Antiphospholipid Syndrome

Table of Contents

1. Overview
2. Antiphospholipid Antibodies
3. Pathogenesis
4. Thrombotic APS
5. Obstetric APS
6. Catastrophic APS (CAPS)
7. Diagnosis
8. Treatment
9. Key Research Papers
10. Featured Videos

Overview

Antiphospholipid syndrome (APS) is an autoimmune acquired thrombophilia in which antiphospholipid antibodies (aPL) drive paradoxical thrombosis — "anticoagulant" in their laboratory name yet prothrombotic in the body. Three major antibody types define the syndrome: lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-β2-glycoprotein I (anti-β2GPI).

Classification requires at least one clinical criterion — either a confirmed thrombotic event or pregnancy morbidity — plus at least one laboratory criterion confirmed on two or more occasions at least 12 weeks apart (Sapporo/revised criteria). This mandatory interval excludes transient aPL that arise with infections and carry no lasting risk.

Primary APS occurs in the absence of any identifiable underlying disease. Secondary APS is most commonly associated with systemic lupus erythematosus (SLE): 40–50% of SLE patients carry aPL, yet only approximately 40% of those ever develop thrombosis. APS is estimated to affect 40–50 per 100,000 people and predominantly strikes women during their childbearing years, though men and older adults are not exempt.

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Antiphospholipid Antibodies

Three major aPL types are recognized in the classification criteria, each detected by a different method:

1. Lupus anticoagulant (LA) — detected by clotting-based functional assays, most commonly the dilute Russell viper venom test (dRVVT) with a mixing study. In the laboratory LA prolongs the PTT, yet in the living patient it strongly promotes clotting. LA is the most thrombogenic of the three aPL types.
2. Anticardiolipin antibodies (aCL) IgG/IgM — detected by ELISA. IgG isotype carries greater thrombotic risk than IgM. Historically, aCL cross-reacts with the cardiolipin antigen used in syphilis screening (RPR/VDRL), causing false-positive syphilis tests in APS patients — a clinically important pitfall.
3. Anti-β2-glycoprotein I (anti-β2GPI) IgG/IgM — the most specific aPL; β2-GPI is now recognized as the actual molecular target for most aPL, not phospholipid itself. Detected by ELISA.

Triple positivity — simultaneous presence of LA, aCL, and anti-β2GPI — confers the highest thrombotic and obstetric risk and is a contraindication to direct oral anticoagulants (DOACs). Persistent positivity (confirmed on at least two tests at least 12 weeks apart) is required by diagnostic criteria; transient aPL arising during infections resolve spontaneously and do not warrant long-term anticoagulation.

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Pathogenesis

The core mechanism begins when β2-GPI binds to anionic phospholipid membranes, presenting itself as a target for aPL. Antibody binding triggers several converging prothrombotic cascades:

1. Endothelial activation: upregulation of adhesion molecules (ICAM-1, VCAM-1, E-selectin), increased tissue factor expression, and release of inflammatory cytokines create a procoagulant endothelial surface.
2. Platelet activation: aPL-β2GPI complexes enhance platelet adhesion and aggregation, amplifying thrombus formation.
3. Complement activation: C3 and C5 components are activated; C5a generation is particularly critical in obstetric APS. Mouse models have demonstrated that complement inhibition prevents aPL-induced pregnancy loss, establishing a causal role distinct from simple vascular thrombosis.
4. Inhibition of natural anticoagulants: the annexin V anticoagulant shield is displaced from trophoblast membranes; the protein C pathway is inhibited; tissue factor pathway inhibitor (TFPI) is reduced — the net result is a strongly prothrombotic state.

In obstetric APS specifically, complement activation at the placental interface injures trophoblasts, impairs spiral artery remodeling, and triggers decidual inflammation, leading to placental insufficiency and fetal loss independent of large-vessel thrombosis.

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Thrombotic APS

Venous thrombosis is the most common presentation: deep vein thrombosis (DVT) and pulmonary embolism (PE) account for the majority of events. Less common venous sites include cerebral venous sinus thrombosis, Budd-Chiari syndrome, renal vein thrombosis, and portal vein thrombosis.

Arterial thrombosis most frequently manifests as stroke or transient ischemic attack (TIA) — any young patient with an unexplained ischemic stroke should be screened for aPL. Other arterial events include myocardial infarction, peripheral arterial occlusion, and retinal artery occlusion.

