Clinical and serological markers of antiphospholipid syndrome in Saudi Arabia: A multicenter retrospective study

INTRODUCTION

Antiphospholipid syndrome (APS) is an autoimmune systemic disorder characterized by the persistent presence of antiphospholipid antibodies (aPL), such as anticardiolipin antibodies (aCL; immunoglobulin G [IgG] or immunoglobulin M [IgM]), anti-beta2 glycoprotein I antibodies (B2GPI; IgG or IgM), and lupus anticoagulant (LA). These antibodies target phospholipids, resulting in thrombotic and/or adverse obstetric outcomes.^[1] A severe form of the syndrome, known as catastrophic APS, is characterized by extensive microangiopathy affecting multiple organs in a short period, with a mortality rate of approximately 30%, despite current treatment options.^[2] APS can manifest as an independent syndrome (primary APS or PAPS) or in association with other autoimmune diseases, particularly systemic lupus erythematosus (SLE). The latter is classified as secondary APS or SAPS.

Epidemiological studies estimate the incidence of APS to be approximately 50 cases per 100,000 individuals.^[3] The highest risk associated with recurrent thrombosis in APS was observed in patients positive for aPL in all three assays (triple-positive), followed by those positive for LA.^[4] Sex-based differences in APS clinical manifestations and outcomes have been widely reported. For instance, epidemiological studies indicate a higher prevalence of APS in females, with a female-to-male ratio of approximately 3.5:1. Female patients typically manifest at an earlier age and are more prone to cerebral venous sinus thrombosis (CVST). In contrast, male patients are more likely to experience gastrointestinal complications, arterial events such as myocardial infarction, and recurrent thrombosis.^[5,6] Furthermore, patients with SAPS are generally younger, exhibit a higher female predominance, and present with a higher frequency of thrombocytopenia and hemolytic anemia compared to PAPS patients.^[7,8]

Several international studies have investigated the clinical and laboratory characteristics of APS. A large multinational study across 13 European countries provided detailed insight into 1000 APS patients from Europe in 2002.^[9] In addition, research has been conducted on APS disease characteristics across various nations, including China, Italy, Colombia, and Egypt.^[5,6,10-13] Despite extensive international studies on APS, regional studies exploring sex-based differences in Saudi Arabian patients remain scarce. This study aims to address this gap by analyzing the clinical and laboratory features of APS and identifying disease expression patterns based on gender and APS type. The findings will contribute to a better understanding of disease variation and highlight key differences and similarities in the clinical and immunological presentation at the time of diagnosis between PAPS versus SAPS groups, and between male and female APS patients.

MATERIALS AND METHODS

RESULTS

This retrospective cohort study included 200 patients with APS (100 males and 100 females: 76% with PAPS and 24% with SAPS). The distribution of males and females among the PAPS and SAPS groups was not equal; the PAPS group had more males, while the SAPS group had more females, and the difference in distribution was statistically significant (P = 0.02). The mean age of the patients was 39.01 ± 11.69 years, with a 95% CI for the mean of 37.37–40.64.

The analysis revealed that the male group had a significantly higher mean age than the female group (P = 0.03). The prevalence of venous thrombosis in the total patient population was 43.5%, with males (57%) exhibiting a statistically significant (P ≤ 0.001) higher rate than females (30%). The study showed that 22% of the patients had deep vein thrombosis (DVT), and 19% had pulmonary embolism (PE), with a significantly higher rate in males than in females (P < 0.05). The prevalence of portal vein thrombosis (PVT) among all participants was 5.5%, with males (9%) having significantly (P = 0.03) higher rates than females (2%). Among the study participants, CVST was observed in 5.5% of cases, with a slight sex disparity: 5% in men and 6% in women. This difference was not statistically significant (P = 0.756).

Arterial thrombosis was observed in 15.5% of the participants, with a significant gender difference. Males (23%) had statistically significant (P = 0.003) higher rates than females (8%). Similarly, 11% of all participants experienced a stroke, with males (15%) showing higher rates than females (7%); however, the difference in stroke rate was not statistically significant (P = 0.071). The prevalence of migraine among all participants was 6%, with females (10%) exhibiting a statistically significant (P = 0.017) higher rate than males (2%). The prevalence of seizures among all participants was 4%, and no significant differences were observed between males and females. Obstetric complications were observed in 47% of the female participants. Among all participants, thrombocytopenia was observed in 10% of the cases, with no statistically significant differences between the male and female groups (P = 0.637).

