Impact of IV Iron on Bleeding Symptoms in Iron Deficient Patients With Inherited Bleeding Disorders: a Single-arm Prospective Observational Study

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.