Approach, diagnosis and treatment and recent advances in cases of iron overload

1. Presented by:
Dr. Chetan Agarwal
DNB SS Resident
Moderator:
Dr. (Col) Jasjit Singh
HOD Clinical Hematology
Dept of Hematology
Sir Ganga Ram Hospital

2. Normal Iron Physiology
Suspecting Iron Overload
Causes of Iron Overload
Sequelae of Excess iron
Workup
Treatment

4.  Normal iron content: 3 to 5 gm
 Exists in the following forms:
 Hb in circulating RBCs: Approx. 2.5 gms
 Iron-containing proteins other than Hb (eg, Myoglobin, Cytochromes,
Catalase): 400 mg
 Iron bound to transferrin in plasma: 3 to 7 mg
 Storage iron in the form of ferritin or hemosiderin: 1-2gm
 Recycling – Breakdown of senescent RBCs in RE system in the Liver, Spleen,
and Bone marrow.

5.  Daily Iron Intake: 10-20mg
 Daily Iron absorbed 1-2mg
 Absorbed in Duodenum & Jejunum
 Daily Iron loss 1-2mg
 Heme iron (eg, iron in meats) is better absorbed than non-heme iron
(eg, iron from vegetable sources).
 No physiologic mechanisms to eliminate iron
 Removal of iron from the body is not regulated
 Absorption of iron from intestinal cells and the release of storage
iron from macrophages is highly controlled

6. Total body iron is determined by the balance b/w iron intake & loss
INTAKE LOSS

9.  Family history of Hereditary Hemochromatosis (HH)
 Multiple red blood cell transfusions for anemia other than iron
deficiency
 Unexplained organ damage such as Liver disease, Cardiac disease,
Endocrine disease
 Incidental finding of increased serum ferritin or increased
transferrin saturation (TSAT)

10.  Biochemical bnormalities in
liver function
 Inflammation,
 Fibrosis
 Cirrhosis
CARDIAC INVOLVEMENT
 Cardiomyopathy
 Pulmonary HTN
 Heart failure
 Arrhythmias
HEPATIC INVOLVEMENT

11.  Diabetes Mellitus
ENDOCRINE INVOLVEMENT
 Hypogonadism
 Decreased Libido
 Impotence
PANCREATIC INVOLVEMENT SKIN INVOLVEMENT
 Bronze diabetes
JOINT INVOLVEMENT
 Arthropathy
 2nd MCP joint
 3rd MCP joint
 Chondrocalcinosis

13.  INCREASED INTAKE
 INCREASED ABSORPTION

15.  Tx given for anemia not
caused by iron deficiency.
 Β-Thalassemia
 SCD
 Hemolytic anaemia eg PK
Deficiency
 Aplastic anemia
 MDS
 Tx >15 to 20 units of RBCs in
Adults
 Tx >10 units in smaller children
 Each unit of RBCs has 250 mg of
Iron.
 Blackfan-Diamond
syndrome
 Hematologic malignancies
 Hematopoietic cell
transplantation.

16.  RBC precursors are destroyed by apoptosis
 Intense erythroid hyperplasia in the bone marrow
 Inhibition of Hepcidin
 Low peripheral blood reticulocyte count.
Most commonly seen in
 Thalassemia
 Pyruvate kinase (PK) deficiency
 Congenital dyserythropoietic anemia
 Some sideroblastic anemias.

17. Organ damage from reactive oxygen species
 Binding of iron to other proteins and molecules:
 Albumin, Citrate, Acetate, and others
 This iron is referred to as non-transferrin-bound iron (NTBI)
 Appear when TSAT > 35%
 Rises significantly with TSAT > 70%
 NTBI is taken up by cells that have active uptake mechanisms such as the
L-type calcium channel. Eg. Hepatocytes, Heart, and Endocrine organs.

