Antiphospholipid Syndrome (Antiphospholipid Antibody Syndrome, APS, APLS)

Article Author:
Jean Bustamante
Article Author:
Amandeep Goyal
Article Author:
Pankaj Bansal
Article Editor:
Mayank Singhal
Updated:
5/12/2020 11:16:21 PM
PubMed Link:
Antiphospholipid Syndrome (Antiphospholipid Antibody Syndrome, APS, APLS)

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

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 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.

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

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 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 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.

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.


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