What are the phenotypes of thalassemia that require treatment?
How do we treat?
Supportive therapy
Curative therapy
Future therapy
What are the supportive therapies?
Transfusion of blood
Chelation of iron
Treatment of endocrinopathies
Treatment of osteoporosis/osteopenia
Treatment of cardiac ailments
Treatment of leg ulcers
Proper vaccination
What are the goals of transfusion?
Goals of transfusion:
Achievement of optimal posttransfusion hemoglobin.
Avoidance of transfusion reactions
Use of donor erythrocytes with optimal recovery and half-life in the recipient
What are the indications of transfusion in thalassemia?
Confirmed diagnosis of thalassemia &
Hemoglobin level < 7g/dl on 2 occasions,> 2 weeks apart
OR
Even if hemoglobin levels are > 7g/dl, and evidence of [ineffective erythropoiesis]
Facial changes
Poor growth
Fractures
Clinically significant extramedullary hematopoiesis.
What is the standard Transfusion Regimen for Thalassemia Major?
Regular blood transfusions administered every 2-5 weeks.
Maintain the pre-transfusion Hb >9-10.5g/dl.
What is the rationale for maintaining pre-transfusion of 9-10.5?
Promotes normal growth
Allows normal physical activities
Adequately suppresses bone marrow activity in most patients
minimize transfusion iron accumulation.
What is hyper transfusion?
Transfusion of blood in thalassemia patients with the aim of maintaining the pre-transfusion Hb at 9 to 10.5 gm/dl
It is also known as moderate transfusion in Europe.
This target helps by preventing anemia related symptoms, promotes growth, suppresses extramedullary hematopoiesis as well as prevents hyper viscosity and iron toxicity related complications of super transfusion.
What is super transfusion?
Transfusion of blood in thalassemia patients with the aim of maintaining the pre-transfusion Hb at 12 g/dl.
When we aim for such high Hb levels there are risk of iron toxicity and hyper viscosity.
What is the ideal blood product to be transfused?
Group and type specific blood
Packed red blood cell
Ideal hematocrit is 65-75%
Minimum Hb content of 40 gm.
Leukoreduced
Irradiated
Transfuse blood within 2 weeks of blood collection.
Screening:
Hepatitis B
Hepatitis C
HIV
Syphilis
In some countries, other infectious diseases
Malaria
HTLV I/II
Toxoplasma
Hepatitis A
West Nile virus
Chagas disease
How to calculate the amount of blood required?
(Post-transfusion target- pre trans Hb) x 3 x body weight
Hematocrit of the transfused packed cells
For e.g.
If pre-transfusion Hb is 7 and post transfusion 12 with body weight of 20 kg.
The hematocrit of packed RBC is 65%.
Amount of blood transfused will be (12-7) x 3 x20 /0.65 = 460 ml
Blood is transfused at 10-15 ml/kg at the rate of 3ml/kg/hour and reducing the rate to 2 ml/kg/hr in a child with cardiac problems.
IV lasix is given midway transfusion
If multiple transfusions are required a gap of 24 hour between transfusion is appropriate to prevent transfusion related complications.
What is day care transfusion?
Previously the thalassemia patients were admitted for transfusions. But in most of the centers in the world the transfusions are done in day care clinic.
This has lots of benefits:
Low economic burden
Children can be with their parents so anxiety is reduced
Low risk of hospital acquired infections.
Less school absenteeism.
ALONG WITH BLOOD TRANSFUSION FOLIC ACID SUPPLEMENATION @ 1 OR 2 MG PER DAY.
What is the effect of blood transfusion on iron stores of body?
Non-transferrin bound iron level is high in thalassemia before transfusion and this further increased with frequent transfusions.
Free Iron has many ill effects in our body as discussed.
Iron deposition in liver can lead to liver fibrosis and cancer on long run.
Cardiac deposition has adverse effects and 70% of transfusion dependent thalassemia patients die of cardiac causes.
Endocrinopathies are caused by iron deposition.
IRON CHELATORS CAN REDUCE IRON DEPOSITION IN ALMOST ALL ENDOCRINE GLANDS EXCEPT PITUITARY.
What are the methods of identifying iron overload?
Serum ferritin level
Serum iron level
MRI of liver
Liver biopsy
T2 weighted MRI of heart
What are the indications of starting iron chelation?
Chelation therapy should be started when:
Serum ferritin level > 1000 ng/mL or above.
More than 10 transfusions
Hepatic iron concentration > 3.2 mg/g dry weight.
Cardiac T2* is <20 milliseconds
What are the chelating agents?
