9  Hematology Through a Gender Lens

9.1 Session Overview

Session Details
Session Hematology Through a Gender Lens: Evolving Insights into Unique and Underrecognized Challenges in Hematology
Speaker Sarah O’Brien, MD, MSc
Affiliation Nationwide Children’s Hospital / The Ohio State University College of Medicine, Columbus, OH
Focus ITP, hemophilia, and iron deficiency across the reproductive life stages

Dr. O’Brien distills ASH 2025 evidence on three conditions that disproportionately burden women and female patients: immune thrombocytopenia (ITP) in pregnancy and menstruation, females affected by hemophilia A, and iron deficiency in menstruating and pregnant individuals [slide p.3]. Using illustrative patient vignettes, she shows how routine encounters can miss the diagnosis—and how emerging data from LUNA3, the U.S. 8CHECK program, and multidisciplinary QI projects are reshaping screening, genetic testing, and treatment across the reproductive life course.

9.2 Speaker Spotlight

Sarah O’Brien, MD, MSc is a pediatric hematologist at Nationwide Children’s Hospital and Professor of Pediatrics at The Ohio State University. Her research program centers on bleeding disorders in women and girls, with particular focus on heavy menstrual bleeding as a presenting manifestation of inherited hemostatic defects. She has led multi-institutional studies establishing evidence-based screening algorithms for adolescents with HMB and is a key advocate for sex-disaggregated hematology research.

9.3 What’s New in 2025–2026

9.3.1 ITP in Pregnancy: A Practical Framework

Matusiak, Malinowski, and Arnold’s 2025 Hematology Am Soc Hematol Educ Program review frames how to approach low platelets during pregnancy [slide p.5]:

  • Differential by frequency: Gestational (physiologic) thrombocytopenia accounts for ~75% of cases, hypertensive disorders of pregnancy 20%, immune disorders of pregnancy (including ITP) only ~4%, and other causes 1% [slide p.5].
  • Clues favoring ITP over gestational thrombocytopenia: platelet increase after IVIG or steroids; severe thrombocytopenia (<20 ×10⁹/L) at any time; thrombocytopenia early in or predating pregnancy; and variability in platelet count over time [slide p.5].
  • Maternal and neonatal risk: bleeding risk during pregnancy is similar to non-pregnant ITP; postpartum hemorrhage risk is ~10–15%; severe neonatal thrombocytopenia also occurs in ~10–15%; and maternal platelet count may or may not predict neonatal thrombocytopenia [slide p.5].
  • Treatment sequence: prednisone or IVIG remain first-line when treatment is required; second-line agents should generally be limited to the end of pregnancy. There is significant experience with rituximab (expect delayed time to response) and with thrombopoietin receptor agonists (consider the increased risk of VTE) [slide p.6].

9.3.2 Menstrual Bleeding and Reproductive Health in ITP: LUNA3 Subanalysis

Heavy menstrual bleeding (HMB) is a dominant, often underappreciated quality-of-life problem in ITP. In prior work cited by Dr. O’Brien, HMB has been identified in up to 55% of premenopausal women with ITP at diagnosis and up to 79% during the disease course [slide p.8]. Impact on health-related quality of life correlates with low platelet counts and higher fatigue, even when iron studies are normal [slide p.8].

Michelle Lambert and colleagues presented a women’s reproductive health subgroup analysis of the Phase 3 LUNA3 trial of rilzabrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor that modulates multiple immune targets [slide p.9]:

  • Design: Adults with persistent or chronic ITP randomized 2:1 to rilzabrutinib 400 mg BID (n=133) or placebo (n=69) for up to 24 weeks, with women’s reproductive health captured via the ITP-PAQ during the double-blind period [slide p.9].
  • Platelet response: Durable response (platelets ≥50 ×10⁹/L for at least two-thirds of ≥8 of the last 12 weeks of the 24-week double-blind period, without rescue therapy) was achieved by 33% of rilzabrutinib-treated patients versus 0% on placebo [slide p.10].
  • Tranexamic acid use (a proxy for HMB burden) during the double-blind period was lowest in rilzabrutinib durable responders (7%) compared with rilzabrutinib non-durable responders (17%) and placebo (25%) [slide p.11].
  • Patient-reported outcomes: Rilzabrutinib durable responders exceeded the minimally important difference on all six ITP-PAQ items 35–40 at week 25, with especially meaningful improvements in heavy menstrual bleeding and bleeding duration, while maintaining hemoglobin levels [slide p.12, slide p.13].
  • Interpretation: These exploratory findings suggest rilzabrutinib can improve HRQoL and bleeding outcomes in ITP through multi-immune modulation; larger studies focused on women’s health outcomes are still needed [slide p.13].

