Szuber Natasha, Guglielmelli Paola, Gangat Naseema
Division of Hematology, Department of Internal Medicine, Université de Montréal, Montréal, Quebec, Canada.
Department of Experimental and Clinical Medicine, CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, Italy.
Am J Hematol. 2025 Jun;100 Suppl 4(Suppl 4):74-87. doi: 10.1002/ajh.27665. Epub 2025 Mar 14.
Sex and gender have emerged as central modifiers of disease biology, phenotype, and clinical outcomes in myeloproliferative neoplasms (MPNs). This review will uniquely highlight issues affecting women with MPN and articulate their relevant determinants.
A higher overall prevalence of MPN has been established in women. The incidence of essential thrombocythemia (ET) predominates, while, conversely, polycythemia vera (PV) and myelofibrosis (MF) are seen in lower frequencies as compared to men. Diagnostic criteria are dictated by sex-driven physiological variances in hemoglobin and hematocrit levels in PV, mandating separate diagnostic thresholds, respectively: > 16.0 g/dL and > 48% in women vs. > 16.5 and > 49% in men.
Women with MPN harbor fewer acquired somatic mutations and a lower frequency of high-risk mutations than their male counterparts; lower JAK2V617F driver variant allele frequency and attenuated allele burden kinetics have also been reported. Women with MPN are younger at diagnosis than men and, contingent on subtype, display more indolent disease features. Importantly, validated symptom burden assessments consistently disclose higher scores in women vs. men.
Women with MPN have a unique thrombotic diathesis with respect to men, more frequently involving the splanchnic venous system in those ultimately diagnosed with PV. Outcomes data depict female sex as a variable associated with more favorable clinical trajectories, including lower rates of MF/leukemic transformation and secondary cancers, as well as improved overall survival rates vis-à-vis men.
LIFE-CYCLE WINDOWS, PREGNANCY, AND POSTPARTUM: Potential challenges at each significant life stage will be addressed: puberty, preconception and fertility, and perimenopause; these include issues surrounding oral contraceptives and hormone use. Prospective studies suggest overall favorable maternal and fetal outcomes with pregnancy in women with MPN. Full details on risks and reported outcomes will be discussed, as well as a risk-adapted approach to management informed by obstetric and thrombosis history. Recommendations include aspirin 81 mg daily in all patients and cytoreduction with interferon-α in those with antecedent thrombosis, as well as in low-risk cases with higher-risk features (e.g., poorly controlled hematocrit and recurrent fetal loss). Antepartum anticoagulation with low molecular weight heparin (LMWH) is recommended in cases with previous venous thromboembolism.
This review highlights female sex and gender as critical drivers of MPN incidence, presentation, and natural history. It further outlines the impact and management of MPN as related to unique female reproductive phases. A sex-informed lens will be required in order to recalibrate current prognostic tools, a requisite to refining patient counselling and clinical decision-making in line with precision medicine. Moreover, while several mechanisms underpinning sex-defined discrepancies have been defined, these mandate further prospective study. Finally, sex and gender-based differences must be weighted in clinical trials with systematized procedures to correct participation imbalances in favor of sex and gender equity.
性别已成为骨髓增殖性肿瘤（MPN）疾病生物学、表型及临床结局的核心影响因素。本综述将特别关注影响MPN女性患者的问题，并阐明其相关决定因素。
已证实女性MPN的总体患病率较高。原发性血小板增多症（ET）的发病率占主导，相反，真性红细胞增多症（PV）和骨髓纤维化（MF）的发病率低于男性。PV的诊断标准受性别驱动的血红蛋白和血细胞比容水平生理差异影响，分别规定了不同的诊断阈值：女性血红蛋白>16.0g/dL且血细胞比容>48%，男性血红蛋白>16.5g/dL且血细胞比容>49%。
与男性MPN患者相比，女性患者获得性体细胞突变较少，高危突变频率较低；也有报道称女性JAK2V617F驱动变异等位基因频率较低且等位基因负荷动力学减弱。MPN女性患者诊断时年龄比男性小，且根据亚型不同，表现出更惰性的疾病特征。重要的是，经过验证的症状负担评估一致显示女性得分高于男性。
与男性相比，MPN女性患者有独特的血栓形成素质，最终诊断为PV的患者更常累及内脏静脉系统。结局数据表明，女性是与更有利临床病程相关的变量，包括MF/白血病转化和继发性癌症发生率较低，以及总体生存率高于男性。
生命周期阶段、妊娠与产后：将探讨每个重要生命阶段的潜在挑战：青春期、孕前与生育以及围绝经期；这些包括口服避孕药和激素使用相关问题。前瞻性研究表明，MPN女性患者妊娠时母婴总体结局良好。将讨论风险和报告结局的详细信息，以及根据产科和血栓形成病史采取的风险适应性管理方法。建议包括所有患者每日服用81mg阿司匹林，有既往血栓形成的患者以及具有高风险特征的低风险病例（如血细胞比容控制不佳和反复流产）使用干扰素-α进行细胞减灭治疗。既往有静脉血栓栓塞的患者建议在产前使用低分子量肝素（LMWH）进行抗凝。
本综述强调性别是MPN发病率、表现及自然史的关键驱动因素。它进一步概述了MPN与女性独特生殖阶段相关的影响及管理。为了重新校准当前的预后工具，需要从性别角度进行考量，这是根据精准医学优化患者咨询和临床决策的必要条件。此外，虽然已确定了一些导致性别差异的机制，但这些仍需进一步的前瞻性研究。最后，在临床试验中必须权衡基于性别的差异，并采用系统化程序纠正参与不平衡，以促进性别平等。
