How does antiphospholipid syndrome typically present in adults, what is the typical age of symptom onset, and what causes it?

Antiphospholipid Syndrome: Clinical Presentation, Age of Onset, and Etiology

Clinical Presentation

Antiphospholipid syndrome (APS) most commonly presents with venous thrombosis (particularly deep vein thrombosis and pulmonary embolism), arterial thrombosis (especially cerebral artery thrombosis/stroke), and recurrent pregnancy loss, occurring in patients with persistently positive antiphospholipid antibodies. 1, 2

Thrombotic Manifestations

• Deep venous thromboses, pulmonary embolism, and cerebral arterial thrombosis are the most frequent events, each occurring in approximately one-third of patients 2
• Venous thrombosis is more common than arterial thrombosis overall 1, 3
• Thrombosis can affect any vascular bed, including unusual sites such as hepatic veins, renal vessels, and retinal vessels 3
• Microvascular thrombosis can occur, leading to multi-organ involvement 1

Obstetric Manifestations

• Recurrent spontaneous abortions (≥3 consecutive losses before 10 weeks gestation) occur in approximately 10% of women with antiphospholipid antibodies 4, 2
• Unexplained fetal death at ≥10 weeks gestation 4
• Premature delivery before 34 weeks due to preeclampsia or placental insufficiency with fetal growth restriction 4
• Placental vessel thrombosis is considered the underlying mechanism 2

Hematologic Manifestations

• Thrombocytopenia (variable degree) is reported in approximately 20-25% of patients 2
• Coombs-positive hemolytic anemia can occur 1

Other Clinical Features

• Skin manifestations: livedo reticularis, skin necrosis, cutaneous ulcerations 1, 5, 2
• Cardiac: heart valve disease (particularly mitral and aortic valve thickening or vegetations) 1
• Renal: renal microangiopathy 1
• Neurologic: dementia, other neuropsychiatric events, transverse myelitis 1, 2
• Catastrophic APS (CAPS): rare presentation with excessive thrombosis at multiple sites, usually affecting small vessels, leading to multi-organ dysfunction and organ failure 1, 2

Age of Symptom Onset

APS predominantly affects young adults, with 50% of patients presenting before age 40 years and the strongest thrombotic associations occurring in patients under 50 years of age. 4, 2

Age Distribution

• Mean and median age at presentation is approximately 41 years (range 29-75 years) based on cerebral venous thrombosis cases 6
• Young adults under 50 years have the strongest association between antiphospholipid antibodies and thrombotic events, particularly stroke, with 9.7% of ischemic stroke patients having demonstrable anticardiolipin antibodies compared to 4.3% of controls 4
• 50% of patients enrolled in the Italian Registry were aged less than 40 years 2
• APS can occur at any age, with cases reported in children and adolescents (recurrent deep vein thrombosis, pulmonary emboli) as well as in patients over 60 years 4

Gender Distribution

• Slight female predominance in most series, though some studies show male predominance (54%) in specific thrombotic presentations 6
• Female predominance is more pronounced in obstetric APS by definition 3

Etiology and Pathogenesis

APS is an autoimmune-mediated acquired thrombophilia caused by autoantibodies directed against phospholipid-binding plasma proteins, particularly beta-2-glycoprotein I (β2GPI), though the exact trigger for autoantibody production remains unknown. 1, 3

Autoimmune Mechanism

• Antiphospholipid antibodies (aPL) are directed against phospholipid-binding plasma proteins, such as β2-glycoprotein I, rather than phospholipids themselves 1
• The antibodies include lupus anticoagulant (LA), anti-cardiolipin antibodies, and anti-β2-glycoprotein I antibodies 1
• "Triple positivity" (positive for all three antibody types) indicates the highest thrombotic risk 7

Classification by Association

• Primary APS: occurs in the absence of any underlying disease (approximately 50% of cases) 3, 2
• Secondary APS: associated with other autoimmune disorders, most commonly systemic lupus erythematosus (SLE), or other autoimmune, neoplastic, or pathological conditions 1, 3, 2
• SLE is the most significant associated condition, with higher aPL antibody prevalence in lupus patients 4

Genetic and Environmental Factors

• Inherited thrombophilias (Factor V Leiden, prothrombin G20210A mutation, MTHFR C677T polymorphism) increase risk, with stronger associations in young patients (<55 years) 4
• Family history of thrombotic events is a key risk factor 4
• Stress has been suggested as an important risk factor for disease onset at all ages 6
• The exact environmental trigger for autoantibody production remains unknown 3

Pathophysiologic Mechanisms

• Complex interactions between aPL, phospholipid-binding proteins, and the coagulation cascade lead to a prothrombotic state 8
• Different, not mutually exclusive models have been proposed, but the exact pathogenetic mechanism remains incompletely understood 3
• Both thrombotic and inflammatory/autoimmune mechanisms contribute to clinical manifestations, explaining why some features do not respond to anticoagulation alone 5