Comprehensive Care for Thalassemia

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8/21/2018

APHON SEPTEMBER 2018

Comprehensive Care for Patients with Thalassemia SUSAN HARVEY CPNP-AC, MSN, RN ANNIE BROUWER BSN, RN, CPHON

Financial Disclosures Nothing to disclose

Learning Objectives 1

Understand the basic pathophysiology of thalassemia

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Know the different types of thalassemia

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Understand criteria for and when to transfuse

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Recognize implications on organ systems for transfusion dependent thalassemia

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Develop a basic grasp of the medical, psychosocial, and nursing needs of thalassemia

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Normal Hemoglobin Structure

Coding Genes Chromosome 11: Coding genes of the β-globin cluster

Chromosome 16: Coding genes of the α-globin cluster

Composition of Common Hemoglobins Name

Description

Formula

Hb A

Adult Hb

α2β2

Hb A2

Minor Adult Hb

α2δ2

Hb F

Fetal Hb

α2γ2

Hb Portland 1

Embryonic Hb

ζ2γ2

Hb Portland 2

Embryonic Hb

ζ2β2

Hb Gower 1

Embryonic Hb

ζ2ε2

Hb Gower 2

Embryonic Hb

α2ε2

Hb H

Abnormal Hb

β4

Hb Barts

Abnormal Hb

γ2

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Pathophysiology of Thalassemia Decreased production of α or β globin chains Imbalance between α and β chains Globins in excess precipitate and damage the RBC membrane Ineffective erythropoiesis

Anemia

Bone Marrow Expansion

Extramedullary Hematopoiesis

Increased Intestinal Iron Absorption

Typical Genetic Mutations in the Thalassemias •

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Alpha Thalassemia – Deletions – Segments of DNA containing α globin genes absent Beta Thalassemia – Point mutations (more common) or deletions (less common) – Disrupt regulatory elements of gene expression – Decreased (β+) or absent (β0) production of β globin

Nomenclature •

Genetic Defect – Alpha thalassemia: defect in alpha globins – Beta thalassemia: defect in beta globins

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Clinical Severity – Minor: mild anemia, asymptomatic trait state – Intermedia: moderate anemia, intermittent transfusions – Major: severe anemia, transfusion-dependent

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Geographic Distribution of α-Thalassemia

Clinical Manifestations of the Thalassemias • Underproduction of normal hemoglobin – – – –

Small RBCs = low mean corpuscular volume (↓MCV) Low mean hemoglobin concentration (↓MCH, ↓MCHC) Uniform RBCs = normal red cell distribution width (RDW) Compensatory increase in RBC production = ↑RBC

• Decreased red cell survival – –

– – –

Increased reticulocyte count Increased release of intracellular RBC contents • Indirect unconjugated bilirubin • LDH • AST Splenomegaly Bilirubin gallstones Anemia: depending on genotype/phenotype

Peripheral Blood Smear Normal Blood Smear

Thalassemia Minor

Target cells

Hypochromia, microcytosis

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Alpha Thalassemia Syndromes Normal

α-thalassemia silent carrier (1 gene deletion) α-thalassemia trait (2 gene deletion)

Thalassemia minor

Hb H Disease

Thalassemia intermedia

Hydrops fetalis

Thalassemia major

Alpha Thalassemia (2-Gene Deletion) Trans: African

Cis: Asian

Diagnosis of Alpha Thalassemia •

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CBC, hematologic features – If 2 genes deleted: microcytosis – If 3 genes deleted: anemia, microcytosis Hemoglobin electrophoresis – Normal: alpha is part of every hgb, no difference in relative quantities -? Diagnosis of exclusion:

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DNA testing definitive (not widely available)

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microcytosis without iron deficiency and with a normal electrophoresis

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Alpha Thalassemia

Treatment of Alpha Thalassemia

Name

Phenotype

Average Hgb

Silent carrier

Typically asymptomaticonly detected by DNA testing

Normal

Constant Spring

Form of silent carrier, discovered in Jamaica

Normal

Alpha Trait

Typically asymptomaticoften mistaken for iron deficiency anemia

Mild anemia, low MCV

HbH disease

Can have severe anemia, splenomegaly, bone deformities, fatigue

HbH Constant Spring

Often transfusion dependent

Homozygous Constant Spring

Similar to HbH disease

Hydrops Fetalis of Alpha Thal major

Severe, often requires intrauterine transfusions, or in utero stem cell transplant