19.  Excess iron can chemically interact with hydrogen peroxide, acting
as a Fenton reagent and catalyzing the Haber-Weiss reactions
 H2O2 + Fe(2+) OH- + Fe(3+) + OH● (hydroxyl radical)

O2- (superoxide anion) + Fe (3+) O2 + Fe(2+)
 SUM: H2O2 + O2- O2 + OH- + OH●
Hebbel RP. Auto-oxidation and a membrane-associated 'Fenton reagent': a possible explanation for
development of membrane lesions in sickle erythrocytes. Clin Haematol. 1985;14:129.

20.  ROS cause Tissue damage, Inflammation, and Fibrosis
 Liver, Heart, Joints, Endocrine organs appear to be especially
susceptible.
 By the time clinical findings like hepatic fibrosis, heart failure,
cardiac conduction defect develop, significant iron deposition and
tissue injury has occurred.
 Some of the toxicity of iron may be abrogated by the body's
antioxidant defenses such as glutathione-S-transferase (GST)
 Genetic variants in the GST system that modulate the clinical
manifestations of iron toxicity in individuals with iron overload are
under investigation

22.  CBC with RBC indices
 Iron studies: Serum Ferritin and Transferrin saturation
 Metabolic panel including hepatic enzymes (ALT & AST])
 Increased serum ferritin:
 Men: >200 to 300 mcg/L
 Women: >150 to 200mcg/L
 Increased transferrin saturation >=45%
 Hepcidin measurement (serum and urine using mass
spectrometry)

23.  Serum Iron (Male: 78-178ug/ml, Female: 56-156ug/ml)
 Serum Ferritin (Male: 17-300ng/ml, Female: 7-280ng/ml)
 Serum transferrin
 Transferrin saturation (TSAT) is calculated as the ratio of serum
iron to TIBC and expressed as a percentage (TSAT = iron ÷ TIBC x
100)
 ≥45 percent in males or ≥40 percent in females
 Most useful for evaluating iron overload are the Ferritin and TSAT

24. Copyrights apply

25.  Confounding Factors:
 Liver disease: Ferritin and TSAT can be elevated
 Dying hepatocytes release storage iron into the circulation
 Alcohol suppress hepcidin synthesis
 Alcohol suppresses liver transferrin synthesis
 Ferritin is also an acute phase reactant
 CRP can be done to R/O Inflammation/ Infection

26.  Correlation between the ferritin level and the total body iron
burden:
 Ferritin 500 to 1000 ng/mL: severe iron overload unlikely
 Ferritin 3000 to 4000 ng/mL: substantial iron burden
 But high discordance b/w individuals & b/w measurements for the
same individual *
 Correlation between iron stores and ferritin levels is only reliable up
to a ferritin level of 3000 to 4000 ng/mL **
*Wood JC. Guidelines for quantifying iron overload. Hematology Am Soc Hematol Educ Program. 2014
Dec;2014(1):210-5. Epub 2014 Nov 18.
**Schram AM, Campigotto F, Mullally A, Fogerty A, Massarotti E, Neuberg D et al. Marked
hyperferritinemia does not predict for HLH in the adult population. Blood. 2015;125:1548.

28.  MRI
 CT-SCAN
 SUPERCONDUCTING QUANTUM INTERFERENCE DEVICE
(SQUID)

29.  T2*, R2, and R2* measurement increasingly accurate for Hepatic &
Cardiac iron deposition
 Combined liver and cardiac MRI used to confirm iron overload in
individuals with increased Ferritin and Transferrin saturation
 Replaced Direct tissue biopsy
 Non Invasive
 Cost Effective

30.  Cardiac T2* (Normal >20 milliseconds)
 Better predictor of heart failure or arrhythmia than liver T2* or
serum ferritin
 <20 milliseconds: Cardiac iron overload.
 <10 milliseconds:
 Severe myocardial iron loading
 High risk of Cardiac failure and/or Arrhythmias.
Kirk P, Roughton M, Porter JB, Walker JM, Tanner MA, Patel J et al. Cardiac T2* magnetic resonance for
prediction of cardiac complications in thalassemia major. Circulation. 2009;120:1961.

