Transfusion, iron overload

TfR is low in these patients, PIT is normal and most iron is stored in hepatocytes. In patients with hypoplastic anaemias and with transfusion iron overload, the BM cannot utilize iron, resulting in low TfR expression and decreased iron absorption. Quantitative analysis of all iron fluxes, which can be deduced from Figure 9.1, can assist in understanding the clinical expression of mutations of proteins involved in iron transport. 

Assessing transfusion iron overload with precision for possible toxic evaluations and its treatment with chelation therapy requires reliable monitoring end points and procedures. Liver iron content is an important variable for such monitoring that may also be measured using standardised MRI sequences. A study compared liver iron content of 68 patients obtained using gradient-echo sequences and mean liver proton transverse relaxation acquired with spin-echo sequences. The authors suggested that a difference in results from the two techniques may lead to a difference in chelation decisions in patients [122 ]. 

A major theme in the 2012-2013 time period was comparisons of multidrug therapies against single-drug regimens. These are reviewed at the end of this section. An excellent review discusses the pros and cons of different iron chelation therapies together with associated side effects [1 ]. A major review comparing deferoxamine, deferiprone and deferasirox for the treatment of transfusion iron overload can also be foxmd [6 ]. 

Desferrioxamine (Df) has a dissociation constant for binding to Fe at IO M which provides the very high specificity for the chelation of iron required for the treatment of patients with transfusion iron overload [114-116]. As such Df has been very closely monitored as clinical agent for 20 years. The main clinical drawback of desferrioxamine is that the chelator can only be administered by intramuscular injection (usually to Sickle Cell Disease patients in crisis). There has been an active program to introduce new orally active iron chelators [114-116]. 

Hereditary hemochromatosis is an autosomal recessive disease of increased intestinal iron absorption and deposition in hepatic, cardiac, and pancreatic tissue. Hepatic iron overload results in the development of fibrosis, hepatic scarring, cirrhosis, and hepatocellular carcinoma. Hemochromatosis can also be caused by repeated blood transfusions, but this mechanism rarely leads to cirrhosis. 

Chronic transfusion is indicated to prevent stroke and stroke recurrence in children. Transfusion frequency is usually every 3 to 4 weeks and should be adjusted to maintain HbS of less than 30% of total hemoglobin. The optimal duration is unknown. Risks include alloimmunization, hyperviscosity, viral transmission (requiring hepatitis A and B vaccination), volume and iron overload, and transfusion reactions. 

A second form of storage iron is haemosiderin (Weir et al., 1984). This is deposited in humans as a response to the condition of iron overload. Haemosiderin forms as insoluble granules with electron dense cores surrounded by a protein shell. It exists in two forms primary haemosiderin is the result of iron overload due to excessive adsorption of iron in the gut, whereas the secondary form is caused by the numerous blood transfusions which are used to treat thallassaemia (a form of anaemia). Electron diffraction indicated that the iron core in primary haemosiderin is a 3-line ferrihydrite with magnetic hyperfine splitting only below 4 K and, in the secondary form, consists of poorly ordered goethite. As goethite is less soluble in ammonium oxalate buffer solution (pH 3) it has a lower intrinsic toxicity (Mann et al., 1988). 

Deravirdine (Rescnptor) [Antiretroviral/NNRTI] Uses HIV Infxn Action Nonnucleoside RT inhibitor Dose 400 mg PO tid Caution [C, ] CDC recommends HIV-infected mothers not to breast-feed (transmission risk) w/ renal/hepatic impair Contra Use w/ drugs dependent on CYP3A for clearance (Table VI-8) Disp Tabs SE Fat redistribution, immune reconstitution synd, HA, fatigue, rash, T transaminases, N/V/D Interactions T Effects W/ fluoxetine T effects OF benzodiazepines, cisapride, clarithromycin, dapsone, ergotamine, indinavir, lovastatin, midazolam, nifedipine, quinidine, ritonavir, simvastatin, terfena-dine, triazolam, warfarin effects W/ antacids, barbiturates, carbamazepine, cimetidine, famotidine, lansoprazole, nizatidine, phenobarbital, phenytoin, ranitidine, rifabutin, rifampin effects OF didanosine EMS Use of benzodiazepines and CCBs should be avoided may cause a widespread rash located on upper body and arms OD May cause an extension of nl SEs symptomatic and supportive Deferasirox (Exjade) [Iron Chelator] Uses Chronic iron overload d/t transfusion in pts >2 y Action Oral iron chelator Dose Initial 20 mg/kg... 

