Antiphospholipid Antibody syndrome

Only a small proportion of the population — around 1 in every 2000 people — develop the antiphospholipid syndrome (APS), a syndrome-complex of autoantibodies that predispose to clotting in both the venous and arterial systems, and that carries a specific risk of recurrent foetal loss.¹ Many, but by no means all, affected patients have an existing diagnosis of systemic lupus erythematosus (SLE).

Diagnosis

The diagnosis requires clinical evidence of thrombosis or pregnancy morbidity, together with serological demonstration of at least one of three antibodies:

• Anti-cardiolipin antibodies (ACA)
• Antibodies to beta-2-glycoprotein 1 (anti-β2GPI)
• The lupus anticoagulant (LAC)

Cardiolipin: a mitochondrial phospholipid

Cardiolipin is an important structural component of the inner mitochondrial membrane, where it makes up around 20% of the total lipid composition. Outside mitochondria, it is found almost exclusively in the membranes of most bacteria — a similarity thought to reflect the endosymbiotic origin of mitochondria. Within the inner mitochondrial membrane, cardiolipin is essential for the optimal function of numerous enzymes involved in energy metabolism. It takes its name from its original source: it was first isolated from beef heart in the early 1940s.

The three antibodies

Anti-cardiolipin antibodies are IgG or IgM antibodies directed against cardiolipin — a negatively charged, uniquely dimeric phospholipid that helps maintain the structural integrity of the mitochondrial membrane. This is also the antibody responsible for the false-positive reactions seen on VDRL testing for syphilis. There is a recognised increased incidence of ACA in Behçet’s disease.

Anti-β2-glycoprotein 1 antibodies target beta-2-glycoprotein 1 (β2GPI), also known as Apolipoprotein H (Apo-H) — a cardiolipin-binding protein synthesised in the liver that also activates lipoprotein lipase. β2GPI is built from five homologous domains: domain V binds the anionic phospholipid surface, while the pathogenic anti-β2GPI antibody binds domain I.

Individually, these antibodies are low-affinity, and a single antibody binding a single β2GPI molecule does not produce stable, pathogenic binding. Once several β2GPI molecules dock onto a phospholipid surface via domain V and open into this exposed conformation, a single bivalent IgG antibody can cross-link domain I on two adjacent β2GPI molecules simultaneously. This cross-linking — not simple high-affinity 1:1 binding — is what produces a stable, high-avidity complex, and it explains why anti-β2GPI binding shows a sharp antigen-density threshold in the laboratory rather than conventional binding kinetics.² This same clustering is thought to trigger downstream cell signalling, for instance via receptors such as ApoER2′ on platelets, monocytes, and endothelium.

Domain V’s membrane anchor isn’t a simple 1:1 or paired contact. Structural and mutagenesis studies describe three distinct contact elements — a hydrophobic loop that inserts into the lipid tail region, plus a lysine-rich loop and a separate lysine pair — which together make distributed electrostatic contact across a cluster of several nearby anionic phospholipid head groups (phosphatidylserine, cardiolipin) rather than binding a fixed, small number of lipid molecules.

The lupus anticoagulant is an immunoglobulin that paradoxically prolongs the aPTT clotting assay in the laboratory — hence the historical misnomer “anticoagulant” — even though it behaves as a pro-coagulant in vivo, through its interaction with phospholipids on the platelet membrane. Because LAC is a functional (rather than a single-antigen) assay, and the antibody population is heterogeneous, several different assays are typically combined to improve diagnostic sensitivity — commonly dilute prothrombin time (dPT), dilute Russell viper venom time (dRVVT), kaolin clotting time (KCT), and silica clotting time (SCT).

Each assay activates clotting at a different point but converges on the same phospholipid-dependent step — the prothrombinase complex, where factors Xa and Va assemble on a phospholipid surface to convert prothrombin to thrombin. This is the step LAC antibodies interfere with, which is why these assays are run with a diluted phospholipid reagent (or, for KCT/SCT, no added phospholipid at all, relying only on trace phospholipid in the sample) — diluting the phospholipid makes the assay maximally sensitive to an antibody competing for that same surface. The confirmatory step repeats the test with excess phospholipid: if the prolonged clotting time now corrects, phospholipid-dependence — and therefore a lupus anticoagulant — is confirmed.

So the real common thread isn’t “these are all antibodies against phospholipids” — it’s that a phospholipid surface is mechanistically required for each one to matter, whether as the antigen itself, the docking platform that exposes the real protein antigen, or the reaction substrate the antibody happens to interfere with. “Antiphospholipid antibodies” is really a historical/functional grouping rather than a statement that they all bind the same kind of molecule — most of the real pathology in APS is protein-directed (β2GPI, prothrombin), riding on a phospholipid membrane.

Clinical presentation

Patients with APS most commonly present with:

• Recurrent venous thromboembolism (VTE)
• Cerebral ischaemic events — TIA, stroke, or ocular ischaemia
• Verrucous (Libman-Sacks) endocarditis
• Necrotising purpura
• Spontaneous miscarriage

Less commonly, APS can present with pulmonary hypertension, epilepsy, migraine-like syndromes, transverse myelopathy, thrombocytopenia (which is actually fairly common), and/or haemolytic anaemia. The diagnostic paradox worth remembering is that the aPTT may come back elevated despite the underlying prothrombotic state.

Associations

APS is an acquired condition, often — but by no means always — associated with lupus. Like lupus, it can also be:

• Drug-related, particularly with chlorpromazine and hydralazine
• Triggered by opportunistic infection
• Seen in the context of sepsis and thrombotic microangiopathy

Management

• Anticoagulation: heparin, then warfarin (in non-pregnant patients), targeting an INR of 2.0–3.0. Higher-intensity anticoagulation (INR 3.0–4.0) is generally reserved for patients who re-thrombose despite adequate standard-intensity anticoagulation, rather than used as a routine first-line target.
• Low-dose aspirin, including during pregnancy
• Hydroxychloroquine (Plaquenil) — the drug of choice where APS is associated with SLE
• Immunotherapy in severe or refractory cases — the anti-CD20 monoclonal antibody rituximab, or even eculizumab
• Plasmapheresis
• Statins — these help prevent antiphospholipid antibody-induced up-regulation of tissue factor, though they are contraindicated in pregnancy

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References

1. Duarte-García A, Pham MM, Crowson CS, et al. “The Epidemiology of Antiphospholipid Syndrome: A Population-Based Study.” Arthritis & Rheumatology. 2019;71(9):1545-1552.
2. Reddel SW, Wang YX, Krilis SA. “Anti-β2-glycoprotein I autoantibodies require an antigen density threshold, consistent with divalent binding.” Lupus. 2003;12(9):664-670.
3. Cade, J.F. Critical Care Compendium: 1001 Topics in Intensive Care & Acute Medicine (p. 37). Cambridge University Press.
4. Papadakis, Maxine A.; McPhee, Stephen J.; Rabow, Michael W.; McQuaid, Kenneth R. CURRENT Medical Diagnosis and Treatment 2023. McGraw Hill LLC.

Image reference sources

• Smith, Larry J. “Antiphospholipid Antibody Syndrome.” Amer Soc Clin Lab Sc. Jan 2017;30(1):7-14.
• Willis R, Gonzalez EB. “Pathogenetic mechanisms of antiphospholipid antibody production in antiphospholipid syndrome.” World J Rheumatol. 2015;5(2):59-68. DOI: 10.5499/wjr.v5.i2.59