31.  T2 and R2 (FerriScan) measurements are increasingly accurate for
determining hepatic iron deposition and quantifying its severity
 Estimates hepatic iron concentration in patients with transfusion
dependent thalassemia and sickle cell disease.
 A liver iron concentration (LIC) >3 mg Fe/g dry weight s/o Iron
ovrload
 LIC of over 5 to 7 is used to indicate the need for treatment.

33.  Limited sensitivity (63%)
 Elevated hepatic CT density a/w Elevated serum Ferritin indicates
Iron Overload
 Normal hepatic CT density does not exclude iron overload.
 Not sensitive when Serum Ferritin <1000 mcg/L.
 Involves radiation exposure
 Dual-energy scans are required to compensate for background
attenuation
 Used when no access to MRI.

35.  Magnetic measurements of iron in patients with iron overload are
quantitatively equivalent to biochemical determinations on tissue
obtained by biopsy.
 Monitoring the clinical response to chelation therapy.
 High complexity
 High cost
 High technical demands (Liquid helium–cooled superconducting
instruments)

36. Liver biopsy
Elevated NT-proBNP
Endomyocardial biopsy

37.  Considered by some as Gold standard
 Indications of Liver biopsy-:
 No access to MRI/ CT
 E/O of Liver injury
 Concomitant viral hepatitis
 Pre-hematopoietic stem cell transplant (pre-HSCT) setting
 Cases where Liver histology assessment is important.

38.  Examples:
 Individuals with elevated hepatic enzymes and a very high ferritin
(eg, >1000 ng/mL ) in whom it is not clear which came first
 Individuals with Thal prior to HSCT with concern for hepatic
fibrosis
 Individuals with other causes of liver injury for whom the severity
of iron overload and extent of liver injury are unclear from other
testing.
 Majority of patients do not require a liver (or other) biopsy since
noninvasive MRI is available

40.  Elevated NT-proBNP levels in cardiac hemosiderosis
 Endomyocardial biopsy
 Individuals with heart failure or conduction defects with elevated
cardiac iron on MRI
 Cardiac biopsy done for other indications may reveal iron overload

43. The Challenge of Iron Chelation—
A Question of Balance
Too much iron Too much chelator
•
•
•
•
•
•
Uncoordinated iron
Free-radical generation
Organ damage
Growth failure
Organ failure
Cardiac death
•
•
•
•
•
Uncoordinated chelator
Inhibition of
Metalloenzymes
Neurotoxicity
Growth failure
Bone marrow toxicity

44. Copyrights apply

45. DESFERROXAMIN
E
DEFERIPRONE
XJADE
DEFERASIRO
X
JadeNu
DEFERASIROX

46. Timeline
2009
2005
2000
1960
JadeNu
DEFERASIRO
X
Exjade
DEFERASIRO
X
Deferiprone
DESFEROXAMINE

47.  Each unit of blood contains approx 200 to 250 mg of iron.
 Chelation therapy started
 After the first 10 to 25 transfusions
 Serum ferritin is greater than 1000 mcg/L
 Liver iron concentration (LIC) is greater than 3 mg Fe/g dry
weight
 Cardiac T2* is <20 milliseconds
 As early as 2 yrs of age in those with beta thalassemia major
 Later in those with various forms of thalassemia intermedia and
transfusion-independent thalassemia
Aydinok Y, Kattamis A, Viprakasit V. Current approach to iron chelation in children. Br J Haematol.
2014;165(6):745.

