2.5 CONTACT HOURS trait What every NP should know

By Melissa Santiago, MSN, BA, PNP

patient you are familiar with comes to your office creased and may be responsible for the increase in patients complaining of moderate fatigue. On physical with thalassemia detected in newborn screening programs.3 A exam, you discover pallor. As part of your workup, One lab that confirms thalassemia diagnoses contends that you order a complete blood cell (CBC) count, which returns the thalassemia syndromes are far more diverse and preva- with a mild microcytic, hypochromic . You know that lent in the United States than once thought. Their patients the most common causes of in children represent people of all ethnicities, some with no clear links are irondeficiency anemia and the thalassemia traits. But to the areas of the world where the thalassemia syndromes what are the thalassemia traits? And how do you tell them are endemic.4 It is estimated that in the United States, there apart from irondeficiency anemia? are at least 2 million carriers for the thalassemia traits.5 The thalassemia syndromes are a heterogeneous group of inherited disorders of synthesis. They are a ■ The normal hemoglobin type of and are disorders of decreased glo- Humans produce six different through- bin chain production. The term “thalassemia” is derived from out their life cycles, three of which are usually only produced the Greek root words for “anemia” and “sea” because the tha- during fetal life. The hemoglobin molecule is typically formed lassemia syndromes were initially believed to be restricted to by two pairs of chains with a compound joined populations around the Mediterranean Sea.1 Now recognized to each chain. In most adults, 97% of the hemoglobin pro- as a global health concern, the thalassemia syndromes are en- duced is (HbA), which has two alpha-globin demic to the Mediterranean region, the Middle East, India, chains and two beta-globin chains. The remaining 2% to 3% Southeast Asia, Oceania, and sub-Saharan Africa. of adult hemoglobin is , which is composed The thalassemia syndromes are the most common ge- of a pair of alpha-globin chains and a pair of delta-globin netic disorder of humans. Estimates of the number of he- chains. In some adults, HbF, which is com- moglobinopathy carriers may be as many as 270 million posed of two alpha- and two gamma-, may continue people worldwide.2 Each year, it is estimated that there are to be produced, but it does not typically exceed 2% of the 300,000 to 500,000 infants born with serious hemoglo- hemoglobin production (see Compositions of human hemo- binopathies, including serious . globins and The normal hemoglobin molecule).6 In the United States, there are currently about 100 mil- The genes that code for the globin chains are found on lion people whose ethnic backgrounds are high risk for chromosomes 11 and 16. There are two genes on each chro- carrier frequencies of the thalassemia syndromes.2 The de- mosome 16 that code for alpha-globins, so most people have mography of people who are diagnosed in the United States four genes that code for alpha-globin. Most people with nor- with the thalassemia syndromes has changed over the years mal hemoglobin have two beta-globin genes, one gene on due to several factors. Declining immigration from the each chromosome 11.7 Mediterranean regions, improvements in therapy, and ef- fective genetic counseling programs have resulted in a de- ■ Classification cline in pediatric thalassemic patients of Mediterranean The thalassemias are classified according to the molecular heritage. Immigration from Asia, on the other hand, has in- basis of the globin chain deficit. If the deficiency is a result www.tnpj.com The Nurse Practitioner • December 2009 15 Thalassemia trait: What every NP should know

tween the minor and major forms. The major forms of tha- Compositions of human lassemia are out of the scope of this article. Instead, this dis- cussion will cover the minor forms, which tend to be clinically Type of Composition Comment 1 hemoglobin mild, if not asymptomatic.

Fetal – F α , γ Normal 2 2 ■ Molecular basis of pathology alpha-globin , hemoglobin 2 The alpha-thalassemias are among the most commonly in- gamma-globin2 herited disorders in humans. There are a total of four alpha- Adult – A α , β Normal 2 2 globin genes, two genes per haploid genome. As a result, the alpha-globin2, hemoglobin

beta-globin2 descriptions of the alpha-thalassemias are based on the out- 1 α δ put of all four of the alpha-globin genes. Adult 2 – A2 2, 2 Normal

alpha-globin2, hemoglobin There are two beta-globin genes controlling the pro-

delta-globin2 duction of beta-globin, one on each copy of chromosome γ 11. The beta-globin gene may have a mutation that results Bart’s 4 Abnormal β0 gamma-globin4 hemoglobin in the production of no beta-globin, noted as , or it may β have a mutation that results in reduced production of beta- H 4 Abnormal β+ 1 beta-globin4 hemoglobin globin, noted as . Beta-thalassemia trait occurs when a person acquires a normal beta-globin gene and a tha- lassemic beta-globin gene, or two thalassemic beta-globin The normal hemoglobin molecule genes that still produce minimal to moderate amounts of beta-globin chains (see Possible genotypes of the thalassemia This illustration represents the structure of the normal 8 hemoglobin molecule, showing the four subunits. traits).