9.3.3 Females Affected by Hemophilia A: The 8CHECK Program

The patient vignette sets the stage: a 29-year-old pregnant woman with a family history of hemophilia in her maternal uncle and great-grandfather, past heavy menstrual bleeding, four days of bleeding after wisdom teeth removal, and factor levels of FVIII 97% and FIX 94%. She is reassured and planned for routine spontaneous vaginal delivery—a missed opportunity [slide p.15].

The U.S. 8CHECK program (Johnson, Fletcher, Aires, Sandoval, Konkle) offers free genetic testing to individuals with hemophilia A (FVIII <40%) or females with a first-degree (occasionally more distant) relative with hemophilia A [slide p.16]:

  • Cohort: From March 2024 to July 2025, 531 samples from eligible females were submitted; mean age at testing 25.1 years (range 0.04–83.1) [slide p.16].
  • Yield: An F8 variant was identified in 62% (n=329); no variant was found in 38% (n=202) [slide p.16].
  • Variant spectrum: Missense variants accounted for 47.1% and intron 1 or 22 inversions for 28.6%, with smaller contributions from stop-gain, frameshift, large structural, synonymous, splice, and compound variants [slide p.17].
  • Role of family history: 88.1% of females tested reported a family history of hemophilia A, and genotyping yield was dramatically higher in those with a family history (67.5%) than in those without (18.6%) [slide p.17].

A critical diagnostic message: females with F8 variants had overall lower FVIII levels than genotype-negative females (mean 50.4% vs 66.4%, p=0.004), but with substantial overlap—and 52% of those who reported excessive bleeding had FVIII ≥40% [slide p.18]. A “normal” factor activity therefore does not exclude a single F8 gene variant in a female with a family history of hemophilia, and should not be used in isolation to rule out disease [slide p.18, slide p.19].

9.3.4 Iron Deficiency Across the Reproductive Life Course

Iron is a critical micronutrient for erythropoiesis, DNA synthesis, immune function, and organ and tissue integrity; iron deficiency (ID) increases the risk of anemia and affects overall health and wellbeing [slide p.21]. ID is the most prevalent nutritional deficiency in the world, and iron-deficiency anemia (IDA) contributes to chronic fatigue, cognitive impairment, diminished physical function, impaired development, and poor HRQoL—making equitable screening and treatment a health-equity priority for women and girls [slide p.22].

9.3.4.1 Adolescents: Don’t Rely on MCV

In a 16-year-old with fatigue, HMB, and “normal” CBC (Hgb 12.7 g/dL, MCV 85 fL), the pediatrician’s reassurance is the wrong call [slide p.23]. Duc and Haley’s retrospective chart review of patients aged 14–21 (January 2015–January 2023) tested the value of red-cell indices for detecting ID [slide p.24]:

  • MCV and ferritin showed only a modest positive correlation (r = 0.3); MCV alone is an unreliable marker for iron deficiency [slide p.25].
  • 77.2% of patients were normocytic, and among those normocytic patients, 44.9% had ferritin <15 ng/mL—i.e., reliance on CBC morphology will miss iron deficiency in adolescents [slide p.25].

9.3.4.2 Oral Iron Adherence Is a Real-World Bottleneck

Sheedy and Amos evaluated oral iron in adolescent females with iron deficiency due to HMB [slide p.27]:

  • 68% remained iron deficient at the end of the study period.
  • 58% reported barriers to compliance and 36% reported side effects.
  • 20% of those prescribed oral iron never took it.
  • With increasing age, the odds of resolution decreased by 57%.
  • IV iron produced faster resolution of ID, a large portion of the population eventually required IV iron, and older adolescents or those with poor tolerance may benefit from earlier IV iron [slide p.27].

