AGA Clinical Practice Update on Management of Iron Deficiency Anemia: Expert Review.

DESCRIPTION: In this Clinical Practice Update (CPU), we will Best Practice Advice (BPA) guidance on the appropriate management of iron deficiency anemia. METHODS: This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPUC and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Since systematic reviews were not performed, these BPA statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. BEST PRACTICE ADVICE 1: No single formulation of oral iron has any advantages over any other. Ferrous sulfate is preferred as the least expensive iron formulation. BEST PRACTICE ADVICE 2: Give oral iron once a day at most. Every-other-day iron dosing may be better tolerated for some patients with similar or equal rates of iron absorption as daily dosing. BEST PRACTICE ADVICE 3: Add vitamin C to oral iron supplementation to improve absorption. BEST PRACTICE ADVICE 4: Intravenous iron should be used if the patient does not tolerate oral iron, ferritin levels do not improve with a trial of oral iron, or the patient has a condition in which oral iron is not likely to be absorbed. BEST PRACTICE ADVICE 5: Intravenous iron formulations that can replace iron deficits with 1 or 2 infusions are preferred over those that require more than 2 infusions. BEST PRACTICE ADVICE 6: All intravenous iron formulations have similar risks; true anaphylaxis is very rare. The vast majority of reactions to intravenous iron are complement activation-related pseudo-allergy (infusion reactions) and should be treated as such. BEST PRACTICE ADVICE 7: Intravenous iron therapy should be used in individuals who have undergone bariatric procedures, particularly those that are likely to disrupt normal duodenal iron absorption, and have iron-deficiency anemia with no identifiable source of chronic gastrointestinal blood loss. BEST PRACTICE ADVICE 8: In individuals with inflammatory bowel disease and iron-deficiency anemia, clinicians first should determine whether iron-deficiency anemia is owing to inadequate intake or absorption, or loss of iron, typically from gastrointestinal bleeding. Active inflammation should be treated effectively to enhance iron absorption or reduce iron depletion. BEST PRACTICE ADVICE 9: Intravenous iron therapy should be given in individuals with inflammatory bowel disease, iron-deficiency anemia, and active inflammation with compromised absorption. BEST PRACTICE ADVICE 10: In individuals with portal hypertensive gastropathy and iron-deficiency anemia, oral iron supplements initially should be used to replenish iron stores. Intravenous iron therapy should be used in patients with ongoing bleeding who do not respond to oral iron therapy. BEST PRACTICE ADVICE 11: In individuals with portal hypertensive gastropathy and iron-deficiency anemia without another identified source of chronic blood loss, treatment of portal hypertension with nonselective ß-blockers can be considered. BEST PRACTICE ADVICE 12: In individuals with iron-deficiency anemia secondary to gastric antral vascular ectasia who have an inadequate response to iron replacement, consider endoscopic therapy with endoscopic band ligation or thermal methods such as argon plasma coagulation. BEST PRACTICE ADVICE 13: In patients with iron-deficiency anemia and celiac disease, ensure adherence to a gluten-free diet to improve iron absorption. Consider oral iron supplementation based on the severity of iron deficiency and patient tolerance, followed by intravenous iron therapy if iron stores do not improve. BEST PRACTICE ADVICE 14: Deep enteroscopy performed in patients with iron-deficiency anemia suspected to have small-bowel bleeding angioectasias should be performed with a distal attachment to improve detection and facilitate treatment. Small-bowel angioectasias may be treated with ablative thermal therapies such as argon plasma coagulation or with mechanical methods such as hemostatic clips. BEST PRACTICE ADVICE 15: Endoscopic treatment of angioectasias should be accompanied with iron replacement. Medical therapy for small-bowel angioectasias should be reserved for compassionate treatment in refractory cases when iron replacement and endoscopic therapy are ineffective.

Serum ferritin and risk of colonic neoplasia: Implications for the workup and treatment of iron deficiency.

