Chapter 369: Antiphospholipid Syndrome¶
Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology
Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition
🔑 Key Clinical Points¶
- APS is an autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or venous thrombosis, microvascular manifestations, and/or pregnancy morbidity.
- Incidence is estimated at 1–2 cases per 100,000 persons per year; prevalence in general population is 40–50 per 100,000.
- Major autoantibodies are directed against phospholipid-binding plasma proteins such as β-glycoprotein I (βGPI) and prothrombin.
- Diagnosis requires at least 3 points from clinical domains and 3 points from laboratory domains according to 2023 ACR/EULAR criteria.
- Lupus anticoagulant (LA) testing includes a three-step procedure: screening (aPTT/DRVVT), mixing study, and confirmation.
- Catastrophic APS (CAPS) is a rare, life-threatening, rapidly progressive thromboembolic disease involving simultaneously three or more organs.
- Differential diagnosis is based on the exclusion of other inherited or acquired causes of thrombophilia and other causes of thrombosis.
- Clinical manifestations with other equally or more likely explanations than APS will not be counted for classification.
📑 Table of Contents¶
- 1. DEFINITION & OVERVIEW
- 1.1 Autoantibodies
- 2. EPIDEMIOLOGY
- 3. ETIOLOGY & PATHOPHYSIOLOGY
- 4. CLINICAL FEATURES
- 4.1 Venous Thrombosis and Skin Manifestations
- 4.2 Arterial Thrombosis and Cardiac Manifestations
- 4.3 Neurologic Manifestations
- 4.4 Renal Manifestations
- 4.5 Obstetric Manifestations
- 4.6 Fetal Manifestations
- 4.7 Hematologic Manifestations
- 4.8 Musculoskeletal Manifestations
- 5. DIFFERENTIAL DIAGNOSIS
- 6. INVESTIGATIONS & DIAGNOSIS
- 6.1 Laboratory Domains (aPL)
- 7. MANAGEMENT & TREATMENT
- 8. PROGNOSIS & COMPLICATIONS
- 9. SPECIAL CONSIDERATIONS
- 10. KEY PEARLS & CLINICAL TRAPS
- Figures & Illustrations
📋 Figures in This Chapter¶
| # | Type | Description |
|---|---|---|
| 1 | 🖼 Figure | Figure / Illustration |
1. DEFINITION & OVERVIEW¶
Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or venous thrombosis, microvascular manifestations, and/or pregnancy morbidity. It affects primarily young females. APS may occur alone (primary) or in association with other autoimmune diseases, mainly systemic lupus erythematosus (SLE). Catastrophic APS (CAPS) is a rare, life-threatening, rapidly progressive thromboembolic disease involving simultaneously three or more organs.
1.1 Autoantibodies¶
The major autoantibodies detected in APS patients are directed against phospholipid-binding plasma proteins such as β-glycoprotein I (βGPI) and prothrombin. The plasma protein βGPI is a 43-kDa plasma apolipoprotein, which consists of 326 amino acids arranged in five domains (I through V). The presence of anti–domain I IgG antibodies has been associated with increased thrombotic risk. Recent evidence from animal studies has shown that the antithrombotic function of βGPI is dependent on its fifth domain (domain V). Another group of antibodies against phospholipid-binding proteins, termed lupus anticoagulant (LA), prolongs clotting time in vitro, which is not corrected by adding normal plasma. Anticardiolipin and anti–βGPI IgG/IgM antibodies are measured by standardized enzyme-linked immunosorbent assays (ELISA); βGPI in combination with cardiolipin or βGPI in the absence of cardiolipin serve as target antigens, respectively. LA testing includes a three-step procedure: (1) screening including testing with activated partial thromboplastin time (aPTT) and dilute Russel viper venom test (DRVVT); (2) mixing study; and (3) confirmation. In patients receiving anticoagulation treatment, LA test positivity should be interpreted with caution. In patients with features highly reminiscent of APS in the absence of classical antiphospholipid antibodies (aPL), testing for antiphosphatidylserine/prothrombin antibodies may have a valuable diagnostic role.