Several noncriteria manifestations are highly characteristic of APS vasculopathy:

• Livedo reticularis: a net-like purplish skin discoloration, especially over the extremities; strongly associated with arterial events. The combination of livedo reticularis and recurrent stroke is called Sneddon syndrome, many cases of which are aPL-driven.
• Libman-Sacks endocarditis: sterile verrucous (warty) vegetations found particularly on the atrial surface of the mitral valve leaflets. These can cause valve thickening, regurgitation, and embolic stroke, and are best detected by transesophageal echocardiography.
• Thrombocytopenia: typically mild to moderate (platelet count usually above 50,000/µL); rarely causes clinically significant bleeding — the paradox of thrombocytopenia coexisting with thrombosis is a hallmark of APS.
• Autoimmune hemolytic anemia: Coombs-positive hemolysis occurs in a subset of patients.
• Cognitive and neurological manifestations: headache, migraine, seizures, and cognitive decline; white matter lesions on brain MRI are common and may reflect cumulative microvascular injury.

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Obstetric APS

Obstetric APS is defined by characteristic pregnancy complications in the setting of confirmed aPL positivity. The classification criteria include any one of:

• Three or more consecutive unexplained pregnancy losses before 10 weeks of gestation
• One or more fetal deaths at or after 10 weeks of gestation (morphologically normal fetus)
• One or more premature births before 34 weeks of gestation due to severe preeclampsia, eclampsia, or placental insufficiency

The underlying mechanisms are twofold: placental thrombosis from the prothrombotic antibodies and, distinctly, complement-mediated trophoblast injury with impaired spiral artery remodeling leading to uteroplacental insufficiency. This explains why anticoagulation alone is sometimes insufficient — the complement arm operates independently of coagulation.

Clinically, obstetric APS presents as early severe preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), fetal growth restriction, and placental abruption. APS is responsible for approximately 15% of cases of recurrent pregnancy loss overall. With appropriate treatment — low-molecular-weight heparin combined with low-dose aspirin — more than 70% of pregnancies reach a successful outcome, compared to a loss rate approaching 80% without treatment.

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Catastrophic APS (CAPS)

Catastrophic APS (CAPS) affects fewer than 1% of APS patients but carries a mortality of approximately 50%. It is defined by the simultaneous thrombosis of three or more organ systems developing over days to weeks, with pathological confirmation of small-vessel occlusion (microvascular thrombosis). The kidneys, lungs, brain, heart, and skin are most commonly involved.

The international CAPS Registry has identified common precipitating triggers: infections (most frequently), surgical procedures, withdrawal of oral contraceptive pills, and non-compliance with anticoagulation (particularly warfarin interruption).

CAPS classification criteria require: involvement of three or more organs or tissues; simultaneous development within one week; histopathological confirmation of small-vessel occlusion; and confirmed aPL (LA or aCL at medium-to-high titre).

Treatment is intensive and combines three simultaneous strategies:

1. Anticoagulation with intravenous unfractionated heparin (to treat and prevent further thrombosis)
2. High-dose corticosteroids — methylprednisolone 500–1000 mg/day for three days (to suppress the cytokine storm)
3. IVIG (2 g/kg over 5 days) or plasma exchange (to remove circulating aPL)

For refractory CAPS, rituximab (B-cell depletion) or eculizumab (terminal complement inhibition) has been used with reported benefit in case series.

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Diagnosis

Clinical assessment focuses on a detailed thrombosis history (site, type, provoked versus unprovoked, recurrence) and a comprehensive obstetric history (number of losses, gestational age, complications such as preeclampsia or IUGR).

Laboratory testing must evaluate all three aPL types:

• Lupus anticoagulant: dRVVT (preferred) with a mixing study to confirm an inhibitor; hexagonal phase phospholipid correction confirms phospholipid-dependence. Anticoagulation can interfere with LA testing — interpretation requires knowledge of current therapy.
• Anticardiolipin antibodies (aCL) IgG/IgM: by ELISA; only IgG and IgM are included in diagnostic criteria (IgA is not). A result above the 99th percentile of a healthy control population on two tests at least 12 weeks apart constitutes a positive criterion.
• Anti-β2GPI IgG/IgM: by ELISA; same threshold and persistence requirements as aCL.

False-positive aPL can arise with infections (syphilis, hepatitis C, HIV, malaria), certain drugs (procainamide, hydralazine, phenothiazines), and autoimmune disease flares — making the mandatory 12-week confirmatory interval essential.