Iron deficiency is the most common extraintestinal sign of colonic neoplasia, including colorectal cancer (CRC) and other lower gastrointestinal pathology. Both upper endoscopy and colonoscopy is usually recommended in the work-up of patients with unexplained iron deficiency, particularly in men and postmenopausal women. As the incidence of early-onset CRC (age <50 years) rises in the United States, there is an increasing need to identify risk predictors to aid in the early detection of CRC. It remains unknown if serum ferritin (SF), and what specific threshold, can be used as a marker to stratify those at risk for CRC and other lower gastrointestinal pathology. In this current review of the literature, we aimed to review guidelines for diagnostic workup of colonic neoplasia in the setting of iron deficiency and examine the association and specific thresholds of SF and risk of CRC by age. Some of the published findings are conflicting, and conclusions specific to younger patients are limited. Though further investigation is warranted, the cumulative findings suggest that SF, in addition to considering the clinical context and screening guidelines, may have potential utility in the assessment of colonic neoplasia.

Dermatologic manifestations of hematologic disorders.

Distinguishing key morphologic features and understanding the pathophysiology of common cutaneous manifestations of hematologic disorders is essential to ensure prompt and appropriate treatment. In fact, classic cutaneous signs may provide the first clue to the diagnosis of an underlying hematologic disease. Disorders of coagulation, vascular abnormalities, or cutaneous infiltration and deposition are responsible for the underlying pathophysiology of cutaneous manifestations in the majority of cases. Hematologists often feel ill-equipped in identifying morphologic changes in the skin. Thus, the purpose of this review is to provide a comprehensive overview of classic cutaneous manifestations and diagnostic considerations of the associated hematologic conditions. Though there is a specific focus on non-malignant disorders, those straddling the spectrum of malignancy are also discussed. In many disease states, the skin may serve as an important marker of an emerging hematologic disorder, so close collaboration and multidisciplinary input remain essential to provide optimal and timely care for these patients.

Factor XI Inhibition for the Prevention of Catheter-Associated Thrombosis in Patients With Cancer Undergoing Central Line Placement: A Phase 2 Clinical Trial.

BACKGROUND: Despite the ubiquitous utilization of central venous catheters in clinical practice, their use commonly provokes thromboembolism. No prophylactic strategy has shown sufficient efficacy to justify routine use. Coagulation factors FXI (factor XI) and FXII (factor XII) represent novel targets for device-associated thrombosis, which may mitigate bleeding risk. Our objective was to evaluate the safety and efficacy of an anti-FXI mAb (monoclonal antibody), gruticibart (AB023), in a prospective, single-arm study of patients with cancer receiving central line placement. METHODS: We enrolled ambulatory cancer patients undergoing central line placement to receive a single dose of gruticibart (2 mg/kg) administered through the venous catheter within 24 hours of placement and a follow-up surveillance ultrasound at day 14 for evaluation of catheter thrombosis. A parallel, noninterventional study was used as a comparator. RESULTS: In total, 22 subjects (n=11 per study) were enrolled. The overall incidence of catheter-associated thrombosis was 12.5% in the interventional study and 40.0% in the control study. The anti-FXI mAb, gruticibart, significantly prolonged the activated partial thromboplastin time in all subjects on day 14 compared with baseline (P<0.001). Gruticibart was well tolerated and without infusion reactions, drug-related adverse events, or clinically relevant bleeding. Platelet flow cytometry demonstrated no difference in platelet activation following administration of gruticibart. T (thrombin)-AT (antithrombin) and activated FXI-AT complexes increased following central line placement in the control study, which was not demonstrated in our intervention study. CRP (C-reactive protein) did not significantly increase on day 14 in those who received gruticibart, but it did significantly increase in the noninterventional study. CONCLUSIONS: FXI inhibition with gruticibart was well tolerated without any significant adverse or bleeding-related events and resulted in a lower incidence of catheter-associated thrombosis on surveillance ultrasound compared with the published literature and our internal control study. These findings suggest that targeting FXI could represent a safe intervention to prevent catheter thrombosis. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04465760.

