Thalassemia Management

Gader M. Alkusayer INTERN Hematology Rashid Hospital 20 July .2011

Outline
Case presentation Haemoglobin Anemia Types Approach Thalassemia Differentiation of thalassaemia major and thalassaemia intermedia

Epidemiology Pathophysiology Diagnosis Clinical manifestations Complications Prognosis Management Standards of Care Guidelines for Thalassemia - 2009

Case presentation
27 years old gentleman from Pakistan Known case of:
Beta Thalassemia since birth
on regular blood transfusions and Iron chelation therapy

Hepatitis C and liver cirrhosis, Hypoganadizm, hypoadrenalism, and DM

Refered from GS team on 04/07/2011 for splenectomy.

Case presentation
Recently blood transfusion requirements increased so he was referred to RH for splenectomy. Medical problems on admission:
Anaemia Low platelet count Severely disturbed coagulation ? Cardiac status

Case presentation
Past medical Hx:
Beta Thalassemia since birth on regular blood transfusions and Iron chelating therapy.
Hepatitis C (2005) and liver cirrhosis (2008) complicated to:
Grade I oesophageal varices (2010), Hyperspleenism (2011)

2008: Hypoganadizm, hypoadrenalism, DM, arrhythmia.

Case presentation
Family history:
7 siblings: 1 brother and 1 sister have TM Mother and father are carriers

Social history:
not smoking or drinking alcohol.

Medication and allergic history:

Medication:
Propranolol 10mg BD Magnesium 250mg BD Lantus 4U HS Vitamin D 50,000 IV once / 3W Vitamin C 100mg OD Folic acid 5mg OD Desferal 3gm 6d/1W Alendronate 70mg once/week Calcium carbonate 600mg OD

Not known for any allergy.

Case presentation
Physical examination on admission:
Conscious, alert and oriented. Signs of pallor (pale skin, mucosal lining and nails bed). Vitally stable. Chest: clear. CVS: S1 + S2 no murmurs Abdomen:
soft, lax, no tenderness Hepatosplenomegaly : Liver: 7cm below costal margin Spleen: 6cm below costal margin

Case presentation
Laboratory values on admission:
test WBC Hb Plat MCV MCH HTC RDW Test LDH GGT ASAT result 1.8 7.3 55 84.7 28.5 21.6 17.5 result 252 27 96 LFT Test PT INR PTT test Albumin Alk. Phos ALAT T. Bilir. TP Globulin result 16.8 1.47 45.5 resul t 2.9 109 66 2.7 9.1 6.2

CB C

Case presentation
Plan:
For splenectomy Vitamin K 10mg PO 3/7 Echo Coagulation follow up PRBC 2U

Follow up
05/07/2011:
Transfuse FFP 4U Transfuse PRBC 2U Lasix 20mg iv Continue Vit. K

06/07/2011 09/07/2011:
Transfuse FFP 4U

Follow up
10/07/2011:
Splenectomy planed on 13/07/2011 Transfuse FFP 4U daily On operation day to give:
FFP 6U Cryoprecipitate 10U NOVO 7

Follow up
12/07/2011:
Developed mild breathing difficulty.
No finding on examination.

Received Cryo 4U

Follow up
13/07/2011:
Complain of diarrhia, abdominal pain. SoB still there. Plan:
Chest X-ray. Postpone surgery to 17/07/2011

Chest X-Ray
13/07/2011

Follow up
14/07/2011 17/07/2011:
Vit. K 10mg OD Cryo 4U FFP 4U Prednisolone 20mg BD Ciprofloxacin 500mg BD Transfuse Plat. 6U PRBC 2U

Follow up
17/07/2011:
For splenectomy today Labs Chest Xray To give factor 7 Intra 30mcg/kg when start operating and to repeat it after 30min. FFP 4U and 6U postop PRBC 2U stat and prepare 6U for surgery. Cryo 4U
test
WBC Hb Plat result 1.7 6.1 47 84.5 289 17.8 18 result 21.7 1.74 45.9