9.3.4.3 Pregnancy: Universal Early Screening Is Warranted

A 28-year-old G1P0 at 12 weeks with a ferritin of 18 ng/mL (reference 16–154) is wrongly reassured that her ferritin is “normal” [slide p.28]. Iron requirements rise through pregnancy, and IDA in pregnancy is associated with low birth weight/fetal growth restriction, neurodevelopmental disorders, preterm birth, mood disorders and fatigue, and postpartum hemorrhage/blood transfusions [slide p.29]. Current guidelines generally do not recommend checking iron studies in the absence of anemia (Hgb <11 g/dL), which leaves most non-anemic iron deficiency undetected [slide p.29].

Detlefs, Patel, Powers, and Sukumar enrolled 200 participants <13 weeks gestation and defined ID as ferritin <30 ng/mL, or ferritin <50 ng/mL with transferrin saturation <20%; anemia was defined as Hgb <11 g/dL [slide p.30]. Over half of women presenting for their first obstetric visit were iron deficient, and multivariable logistic regression identified pagophagia (p=0.006), prior iron supplement use (p=0.03), and BMI (p=0.007) as predictors of iron deficiency—supporting universal screening at the first OB visit [slide p.30].

9.3.4.4 ASH 2024 Iron Deficiency Guideline: Ferritin Thresholds

The ASH Guideline Panel’s diagnostic thresholds unify practice across populations [slide p.31]:

  • Pregnant individuals: serum ferritin ≤30 ng/mL (conditional, low-certainty evidence), with an explicit recommendation against a ≤15 ng/mL threshold.
  • Menstruating individuals: ≤30 ng/mL.
  • General adult population: ≤30 ng/mL.
  • Children 9 months to 4 years: ≤20 ng/mL [slide p.31, slide p.37].

9.3.4.5 Operationalizing the Guideline: A Multidisciplinary QI Project

Godby and colleagues implemented a multidisciplinary (obstetrics, hematology, patient blood management) quality-improvement initiative standardizing screening and treatment of ID in pregnancy, defining ID as ferritin <50 ng/mL and anemia as Hgb <11 g/dL [slide p.32]. Their post-intervention flowchart screens at 8–12 weeks and 24–28 weeks, treating early ID with oral iron and late ID with 1 gram of low-molecular-weight iron dextran IV regardless of anemia status [slide p.33]:

  • Screening for iron deficiency in pregnancy rose from roughly 10% to over 60% of pregnancies after project initiation [slide p.36].
  • IV iron use increased more than 20-fold: 18 iron dextran infusions pre-intervention (0.9% of 2,097 pregnancies) to 529 infusions post-intervention (21% of 2,429 pregnancies) [slide p.35].
  • Median hemoglobin rose by more than 1 g/dL in those receiving IV iron, with a signal toward fewer peripartum transfusions (3.1% → 2.7%) [slide p.34, slide p.35, slide p.36].
  • Hemoglobin also increased after IV iron in patients whose ferritin was >30 ng/mL and/or Hgb >11 g/dL, reinforcing that non-anemic ID is clinically meaningful [slide p.36].
Asia-Pacific Perspective on Iron Deficiency and Women’s Hematology

Iron deficiency and iron-deficiency anemia in reproductive-age women and pregnancy are among the highest-burden hematologic conditions across much of the Asia-Pacific region, compounded by dietary iron bioavailability, thalassemia trait (which complicates MCV interpretation), and variable access to IV iron formulations. The Duc/Haley and Detlefs datasets argue for routine ferritin—not MCV alone—in adolescents with HMB and at the first antenatal visit [slide p.25, slide p.30]. Regional programs should consider adopting the ASH ≤30 ng/mL ferritin threshold and exploring low-molecular-weight iron dextran or other IV iron preparations where oral iron adherence is poor [slide p.31, slide p.33].

