High-Intensity IV Iron Replacement for Chronic Bleeding in HHT: A Case Series

Clinical Context and Disease Burden

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vasculopathy that affects approximately 1 in 3800 to 5000 individuals, making it the second most common inherited bleeding disorder worldwide.^1,2 HHT is caused by loss-of-function pathogenic variants in genes encoding proteins of the BMP signaling pathway, particularly the BMP9/BMP10-ALK1-endoglin-SMAD4 axis.^2,3 Disease-causing variants most commonly involve ENG (HHT1) and ACVRL1 (HHT2), resulting in the formation of fragile mucocutaneous telangiectasias and visceral arteriovenous malformations (AVMs). These vascular lesions may involve the lungs, liver, gastrointestinal (GI) tract, brain, and other organs.^2,4

The cardinal manifestation of HHT is recurrent epistaxis, which occurs in approximately 95% of patients and may range from mild intermittent bleeding to severe, daily, life-altering hemorrhage. Chronic GI bleeding affects approximately one-third of patients, and heavy menstrual bleeding has been reported in approximately 35% of postmenarchal patients.^4,5 Visceral AVMs may produce additional serious complications, including embolic and hemorrhagic stroke, pulmonary hemorrhage, brain abscess, high-output cardiac failure, and chronic liver disease.^6,7

The cumulative effect of chronic, recurrent, and often occult bleeding is persistent iron deficiency anemia. Data from the Comprehensive HHT Outcomes Registry of the United States, a prospective 15-center registry of 600 unselected patients, found that 68.0% of participants had iron deficiency and/or anemia, 41.0% required intravenous (IV) iron, and 25.0% required red blood cell transfusions.⁵ In a large US claims-based analysis of more than 24,000 patients with HHT, anemia affected approximately 57.0%; among those with anemia, approximately 44.0% required hematologic support with iron infusions and/or red cell transfusions.⁸

In the Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia (Second International HHT Guidelines), universal screening for iron deficiency and anemia is recommended in all adults with HHT. Initial therapy generally includes oral iron supplementation, with escalation to IV iron replacement when oral therapy is ineffective, not absorbed, or not tolerated; or when patients present with severe anemia.⁹ In patients with refractory anemia or severe chronic bleeding, regularly scheduled iron infusions may be required, with an initial IV dose of 1 g administered as a single infusion or divided doses.⁹

The guidelines classify HHT-related GI bleeding severity by hematologic support requirements: mild disease when hemoglobin goals are met with oral iron, moderate disease when hemoglobin goals are met with IV iron, and severe disease when hemoglobin goals are not met despite adequate iron replacement or when transfusions are required.⁹ The 2025 International Consensus Report built on this framework by introducing red-cell unit equivalents (RUEs), where 1 RUE equals either 1 unit of red blood cells or 250 mg of elemental iron, to standardize measurement of hematologic support requirements across both iron infusion and transfusion modalities.⁴ The consensus report also includes a category for patients with very severe disease, who require regular red-cell transfusions, usually at least weekly, to maintain an acceptable hemoglobin.⁴ Importantly, this consensus panel emphasized that, in the absence of concurrent bone marrow pathology, IV iron can function as a delayed-onset red-cell transfusion in patients with HHT.⁴

Despite these frameworks, a critical clinical question remains: whether more dose-intensive IV iron replacement is necessary for long-term hemoglobin stability in patients with moderate to severe HHT-related bleeding. Standard hematologic approaches to iron deficiency anemia typically involve episodic repletion followed by reassessment. However, the relentless and recurrent nature of HHT-associated bleeding may require a fundamentally different paradigm.

For the purposes of this case series, high-intensity IV iron was defined as administration of 500 mg or more of elemental iron per treatment episode/infusion. Standard-intensity IV iron was defined as administration of less than 500 mg of elemental iron per treatment episode/infusion. This threshold was selected to distinguish dose-intensive replacement strategies from lower-dose episodic repletion approaches commonly used in patients with general iron deficiency anemia.

