# Antiphospholipid Syndrome

## Introduction

Antiphospholipid syndrome is a systemic autoimmune thrombotic disorder defined by the occurrence of vascular thrombosis and/or pregnancy morbidity in the presence of persistently positive antiphospholipid antibodies. The disease exists in two major forms. Primary APS, accounting for approximately 50 percent of cases, occurs in the absence of an underlying autoimmune disease. Secondary APS is associated with another autoimmune condition, most commonly systemic lupus erythematosus. Catastrophic APS, also known as CAPS, represents a rare but life-threatening variant characterized by a multiorgan thrombotic storm that can progress to fatal multiorgan failure within days.

## Pathogenesis

### Antiphospholipid Antibodies

Antiphospholipid antibodies do not target phospholipids directly but rather target phospholipid-binding proteins, primarily beta-2 glycoprotein I. Beta-2 glycoprotein I binds to anionic phospholipids on cell surfaces, and antibodies directed against this protein activate endothelial cells, platelets, monocytes, and the complement cascade. The pathogenesis of thrombotic events in APS is best understood through the "two-hit hypothesis," which posits that antiphospholipid antibodies prime the vascular and coagulation systems as a first hit, while a second trigger such as infection, surgery, immobilization, or oral contraceptive use initiates the actual thrombotic event. This model explains why not all individuals with antiphospholipid antibodies develop thrombosis; indeed, approximately 50 percent of persistently aPL-positive individuals never experience a clinical event.

### Mechanisms of Thrombosis

The thrombotic mechanisms in APS are multifaceted and synergistic. Endothelial activation leads to the upregulation of tissue factor and adhesion molecules including ICAM-1, VCAM-1, and E-selectin, converting the endothelial surface from an anticoagulant to a prothrombotic state. Platelet activation occurs through the GPIIb/IIIa and GPIb-V-IX pathways, lowering the threshold for platelet aggregation and thrombus formation. Complement activation, particularly the generation of C5a, plays a central role in thrombosis, as supported by animal models and clinical reports of successful eculizumab treatment in refractory cases. Antiphospholipid antibodies also interfere with natural anticoagulant pathways by inhibiting protein C, protein S, and antithrombin function. Disruption of the annexin A5 crystalline shield on trophoblast and endothelial surfaces exposes the underlying procoagulant phospholipid surface. Additionally, aPL antibodies enhance NETosis, the formation of neutrophil extracellular traps, which promotes thromboinflammation and further amplifies the thrombotic cascade.

## Diagnosis

### 2023 ACR/EULAR APS Classification Criteria

The 2023 ACR/EULAR classification criteria for antiphospholipid syndrome replaced the 2006 revised Sapporo criteria and introduced a more sophisticated weighted scoring approach. The entry criterion requires at least one positive antiphospholipid antibody test and at least one clinical APS domain manifestation.

The laboratory criteria are weighted on a scale of 1 to 7 points and require that aPL positivity be confirmed on at least two occasions separated by at least 12 weeks. Lupus anticoagulant is the most thrombogenic of the three aPL types and carries the strongest association with thrombosis. Anti-cardiolipin antibodies of IgG or IgM isotype are significant when present at medium to high titer, defined as greater than 40 GPL or MPL units or above the 99th percentile. Anti-beta-2 glycoprotein I antibodies of IgG or IgM isotype are similarly weighted at medium to high titer. Triple positivity, defined as the simultaneous presence of lupus anticoagulant, anti-cardiolipin, and anti-beta-2 glycoprotein I antibodies, confers the highest thrombotic risk, with an annual event rate of approximately 5 to 10 percent.

The clinical criteria span multiple domains with weighted scoring. Macrovascular events include venous thromboembolism (deep vein thrombosis and pulmonary embolism) and arterial thrombosis (stroke, myocardial infarction, and limb ischemia). Microvascular manifestations encompass renal, pulmonary, cerebral, and adrenal microangiopathy. Obstetric criteria include recurrent early miscarriage, fetal death after 10 weeks of gestation, and preeclampsia or HELLP syndrome with preterm delivery. Cardiac valve disease, specifically Libman-Sacks endocarditis and valve thickening, and hematologic features such as thrombocytopenia are also included. Classification as APS requires at least 3 points in the clinical domain and at least 3 points in the laboratory domain.