48.  Available for > 3 decades with improving survival
 Hexadentate molecule isolated from
Streptomyces Pilosus in 1960
 Not absorbed from gut
 Short half-life (8-10 min)
 Continuous infusion 8 –12 hrs/day, 5 – 7 days/week
(40–50 mg/kg)
 Commenced after 15–20 transfusions or when
ferritin >1000 µg/L
 S/E: Audiometric, retinopathic, and growth
effects at high doses and low iron loading
 Compliance often is poor, leading to variable
outcome

49.  Acute iron toxicity: Adult IV route is preferred
 Cardiovascular collapse or Systemic symptoms (coma, shock,
metabolic acidosis, or gastrointestinal bleeding)
 Severe intoxications (peak serum iron level >500 mcg/dL) (Perrone
2015)
 IM route may be used but is not preferred and rarely indicated.
 IM, IV: Initial: 1,000 mg f/b 500 mg every 4 hours for 2 doses;
 Subsequent doses of 500 mg every 4 to 12 hours based on clinical
response
 Maximum recommended dose: 6,000 mg/day

50.  Chronic iron overload: Adult
 IM: 500 to 1,000 mg/day (maximum: 1000 mg/day)
 IV: 40 to 50 mg/kg/day (maximum: 60 mg/kg/day) over 8 to 12 hours
for 5 to 7 days per week
 SC: 40–50 mg/kg

51. Acute Iron Intoxication: Pediatric dosing
 IV route is preferred*
 Continuous IV infusion:
 Initial: 15 mg/kg/hour and reduce rate as clinically indicated *
 Maximum daily dose: 80 mg/kg/day and not to exceed 6 g/day *
*Desferal prescribing information [Canada; UK] 2010)

52. Chronic Iron Overload: Pediatric dosing
 IV: Children and Growing Adolescents:
 20 to 40 mg/kg/day over 8 to 12 hours, 5 to 7 days per week, usual
maximum daily dose: 40 mg/kg/day
 Adolescents once growth has ceased:
 40 to 50 mg/kg/day over 8 to 12 hours, 5 to 7 days per week, usual
maximum daily dose: 60 mg/kg/day
 Subcutaneous infusion via a portable, controlled infusion device:
 20 to 40 mg/kg/day over 8 to 12 hours 3 to 7 days per week;
maximum daily dose: 2,000 mg/day. (Vlachos 2008).

53.  Bidentate
 Absorbed from GIT
 T1/2: 90 mins
 Excreted in Urine
 Lower cost
 S/E: Nausea,Vomitting, Arthropahy, Agranulocytosis (ANC<1500 but
>500)
 Ease of administration.
 Oral solution
 500 mg tablet
 2 different 1,000 mg tablet formulations (Twice-a-day formulation/
Thrice a-day formulation)

54.  Transfusional iron overload: Adult dosing
 Initial: 75 mg/kg/day in 2 divided doses (using 1,000 mg twice-a-day
tablet formulation only) or in 3 divided doses (using oral solution,
500 mg tablet, or 1,000 mg 3-times-a-day tablet formulation);
 Individualize dose based on response and therapeutic goal.
 Dosing may start at 45 mg/kg/day and be increased weekly by 15
mg/kg/day increments until 75 mg/kg/day is achieved to minimize GI
upset.
 Maximum dose: 99 mg/kg/day.

55.  Dosing and monitoring of treatment –
 Dosing should be tailored to achieve
 Serum ferritin levels <1000 mcg/L, .
 LIC <7 mg Fe/g dry weight
 Cardiac T2* by MRI >20 milliseconds.
 Chelation therapy is held or reduced when the ferritin level falls to
less than 300 to 500 mcg/L and/or LIC falls below 3 mg/g dry weight

56.  Transfusional iron overload: Pediatric dosing
 Children <8 years:
 Oral solution: 25 mg/kg/dose 3 times daily; round dose to the nearest
250 mg (2.5 mL);
 May consider a lower dose of 15 mg/kg/dose 3 times a day titrated in
15 mg/kg increments at weekly intervals to minimize GI side affects
(Botzenhardt 2018; Maggio 2020; manufacturer's labeling).