β β 2 1 ■ Pathophysiology The thalassemia syndromes are a result of the deletion or mutation of one or more of the genes that code for the al- pha-globin chains or the beta-globin chains, which causes an imbalance in the rates of globin-chain production. Nor- mally, alpha- and beta-globin chains are produced at an identical rate. A mutated gene cannot produce as many globins as a nonmutated chain, resulting in a build-up of nonmutated gene chains within the cells and impaired hemoglobin production.1

Alpha-thalassemia In alpha-thalassemia, there is an excess of the beta-globin α α chains, which form soluble tetramers, β , called hemoglobin 2 1 4 H (HbH). In utero, there are also excess gamma-globins γ γ ( - globins) that form tetramers, 4, called hemoglobin Barts of a mutation in the beta-globin gene, then it is beta- (Hb Barts). In babies born with the alpha-thalassemia traits, thalassemia. When one of the alpha-globin genes is mutated it is possible to find Hb Barts and HbH in the cord blood, or absent, it is alpha-thalassemia.1 though they become undetectable during growth due to the The thalassemias are also classified according to the transition from fetal type hemoglobins to adult types. Beta- form of the illness. Thalassemia major is severe and requires globins no longer have to compete with the gamma-globins frequent blood transfusions for the patient to survive. Beta- for available alpha-globin, so fewer HbH are created, and no thalassemia major is also known as Cooley’s anemia and re- Hb Barts are produced.9 quires lifelong blood transfusions. Alpha-thalassemia major In alpha-thalassemia, the creation of HbH is associated is also referred to as hydrops fetalis or hemoglobin Bart’s with the formation of Heinz bodies. The removal of these hydrops syndrome, and often results in death. bodies results in the mechanical destruction of the red blood Thalassemia intermedia is a term to describe patients cell (RBC). Some of the other excess beta- globins become with beta-thalassemia in whom the clinical severity falls be- associated with RBC membranes. The association of beta-