Sex, lies, and iron deficiency: a call to change ferritin reference ranges.

Iron deficiency is a very common and treatable disorder. Of all the tests available to diagnose iron deficiency, the serum ferritin is the most able to discriminate iron deficiency from other disorders. However, the reference range for ferritin in many laboratories will lead to underdiagnosis of iron deficiency in women. Studies have shown that 30%-50% of healthy women will have no marrow iron stores, so basing ferritin cutoffs on the lowest 2.5% of sampled ferritins is not appropriate. In addition, several lines of evidence suggest the body physiologic ferritin "cutoff" is 50  ng/mL. Work is needed to establish more realistic ferritin ranges to avoid underdiagnosing a readily treatable disorder.

Estrogen-based hormonal therapy and the risk of thrombosis in COVID-19 patients.

OBJECTIVE: Estrogen-containing contraceptives and hormone replacement therapy are used commonly, however, the risks of venous and arterial thrombosis imparted by such medications during COVID-19 infection or other similar viral infections remain undescribed. METHODS: To assess the risk of venous and arterial thrombosis in patients receiving oral estrogen-containing therapy (ECT) with COVID-19 as compared to those receiving non-estrogen-based hormonal therapy, we conducted a multicenter cohort study of 991 patients with confirmed COVID-19 infection, 466 receiving estrogen-containing hormonal therapy, and 525 receiving progestin-only or topical therapy. RESULTS: The use of estrogen-containing therapy was found to significantly increase the risk of venous thromboembolism (VTE) following COVID-19 diagnosis after controlling for age (HR 5.46 [95% CI 1.12-26.7, p = .036]). This risk was highest in patients over age 50, with 8.6% of patients receiving estrogen-containing therapy diagnosed with VTE compared to 0.9% of those receiving non-estrogen-based therapies (p = .026). The risk of arterial thrombosis was not significantly associated with oral estrogen use. CONCLUSIONS: These results suggest that estrogen-containing therapy is associated with a significantly increased risk of VTE in COVID-19 patients, especially in older individuals. These findings may guide provider counseling and management of patients with COVID-19 on estrogen-containing therapy.

Hematologic concerns in transgender patients.

Patients with gender dysphoria are increasingly seeking gender-affirming therapies, which can have adverse hematologic effects. For example, estrogen can increase the risk for arterial and venous thrombosis, whereas testosterone can cause erythrocytosis. This article reviews the hematologic issues associated with gender-affirming hormone therapies and discusses ways to lessen and monitor the risks. Common consult scenarios are also addressed.

Platelet reactivity and platelet count in women with iron deficiency treated with intravenous iron.

Background: Iron deficiency anemia (IDA) and heavy menstrual bleeding are prevalent, interrelated issues impacting over 300 million premenopausal women worldwide. IDA is generally associated with increased platelet counts; however, the effects of IDA and its correction on platelet function in premenopausal women remain unknown. Objectives: We sought to determine how IDA and intravenous iron affect platelet count and platelet function in premenopausal women. Methods: Hematologic indices were assessed in a multicenter, retrospective cohort of 231 women repleted with intravenous iron. Pre- and postinfusion blood samples were then obtained from a prospective cohort of 13 women to analyze the effect of intravenous iron on hematologic parameters as well as platelet function with flow cytometry and platelet aggregation assays under physiologic shear. Results: Following iron replacement, anemia improved, and mean platelet counts decreased by 26.5 and 16.0 K/mm3 in the retrospective and prospective cohorts, respectively. Replacement reduced baseline platelet surface P-selectin levels while enhancing platelet secretory responses to agonists, including collagen-related peptide and ADP. Platelet adhesion and aggregation on collagen under physiologic shear also significantly increased following repletion. Conclusion: We find that intravenous iron improves anemia while restoring platelet counts and platelet secretory responses in premenopausal women with iron deficiency. Our results suggest that iron deficiency as well as iron replacement can have a range of effects on platelet production and function. Consequently, platelet reactivity profiles should be further examined in women and other groups with IDA where replacement offers a promising means to improve anemia as well as quality of life.

