Antiphospholipid Syndrome 

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Overview

Antiphospholipid Syndrome (APS) is an acquired autoimmune thrombophilia characterized by recurrent venous or arterial thromboses and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL). APS may occur as a primary condition or secondary to systemic lupus erythematosus (SLE). Prevalence of aPL in the general population is ~2%, but true APS is rare (~40–50 per 100,000); female predominance (F:M = 3:1). APS is a leading cause of recurrent pregnancy loss and unexplained thrombosis in young individuals.

Definition

Antiphospholipid antibodies (aPL): Autoantibodies directed against phospholipid-binding proteins such as β2-glycoprotein I or cardiolipin.
Lupus anticoagulant (LA): A misnomer; it causes in vitro prolongation of clotting tests but is prothrombotic in vivo.
Thrombophilia: A disorder that increases the risk of thrombosis.
Catastrophic APS (CAPS): A rare and life-threatening form of APS with multiorgan thrombosis over days.

Anatomy and Physiology

Steps in thrombosis

  1. Endothelial Injury
    • Exposes subendothelial collagen and tissue factor (TF)
    • Activates platelets and the coagulation cascade
    • Major trigger for arterial thrombosis
  2. Platelet Adhesion and Activation
    • Von Willebrand factor (vWF) binds platelets to exposed collagen via GPIb
    • Platelets become activated → change shape and release granules (ADP, thromboxane A₂)
    • Activated platelets express GPIIb/IIIa receptors → aggregation
  3. Coagulation Cascade Activation
    • Tissue factor activates extrinsic pathway (Factor VII) → thrombin generation
    • Thrombin converts fibrinogen to fibrin, stabilizing the clot
    • Amplification loops involve intrinsic factors (VIII, IX, XI)
  4. Clot Stabilization
    • Fibrin cross-linking forms a mesh
    • Platelet-fibrin plug stabilizes the thrombus
    • Involves Factor XIII for cross-linking
  5. Regulation and Resolution
    • Natural anticoagulants: antithrombin III, protein C/S, tissue factor pathway inhibitor (TFPI)
    • Fibrinolysis: Plasmin degrades fibrin → clot breakdown
    • Balance prevents excessive clotting

Virchow’s Triad (Pathological Thrombosis)

Three major contributors to thrombosis:

  • Endothelial injury
  • Abnormal blood flow (stasis or turbulence)
  • Hypercoagulability (inherited or acquired)

Aetiology and Risk Factors

Aetiology

  • Autoimmune production of antiphospholipid antibodies targeting β2-glycoprotein I, cardiolipin, or prothrombin.
  • Primary (idiopathic) or secondary (most often to SLE).

Risk Factors

  • Female sex
  • Co-existing autoimmune disease (esp. SLE)
  • Infections (e.g. HIV, hepatitis C, syphilis – can transiently raise aPL)
  • Certain medications (e.g. chlorpromazine, hydralazine)
  • Smoking, estrogen therapy, pregnancy, prolonged immobility

Pathophysiology

  • Trigger (genetic or environmental) → immune response → formation of aPL.
  • aPL bind to β2-glycoprotein I on endothelial cells and platelets → activation of procoagulant pathways.
  • Complement activation contributes to pregnancy complications.
  • Results in:
    • Arterial/venous thrombosis
    • Placental insufficiency → miscarriage
    • Cardiac and neurological sequelae

Despite prolonged aPTT on labs, APS is prothrombotic due to antibody-mediated vascular injury.

Clinical Manifestations

SystemManifestations
VascularDVT, PE, stroke, TIA, retinal thrombosis
ObstetricRecurrent miscarriage (>10 weeks), fetal death, preeclampsia, IUGR
CardiacLibman-Sacks endocarditis, valvular thickening
HematologicalThrombocytopenia
DermatologicLivedo reticularis, ulcers
NeurologicalSeizures, cognitive dysfunction, chorea
RenalThrombotic microangiopathy, hypertension
Catastrophic APSRapid multiorgan thromboses, DIC-like picture

Remember

Suspect APS in young patients with unprovoked thrombosis, especially arterial or recurrent pregnancy loss.

