Antiphospholipid Syndrome (APS)

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 a 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 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%. [rx] 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.[rx] Severe thrombocytopenia leading to hemorrhage is rare. A 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 (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.[rx]

Preliminary criteria for the classification of CAPS were published in 2003. [rx] 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.

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 antibodies. 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. [rx]

Lupus Anticoagulant Test

The lupus anticoagulant test is the strongest predictor of 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 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

The most common blood tests used to detect antiphospholipid antibodies are anticardiolipin antibody immunoassays (which, despite the name, detect mainly antibodies to beta-2-glycoprotein I), anti-beta-2-glycoprotein antibody immunoassays, and lupus anticoagulant tests (coagulation assays that detect subsets of anti-beta-2-glycoprotein I antibodies and anti-prothrombin antibodies). Positive tests should be repeated because antiphospholipid antibodies can be present in short intervals (transiently) due to other reasons such as infection or drug use. Borderline negative tests may need to be repeated because individuals with APS have initially tested negative for the antiphospholipid antibodies.

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 to 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 were updated in 2006. [rx] 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