discussion about anemias and hematopoietic growth factors and the relevant clinical issues. drugs causing Neutropenia, and Thrombocytopenia

2. By
M. H. Farjoo M.D., Ph.D.
Shahid Beheshti University of Medical Science
Agents Used in Anemias;
Hematopoietic Growth Factors

3. Agents Used in Anemias;
Hematopoietic Growth Factors
 Introduction
 Iron
 Folic Acid
 Vitamin B12
 Pyridoxine
 Hematopoietic Growth Factors
 Effect of Drugs on blood cells
 Novel Treatments

6. Iron
 Excess iron is stored as ferritin, consisting of ferric
hydroxide covered by apoferritin.
 The serum ferritin is in equilibrium with storage ferritin, so
the serum ferritin is used to estimate iron stores.
 Healthy people lose 1-2 mg iron daily but menstruating
women lose 30 mg of iron with each menstrual period.
 Thus, many premenopausal women have iron deficiency.
 Iron deficiency anemia in men and postmenopausal women
should be evaluated for occult GI bleeding.

7.  Oral ferrous sulfate is the treatment of choice for iron
deficiency.
 All iron salts are absorbed to approximately the same
extent.
 Oral and parenteral iron have the same efficacy (if GI
tract absorption is normal).
 The effectiveness of treatment is made only 3–4 weeks
after the start of treatment.
 Ascorbic acid (≥200 mg) increases the absorption of
iron by at least 30%, but increases the incidence of side
effects.
Iron

8. Iron
 In iron deficiency, 25% of oral iron is absorbed and 50-
100 mg of iron is incorporated into hemoglobin daily.
 Therefore, 200-400 mg of iron should be given daily to
correct iron deficiency most rapidly.
 Adverse effects of oral iron include nausea, epigastric
discomfort, abdominal cramps, constipation, and
diarrhea.
 They can be overcome by lowering the daily dose or
taking the tablets with meals or changing the iron salt.

10. ‫آهن‬ ‫قرص‬

11. Syrup Ferrous Sulfate
200 mg = 40 mg elemental iron
Price in Iran: ? Toman

12. Drop ferrous sulfate
125 mg = 25 mg elemental iron
Price in Iran: ? Toman

13. Tablet Ferrous fumarate, 60 mg elemental iron
Price in Iran: ? Toman

14. Cap. ferrous-glycine-sulfate
567.66 mg = 100 mg elemental iron
Price in Iran: 16,500 Toman

15. Capsule Easy Iron 28 (& 25) mg
Price in Iran: ~ 57,000 Toman

16. ‫لیپوزومال‬ ‫آهن‬

17. Ferrous fumarate molecular weight = 170 g/mol
Ferrous molecular weight = 56 g/mol
350 mg of ferrous fumarate = 115 mg iron
Price in Iran: 15,000 Toman

18. Capsule Hematinic
350 mg = 115 mg elemental iron
Price in Iran: 28,000 Toman

19. Feroglobin syrup
Price in Iran: 35,000 Toman

20. Feroglobin syrup
‫عنوان‬ ‫مقدار‬(‫در‬10‫لیتر‬ ‫میلی‬) ‫روزانه‬ ‫نیاز‬
Vitamin B1 10 mg 286 %
Vitamin B2 2 mg 63 %
Vitamin B6 2 mg 100 %
Vitamin B12 10 µg 500 %
Folic Acid 100 µg 75 %
Dexpanthenol 4 mg
Calcium Glycerophosphate 20 mg
Vitamin B3 20 mg
Iron (Elemental) 20 mg 50 %
Zinc (Elemental) 6 mg 33 %
Vitamin C 64 mg
Copper 0.4 mg
Manganese 0.5 mg
Lysine HCL 40 mg
Honey 200 mg
Malt Extract 1000 mg

21. Comparison of Iron preparations in Iran

23. Parenteral Iron
 Parenteral iron is used:
 In those who require hemodialysis and erythropoietin.
 After gastrectomy or small bowel resection
 IBD involving the proximal small bowel
 Malabsorption syndromes

24. Parenteral Iron
 Parenteral iron bypasses regulatory systems and can
deliver more iron than can be safely stored.
 Large IV dose of iron improves hematologic status
faster than oral iron for 1–3 weeks.
 However, the final response is no better than that seen
with oral iron.
 Iron stores is estimated by serum ferritin and the
transferrin saturation.

