Lupus Anticoagulant and Complement C4 Consumption in Antiphospholipid Antibody Testing: Disentangling Inflammation...

Antiphospholipid antibodies (aPL) define the laboratory criteria for antiphospholipid syndrome (APS), but their relationships with complement consumption, inflammation, and modifiers such as sex remain uncertain. Our central hypothesis was that C4 consumption represents a more specific indicator of immune-complex-driven autoimmunity than composite complement definitions or CRP, which more often reflect nonspecific inflammatory activation.

We retrospectively analyzed 1260 patients tested for lupus anticoagulant (LA), anticardiolipin (aCL), and anti-β2-glycoprotein I (anti-β2GPI), with complement (C3, C4) and C-reactive protein (CRP) available in subsets. This retrospective, fully anonymized laboratory study was approved by the Institutional Review Board. Patients were grouped into eight serological phenotypes. Multivariable logistic regression examined associations with low complement, low C4, and CRP > 1.0 mg/dL, adjusting for sex and inpatient status. Principal component analysis (PCA) identified four components explaining ~86% of variance; clustering was exploratory.

Low C4 was most strongly associated with LA + aCL and triple-positive profiles and showed good discrimination (AUC 0.84), whereas composite definitions of low complement were less informative (AUC 0.73). Anti-β2GPI-only positivity was linked only to the composite low complement outcome. Low complement occurred more frequently in women. CRP elevation was mainly associated with inpatient status (aOR = 3) and was more common in men, with weaker associations observed for LA-only and multi-positive profiles. The CRP model showed only fair discrimination (AUC 0.68).

C4 showed the strongest association in this dataset, whereas CRP largely reflected nonspecific inflammation, especially in hospitalized men. Observed sex-associated patterns were present, with women more often showing complement consumption and men more often showing CRP elevations. These findings indicate that C4 showed a clearer analytical signal than composite definitions, while CRP should be interpreted cautiously. Prospective studies with linked clinical outcomes are needed for validation.