57.  Transfusional iron overload: Pediatric dosing
 Children ≥8 years and Adolescents:
 Three-times-daily dosing:
 Oral solution: 3-times-daily 500 mg 25 mg/kg/dose 3 times daily; round dose to the
nearest 250 mg (2.5 mL);
 Tablets: 1,000 mg tablet formulations, round dose to the nearest 1/2 tablet; may
consider a lower initial dose of 15 mg/kg/dose 3 times a day titrated in 15 mg/kg
increments at weekly intervals to minimize GI side effects when initiating
therapy.
 Two-times-daily dosing: 1,000 mg tablet formulation:
 Oral: Initial: 37.5 mg/kg/dose every 12 hours; round dose to the nearest 500 mg;
may consider a lower dose of 22.5 mg/kg/dose every 12 hours titrated in 15 mg/kg
increments at weekly intervals to minimize GI side effects when initiating
therapy.

58.  Transfusional iron overload: Pediatric dosing
 Maintenance dosing:
 Monitor serum ferritin every 2 to 3 months with therapy
 Individualize dose based on response and therapeutic goals for
 Not to exceed maximum daily dose: 99 to 100 mg/kg/day (Maggio
2020)
 If serum ferritin falls consistently below 500 mcg/L, consider
temporary treatment interruption until serum ferritin rises above
500 mcg/L.(Maggio 2020)

59.  Tridentate
 T ½ :12-18 hours
 OD administration, empty stomach
 Orally, Absorbed in GIT
 Suspension in Water or Apple or Orange juice
 90% excreted in stool, 10% excreted in Urine
 S/E: Skin rashes, Diarrhea, Nausea, Vomiting, Mild increase in
Creatinine ,
 ARF, Hepatic failure and Death (In patients with comorbidities and
advanced stage disease)

60.  C/I in adult and pediatric patients with eGFR less than 40
mL/min/1.73 m2
 Measure serum creatinine in duplicate prior to initiation of therapy.
 Monitor renal function at least monthly in patients with baseline
renal impairment or increased risk of acute renal failure
 Measure SGOT/PT and Bilirubin prior to initiating treatment, every
2 weeks during the first month, and at least monthly thereafter.
 Avoid Deferasirox in Child-Pugh class C
 Reduce the dose in Child-Pugh class B
 GI hemorrhages in elderly with advanced hematologic malignancies
and/or low platelet counts.

61.  Tx Dependent Thalassemia
 Transfusion of ≥100 mL/kg
of packed red blood cells
 ≥20 units
 Serum ferritin consistently
>1,000 mcg/L
 Non Transfusion Dependent
Thalassemia
 Hepatic iron concentration
≥5 mg Fe/g dry weight and
 Serum ferritin >300 mcg/L).

62.  Initial: 20 mg/kg once daily
 Maintenance:
 Adjust dose every 3 to 6 months based ferritin
 Adjust by 5 or 10 mg/kg/day;
 Titrate to individual response and treatment goals.
 Patients not adequately controlled with 30 mg/kg/day, doses up to 40
mg/kg/day may be considered for serum ferritin levels persistently >2,500
mcg/L and not decreasing over time
 Doses >40 mg/kg/day are not recommended
 Serum ferritin <1,000 mcg/L at 2 consecutive visitsconsider dose
reduction (esp if dose is >25 mg/kg/day)
 If serum ferritin falls to <500 mcg/L, stop therapy and continue monitoring
monthly.

63.  New Tablet formulation of Deferasirox
 Initial: 14 mg/kg once daily
 Maintenance: Adjust dose every 3 to 6 months based on serum ferritin trends;
adjust by 3.5 or 7 mg/kg/day; titrate to individual response and treatment goals.
 In patients not adequately controlled with 21 mg/kg/day, doses up to 28 mg/kg/day
may be considered for serum ferritin levels persistently >2,500 mcg/L and not
decreasing over time
 Doses >28 mg/kg/day not recommended.
 If serum ferritin falls to <1,000 mcg/L at 2 consecutive visits, consider dose
reduction (especially if dose is >17.5 mg/kg/day).
 If serum ferritin falls to <500 mcg/L, stop therapy and continue monitoring
monthly.