16 The Nurse Practitioner • Vol. 34, No. 12 www.tnpj.com Thalassemia trait: What every NP should know

another illness. In other cases, the mild anemia may alert Possible genotypes of the thalassemia traits the healthcare provider during a routine visit. Thalassemia trait may be manifested by pallor, fatigue, or other nonspe- Type of Genotype Alternative cific complaints associated with anemia. There may be a alpha-thalassemia names family history of anemia; often it has been mistakenly di- αα αα Normal genotype, / agnosed as iron deficiency. The family’s ethnic origin may no thalassemia be suggestive of a thalassemia trait if they are from the Tr a i t αT/αT Minor, Mediterranean region, Africa, or Southeast Asia, but being TT/αα or α–/α– alpha-thalassemia-1 of another ethnicity does not rule out a thalassemia trait. ––/αα trait There is frequently a marked microcytosis, with a (MCV) lower than normal for age, and Silent α–/αα Minima or αT/αα alpha-thalassemia-2 mild to moderate hypochromia of the RBCs in alpha- trait thalassemia trait.13 The characteristic RBC count index find- ings for beta-thalassemia trait are a high RBC count, mild Type of Genotype Alternative anemia, and microcytic, hypochromic cells. Thus, the MCV beta-thalassemia names and the mean corpuscular hemoglobin (MCH) are usually Normal genotype, β/β reduced, while the mean corpuscular hemoglobin concen- no thalassemia tration (MCHC) tends to remain in the normal range of Tr a i t β+/β Minor values. Mild splenomegaly may be found in people with β0/β beta-thalassemia trait.1 (see Comparison of lab values in iron deficiency and thalassemia traits). globins to the alpha-thalassemic RBC count results in in- creased cellular hydration and hyperstability. The heme ■ Diagnosis groups associated with the beta-chains seem to become de- Diagnosing the thalassemia traits can be difficult because graded and oxidized, resulting in damage to the membrane.1 the lab values may mimic iron deficiency; there may even be concurrent iron deficiency. If anemia is found on a routine Beta-thalassemia CBC, the first step is to check the MCV. If the MCV is below Beta-thalassemia results from impaired production of the the expected range for age, further investigation should be beta-globins, which leads to an excess accumulation of the initiated.14 The Mentzer index (MI; MCV/RBC) may be a alpha-globin chains. The extra alpha-globins precipitate and helpful screening tool in determining the next steps.15,16 AMI form inclusion bodies in the RBC, which may be apparent over 13 is suggestive of an iron deficiency rather than a tha- in most mild, beta-thalassemia traits.9 The RBC in a patient lassemia trait. If a patient has a low MCV, a serum ferritin with beta-thalassemia trait is more rigid and dehydrated level should be obtained. However, if a patient has a low than a normal RBC.1 MCV and the MI is less than 13, this suggests a thalassemia trait, and a serum ferritin as well as a hemoglobin elec- ■ Role of malaria trophoresis should be performed. Due to similarities in the distributions of malaria and the If the ferritin is low, the iron deficiency should be cor- thalassemias, it was hypothesized early on that the develop- rected, and the MCV reinterpreted afterward. If the ferritin ment of the heterozygous state of thalassemia, or the tha- is normal, a hemoglobin electrophoresis on cellulose acetate lassemia traits, was positively selected for in the face of at a pH of 8.2 to 8.6 will identify hemoglobins A, F, and a malarial infection. Alpha-thalassemia may offer some gen- number of other hemoglobin variants, along with the eral protection against hospitalization from infectious dis- estimation of the HbA2 level. People with an elevated level eases, specifically from severe malaria and anemia.1,10,11 A of HbA2 along with hypochromic, microcytic RBCs have a recent study suggests that beta-thalassemic patients may be beta-thalassemia trait (see Peripheral blood erythrocytes in protected from malaria by an enhanced phagocytosis of the thalassemia). If the HbA2 is borderline high to normal, it is early intraerythrocytic form of malaria, called rings, in beta- likely that they have alpha-thalassemia or a combination of thalassemic cells.12 alpha-.1,17 Alpha-thalassemia trait is often regarded as a diagnosis of exclusion because the hemoglo- ■ Clinical manifestations bin electrophoresis does not definitively prove it is an alpha- The thalassemia trait may be diagnosed as part of a family thalassemia trait. The definitive testing for alpha-thalassemia study, a population study, or an incidental finding during traits would be genetic testing that can determine the exact www.tnpj.com The Nurse Practitioner • December 2009 17 Thalassemia trait: What every NP should know

Comparison of lab values in iron deficiency and thalassemia traits

Iron deficiency Beta thalassemia Alpha thalassemia Iron deficiency + trait trait thalassemia trait

MCV Low Low Low Low

RDW High Normal Normal-high High

RBC count number Low Normal-high Normal-high Normal-low

MI (MCV/RBC) >13 <13 <13 <13

Ferritin Low Normal Normal Low

Transferrin saturation Low Normal Normal Low (serum iron/TIBC) x 100

Hemoglobin Normal-low Increased HbA2 Normal Low-normal electrophoresis (3.5%-7%), ±increased HbF

