Hemoglobin is the iron-containing protein in red blood cells that carries oxygen to cells throughout the body. Hemoglobin consists of four protein subunits, typically two subunits of beta-globin and two subunits of another protein called alpha-globin.
Major -usually appears in an infant after three months of age and causes life-threatening anemia
Ineffective erythropoiesis is the active erythropoiesis with premature death of created red blood cells RBCs, a decreased output of red blood cells from the bone marrow and consequently anemia.Extramedullary hematopoiesis refers to hematopoiesis(formation of blood cellular components) occurring outside of the medulla of the bone.Erythroid hyperplasia is excessive growth of immature red blood cells.Hepatomegaly is the condition of having an enlarged liver
Chronic hepatitis is the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ.Splenomegaly is the enlargement of the spleenExtravascular hemolysis occurs when RBCs are phagocytized by macrophages in the spleen, liver and bone marrow.portal hypertension is hypertension (high blood pressure) in the portal vein and its tributaries
THALASSEMIA• Thalassemia is an inherited blood disorder in which the body produces an abnormal form of hemoglobin which results in excessive destruction of red blood cells and further leads to anemia. • TYPES OF THALASSEMIA: ALPHA THALASSEMIA BETA THALASSEMIA
Alpha Thalassemia Alpha thalassemia is the result of changes in the genes for the alpha globin component of hemoglobin.
ETIOLOGYMutation in the DNA of cells that produce hemoglobinInheritance
PathophysiologyAlpha thalassemia results when there is disturbance in production of α-globin from any or all four of the α- globin genes. Genes are responsible for regulating the synthesis and structure of different globins which are divided into 2 clusters. The α-globin genes are encoded on chromosome 16 and the γ, δ, and β-globin genes are encoded on chromosome 11 A normal person carries a linked pair of alpha globin genes, 2 each from maternal and paternal chromosome.
PathophysiologyTherefore, alpha thalassemia occurs when there is a disturbance in production of α-globin from any or all four of the α-globin genes.When functional point mutations, frame shift mutations, nonsense mutations, and chain termination mutations occur within or around the coding sequences of the alpha-globin gene cluster hemoglobin is impaired.When that occurs, protein synthesis may be inhibited.
Pathophysiology Normal production of alpha chains is absent which results in excess production of gamma- globin chains in the fetus and newborn or beta- globin chains in children and adults. The β-globin chains are capable of forming soluble tetramers (beta-4, or HbH) This form of hemoglobin is still unstable and precipitates within the cell, forming insoluble inclusions called Heinz bodies These Heinz bodies damage the red blood cells. This further results in damage to erythrocyte precursors and ineffective erythropoiesis in the bone marrow, hypochromia and microcytosis of circulating red blood cells
Mutated ThalassemiaAlpha (0) thalassemia – More than 20 mutations have been found.Those that result in the functional depletion of both pair of α -globin genesIndividuals with this disorder are not able to produce any functional α -globin and thus are unable to make any functional hemoglobin A, F, or A2.This leads to the development of hydrops fetalis or hemoglobin Bart (excess buildup of fluid before birth)
Mutated Thalassemia Alpha (+) thalassemia –More than 15 different genetic mutations that result in decreased production of α -globin usually due to the functional deletion of 1 of the 4 alpha globin genes. Further classification of Alpha (+) thalassemia: A- Thalassemia (-α/α α) Characterized by inheritance of 3 normal α-genes. Patients clinically known as silent carriers of alpha thalassemia. Also known as alpha thalassemia minima, alpha thalassemia-2 trait, and heterozygosity for alpha (+) thalassemia minor
Clinical Presentation Shortage of red blood cells- Anemia Pale skin Weakness Fatigue Enlarged liver and spleen- hepatosplenomegaly
Clinical Presentation Heart defects Abnormalities of the urinary system or genitalia Hb Bart syndrome can cause complications in pregnancy such as• High blood pressure• Premature delivery• Abnormal bleeding• Jaundice
Treatment of Alpha Thalassemia• Treatment for thalassemia often involves regular blood transfusions and folate supplements.• If you receive blood transfusions, you should not take iron supplements. Doing so can cause a high amount of iron to build up in the body, which can be harmful.• Persons who receive significant numbers of blood transfusions need a treatment called chelation therapy to remove excess iron from the body.• Bone marrow transplant may help treat the disease in some patients, especially children.
Surgical Treatment – Perform splenectomy if transfusion requirements are increasing. – Surgical or orthodontic correction may be necessary to correct skeletal deformities of the skull and maxilla caused by erythroid hyperplasia.