64.  Exjade:
 Initial: 10 mg/kg once daily.
 Consider increasing to 20 mg/kg once daily after 4 weeks if baseline
hepatic iron concentration is >15 mg Fe/g dry weight.
 Maintenance: Dependent upon serum ferritin measurements
(monthly) and hepatic iron concentrations (every 6 months):
 If serum ferritin is <300 mcg/L: Interrupt therapy and obtain
hepatic iron concentration

65.  EXJADE
 If hepatic iron concentration:
 <3 mg Fe/g dry weight: Interrupt therapy
 Resume treatment when hepatic iron concentration is >5 mg Fe/g
dry weight
 5 to 7 mg Fe/g dry weight: Continue treatment at a dose of no
more than 10 mg/kg/day
 >7 mg Fe/g dry weight: Increase dose up to 20 mg/kg/day;
Maximum dose: 20 mg/kg/day

66.  JadeNu
 Initial: 7 mg/kg once daily.
 Consider increasing to 14 mg/kg once daily after 4 weeks if baseline
hepatic iron concentration is >15 mg Fe/g dry weight.
 Maintenance: Dependent upon serum ferritin measurements
(monthly) and hepatic iron concentrations (every 6 months):
 If serum ferritin is <300 mcg/L: Interrupt therapy and obtain
hepatic iron concentration

67.  JadeNu
 If hepatic iron concentration:
 <3 mg Fe/g dry weight: Interrupt therapy; resume treatment when
hepatic iron concentration is >5 mg Fe/g dry weight
 3 to 7 mg Fe/g dry weight: Continue treatment at a dose of no more
than 7 mg/kg/day
 >7 mg Fe/g dry weight: Increase dose up to 14 mg/kg/day; Maximum
dose: 14 mg/kg/day

68.  An LIC >15 mg Fe/g,
 Serum ferritin >2500
 Cardiac T2* MRI <15 msec
 Fall in the LVEF
 Revision of the dose or frequency of Deferoxamine infusions or
 Switching to another chelator,
 Prospective randomized trials have confirmed the superiority
of Deferiprone, either alone or in combination with deferoxamine,
compared with deferoxamine alone, for the treatment of
established iron-induced cardiac disease *#
*Improving survival with deferiprone treatment in patients with thalassemia major: a prospective multicenter randomised clinical trial under
the auspices of the Italian Society for Thalassemia and Hemoglobinopathies. Maggio A, Vitrano A, Capra M, Cuccia L, Gagliardotto F. Blood
Cells Mol Dis. 2009 May;42:247-51.
#Increased survival and reversion of iron-induced cardiac disease in patients with thalassemia major receiving intensive combined chelation
therapy as compared to desferoxamine alone. Lai ME, Grady RW, Vacquer S, Pepe A,Carta MP, Bina P. Blood Cells Mol Dis.2010 Aug;45:136-9.

69.  Serum (or plasma) ferritin :
 Performed in duplicate before chelation therapy is initiated to
establish a baseline level
 Repeated every three month
 Additional monitoring –
 Depending upon the chelating agent(s) chosen, additional
monitoring, e.g.
 Growth retardation,
 Renal & Hepatic Fx
 Complete blood count, Absolute neutrophil count

70.  Successful iron chelation is present
 Serum ferritin fall <1000 mcg/L
 LIC is in the range of 3 to 7 mg/g dry weight
 Cardiac T2* is >20 milliseconds.
 Current dosing is continued
 Levels remain stable or are improving with time
 Current dosing is withheld
 Current dosing is discontinued
 Ferritin is <300 to 500 mcg/L
 LIC becomes <3 mg/g dry weight.

