Antiphospholipid Syndrome¶
Chapter 369 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 369
Key Clinical Points¶
- APS is an autoantibody-mediated acquired thrombophilia characterized by arterial/venous thrombosis, microvascular manifestations, and/or pregnancy morbidity.
- Diagnosis requires ≥3 points from clinical domains and ≥3 points from laboratory domains (2023 ACR/EULAR criteria).
- Key antibodies include β-glycoprotein I (βGPI), lupus anticoagulant (LA), and anticardiolipin (aCL).
- Catastrophic APS (CAPS) is a rare, life-threatening condition involving simultaneous thrombosis in ≥3 organs.
- Livedo reticularis is a common microvascular manifestation; Libman-Sacks endocarditis involves small (<1 cm) valve vegetations.
- Pregnancy morbidity includes preeclampsia, eclampsia, and various fetal losses (early/late).
- Approximately 1/3 of SLE patients have aPL antibodies, with 10–15% developing APS.
- Pathophysiology involves endothelial injury, pro-inflammatory states, and type I interferon pathway activation.
- Management centers on anticoagulation for both treatment and prevention.
- Antiphosphatidylserine/prothrombin testing is useful when clinical features are present but aPL antibodies are absent.
DEFINITION & CLASSIFICATION¶
• Definition (Harrison's 22e): antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or venous thrombosis, microvascular manifestations, and/or pregnancy morbidity. • Target Population: Primarily affects young females. • Primary vs. Secondary: Can occur alone (primary) or with other autoimmune diseases, most commonly systemic lupus erythematosus (SLE). • Catastrophic APS (CAPS): • Rare, life-threatening, rapidly progressive thromboembolic disease. • Involves simultaneous thrombosis in ≥3 organs.
EPIDEMIOLOGY¶
• Incidence: 1–2 cases per 100,000 persons per year. • Prevalence: 40–50 per 100,000 in the general population. • aPL Antibodies: Present in 1–5% of the general population; prevalence increases with age (though ability to cause thrombosis in elderly is uncertain). • SLE Association: 1/3 of patients with SLE possess aPL antibodies → 10–15% of these patients develop APS.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Initiating Events: Endothelial injury from infections, oxidative stress, or physical stress (surgery/trauma) on a genetic background (HLA locus). • Mechanism of Injury: • Endothelial cell apoptosis → autoantigen presentation → autoimmune response. • Binding of aPL to damaged cells → pro-inflammatory and pro-thrombotic state. • Cellular Activation: Involves monocytes, platelets, adhesion molecules, proinflammatory cytokines, complement, neutrophils, and neutrophil extracellular trap (NET) formation. • Immune Signaling: Type I interferon pathway activation and imbalance between type I and III interferons are linked to thrombosis and obstetric complications.
CLINICAL FEATURES¶
• Venous Thrombosis & Skin (Table 1): • Deep-vein thrombosis: 39% • Livedo reticularis: 24% • Pulmonary embolism: 14% • Superficial thrombophlebitis: 12% • Other sites: 11% • Arterial Thrombosis & Cardiac: • Stroke: 20% • Cardiac valve thickening/dysfunction or Libman-Sacks vegetations: 14% • Transient ischemic attack (TIA): 11% • Myocardial ischemia/coronary bypass thrombosis: 10% • Retinal artery thrombosis/amaurosis fugax: 7% • Neurologic Manifestations: • Migraine: 20% • Epilepsy: 7% • Chorea: 1% • Microvascular & Renal (Table 4): • Livedo reticularis (mottled, lace-like pattern) and Livedo racemosa (broken/asymmetric). • Livedoid vasculopathy (painful papules or lower limb ulcers). • aPL-nephropathy: Hypertension, proteinuria, hematuria, and renal insufficiency. • Renal Artery/Vein/Glomerular Thrombosis & Fibrous Intima Hyperplasia: 3%. • Obstetric & Fetal (Tables 5 & 6): • Preeclampsia: 10% • Eclampsia: 4% • Early fetal loss (<10 weeks): 35% • Late fetal loss (≥10 weeks): 17% • Premature birth (live births): 11% • Hematologic & Musculoskeletal (Tables 7 & 8): • Thrombocytopenia: 30% • Autoimmune hemolytic anemia: 10% • Arthralgias: 39% • Arthritis: 27%.
DIFFERENTIAL DIAGNOSIS¶
• Exclusion Criteria: Must exclude other inherited or acquired causes of thrombophilia, Coombs-positive hemolytic anemia, and thrombocytopenia. • Livedo Reticularis Differentials: May also indicate disorders affecting the vascular wall (e.g., atherosclerosis, polyarteritis nodosa, SLE, cryoglobulinemia, lymphomas) or the vascular lumen.
DIAGNOSTIC APPROACH¶
- Initial Clinical Suspicion: Consider APS in cases of thrombosis, cerebral vascular accidents in individuals <55 years of age, pregnancy morbidity, livedo reticularis, or thrombocytopenia.
- Laboratory Testing: Measure aPL antibodies (LA, aCL, and anti-βGPI).