3 most commonly used agents are:
Desferrioxamine
Deferasirox
Deferiprone
No single or combination of agents are considered gold standard.
The choice of agent depends on iron load, choice of patients, cost and adverse events.
What is Desferrioxamine and how does it act?
It is hexa dentate chelator.
It cannot easily mobilize iron from intracellular compartment due to its high molecular weight.
It slowly binds iron to form Ferrioxamine and does not bind with iron from transferrin.
1 g of desferrioxamine binds 93 mg of iron.
It has a half-life of 8-10 minutes
Dose: 20-40 mg/kg/day
Subcutaneous infusion over 8-10 hours for 5-7 days a week.
What is IV Intravenous desferal?
Intravenous desferal is IV desferrioxamine which can be given when there is high iron overload like
High ferritin
Cardiac complications
Prior to stem cell transplantation
The dose for intravenous desferrioxamine is 50 to 100 mg/kg body weight.
What are the side effects of Desferrioxamine?
Side effects of DFO:
Effects on the eye- decreased visual field defects, visual acuity, retinitis pigmentosa
Sensory hearing loss
Growth retardation – skeletal dysplasia occur
Local skin reactions
Severe hypersensitivity
What is Deferiprone?
It is water soluble bidentate molecule.
It is an oral drug.
It has good effect in intracellular stored iron thus it mobilizes iron from transferrin, ferritin and
Hemosiderin.
Half-life: ~4 hours.
Given 3 times a day.
Dose: 75mg/kg/day up to 100mg/kg/day.
What are the side effects of Deferiprone?
Neutropenia, thrombocytopenia
Arthropathy
Gastrointestinal side-effects
Increase in liver enzymes [transient]
It also chelates zinc in addition to iron and therefore, zinc supplementation is mandatory in those receiving deferiprone.
What is Deferasirox?
It is a tridentate chelator.
It is an oral drug.
Longer half-life allows for once a day
Dose: 20-40 mg/kg/day
Good decrease in serum ferritin, cardiac iron and liver iron
What are the Side-effects?
Gastrointestinal side-effects
Skin rashes
Renal effects
Hepatic effects
What is shuttle hypothesis?
The low molecular weight bidentate chelator i.e. Deferiprone can chelate intracellular iron and bring it to plasma where the high molecular weight hexa-dentate chelator i.e. Desferrioxamine(which is a more powerful chelator but cannot enter into cell because of high molecular weight) can bind thus increasing the efficacy of chelation.
This combination of chelation is called Shuttle hypothesis.
Note: Deferiprone are not usually considered as first line agent because there aren't enough studies demonstrating the efficacy however because it is cheaper and has good compliance it is used in our parts of the world.
What is the role of calcium channel blockers in treatment of iron overload?
Iron uses high capacity calcium channels to enter heart, pancreas and other organs.
Blockage of these channels provides theoretical benefit.
Addition of CCB like amlodipine can be benefit but additional data are required validate this theory.
What is the role of LUSPATERCEPT?
Previously known as ACE-536
It is approved for use in adults (> 18 years of age) who require chronic transfusion.
It is given SC 1 mg/kg every 3 weeks.
Avoided in children, pregnant women and post splenectomy.
Exact mechanism is unknown but it is believed to inhibit activin and other members of TGF-beta signaling thus referred as activin receptor IIA (ActRIIA) ligand traps.
What are the curative therapies?
At present hematopoietic stem cell transplantation is the only available curative treatment.
Bone marrow transplantation offers the potential permanent cure, if an HLA-matched sibling donor is available.
Should be offered to thalassemia patients at an early age, or before complications due to iron overload have developed if an HLA identical sibling is available
Either bone marrow or cord blood from an HLA identical sibling can be used
Though expensive, it is cost-effective when compared with the long-term ideal treatment.
Frequent blood transfusion hospitalization and pricks can be avoided.
What are the factors on which outcome of this HSCT depends?
It depends on following 3 factors:
1. Hepatomegaly
2. Hepatic fibrosis
3. Irregular chelation.
As per these factors patients are classified into three classes as follows:
1. Class I: None of the above factors.
2. Class II: One or two factors.
3. Class III: All of the above.
For those with none of these factors (Class I), the success rate is about 93 percent, with one or two factors (Class II), it is 85 percent and with all three factors (Class III), it drops to a very low figure of 60 percent.
This system of classification is Lucarelli classification.
What are the experimental therapies?
Hydroxyurea
Butyrates
5-azacytidine
The idea is to increase HbF synthesis thus preventing alpha chain precipitation.
Why hydroxyurea in thalassemia isn't as effective as in sickle cell?
Many patients with thalassemia are transfusion-dependent.