CBC

MCV MCH HTC RDW

Test PT INR PTT

Chest X-Ray
AM: 17/07/2011

Splenectomy

Splenectomy

Splenectomy

cholecystectomy

Chest X-Ray
PM: 17/07/2011

Chest X-Ray
AM: 19/07/2011

Hemoglobin
Tetramer of 4 globin chains (proteins) Each with a heme group containing iron Can be distinguished by electrophoresis Chain types
Alpha Beta Gamma Delta Zeta and epsilon are embryonic

Fetal and Neonatal Hemoglobins

Hemoglobin type Fetal Designation Hgb F (alpha2 + gamma 2) Amount % birth 60 - 85 15 - 40 1 After 1 year 02 96 98 1-3

Adult (major) Hgb A 95% (alpha2 +beta 2) Adult (minor) Hgb A2 (alpha 2 + delta2)

About Hemoglobin
Hemoglobin binds oxygen and carries it to tissues Erythrocytes (red blood cells) consist mainly of hemoglobin Function of red blood cell dependent on:
Hemoglobin type and content Membrane stability Energy production

RBC
Formed in bone marrow Life span is 120 days (+/- 20 days) Cleared in spleen Reticulocytes are newly formed RBC in circulation If no new production, Hgb drops 1 gm/week

Anemia
Hgb > 2 standard deviations below the mean for age. General mechanisms
hgb loss (usually bleeding) hgb production destruction of RBC

Anemia Approach
History
Diet Blood loss Family history Recent illness Past history of anemia and cause
Evaluate conjunctiva and mucous membranes for paleness Cardiovascular system for murmur Liver Spleen Lymph nodes Look for jaundice or purpura

Physical Examination

Anemia Approach
Labs
Complete blood count with differential and platelets Evaluation of smear with red cell indices Reticulocyte count

Other tests
Serum bilirubin, LDH, hgb electrophoresis, quantitative hgb A2 and F

Anemia Approach
Hypochromic Microcytic

smear

Normochromic Normocytic

Macrochromic

Hypocromic Microcytic Anemia

Appearance:
Weakly staining, small in size

Mechanism:
Decreased hgb synthesis secondary to decreased heme synthesis

Hypocromic Microcytic Anemia

Causes:
Childhood:
iron deficiency anemia, thalassemia

Adulthood:
iron deficiency anemia sideroblastic anemia, congenital or acquired anemia of chronic disease lead poisoning (rare) pyridoxine deficiency myeloma

Thalassemia
group of inherited disorders (autosomal recessive) that affect the synthesis of hemoglobin; characterized by a reduced or absent output of one or more of the globin chains of adult hemoglobin . The name is derived from the Greek words Thalasso = Sea" and "Hemia = Blood" in reference to anemia of the sea.

Thalassemiacont
Mutations in a given globin gene can cause a decrease in production of that globin, resulting in deficiency Depending on the involved genes, the defect is classified as:
-thalassaemia -thalassaemia

Alpha Thalassemia
mutation of 1 or more of the 4 alpha globin genes on chromosome 16 severity of disease depends on number of genes affected results in an excess of beta globins Subtypes:
Silent Carriers -thalassaemia trait Hgb H disease -thalassaemia major

Silent Carriers (heterozygotes +/-)

3 functional alpha globin genes No symptoms, but thalassemia could potentially appear in offspring

Alpha Thalassemia Trait

2 functional globin genes results in smaller blood cells that are lighter in color no serious symptoms, except slight anemia

Hemoglobin H Disease
1 functional globin gene results in very lightly colored red blood cells and possible severe anemia hemoglobin H is susceptible to oxidation, therefore oxidant drugs and foods are avoided treated with folate to aid blood cell production

Alpha Thalassemia Major

no functional globin genes death before birth (embryonic lethality)

Beta Thalassemia
mutations on chromosome 11 hundreds of mutations possible in the beta globin gene, therefore beta thalassemia is more diverse Results in excess of alpha globins Subtypes:
Minor Intermedia Major or Cooleys anemia

-thalassaemia Minor
slight lack of beta globin smaller red blood cells that are lighter in colour due to lack of hemoglobin no major symptoms except slight anemia

-thalassaemia Intermedia
lack of beta globin is more significant bony deformities can be seen. causes late development, exercise intolerance, and high levels of iron in blood due to reabsorption in the GI tract if unable to maintain hemoglobin levels between 6 7 gm/dl, transfusion or splenectomy is recommended