FOLIC ACID - ORAL• BRAND NAME(S): FA-8• USES – Folic acid is the man-made form of folate which is a B6- vitamin naturally found in some foods. – It is needed to form healthy cells, especially red blood cells. – Active forms of folic acid are: L-methylfolate and levomefolate – Folic acid supplements are used to treat or prevent low folate levels.
Dosage• Taken orally with or without food once daily.• However, recommended dose for deficiency states is 250-1000 mcg (micrograms) per day
SIDE EFFECTS – Folic acid usually has very few side effects – Possible side effects include: • Serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), dizziness, trouble breathing
• Folic acid is safe to take during pregnancy when used as directed. It is included in prenatal vitamin products.• Certain spinal cord birth defects may be prevented by taking adequate amounts of folic acid during pregnancy.
DRUG INTERACTIONS – Fosphenytoin (Cerebyx)Taking folic acid along with fosphenytoin (Cerebyx) mightdecrease the effectiveness of the drug for preventing seizuressince folic acid increase the breakdown of the drug.– Methotrexate (MTX, Rheumatrex)Folic acid decrease the effectiveness of methotrexate.- Phenobarbital (Luminal).Taking folic acid can decrease how well phenobarbital (Luminal) works for preventing seizures.
DRUG INTERACTIONS – Primidone (Mysoline). Folic acid can decrease the effectiveness of primidone for preventing seizures. – Pyrimethamine (Daraprim). It is used to treat parasite infections. Folic acid might decrease the effectiveness of pyrimethamine (Daraprim)
FOLIC ACID - INJECTION• BRAND NAME(S): Folvite• USES: Folic acid is used to treat or prevent – certain anemias caused by poor diet, – pregnancy, – alcoholism, – Liver disease, – certain stomach/intestinal problems, – kidney dialysis, or – relieve symptoms such as unusual tiredness and diarrhea
• ADMINISTRATION: This medication is given by IM, IV OR SC usually once a day.• DOSAGE:- 1-5 mg/day
DRUG INTERACTIONS• Chloramphenicol-cause depletion of folic acid.• Folic acid does not correct folate deficiency due to dihydrofolate reductase inhibitor such as methotrexate. Methotrexate, trimethoprim, and pyrimethamine prevent the reduction of folic acid to tetrahydrofolate.• Sulphasalazine depresses folic acid absorption.• Folic acid is incompatible with oxidising and reducing agents and ions with heavy metals.• Folic acid may affect certain laboratory tests for vitamin B12 deficiency, resulting in false test results. Untreated vitamin B12 deficiency may result in serious nerve problems (e.g., peripheral neuropathy with numbness/tingling symptoms).
DEFEROXAMINE - INJECTION• BRAND NAME(S): Desferal• Deferoxamine is an iron-binding agent that belongs to a class of drugs known as heavy metal antagonists. It works by helping the kidneys and gallbladder get rid of the extra iron.Mechanism of Action• Deferoxamine works in treating iron toxicity by binding trivalent (ferric) iron (for which it has a strong affinity), forming ferrioxamine, a stable complex which is eliminated via the kidneys.
Uses• This medication is used along with other treatments (such as syrup of ipecac) to treat sudden iron poisoning.• It is most effective when given as soon as possible after the iron was eaten.• This medication can also be used to help get rid of iron in patients with high iron levels due to many blood transfusions.• This medication is not recommended for use in children less than 3 years old• This drug may also be used to treat high levels of aluminum in dialysis patients and people with aluminum poisoning.
ADMINISTRATION & DOSAGE• This medication is administered via IM, IV or SC.• Intramuscular Administration: A dose of 1000 mg should be administered initially. This may be followed by 500 mg every 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered every 4-12 hours. The total amount administered should not exceed 6000 mg in 24 hours.
ADMINISTRATION & DOSAGE• Subcutaneous Administration: A daily dose of 1000-2000 mg/day should be administered over 8-24 hours, utilizing a small portable pump capable of providing continuous mini- infusion. The duration of infusion must be individualized. In some patients, as much iron will be excreted after a short infusion of 8-12 hours as with the same dose given over 24 hours.