Additional workup at the time of a thrombotic event typically includes a comprehensive hypercoagulable panel (protein C, protein S, antithrombin, factor V Leiden, prothrombin G20210A mutation), CBC, renal and hepatic function tests, transthoracic echocardiography (to detect Libman-Sacks vegetations), and brain MRI with FLAIR sequences to characterize white matter disease burden.

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Treatment

Thrombotic APS: Warfarin remains the standard of care. Direct oral anticoagulants (DOACs) are inferior for APS: the TRAPS trial (2018) randomized aPL-positive patients with prior thrombosis to rivaroxaban versus warfarin and found significantly more thromboembolic events and major bleeding with rivaroxaban. DOACs are contraindicated in triple-positive APS per international guidelines.

• Target INR 2–3 for venous APS.
• Arterial APS: INR 2–3 versus 3–4 is debated; many specialists target INR 3–4 for recurrent arterial events.
• Duration: lifelong anticoagulation is standard for unprovoked APS thrombosis given the high recurrence risk on stopping.
• Add low-dose aspirin (81 mg) for patients with arterial APS events.

Obstetric APS: The standard regimen is prophylactic-dose low-molecular-weight heparin (LMWH) started early in pregnancy and continued through 6 weeks postpartum, combined with low-dose aspirin (81 mg) initiated before conception or at a positive pregnancy test and continued throughout. Warfarin is contraindicated in pregnancy (crosses the placenta, teratogenic in the first trimester, causes fetal hemorrhage). This combination reduces pregnancy loss from approximately 80% to a success rate above 75%.

Hydroxychloroquine (HCQ): provides additive antithrombotic benefit, particularly in SLE-associated APS, by stabilizing anionic phospholipid-protein complexes and reducing platelet aggregation. It is also considered for primary APS patients with high aPL titers and no prior thrombosis.

Primary thromboprophylaxis (no prior thrombosis, aPL positive): evidence is limited; low-dose aspirin with or without hydroxychloroquine is used in high-risk profiles, especially triple-positive patients.

Statins — with anti-inflammatory properties and capacity to reduce endothelial tissue factor expression — are used as adjunctive therapy in select patients, though randomized trial data are limited.

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Key Research Papers

1. Miyakis S et al. "International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS)." J Thromb Haemost. 2006;4(2):295–306. PMID 16420554
2. Ruiz-Irastorza G et al. "Antiphospholipid syndrome." Lancet. 2010;376(9751):1498–509. PMID 20822807
3. Pengo V et al. (TRAPS trial) "Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome." Blood. 2018;132(13):1365–1371. PMID 29976693
4. Tektonidou MG et al. "EULAR recommendations for the management of antiphospholipid syndrome in adults." Ann Rheum Dis. 2019;78(10):1296–1304. PMID 31461941
5. Meroni PL et al. "Pathogenesis of antiphospholipid syndrome: understanding the antibodies." Nat Rev Rheumatol. 2011;7(6):330–339. PMID 21556027
6. Agmon-Levin N et al. "Antiphospholipid syndrome (Hughes syndrome) — a disease by itself." J Autoimmun. 2010;34(3):J221–7. PMID 20129750
7. Cervera R et al. "Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients." Ann Rheum Dis. 2015;74(6):1011–8. PMID 24464962
8. Berman H et al. "Rituximab in refractory obstetric antiphospholipid syndrome." Arthritis Care Res. 2013;65(8):1278–1283. PMID 23554279
9. Lockshin MD et al. "Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies." Arthritis Rheum. 2012;64(7):2311–8. PMID 22275174
10. Sciascia S et al. "Global anti-phospholipid syndrome score in primary APS." Rheumatology. 2015;54(1):134–138. PMID 24934968
11. Negrini S et al. "Antiphospholipid syndrome: still an enigma." Autoimmun Rev. 2017;16(12):1221–1229. PMID 29037904
12. Erkan D et al. "Management of the controversial aspects of antiphospholipid syndrome pregnancies." Ann Rheum Dis. 2013;72 Suppl 2:ii15–9. PMID 23253921

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Connections

• Hematology
• Deep Vein Thrombosis
• Systemic Lupus Erythematosus
• Paroxysmal Nocturnal Hemoglobinuria
• Von Willebrand Disease
• Stroke
• Aplastic Anemia

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Featured Videos