Although anemia management remains central to HHT care, treatment of HHT-related bleeding is evolving. Current management may include local measures for epistaxis, endoscopic therapy for GI bleeding, antifibrinolytic therapy such as tranexamic acid, red blood cell transfusion when clinically necessary, or systemic antiangiogenic therapy in selected patients. Intravenous bevacizumab, a VEGF inhibitor, has been used off label in specialized HHT centers for refractory bleeding and anemia. The Second International HHT Guidelines recommend considering IV bevacizumab (Avastin; Genentech) or other systemic antiangiogenic therapy for moderate to severe HHT-related GI bleeding and also recommend considering IV bevacizumab for patients with symptomatic high-output cardiac failure due to liver vascular malformations who have not responded sufficiently to first-line management.⁹ Retrospective multicenter data from the InHIBIT-Bleed study also support systemic bevacizumab as a treatment approach for severe HHT-associated bleeding and anemia requiring hematologic support, with reported reductions in bleeding-related hematologic support needs.¹

Beyond bevacizumab, several investigational and emerging agents are under study to mitigate bleeding burden in HHT. In the phase 2 randomized PATH-HHT trial (NCT03910244), pomalidomide (Pomalyst; Bristol Myers Squibb) significantly reduced epistaxis severity; subsequent longitudinal assessment in the observational PATH-HHT ATLAS study (NCT07018401) demonstrated sustained control of nasal bleeding, though benefits were less pronounced for GI bleeding.^7,10 Engasertib, an investigational oral therapy evaluated in a proof-of-concept randomized placebo-controlled trial, was associated with decreases in epistaxis frequency and duration; the efficacy findings should be interpreted as exploratory.⁶ These therapies highlight the rapidly evolving HHT treatment landscape. However, even with bleeding-directed therapy, many patients continue to require ongoing hematologic support with IV iron and/or red cell transfusions. Therefore, optimizing IV iron replacement remains clinically important, especially for patients whose ongoing iron losses exceed the replacement capacity of standard repletion strategies.

Study Objectives

This case series sought to describe real-world patterns of IV iron utilization in patients with HHT-related iron deficiency anemia and to illustrate how IV iron treatment intensity and dosing frequency may influence hemoglobin stability in the setting of chronic bleeding.

Specifically, the objectives were as follows:

• Present 3 cases of patients with HHT-related iron deficiency anemia managed with different IV iron strategies.
• Describe the relationships among IV iron dosing intensity, dosing frequency, and hemoglobin stability.
• Evaluate whether higher-intensity or more frequent IV iron replacement was associated with improved hematologic parameters in selected patients.
• Highlight the need for individualized, severity-based IV iron maintenance strategies in HHT.

Case Series

Three cases were selected from patients treated within Texas Oncology to illustrate different patterns of IV iron utilization in HHT-related chronic bleeding. Cases were selected based on the availability of complete clinical and laboratory data, documented treatment records, and management of HHT-related symptoms with IV iron therapy. These cases illustrate different patterns of IV iron utilization in patients with HHT-related chronic bleeding and demonstrate the practical challenges of managing iron deficiency anemia in a disease characterized by recurrent epistaxis, GI blood loss, and variable bleeding severity over time.

The cases were reviewed for baseline presentation, suspected bleeding source, IV iron formulation, dose and frequency of IV iron, hemoglobin response, iron indices, need for escalation of therapy, and approximate RUE utilization where applicable.

Case 1: Recurrent Iron Deficiency Anemia Managed With Iron Sucrose

SS is a 58-year-old woman with HHT who presented with recurrent epistaxis and subsequent iron deficiency anemia. Initial evaluation on April 1, 2024, demonstrated severe anemia and iron deficiency, with hemoglobin of 7.7 g/dL, hematocrit of 28.0%, ferritin of 9.0 µg/L, and iron saturation of 1.3%.

Iron sucrose was initiated on April 12, 2024, at 200 mg weekly for 5 doses (TABLE 1). She completed 3 additional 5-dose iron sucrose (Venofer; American Regent, Inc) courses initiated on June 7, 2024; September 27, 2024; and January 14, 2025. Across the observed period, this represented a cumulative exposure of 4000 mg of elemental iron, equivalent to approximately 16 RUEs using the 2025 consensus framework. Despite repeated IV iron treatment courses, hemoglobin remained persistently low over several months, with recurrent decline in iron indices between treatment courses.

