Women with sickle cell disease experience significant inflammatory marker fluctuations throughout their menstrual cycle, with C-reactive protein levels more than ten times higher during the follicular phase compared to the luteal phase, according to new research published in Blood Vessels, Thrombosis & Hemostasis. This finding provides critical insight into the long-reported phenomenon of menstrual cycle-related pain crises in female sickle cell patients.
A groundbreaking study has identified a potential biological mechanism behind the observation that women with sickle cell disease (SCD) often experience painful vaso-occlusive events (VOEs) clustered around their menstrual periods. The research, led by investigators at the University of Pennsylvania, has documented significant cyclical variation in C-reactive protein (CRP) – a key inflammatory marker associated with VOE risk – across the menstrual cycle in women with SCD.
Inflammatory patterns mirror clinical observations
The study conducted by Dr Jessica Wu and colleagues analysed plasma samples from 31 individuals with confirmed SCD, including 13 female and 18 male patients. The researchers measured CRP in all samples and female sex hormones in samples from female patients to determine menstrual cycle phase at the time of collection.
While no significant differences in median CRP levels were observed between male and female participants overall (4.45 vs 3.88 mg/L, p=0.89), a striking pattern emerged when comparing samples from women in different phases of their menstrual cycle. CRP levels were significantly higher during the follicular phase compared to the luteal phase (8.80 vs 0.82 mg/L, p=0.03).
“The amount of inflammation is significantly elevated in the follicular phase, or first half, of the menstrual cycle in female patients with SCD,” said Dr Wu. “This observation correlates with what we see in the literature, that this is the time in which this patient population has the most VOEs.”
Amplified inflammatory response
The researchers note that this pattern mirrors CRP fluctuations seen in the general female population, but with a much greater magnitude of elevation in women with SCD. During the follicular phase, median CRP levels in women with SCD (8.80 mg/L) were markedly higher than levels typically observed in healthy women (0.74 mg/L).
Other markers also showed a trend toward elevation in the follicular phase, including neutrophil and platelet counts, aspartate aminotransferase, cortisol, and thrombin-antithrombin complexes. Most notably, platelet counts in females during the follicular phase were significantly elevated compared to males (383k/µL vs 219k/µL, p<0.001).
In the published paper, the authors explain: “VOEs are a crucial target for intervention among individuals with SCD, yet perimenstrual VOE pathophysiology remains poorly understood. These results suggest a cyclic pattern of inflammation across the menstrual cycle in females with SCD that may contribute to perimenstrual VOEs.”
Implications for clinical management
The findings could have important implications for clinical care, suggesting a potential target for intervention in menstrual cycle-related SCD pain management.
“Many hormonal contraceptives can suppress menstruation or suppress the hormone fluctuations that occur from cycle to cycle, so contraceptives could help these patients manage their pain crises,” Dr Wu noted. “SCD is a really debilitating and painful disease. The more data we have about how it presents in female patients, the better we can counsel them on anticipating and managing their pain.”
The authors acknowledge that further research is needed, noting in their paper: “These findings warrant prospective validation, exploration of the menstrual patterns of other markers associated with SCD pathophysiology, and correlation with clinical symptomatology. Further study of perimenstrual VOEs may support therapeutic strategies, including hormonal contraceptives, outside of the typical armamentarium of SCD treatments.”
Study limitations
The researchers emphasised several limitations, including the study’s small sample size and cross-sectional design. Since each participant contributed only one sample, the researchers were unable to track biomarker changes within individuals across their menstrual cycles. Additionally, the team lacked clinical menstrual cycle data, instead relying on sex hormone laboratory measurements to determine cycle phase.
The team plans to validate their findings through prospective studies with larger sample sizes and to explore menstrual patterns of other biomarkers associated with SCD, as well as correlation with clinical symptoms.