- Classification (2023 ACR/EULAR Criteria): Diagnosis requires ≥3 points from clinical domains AND ≥3 points from laboratory domains. • Clinical Domains (Table 3): • Venous thromboembolism (VTE) (1-3 pts) • Microvascular events (2-5 pts) • Cardiac valve disease (2-4 pts) • Arterial thrombosis (2-4 pts) • Obstetric complications (1-4 pts) • Hematologic manifestations (2 pts) • Laboratory Domains (Table 3): • Lupus anticoagulant (LA) test: One time positive (1); Persistent (5). • Anticardiolipin (aCL) and/or anti-βGPI antibodies (persistent):
- Moderate (49–70 units) IgG aCL and/or anti-β2GPI (4 pts)
- High (>70) IgG aCL and/or (5 pts)
- High (80–100) IgG aCL and anti-β2GPI (7 pts)
- Low (10–49) units IgG aCL and/or (3 pts).
MANAGEMENT & TREATMENT¶
- Anticoagulation: Primary treatment for thrombosis prevention and management.
- Monitoring: • LA test positivity must be interpreted with caution in patients currently receiving anticoagulation.
- Alternative Testing: If clinical features are highly suggestive of APS but classical aPL antibodies are absent, test for antiphosphatidylserine/prothrombin antibodies.
COMPLICATIONS & PROGNOSIS¶
• Catastrophic APS (CAPS): Rapidly progressive, life-threatening multi-organ involvement. • Recurrent Thrombosis: Major complication of the disease. • Pregnancy Morbidity: Includes fetal death, preeclampsia, eclampsia, and placental insufficiency with growth restriction or infarction.
SPECIAL POPULATIONS¶
• Pregnancy: High risk for preeclampsia, eclampsia, and various fetal losses (early/late) and premature birth. • Elderly: It is unclear if aPL antibodies are capable of inducing thrombotic events in this population. • SLE Patients: 1/3 have aPL; 10–15% develop full APS.
KEY PEARLS & HIGH-YIELD POINTS¶
• Target Population: Primarily young females. • Clinical Rule: Manifestations with other equally or more likely explanations will not count toward ACR/EULAR classification. • Libman-Sacks Endocarditis: Characterized by small (<1 cm) valve vegetations (Figure 1). • Microvascular Markers: Livedo reticularis and aPL-nephropathy are key indicators. • Hematology: Thrombocytopenia and autoimmune hemolytic anemia are primary hematologic findings.
Reference Tables¶
TABLE 369-1 Clinical Features of Antiphospholipid Syndrome MANIFESTATION Venous Thrombosis and Skin Manifestations…¶
Harrison's 22e, p.2838
| MANIFESTATION | % |
|---|---|
| Venous Thrombosis and Skin Manifestations | |
| Deep-vein thrombosis Livedo reticularis Pulmonary embolism Superficial thrombophlebitis Thrombosis in various other sites |
39 24 14 12 11 |
| Arterial Thrombosis and Cardiac Manifestations |
TABLE 369-2 2023 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR)…¶
Harrison's 22e, p.2838
| Clinical Domains | |
|---|---|
| DOMAINS/CRITERIA | POINTS |
| Venous thromboembolism (VTE) • With high-risk VTE profile • Without a high-risk VTE profile Microvascular events Suspected (any of below) • Livedo racemosa (exam) • Livedoid vasculopathy lesions (exam) • Acute/chronic aPL-nephropathy (exam or lab) • Pulmonary hemorrhage (symptoms and imaging) Established (any of below) • Livedoid vasculopathy (pathology) • Acute/chronic aPL-nephropathy (pathology) • Pulmonary hemorrhage (BAL or pathology) • Myocardial disease (imaging or pathology) • Adrenal hemorrhage (imaging or pathology) Cardiac valve disease • Thickening • Vegetation Arterial thrombosis • With high-risk CVD profile • Without high-risk CVD profile Obstetric complications • >3 consecutive prefetal (<10 w) and/or early fetal deaths (10w0d–15w6d) • Fetal death (16w0d–33w6d) in the absence of preeclampsia (PEC) with severe features or placental insufficiency (PI) with severe features • PEC with severe features (<34w0d) or PI with severe features (<34w0d) with/without fetal death • PEC with severe features (<34w0d) and PI with severe features (<34w0d) with/without fetal death Hematologic manifestations • Thrombocytopenia (otherwise unexplained lowest platelet count ever between 20 and 130 × 109/L) |
1 3 2 5 2 4 2 4 1 1 3 4 2 |
| Laboratory Domains (aPL) | |
| DOMAINS/CRITERIA | POINTS |
| Lupus anticoagulant (LA) test • One time positive • Persistent Anticardiolipin (aCL) and/or anti-βGPI antibodies (persistent) 2 • Moderate (40–79 units) or high (≥80 units) IgM aCL and/or anti-βGPI 2 • Moderate (40–79 units) IgG aCL and/or anti-βGPI 2 • High (≥80 units) positive IgG aCL or anti-βGPI 2 • High (≥80 units) IgG aCL and anti-βGPI 2 |
1 5 1 4 5 7 |
| Neurologic Manifestations of Uncertain Etiology | |
| Migraine Epilepsy Chorea Cerebellar ataxia Transverse myelopathy |
20 7 1 1 0.5 |
| Renal Manifestations Due to Various Reasons (Renal Artery/Renal Vein/Glomerular Thrombosis, Fibrous Intima Hyperplasia) |
3 |
| Musculoskeletal Manifestations | |
| Obstetric Manifestations (Referred to the Number of Pregnancies) | |
| Preeclampsia Eclampsia |
10 4 |
| Fetal Manifestations (Referred to the Number of Pregnancies) | |
| Hematologic Manifestations | |
| Thrombocytopenia Autoimmune hemolytic anemia |
30 10 |