This study identified LA in 89.5% of participants, with 43.5% showing a weak ratio, 35% showing a moderate ratio, and 21% showing a strong ratio. No statistically significant difference was observed between males and females (P = 0.92). aCL IgG was identified in 30.5% of the cohort, with males being higher than females; however, the difference was not statistically significant (P = 0.25). Similarly, aCL IgM was identified in 32.5% of the cohort, with males being higher than females, although the difference was not statistically significant (P = 0.174). IgG B2GPI was identified in 28.5% of the cohort, with females being higher than males; however, the difference was not statistically significant (P = 0.434). Similarly, IgM B2GPI was identified in 25.5% of the cohort, with females being higher than males; this difference was statistically significant (P = 0.035). Among all the study participants, 12.5% expressed triple-positive aPL, with a higher occurrence observed in women than in men. However, this gender-based difference was not statistically significant (P = 0.285). Table 1 presents a comprehensive comparison of demographic data, clinical characteristics, and laboratory findings among the total cohort of male and female APS patients. Figure 1 illustrates the rate of thrombosis in the male and female groups.

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Figure 1:

Thrombosis rate in the male and female groups. DVT: Deep vein thrombosis, PE: Pulmonary embolism, PVT: Portal vein thrombosis, and CVST: Cerebral venous sinus thrombosis

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The study showed that the PAPS group (38.72 ± 11.52) had a lower mean age than the SAPS group (39.9 ± 12.27), but the difference was not statistically significant (P = 0.546). Patients in the PAPS group had a much higher rate of venous thrombosis (DVT, PE, PVT, and CVST), arterial thrombosis, stroke, and obstetric complications, whereas those in the SAPS group had a much higher rate of migraine, seizures, thrombocytopenia, and hemolytic anemia. The differences were statistically significant for venous thrombosis, DVT, thrombocytopenia, and hemolytic anemia (P < 0.05).

This study identified LA in 90.7% of the PAPS group, with 46.3% showing a weak ratio, 35.5% showing a moderate ratio, and 18% showing a strong ratio. In the SAPS group, LA was detected in 85% of the cases, with 34% showing a weak ratio, 34% showing a moderate ratio, and 31.7% showing a strong ratio. The difference in LA expression between the PAPS and SAPS groups was not statistically significant (P = 0.146). aCL IgG was identified in 27% of the PAPS group and in 41.6% of the SAPS group; however, the difference was not statistically significant (P = 0.132). Similarly, aCL IgM was identified in 29% of the PAPS group and in 43.7% of the SAPS group; however, the difference was not statistically significant (P = 0.056).

IgG B2GPI was identified in 24.3% of patients in the PAPS group and in 41.6% of patients in the SAPS group; the difference was statistically significant (P = 0.02). Similarly, IgM B2GPI was identified in 22.3% of the PAPS group and 35.4% of the SAPS group; the difference was not statistically significant (P = 0.071). Triple-positive aPL was observed in 9.2% of the PAPS group and 23% of the SAPS group; this difference was statistically significant (P = 0.012). Table 2 presents a comprehensive comparison of the demographic data, clinical characteristics, and laboratory findings of the patients with PAPS and SAPS. Figure 2 illustrates the rate of thrombosis in the PAPS and SAPS groups.

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Figure 2:

Thrombosis rate in the primary antiphospholipid syndrome (PAPS) and secondary antiphospholipid syndrome groups (SAPS). DVT: Deep vein thrombosis, PE: Pulmonary embolism, PVT: Portal vein thrombosis, and CVST: Cerebral venous sinus thrombosis

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DISCUSSION

This study aims to assess the clinical and laboratory features of APS patients and to determine the impact of patient gender and APS type on clinical and immunological patterns. The study enrolled 200 patients with APS, with a male-to-female ratio of 1:1, 76% with PAPS, and 24% with SAPS. Clinical and experimental studies have indicated that gender influences autoimmune responses. Females tended to exhibit stronger immunoreactivity and a higher incidence of autoimmune disease than males. These findings highlight the role of sex hormones in immune system modulation.^[15]

This study revealed that the clinical presentation of APS patients differs between male and female patients. Males had a higher mean age and a higher risk of thrombosis. Several factors could explain this observation, including the fact that males have a higher risk of atherosclerosis.^[16] Another explanation is variations in growth hormone (GH) secretion rhythms, where males secrete GH in a pulsatile pattern, while females secrete GH continuously. Gender-specific GH patterns significantly influence the expression of coagulation inhibitor genes in the liver, and GH affects resistance to activated protein C. These alterations contribute to an increased risk of thrombosis in males.^[17]