•

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Most people require no therapy – Hb H Disease: May require intermittent transfusions – May account for mild anemia, splenomegaly, bilirubin gallstones – Iron should not be prescribed for microcytosis Genetic counseling implications – Avoid fetal hydrops – prenatal testing – In utero bone marrow transplant for fetal hydrops

Beta Thalassemia Syndromes Genotype

Description

β/β

Normal

β/β0 β/β+ βE/βE

Beta thalassemia trait (minor)

β+/β+ β+/β0 βE/β+ βE/β0

Beta thalassemia intermedia

β0/β0

Beta thalassemia major (Cooley’s Anemia) βE – Hb E results from a point mutation that creates unstable mRNA  less production

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Splenomegaly

Cooley’s Anemia Dense skull/marrow expansion “hair on end”

Osteopenia/bone changes • •

Diagnosis of Beta Thalassemia

Iron overload Growth and endocrine failure

CBC, hematologic Carrier of trait usually microcytic with little or no anemia parameters

Hemoglobin ↑ Hb A2, F in milder forms electrophor No Hb A in Cooley’s Anemia esis Must be sure person is not iron deficient

DNA analysis (not widely available)

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Treatment of Cooley’s Anemia

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Transfusion therapy – Maintain hemoglobin of 9-10 g/dL – Results in iron overload Induction of fetal hemoglobin – Hydroxyurea therapy – Butyrate therapy Bone marrow transplant – Standard of care in beta thalassemia major

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Example of Comprehensive Thalassemia Clinic o Part of our overall Hemoglobinopathy clinic (includes sickle cell) o Includes 3 MDs, 1 NP, 2 RNs, Genetic Counselor, Social Work, Psychologist, RD, Dentist, infusion center RNs o Comprehensive clinic every Thursday o Transfusions 5 days a week

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Case Study 10 year old Burmese female who presented to the hematology clinic 1 week after immigrating from a Thailand refugee camp. She was diagnosed with Beta Thalassemia Major when she was 12 months old. Per mother, she was transfused only 1-2 times a year up until 3 months ago. She has complained of fatigue, poor sleep, dyspnea, and nausea for most of her life. She is often so weak that her parents have to carry her to the bathroom. Records from Myanmar and Thailand show a hemoglobin electrophoresis from 1 year of age with 21.9% HbF, 9% HbA2. Her hemoglobin as been chronically between 3.3-6.0 g/dL. She has had documented hepatosplenomegaly since 2008. Transfusions were not listed in outside records, but based on changes in hemoglobin, she likely received 4-6 transfusions per year. She has been on Vitamin C supplementation and multivitamins for most of her life. She was started on deferiprone and folic acid in the last year.

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Case Study Continued: multi-disciplinary and comprehensive care for O.N included Arranging transportation to clinic every 2-3 weeks Scheduling Burmese interpreters for 4-5 hours per visit and translating all discharge instructions Creating an adaptive care plan for all IV starts that included a primary RN and child life specialist Arranging all specialty follow ups on days of transfusions and often accompanying her Picking up medications at the hospital Walgreens and working with 2 specialty pharmacies and coordinating deliveries Arranging hospital admission for dental procedure due to family being without a cell phone Coordinating a conference call with principal and school nurse to set up IEP and advocate for school resources

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Transfusions:

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Iron Overload and chelation

Chelation Different options for chelation  Deferasirox (exjade, Jadenu) most commonly used  Deferiprone- monitor closely for agranulocytosis, neutropenia  Desferal/ Deferoxamine

Cardiac Complications 1.

Iron overload complications

 1960’s average life span for

a. b. c.

transfusion dependent thalassemia was 5-6 years  1970’s average life span was 15

2.

Non-iron overload complications a. b.

years- patients dying of cardiomyopathy from iron overload

c. d.

 Complications from iron overload and at risk for non-iron overload cardiac

e.

complications 3.

Reversible myocyte failure Arrhythmia, including heart block Arterial changes- loss of vascular compliance

Pulmonary hypertension Arrythymia- particularly atrial fibrillation (AF) later in life Thrombotic stroke- linked to AF Cardiac function changes due to restriction/ diastolic dysfunction/ fibrosis Arterial changes, loss of vascular compliance

n

4.