### Laboratory Testing Nuances

Lupus anticoagulant is a functional assay that identifies antibodies interfering with phospholipid-dependent coagulation tests. The characteristic finding is a prolonged aPTT that does not correct with a mixing study but normalizes with the addition of excess phospholipid, confirmed by phospholipid-dependent tests such as the dilute Russell viper venom time and silica clotting time. A critical limitation is that lupus anticoagulant testing produces false-positive results in patients receiving anticoagulation, particularly direct oral anticoagulants, which can interfere with the clotting-based assay. Anti-cardiolipin and anti-beta-2 glycoprotein I antibodies are measured by ELISA and standardized in GPL and MPL units. Persistence of positivity must be confirmed by repeat testing at 12 weeks or longer, as transient positivity is common with infections and does not warrant long-term anticoagulation. The IgG isotype is more clinically significant than IgM for both anti-cardiolipin and anti-beta-2 glycoprotein I antibodies. Non-criteria antiphospholipid antibodies, particularly anti-phosphatidylserine/prothrombin antibodies, are emerging as biomarkers that may identify patients with seronegative APS who test negative for the three conventional aPL tests yet have clinical features consistent with the syndrome.

<image>A risk stratification pyramid for antiphospholipid syndrome based on antibody profile. At the base (lowest risk), show single antibody positivity at low titer. In the middle tier, show double positivity or single antibody at high titer. At the apex (highest risk), show triple positivity (LA + aCL + anti-β2GPI). On the right side, list the approximate annual thrombotic risk for each tier: single low-titer (~1%), double positive (~3-4%), triple positive (~5-10%). Include annotations for each antibody type: LA (most thrombogenic, functional assay), aCL IgG (ELISA), anti-β2GPI IgG (ELISA). Add a note that lupus anticoagulant is the strongest single predictor of thrombosis.</image>

| aPL Test | Method | Most Thrombogenic? | Affected by Anticoagulants? | IgG vs IgM | Key Pearl |
|---------|--------|-------------------|---------------------------|-----------|-----------|
| Lupus anticoagulant (LA) | Functional clotting assay (dRVVT, SCT) | **Yes** (strongest predictor) | **Yes** — DOACs and heparin cause false positives | N/A (functional assay) | Prolonged aPTT that does not correct on mixing; normalizes with excess phospholipid |
| Anti-cardiolipin (aCL) | ELISA (GPL/MPL units) | Moderate | No | IgG more significant than IgM | Medium-high titer (>40 GPL/MPL or >99th percentile) required |
| Anti-beta-2 glycoprotein I (anti-β2GPI) | ELISA | Moderate | No | IgG more significant than IgM | Target of pathogenic antibodies (β2GPI on cell surfaces) |
| **Triple positivity** (LA + aCL + anti-β2GPI) | All three positive | **Highest risk** (~5–10%/year thrombosis) | — | — | DOACs contraindicated (TRAPS trial); warfarin mandatory |

## Clinical Manifestations

### Venous Thromboembolism

Deep vein thrombosis and pulmonary embolism constitute the most common thrombotic manifestation of APS, accounting for approximately 60 percent of thrombotic events. While lower extremity DVT is the typical presentation, APS is distinguished by its propensity to cause thrombosis at unusual sites, including cerebral venous sinus thrombosis, hepatic vein thrombosis manifesting as Budd-Chiari syndrome, renal vein thrombosis, and adrenal vein thrombosis leading to adrenal insufficiency from hemorrhagic infarction. Without anticoagulation, the recurrence rate for thrombotic events is alarmingly high, estimated at 20 to 30 percent per year.

### Arterial Thrombosis

Stroke and transient ischemic attack represent the most common arterial manifestations of APS, frequently occurring in young patients under 50 years of age without traditional cardiovascular risk factors. Myocardial infarction in a young patient lacking conventional risk factors should prompt consideration of APS. Peripheral arterial thrombosis and mesenteric ischemia are additional arterial manifestations. Livedo reticularis, a violaceous, non-blanching reticular pattern on the skin, is commonly associated with APS and, when combined with cerebrovascular events, defines Sneddon syndrome.

### Obstetric APS

Obstetric APS encompasses several patterns of pregnancy morbidity. Recurrent early miscarriage is defined as three or more consecutive pregnancy losses before 10 weeks of gestation. Late fetal death involves one or more unexplained fetal deaths at or beyond 10 weeks of gestation. Preeclampsia and HELLP syndrome with premature delivery before 34 weeks reflect severe placental vascular insufficiency. Placental insufficiency may also manifest as intrauterine growth restriction and oligohydramnios. The underlying placental pathology includes placental infarction, decidual vasculopathy, and extensive fibrin deposition, all reflecting the microvascular thrombotic process driven by antiphospholipid antibodies.