9.3.5 The Take-Home Picture: Interlocking Conditions Across the Life Course

Dr. O’Brien’s closing “infinity” schematic (adapted from Michelle Sholzberg) ties the session together: iron deficiency, anemia, heavy menstrual bleeding, pregnancy, lactation, postpartum hemorrhage, ITP, and sickle cell disease are biologically and clinically interlocking conditions that recur across a woman’s life course—and each touchpoint (first OB visit, adolescent HMB workup, ITP diagnosis, family history of hemophilia) is an opportunity to intervene earlier [slide p.38].

9.4 Clinical Pearls

Five Key Takeaways
  1. Think ITP—not just gestational thrombocytopenia—when the clues fit. Severe thrombocytopenia (<20 ×10⁹/L), onset early in or predating pregnancy, platelet variability over time, or response to IVIG/steroids all argue for ITP; first-line therapy remains prednisone or IVIG, and TPO-RAs require weighing an increased VTE risk [slide p.5, slide p.6].
  2. Treat HMB as a core ITP outcome. Up to 79% of premenopausal women with ITP experience HMB during the disease; in the LUNA3 subanalysis, rilzabrutinib durable responders showed meaningful improvements in heavy menstrual bleeding and bleeding duration and used less tranexamic acid than placebo (7% vs 25%) [slide p.8, slide p.11, slide p.12].
  3. A “normal” factor level does not rule out hemophilia in a female with a family history. In the 8CHECK program, 62% of eligible females harbored an F8 variant, and 52% of those reporting excessive bleeding had FVIII ≥40%—genetic testing is essential, especially when family history is present (genotyping yield 67.5% vs 18.6%) [slide p.16, slide p.17, slide p.18].
  4. Don’t use MCV to rule out iron deficiency in adolescents. MCV and ferritin correlate only weakly (r=0.3); 77.2% of adolescents studied were normocytic and 44.9% of those had ferritin <15 ng/mL. Check ferritin—and anticipate oral iron adherence problems (68% still deficient at end of study; 20% never took it) [slide p.25, slide p.27].
  5. Screen every pregnant patient for iron deficiency at the first visit. Over half of women presenting <13 weeks were iron deficient; the ASH Guideline threshold is ferritin ≤30 ng/mL in pregnant, menstruating, and general adult populations, and standardized multidisciplinary programs can lift screening from ~10% to >60% and cut peripartum transfusions [slide p.30, slide p.31, slide p.36].

9.5 Key References

  1. Matusiak K, Malinowski KA, Arnold DM. A practical approach to immune thrombocytopenia in pregnancy. Hematol Am Soc Hematol Educ Program. 2025 [slide p.5].
  2. van Dijk WEM, et al. Heavy menstrual bleeding in women with immune thrombocytopenia. Br J Haematol. 2022;198:753–764 [slide p.8].
  3. Lambert MP, et al. Reproductive Health in Patients with Primary Immune Thrombocytopenia Receiving Rilzabrutinib: A Subgroup Analysis from the Phase 3 LUNA3 Multicenter Study. ASH 2025 [slide p.9–13].
  4. Johnson J, Fletcher SN, Aires L, Sandoval C, Konkle BA. Females Affected by Hemophilia A: Data from the United States 8CHECK Program. ASH 2025 [slide p.16–18].
  5. Duc L, Haley K. Red Cell Indices in Adolescents with Iron Deficiency and Heavy Menstrual Bleeding. ASH 2025 [slide p.24–25].
  6. Sheedy K, Amos L. Adherence to oral iron in adolescent females with iron deficiency secondary to heavy menstrual bleeding. ASH 2025 [slide p.27].
  7. Detlefs S, Patel C, Powers J, Sukumar S. Prediction and prevalence of non-anemic iron deficiency (NAID) in early pregnancy. ASH 2025 [slide p.30].
  8. ASH Guideline Panel. ASH Recommendations for Diagnosis of Iron Deficiency (serum ferritin thresholds by population) [slide p.31, slide p.37].
  9. Godby R, et al. Implementation of a multidisciplinary quality improvement project standardizing an approach to screening and treating iron deficiency in pregnancy. ASH 2025 [slide p.32–36].