Hyper transfusion suppresses endogenous erythropoiesis, particularly of hydroxyurea-responsive types of cells.
What is the role of erythropoietin?
As of now no practical utility of EPO but can be used in combination with hydroxyurea
Since reactive oxygen species are present in thalassemia antioxidants can be theoretically useful. Vitamin E and other antioxidants can be used but practical benefit is yet to be determined.
What is the status of gene therapy?
In 2019, the European Medicines Agency (EMA) approved a lentiviral product containing approximately 24 to 400 million autologous CD34+ cells transduced with a beta globin variant (T87Q) for individuals 12 years and older who have transfusion-dependent beta thalassemia with a non-beta0/beta0 genotype (ie, they must have at least one beta+ variant).
Gene therapy is challenging.
What are the indications of splenectomy?
Splenectomy may be appropriate for individuals with thalassemia (typically beta thalassemia) who have one or more of the following findings.
Severe anemia due to thalassemia (e g, persistent symptomatic anemia not due to iron deficiency or other non-thalassemia conditions).
A dramatic increase in transfusion requirement (e.g., doubling of transfusion requirement over the course of one year).
Hypersplenism leading to other cytopenia (leukopenia [e.g., absolute neutrophil count below 1000/microL], thrombocytopenia with a platelet count <10,000/microL).
Symptomatic splenomegaly (e.g., abdominal discomfort, early satiety).
Splenic infarction or splenic vein thrombosis.
What are the approaches of splenectomy?
Open splenectomy
Laparoscopic splenectomy
Partial splenectomy
Reduction of splenic tissue by embolization
What vaccines are given in splenectomized patients?
What antibiotic prophylaxis is necessary post-splenectomy?
What are complications of splenectomy?
Sepsis
Hypercoagulability
Pulmonary hypertension
Iron overload
What are the endocrine abnormalities associated with thalassemia and how to treat?
What are the infections associated with thalassemia?
Hepatitis B and C
HIV
Yersinia spp.
Malaria
CMV
Yersinia spp. infection is known to occur in iron overloaded125,126 and desferrioxamine-treated patients.
If a patient on desferrioxamine comes with symptoms of abdominal pain, diarrhea and vomiting, desferrioxamine should be stopped immediately
Appropriate stool culture or blood serology undertaken and
Treatment with cotrimoxazole or aminoglycoside given
How can we prevent infections?
Always administered screened blood products.
Annual serological screening tests should be done.
Annual vaccination for influenza.
What are the cardiac complications and how to manage?
Cardiac iron accumulation is the single greatest risk factor for cardiac dysfunction in thalassemia.
Exposure to high circulating nontransferrin bound iron species for long periods of time.
Once inside the heart, labile iron is quickly bound to ferritin and degraded to hemosiderin.
This buffering mechanism is vital to survival and creates a clinically-silent condition where cardiac iron stores are increased but toxic labile iron species are not present
Eventually, iron buffering mechanisms in the heart fail.
How do we investigate for cardiac problems in thalassemia?
ECG
Echocardiography
Cardiac MRI
The cardiac T2* parameter has been validated as an accurate reflection of cardiac iron content and should be done in every transfused thalassemia patient from as early an age as practicable,
10 years in most centers
7 years in some cases, if suspicion of a high iron burden.
How to manage?
Regular chelation therapy and maintenance of CMR T2* > 20 ms.
Echocardiographic - pulmonary hypertension - annually
TR velocity > 3 m/s should undergo cardiac catheterization if proximate cause cannot be identified and corrected
Lifestyle choices- smoking cessation, regular physical activity, weight control, vegetable and nitrate rich diet
Treatment of myocardial dysfunction is best undertaken using a group of drugs Including ACE Inhibitors, beta-blockers and aldosterone antagonists
What are the liver related complications and how to treat?
Adequate iron chelation is the treatment.
What are the causes of osteoporosis?
Marrow expansion causes mechanical interruption of bone formation, leading to cortical thinning, and fragility of the bones.
Endocrine complications: Hypothyroidism, hypoparathyroidism, diabetes mellitus, and mainly hypogonadism is considered as major causes of osteopenia /osteoporosis.
Iron deposition in the bone impairs osteoid maturation and inhibits mineralization locally, resulting in focal osteomalacia
How do we manage?
Annual checking of BMD starting in adolescence is considered indispensable.
For Osteopenia only ==== Diet + exercise + calcium
Osteoporosis === Diet + exercise + calcium +bisphosphonates
Established osteoporosis === Diet + exercise + calcium +bisphosphonates + treatment of fractures
ROUTINE MONITORING AND EVALUATION
Excellent notes
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