### Non-criteria Manifestations

Several clinically important manifestations of APS are not included in the formal classification criteria but are increasingly recognized. Thrombocytopenia, typically moderate with platelet counts in the 50,000 to 100,000 range, occurs frequently but rarely causes clinically significant bleeding. Livedo reticularis and livedo racemosa are common cutaneous findings. Cardiac valve disease, particularly Libman-Sacks endocarditis presenting as verrucous vegetations typically on the mitral valve, can cause valvular dysfunction and serve as a source of emboli. APS nephropathy is a distinct entity from lupus nephritis, characterized by thrombotic microangiopathy, fibrous intimal hyperplasia of interlobular arteries, and focal cortical atrophy on renal biopsy. Cognitive dysfunction, often described as brain fog with memory impairment, affects many patients. Other non-criteria manifestations include skin ulcers, chorea, and transverse myelitis.

### Catastrophic APS (CAPS)

Catastrophic APS is defined by the involvement of three or more organs within one week, with histologic confirmation of small vessel thrombosis in the presence of confirmed antiphospholipid antibodies. Despite aggressive treatment, mortality remains devastatingly high at 30 to 50 percent. The most common triggers are infection, surgery, anticoagulation withdrawal, and malignancy. The organs most frequently affected are the kidneys in approximately 70 percent, the lungs in 60 percent, the central nervous system in 50 percent, the heart in 50 percent, and the skin in 50 percent. The treatment approach is "triple therapy" consisting of anticoagulation, high-dose glucocorticoids, and plasma exchange or intravenous immunoglobulin. Rituximab or eculizumab is added for refractory cases. Data from the international CAPS Registry support this multimodal approach and demonstrate that early aggressive intervention is essential for survival.

## Management

### Thrombotic APS

#### Primary Thromboprophylaxis (aPL-positive, no prior thrombosis)

For patients with a low-risk antibody profile, defined as a single antiphospholipid antibody at low titer, management consists of lifestyle modification and low-dose aspirin at 81 to 100 milligrams daily in patients with SLE. For patients with a high-risk profile, particularly those who are triple positive, lupus anticoagulant positive, or have high-titer antibodies, low-dose aspirin is recommended, and hydroxychloroquine should be considered in patients with SLE. Perioperative thromboprophylaxis with low-molecular-weight heparin is indicated for periods of immobilization or surgery.

#### Secondary Thromboprophylaxis (prior thrombosis)

For patients with prior venous thrombosis, warfarin with a target INR of 2.0 to 3.0 is the standard of care, and treatment should be continued indefinitely. Several landmark trials have defined the evidence base for anticoagulation choices. The RAPS trial suggested that rivaroxaban at 20 milligrams daily was non-inferior to warfarin for venous APS. However, the TRAPS trial, which enrolled only triple-positive APS patients, was stopped early because rivaroxaban was inferior to warfarin, with a significantly higher rate of arterial thrombotic events. The ASTRO-APS trial similarly demonstrated increased thrombotic events with apixaban compared to warfarin in aPL-positive patients. Based on these findings, direct oral anticoagulants are not recommended for APS, particularly in patients who are triple positive or who have had arterial thrombosis, as reinforced by the 2019 EULAR recommendation.

For patients with prior arterial thrombosis, warfarin with a target INR of 2.0 to 3.0, or in some guidelines 3.0 to 4.0, is recommended, with some clinicians adding aspirin. The ALIWAPAS trial demonstrated that a higher-intensity INR target of 3.0 to 4.0 did not reduce recurrence compared to 2.0 to 3.0 but did increase bleeding, tempering enthusiasm for higher-intensity anticoagulation. For patients with refractory or recurrent thrombosis despite adequate warfarin therapy, adjunctive therapies include hydroxychloroquine, statins, aspirin, and in select cases rituximab or eculizumab.

