Antiphospholipid Syndrome¶
Chapter 369 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders
KEY CLINICAL POINTS¶
- APS is an autoimmune thrombophilia characterized by recurrent thrombosis, pregnancy morbidity, and microvascular lesions.
- Diagnosis requires meeting ACR/EULAR criteria: ≥ 3 clinical points + ≥ 3 laboratory points (LA, aCL, anti- β GPI).
- Thrombosis occurs in venous (deep vein thrombosis, pulmonary embolism) and arterial (stroke, myocardial infarction) systems.
- Pregnancy complications include recurrent miscarriage, preeclampsia, and placental insufficiency.
- CAPS is a rare, life-threatening form with multi-organ thrombosis and rapid progression.
1. DEFINITION & OVERVIEW¶
Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by recurrent arterial/venous thrombosis, pregnancy morbidity, and/or microvascular lesions. It primarily affects young women and may occur alone (primary APS) or with autoimmune diseases like SLE (secondary APS). Catastrophic APS (CAPS) is a severe, rapidly progressive form involving thrombosis in ≥ 3 organs.
Table 369-1: Clinical Features of Antiphospholipid Syndrome¶
| MANIFESTATION | % |
|---|---|
| Deep-vein thrombosis | 39 |
| Livedo reticularis | 24 |
| Pulmonary embolism | 14 |
| Superficial thrombophlebitis | 12 |
| Thrombosis in various other sites | 11 |
| Stroke | 20 |
| Cardiac valve thickening/dysfunction and/or Libman-Sacks vegetations | 14 |
| Transient ischemic attack | 11 |
| Myocardial ischemia (infarction or angina) and coronary bypass graft thrombosis | 10 |
| Leg ulcers and/or digital gangrene | 9 |
| Retinal artery thrombosis/amaurosis fugax | 7 |
| Ischemia of visceral organs or avascular necrosis of bone | 6 |
| Multi-infarct dementia | 3 |
| MANIFESTATION | % |
|---|---|
| Migraine | 20 |
| Epilepsy | 7 |
| Chorea | 1 |
| Cerebellar ataxia | 1 |
| Transverse myelopathy | 0.5 |
| Renal Manifestations Due to Various Reasons | 3 |
| Arthralgias | 39 |
| Arthritis | 27 |
| Preeclampsia | 10 |
| Eclampsia | 4 |
| Early fetal loss (<10 weeks) | 35 |
| Late fetal loss (‡10 weeks) | 17 |
| Premature birth among live births | 11 |
| Thrombocytopenia | 30 |
| Autoimmune hemolytic anemia | 10 |
Table 369-2: 2023 ACR/EULAR Classification Criteria for APS¶
| DOMAINS/CRITERIA | POINTS |
|---|---|
| Venous thromboembolism (VTE) | 1 |
| (cid:127) With high-risk VTE profile | 3 |
| (cid:127) Without a high-risk VTE profile | 2 |
| Microvascular events | 5 |
| (cid:127) Livedo racemosa (exam) | 2 |
| (cid:127) Livedoid vasculopathy lesions (exam) | 2 |
| (cid:127) Acute/chronic aPL-nephropathy (exam or lab) | 2 |
| (cid:127) Pulmonary hemorrhage (symptoms and imaging) | 2 |
| Established (any of below) | 5 |
| (cid:127) Livedoid vasculopathy (pathology) | 2 |
| (cid:127) Acute/chronic aPL-nephropathy (pathology) | 2 |
| (cid:127) Pulmonary hemorrhage (BAL or pathology) | 2 |
| (cid:127) Myocardial disease (imaging or pathology) | 2 |
| (cid:127) Adrenal hemorrhage (imaging or pathology) | 2 |
| Cardiac valve disease | 4 |
| (cid:127) Thickening | 2 |
| (cid:127) Vegetation | 4 |
| Arterial thrombosis | 4 |
| (cid:127) With high-risk CVD profile | 2 |
| DOMAINS/CRITERIA | POINTS |
|---|---|
| (cid:127) Without high-risk CVD profile | 4 |
| Obstetric complications | 4 |
| (cid:127) >3 consecutive prefetal (<10 w) and/or early fetal deaths (10w0d–15w6d) | 1 |
| (cid:127) Fetal death (16w0d–33w6d) in absence of preeclampsia (PEC) with severe features or placental insufficiency (PI) with severe features | 1 |
| (cid:127) PEC with severe features (<34w0d) or PI with severe features (<34w0d) with/without fetal death | 3 |
| (cid:127) PEC with severe features (<34w0d) and PI with severe features (<34w0d) with/without fetal death | 4 |
| Hematologic manifestations | 2 |
| (cid:127) Thrombocytopenia (otherwise unexplained lowest platelet count ever between 20 and 130 × 109/L) | 2 |
| Lupus anticoagulant (LA) test | 5 |
| (cid:127) One time positive | 1 |
| (cid:127) Persistent | 5 |
| Anticardiolipin (aCL) and/or anti-bGPI antibodies (persistent) | 7 |
| (cid:127) Moderate (40–79 units) or high (‡80 units) IgM aCL and/or anti-bGPI | 1 |
| (cid:127) Moderate (40–79 units) IgG aCL and/or anti-bGPI | 4 |
| (cid:127) High (‡80 units) positive IgG aCL or anti-bGPI | 5 |
| (cid:127) High (‡80 units) IgG aCL and anti-bGPI | 7 |
1.1 Autoantibodies¶
Key autoantibodies include lupus anticoagulant (LA), anticardiolipin (aCL), and anti- β 2-glycoprotein I (anti- β GPI). LA prolongs clotting time in vitro and is not corrected by normal plasma. Anti- β GPI antibodies are associated with increased thrombotic risk.
