Transfusion-Induced Iron Overload

The dynamics of iron regulation in the body is multifaceted and is altered in transfusion-induced iron overload.

Hepcidin, a 25-amino acid peptide synthesized in liver, is also known as the “iron hormone."[5] Circulating hepcidin reduces iron export into the plasma by binding to the iron export protein ferroportin 1 (FPN1) on the surface of enterocytes, macrophages, and other cells and causing its internalization and degradation. Thus, iron-deficiency states exhibit reduced hepcidin and iron-excess states have high levels of hepcidin to maintain the amount of iron secreted into the circulation.[6]

Several factors can influence hepcidin production, including the HFE gene, hypoxia, and increased erythropoietin production.[7] Most forms of hereditary hemochromatosis exhibit a deficiency of hepcidin.[8]

In some disorders, such as β-thalassemia, excessive intestinal absorption also adds to the transfusion-induced iron overload. In thalassemia intermedia, high erythropoietic drive causes hepcidin deficiency. The lack of hepcidin results in hyperabsorption of dietary iron and body iron overload. In contrast, in thalassemia major, transfusions decrease erythropoietic drive and increase the iron load, resulting in relatively higher hepcidin levels. In the presence of higher hepcidin levels, dietary iron absorption is moderated and macrophages retain iron, but body iron stores increase due to the inability to excrete iron in transfused red blood cells.[9]

When the plasma iron-binding protein transferrin is oversaturated, as in transfusion-induced iron overload, the excess iron circulates as relatively free non–transferrin-bound iron (NTBI). This NTBI is rapidly taken up by liver and other tissues. Transferrin-bound iron (TBI) is also taken up by these cells through the hepcidin mechanism, which is increased in such states.[10] It is this excessive iron that damages tissues.

A specific portion of NTBI is the chelatable labile plasma iron (LPI), which is not found in healthy individuals.[11] This is the most toxic component due to high reduction-oxidation (redox) potential that generates oxygen-free radicals such as superoxide anion in the cells, which damages DNA, proteins, and membrane lipids in the cell.[12]  Iron toxicity occurs as a result of the ferrous reactive forms of iron that reacts with oxidants, forming a complex that rapidly degrades proteins and DNA of a cell. High levels of reactive oxygen species are then produced, damaging the structure and genetic material of tissues.[13]

Reduced marrow activity also has a significant effect on the level of NTBI/LPI. In patients with marrow failure or ineffective erythropoiesis, which are the same patients who typically require chronic blood transfusion, levels of NTBI are much higher.[13]  In addition, hyperabsoroption of iron from the diet is observed in patients with ineffective erythropoiesis, making them iron loaded even in the absence of blood transfusion.[13]

Hemosiderin is an abnormal, insoluble form of iron storage. It consists of ferritin trapped in lysosomal membranes.[14] Unlike ferritin, it does not circulate in blood but is deposited in tissues and is unavailable when cells need iron.[15]

Major organs affected by this surplus iron include the heart, lung, liver, and endocrine glands. See Complications

Frequency

United States

Amongst 342 patients with transfusion-dependent thalassemia in the National Institutes of Health (NIH) registry, 23% had iron overload as documented by a liver iron concentration of 15 mg/g dry weight or greater.[16] Around 15,000 patients with sickle cell disorder and estimated and 5,000 with myelodysplastic syndromes and other acquired refractory anemias require blood transfusions.[17]

International

In a Japanese cohort of transfusion-dependent patients with myelodysplastic syndrome and aplastic anemia, one third of all deaths were attributable to iron overload (97% of the deceased had a serum ferritin >1000 ng/mL). Cardiac failure was responsible for 24% and liver failure for 7% of all deaths. On average, each patient was transfused with more than 60 units of red blood cells per year.[18]

In a Greek population of thalassemia major patients who were transfusion dependent, 51% had moderate (defined as serum ferritin > 2000 mcg/L) to severe iron overload (defined as serum ferritin > 4000 mcg/L).[19]

Mortality/Morbidity

Mortality in chronically transfused patients with thalassemia and sickle cell disease is 3 times that of the general United States population. The most common cause of morbidity is cardiomyopathy (30%) that is induced by iron overload.[20]

Race

The prevalence of mild to moderate iron overload was similar in black and white veterans in one autopsy study that evaluated the hepatic iron concentration of 256 specimens.[21]