On May 31, 2024, the patient’s hemoglobin was 7.3 g/dL, hematocrit was 27.9%, and ferritin had increased to 41.0 µg/L. By September 3, 2024, the patient’s hemoglobin was 8.0 g/dL, hematocrit was 28.7%, ferritin had declined to 16.0 µg/L, and iron saturation was 3.0%. On December 2, 2024, the patient’s hemoglobin remained low at 7.6 g/dL, hematocrit was 26.3%, and ferritin was 31.0µg/L. Because of persistent severe anemia, the patient subsequently required a red blood cell transfusion on December 19, 2024.

Following blood transfusion, laboratory values on January 14, 2025, showed partial improvement, with the patient’s hemoglobin of 9.3 g/dL, hematocrit of 32.7%, ferritin of 97.0µg/L, and iron saturation of 7.0%. Importantly, the improvement in hemoglobin and hematocrit observed at this time cannot be attributed to IV iron therapy alone and likely reflects, at least in part, the recent blood transfusion.

Overall, this case demonstrates persistent HHT-related anemia despite repeated low-dose IV iron replacement with Venofer. Although iron stores increased transiently following treatment, hemoglobin remained severely reduced and ultimately required red blood cell transfusion for additional hematologic support. The case illustrates how low-dose episodic IV iron may be insufficient when ongoing blood loss exceeds the rate of iron replacement and supports consideration of more intensive or maintenance-based iron strategies in selected patients with HHT.

Case 2: Long-Term Iron Sucrose Maintenance With Escalation From Monthly to Every-2-Week Dosing

AD is a 45-year-old woman with HHT and recurrent, persistent iron deficiency anemia suspected to be secondary to chronic GI blood loss. She had required long-term IV iron support and had been receiving iron sucrose 400 mg approximately every 4 weeks as needed since August 27, 2018, with relatively consistent treatment aside from intermittent gaps.

While receiving monthly iron sucrose from August 27, 2018 through December 17, 2025, the patient’s hemoglobin generally ranged from 9.0 to 12.0 g/dL, with most values in the low 10.0 to mid-11.0 g/dL range. Because laboratory values remained relatively consistent during that period, Table 2 does not include each intervening data point. Instead, the table begins with November 19, 2025, when the existing monthly regimen began to appear insufficient to fully offset ongoing iron losses. On November 19, 2025, hemoglobin was 10.3 g/dL, hematocrit was 36.2%, and iron saturation was 6.0%. On December 17, 2025, hemoglobin remained 10.3 g/dL, hematocrit was 35.7%, and iron saturation was 7.0% (TABLE 2)

In 2023, given ongoing HHT-related blood loss and persistent iron deficiency despite long-term IV iron support, bevacizumab was discussed as a potential bleeding-directed therapy. After discussion, the patient elected not to proceed with bevacizumab, and management remained focused on supportive hematologic therapy with IV iron.

The patient’s January 2026 iron sucrose dose was delayed, and laboratory evaluation on January 14, 2026, showed worsening anemia and iron depletion, with hemoglobin of 9.3 g/dL, hematocrit of 32.5%, iron saturation of 7.0%, and ferritin of 11.0 µg/L. Due to persistent anemia and ongoing iron deficiency, the patient’s iron sucrose regimen was increased from 400 mg every 4 weeks to 400 mg every 2 weeks beginning February 11, 2026. At the time of escalation, the patient’s hemoglobin had declined to 8.3 g/dL, hematocrit was 31%, iron saturation was 4.0%, and ferritin was 4.0 µg/L.

Following escalation to every-2-week iron sucrose dosing, hemoglobin and ferritin gradually improved. Hemoglobin increased from 8.3 g/dL on February 11, 2026, to 11.0 g/dL by May 27, 2026, and ferritin increased from 4.0 µg/L to 48.0 µg/L. The escalated regimen delivered 800 mg of elemental iron per 4-week period, equivalent to approximately 3.2 RUEs. The patient’s iron saturation remained persistently low, ranging from 4% to 9%, suggesting continued iron utilization and ongoing blood loss despite improved hematologic support.

This case highlights the importance of dosing frequency in HHT-related chronic blood loss, particularly when bleeding-directed systemic therapy is not pursued. Monthly iron sucrose provided partial support but did not fully correct iron deficiency, and a delayed dose was followed by worsening anemia. Escalation to every-2-week dosing increased the need for ongoing hematologic support and was associated with a gradual improvement in hemoglobin, hematocrit, and ferritin.