Response to iron therapy Improves No change No change Improves

Other Presence of basophilic stippling on blood smear

lassemia traits). Another consideration in the investigation Peripheral blood erythrocytes in thalassemia of microcytic are that lead poisoning may present as a microcytic anemia, so testing for lead exposure may be Blood smears will show hypochromic and microcytic warranted. Anemia of chronic disease may also present as a erythrocytes in the patient with thalassemia. microcytic anemia, although it more commonly presents as normocytic anemia. If anemia of chronic disease is sus- pected, a lab workup for inflammatory markers should be done.16 There have been several studies that attempted to assess the sensitivity and specificity of various RBC count indices to discriminate between iron deficiency anemia and the tha- lassemia traits. Each study has come to a different conclu- sion as to which index is the most accurate for elucidating the difference between the two anemias (see Selected dis- criminatory RBC count indices). Several authors suggest the MI is suggested by several authors to determine the source 16–18 Source: Rubin R, Strayer D. eds. Rubin’s Pathology: Clinicopathologic of the anemias. However, one study found that the Eng- Foundations of Medicine. 5th ed. Philadelphia, PA: Wolters Kluwer/ land and Fraser (E&F) index had the highest sensitivity to Lippincott Williams & Wilkins; 2008:871. differentiate between iron deficiency anemia and tha- lassemia.19 A second study found the best index was the number of deletions of the alpha-globin genes. These tests, Green and King (G&K) index,20 while a third found that the however, are expensive. Shine and Lal, Srivastava, and MIs were all useful to discrim- If the MI is less than 13, a hemoglobin electrophoresis inate between the anemias.21 Thus, it is difficult to say with and serum ferritin study should be done together. Iron de- absolute certainty that any one of these indexes might be ficiency may obscure the results of the hemoglobin elec- used for consistent, accurate diagnosis of thalassemia trait trophoresis if thalassemia trait is present and may falsely versus iron deficiency anemia. However, they appear to be normalize the results (see Algorithm for diagnosing tha- useful in screening for thalassemia.

18 The Nurse Practitioner • Vol. 34, No. 12 www.tnpj.com Thalassemia trait: What every NP should know

Algorithm for diagnosing thalassemia traits

MCV low for age

<13Mentzer’s index >13

Serum ferrtin

Initiate iron Normal Low therapy, recheck MCV

Hemoglobin Low electrophoresis

Normal Elevated A2 Fast moving Abnormal Normal ± elevated hemoglobin hemoglobin HbF (HbH)

Probable Beta-thalassemia Likely Hemoglobin Iron alpha-thalassemia triat alpha-thalassemias variant deficiency triat syndrome

■ Related health issues During pregnancy, the thalassemia traits are generally Since the thalassemia traits are such a common, chronic well tolerated. However, a few considerations must be made. condition, there are some specific health conditions to con- In pregnant patients with beta-thalassemia trait, the hemo- sider when managing these patients. Only one study so far globin may fall to a lower level versus patients without the has linked thalassemia trait with an increased risk of trait. In cases where patients experience severe anemia, ery- asthma.22 Patients with the beta-thalassemia trait may be thropoietin has been used successfully to increase erythro- protected from hyperlipidemia. Several studies have docu- poiesis and fetal hemoglobin levels. A folic acid supplement mented that total cholesterol and low-density lipoprotein should be given to women with beta-thalassemia trait be- levels are significantly lower in those with beta-thalassemia cause beta-thalassemia trait can create a slight folic acid de- traits than in the general population.23,24 Although this may ficiency due to the increased erythpoiesis.7 Pregnant patients be beneficial, it may also predispose the patient to mood with beta-thalassemia minor may also be at risk for experi- disorders. Lower rates of cholesterol seem to be linked to encing intrauterine growth retardation, so these patients increased impulsiveness, so patients with thalassemic traits should be monitored closely for early detection of the con- might be more likely to experience mood disorder.24 There dition.27 is a possible link between thalassemia traits and bipolar It may be advisable to educate parents of children with disorder.25 A small study on beta-thalassemia trait as a risk thalassemia minor that a transient aplastic crisis is a possi- factor of depression found no correlation among young ble complication of parvovirus infection, since the patient adults, but the authors note that at older ages further study may have a decrease in erythrocytes.28 Parvovirus causes is needed.26 an aplasia of the RBC for 7 to 10 days that rarely causes a www.tnpj.com The Nurse Practitioner • December 2009 19 Thalassemia trait: What every NP should know

Selected discriminatory RBC count indices

Formula name Formula Value favoring Value favoring thalassemia iron deficiency RBC RBC count value >5 <5 Red cell distribution width (RDW) RDW value <14 >14 RDW index MCV x (RDW/RBC) <220 >220 Mentzer index (MI) MCV/RBC <13 >13 Shine and Lal index (S&L) (MCV)2 x MCH x 0.01 <1,530 >1,530 Srivastava index (SI) MCH/RBC <4.4 >4.4 Ricerca index (RI) RDW/RBC <3.3 >3.3 E&F index MCV – RBC – (Hb x 5) - k <0 >0 k is a constant determined by the method used to calibrate the Coulter counter

