# Identification of Three Distinct Subgroups in Antiphospholipid Syndrome: Implication for Sex Differences and Prognostic Outcomes from a Multicenter Study

## TL;DR

This study identifies three distinct subgroups of antiphospholipid syndrome with unique clinical features and outcomes, highlighting sex differences and a key molecule linked to poor prognosis.

## Contribution

The study reveals three distinct APS subgroups with unique clinical and molecular profiles, including sex-based distinctions and a key prognostic molecule.

## Key findings

- Three APS subgroups were identified with distinct clinical features and prognostic outcomes.
- Cluster 1 is predominantly female with high pregnancy morbidity and favorable prognosis.
- Male tAPS is associated with high thrombosis and poor prognosis, linked to insulin-like growth factor 1.

## Abstract

Antiphospholipid syndrome (APS) is a heterogeneous autoimmune disease with persistent antiphospholipid antibodies. This study aimed to identify unrecognized APS subgroups from multicenter cohorts (n = 760, training: n = 415; validation: n = 345). Patients are stratified through unsupervised K‐means clustering analysis. Prognostic outcomes are evaluated using Kaplan‐Meier survival analyses. Proteomic analysis is conducted on primary APS patients (n = 36) and healthy controls (n = 12). Key molecule insulin‐like growth factor 1 is validated using ELISA. Three clusters are identified. Cluster 1 (n = 320, 42.1%) is completely consisted of females (100%), with predominant occurrence of pregnancy morbidity (88.8%) but low incidences of thrombocytopenia (18.4%) and thrombosis (15.0%), and a favorable prognosis. Cluster 2 (n = 309, 40.7%) is predominantly female (99.4%) and characterized by high thrombosis (85.8%) and thrombocytopenia (46.6%), low pregnancy morbidity (13.6%), and poor prognosis. Cluster 3 (n = 131, 17.2%) is predominantly male (99.2%), exhibiting highest thrombosis (96.2%) and moderate thrombocytopenia (32.8%), with worst prognosis. Immunological and proteomic analyses clearly differentiated three clusters. This study reveals a distinct difference between obstetric and thrombotic APS, and a sex‐based distinction within thrombotic APS. Three APS subgroups display unique clinical and molecular characteristics, and marked difference in prognostic outcomes.

A large‐scale, multicenter, and two‐stage study is conducted to define antiphospholipid syndrome (APS) subgroups. By applying unsupervised K‐means clustering algorithm, the authors identified three distinct APS subgroups: obstetric APS, female thrombotic APS (tAPS), and male tAPS, which display marked differences in clinical manifestations and prognosis. Insulin‐like growth factor 1 is identified as key molecule linked to poor prognosis in male tAPS.