Case 3: Severe HHT-Related Anemia With Escalation From Iron Sucrose to High-Dose Ferric Derisomaltose

MW is a 56-year-old man with HHT who presented in June 2024 with frequent epistaxis and GI bleeding complicated by severe iron deficiency anemia. He initially presented to the emergency department on June 1, 2024, with hemoglobin of 6.0 g/dL, ferritin of 3.0 µg/L, and iron saturation of 4% (TABLE 3).

On June 20, 2024, he was started on 300 mg of iron sucrose weekly for 5 doses and completed the planned course. Follow-up laboratory evaluation on July 30, 2024, showed persistent severe anemia and iron deficiency, with hemoglobin of 6.5 g/dL, hematocrit of 25.5%, iron saturation of 4.0%, and ferritin of 20.0 µg/L. Due to insurance and scheduling barriers, he was restarted on 300 mg of iron sucrose weekly for 4 doses beginning August 12, 2024, and completed that course as well.

Despite completing multiple courses of iron sucrose, his laboratory values remained severely abnormal. On September 6, 2024, his hemoglobin was 6.7 g/dL, hematocrit was 26.3%, iron saturation was 5.0%, and ferritin was 21.0 µg/L. Given the severity and persistence of the patient’s blood loss, the preferred treatment strategy was ferric derisomaltose (Monoferric; Pharmacosmos) 1000 mg once weekly or 16 RUEs over a 4-week period, with the goal of limiting the number of infusion visits. However, insurance denied coverage for this regimen.

Instead, insurance authorized iron sucrose 200 mg every 3 days indefinitely. Although this increased treatment frequency, the regimen provided only approximately 1867 mg of elemental iron per 4-week period, equivalent to approximately 7.5 RUEs—less than half of the intended iron replacement with weekly ferric derisomaltose—and required very frequent infusion encounters. Despite continued frequent iron sucrose dosing, the patient’s anemia persisted. On October 1, 2024, hemoglobin was 6.8 g/dL, hematocrit was 26.1%, ferritin was 33.0 µg/L, and iron saturation was 5.0%.

Given the lack of meaningful hematologic improvement despite frequent low-dose IV iron, iron sucrose 200 mg every 3 days was discontinued on October 11, 2024. Transition to ferric derisomaltose required an insurance appeal demonstrating that frequent iron sucrose dosing had been insufficient to correct the patient’s severe anemia and ongoing iron deficiency. After coverage was obtained, the patient was transitioned to ferric derisomaltose 1000 mg weekly. This regimen delivered 4 RUEs per week, or approximately 16 RUEs per 4-week period, with substantially greater elemental iron delivery per treatment encounter. At the time of transition on October 11, 2024, the patient’s hemoglobin was 7.7 g/dL, hematocrit was 30.3%, iron saturation was 11.0%, and ferritin was 67.0 µg/L.

Following initiation of weekly ferric derisomaltose, the patient demonstrated substantial hematologic improvement, although the recovery was not completely linear. Hemoglobin increased from 7.7 g/dL on October 11, 2024, to 9.2 g/dL on October 18, 2024, and 9.9 g/dL on October 25, 2024. A minor decrease to 9.6 g/dL was observed on November 8, 2024; however, the patient’s hemoglobin subsequently increased to 10.6 g/dL by November 15, 2024, and 11.6 g/dL by November 22, 2024. On December 4, 2024, hemoglobin remained stable at 11.9 g/dL, hematocrit was 39.2%, iron saturation was 14.0%, and ferritin was 101.0 µg/L.

The patient was referred to an HHT Center of Excellence for additional evaluation and treatment. Given the high cumulative IV iron exposure, monitoring for potential bone effects and hypophosphatemia was planned once the patient was able to establish care.

This case illustrates that, in patients with severe HHT-related bleeding, repeated low-dose IV iron may increase treatment burden and cumulative iron exposure without achieving adequate hematologic recovery when ongoing blood loss exceeds the rate of replacement. Despite frequent iron sucrose infusions, the patient remained markedly anemic and iron deficient, with persistent fatigue and frequent clinic visits adding to the overall burden of care. The delay in transitioning to a higher-dose iron replacement strategy therefore had implications not only for hematologic recovery but also for quality of life.Escalation to a higher-dose strategy with weekly ferric derisomaltose was associated with a clear and sustained improvement in hemoglobin, which increased from 7.7 g/dL to 11.9 g/dL over the observed period. Other hematologic and iron indices also improved overall but showed greater variability: hematocrit fluctuated during treatment, while ferritin and iron saturation increased from baseline but did not rise consistently and remained variable over time. These findings suggest that earlier intensification of iron replacement may help achieve more meaningful hematologic recovery while reducing prolonged exposure to ineffective low-dose therapy and repeated infusion encounters.