Analysis of Adverse Events and Intravenous Iron Infusion Formulations in Adults With and Without Prior Infusion Reactions.

Importance: Although iron deficiency is common, it remains unclear which iron repletion strategy is associated with the lowest rate of infusion-related adverse events, and how patients with history of infusion reaction should be managed. Objective: To evaluate rates of infusion reactions among 4 commonly used intravenous iron repletion strategies and determine how readministration was managed in patients with history of reaction. Design, Setting, and Participants: This cohort study included all patients receiving intravenous iron infusion from January 1, 2015, to September 7, 2021, at 6 centers in Portland, Oregon. Participants included a total of 12 237 patients with iron deficiency, not restricted by etiology. Statistical analysis was performed from September to October 2021. Exposures: Type of intravenous iron formulation and concurrent administration of diphenhydramine, epinephrine, famotidine, and/or hydrocortisone, used as surrogate maker of infusion reaction. Main Outcomes and Measures: Incidence of adverse events, including severe events requiring epinephrine, stratified by type of iron formulation, and in patients who received premedication or with history of infusion-related reaction receiving subsequent doses. Results: Among 35 737 unique iron infusions (12 237 patients [9480 (77.5%) women; 717 (5.9%) Black; 10 250 (83.7%) White; mean (SD) age of 51 (20) years]), comprising 22 309 iron sucrose doses, 9067 iron dextran total doses (1771 preceded by test dose, 56 test doses alone), 3147 ferumoxytol doses, and 1214 ferric carboxymaltose doses, incidence of adverse events was 3.9% (n = 1389; 95% CI, 3.7%-4.1%). Rate of infusion events differed among iron formulations: 4.3% (n = 970; 95% CI, 4.1%-4.6%) iron sucrose, 3.8% (n = 345, 95% CI: 3.4%-4.2%) iron dextran (test and full doses or test dose alone), 1.8% (n = 57; 95% CI, 1.4%-2.3%) ferumoxytol, and 1.4% (n = 17, 95% CI, 0.8%-2.3%) ferric carboxymaltose (P < .001). Severe adverse events were exceedingly rare with only 2 documented epinephrine administrations, both associated with iron dextran. Incidence of adverse events among those who received premedication was 23-fold higher compared with those who did not (38.6% vs 1.7%, χ21 = 7324.8; P < .001). Among 873 patients with history of infusion reaction who underwent readministration, the majority received the same formulation, which was associated with significantly higher reaction rate particularly if premedication was administered (68% [95% CI, 64%-72%] vs 32% [95% CI, 26%-41%], respectively), compared with those who received an alternate formulation (21% [95% CI, 11%-35%] vs 5% [95% CI, 2%-12%], respectively) (P < .001). Conclusions and Relevance: These data, and the preponderance of published evidence, suggest that intravenous iron is generally well tolerated with exceedingly low risk of severe reaction, use of premedication and test doses are unnecessary, and that optimal prevention and management of infusion-related reactions warrant further study.

Anemia at Altitude: Iron Deficiency and Other Acquired Anemias.

DeLoughery, Thomas G. Anemia at altitude: iron deficiency and other acquired anemias. High Alt Med Biol. 22:245-248, 2021.-Acquired anemias are common throughout the world. This article will discuss iron deficiency and other acquired causes of anemia such as inflammation and renal disease. Iron deficiency with or without anemia can detract from performance and may be a risk factor for altitude sickness. Anyone considering going to altitude should be screened for iron deficiency with a serum ferritin if they have risk factors for iron deficiency. The effects of other acquired anemias are less well defined. Several other diseases can also lead to anemia, and altitude challenges are more related to the underlying disease than to anemia.

Graft-versus-host disease after liver transplantation is associated with bone marrow failure, hemophagocytosis, and DNMT3A mutations.