2.

5.

2

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Monitoring for Cardiac Complications

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2

3

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Cardiac MRI

Echocardiagram

ECG

Thiamine, carnitine, Vitamin D and Selenium levels

Serologies for Hepatitis C

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Liver Disease 2 Primary Causes: 1. Iron Overload 2. Chronic Hepatitis (typically hepatitis C)

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The Spleen •

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Increased destruction of red cells by the reticuloendothelial system, and primarily by the spleen can result in splenomegaly Seen most profoundly in those that are inadequately transfused, but can occur in adequately transfused patients Splenectomy previously common but now rare due to the risk of venous thrombosis, pulmonary hypertension, and serious infections post splenectomy

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Infections Therapy related • Allogenic blood transfusion • Splenectomy • Iron Chelation medications • Central lines Disease related • Ineffective erythropoiesis • Hemolysis • Anemia

Prevention/ monitoring: • Leukodepleted, CMV negative pRBCs that are less than 2 weeks old • PCN prophylaxis for splenectomy patients + prompt eval for ALL fevers • Hold deferiprone for ANC <1000 • Hold deferiprone for any febrile illness until bacterial sepsis is ruled out • Annual serologies for HIV, hepatitis B and C

Endocrine Disease  Endocrine dysfunction one of the most common complications in Beta Thalassemia major  Improved outcomes now with early introduction of chelators, but still often have issues with delayed growth and puberty  Maintain Hgb trough at >9 g/dL  Proper chelation VERY important  Close monitoring of growth curves, monitoring and correction of nutritional deficiencies, and tanner staging are crucial  Become buddies with your dietitian and endocrinologist colleagues

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Treatment/ Prevention of Growth Retardation 1

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Blood transfusions —> improvement of nutrients, O2 to liver, endocrine glands and growth plate Fe chelation —> prevents side rodeos is of liver, heart, pituitary, pancreas, and growth plate

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Improve nutrition —> improves macro & micronutrient supply to liver, glands, growth plate

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Correct GH-IGF-1 deficiency —> stimulates bone growth and bone mineral accumulation

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Induce puberty pen in hypogonadism —> directly stimulates protein anabolism in muscles and bones

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Osteoporosis  Affects 40-50% of patients with thalassemia major  Causes: genetic, endocrine complications (hypogonadism), iron overload, bone marrow expansion, vitamin deficiencies, decreased physical exercise  Leads to bone destruction through increased osteoclasts function and/ or reduced osteoblast activity

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Management of Osteoporosis      

Annual bone marrow density starting at 10 years of age or adolescence Encourage physical activity Discourage smoking Diet/ vitamins with high calcium and Vitamin D Good Iron chelation If bone density decreased, bisphosphonates given with calcium and vitamin D for no longer than 2 years

Dental Care 1. 2. 3. 4. 5.

Oro- Facial Manifestations Higher prevalence of dental caries Maxillofacial deformity ALL patients need good dental care and good communication between Hematology and Dental team Encourage monthly transfusions within one week of dental procedures

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Hematopoietic Stem Cell Transplant and Gene Therapy HSCT:

Gene Therapy:

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Curative

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Best if matched sibling

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donor available •

Good success rates

Multiple centers with open clinical trials

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Not curative, but typically raises Hgb baseline to 8.510.5 g/dL for transfusion dependent thalassemia

Nursing Considerations Nursing: a familiar face and point person for the patient and family Assessment of language and literacy barriers Multi-disciplinary approach for financial, insurance, transportation and coping issues Care coordination and comprehensive care scheduling- coordinating referrals on transfusion days Advocating for proper school integration for immigrants and refugees Helping patients live positively with thalassemia and encouraging interaction and shared experiences (camp, Cooley’s conference, art areas in clinic)

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References Cooley’s Anemia Foundation (2018). About Thalassemia. Retrieved from http://www.thalassemia.org/learn-about-thalassemia/about-thalassemia/ Capellini, MD Cohen A, Porter J, Taher A, Viprakasit V. Guidelines for the Management of Transfusion Dependent Thalassemia. 3rd ed. 2014. Thalassemia International Federation.Cyprus.

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