G&K index ([MCV]2 x RDW)/(Hb x 100) <72 >72

problem in patients without a hemoglobinopathy. There to the NP to become familiar with the disorders and pro- have been a few cases of transient associated vide patient education and counseling about genetic testing with thalassemia minor and infection with parvovirus B19.1 for these traits. The NP should also be familiar with special- ists for referral if the parents decide to explore genetic coun- ■ Role of the NP seling.31 The NP’s role in providing care to patients with thalassemia The NP may also play a vital role in stimulating aware- trait is multifaceted. The first is the prompt recognition and ness of the need for more research into the thalassemia traits. careful diagnosis of the trait. It is important to differentiate Much research into the thalassemias in the past has focused between thalassemia and irondeficiency anemia to avoid on the major types, and comparatively little research has unnecessary iron supplementation. However, irondeficiency been done with the thalassemia traits. Because the hemody- anemia may also occur with the thalassemia, confounding namics of a patient with thalassemia trait may be slightly the issue. The NP must correctly interpret the results of a altered, a variety of other systems may be affected. More re- CBC and use one of the indexes discussed when microcyto- search is needed to conclusively say whether or not the tha- sis is found. Evaluation of the RDW and iron studies may lassemia traits are associated with any other illnesses or if need to be performed to differentiate between the two or they offer protective factors against other illnesses. to find concurrent thalassemia trait and irondeficiency anemia. It is also important for NPs to properly interpret the re- REFERENCES 1. Weatherall DJ. The Thalassemia Syndromes. 4th ed. Oxford: Malden, MA: sults of a newborn screening. Newborn screening for sickle Blackwell Science; 2001. cell disease is required in nearly every state, and a hemoglo- 2. Chui DHK, Cunningham MJ, Luo H, Wolfe LC, Neufeld E J, Steinberg MH. bin variant may be picked up incidentally on the newborn Screening and counseling for thalassemia. Blood. 2006;107(4):1735-1737. 29 3. Vichinsky EP, MacKlin EA, Waye JS, Lorey F, Olivieri NF. Changes in the epi- screening. This is particularly critical for the diagnosis of demiology of thalassemia in North America: a new minority disease. Pedi- alpha-thalassemia trait, as Bart’s hemoglobin may be tran- atrics. 2005;116(6):e818-e825. siently detected in the cord or newborn blood, but disap- 4. Luo H-y, Boudreaux J, Steinberg MH, Chui DHK. Patients with thalassemia in the United States. Blood. 2005;105(12):4896-4897. pears rapidly as the newborn transitions to mainly adult-type 5. Northern California Comprehensive Thalassemia Center. Thalassemia trait. hemoglobin.30 http://www.thalassemia.com/thal_trait.html. Diagnosis must be followed by counseling the family. If 6. Steinberg MH, Benz EJ. Pathobiology of the human erythrocyte and its he- moglobins. In: RL Hoffman, ed. Hematology: Basic Principles and Practice. a family presents with a child with beta-thalassemia, it is 4th ed. Philadelphia, PA: Churchilll Livingstone; 2005:356-371. likely that at least one parent has the trait as well. If both par- 7. Rappaport VJ, Velazquez M, Williams K. in pregnancy. Obstet Gynecol Clin N Am. 2004;31(2):287-317. ents have the trait, it is highly likely that any future children 8. Birgens H, Ljung R. The thalassaemia syndromes. Scand J Clin Lab Invest. will have a major thalassemia syndrome. It is therefore up 2007;67(1):11-26.