71.  Increase in dosing
 Ferritin and LIC increasing when averaged over a minimum period
of 6 months.
 Expert guidance on this issue does not exist
 Increase dosing only when major changes in ferritin and LIC have
occurred:
 eg, doubling of these levels during a period of one year

72.  Indications
 An LIC >15 mg Fe/g
 Serum ferritin >2500
 Cardiac T2* MRI <15
milliseconds
 Fall in the LVEF
 Cardiac siderosis
 Cardiac failure
 Arrhythmia
 Treatment
 Escalation to maximal allowed
doses
 Switching to another chelating
agent
 Use of combined chelating agents.
 Deferiprone + Deferasirox
 Deferiprone+Deferoxamine

73.  Combined treatment has been more effective than single-agent iron
chelation for mild to moderate degrees of hepatic and cardiac iron
overload
 Two different iron chelators appear to remove iron from tissue stores
via different mechanisms*
 Combination therapy has also been effective in smaller studies in
unstable patients with severe degrees of cardiac siderosis and impaired
left ventricular function#
*Specific iron chelators determine the route of ferritin degradation. De Domenico I, Ward DM, Kaplan J.
Blood. 2009;114(20):4546. Epub 2009 Aug 11.
#Normalisation of total body iron load with very intensive combined chelation reverses cardiac and
endocrine complications of thalassaemia major. Farmaki K, Tzoumari I, Pappa C, Chouliaras G, Berdoukas
V. Br J Haematol. 2010;148(3):466. Epub 2009 Nov 12.

75.  DFP on each day of the week + S/C DFO infusions given on some or
all of these days was introduced in 1998 for patients inadequately
chelated by maximum tolerated doses of DFP
 Effect of the combined drugs on iron excretion has been found on the
basis of urine iron excretion and iron balance studies : Additive or even
Synergistic
 Shuttle mechanism: DFP entering cells and removing iron, which is
then passed on to DFO for excretion in urine or feces. The DFP may
reenter cells and extract more iron.
 DFP is capable of rapidly accessing NTBI fractions in plasma &
transferring this iron to DFO. Shuttling of iron from DFP to DFO also
applies to iron removed from transferrin.

76. DFP given orally binds
iron from transferrin,
NTBI, and intracellular
compartments and
transfers some of this
iron to DFO.
The free DFP is then
available to bind more
iron. Some DFO also
enters cells to bind iron
directly

77.  DFO 40 mg/kg/d given at night
 Effectively removes LPI at night
 No protection during the day
 DFP 75 mg/kg/d given during the day
 Intermittent decrease in LPI during the day
 Rebound effect at night
 DFO 40mg/kg/d given at night + DFP 75 mg/kg/d given during
the day
 Provides 24 hour protection against LPI
Cabantchik ZI, Breuer W, Zanninelli G, Cianciulli P. LPI-labile plasma iron in iron overload. Best Pract
Res Clin Haematol. 2005 Jun;18(2):277-87.

78. TIF GUIDELINES
 Combined therapy can control iron overload in Liver and Heart
where monotherapy is not having desired effects
 If patient not doing well on monotherapy, combined t/t offers an
additional approach (as does intensive therapy with atleast
50mg/kg/day of DFX for as many hours a day as is practicable
 Patients with very high levels of heart iron or cardiac dysfunction,
24 hour t/t with DFO and daily therapy with DFX strongly
considered
 Formal safety data on combination therapy is limited
 Agranulocytosis more common with combination regimen.

79.  Acute decompensated heart failure
 Major cause of death
 Medical emergency.
 T/t: High-dose continuous intravenous deferoxamine +
oral deferiprone

81. CORDELIA was a prospective,
randomized comparison of
Deferasirox (target dose 40 mg/kg
per day) vs
Subcutaneous deferoxamine (50-
60 mg/kg per day for 5-7
days/week) for myocardial iron
removal in 197 β-thalassemia
major patients with myocardial
siderosis (T2* 6-20 milliseconds)
and no signs of cardiac
dysfunction (mean age, 19.8
years).
CONCLUSION
In β-thalassemia major
patients with severe iron
burden, deferasirox was
noninferior to deferoxamine
for myocardial iron removal
with a trend toward
superiority for deferasirox.