1.2 Pathophysiology¶
APS involves endothelial injury from infections, oxidative stress, or trauma in a genetic background. aPL antibodies bind to endothelial cells, activating monocytes/platelets, complement, and neutrophils. Type I/III interferon imbalance and NET formation contribute to thrombosis.
2. EPIDEMIOLOGY¶
APS incidence is 1–2 per 100,000/year; prevalence is 40–50 per 100,000. APL antibodies occur in 1–5% of the general population, increasing with age. 1/3 of SLE patients have these antibodies, with 10–15% developing APS. CAPS is rare but life-threatening.
2.1 Risk Factors¶
Genetic predisposition (HLA alleles), infections, oxidative stress, trauma, and autoimmune diseases (especially SLE).
2.2 Demographics¶
Primarily affects young women. APL antibodies in elderly may not induce thrombosis.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
APS arises from endothelial injury (infections, trauma, surgery) in a genetic background. aPL antibodies bind to endothelial cells, activating monocytes/platelets, complement, and neutrophils. Type I/III interferon imbalance and NET formation contribute to thrombosis.
3.1 Molecular Mechanisms¶
β 2-glycoprotein I ( β GPI) is a key target. Anti- β GPI antibodies increase thrombotic risk. LA prolongs clotting time in vitro.
4. CLINICAL FEATURES¶
Venous thrombosis (DVT, PE), arterial thrombosis (stroke, MI), microvascular lesions (livedo reticularis, aPL-nephropathy), pregnancy complications (miscarriage, preeclampsia), and cardiac valve abnormalities.
4.1 Thrombosis Types¶
Venous: DVT, PE, Budd-Chiari syndrome. Arterial: Stroke, TIA, peripheral artery occlusion. Microvascular: Livedo patterns, aPL-nephropathy.
4.2 Pregnancy Morbidity¶
Recurrent miscarriage, preeclampsia, eclampsia, placental insufficiency, and intrauterine growth restriction.
5. DIFFERENTIAL DIAGNOSIS¶
Exclude inherited thrombophilia (Chap. 121), Coombs-positive hemolytic anemia (Chap. 105), and thrombocytopenia (Chap. 120). Consider vasculitis (e.g., polyarteritis nodosa), SLE, and malignancies.
6. INVESTIGATIONS & DIAGNOSIS¶
Measure aCL, anti- β GPI, and LA. LA testing involves aPTT, DRVVT, mixing studies, and confirmation. Anti- β GPI and aCL are measured by ELISA. CAPS requires rapid diagnosis due to severity.
6.1 Diagnostic Criteria¶
ACR/EULAR criteria: ≥ 3 clinical points + ≥ 3 laboratory points (LA, aCL, anti- β GPI). Exclude other causes of thrombophilia.
7. MANAGEMENT & TREATMENT¶
Anticoagulation with heparin, warfarin, or LMWH. Low-dose aspirin for low-risk patients. Heparin for acute thrombosis. Pregnancy management includes LMWH and close monitoring. CAPS requires aggressive anticoagulation and immunosuppression.
7.1 Anticoagulation¶
Warfarin (INR 2–3) or LMWH for long-term. Heparin for acute thrombosis. Avoid NSAIDs in patients with renal impairment.
8. PROGNOSIS & COMPLICATIONS¶
APS is associated with recurrent thrombosis, pregnancy loss, and organ damage. CAPS has high mortality without treatment. Long-term complications include stroke, pulmonary hypertension, and renal failure.
8.1 Complications¶
Thrombotic events, obstetric morbidity, cardiac valve disease, and renal failure. CAPS is a medical emergency requiring immediate intervention.
9. SPECIAL CONSIDERATIONS¶
Pregnancy requires LMWH and close monitoring. SLE patients with APS need tailored anticoagulation. Elderly patients may have APL antibodies without thrombosis. CAPS requires multidisciplinary management.
10. KEY POINTS & CLINICAL PEARLS¶
- APS is diagnosed using ACR/EULAR criteria with clinical and laboratory evidence.
- Anticoagulation is the cornerstone of management.
- CAPS is a life-threatening condition requiring immediate treatment.
- Pregnancy complications are a key feature in women with APS.
- APL antibodies increase thrombotic risk, especially in SLE patients.