Sex

An analysis of data from 1861 patients with β-thalassemia major from Italy showed that failure of puberty was the major clinical endocrine problem in these patients, and it was present in 51% of boys and 47% of girls, all older than 15 years. Secondary amenorrhea was recorded in 23% of the patients with β-thalassemia major.[22]

Age

Several distinct groups can be recognized in terms of the initiation of transfusion therapy. The average age of patients undergoing transfusion initiation is 4 years in thalassemia and 13 years in sickle cell disease[20] ; in adults, the average age at transfusion initiation is in the 40s for aplastic anemia,[23] and in the 60s for myelodysplasia.[24]

Patients with transfusion-induced iron overload typically have underlying anemia and transfusion dependence. The clinician should ask about the following:

• Duration of transfusion dependenc
• Number of transfusions each year
• Chelation history and compliance

Patients may complain of weight loss, fatigue, and arthralgia, along with cardiac, gastrointestinal, and endocrine manifestations.

Cardiac manifestations (related to heart failure) may include the following:

• Dyspnea
• Orthopnea
• Paroxysmal nocturnal dyspnea
• Swelling of lower extremities

Gastrointestinal signs and symptoms (related to cirrhosis) may include the following:

• Abdominal distention
• Abdominal pain
• Hematemesis
• Melena
• Encephalopathy

Endocrine manifestations may include the following:

• Stunted growth
• Delayed puberty
• Decreased libido
• Delayed menarche
• Diabetes mellitus (ie, polyuria, polydipsia, polyphagia)

General physical examination findings in patients with transfusion-induced iron overload may include the following:

• Bronze/gray skin color
• Bruising
• Cachexia
• Dwarfism
• Delayed breast development in pubertal girls
• Soft, small testes in males

Cardiac findings may include the following:

• Jugular venous distention
• S3 rhythm
• Pleural effusion
• Peripheral edema

Pulmonary findings may include the following:

• Lung crepitations
• Loud P ₂

Abdominal findings may include the following:

• Ascites
• Tenderness
• Hepatomegaly
• Splenomegaly
• Caput medusa
• Umbilical hernia

Neurologic findings related to cirrhosis may include the following:

• Asterixis
• Encephalopathy

Transfusion dependence due to the following are among the causes of transfusion-induced iron overload:

• Sickle cell disease
• β-thalassemia major
• Aplastic anemia
• Hemolytic anemia
• Blackfan-Diamond syndrome
• Myelodysplastic syndrome
• Leukemia

Cardiac involvement is a major determinant of the prognosis in iron-overload states.[25]  Hypertrophy and dilatation are common. Abnormal cardiac function can be observed in the absence of overt heart failure.[26]  The average time for the development of heart failure in transfused, unchelated patients is 10 years.[27]

Iron chelation can reverse cardiac changes and improve performance.[28]  In a murine model of beta-thalassemia, the myocardial damage with increased interstitial fibrosis and remodelling appears to start before any significant myocardial iron deposits can be demonstrated, suggesting additional mechanisms of cardiac failure pathogenesis in thalassemia.[29]

Pulmonary hypertension appears to be less common in thalassemia major patients who undergo transfusion, probably due to the correction of hypoxia, and it is more common in the less transfused thalassemia intermedia patients.[30]  More than one third of transfusion-dependent patients with β-thalassemia major exhibit a restrictive lung function defect, which may improve with chelation therapy.[31]

Liver involvement is common in those who undergo long-term transfusions. Early cirrhotic changes can be observed as early as age 7 years in some people with thalassemia.[32]  Upregulation of the transport of NTBI is observed in cultured hepatocytes and is likely to occur in vivo.[33]  Once cirrhosis develops, the risk of hepatocellular carcinoma (HCC) is increased.