ADMINISTRATION & DOSAGE• Intravenous Administration• THIS ROUTE SHOULD BE USED ONLY FOR PATIENTS IN A STATE OF CARDIOVASCULAR COLLAPSE AND THEN ONLY BY SLOW INFUSION BECAUSE DEFEROXAMINE CAN CAUSE HEART PROBLEMS.• THE RATE OF INFUSION SHOULD NOT EXCEED 15 MG/KG/HR FOR THE FIRST 1000 MG ADMINISTERED. SUBSEQUENT IV DOSING, IF NEEDED, MUST BE AT A SLOWER RATE, NOT TO EXCEED 125 MG/HR.• This may be followed by 500 mg over 4 hours for two doses. Depending upon the clinical response, subsequent doses of 500 mg may be administered over 4-12 hours. The total amount administered should not exceed 6000 mg in 24 hours.• As soon as the clinical condition of the patient permits, intravenous administration should be discontinued and the drug should be administered intramuscularly.
SIDE EFFECTS – fast heartbeats; – blue lips, skin, or fingernails; – severe, watery, bloody diarrhea with cramping; – cough, wheezing, gasping, or other breathing problems; – stuffy nose, fever, redness or swelling around your nose and eyes, scabbing inside your nose; – stomach or back pain, coughing up blood; – easy bruising or bleeding, unusual weakness; – urinating less than usual or not at all; – vision or hearing problems; or – leg cramps, bone problems, or growth changes (in a child using this medication).
SIDE EFFECTS• Less serious side effects: – numbness or burning pain anywhere in the body; – warmth, redness, or tingly feeling under the skin; – mild itching or skin rash; – mild diarrhea, nausea, or upset stomach; – dizziness; – reddish colored urine; or – pain, burning, swelling, redness, irritation, or a hard lump where the medicine was injected.
PRECAUTIONS• Before using this medication, confirm with a health professional if you have kidney problems, rheumatoid arthritis, diabetes, or any fungal infection.• If you are using this medication for aluminum poisoning, consult a doctor if you experience symptoms such as seizures, decreased calcium levels in the blood, hyperparathyroidism.• This drug may make you dizzy or cause blurred vision. Do not drive, use machinery, or do any activity that requires alertness or clear vision until you are sure you can perform such activities safely.
PRECAUTIONS• Limit intake alcoholic beverages.• Children (especially those younger than 3 years of age) may be more sensitive to the side effects of this drug, especially the effects on bone growth.• Older adults may be more sensitive to the side effects of this drug, especially vision/hearing problems.• During pregnancy, this medication should be used only when clearly needed
DRUG INTERACTIONS• Vitamin C: Patients with iron overload usually become vitamin C deficient, probably because iron oxidizes the vitamin. Vitamin C increases availability of iron for chelation. As an addidtive to iron chelation therapy, vitamin C in doses up to 200 mg for adults may be given in divided doses, starting after an initial month of regular treatment with Desferal. In general, 50 mg daily suffices for children under 10 years old and 100 mg daily for older children.• Prochlorperazine: Concurrent treatment with Desferal (deferoxamine) and prochlorperazine, a phenothiazine derivative, may lead to temporary impairment of consciousness.• Gallium-67: Imaging results may be distorted because of the rapid urinary excretion of Desferal (deferoxamine) bound gallium-67. Discontinuation of Desferal (deferoxamine) 48 hours prior to scintigraphy is advisable.
BETA THALASSEMIABeta thalassemia is a genetic blood disorder that reduces the production of hemoglobin.
Beta Thalassemia• Specifically, it is characterized by a genetic deficiency in the synthesis of beta- globin chains.• Beta-globin is a component (subunit) of hemoglobin.
Types Thalassemia Major (Cooleys anemia) Thalassemia Minor -severe form of beta thalassemia - presence of one normal gene and one with a - presence of two mutation abnormal genes that cause either a severe - causes mild to decrease or complete moderate mild lack of beta globin anemia. production.
Etiology • Beta thalassemia is caused by a deficiency of Beta globin inherited in an autosomal recessive pattern, which means both copies of the HBB(Hemoglobin beta) gene in each cell have mutations. • The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
Etiology-cont’d• The HBB gene provides instructions for making a protein called beta-globin.• When there is a mutations in the HBB gene, it prevents the production of any beta-globin.• The absence of beta-globin is referred to as beta- zero (B0) thalassemia.• Other HBB gene mutations allow some beta-globin to be produced but in reduced amounts. A reduced amount of beta-globin is called beta-plus (B+) thalassemia.
Etiology-cont’d• A lack of beta-globin leads to a reduced amount of functional hemoglobin. Without sufficient hemoglobin, red blood cells do not develop normally, causing a shortage of mature red blood cells.• The low number of mature red blood cells leads to anemia and other associated health problems in people with beta thalassemia.