Discussion: Bridging the Management Gap

HHT creates a different iron-replacement problem than most other causes of iron deficiency anemia. In typical microcytic or general iron deficiency anemia, iron repletion is usually treated as a time-limited intervention: Restore the iron stores, correct the anemia, and address the underlying cause.^11-13 That framework is useful for static or reversible deficits, but it does not fully fit a disorder defined by ongoing vascular blood loss.

In HHT, the bleeding source is intrinsic to the disease. Bleeding may be multifocal, recurrent, progressive, and not always amenable to definitive correction. A standard static-deficit model, in which clinicians calculate a 1-time iron deficit, administer a repletion course, and reassess, may therefore leave patients cycling between temporary repletion and recurrent depletion.¹¹

A maintenance-oriented model may be more appropriate for patients with moderate to severe HHT-related bleeding. In this framework, iron delivery is calibrated to ongoing losses rather than to a single baseline deficit. The 2025 consensus report’s description of IV iron as a delayed-onset red-cell transfusion reinforces this concept: Patients with severe chronic bleeding may require regular, protocol-driven IV iron to sustain endogenous erythropoiesis.⁴

The 3 cases presented here illustrate the heterogeneity of HHT-related anemia management. Case 1 showed recurrent anemia despite repeated completed iron sucrose courses, with transient ferritin improvement but persistent anemia and low iron saturation. Case 2 showed that increasing iron sucrose frequency from monthly to every 2 weeks was associated with gradual improvement in hemoglobin and ferritin when bevacizumab was not pursued. Case 3 showed that severe HHT-related anemia can remain refractory despite frequent iron sucrose dosing, with substantial improvement after transition to high-dose ferric derisomaltose.

Several practical observations emerge from these cases. First, episodic low-dose IV iron may be insufficient when HHT-related blood loss is persistent. Second, dosing frequency matters; even a lower-dose product may provide better support when administered on a scheduled maintenance basis. Third, in patients with severe bleeding and profound iron deficiency, higher-dose IV iron may be needed to deliver enough iron to achieve meaningful hemoglobin recovery. Importantly, these patterns were not explained by missed case-study treatment courses.

Case 3 also highlights the practical and quality-of-life burden created by payer- or product-driven low-dose iron replacement strategies. Although iron sucrose 200 mg every 3 days increased the frequency of iron replacement, it required repeated infusion visits and resulted in cumulative IV iron exposure without meaningful hematologic recovery. Despite frequent treatment, the patient remained significantly fatigued, with ongoing symptoms adversely affecting their quality of life. In contrast, higher-dose IV iron formulations can deliver substantially more elemental iron per infusion, potentially reducing the number of treatment encounters while more effectively matching replacement to ongoing blood loss. For patients requiring long-term iron maintenance, earlier escalation to an adequately dosed regimen may therefore improve both hematologic outcomes and treatment burden. Bleeding-directed therapies remain important, but they do not remove the need for individualized iron replacement. Local nasal therapies, laser or ablative procedures, endoscopic interventions for GI bleeding, antifibrinolytic therapy, and systemic antiangiogenic therapy may reduce bleeding burden in selected patients. IV bevacizumab has emerged as an important off-label systemic option in specialized HHT care, particularly for patients with refractory bleeding and anemia. Guideline-supported uses include consideration of IV bevacizumab or other systemic antiangiogenic therapy for moderate to severe HHT-related GI bleeding and consideration of IV bevacizumab for symptomatic high-output cardiac failure due to liver vascular malformations after inadequate response to first-line management.⁹ These treatments are best viewed as complementary to, rather than replacements for, optimized hematologic support.

The investigational treatment landscape is also changing. Pomalidomide and engasertib have shown promising bleeding-related outcomes in randomized trials, suggesting that future HHT management may increasingly include disease-modifying or bleeding-modifying systemic therapy.^6,7 However, these therapies have practical limitations, including access, insurance approval, adverse effect profiles, patient selection, reproductive safety considerations, and uncertainty regarding long-term durability. Therefore, IV iron replacement remains a critical component of care, both as supportive therapy and as a measurable marker of bleeding burden.