Endocrine dysfunction affects virtually all glands. Pituitary involvement causes delayed puberty in more than 50% of patients.[34]  Destruction of pancreatic beta cells, insulin resistance, or both may result in diabetes mellitus.[35]  Even those without diabetes may have abnormal glucose metabolism.[35]  Thyroid, parathyroid, and exocrine pancreas are also affected.[36]  In one study involving patients with chronic anemia with transfusion-induced iron overload, free T3 and free T4 were decreased and thyrotropin-stimulating hormone was higher than normal.[37]  

Neutrophils from patients with secondary iron overload have an increased iron and ferritin content and a phagocytosis defect.[38] Yersinia enterocolitica seems to have affinity for those loaded with iron, causing abdominal infections[39]  and hepatic abscesses.[40]  Deferoxamine seems to worsen the infection and should be discontinued in cases in which active abdominal symptoms are present.[41]

Degenerative arthropathy in thalassemia is also a sequela of iron overload.[42]

To date, no perfect laboratory marker for iron overload exists.

Serum iron studies

Serum ferritin has been extensively used as an easily accessible serum marker for transfusion-induced iron overload. The ferritin level that has been used as a cutoff point for iron toxicity has varied in studies from 1000 ng/mL to 3000 ng/mL.[44, 45] The major drawbacks of ferritin are a lack of specificity and interpatient variability.[45] Inflammation, disseminated malignancy, and chronic diseases can also cause large amounts of ferritin to be released in the circulation, making a single elevated reading unreliable.[46]

Low serum ferritin levels may be misleading by providing a false sense of security when patients are at risk of end-organ damage such as cardiomyopathy.[47] Ferritin has also been shown to have a prognostic value. In one study of β-thalassemia major, for patients in whom more than 67% of ferritin measurements exceeded 2500 ng/mL, the estimated disease-free survival was 38% after 10 years of therapy and 18% after 15 years.[25]

Serum iron is increased in cases of iron overload and the total iron-binding capacity (TIBC) is decreased. The relationship between serum iron and total body iron is nonlinear, and the results are dependent on the method used.[48]

Transferrin saturation can be easily measured and is a surrogate marker for NTBI, although this is far from perfect.[49] A transferrin saturation above 50% is suggestive of a high iron load, but this is a dynamic number and may vary with inflammation.

NTBI and LPI are very specific for iron overload and have promising value as monitoring parameters for clinical response to chelation therapy.[50] However, the lack of a standardized assay and limited data for general use for transfusion-induced iron overload makes it necessary to further investigate the use of NTBI and LPI.

Hepcidin measurement in serum and urine have been performed using mass spectrometry, and this may be a feasible marker in the future.[51]

The patient's complete blood cell (CBC) count should be monitored for the hemoglobin/hematocrit to maintain a high threshold for transfusion. Liver function tests, especially alanine aminotransferase (ALT) and aspartate aminotransferase (AST), should be monitored. In patients who develop diabetes mellitus, the usual parameters, such as hemoglobin A1C (HbA1C) and glucose, should be monitored.

Computed tomography (CT) scanning has a limited sensitivity (63%) for the assessment of hepatic iron overload.[52] An elevated hepatic CT density associated with an elevated serum ferritin indicates iron overload; however, a normal hepatic CT density does not exclude iron overload.[53] CT scanning is not sensitive when serum ferritin is less than 1000 mcg/L.[54]

Superconducting quantum interference device (SQUID) magnetic measurements of liver iron in patients with iron overload are quantitatively equivalent to biochemical determinations on tissue obtained by biopsy.[55] SQUID can also measure spleen iron content and can be used for monitoring the clinical response to chelation therapy.[56] However, the complexity, cost, and technical demands of the liquid helium–cooled superconducting instruments required at present necessitate restricted clinical access to this method.[57] The latest generation SQUID can be used at room temperature.[58]

Magnetic resonance imaging (MRI) is the noninvasive means of imaging choice and can detect iron deposition in the liver, heart,[59] joints, and pituitary. MRI assessment of myocardial iron loading with the use of gradient echo T2* measurements has reliable reproducibility and has been validated in multiple centers.[60] Quantitative R2* MRI using the transverse magnetic relaxation rate is useful for the measurement of hepatic iron content at facilities with experienced personnel and the proper equipment.58 Liver iron content estimated by MRI was found to be strongly correlated to that measured by liver biopsy in many studies.[61] ​

MRI is useful to assess pituitary iron overload in patients with transfusional hemochromatosis and secondary hypogonadism by detection of a significant decreased signal intensity of the anterior lobe of the pituitary gland on T2-weighted images.[62] The degree of reduction of the pituitary-to-fat signal intensity ratio correlates with the presence of hypogonadotropic hypogonadism, with a sensitivity of 90%, a specificity of 89%, and an overall accuracy of 89%.[63]

