What are the signs and symptoms of anti-phospholipid antibody syndrome (APS)?

Signs and Symptoms of Antiphospholipid Antibody Syndrome

Antiphospholipid antibody syndrome (APS) presents with two major clinical categories: thrombotic manifestations (venous or arterial) and pregnancy-related complications, often accompanied by characteristic non-thrombotic features including thrombocytopenia, livedo reticularis, and cardiac valve abnormalities. 1

Thrombotic Manifestations

Venous Thrombosis

• Deep vein thrombosis (DVT) is the most common venous manifestation 2
• Pulmonary embolism occurs as a consequence of venous thromboembolism 2
• Cerebral venous thrombosis represents thrombosis at unusual sites 2
• Venous thrombosis is more strongly associated with high triglycerides, hereditary thrombophilia, and anticardiolipin IgG >40 GPL 3

Arterial Thrombosis

• Stroke is the predominant arterial manifestation, particularly in patients under 50 years of age 2
• Myocardial infarction can occur as part of the arterial thrombotic spectrum 2
• Arterial thrombosis is strongly associated with hypertension and elevated homocysteine levels 3
• The association between antiphospholipid antibodies and stroke is strongest for young adults (<50 years of age) 2

Pregnancy-Related Manifestations

Early Pregnancy Complications

• Recurrent early pregnancy loss: three or more consecutive losses prior to 10 weeks' gestation 2
• Recurrent pregnancy loss occurs in approximately 20% of women with antiphospholipid antibodies 4

Late Pregnancy Complications

• Fetal loss: one or more unexplained deaths of morphologically normal fetuses at or after 10 weeks' gestation 2
• Preterm delivery before 34 weeks due to severe preeclampsia, eclampsia, or placental insufficiency 2
• Intrauterine growth restriction (IUGR): occurs in 18-21% of pregnancies with APS 5
• Preeclampsia: occurs in 10-20% of APS pregnancies 5
• HELLP syndrome/eclampsia: rates approximate 1.0-5.0% depending on whether APS is primary or SLE-related 5

Non-Thrombotic Clinical Features

Hematologic Manifestations

• Thrombocytopenia is a common finding in APS 1, 6
• Autoimmune hemolytic anemia can occur 6

Dermatologic Manifestations

• Livedo reticularis: a characteristic mottled, net-like pattern on the skin 1, 6
• Cutaneous ulcerations may develop 6

Cardiac Manifestations

• Valvular heart disease: cardiac valve abnormalities are associated features 1, 6

Renal Manifestations

• Nephropathy: kidney involvement can occur as part of the syndrome 6

Neurological Manifestations

• Transient ischemic attacks (TIA) are part of the cerebrovascular spectrum 2
• Neurological manifestations beyond stroke can occur 1

Catastrophic Antiphospholipid Syndrome

Catastrophic APS is a rare but life-threatening variant characterized by:

• Multi-organ thrombosis occurring over a short period (days to weeks) 1
• Venous and arterial occlusive disease in multiple organs 2
• This represents the most severe form of APS requiring aggressive treatment 1

Risk Stratification by Antibody Profile

High-Risk Profiles

• Triple positivity (positive lupus anticoagulant, anticardiolipin antibodies, and anti-β2 glycoprotein-I antibodies) indicates the highest risk for thrombotic events 2, 1
• Triple-positive patients show the strongest association with both thrombotic and obstetric APS 2
• Lupus anticoagulant positivity, independent of other antibodies, is the main predictor for thrombotic events and adverse pregnancy outcomes 2

Moderate-Risk Profiles

• Double positivity (two of the three antibody types positive) indicates intermediate risk 2

Lower-Risk Profiles

• Single positivity (only one antibody type positive) is less likely to develop APS-related events 2

Associated Conditions

• Systemic lupus erythematosus (SLE): 37% of women with SLE have antiphospholipid antibodies 4
• The frequency of thrombosis and pregnancy loss is greater in APS associated with SLE than in primary APS 3
• APS can occur as a primary condition or secondary to other autoimmune diseases 1

Key Clinical Pitfalls

• Age matters: The association between antiphospholipid antibodies and clinical events is strongest in patients under 50-55 years of age 2
• Not all antibody-positive patients develop symptoms: In most series, only a minority of patients with antiphospholipid antibodies develop clinical manifestations 3
• Antibody titers matter: Medium to high titers (≥40 units or ≥99th percentile) are required for diagnosis, as lower titers have uncertain clinical significance 2
• Persistence is required: Antibodies must be detected on two separate occasions at least 12 weeks apart to meet diagnostic criteria 2, 1
• Multiple mechanisms: The pathophysiology includes decreased prostacyclin formation, increased thromboxane production, decreased protein C activation, and inhibition of fibrinolysis 4