25. Laboratory results in iron deficiency
anemia

26. Parenteral Iron
 Iron dextran is given by deep IM injection or IV
infusion.
 IV infusion is most common rout and for IM injection
Z track technique should be used.
 Local reactions and possibility of malignant change at
the site of injection, make IM injection inappropriate
except when the IV route is inaccessible.

27. Parenteral Iron
 It rarely causes anaphylaxis and death, so a small test
dose should always be given before IM or IV doses.
 For test, 25 mg of dextran is infused over a period of
15 minutes, and the patient is observed for 1 hr.
 Use iron dextran with extreme caution in patients
with rheumatoid arthritis or during the acute phase of
an inflammatory illness.

28. Z Track Injection

29.  Iron sucrose appears to be better tolerated and to
cause fewer adverse events than iron dextran
 This agent is FDA-approved for iron deficiency in
chronic kidney disease.
 Chronic use has the potential to cause renal
tubulointerstitial damage.
Parenteral Iron

30. Maltofer (Iron hydroxide polymaltose)
50mg/ml 2ml

31. Venofer, iron-hydroxide sucrose, 100
mg

32. Ferric Carboxymaltose 50 mg/1mL, 10 ml
Price in Iran: 315,000 Toman

33. Acute Iron Toxicity
 Adults tolerate large doses of oral iron but 10 tablets of
any iron salt can be lethal in children (12 to 24 months).
 Toxicity causes vomiting, abdominal pain, and bloody
diarrhea.
 Of particular concern are pallor or cyanosis, lassitude,
drowsiness, and hyperventilation due to acidosis.
 If death does not occur within 6 h, there may be a
transient period of apparent recovery, followed by death
in 12–24 h (because of acidosis).
 With early treatment, the mortality can be reduced from
45% to about 1%.

34. Acute Iron Toxicity (Cont’d)
 Whole bowel irrigation should be performed.
 Deferoxamine (iron-chelating agent) is given
systemically to bind absorbed iron and to promote its
excretion in urine and feces.
 Activated charcoal, does not bind iron and is NOT
effective.
 Appropriate supportive therapy for GI bleeding,
metabolic acidosis, and shock must also be provided.

35. Deferoxamine (Desferal)

36. Activated Charcoal

37. Activated Charcoal Tablet
Price of each pack: 39,000 Toman

38. Activated Charcoal

39. Chronic Iron Toxicity
 Chronic toxicity (hemochromatosis) results when
excess iron is deposited in the heart, liver, and
pancreas.
 It leads to organ failure and death and occurs in:
 Inherited hemochromatosis (excessive iron absorption)
 Receiving many transfusions over long periods
(Thalassemia major).
 Oral deferasirox is used for chronic iron overload,
and is as effective as deferoxamine.

40. Deferasirox Tablet 125 / 500 mg
Price in Iran:
28,000 Toman (manufactured product)
616,000 Toman (imported product)

41. hemochromatosis

42. A 62-year-old woman, whose serum ferritin concentration was 3583 ng/ml (normal
range, 30 to 300). Liver is seen as a darkened organ (Panel A).
After 32 phlebotomies within14 months (total blood volume removed, 16 liters), the
serum ferritin concentration was 606 ng/ml (Panel B).
she is currently being treated with phlebotomy. The disease is genetic.
Hemochromatosis

43. Thalassemia gene therapy

45. Folic Acid
 Folic acid is required for the synthesis of amino acids
and DNA.
 Only 5-20 mg of folates are stored in the liver.
 Megaloblastic anemia can develop within 1-6 months
after the intake of folic acid stops.
 Oral drug is well absorbed even in malabsorption
syndromes.
 1 mg folic acid orally daily is sufficient for full
recovery in almost all patients.

46. Folic Acid
 Folic acid deficiency is seen in:
 Alcohol dependence and liver disease (poor diet and
diminished hepatic storage)
 Pregnancy and hemolytic anemia (increased folate
requirement)
 Malabsorption syndromes
 Renal dialysis (dialysis removes folates)
 Some drug ingestion: methotrexate, trimethoprim and
pyrimethamine (inhibit dihydrofolate reductase)

51. Vitamin B12
 The dietary source of vitamin B12 is meat (especially
liver), egg, and dairy products.
 B12 is stored in the liver with a storage pool of 3000-
5000 mcg.
 Daily requirements are 2 mcg, it would take 5 years
for megaloblastic anemia to develop.

