Genetic Associations and Platelet Count Trajectories in Gestational Thrombocytopenia and Immune Thrombocytopenia during Pregnancy

Introduction

Thrombocytopenia, defined as a platelet count less than 150×10⁹/L, affects 5% to 12% of pregnancies. Gestational thrombocytopenia (GT) accounts for approximately 70% of these cases, presenting as a mild to moderate decrease in platelet count, usually in the late second or third trimester, and typically resolving postpartum. Immune thrombocytopenia (ITP) contributes to 3% of cases and presents with mild to moderate thrombocytopenia. Both conditions pose diagnostic challenges due to overlapping presentations and the lack of specific markers, complicating differentiation solely on the basis of platelet counts. In GT, platelet counts typically remain above 70×10⁹/L with minimal hemorrhage risk, whereas ITP can involve significant bleeding and lower counts, especially in severe cases. This clinical overlap necessitates advanced diagnostic approaches.

Methods

This study included 2135 pregnant women who were diagnosed with thrombocytopenia between 2000 and 2024 at Peking University People’s Hospital, Beijing, China. Among them, 1556 had GT, and 50 had ITP. Genomic DNA was extracted from peripheral blood samples and genotyped via high-throughput sequencing. Quality control excluded SNPs with a call rate less than 95%, minor allele frequency less than 1%, and those deviating from Hardy‒Weinberg equilibrium. Statistical analyses compared platelet count trajectories and genetic associations among the GT, ITP, and control groups. Platelet count trajectories were assessed via linear mixed models, with fixed effects for hospital site, maternal age, and gestational age and random effects for repeated measures. Genome-wide association studies (GWASs) identified genetic loci associated with platelet counts and the development of GT and ITP. Principal components analysis (PCA) accounted for population stratification. Meta-analyses combined results from different trimesters. The internal replication divided the cohort by diagnosis year (2000-2012 and 2013-2024), and the GWAS analyses were repeated. A variant was replicated if it showed the same effect direction and achieved Bonferroni-corrected significance in both subsets. External validation compared significant loci with BioBank Japan Project GWAS findings.

Results

Platelet counts in GT patients gradually decline throughout pregnancy, reaching their lowest point at delivery, and typically recover 4 to 8 weeks postpartum without intervention. Specifically, the mean platelet count in GT patients decreased from 150×10⁹/L in the first trimester to 90×10⁹/L at delivery. In contrast, ITP patients, who often require treatment starting in the third trimester, exhibit earlier platelet recovery posttreatment, with a significant increase in platelet counts within a week of initiating therapy. The mean time to response was 4.39±2.54 days for combination therapy and 7.29±5.01 days for prednisone monotherapy (p<0.001). The PEAR1 variant rs12041331-G was significantly associated with GT, with carriers showing a more rapid decline in platelet counts during the second and third trimesters (p<0.01). Specifically, compared with noncarriers, carriers of this variant had a 20% faster decline in platelet counts. However, the TUBB1 missense variant rs415064-C, which results in an amino acid substitution in the tubulin beta-1 chain, was significantly associated with an increased risk of ITP (odds ratio: 2.01, 95% CI: 1.61-2.51, p=7.37×10^-10). This variant affects platelet generation and morphology, suggesting that it could serve as a genetic marker for ITP.

Conclusion

This study elucidates the distinct platelet count trajectories and genetic associations between gestational GT and ITP during pregnancy. Our findings show that while GT patients experience a gradual decline in platelet counts, which reach their lowest level at delivery, ITP patients exhibit earlier platelet recovery posttreatment. The PEAR1 variant is significantly associated with GT, leading to a rapid decline in platelet counts during pregnancy. Conversely, the TUBB1 variant is strongly associated with an increased risk of ITP, affecting platelet generation and morphology. These gene variants can assist in distinguishing between GT and ITP.