Clinical Presentations Thalassemia minor- characterized by mild anemia Symptoms of beta thalassemia major appear in the first two years of life. • Fatigue and weakness • Pale skin or jaundice (yellowing of the skin) • Protruding abdomen with enlarged spleen and liver
Clinical Presentations• Dark urine• Abnormal facial bones and poor growth• A poor appetite.• Adolescents with the severe form of beta thalassemia may experience delayed puberty.
Pathophysiology• In Beta thalassemia major, patients have severe anemia, ineffective erythropoiesis, extramedullary hematopoiesis, and iron overload resulting from transfusion and increased iron absorption.• The skin may show pallor from anemia and jaundice from hyperbilirubinemia.• The skull and other bones may be deformed secondary to erythroid hyperplasia with intramedullary expansion and cortical bone thinning.• Heart examination may reveal findings of cardiac failure and arrhythmia, related to either severe anemia or iron overload.
Pathophysiology- Cont’d• Abdominal examination may reveal changes in the liver, gallbladder, and spleen.• Patients who have received blood transfusions may have hepatomegaly or chronic hepatitis due to iron overload.• The gallbladder may contain bilirubin stones formed as a result of the patients lifelong hemolytic state.
Pathophysiology- Cont’d• Splenomegaly typically is observed as part of the extramedullary hematopoiesis or as a hypertrophic response related to the extravascular hemolysis.• In addition to cardiac dysfunction, hepatomegaly, and hepatitis, iron overload can also cause endocrine dysfunction, especially affecting the pancreas, testes, and thyroid.• Transfusion-associated viral hepatitis resulting in cirrhosis or portal hypertension also may be seen.
Surgical Treatment• Splenectomy- decrease transfusion requirements• Cholecystectomy- Patients with thalassemia minor may have bilirubin stones in their gallbladder and, if symptomatic, may require treatment. Perform a cholecystectomy using a laparoscope or carry out the procedure at the same time as the splenectomy.
TreatmentTreatment for beta thalassemia involves iron chelation.1. Deferoxamine2. DeferasiroxDeferoxamine is an intravenously administered chelation agent.Desferal (deferoxamine) chelates iron by forming a stable complex that prevents the iron from entering into further chemical reactions. It readily chelates iron from ferritin and hemosiderin but not readily from transferrin; it does not combine with the iron from cytochromes and hemoglobin. It does not cause any demonstrable increase in the excretion of electrolytes or trace metals.
Adverse Effects• Hypotension (with too rapid IV infusion)• Pulmonary edema with over 24 hr IV infusion• Anaphylaxis (rare)• Renal failure• Hepatic dysfunction• Yersinia enterocolitica, Y. pseudotuberculosis, and fungal infectionsCautions• In acute iron toxicity, give IV only to patients with cardiovascular collapse or in shock• Do NOT administer by rapid IV• Increased serum creatinine (possibly dose related); acute renal failure and renal tubular disorder reported• NOT a substitute for standard measures generally used in iron toxicity (eg, induced emesis, gastric lavage)• Risk of potentially fatal infections
Drug InteractionsThere are a number of drug interactions that should be monitored closely when giving Deferoxamine e.g.:• ascorbic acid• calcium carbonate calcium carbonate• ferric carboxymaltose• ferric gluconate• ferrous fumarate• polysaccharide iron• prochlorperazine• sodium bicarbonate• sodium bicarbonate• aluminum hydroxide- deferoxamine decreases levels of aluminum hydroxide by inhibition of GI absorption. Applies only to oral form of both agents.• sodium citrate/citric acid- deferoxamine decreases levels of sodium citrate/citric acid by inhibition of GI absorption. Applies only to oral form of both agents.
Dosing Forms & StrengthsPowder for injection• 500mg/vial• 2g/vialAcute Iron Poisoning• Initial 1 g IM (ALL patients not in shock) or slow IV infusion (ONLY patients with cardiovascular collapse or shock), THEN;• 500 mg IM/IV q4hr x2, THEN;• Depending on clinical circumstance, may administer additional doses of 500 mg IM/IV q4-12hr PRN;• IV infusion rate: initial 1 g at 15 mg/kg/hr, all subsequent doses no more than 125 mg/hr;• No more than 6 g/day (IM or IV), but in severe cases should continue infusion up to 24 hours
Dosing Forms & StrengthsChronic Iron Overload• 500-1000 mg IM everyday, PLUS• 2000 mg IV infusion at no more than 15 mg/kg/hr with (but separately) each unit of blood transfused• No more than 1 g/day (without transfusion); 6 g/day (with transfusion)• Alternatively, 1-2 g/day SC infusion over 8-24 hours
Deferasirox- ExjadeMechanism of Action• Exjade (deferasirox) is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox.
