This document discusses iron overload and its management. It begins by describing normal iron physiology and causes of excess iron accumulation, including hereditary hemochromatosis and multiple blood transfusions. Signs of iron overload include organ damage to the liver, heart, endocrine glands, and joints. Diagnosis involves blood tests of ferritin and transferrin saturation as well as MRI to measure iron levels. Treatment involves iron chelation therapy using drugs like deferoxamine, deferiprone, and deferasirox to remove excess iron from the body.
Rolla Abu-Arja, clinical director of pediatric bone marrow transplant in Nationwide Children's Hospital (Columbus, OH) discusses iron overload in hematopoetic cell transplantation.
Rolla Abu-Arja, clinical director of pediatric bone marrow transplant in Nationwide Children's Hospital (Columbus, OH) discusses iron overload in hematopoetic cell transplantation.
This is a comprehensive review of the physiology and pathophysiology of iron deficiency anemia and the evolution of its treatment with parenteral iron to the current recommendations. In our practice, in an attempt to minimize allogenic blood transfusions, we optimize preoperatively patients with iron deficiency anemia by means if intravenous iron replacement.
This is a slide presentation for MBBS students. a brief overview of hemochromatosis, an iron overload condition. overview of hemochromatosis, pathophysiology, clinical features, approach, and management
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
This is a comprehensive review of the physiology and pathophysiology of iron deficiency anemia and the evolution of its treatment with parenteral iron to the current recommendations. In our practice, in an attempt to minimize allogenic blood transfusions, we optimize preoperatively patients with iron deficiency anemia by means if intravenous iron replacement.
This is a slide presentation for MBBS students. a brief overview of hemochromatosis, an iron overload condition. overview of hemochromatosis, pathophysiology, clinical features, approach, and management
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
1. Presented by:
Dr. Chetan Agarwal
DNB SS Resident
Moderator:
Dr. (Col) Jasjit Singh
HOD Clinical Hematology
Dept of Hematology
Sir Ganga Ram Hospital
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
7.
8.
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)
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.
18.
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
21.
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
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.
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.
32.
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.
34.
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)
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
39.
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
41.
42.
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
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 visitsconsider 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.
74.
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
80.
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.
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.