In addition, MRI can be used for the accurate detection of hemochromatosis in the joints of thalassemia patients receiving multiple transfusions.[64] However, iron deposition in the pancreas cannot be reliably predicted by MRI.[65] MRI mapping accurately estimates hepatic iron concentration in patients with transfusion-dependent thalassemia and sickle cell disease.[66] MRI is rapid, noninvasive, and cost effective, and could limit the use of liver biopsy to assess liver iron content.[67]

When peripheral flow cytometry is performed, patients with transfusion-induced iron overload seem to exhibit a high expression of CD2 and a low expression of CD38 surface markers on the helper T (Th)-cell subset.[68]

Elevated NT-proBNP levels appear to predict cardiac hemosiderosis as demonstrated by T2-weighted MRI in thalassemia even when the ejection fraction is preserved.[69]

Liver biopsy is the criterion standard for measuring iron deposition in the liver and a surrogate for other organs. The hepatic iron concentration is a reliable indicator of total body iron stores.[70] Liver iron concentration (LIC) is measured in mg/g of dry weight of liver and may vary up to 23% between fresh and paraffin-embedded samples.[71] A poor correlation is observed between serum ferritin and the quantitative iron on liver biopsy.[72] CT-guided and transjugular liver biopsies appear less risky. Complications of liver biopsies are reported in 0.06-0.32% of the patients. Death as a direct result of liver biopsy is extremely rare (0.009-0.12%).[73]

Endomyocardial biopsy is an insensitive method of determining early myocardial iron deposition because of the location of the iron and the variability of the sampling.[74]

Iron accumulation and fibrosis are the common features found in patients with thalassemia and liver damage, except that thalassemia/hemoglobin H disease exhibit lesser hepatic damage. The degrees of iron deposition and fibrosis are higher in splenectomized and cirrhotic individuals than in nonsplenectomized and noncirrhotic patients.[75]

The subcellular changes on electron microscopy are swollen mitochondria, with the presence of an electron-dense matrix and ruptured mitochondrial membrane. Proliferation of smooth endoplasmic reticulum (ER), and dilatated rough ER are observed. Increases in lysosomal hemosiderin in hepatocytes and in Kupffer cells are demonstrated. The pattern of liver cell damage is similar to that of viral hepatitis.[75]

Hepatic iron overload is classified as mild (< 7 mg/g dry weight), moderate (7-15 mg/g dry weight), or severe (>15 mg/g dry weight).[76]

Iron chelation therapy

The primary goal of iron chelation therapy is to prevent the accumulation of iron reaching harmful levels by matching iron intake from blood transfusion, with iron excreted by iron chelation.[77]  Although non–transferrin-bound iron and liver deposits are chelatable to a degree, iron that is deposited in other organs such as the heart is not readily chelated, making cardiac failure a leading cause of death in patients who undergo long-term transfusions.[78]  Autopsy studies in the 1970s[79]  and MRI data[80] obtained more recently show that after receiving 75 or more units of transfused blood, more than 50% of patients have excess iron in their myocardium.

The initiation of chelation therapy thus is a decision that has to be individualized. When to start chelation depends on the number of transfusions that were already given, the extent of iron deposition in the liver and the heart and the corresponding degree of dysfunction in these organs, and the type of transfusion regimen.[81]  

In general, chelation therapy is started in individuals who have received regular transfusions for 1 to 2 years, whose serum ferritin levels exceed at least 1000 to 1500 mcg/L, or whose liver iron levels are > 3 to 5 mg/g dry weight.[82] This corresponds to approximately a total of 120 to 200 mL of transfused RBCs per kilogram.[82]  The American Academy of Pediatrics suggests that children receiving chelation therapy should maintain a serum ferritin level of < 1500 ng/mL or liver iron < 7 mg/g dry weight.[82]

Three agents are approved for iron chelation therapy:

• Deferoxamine
• Deferiprone
• Deferasirox

Deferoxamine

Deferoxamine (DFO; Desferal) has been used for more than 30 years for iron chelation. However, it is a parenteral drug that requires subcutaneous or intravenous infusions because of its short half-life and poor oral bioavailability, making compliance an issue.[83]  The only randomized trial comparing chelation with intramuscular deferoxamine to no chelation was small and involved 20 children with thalassemia. At about 6 years, the mean hepatic iron concentration in liver tissue was 42 mg/g in the untreated group and 26 mg/g in the deferoxamine group.[84] At 14 years, 6 deaths had occurred in the untreated group compared with 1 in the treated group.[85]