2. EPIDEMIOLOGY¶
The incidence of APS is estimated to be 1–2 cases per 100,000 persons per year. The prevalence of APS in the general population is estimated to be 40–50 per 100,000. APL antibodies occur in 1–5% of the general population. Their prevalence increases with age; however, it is questionable whether they are able to induce thrombotic events in elderly individuals. Moreover, one-third of patients with SLE (Chap. 368) possess these antibodies and 10–15% of them develop APS.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
The initiating events for the induction of antibodies to phospholipid-binding proteins seem to be endothelial injury induced by infections, oxidative stress, and major physical stresses such as surgery or trauma in an appropriate genetic background, given the previously demonstrated associations with alleles within the human leukocyte antigen (HLA) locus. These contributors seem to induce increased apoptosis of the vessel endothelial cells, autoantigen presentation, and subsequent initiation of autoimmune response. The binding of aPL to the disrupted endothelial cells leads to a proinflammatory and prothrombotic state involving monocytes and platelets activation, adhesion molecules and proinflammatory cytokines production, complement and neutrophil activation, neutrophil extracellular trap (NET) formation, and thrombus formation. Recently, type I interferon pathway activation and an imbalance between type I and III interferons have been proposed as potential mechanisms of thrombotic events and APS-related obstetric complications.
4. CLINICAL FEATURES¶
Clinical manifestations include venous or arterial thrombosis, microvascular events, and/or pregnancy morbidity. Deep venous thrombosis occurs primarily in the lower extremities and often causes pulmonary emboli. Thrombosis of the pulmonary arteries leads to pulmonary hypertension and thrombosis of hepatic veins to Budd-Chiari syndrome. Cerebral venous thrombosis presents with signs and symptoms of intracranial hypertension and focal neurologic deficits. Other venous thrombosis manifestations include retinal vein thrombosis and renal, mesenteric, or splanchnic vein thrombosis. Arterial thrombosis affects more commonly the arteries of the brain and is manifested as transient ischemic attack, stroke, migraines, or cognitive dysfunction. Peripheral artery thrombosis presents with acute limb ischemia, ischemic leg ulcers, or digital gangrene. Thrombosis of other arteries leads to myocardial infarction, retinal artery occlusion, renal artery stenosis, and infarcts of spleen, liver, and adrenals. Microvascular manifestations include livedo reticularis, which consists of a mottled reticular vascular pattern that appears as a lace-like, purplish discoloration of the skin; livedo racemosa, characterized by a broken, irregular, and asymmetric pattern; and livedoid vasculopathy, which presents with painful papules or lower limb ulcers. Another microvascular feature of APS is the so-called aPL-nephropathy, manifested with hypertension, proteinuria (mild to nephrotic range), hematuria, and mild renal insufficiency. Histologically, the acute phase is characterized by thrombotic microangiopathy lesions in the glomerular capillaries and/or arterioles. In a chronic phase, fibrous intima hyperplasia, fibrous and/or fibrocellular arteriolar occlusions, and focal cortical atrophy are present. Additional rare microvascular manifestations are pulmonary hemorrhage, myocardial disease confirmed by magnetic resonance imaging or histologically, and adrenal hemorrhage. Cardiac valve manifestations include valve thickening or vegetations. Libman-Sacks endocarditis consists of small (usually <1 cm) valve vegetations, histologically characterized by organized platelet-fibrin microthrombi surrounded by growing fibroblasts and macrophages. Premature atherosclerosis has been also recognized as a feature of APS. Thrombocytopenia and autoimmune hemolytic anemia are the main hematologic manifestations of APS. Musculoskeletal manifestations may also occur in APS including arthralgias/arthritis, avascular bone necrosis, bone marrow necrosis, nontraumatic fractures, and osteoporosis.
4.1 Venous Thrombosis and Skin Manifestations¶
Deep-vein thrombosis (39%), Livedo reticularis (24%), Pulmonary embolism (14%), Superficial thrombophlebitis (12%), Thrombosis in various other sites (11%). Livedo reticularis with or without a painful ulceration on the lower extremities may be also a manifestation of disorders affecting (1) the vascular wall, such as atherosclerosis, polyarteritis nodosa, SLE, cryoglobulinemia, and lymphomas; or (2) the vascular lumen, such as atherosclerosis, polyarteritis nodosa, SLE, cryoglobulinemia, and lymphomas.
Table 1 — 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 |
4.2 Arterial Thrombosis and Cardiac Manifestations¶
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%), Arterial thrombosis in the extremities (7%), Retinal artery thrombosis/amaurosis fugax (7%), Ischemia of visceral organs or avascular necrosis of bone (6%), Multi-infarct dementia (3%).
Table 2 — TABLE 369-1 Clinical Features of Antiphospholipid Syndrome (Continued)¶
| MANIFESTATION | % |
|---|---|
| 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 |
| Arterial thrombosis in the extremities | 7 |
| Retinal artery thrombosis/amaurosis fugax | 7 |
| Ischemia of visceral organs or avascular necrosis of bone | 6 |
| Multi-infarct dementia | 3 |
4.3 Neurologic Manifestations¶
Migraine (20%), Epilepsy (7%), Chorea (1%), Cerebellar ataxia (1%), Transverse myelopathy (0.5%).
