Antiphospholipid Syndrome-Diagnostic and Methodologic Approach

Abstract

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by venous and arterial thrombosis and obstetric complications, driven by antiphospholipid antibodies (APLAs). This review synthesizes the latest advancements and current understanding, diagnosis, and treatment of APS. APLAs, including lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-β2-glycoprotein I (aβ2-GPI), interfere with coagulation and endothelial function, as well as with placental health. APS can be primary or secondary; it is often associated with systemic autoimmune diseases like lupus. The pathogenesis of APS remains only partially understood. APLAs promote thrombosis through endothelial damage, platelet activation, and inflammatory signaling pathways. Laboratory diagnosis relies on persistent positivity for APLAs and LAC through tests like ELISA and clotting assays, following a three-step confirmation process. New integrated test systems have been introduced to improve standardization. Classification criteria have evolved, with the 2023 EULAR-ACR criteria providing a weighted, domain-based scoring system, enhancing diagnostic precision. Catastrophic APS (CAPS) is a severe, rare manifestation of APS, characterized by multi-organ failure due to rapid, widespread microthrombosis and systemic inflammation, which requires urgent anticoagulation. Seronegative APS is proposed for patients with clinical features of APS but negative standard antibody tests, possibly due to non-criteria antibodies or transient immunosuppression. Treatment primarily involves long-term anticoagulation with vitamin K antagonists; direct oral anticoagulants are generally not recommended. APS diagnosis and management remain complex due to clinical heterogeneity and laboratory challenges. Continued refinement of diagnostic tools and criteria is essential for improving outcomes in this life-threatening condition.

Keywords: antiphospholipid antibodies; antiphospholipid syndrome; catastrophic APS; lupus anticoagulant.

Figure 1

The interaction between β2-microglobulin, phospholipids of plasma membranes, and antiphospholipid antibodies leads to the activation of target cells, including platelets, monocytes, macrophages, neutrophils, and endothelial cells. β2-microglobulin undergoes conformational changes in the blood plasma under the influence of extrinsic and intrinsic factors. In circular and S-shaped forms, it attaches to membrane phospholipids but has no ability to bind to antibodies. Only the J-shaped form has this ability, because this form has a cryptic epitope available for interaction with antibodies [25,26].

Figure 2

Comparison of methods for detecting antiphospholipid antibodies on the example of β2-glycoprotein. Conventional tests for antiphospholipid antibodies use a mixture of phospholipids, calcium ions, and coagulation activators to detect a broad range of antibodies in patient serum. These tests identify both clinically significant and insignificant antibodies and often produce cross-reactions. As such, they are primarily used for screening purposes. In contrast, modern assays incorporate phospholipids and highly specific monoclonal antibodies that bind to a single antigenic site on β2-glycoprotein, but only when its conformation reflects in vivo conditions that lead to antibody production. These advanced tests detect only clinically relevant antibodies and are used for the definitive diagnosis of antiphospholipid syndrome.