Additional Risk Factors Associated with Thrombosis and Pregnancy Morbidity in a Unique Cohort of Antiphospholipid Antibody-Positive Patients

Additional Risk Factors Associated with Thrombosis and Pregnancy Morbidity in a Unique Cohort of Antiphospholipid Antibody-Positive Patients

Antiphospholipid syndrome (APS) is an autoimmune prothrombotic condition characterized by significant morbidity, including arterial thrombosis, venous thrombosis, and pregnancy morbidities such as premature births, preeclampsia, placental insufficiency, and recurrent spontaneous abortions. The syndrome is diagnosed based on the presence of one or more antiphospholipid antibodies (aPL) in conjunction with clinical manifestations. However, not all aPL-positive individuals develop clinical symptoms, suggesting that additional risk factors may play a role in the progression from aPL positivity to APS. This study aimed to identify these additional risk factors in a large cohort of Chinese aPL-positive patients, focusing on arterial thrombosis, venous thrombosis, and pregnancy morbidities.

The study was conducted as a cross-sectional cohort analysis of 453 consecutive patients with documented positive aPL who attended Peking University People’s Hospital. Among these, 297 patients had persistent aPL positivity, defined as the presence of one or more “criteria” aPL (anticardiolipin [aCL] IgG or IgM, anti-beta2-glycoprotein-I [anti-b2GPI] IgG or IgM, and lupus anticoagulant [LA]) for at least 12 weeks. Patients were categorized into asymptomatic aPL carriers and those with thrombotic or obstetric APS. The study employed univariate and multivariable logistic regression analyses to evaluate the association between various risk factors and APS clinical manifestations. Additionally, circulating markers of neutrophil extracellular traps (NETs), specifically cell-free DNA and citrullinated histone H3 (Cit-H3), were assessed to explore their role in APS pathogenesis.

The cohort consisted of 297 patients, with 154 experiencing APS clinical manifestations and 143 being asymptomatic carriers. Among the APS patients, 85 had arterial thrombosis, 76 had venous thrombosis, 26 had both arterial and venous thrombosis, 34 had pregnancy morbidities, and 15 had both thrombosis and pregnancy morbidities. The mean age of the cohort was 43.1 years, with 79.1% being female. Additionally, 142 patients had underlying autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis, mixed connective tissue disease, undifferentiated connective tissue disease, systemic vasculitis, and adult-onset Still’s disease.

The study identified several additional risk factors associated with arterial thrombosis among aPL-positive carriers. Smoking was found to be a significant risk factor, with an odds ratio (OR) of 6.137 (95% confidence interval [CI] = 2.408–15.637, P = 0.0001). Hypertension also demonstrated a significant association, with an OR of 2.368 (95% CI = 1.249–4.491, P = 0.008). The presence of underlying autoimmune disease was another critical risk factor, with an OR of 4.401 (95% CI = 2.387–8.113, P < 0.001). For venous thrombosis, smoking (OR = 4.594, 95% CI = 1.681–12.553, P = 0.029) and underlying autoimmune disease (OR = 6.330, 95% CI = 3.355–11.940, P < 0.001) were significant risk factors. In the context of pregnancy morbidities, only the presence of underlying autoimmune disease showed a significant association, with an OR of 3.301 (95% CI = 1.407–7.744, P = 0.006).

The study also explored the role of NETs in APS pathogenesis. Elevated levels of cell-free DNA and Cit-H3 were observed in APS patients and aPL-positive patients with autoimmune diseases compared to aPL carriers without autoimmune diseases. Furthermore, neutrophils conditioned with sera from APS patients exhibited heightened NETosis potential compared to those treated with sera from aPL carriers without autoimmune diseases. These findings suggest that NETs may act as a prothrombotic scaffold, promoting platelet activation and tissue factor adhesion in APS patients.

The study’s findings align with previous research highlighting the role of hypertension, smoking, and underlying autoimmune diseases as risk factors for thrombosis in aPL-positive patients. Hypertension has been consistently associated with arterial thrombosis in various studies, including those involving European and North American cohorts. Smoking, while showing conflicting results in different studies, was strongly associated with both arterial and venous thrombosis in this Chinese cohort. The presence of underlying autoimmune diseases, particularly SLE, has been previously linked to increased thrombotic risk in aPL-positive patients. The study’s focus on a Chinese population provides valuable insights into the ethnic differences in APS risk factors.

The study also contributes to the understanding of pregnancy morbidities in aPL-positive patients. While the presence of underlying autoimmune disease was the only significant risk factor identified, the study underscores the need for further research into non-traditional APS risk factors, such as complement activation and angiogenic factors, to better predict pregnancy outcomes in this population.

The strengths of this study include its large size, rigorous clinical and laboratory definitions, and consideration of multiple clinical, demographic, and laboratory variables. However, the cross-sectional design limits the ability to establish causal relationships between risk factors and clinical outcomes. Additionally, the study did not account for medication use or genetic thrombophilia risks, which may be confounding variables. Information on peripartum management and underlying autoimmune disease activities was also lacking, potentially affecting the analysis of pregnancy morbidities.

In conclusion, this study identifies several additional risk factors for APS clinical manifestations in a large cohort of Chinese aPL-positive patients. Hypertension, smoking, and underlying autoimmune diseases were significant risk factors for arterial and venous thrombosis, while the presence of autoimmune disease was associated with pregnancy morbidities. The study also highlights the potential role of NETs in APS pathogenesis. These findings may help physicians risk-stratify aPL-positive Asian patients and guide future research into the mechanisms underlying APS. Longitudinal studies are needed to confirm these findings and explore the chronology between risk factors and APS clinical manifestations.

doi.org/10.1097/CM9.0000000000001964

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