52. Vitamin B12
 The most common causes of vitamin B12 deficiency
are:
 Pernicious anemia (defective secretion of intrinsic
factor)
 Partial/total gastrectomy (intrinsic factor secreting
cells removed)
 Abnormality in the distal ileum

53. Vitamin B12, 1,000 μg/1mL
Price of each pack: 20,000 Toman

54.  Patients with sideroblastic anemia have impaired
hemoglobin synthesis.
 Pyridoxine corrects sideroblastic anemias associated
with isoniazid and pyrazinamide, which act as
vitamin B6 antagonists.
Vitamin B6 (Pyridoxine)

55. Vitamin B6 300 mg (100 mg/mL, 3 ml)
Price in Iran: 20,000 Toman

56. Vitamin B6 100 mg (50 mg/mL, 2 ml)
Price in Iran: 16,000 Toman

57. Ampoule Vitamin B Complex
Each ampoule (2 ml) contains:
1. Vit. B1 (Thiamine) 10 mg
2. Vit. B2 (Riboflavin) 4 mg
3. Vit. B3 (Nicotinamide/Niacinamide)
40 mg
4. Dexpanthenol (derivative of Vit. B5)
6 mg
5. Vit. B6 (Pyridoxine) 4 mg
There is NOT Vit. B12 in B-complex
ampoule / tablet

58. Dexpanthenol Cream 5% / 30 g
Price in Iran: 5,000 Toman

59. Tablet Vitamin B Complex

60. Vitamin B1 (100 mg) / B6 (100 mg) / B12 (1,000 μg) (3 mL)
Price in Iran: 15,000 Toman

61. Vitamin B1 (100 mg) / B6 (100 mg) / B12 (1,000 μg) (3 mL)
Price in Iran: 21,000 Toman

62. Vitamin B1 (100 mg) / B6 (100 mg) / B12 (1,000 μg) (3 mL)
Price in Iran: 21,000 Toman

64. Erythropoietin
 Recombinant human erythropoietin (Epoetin alfa) is
produced in a mammalian cell expression system.
 It is not cleared by dialysis.
 Darbepoetin alfa (not yet in Iran) is a derivativee with
2 to 3 times longer half-life.

65. Erythropoietin
 An inverse relationship exists between the hematocrit
level and erythropoietin level.
 The most important exception is in the anemia of chronic
renal failure.
 These patients are most likely to respond to exogenous
erythropoietin.
 Failure to respond to erythropoietin is due to concurrent
iron or Folate deficiency.

66. Erythropoietin
 In primary bone marrow disorders and nutritional and
secondary anemias, endogenous erythropoietin is
already high.
 Erythropoietin therapy in these conditions is not usually
beneficial.
 But in selected patients, erythropoietin may be useful
for primary bone marrow disorders and secondary
anemias.
 They are patients who have disproportionately low
serum erythropoietin levels for their degree of anemia.

67. Erythropoietin
 Erythropoietin is also used for:
 Anemia by zidovudine in HIV and anemia of
prematurity.
 To accelerate erythropoiesis after phlebotomies for
autologous transfusion for elective surgery.
 For treatment of iron overload (hemochromatosis).
 Erythropoietin is banned by the international olympic
committee.
 Its side effects includes hypertension and thrombotic
complications.

68. Epoetin alfa (Eprex)

69. Epoetin (beta) Injection 4000 IU/0.3 ml
Price in Iran: 110,000 Toman
It seems there is no
significant difference between
efficacy of epoetin beta and
epoetin alfa

70. Myeloid Growth Factors
 Myeloid growth factors consist of:
 G-CSF: Granulocyte Colony-Stimulating Factor
(Filgrastim)
 GM-CSF: Granulocyte-Macrophage Colony-
Stimulating Factor (Sargramostim, Molgramostim)
 G-CSF and GM-CSF are used for treating some kinds
of neutropenia

71. G-CSF
 The most important role of G-CSF in transplantation is
mobilization of peripheral blood stem cells (PBSCs).
 Splenic rupture is a rare but serious complication of G-
CSF.
 Pegfilgrastim, has a much longer half-life than
filgrastim.
 Pegfilgrastim is injected once per myelo- suppressive
chemotherapy cycle instead of daily for several days.