Precautions• Do not take with aluminum-containing antacids• Concomitant cholestyramine -Coadministration with a single dose of cholestyramine decreases deferasirox AUC by 45%; avoid concomitant use. If coadministration is necessary, consider increasing initial deferasirox dose to 30 mg/kg and monitor serum ferritin levels and clinical responses for further dose modification.• Risk of hepatic failure, some with fatal outcome; most occurred with age >55 yr and with comorbid conditions (eg, liver cirrhosis, multiorgan failure)
Drug InteractionsThere are approximately thirteen (13) minor drug interactions. Two of these are:• Galantamine- deferasirox will decrease the level or effect of galantamine by affecting hepatic/intestinal enzyme CYP3A4 metabolism.• Imipramine- deferasirox will decrease the level or effect of imipramine by affecting hepatic/intestinal enzyme CYP3A4 metabolism.In addition there are 217 interactions that should closely monitored. E.g.:• Amlodipine• Aspirin- Combination may increase GI bleeding, ulceration and irritation. Use with caution.• Atorvastatin• Cyclosporine• Vancomycin- Coadministration of deferasirox with potentially nephrotoxic drugs, including vancomycin may increase the risk of this toxicity. Monitor serum creatinine and/or creatinine clearance in patients.
Dosing Forms & StrengthsTablets• 125mg• 250mg• 500mgIron Overload Due to Blood Transfusion• 20 mg/kg PO qd, titrate based on serum ferritin, not to exceed 30 mg/kg qd• Coadministration with potent UGT1A1 inducers (eg, rifampin, phenytoin,phenobarbital, ritonavir) or cholestyramine: Consider increasing intial dose to 30 mg/kg; these drugs decrease systemic exposure (AUC)
Administration• Do not chew tablet; disperse table in water, apple juice, or orange juice• <1 g in 3.5 oz liquid; >1 g in 7 oz liquid• Take on empty stomach at least 30 minutes prior to foodRenal & Hepatic Impairment• Renal impairment• Reduce daily dose by 10mg/kg if serum creatinine increases by >33% (on 2 consectutive visits) above pretreatment levels• Hepatic impairment• Moderate (Child-Pugh B): Decrease initial dose by 50%• Severe (Child-Pugh C): Avoid use
References• American College of Obstetricians and Gynecologists (ACOG). Hemoglobinopathies in Pregnancy. ACOG Practice Bulletin, number 78, January 2007.• Beta Thalassemia. (Sept 2, 2011). Retrieved from http://emedicine.medscape.com/article/206490-overview• Bleibel, S. et al. Thalassemia, Alpha. Retrieved: 29 September, 2011 from http://emedicine.medscape.com/article/206397-overview#a0104• Cohen, A.R., et al. Thalassemia. Hematology 2004, American Society of Hematology, pages 14-34.• Cooley’s Anemia Foundation. About Thalassemia. Updated 2007.• Cunningham, M.J. Update on Thalassemia: Clinical Care and Complications. Pediatric Clinics of North America, volume 55, April 2008, pages 447-460.• Deferoxamine [Pharm GKB]. (n.d.). Retrieved from http://www.pharmgkb.org/do/serve?objId=PA164746490&objCls=Drug#tabview=tab1• Di Bartolomeo, P., et al. Long-term Results of Survival in Patients with Thalassemia Major Treated with Bone Marrow Transplantation. American Journal of Hematology, February 13, 2008 (Epub ahead of print).• Exjade (Deferasirox) Drug Information… (Aug 19, 2011). Retrieved from http://www.rxlist.com/exjade- drug.htm• Food and Drug Administration (FDA). FDA Approves First Oral Drug for Chronic Iron Overload. FDA News, November 9, 2005• Food and Drug Administration (FDA). FDA Approves First Oral Drug for Chronic Iron Overload. FDA News, November 9, 2005.• Linda J. Vorvick, MD, Medical Director, MEDEX Northwest Division of Physician Assistant Studies, University of Washington, School of Medicine; and Yi-Bin Chen, MD, Leukemia/Bone Marrow Transplant Program, Massachusetts General Hospital; and David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc., Review Date: 1/31/2010,Thalassemia, retrieved on 2011-09-30, http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001613/• Lucile Packard Children’s Hospital at Standford. 2011. Alpha Thalassemia. Retrieved: 29 September, 2011 from http://www.lpch.org/DiseaseHealthInfo/HealthLibrary/hematology/thalapth.html th