The clinical consequences of failing to meet the physiologic demands of chronic bleeding extend beyond laboratory abnormalities. Chronic iron deficiency anemia in HHT is associated with fatigue, reduced functional capacity, impaired cognition, reduced health-related quality of life, and psychological distress. Severe epistaxis has been associated with higher rates of depression, anxiety, and fatigue.¹⁴ Anemia may also become severe enough to contribute to end-organ damage or acute coronary syndromes.⁸

The economic consequences are equally important. Patients with HHT requiring hematologic support incur mean per-patient-per-year costs of approximately $40,000, comparable to chronic high-cost conditions such as cystic fibrosis.⁸ If proactive IV iron maintenance reduces transfusion requirements, emergency department visits, hospitalization, or severe hemoglobin nadirs, it may have meaningful clinical and economic implications.

The broader clinical lesson is that reactive, low-dose IV iron strategies may be insufficient for some patients with HHT. Current gaps include the absence of HHT-specific IV iron maintenance protocols, clinician-to-clinician variability, payer-driven product limitations, infusion-visit burden, and continued reliance on general iron-deficiency paradigms for a disease with fundamentally different iron kinetics.⁴

The Second International HHT Guidelines acknowledge that regularly scheduled iron infusions may be required in refractory cases but do not specify dose, frequency, or duration.⁹ This leaves substantial room for underdosing, delayed repletion, and recurrent symptomatic anemia. A more proactive approach may involve early identification of patients whose iron losses exceed standard replacement, initiation of scheduled maintenance IV iron, and longitudinal monitoring using standardized end points such as hemoglobin stability, ferritin trends, iron saturation, transfusion requirements, and RUE utilization.

The rationale for dose-intensive or frequency-intensive IV iron management rests on several practical principles, as follows:

1. HHT-related iron loss is often continuous and may exceed replacement provided by standard episodic protocols.
2. Higher-dose IV iron administration may allow faster and more sustained restoration of iron stores.
3. More frequent scheduled IV iron may be necessary when lower-dose products are used.
4. Modern IV iron formulations allow administration of larger single doses with generally favorable safety profiles when used appropriately.
5. Regular maintenance IV iron may reduce downstream complications of recurrent severe anemia.
6. Standardized hematologic support metrics such as RUEs provide a framework for comparing treatment intensity across patients and centers.

Formulation-Specific Safety Considerations

When higher-dose or more frequent IV iron is used, formulation-specific safety risks should be part of product selection. Repeated exposure to certain IV iron formulations has been associated with hypophosphatemia, osteomalacia, and fractures. This is particularly relevant in HHT because patients may require repeated or long-term IV iron rather than isolated repletion courses. Ferric carboxymaltose (Injectafer; American Regent, Inc) has been linked to higher rates of hypophosphatemia and, in a recent study, a higher fracture risk compared with ferric derisomaltose.^15,16 This concern has gained additional significance with the FDA’s September 2026 addition of a boxed warning for symptomatic hypophosphatemia to ferric carboxymaltose labeling. Ferric carboxymaltose’s labeling also identifies HHT as a potential risk factor for hypophosphatemia.¹⁷ For patients receiving repeated courses or formulations associated with phosphate wasting, clinicians should consider monitoring serum phosphate, vitamin D status, bone symptoms, and fracture risk.

Hypersensitivity risk is another important consideration when selecting high-dose-capable IV iron products. Although serious reactions are uncommon, some IV iron formulations, including ferumoxytol (Feraheme; AMAG Pharmaceuticals) and iron dextran (INFeD; AbbVie), carry boxed warnings for serious hypersensitivity or anaphylactic-type reactions.^18,19 Other formulations, including ferric derisomaltose and ferric carboxymaltose, also carry warnings for serious hypersensitivity reactions.^17,20 These risks should not preclude use when IV iron is clinically necessary, but they reinforce the need for appropriate patient selection, infusion monitoring, availability of personnel and medications to manage anaphylaxis, and individualized risk-benefit assessment.

Together, these safety considerations support a balanced approach. High-intensity IV iron may be appropriate when ongoing HHT-related blood loss exceeds standard replacement strategies, but formulation choice should consider more than dose convenience and payer coverage. Hypophosphatemia risk, bone health, hypersensitivity history, prior infusion reactions, and anticipated lifetime exposure should all inform the treatment plan.