72. Filgrastim, 300 μg/0.5 ml
Price of each syringe: 56,000 Toman

73. Filgrastim, (300 μg/0.5 ml)
price of each syringe: 130,000 Toman

74. Pegfilgrastim, 6 mg/0.6 ml
Price: 570,000 Toman

75. Other Applications
 Studies show that G-CSF and GM-CSF are safe for
leukemia (AML).
 The growth factors even increase neutrophil recovery
and reduce infection rates and days of hospitalization.
 Both G-CSF and GM-CSF have FDA approval for
treatment of patients with AML.

76. Megakaryocyte Growth Factors
 Megakaryocyte growth factors consist of:
 Thrombopoietin (Not in Iran)
 Interleukin-11 (Not in Iran)
 Eltrombopag
 Romiplostim
 They are used in cirrhotic patients who have low
thrombopoietin levels.

77. Tablet Eltrombopag 25 mg
Price in Iran: ? Toman

78. Romiplostim Injection, 250 μg
Price in Iran: 3,652,000 Toman

79. Clinical uses of hematopoietic growth factors
and similar agents

81. Hemolysis
 A number of drugs can cause hemolysis by various
mechanisms:
 Drug-induced thrombotic microangiopathy (DITMA)
 Immune (antibody-mediated) hemolysis
 Oxidative damage (G6PD deficiency)
 Methemoglobinemia

82. Drugs causing DITMA
Leg cramps, malaria
Quinine
Cancer therapies
Bevacizumab
Bortezomib
Carfilzomib
Docetaxel
Gemcitabine
Imatinib
Ixazomib
Mitomycin
Oxaliplatin
Palbociclib
Pentostatin
Ponatinib
Sunitinib
Antibiotics
Sulfisoxazole
Trimethoprim-sulfamethoxazole
Hemophilia A
Emicizumab
Immunosuppressive therapies
Cyclosporine
Everolimus
Interferons (type 1, alpha and beta)
Intravenous immune globulin (IVIG)
Sirolimus
Tacrolimus
Antiepileptics
Valproic acid
Antipsychotics
Quetiapine
Drugs of abuse
Cocaine
Oxymorphone extended release
Oxycodone

83. Drugs Associated with Autoimmune Hemolytic Anemia
Antibiotics
NSAIDs
analgesic/antipyretics
Anti-cancer drugs Other
•Amoxicillin
•Amphotericin B
•Ampicillin
•Cefazolin
•Cefotaxime
•Cefotetan
•Cefoxitin
•Ceftazidime
•Ceftizoxime
•Ceftriaxone
•Cefuroxime
•Cephalexin
•Cephalothin
•Chloramphenicol
•Ciprofloxacin
•Erythromycin
•Isoniazid
•Levofloxacin
•Mefloquine
•Nafcillin
•P-aminosalicylic acid
•Penicillin
•Piperacillin
•Pyrimethamine
•Quinidine
•Quinine
•Rifampin
•Stibophen
•Streptomycin
•Teicoplanin
•Temafloxacin
•Tetracycline
•Ticarcillin
•Trimethoprim/sulfamethoxazole
•Acetaminophen
•Aspirin
•Azapropazone
•Diclofenac
•Ibuprofen
•Methadone (positive DAT
only)
•Naproxen
•Phenacetin
•Sulfasalazine
•Sulindac
•Tolmetin
•Atezolumab
•Carboplatin
•Cisplatin
•Fluorouracil
•9-hydroxymethyl-ellipticinium
•Imatinib
•Ipilimumab
•Methotrexate
•Nivolumab
•Oxaliplatin
•Pembrolizumab
•Pemetrexed
•Antazoline
•Carbimazole
•Chlorinated hydrocarbon
insecticides
•Chlorpromazine
•Cyclosporin
•Furosemide (positive DAT only)
•Hydrochlorothiazide
•Insulin
•Methadone (positive DAT only)
•Methotrexate
•Probenecid
•Quinidine
•Quinine
•Radiocontrast medium
•Ranitidine
•Triamterene
•Trimellitic anhydride (used in dyes,
resins)

