliminary criteria for the classification of catastrophic antiphospholipid syndrome. Annals of the rheumatic diseases. 2005 Aug:64(8):1205-9     [PubMed PMID: 15708888]

Level 2 (mid-level) evidence

[18]

Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, Khamashta MA, Shoenfeld Y, Catastrophic Antiphospholipid Syndrome Registry Project Group. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus. 2003:12(7):530-4     [PubMed PMID: 12892393]

Level 3 (low-level) evidence

[19]

Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). Journal of thrombosis and haemostasis : JTH. 2006 Feb:4(2):295-306     [PubMed PMID: 16420554]

Level 3 (low-level) evidence

[20]

Wahl DG, Bounameaux H, de Moerloose P, Sarasin FP. Prophylactic antithrombotic therapy for patients with systemic lupus erythematosus with or without antiphospholipid antibodies: do the benefits outweigh the risks? A decision analysis. Archives of internal medicine. 2000 Jul 10:160(13):2042-8     [PubMed PMID: 10888978]


[21]

Garcia DA, Khamashta MA, Crowther MA. How we diagnose and treat thrombotic manifestations of the antiphospholipid syndrome: a case-based review. Blood. 2007 Nov 1:110(9):3122-7     [PubMed PMID: 17644740]

Level 3 (low-level) evidence

[22]

Yelnik CM, Lambert M, Drumez E, Le Guern V, Bacri JL, Guerra MM, Laskin CA, Branch DW, Sammaritano LR, Morel N, Guettrot-Imbert G, Launay D, Hachulla E, Hatron PY, Salmon JE, Costedoat-Chalumeau N. Bleeding complications and antithrombotic treatment in 264 pregnancies in antiphospholipid syndrome. Lupus. 2018 Sep:27(10):1679-1686. doi: 10.1177/0961203318787032. Epub 2018 Jul 17     [PubMed PMID: 30016929]


[23]

Erkan D, Yazici Y, Sobel R, Lockshin MD. Primary antiphospholipid syndrome: functional outcome after 10 years. The Journal of rheumatology. 2000 Dec:27(12):2817-21     [PubMed PMID: 11128669]

Level 2 (mid-level) evidence