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.

Intravenous ferric derisomaltose for the treatment of iron deficiency anemia.

Intravenous (IV) iron is the therapy of choice when oral iron is ineffective or poorly tolerated, yet use has been limited by fears of hypersensitivity reactions (HSRs). Newer formulations that bind iron more tightly and release it more slowly have made the risk of serious or severe HSRs very low. One such formulation, ferric derisomaltose, has been approved in the United States for delivery of 1000 mg iron in a single IV infusion. Ferric derisomaltose rapidly repletes iron parameters with low rates of serious or severe HSRs. Single-infusion iron repletion offers convenience, eliminates adherence concerns, and reduces healthcare resource utilization.

Clinical data for intravenous iron - debunking the hype around hypersensitivity.

BACKGROUND: Reluctance to use intravenous (IV) iron for the treatment of iron deficiency continues due to a perceived high risk of severe hypersensitivity reactions (HSRs). Additionally, it has been hypothesized that 'dextran-derived' IV iron products (e.g., ferumoxytol [FER] and ferric derisomaltose/iron isomaltoside 1000 [FDI]) have a higher risk of severe HSRs than 'non-dextran-derived' products (e.g., ferric carboxymaltose [FCM] and iron sucrose [IS]). In the present analysis, HSR data from head-to-head randomized controlled trials (RCTs) with IV iron products were evaluated to determine if differences in safety signals are present among these IV iron formulations. STUDY DESIGN AND METHODS: Reported serious or moderate-to-severe HSR incidence data from five RCTs (FIRM; FERWON-NEPHRO/-IDA; PHOSPHARE-IDA04/-IDA05) were used to calculate risk differences with 95% confidence intervals (CIs) for FER, FCM, FDI, and IS. The rates and risk differences for these HSRs were compared. RESULTS: The analysis included data for 5247 patients: FER (n = 997), FCM (n = 1117), FDI (n = 2133) and IS (n = 1000). Overall rates of serious or moderate to severe HSRs were low (0.2%-1.7%). The risk differences (95% CIs) showed small differences between the IV iron formulations: FER versus FCM, -0.1 (-0.8 to 0.6); FDI versus IS, 0.1 (-0.3 to 0.5); FDI versus FCM, -0.9 (-3.7 to 1.9). CONCLUSION: RCT evidence confirms a low risk of serious or moderate to severe HSRs with newer IV iron formulations and no significant differences among existing commercially available products. Thus, RCT data show that the supposed classification of dextran-derived versus non-dextran-derived IV iron products has no clinical relevance.

Transfusion replacement strategies in Jehovah's Witnesses and others who decline blood products.

The use of blood transfusions is a mainstay of modern medical practice. Jehovah's Witnesses decline the use of blood transfusions as a matter of faith, however, and other patients do so for personal reasons. In all cases, it is important to document what blood products can or cannot be used. It is also essential to test all patients for iron deficiency, and to address any correctable factors in those who are anemic. This article reviews a variety of options that are available to aid in caring for patients who refuse blood transfusions, ranging from tranexamic acid to erythropoiesis-stimulating agents. With the use of these treatments, patients who decline blood transfusion can be safely managed in situations ranging from elective surgery to stem cell transplant to pregnancy.

Immune Thrombocytopenic Purpura Splenectomy in the Context of New Medical Therapies.