Research indicates that body height plays a significant role in the elevated risk of thrombosis among males, with taller individuals being more likely to have thrombosis than shorter ones. The exact mechanism by which increased body height predisposes individuals to venous thrombosis remains uncertain, although it is hypothesized that stasis due to greater body height may be a key factor.^[18]

An alternative explanation involves gender-based differences in physiological responses to inflammation. Studies have shown that male mice have higher levels of interleukin (IL)-1 β, which may contribute to increased thrombus formation.^[19] Another possible explanation is the difference in environmental factors, such as men being more likely to smoke, which significantly contributes to the disparity in thrombosis risk between males and females.^[20]

In contrast, our findings indicate that females exhibit a greater propensity for CVST and migraines. This disparity may be attributed to hormonal factors, such as the use of oral contraceptives and hormonal fluctuations during pregnancy and the postpartum period.^[21,22]

The study revealed that the clinical presentation and laboratory features of APS patients differed between the PAPS and SAPS groups. The PAPS group had a higher likelihood of developing thrombosis and obstetric complications. This discrepancy may be attributed to several factors, including the observation that patients with PAPS exhibit a more pronounced prothrombotic fibrin clot phenotype, higher levels of oxidative stress and DNA damage, impaired DNA repair mechanisms, and elevated levels of inflammatory markers such as tumor necrosis factor-alpha and IL-6, all of which increase thrombotic risk.^[23-25]

In contrast, the SAPS group had a greater propensity for migraines, seizures, thrombocytopenia, and hemolytic anemia. This difference is mainly attributed to additional autoimmune processes found in conditions such as SLE. These mechanisms intensify hematologic manifestations through processes such as immune complex formation, complement activation, and autoantibody-mediated direct cell destruction.^[26]

This study’s results are consistent with the findings of Hawro T et al., who found that seizures were more common in SAPS than in PAPS. This is primarily due to additional risk factors associated with SLE, including increased central nervous system involvement, thromboembolic events, and the presence of certain autoantibodies.^[27] Table 3 presents a comprehensive comparison of the demographic data, clinical characteristics, and laboratory findings of APS in different countries.

In this study, the mean age of patients with APS was closely aligned with findings from other international studies. The results also revealed that the prevalence of DVT was lower than that reported in previous studies conducted in other regions. The current findings are consistent with those of Truglia et al. and Moschetti et al., who reported that PE occurs in one-fifth of patients with APS.^[5,6] However, the current results differ from several earlier studies that reported varying PE prevalence rates. For example, Cervera et al. and Shi et al. observed a lower prevalence rate,^[9,10] while Huang et al. and Álvarez-López et al. reported a higher prevalence rate.^[11,12] Similarly, the prevalence of stroke in our study is consistent with the findings of Cervera et al. and Shi et al.;^[9,10] however, a higher rate of stroke was observed in other studies.^{[5,6,11,12,28]}

A notable finding of our study was the lower incidence of SLE, affecting only 16% of the participants. This contrasts with findings from other studies, where SLE rates were higher: Cervera et al. reported 36%, Álvarez-López et al. observed 39%, and Shi et al. reported 65%.^[9,10,12] The lower SLE prevalence in our study contributed to a lower proportion of SAPS (24%) compared to findings from earlier studies.

The interpretation of aPL test results requires caution during acute thrombotic events and in patients receiving anticoagulant treatment, as these factors may lead to false-positive or false-negative results, potentially compromising the reliability of the test.^[14] The 2006 revised Sapporo criteria may not capture all clinically diagnosed APS cases, and their inappropriate use may lead to underdiagnosis.^[1] A key strength of this study is its comprehensive assessment of both gender-related differences and APS types in relation to clinical and immunological patterns. However, this study has several limitations, including its retrospective design, relatively small sample size, and potential for selection bias, particularly sampling bias. Since the study was conducted in private hospitals, which may not represent the entire population, this could limit the applicability of our findings to the general population.

CONCLUSION

This is the first large cohort study in Saudi Arabia to assess the clinical and laboratory features of APS patients and the impact of gender and various forms of APS. The findings show significant differences in thrombosis rate and APS markers between males and females, and between PAPS and SAPS groups.