The early use of deferoxamine in an amount proportional to the transfusional iron load reduces the body iron burden and helps protect against diabetes mellitus, cardiac disease, and early death in patients with thalassemia major.[86]  Moreover, deferoxamine halts the progression to cirrhosis of hepatic fibrosis brought about by iron overload.[87]  

The main limitations of deferoxamine as an iron chelator are its short blood circulation time, which necessitates more frequent administration, and its non-preferential distribution into non-target tissues such as the brain, kidney, muscle, and lungs.[88]  

Current research is exploring the use of nanogel-deferoxamine conjugates to improve the performance of deferoxamine. A 2018 study found that nanogel-deferoxamine conjugates reduced the cytotoxicity of deferoxamine and significantly decreased the ferritin levels in iron-overloaded macrophages in vitro. In the same study, in an animal model, nanogel-deferoxamine had a prolonged circulation time and preferential accumulation in the liver and spleen.[89]  

A 2019 study of nanochelators (multiple deferoxamine moieties conjugated on a backbone of polymeric nanoparticles) demonstrated that such nanochelators provide more favorable biodistribution while effectively removing excess iron exclusively via urinary elimination.[88]  These advancements in deferoxamine as an iron chelator promise to provide enhanced safety and efficacy.

Meanwhile, deferiprone and deferasirox offer the convenience of oral iron chelation. However, those agents have significant toxicities (eg, gastrointestinal bleeding, agranulocytosis, neutropenia, thrombocytopenia, hepatic fibrosis, and kidney failure).[88]  Long-term follow-up is required before pumps and needles can be thrown away.

Deferiprone

Deferiprone (Ferriprox) was approved by the US Food and Drug Administration (FDA) in 2011 for transfusional iron overload caused by thalassemia syndromes. This approval was based on serum ferritin level reduction; no controlled trials demonstrated a direct treatment benefit (eg, improvement in disease-related symptoms, functioning, or increased survival).[90]  

In April 2021, the FDA approved deferiprone for transfusional iron overload in adults and children aged 3 years and older with sickle cell disease and other anemias. Approval was based on a controlled noninferiority comparative trial of deferiprone with deferoxamine, based on evaluation of liver iron concentration (LIC). Over 12 months, estimated mean decrease from baseline in LIC was 4.13 for deferiprone and 4.38 for deferoxamine. Upon completion of the first year of therapy, 89 of the 122 patients in the deferiprone group opted to continue with treatment and 45 of the 63 patients in the deferoxamine group opted to switch to deferiprone. LIC continued to decrease over time in the patients receiving deferiprone, with the mean value dropping from 14.93 mg/g at baseline to 12.30 mg/g after 1 year, to 11.19 mg/g after 2 year, and to 10.45 mg/g after 3 years.[90]

At least one study has reported improved cardiac outcomes with deferiprone.[91]  If true, that is a major advantage of this drug because cardiac failure remains the major cause of mortality in thalassemia. An Italian study comparing deferiprone with deferoxamine in thalassemia showed statistically significant improvement in ejection fraction in the deferiprone group at 2 years; however, the clinical significance of this finding (59% vs 62%) is unclear.[92]  In addition, concerns have been raised about bony dysplasia and impaired growth of ulnar epiphysis in Indian children treated with deferiprone.[93]

Deferasirox

Deferasirox (Exjade tablet for oral suspension, Jadenu oral tablet, Jadenu Sprinkles oral granules) is preferred by patients due to its convenient once-daily oral administration[94] and its cost-effectiveness.[95]  The FDA approved Exjade for chronic iron overload from blood transfusions in 2005, and approved Jadenu in 2015. Deferasirox has also been studied in non-transfusion-dependent thalassemia[96] and at both low and high iron burdens.[97] This agent has an acceptable tolerability profile and appears to have similar efficacy to deferoxamine in reducing the iron burden in transfused patients with sickle cell disease.[98]