Table 3 — TABLE 369-1 Clinical Features of Antiphospholipid Syndrome (Neurologic)¶
| MANIFESTATION | % |
|---|---|
| Migraine | 20 |
| Epilepsy | 7 |
| Chorea | 1 |
| Cerebellar ataxia | 1 |
| Transverse myelopathy | 0.5 |
4.4 Renal Manifestations¶
Renal Artery/Renal Vein/Glomerular Thrombosis, Fibrous Intima Hyperplasia (3%).
Table 4 — TABLE 369-1 Clinical Features of Antiphospholipid Syndrome (Renal)¶
| MANIFESTATION | % |
|---|---|
| Renal Artery/Renal Vein/Glomerular Thrombosis, Fibrous Intima Hyperplasia | 3 |
4.5 Obstetric Manifestations¶
Preeclampsia (10%), Eclampsia (4%).
Table 5 — TABLE 369-1 Clinical Features of Antiphospholipid Syndrome (Obstetric)¶
| MANIFESTATION | % |
|---|---|
| Preeclampsia | 10 |
| Eclampsia | 4 |
4.6 Fetal Manifestations¶
Early fetal loss (<10 weeks) (35%), Late fetal loss (≥10 weeks) (17%), Premature birth among the live births (11%).
Table 6 — TABLE 369-1 Clinical Features of Antiphospholipid Syndrome (Fetal)¶
| MANIFESTATION | % |
|---|---|
| Early fetal loss (<10 weeks) | 35 |
| Late fetal loss (≥10 weeks) | 17 |
| Premature birth among the live births | 11 |
4.7 Hematologic Manifestations¶
Thrombocytopenia (30%), Autoimmune hemolytic anemia (10%).
Table 7 — TABLE 369-1 Clinical Features of Antiphospholipid Syndrome (Hematologic)¶
| MANIFESTATION | % |
|---|---|
| Thrombocytopenia | 30 |
| Autoimmune hemolytic anemia | 10 |
4.8 Musculoskeletal Manifestations¶
Arthralgias (39%), Arthritis (27%).
Table 8 — TABLE 369-1 Clinical Features of Antiphospholipid Syndrome (Musculoskeletal)¶
| MANIFESTATION | % |
|---|---|
| Arthralgias | 39 |
| Arthritis | 27 |
5. DIFFERENTIAL DIAGNOSIS¶
Differential diagnosis is based on the exclusion of other inherited or acquired causes of thrombophilia (Chap. 121), Coombs-positive hemolytic anemia (Chap. 105), and thrombocytopenia (Chap. 120). Livedo reticularis with or without a painful ulceration on the lower extremities may be also a manifestation of disorders affecting (1) the vascular wall, such as atherosclerosis, polyarteritis nodosa, SLE, cryoglobulinemia, and lymphomas; or (2) the vascular lumen, such as atherosclerosis, polyarteritis nodosa, SLE, cryoglobulinemia, and lymphomas.
6. INVESTIGATIONS & DIAGNOSIS¶
The diagnosis of APS should be seriously considered in cases of thrombosis, cerebral vascular accidents in individuals <55 years of age, or pregnancy morbidity, in the presence of livedo reticularis or thrombocytopenia. In these cases, aPL antibodies should be measured. According to the 2023 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for APS, the presence of at least 3 points from clinical domains and 3 points from laboratory domains is required to classify APS. Clinical manifestations with other equally or more likely explanations than APS will not be counted. Clinical domains include (1) venous thromboembolism; (2) arterial thrombosis; (3) microvascular events; (4) obstetric complications; (5) cardiac valve disease; and (6) hematologic manifestations, as shown in Table 369-2. Laboratory domains include (1) LA, (2) anticardiolipin (aCL), and/or (3) anti–βGPI antibodies, at moderate (40-79 units) or high titers (≥ 80 units) on two occasions 12 weeks apart.
6.1 Laboratory Domains (aPL)¶
Lupus anticoagulant (LA) test: One time positive (1 point), Persistent (5 points). Anticardiolipin (aCL) and/or anti–βGPI antibodies (persistent): Moderate (40–79 units) or high (≥ 80 units) IgM aCL and/or anti–βGPI (2 points), Moderate (40–79 units) IgG aCL and/or anti–βGPI (4 points), High (≥ 80 units) positive IgG aCL or anti–βGPI (5 points), High (≥ 80 units) IgG aCL and anti–βGPI (7 points).