82. Randomized phase III
trial in 586 regularly
transfused patients
with beta thalassemia
CONCLUSION
Chronic use
of deferasirox (single
oral dose of 30
mg/kg/day) induced
decreases in LIC in
most patients, similar
to that achieved
with deferoxamine(DF
O, ≥50 mg/kg per day),
with minimal short-
term toxicity

83. SCD
Lower HbS levels (ie, to <30 percent of total Hb).
Reduced viscosity
Minimization of excess iron stores compared with simple
BT
Full exchange transfusion:
 Rapid lowering of the HbS to 30% or less
 Correction of Anemia
 Partial exchange transfusion

84.  Indications
 For acute emergencies
 MODS
 Suspected Stroke
 Respiratory compromise
 Acute chest syndrome
 Hypotension is not a contraindication to exchange transfusion
 Automated apheresis preferred over manual exchange-
 Faster, Fewer volume shifts

85.  Formulas used for estimation of simple transfusion and partial exchange
transfusion volumes
 Packed RBC volume for simple transfusion (mL) =
([dHCT - iHCT] x TBV) ÷ rpHCT
 Manual partial exchange volume (mL) =
([dHCT - iHCT] x TBV) ÷ (rpHCT - [(iHCT + dHCT) ÷ 2])
 dHCT : Desired Hctt in %
 iHCT : Initial hematocrit in %
 rpHCT: Hct of the replacement PRBC
(range, 55 to 60 %).
TBV: total blood volume in mL
60 mL/kg in adult women,
70 mL/kg in adult men, 80 mL/kg in
children, 100 mL/kg in infants

86. Iron overload is a leading cause of morbidity, mortality and
organ injury.
Even nontransfused patients develop iron overload
The primary treatment for iron overload in thalassemia is
chelation
Ease of administration, ensuring compliance, is an important
property in choosing an iron chelator.
More randomized controlled trials comparing with more
number of subjects comparing monotherapy and combination
therapy are needed.

88.  Normal CBC
 Increased ferritin
 Increased TSAT
 S/O Hemochromatosis
 Macrocytic Anaemia
 Increased ferritin
 Increased TSAT
 S/O Hemolysis /
Megaloblastic anaemia
 Microcytic Anaemia
 Increased Ferritin
 Increased TSAT
 S/O Thalassemia
 Normocytic Anaemia
 Increased ferritin
 S/O Anaemia of Chronic
Inflammation

89.  Confounding Factors:
 Iron studies abn in individuals with liver disease regardless of the total body
iron burden
 Liver disease: Ferritin and TSAT can be elevated in liver disease
 Dying hepatocytes release storage iron into the circulation
 Alcohol suppress hepcidin synthesis
 Alcohol suppresses liver transferrin synthesis
 Ferritin is also an acute phase reactant
 CRP can be done to R/O Inflammation/ Infection

90.  Flow cytometry
 Helper T (Th)-cell subset showing
 High expression of CD2
 Low expression of CD38 surface markers on the
 Elevated NT-proBNP levels in cardiac hemosiderosis
 Endomyocardial biopsy
 Individuals with heart failure or conduction defects with elevated
cardiac iron on MRI
 Cardiac biopsy done for other indications may reveal iron overload

91. Indications
 Serum ferritin ≥1000 ng/mL and
often ≥500 ng/mL
 Evidence of tissue injury (eg,
increased hepatic transaminase
levels, reduced hormone levels,
reduced cardiac ejection fraction).
 Increased tissue iron by MRI,
other imaging study, or tissue
biopsy.
Containdications
 Anaemia
 Asymptomatic with ferritin levels
<500 ng/mL
 No tissue iron on MRI
 A lack of iron on MRI or other
testing eg. liver biopsy indicates
iron has not accumulated.

92.  Macrocytic Anaemia
 Increased ferritin
 Increased TSAT
 S/O Hemolysis /
Megaloblastic anaemia
 Microcytic Anaemia
 Increased Ferritin
 Increased TSAT
 S/O Thalassemia
 Normocytic Anaemia
 Increased ferritin
 S/O Anaemia of Chronic
Inflammation