In a comparative study of beta-thalassemia patients, noninferiority was demonstrated in the group of patients who were allocated to the higher dose groups (deferasirox doses of 20 or 30 mg/kg) for baseline liver iron concentrations (LIC) of 7 mg/g dry weight or greater when compared with deferoxamine.[99] In another study, deferasirox 20 mg/kg showed similar efficacy to deferoxamine 40 mg/kg in terms of decreases in LIC.[100]  A comparative study of deferoxamine, deferiprone, deferoxamine + deferiprone, and deferasirox in beta-thalassemia patients found after 5 consecutive years of therapy, patients on deferasirox had the highest decrease in the prevalence of any endocrinopathy(diabetes mellitus, hypothyroidism, or hypogonadism). In addition, there was a significant decrease in osteoporosis in patients on deferasirox.[101]

In a phase III study of 586 children with thalassemia that compared deferasirox with deferoxamine at 1 year, 53% of children in the deferasirox group had maintained or reduced hepatic iron concentrations, versus 66% in the deferoxamine group.[102]

A phase II study of deferasirox and deferoxamine in sickle cell disease with transfusional iron overload showed comparable safety profiles. Deferasirox resulted in a median serum ferritin decrease of more than 600 mg/mL at 2 years.[103]

A Cochrane database review by Meerpohl et al of 4 clinical trials (including 2 comparing deferasirox with deferoxamine) concluded that the drugs have similar efficacy and short-term safety profiles. However, the review fell short of recommending deferasirox as first-line treatment, despite patients preferring it over cumbersome deferoxamine administration in patients with thalassemia and transfusional iron overload.[104]

A prospective study of 30 children on deferasirox from Iran demonstrated evidence of decreased glomerular filtration rate and renal tubular dysfunction but the mean serum creatinine level stayed less than 1 mg/dL over a 6 month follow-up.[105] Monitoring of renal function is recommended.[106] Increased hepatotoxicity in patients with MRP2 protein mutation may have some pharmacogenetic component.[107] At least one case of esophagitis has been reported.[108]

Unlike patients with primary hemochromatosis and some other causes of secondary iron overload, patients with transfusion-induced iron overload are already anemic, and therapeutic phlebotomy is not usually an option, except in those with curable disorders such as leukemia that is in complete remission. [109]

Myelodysplastic syndromes are an area of increasing interest for iron chelation, in addition to traditional hemoglobinopathies such as thalassemia.[110, 111]  A 1-year, open-label study in Germany of deferasirox in low-risk and intermediate-risk myelodysplastic syndrome patients with transfusion overload showed a mean decrease from 2447 to 1685 ng/mL in serum ferritin; however, hematological improvement occurred in only 11%, with half the patients unable to complete 1 year of treatment due to adverse effects.[112]  An Italian cohort of 40 patients with myelodysplastic syndromes treated with deferasirox showed similar improvement in serum ferritin and hematological parameters and demonstrated the safety of drug when used concomitantly with azacitidine and lenalidomide.[113]

Aplastic anemia is another area of increasing interest, because iron overload may contribute to ongoing anemia and chelation may revive the damaged marrow.[114, 115]

 

Liver and cardiac transplantation should be considered for appropriate patients with end-stage disease. Combined liver-heart transplants have been carried out successfully in thalassemia patients.[116]

Consultations with the following specialists should be sought in cases of transfusion-induced iron overload:

• Hematologist
• Cardiologist
• Gastroenterologist/Hepatologist
• Endocrinologist

Ascorbic acid (vitamin C) increases the absorption of dietary iron 2.9-3.5 times the normal amount[117] and should probably be avoided, along with alcohol and, of course, iron supplements. However, both green and black tea inhibit absorption of iron in food.[118]

The goals of pharmacotherapy in cases of transfusion-induced iron overload are to protect tissues from damage caused by iron, decrease plasma and cytosolic levels of reactive labile iron to normal, and rid the body of all excess iron, thereby preserving organ function.[13]  Three iron-chelating agents are available: deferoxamine, deferasirox, and deferiprone.

Class Summary

Chelating agents help reduce iron levels in the body by promoting the excretion of chelated iron.

Deferoxamine (Desferal mesylate)

The drug is siderophore (iron-binder) derived from the bacterium Streptomyces pilosus.