Study Limitations

Several limitations must be acknowledged. First, this case series is descriptive and hypothesis-generating; causal conclusions cannot be drawn. Second, the small number of cases limits generalizability. Third, HHT bleeding severity is inherently variable, both between patients and within the same patient over time, making it difficult to attribute hemoglobin changes solely to IV iron dosing strategy rather than fluctuations in disease activity. Fourth, documentation of bleeding frequency, epistaxis severity, GI bleeding, transfusion history, and quality-of-life outcomes may be incomplete. Fifth, treatment selection may have been influenced by clinician preference, payer coverage, product availability, infusion center workflows, and perceived disease severity. Finally, patients may have received or been considered for additional bleeding-directed therapies, such as bevacizumab or referral to an HHT Center of Excellence, which may influence long-term outcomes beyond the observed IV iron treatment period.

This case series also does not systematically evaluate formulation-specific safety outcomes, including hypophosphatemia, osteomalacia, fracture events, or hypersensitivity reactions. Because patients with HHT may require repeated IV iron exposure over long periods, future studies should evaluate not only hematologic efficacy but also product-specific safety, including phosphate monitoring, bone health outcomes, and infusion-related reactions.

Conclusion and Clinical Implications

This case series supports the hypothesis that patients with moderate to severe HHT-related bleeding may require individualized IV iron strategies that account for ongoing iron loss rather than static deficits. Repeated low-dose IV iron may transiently improve ferritin, but selected patients may require more frequent scheduled dosing or high-intensity IV iron replacement to achieve more durable hemoglobin stability.

For the purposes of this case series, high-intensity IV iron was defined as 500 mg or more of elemental iron per treatment episode/infusion. The cases also suggest that dosing frequency and cumulative RUE support are important components of treatment intensity. Case 1 received 4000 mg elemental iron over the observed period, equivalent to approximately 16 RUEs, yet remained persistently anemic. In Case 2, increasing iron sucrose frequency from monthly to every 2 weeks increased support to approximately 3.2 RUEs per 4-week period and was associated with improved hemoglobin and ferritin. In Case 3, persistent severe anemia despite frequent iron sucrose improved after transition to weekly ferric derisomaltose 1000 mg, equivalent to 4 RUEs per week or approximately 16 RUEs per 4-week period.

Clinical implications for anemia management in HHT include:

• The need for individualized, severity-based IV iron dosing protocols that account for ongoing blood loss rather than static iron deficits.
• Consideration of scheduled IV iron maintenance programs for patients with moderate to severe bleeding.
• Recognition that both dose per infusion and dosing frequency may influence hemoglobin stability.
• Use of high-intensity IV iron, defined here as 500 mg or more of elemental iron per treatment episode/infusion, in patients whose ongoing losses exceed standard replacement strategies.
• Adoption of standardized hematologic end points such as RUEs to normalize, track, and compare iron utilization across patients, products, and centers.
• Integration of IV iron strategy into the broader HHT management plan alongside bleeding-reduction therapies, including consideration of bevacizumab, investigational therapies, and referral to HHT specialty centers when appropriate; these approaches should be viewed as complementary rather than competitive with iron replacement.
• Selection of IV iron formulation should account for product-specific safety risks, including hypophosphatemia, osteomalacia, fracture risk, and serious hypersensitivity reactions.
• In patients requiring repeated or high-dose IV iron, particularly with formulations associated with phosphate wasting, clinicians should consider monitoring serum phosphate and assessing for bone pain, weakness, osteomalacia, or fracture risk.
• For IV iron products with boxed warnings or serious hypersensitivity warnings, infusion should occur in settings equipped to recognize and manage anaphylaxis or severe hypersensitivity reactions.

Prospective, multicenter studies with standardized dosing protocols, protocolized hematologic support thresholds, validated patient-reported outcomes, and product-specific safety monitoring are needed to determine the optimal IV iron dosing strategy in HHT. Future research should evaluate whether proactive, individualized IV iron maintenance improves hemoglobin stability, reduces transfusion requirements, decreases health care utilization, improves quality of life, and lowers overall cost of care in patients with HHT-related chronic bleeding.

Author Information

Daniel Kyung Min, PharmD, is the area pharmacy manager for Texas Oncology.

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