Roberts DJ, Rees D, Howard J, Hyde C, Brunskill S. Des-ferrioxamine mesylate for managing transfusional iron overload in people with transfusion-dependent thalas-saemia. Cochrane Database Syst Rev 2005. 

When injected, it forms a stable water-soluble iron complex (ferrioxamine) that prevents the iron from entering into further chemical reactions and is readily excreted in the urine giving the urine a characteristic reddish colour. Some of it is also excreted in the faeces via the bile. It can also chelate aluminium and thus is useful in aluminium overload. It is primarily a chelator used in acute iron poisoning and chronic iron overload as in thalassemia patients needing multiple transfusions. 

Chronic iron overload 0.5 to 1 g IM daily. In addition 2 g IV infusion given separately with each unit of blood transfused. 

It is an orally active iron chelator. It is useful in acute iron poisoning, iron overload in cirrhosis, transfusion siderosis in thalassemia patients. Adverse effects are anorexia, vomiting, altered taste, joint pain and neutropenia. 

Deferasirox dispersible tablet For chronic iron overload due to blood transfusion... 

Chronic iron toxicity (iron overload), also known as hemochromatosis, results when excess iron is deposited in the heart, liver, pancreas, and other organs. It can lead to organ failure and death. It most commonly occurs in patients with inherited hemochromatosis, a disorder characterized by excessive iron absorption, and in patients who receive many red cell transfusions over a long period of time (eg, patients with thalassemia major). 

Erythropoietin has been used successfully to offset the anemia produced by zidovudine treatment in patients with HIV infection and in the treatment of the anemia of prematurity. It can also be used to reduce the need for transfusion in high-risk patients undergoing elective, noncardiac, nonvascular surgery to accelerate erythropoiesis after phlebotomies for autologous transfusion for elective surgery or for treatment of iron overload (hemochromatosis). 

Deferasirox is a tridentate chelator with a high affinity for iron and low affinity for other metals, eg, zinc and copper. It is orally active and well absorbed. In the circulation, it binds iron, and the complex is excreted in the bile. Deferasirox was recently approved for the oral treatment of iron overload caused by blood transfusions, a problem in the treatment of thalassemia and myelodysplastic syndrome. 

Thalassemia Major. Transfusion-dependem thalassemia major patients liuvc abnormal growth and sexual maturation al puberty, presumably as a result of pituitary iron overload. Still poorly understood, this disorder is reported to respond well to deferoxamine iron chelation therapy, particularly if administered before the age of maturity. 

DFO is generally indicated for treatment of acute iron intoxication and chronic iron overload due to transfusion depended anemias (including thalassemia). DFO is not recommended in primary hemochromatosis (PDR). 

Hoffbrand AY Al-Refaie F Davis B, et al. Long-term trial of deferiprone in 51 transfusion-dependent iron overloaded patients. Blood I 998 91 295-300. 

Under normal circumstances, transferrin is one-fourth to one-third saturated with iron. The level of saturation may decrease in systemic infection or cancer and in iron deficiency anemia, the most common nutritional deficiency in the United States. In individuals with iron deficiency anemia, transferrin levels are increased. The level of saturation with iron increases in iron overload syndromes such as hereditary hemochromatosis or as a result of repeated blood transfusions, as is the case in thalassemia patients. Determinations of total plasma iron (TI) and plasma total iron binding capacity (TIBC) are routinely performed in the clinical biochemistry laboratory. The TIBC value reflects transferrin levels in plasma the amount of iron that can be bound by transferrin is equal to TIBC x 0.7. Total plasma iron levels in iron deficiency anemia become abnormal before hemoglobin levels show any change. 

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