-thalassaemia Major
complete absence of beta globin enlarged spleen, lightly colored blood cells severe anemia chronic transfusions required, in conjunction with chelating therapy to reduce iron (desferoxamine)

-thalassaemia Major
Molecular basis:
Patients with -thalassaemia major have inherited two thalassaemia alleles
Located on each copy of chromosome 11

Hypochromic, abnormally shaped red blood cells

Contain significantly reduced amounts of haemoglobin than normal blood cells because of diminished HbA synthesis

Deposition of precipitated aggregates of free -globin chains results in accumulation

Damages erythrocytes, precursor cells in bone marrow

Resulting anaemia so severe that patients usually require chronic blood transfusions

Pathophysiologic Sequelae of Untreated Thalassaemia and Corresponding Clinical Manifestations

Excess free alpha-globin chains Formation of haeme and haemichromes Denaturation Degradation

Iron-mediated toxicity Haemolysis

Ineffective erythropoiesis

Membrane binding of IgG and C3

Removal of damaged red cells

Increased erythropoietin synthesis

Reduced tissue oxygenation

Anaemia

Splenomegaly

Skeletal deformities, osteopaenia .

Erythroid marrow expansion

Increased Iron absorption

Iron overload

Epidemiology
Thalassemias are particularly associated with people of Mediterranean origin, Arabs, and Asians. The Maldives has the highest incidence of Thalassemia in the world with a carrier rate of 18% of the population. The estimated prevalence is 16% in people from Cyprus, 1% in Thailand, and 3-8% in populations from Bangladesh, China, India, Malaysia and Pakistan. UAE:
one in 12 persons in the UAE is a thalassemia carrier

ThalassaemiaGlobal Distribution

Due to the continual migration of populations from one area to another, there is virtually no country of the world now in which thalassaemia does not affect some percentage of the inhabitants

-thalassaemia Major
Clinical features:
Clinical manifestations of anaemia emerge at 6 months2 years
Infants protected by prenatal HbF production

If untreated
Facial and skeletal changes result from bone marrow expansion Average survival <4 years

Clinical manifestations
General appearance
Slated-grey hyperpigmentation (Iron overload) Short stature (growth retardation) Hands
Finger clubbing -> Chronic liver disease Pallor over palmar crease

Face:
Frontal bossing Prominent cheeks Flat nasal bridge Inter-dental widening Jaw protuberance

Eyes
Jaundice Pallor

Clinical manifestations
Chest
Signs of heart failure

Abdomen:
Hepatomegaly (Extramedullary erythropoiesis, iron overload, HCV, HBV infection) Massive splenomegaly Splenectomy scar Insulin injection marks Desferioxamine-infusion pump

B Thal Iron deficiency Anemia

Test / Finding Serum Fe / ferritin TIBC Fe / TIBC Hgb A2 Hgb F MCV/RBC RDW RBC morphology B Thal N N N <13 N Basophilic stippling Iron Deficiency N >13 Slightly abnormal

Basophilic stippling

Hot to Differentiate Major from Intermedia

Thalassaemia Major More Likely Clinical Presentation (years) <2 Hb levels (g/dL) 67 Liver/spleen enlargement Severe Haematologic HbF (%) >50 HbA2 (%) <4 Genetic Parents Both carriers of high HbA2 -thalassaemia Molecular Type of mutation Thalassaemia Intermedia More Likely >2 810 Moderate to severe 1050 (may be up to 100%) >4 1 or both atypical carriers: - High HbF -thalassaemia - Borderline HbA2 Mild/silent

Severe

Laboratory diagnosis
Thalassemia minor:
Blood smear shows hypochromia and microcytosis (similar to Iron Deficiency Anemia). Blood indices:
MCV< 75 fl, Hb usually> 10, Hematocrit> 30%, RDW < 14%.

Hemoglobin A2 often elevated > 3%, sometimes reaching 78%.

Laboratory diagnosis- Cont

Thalassemia major: -Blood smear shows profound microcytic anemia, with extreme hypochromia, tear drop, target cells and nucleated RBCs. -Hemoglobin may be very low at 3-4 g/dl.