84. Unsafe Substances in G6PD deficiency
Medicines and other substances likely to be UNSAFE in moderate-to-
severe G6PD deficiency*[1-3]
Medications
Dapsone (diaminodiphenyl sulfone)
Methylene blue (methylthioninium chloride)
¶
Nitrofurantoin, nifuratel, and nitrofurazone (nitrofural)
Δ
Phenazopyridine (pyridium)
Primaquine
Rasburicase
Chemical exposures and foods
Fava beans
Henna compounds (black and red Egyptian)
Naphthalene (mothballs, lavatory deodorant)
Phenylhydrazine
"RUSH" (isobutyl nitrate, amyl nitrate)

85. Henna compounds

86. Medications that May Cause Methemoglobinemia
Amino salicylic acid (also called PABA)
Clofazimine and Dapsone (for leprosy)
Chloroquine
Local anesthetics even in sprays and creams,
(benzocaine, lidocaine, and prilocaine)
Metoclopramide
Methylene blue*
Nitroglycerin
Phenazopyridine
Primaquine
Rasburicase
Sulfonamides

87. Causes of Drug Induced Splenomegaly
Hematologic (hypersplenic) states
Acute and chronic hemolytic anemias, all etiologies
Following use of recombinant human G-CSF

88. Causes of Hepatomegaly (Non of Them by Drugs)

89. Drug-induced Neutropenia and
Agranulocytosis
 The risk is low and independent of dose, and is very
rare in doses <10 mg/day.
 Risk factors for agranulocytosis include:
 Patients with infectious mononucleosis
 Concomitant use of probenecid and captopril.
 Underlying autoimmune disease
 Combination therapy with an ACEI and interferon

90. Drug-induced Neutropenia and
Agranulocytosis
 Drugs cause neutropenia or agranulocytosis by:
 Antibodies (PTU)
 Direct toxic effects (Clozapine)
 Immune destruction occurs days to weeks after
beginning the drug, with explosive symptoms.
 Rechallenge is associated with a prompt recurrence
even with low doses.

91. Drug-induced Neutropenia and
Agranulocytosis
 With direct toxicity, the time course is slower than
immune mediated.
 Most cases present within the first 6 months and
usually within the first 3 months of drug treatment.
 The neutropenia is asymptomatic or insidious.
 Rechallenge requires both a latent period and high
drug doses before recurrence is observed.
 In both subtypes, neutropenia resolves 1-3 weeks after
cessation of the drug.

92. Drug-induced Neutropenia and
Agranulocytosis
 The diagnosis should be suspected if a patient
develops fever, mouth sores, or gingival inflammation.
 Differential diagnosis is viral infection and nutritional
deficiency (copper or vitamin B12 deficiency).
 The most common agents in agranulocytosis are:
clozapine, thionamides, sulfasalazine, and
trimethoprim-sulfamethoxazole

93.  Risk of drug-induced immune thrombocytopenia
(DITP) from a new drug is rare.
 Patients present within two weeks of drug exposure
with platelet count < 20,000 / microL and / or
bleeding.
 Thrombocytopenia develops within hours if
previously exposed, or within 1-2 weeks for a new
drug.
 After drug discontinuation, platelets return to normal
in a week.
Thrombocytopenia

94. Causes of Drug Induced Thrombocytopenia
Drug-induced
Heparin (NOTE: special case, also can cause thrombosis)
Phenytoin, Carbamazepine, Valproic acid
Sulfonamides (trimethoprim-sulfamethoxazole)
Amiodarone
Cimetidine, Ranitidine
Acetaminophen, Ibuprofen, Naproxen
Furosemide
Beta-lactam antibiotics (penicillins, cephalosporins)
Vancomycin
MMR vaccine
Food and beverages
Walnuts
Certain herbal teas
Alcohol
Nutrient deficiencies (vitamin B12, folate, copper)

96. CAR (chimeric antigen
receptor) T cells

97. CAR T cell drug Kymriah for ALL
Price: 475,000 $

98. NEURONATA-R for ALS (BM-MSC)

99. Iran Ancient Heritage in Louvre Museum (Paris)

100. Thank you
Any question?