It is usually administered as a slow SC infusion through a portable pump. It is freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine, forming a 1:1 hexadentate complex. Its half-life is 20-30 minutes.

Promotes renal and hepatic excretion in urine and bile in feces. Gives urine a red discoloration. Readily chelates iron from ferritin and hemosiderin but not from transferrin. Does not affect iron in the cytochromes or hemoglobin. Most effective when provided to the circulation continuously by infusion. Helps prevent damage to the liver and bone marrow from iron deposition.

May be administered either by IM injection or by slow IV infusion. 

The starting dose in individuals without iron-induced cardiac dysfunction is 30 mg/kg daily infused over 8 to 12 hours, five days per week. Dosing an be changed by 5 to 10 mg every three to six months depending on transfusion burden and iron status of the patient.

Does not effectively chelate other trace metals of nutritional importance. Provided in vials containing 500 mg of lyophilized sterile drug. Two mL of sterile water for injection should be added to each vial, bringing the concentration to 250 mg/mL. For IV use, this may be diluted in 0.9% sterile saline, 5% dextrose solution, or Ringer solution.

Deferasirox (Exjade tablets)

Tablets for oral suspension. Oral iron chelation agent that is demonstrated to reduce the liver iron concentration in adults and children who receive repeated RBC transfusions. Binds iron with high affinity in a 2:1 ratio (tridentate complex). Approved to treat chronic iron overload due to multiple blood transfusions.

Treatment initiation is recommended with evidence of chronic iron overload (ie, transfusion of about 100 mL/kg packed RBCs [about 20 U for a 40-kg person] and a serum ferritin level consistently >1000 mcg/L). 

The dose for deferasirox is 20 mg/kg/day orally once daily, and then increased by 5 to 10 mg every three to six months based on levels of iron stores. 

 

Deferiprone (Ferriprox)

1,2 dimethyl-3-hydroxypyridine-4-one is a member of a family of hydroxypyridine-4-one (HPO) chelators that requires 3 molecules to fully bind iron (III), each molecule providing 2 coordination sites (bidentate chelation). Half-life is approximately 2 hours. Inactive metabolite is predominantly excreted in urine. It is indicated for adults and children aged 3 years and older with iron overload from transfusion for thalassemia syndromes, sickle cell disease, or other anemias. Available as tablets and oral solution.  

Hospital admissions in cases of transfusion-induced iron overload may result from complications of cirrhosis, sepsis, and heart failure, amongst other causes. These cases should be managed with a multidisciplinary team approach.

Compliance with chelation therapy for transfusion-induced iron overload is specific to the treatment center, with better long-term survival in centers that have experience in chelation management than in centers where small numbers of patients are treated.[119]

All patients who are transfusion dependent require careful monitoring of their iron stores. It is advisable to measure ferritin levels at least every 3 months and iron studies every year. Liver iron levels should be measured annually (either by biopsy or noninvasively) and every 3–6 months in patients who undergo intensive chelation for heart failure. If MRI is available, cardiac iron levels and cardiac function should also be measured by MRI yearly and every 6 months in patients who have intensive chelation therapy.[48]

Monitoring liver function test results and kidney function, especially in sickle cell patients, is recommended during chelation therapy.

Complications of iron overload have been steadily falling since the introduction of deferoxamine. For thalassemia major patients in Italy who were started on deferoxamine after subcutaneous infusions became widely available in 1980, death from cardiac disease fell from 5% at 20 years to 1%, and the incidence rates hypogonadism, diabetes, and hypothyroidism also fell significantly.

Better survival has been demonstrated for patients born in more recent years (P< 0.00005) and for females (P = 0.0003). In a study by Borgna-Pignatti et al, 68% of patients were alive at age 35 years, with 67% of the patient deaths due to heart disease.[78] In some patients treated with deferoxamine (particularly those who start treatment late or who fail to comply with treatment), high levels of iron (>15 mg iron per gram of liver dry weight) are still present—a level that is associated with a high risk of cardiac disease and early death over a long period.[86] Failure to control serum ferritin over prolonged periods is also associated with an increased risk of cardiac disease and death.[25]

Compliance is the major limiting factor of chelation therapy in cases of transfusion-induced iron overload, and continuous re-enforcement is needed. Patients should be educated about signs and symptoms of heart failure, cirrhosis, and diabetes.