Complications

Thalassaemia major complications mostly due to iron overload and frequent blood transfusions
Heart failure Infection (blood transfusion, postsplenectomy) Hypogonadism and infertility Diabetes mellitus Hypothyroidism Thrombosis Pulmonary hypertension Leg ulcers Extramedullary haematopoiesis Endocrine disorders (osteoporosis, hypogonadism)

Thalassaemia intermedia complications include

Iron Overload
Iron overload occurs when:
Transfusion of red blood cells (thalassaemia major) Increased absorption of iron from the digestive tract (thalassaemia intermedia)

Because there is no mechanism in humans to excrete the excess iron, this has to be removed by chelation therapy

Iron Overload
1 unit of blood contains approximately 200250 mg of iron
Chronic transfusion-dependent patients have an iron excess of ~ 0.320.64 mg/kg/d

With repeated infusions, iron accumulates

Signs of iron overload can be seen after anywhere from 10 to 20 transfusions.

Normal intestinal iron absorption is about 11.5 mg/d In thalassaemic patients who do not receive any transfusion, iron absorption increases
This represents a supplementary 12 g of iron loading per year

Iron overload can lead to early mortality

Evaluation of Iron Overload

Serum ferritin concentration
Noninvasive Accuracy in iron overload questionable

Liver iron concentration (LIC)

Liver biopsy
Reference standard

MRI
Noninvasive, FDA-approved technique

SQUID: Superconducting Quantum Interference Device:

This imaging modality uses a very lowpower magnetic field with sensitive detectors that measure the interference of iron within the field

Prognosis
Depends on the time of presentation
Related to degree of severity Usually in first few years of life Untreated severe thalassemia
--/--: Prenatal or perinatal death --/- & --/cs: Normal life span with chronic hemolytic anemia

Untreated thalassemia
Major: Death in first or second decade of life Intermedia: Usually normal life span Minor/Minima: Normal life span

Management of B Thal Major

Standards of Care Guidelines for Thalassemia 2009 (published by Childrens Hospital & Research center in Oakland):
DNA Testing Prior to Treatment Decide for regular transfusion:
initial hemoglob in level is well below 6 g/dL.

Management B Thal Major

Splenectomy:
Indicated in the transfusion-dependent patient when hypersplenism blood transfusion requirement and prevents adequate control of body iron with chelation therapy. An enlarged spleenwithout an associated increase in transfusion requirementis not necessarily an indication for surgery. Patients must receive adequate immunization prior to surgery against Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitides.

Management B Thal Major

Splenectomy:
After splenectomy, patients should receive oral penicillin prophylaxis (250 mg twice daily) and be instructed to seek urgent medical attention for a fever over 38C Post-splenectomy thrombocytosis is common, and low-dose aspirin should be given during this time.

 Hep C:
Treatment consists of pegylated interferon alfa given as a subcutaneous injection once a week and oral ribavirin twice daily for patients 18 years and older.

Endocrine dysfunction:
due to iron deposition and toxicity to the endocrine tissue significant morbidity:
Gonadal failure, sterility, growth failure , osteopenia and osteoporosis. Diabetes mellitus.

 Hematopoietic Cell Transplantation:

First performed on thalassemia patient in 1981
Is the only treatment that offers a potential cure for thalassemia at this time.

HCT relies on high-dose chemotherapy to eliminate thalassemiaproducing cells in the marrow and replaces them with healthy donor cells from bone marrow or umbilical cord blood, usually taken from a human-leukocyte antigen (HLA) match.
This therapy should be considered for all patients who have a suitable donor. Early referral to a transplant center is recommended, as HCT has a better outcome in younger patients.

Conclusion
Thalassaemias heterogeneous group of disorders of haemoglobin production
-TM present in first year of life, requires transfusions -TI later presentation, may not require transfusion therapy

Iron overload may be present in both conditions, caused by transfusion therapy or excess GI iron absorption
Current treatment involves chelation therapy

References
Standards of Care Guidelines for Thalassemia 2009 (published by Childrens Hospital & Research center in Oakland): http://www.thalassemia.com/documents/thalhandbook20 08.final.pdf Olivieri, N. F. "The Beta Thalassemias." The New England Journal of Medicine 341 (1999): 99-109.

Forget BG. In Hoffman: Hematology: Basic Principles and Practice, 2005.

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