Diagnosis

2023 ACR/EULAR antiphospholipid syndrome classification criteria

DomainFeature / EventWeighted Points
Entry CriterionAt least one positive aPL test (LA, moderate/high‐titer aCL or anti‑β2GPI IgG/IgM) within 3 years of clinical event★ Required before scoring
Clinical Domains (≥3 pts)
Macrovascular Venous ThrombosisVTE with high-risk profile1
VTE without high-risk features3
Macrovascular Arterial ThrombosisArterial event with CVD risk2
Arterial event without CVD risk4
Microvascular ThrombosisSuspected lesion (e.g. livedo, nephropathy, pulmonary hemorrhage)2
Established pathology 5
Obstetric Morbidity≥3 consecutive early losses (<10 weeks)1
Fetal death (10–33 weeks) without pre‑eclampsia or placental insufficiency3
Fetal death with pre‑eclampsia or placental insufficiency <34 weeks (± fetal death)3
Fetal death with both pre‑eclampsia & placental insufficiency <34 weeks4
Cardiac Valve DiseaseValve thickening (non-infectious)2
Valve vegetation (non-infectious)4
Haematologic ManifestationThrombocytopenia (20–130 × 10⁹/L)2
Laboratory Domains (≥3 pts)
Lupus Anticoagulant (functional assay)Positive (persistent)5
aCL or anti‑β2GPI antibodies (ELISA)Moderate‑titer IgM or IgG (40‑79 U)1
Moderate IgG only4
High‑titer IgG and/or anti‑β2GPI (≥80 U)5
High‑titer IgG in both aCL and anti‑β2GPI7
AntibodyDescription & Clinical Relevance
Anticardiolipin Antibodies (IgG or IgM)• Target cardiolipin, a negatively charged phospholipid located on mitochondrial membranes. 
• May appear transiently at low levels in response to infections, malignancy, or autoimmune conditions—not always pathogenic. 
• IgG subtype is more strongly associated with thrombotic risk than IgM.
Anti-beta2-glycoprotein I Antibodies (IgG or IgM)• Target beta2-glycoprotein I, a plasma protein that inhibits platelet aggregation and regulates the coagulation cascade. 
• IgG antibodies correlate more closely with thrombotic events. 
• IgM antibodies have lower clinical significance.
Lupus Anticoagulant• Refers to a functional group of antibodies (not a single entity) that interfere with phospholipid-dependent clotting assays. 
• Most predictive of thrombotic and obstetric complications in APS. 
• A persistently positive lupus anticoagulant carries higher clinical risk than anticardiolipin or anti-beta2GPI antibodies.

Investigations

  • aPTT (may be prolonged)
  • dRVVT (for Lupus anticoagulant detection)
  • ELISA for anticardiolipin and anti-β2GPI
  • Imaging for thrombosis (US Doppler, CT angio)

Differential Diagnoses

ConditionDistinguishing Features
Inherited thrombophiliaNo aPL; family history; no obstetric loss
DICConsumptive coagulopathy; ↓ fibrinogen
TTPMicroangiopathy, neurologic findings, ADAMTS13 deficiency
SLE aloneMultisystem inflammation but may coexist with APS

Classification

  • Primary APS: No associated autoimmune disease
  • Secondary APS: Associated with SLE or other autoimmune disorders
  • Catastrophic APS (CAPS): Life-threatening; ≥3 organs involved over <1 week, confirmed microthrombosis

Treatment

IndicationTreatment
Acute thrombosisHeparin → warfarin (INR 2–3); lifelong
PregnancyLow-dose aspirin + prophylactic LMWH
Recurrent thrombosisIncrease INR goal to 2.5–3.5 or add aspirin
CAPSHeparin + corticosteroids + IVIG/plasmapheresis

Avoid Direct Oral Anticoagulants (DOACs) in triple-positive patients or arterial events (↑ recurrence risk).

Remember

Long-term warfarin is mainstay for thrombotic APS; DOACs are NOT equivalent in high-risk APS.

Complications and Prognosis

Complications

  • Stroke, PE, MI, fetal loss
  • Catastrophic APS (rare, high mortality)
  • Valve disease (Libman-Sacks)
  • Renal thrombotic microangiopathy

Prognosis

  • Good with appropriate anticoagulation
  • Poor in CAPS or recurrent thrombosis despite therapy

Poor Prognostic Factors:

  • Triple positivity (LA + ACL + β2GPI)
  • CAPS
  • Delay in anticoagulation
  • Coexisting SLE with nephritis

References

  1. Miyakis S, et al. International consensus statement on an update of the classification criteria for definite APS. J Thromb Haemost. 2006;4(2):295–306.
  2. Garcia D, Erkan D. Diagnosis and management of the antiphospholipid syndrome. N Engl J Med. 2018;378(21):2010–2021.
  3. Pengo V, et al. Rivaroxaban vs warfarin in high-risk APS: The TRAPS trial. Blood. 2018;132(13):1365–1371.
  4. Cervera R, et al. Catastrophic APS: clinical and immunologic manifestations and long-term outcomes. Arthritis Rheum. 2009;61(8):1144–1150.
  5. Tektonidou MG, et al. Risk factors for thrombosis in APS. Curr Rheumatol Rep. 2016;18(4):21.

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