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9. Thien SL. Genetic insights into the clinical diversity of beta-thalassemia. Br J 22. Palma-Carlos L, Palma-Carlos AG, Costa AC. “Minor” hemoglobinopathies: Haematol. 2004;124:264-274. a risk factor for asthma. Allergie et immunologie. 2005;37(5):177-182. 10. Mockenhaupt FP, Ehrhardt S, Gellert S, et al. Alpha+-thalassemia protects 23. Karimi M, Marvasti VE, Motazedian S, Sharifian M. Is beta-thalassemia trait a pro- African children from severe malaria. Blood. 2004;104(7):2003-2006. tective factor against hypertension in young adults? Ann Hematol. 2006;85:29-31. 11. Wambua S, Mwangi TW, Kortok M, et al. The effect of alpha +-thalassaemia 24. Namazi MR. Minor thalassemias may be a risk factor for impulsiveness. Med on the incidence of malaria and other diseases in children living on the coast Hypotheses. 2003;60(3):335-336. of Kenya. PLoS Med. 2006;3(5):e158. 25. Bocchetta A. Heterozygous beta-thalassemia as a susceptibility factor in mood 12. Ayi K, Turrini F, Piga A, Arese P. Enhanced phagocytosis of ring-parasitized disorders: excessive prevalence in bipolar patients. Clin Pract Epidemiol Men- mutant erythrocytes: a common mechanism that may explain protection tal Health. 2005;1(1):6. against falciparum malaria in sickle trait and beta-thalassemia trait. Blood. 2004;104(10): 3364-3371. 26. Marvasti VE, Dastoori P, Karimi M. Is beta-thalassemia trait a risk factor for developing depression in young adults? Ann Hematol. 2006;85:873-874. 13. Forget BG. Thalassemia syndromes. In RL Hoffman, ed. Hematology: Basic Prin- ciples and Practice. 4th ed. Philadelphia: Churchilll Livingstone; 2005:485-509. 27. Sheiner EMD, Levy AP, Yerushalmi RMD, Katz MMD. (2004). Beta-thalassemia minor during pregnancy. Obstet Gynecol. 2004;103(6):1273-1277. 14. Sirichotiyakul S, Maneerat J, Sa-nguansermsri T, Dhananjayanonda P, Tong- song T. Sensitivity and specificity of mean corpuscular volume testing for 28. Servey JT, Reamy BV, Hodge J. Clinical presentations of parvovirus B19. Am screening for alpha-thalassemia-1 and beta-thalassemia traits. J Obstet Gy- Fam Physician. 2007;75(3):373-376. naecol Res. 2005;31(3):198-201. 29. National Newborn Screening and Genetics Resource Center. National New- 15. Hermiston ML, Mentzer WC. A practical approach to the evaluation of the born Screening Status Report—State Disorder List; 2008. http://genes-r- anemic child. Pediatr Clin N Am. 2002;49:877-891. us.uthscsa.edu/nbsdisorders.htm. 16. Richardson M. Microcytic anemia. Pediatr Rev. 2007;28:5-14. 30. Cunningham MJ. Update on thalassemia: clinical care and complications. 17. Segel GB, Hirsh MG, Feig SA. Managing anemia in pediatric office practice: Pediatr Clin N Am. 2008;55:447-460. part 1. Pediatr Rev. 2002;23(3):75-84. 31. Cheng TL, Cohn RD, Dover GJ. The genetics revolution and primary care 18. Swartz MK. Hematologic diseases. In Burns CE, Dunn AM, Brady MA, Starr pediatrics. J Am Med Assoc. 2008;299(4):451-453. NB, Blosser CG,eds. Pediatric Primary Care: A Handbook for Nurse Practi- tioners. 4th ed. St. Louis, MO: Saunders; 2004:612-632 ACKNOWLEDGMENT 19. AlFadhli SM, Al-Awadhi AM, AlKhaldi Da. Validity assessment of nine discriminant functions used for the differentiation between iron deficiency The author gratefully acknowledges the assistance of Dr. Ritamarie John of Co- anemia and thalassemia minor. J Trop Pediatr. 2007; 53(2):93-97. lumbia University’s School of Nursing for all her encouragement and assistance 20. Ntaios G, Chatzinikolaou A, Saouli Z, et al. Discrimination indices as screen- in the creation of this article. ing tests for beta-thalassemic trait. Ann Hematol. 2007;86(7):487-491. The author has disclosed that she has no significant relationship or financial in- 21. Rathod DA, Kaur A, Patel V, et al. Usefulness of cell counter-based parame- terest in any commercial companies that pertain to this educational activity. ters and formulas in detection of beta-thalassemia trait in areas of high preva- Melissa Santiago is a pediatric nurse practitioner at the Columbia School of Nurs- lence. Am J Clin Pathol. 2007;128:585-589. ing, New York, N.Y.

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