#### Obstetric APS Management

For patients with a history of recurrent early miscarriage, the standard treatment is low-dose aspirin combined with prophylactic-dose low-molecular-weight heparin, typically enoxaparin 40 milligrams daily. For patients with a history of late fetal loss or prior thrombosis, low-dose aspirin combined with therapeutic-dose LMWH is recommended. Refractory obstetric APS, in which pregnancy losses continue despite standard therapy, may benefit from the addition of hydroxychloroquine, low-dose prednisone, intravenous immunoglobulin, or plasma exchange. The PROMISSE study identified complement activation products, specifically Bb and sC5b-9, as biomarkers of adverse pregnancy outcomes in aPL-positive patients, providing mechanistic support for the role of complement in obstetric APS. Hydroxychloroquine should be continued throughout pregnancy, as it reduces aPL-mediated placental damage and has been shown to improve obstetric outcomes.

<image>A clinical management algorithm for antiphospholipid syndrome. Start with "Confirmed aPL positivity (persistent, ≥12 weeks apart)" and branch into three categories: (1) Asymptomatic aPL carrier → risk stratify by antibody profile (single vs triple positive, titer) → low risk: lifestyle modification ± aspirin in SLE; high risk: aspirin + HCQ. (2) Thrombotic APS → venous (warfarin INR 2-3, indefinite; NO DOACs) vs arterial (warfarin INR 2-3 or 3-4 ± aspirin). (3) Obstetric APS → recurrent early loss (aspirin + prophylactic LMWH) vs late loss/thrombosis history (aspirin + therapeutic LMWH). Include a separate red-bordered box for CAPS: triple therapy (anticoagulation + GC + PLEX/IVIG ± rituximab/eculizumab). Emphasize "NO DOACs" with a warning symbol for triple-positive APS.</image>

## Special Considerations

The overlap between APS and SLE is clinically significant, as approximately 40 percent of SLE patients have antiphospholipid antibodies and 10 to 15 percent develop clinical APS. Distinguishing APS nephropathy from lupus nephritis on renal biopsy is important because the pathologic findings differ: thrombotic microangiopathy on biopsy suggests APS nephropathy, while immune complex-mediated proliferative changes suggest lupus nephritis, though both processes can coexist in the same biopsy specimen.

Pregnancy management in patients with APS and prior thrombosis requires continuation of therapeutic-dose LMWH throughout pregnancy and for 6 weeks postpartum, with transition back to warfarin in the postpartum period. Warfarin monitoring in APS is complicated by the fact that lupus anticoagulant can prolong the PT/INR factitiously, and in such cases chromogenic factor X levels should be used to guide anticoagulation intensity. Statins have demonstrated anti-inflammatory effects that may benefit APS patients, and observational data are supportive of their use as adjunctive therapy.

## Key Clinical Pearls

- DOACs are contraindicated in APS, particularly triple-positive and arterial APS (TRAPS trial)
- Lupus anticoagulant is the single strongest predictor of thrombosis among the three aPL types
- Triple positivity (LA + aCL + anti-β2GPI) carries the highest thrombotic risk
- CAPS requires a high index of suspicion; mortality exceeds 30% even with aggressive treatment
- Certolizumab pegol is the preferred biologic in APS patients with rheumatic disease who need anti-TNF (no Fc-mediated platelet activation)
- Always confirm aPL persistence at ≥12 weeks; transient positivity (infection, medication) is common and does not warrant long-term anticoagulation

<image>A histopathological illustration comparing APS nephropathy and lupus nephritis side by side. Left panel (APS nephropathy): Show thrombotic microangiopathy with fibrin thrombi in glomerular capillaries, fibrous intimal hyperplasia in interlobular arteries, and focal cortical atrophy. Right panel (Lupus nephritis Class IV): Show endocapillary proliferation, wire-loop deposits, and "full house" immunofluorescence. Include labels differentiating the pathologic features: APS = thrombotic/ischemic changes; LN = immune complex-mediated inflammation. Note that both can coexist in the same biopsy.</image>

## References
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2. Pengo V, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome (TRAPS). Blood. 2018;132(13):1365-1371.
3. Tektonidou MG, et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019;78(10):1296-1304.
4. Rodríguez-Pintó I, et al. Catastrophic antiphospholipid syndrome (CAPS): Descriptive analysis of 500 patients from the International CAPS Registry. Autoimmun Rev. 2016;15(12):1120-1124.
5. Salmon JE, et al. Complement activation predicts adverse pregnancy outcome in patients with antiphospholipid antibodies (PROMISSE). Blood. 2011;117(23):6204-6213.