This is a prospective, single-arm, single-center observational study evaluating the impact of intravenous (IV) iron replacement in patients with inherited bleeding disorders and iron deficiency (ferritin <50ng/dL). Subjects will undergo baseline bleeding assessments, quality-of-life measures, and laboratory tests before receiving standard-of-care IV iron. Follow-up blood work and questionnaires will be conducted post-replacement to assess for changes

Iron deficiency is one of the most prevalent nutritional deficiencies globally. In particular, patients with an inherited bleeding disorder are at increased risk of iron deficiency/ iron deficiency anemia given the propensity of this patient population to bleed. The impact of iron deficiency on hemoglobin synthesis is well established as it remains the leading cause of anemia worldwide, especially among menstruating women. Studies have shown a prevalence of iron deficiency as high as 93% in Hemophilia B Carriers , and iron deficiency anemia in 75% of females with von Willebrand Disease. However, platelets are also affected by iron deficiency. The effect of iron deficiency, as described in the past, is primarily seen in platelet production, where iron deficiency anemia (IDA) leads to increased platelet production or thrombocytosis. This is achieved through increased megakaryopoietic differentiation. Nonetheless, little is known about the effect of iron deficiency on platelet function and the mechanism by which it happens. In addition to that, it is unknown whether iron deficiency in patient with an underlying bleeding disorder could mitigate worsening bleeding symptoms.

Studies in mice have demonstrated that platelet function was suppressed in iron-deficient mice, with evidence of iron-dependent platelet activation promoted through calcium mobilization and αIIbβ3 activation. A recent study in women with IDA demonstrated that iron levels may affect platelet function. Flow cytometry showed that women with IDA have quiescent platelets circulating in a degranulated state, which might be refractory to hemostatic activation. That same study showed that iron repletion decreased P-selectin levels and enhanced degranulation of quiescent platelets when exposed to CRP-XL or ADP. That translated into increased adhesion to collagen. A study done in children, adolescents, and young adults highlighted that mean PFA-100 closure times were significantly longer in patients with IDA, with reduced Platelet aggregation with ADP, epinephrine, and ristocetin. That same study showed that treatment with Iron improved platelet aggregation tests and significantly decreased PFA-100.

The clinical relationship between bleeding, platelet function, and iron deficiency remains poorly understood. It is hypothesized that patients with iron deficiency may experience increased bleeding, with anecdotal evidence suggesting that bleeding improves as iron levels are restored. This effect is believed to be mediated by alterations in platelet function. However, the specific cellular and molecular mechanisms underlying platelet hyporesponsiveness in iron deficiency are poorly elucidated. This would particularly impact patients with an underlying inherited bleeding disorder who are at an increased risk of blood loss.

This study addresses the critical gap in understanding the bleeding phenotype in iron-deficient patients with inherited bleeding disorders. To date, no studies have comprehensively evaluated this relationship. The investigator proposes a prospective study to assess bleeding phenotypes through validated bleeding assessment scores and quality of life metrics, pre and post IV iron replacement. Additionally, the investigator will analyze platelet samples pre- and post-treatment to investigate the impact of iron replenishment on platelet function and hemostatic parameters. These findings will provide valuable insights into the interplay between iron deficiency, platelet function, and bleeding severity, advancing our understanding and management of this unique patient population.

Inclusion Criteria:

1. Males and Females > 15 years of age
2. Diagnosed with an Inherited Bleeding Disorder (Von Willebrand disease, platelet disorders, factor deficiencies, or bleeding disorder of unknown cause)
3. Evidence of Iron Deficiency (Ferritin < 50 ng/mL)
4. Receiving IV iron at Hemophilia Center of Western Pennsylvania
5. Willingness to have blood drawn
6. Willing to return to clinic 3 months post infusion for final blood draw, bleeding and quality of life assessments.

Exclusion Criteria:

1. Previous thrombosis, VTE History.
2. Platelet count < 100,000 * 109/L
3. Concomitant use of antiplatelet drugs, anticoagulants, aspirin, NSAIDs.

Patient in the outpatient setting with a bleeding disorder and Iron Deficiency planned for IV Iron as per Standard of care followed at the Hemophilia Center of Western Pennsylvania

The investigators plan to share individual participant data (IPD) that underlie the results reported in the publication, after de-identification. This may include demographic data, primary and secondary outcomes, and relevant covariates. Data will be made available to researchers who provide a methodologically sound proposal for use in academic, non-commercial research. Proposals should be directed to machinnc2@upmc.edu. Access will be granted following approval by our institutional review board or ethics committee and the execution of a data use agreement. Data will be available beginning 6 months after publication and will remain accessible for 5 years.

Data will be available beginning 6 months after publication and will remain accessible for 5 years.

Proposals should be directed to machinnc2@upmc.edu. Access will be granted following approval by our institutional review board or ethics committee and the execution of a data use agreement.