Table 9 — TABLE 369-2 2023 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) Classification Criteria for Antiphospholipid Syndrome¶
| Clinical Domains | DOMAINS/CRITERIA | POINTS |
|---|---|---|
| Venous thromboembolism (VTE) | • With high-risk VTE profile | 1 |
| • Without a high-risk VTE profile | 3 | |
| Microvascular events | Suspected (any of below) | 2 |
| • Livedo racemosa (exam) | ||
| • Livedoid vasculopathy lesions (exam) | ||
| • Acute/chronic aPL-nephropathy (exam or lab) | ||
| • Pulmonary hemorrhage (symptoms and imaging) | ||
| Established (any of below) | 5 | |
| • 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 | 2 |
| • Vegetation | 4 | |
| Arterial thrombosis | • With high-risk CVD profile | 2 |
| • Without high-risk CVD profile | 4 | |
| Obstetric complications | • >3 consecutive prefetal (<10 w) and/or early fetal deaths (10w0d–15w6d) | 1 |
| • Fetal death (16w0d–33w6d) in the absence of preeclampsia (PEC) with severe features or placental insufficiency (PI) with severe features | 3 | |
| • PEC with severe features (<34w0d) or PI with severe features (<34w0d) with/without fetal death | 4 | |
| • PEC with severe features (<34w0d) and PI with severe features (<34w0d) with/without fetal death | 4 | |
| Hematologic manifestations | • Thrombocytopenia (otherwise unexplained lowest platelet count ever between 20 and 130 × 109/L) | 2 |
Table 10 — TABLE 369-2 2023 ACR/EULAR Classification Criteria for Antiphospholipid Syndrome (Laboratory Domains)¶
| Laboratory Domains (aPL) | DOMAINS/CRITERIA | POINTS |
|---|---|---|
| Lupus anticoagulant (LA) test | • One time positive | 1 |
| • Persistent | 5 | |
| Anticardiolipin (aCL) and/or anti–βGPI antibodies (persistent) | • 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 | 4 | |
| • High (≥ 80 units) positive IgG aCL or anti–βGPI | 5 | |
| • High (≥ 80 units) IgG aCL and anti–βGPI | 7 |
7. MANAGEMENT & TREATMENT¶
Management of APS involves anticoagulation for thrombosis prevention and treatment. In patients receiving anticoagulation treatment, LA test positivity should be interpreted with caution. In patients with features highly reminiscent of APS in the absence of classical antiphospholipid antibodies (aPL), testing for antiphosphatidylserine/prothrombin antibodies may have a valuable diagnostic role. Specific pharmacologic details and dosing are not detailed in the provided source text.
8. PROGNOSIS & COMPLICATIONS¶
Catastrophic APS (CAPS) is a rare, life-threatening, rapidly progressive thromboembolic disease involving simultaneously three or more organs. Recurrent thrombosis is a major complication. Pregnancy morbidity manifests with prefetal (<10 weeks of gestation) or fetal death, preeclampsia, eclampsia, and placental insufficiency with intrauterine fetal growth restriction, abnormal umbilical arterial Doppler, and/or infarctions of the placenta.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: Obstetric complications include preeclampsia, eclampsia, and placental insufficiency. Fetal manifestations include early fetal loss (<10 weeks), late fetal loss (≥10 weeks), and premature birth among live births. Elderly: It is questionable whether APL antibodies are able to induce thrombotic events in elderly individuals. SLE Association: One-third of patients with SLE possess these antibodies and 10–15% of them develop APS.
10. KEY PEARLS & CLINICAL TRAPS¶
APS affects primarily young females. Livedo reticularis with or without a painful ulceration on the lower extremities may be also a manifestation of disorders affecting the vascular wall or lumen. Libman-Sacks endocarditis consists of small (usually <1 cm) valve vegetations. Premature atherosclerosis has been also recognized as a feature of APS. Thrombocytopenia and autoimmune hemolytic anemia are the main hematologic manifestations of APS. Clinical manifestations with other equally or more likely explanations than APS will not be counted for classification.
Figures & Illustrations¶
Reproduced from Harrison's 22nd Edition.
Figure 1¶
Caption: Histopathology of Libman-Sacks endocarditis showing small valve vegetations characterized by organized platelet-fibrin microthrombi surrounded by growing fibroblasts and macrophages, or histology of aPL-nephropathy showing thrombotic microangiopathy lesions in glomerular capillaries.
Generated from Harrison's Principles of Internal Medicine, 22nd Edition.