BACKGROUND: As medical therapy improves, splenectomy has been relegated to third- or fourth-line therapy for immune thrombocytopenic purpura (ITP) in many hematologic practices. However, these medications have well-known associated morbidity and changes in treatment algorithms may affect the timing and degree of response to splenectomy as well as complications in heavily treated ITP patients. MATERIALS AND METHODS: This is a retrospective study of consecutive patients who underwent ITP splenectomy from January 1994 to June 2017. Nonresponders after splenectomy and those with recurrent disease were compared to complete responders. RESULTS: The cohort included 84 patients. Median number of medications received before splenectomy was 3 (1-6). 14.3% of patients had a medication-related complication, including heart failure, adrenal insufficiency, diabetes mellitus, infection, and osteoporosis. After splenectomy, 83.5% had a complete response, 7.5% partial response, and 9% no response. Complete response was associated with response to steroids before surgery (P < 0.01). Among responders, 19% had recurrent disease, which was associated with lower platelet count at diagnosis (P < 0.01). Forty-four patients (52.0%) had nonelective splenectomies for persistent bleeding or dangerously low platelets despite maximal medical therapy. Ten patients had Clavien-Dindo grade II or higher surgical complications (11.9%). Seven of these complications were related to recurrent or refractory ITP. CONCLUSIONS: Many ITP patients have complications related to medication use, and 52.0% required nonelective splenectomy despite maximal medical therapy. Earlier splenectomy may avoid medication-related complications and may reduce the complications from splenectomy. Splenectomy remains an effective and safe treatment for ITP.

Prevalence and Clinical Significance of Incidental Vertebral Marrow Signal Abnormality in Thoracolumbar Spine MRI.

STUDY DESIGN: A cross-sectional study. OBJECTIVE: This study investigates the prevalence of incidental vertebral marrow signal abnormality (VMSA) in thoracolumbar spine magnetic resonance imaging (MRI) ordered for the evaluation of back and/or leg pain and assess the clinical work-up for VMSAs. SUMMARY OF BACKGROUND DATA: Patients presenting with back pain are often referred for spine MRI for diagnostic evaluation. VMSA is most frequently found in the lumbar spine and is of clinical concern because it can represent malignancy. Standardized procedures for reporting and managing VMSAs do not exist. METHODS: The radiology database at the Oregon Health & Science University health system was queried to identify patients with thoracolumbar spine MRI scans performed between January 2014 and June 2016. Patients 16 years or older with MRIs ordered by providers at a multidisciplinary spine specialty clinic for the diagnostic evaluation of back and/or leg pain were included. Radiology reports were searched for keywords pertaining to VMSAs, such as "malignancy." Medical records of these patients were further reviewed for the clinical work-up and final diagnoses pertaining to the VMSA. RESULTS: The study sample included 1503 individual patients, of whom 65 (4%) had MRI radiology reports that described a VMSA. Thirty-one (48%) of the 65 patients with VMSAs had further evaluation recommended by radiology. Ten (32%) of these 31 patients were followed clinically without further diagnostic testing for the VMSA. Of the 65 patients with VMSAs, only one was diagnosed with malignancy (multiple myeloma). CONCLUSION: While VMSAs are not frequently found on thoracolumbar MRIs ordered to evaluate back and/or leg pain, there is a large amount of heterogeneity in how these abnormalities are documented and managed. This may indicate the need for clinical guidelines for the reporting and management of VMSAs detected on spine MRI and for improvement in communication between radiologists and ordering providers. LEVEL OF EVIDENCE: 3.

The many roles of tranexamic acid: An overview of the clinical indications for TXA in medical and surgical patients.

Clinically significant bleeding can occur as a consequence of surgery, trauma, obstetric complications, anticoagulation, and a wide variety of disorders of hemostasis. As the causes of bleeding are diverse and not always immediately apparent, the availability of a safe, effective, and non-specific hemostatic agent is vital in a wide range of clinical settings, with antifibrinolytic agents often utilized for this purpose. Tranexamic acid (TXA) is one of the most commonly used and widely researched antifibrinolytic agents; its role in postpartum hemorrhage, menorrhagia, trauma-associated hemorrhage, and surgical bleeding has been well defined. However, the utility of TXA goes beyond these common indications, with accumulating data suggesting its ability to reduce bleeding and improve clinical outcomes in the face of many different hemostatic challenges, without a clear increase in thrombotic risk. Herein, we review the literature and provide practical suggestions for clinical use of TXA across a broad spectrum of bleeding disorders.