Académique Documents
Professionnel Documents
Culture Documents
LEGEND
Remember Book Lecturer Other Trans
Trans Comm
OBJECTIVES
Figure 1. Binding of iron and protoporphyrin to form heme.
At the end of the lecture, the student should be able to: Hemoglobin consists of heme and globin chains. Heme needs
1. Master shadow clone jutsu protoporphyrin and iron where the oxygen attaches to. Protoporphyrin
2. Learn how conquer the iron throne in Westeros accumulation means there is no iron available in the circulation. If there
is decreased iron, the oxygen carrying capacity of RBC is also
I. ANEMIA decreased.
Definition
Decrease in the number of red blood cells (RBC) or quantity of
hemoglobin in the blood which leads to decreased ability of
blood to carry oxygen
Causes:
o Decreased RBC formation or failure in maturation of RBCs
like iron deficiency anemia (IDA), blood loss, or increased
oxygen demand
o Increased RBC destruction as seen in patients suffering
from hemolytic anemia
Types
Based on SIZE
o Microcytic – iron deficiency, anemia of chronic disease,
chronic kidney disease
o Macrocytic – megaloblastic anemia like pernicious anemia
caused by cobalamin deficiency, folic acid deficiency
o Normocytic – chronic infections/diseases like tuberculosis
and chronic renal failure; chronic inflammation like
rheumatoid arthritis
Based on COLOR Figure 2. Absorption, transport, and storage of iron. [Fe2+: reduced
o Hypochromic iron, ferrous iron; Fe3+: oxidized iron, ferric iron; Heme iron:
o Hyperchromic present in food]
o Normochromic
1 of 3
| 3.04 Coagulants/Hematinics
Iron crosses the luminal membrane of the intestinal mucosal Main regulatory mechanism is through hepcidin, which is
cell by two mechanisms: produced in the liver.
o active transport of ferrous iron by the divalent metal Increased/adequate amount of iron = Increased hepcidin
transporter (DMT1) production. It decreases absorption of iron at the intestinal
o absorption of heme iron through heme transporter cells, increases formation of ferritin, and increases recycling in
(HCT1). which the aging RBC engulfed by macrophage.
Once inside the intestinal cell, a portion of the absorbed iron
(Fe2+) attaches to the mucosal ferritin (storage form), but most Low hepcidin concentration = promotes iron release
of it are transported to the bloodstream via ferroportin. High hepcidin concentration = inhibits iron release
In the blood, iron (Fe2+) is transported by transferrin to
erythroid precursors in the bone marrow for synthesis of
hemoglobin or to hepatocytes for storage as ferritin. Iron Requirements
Fe2+ must be converted to Fe3+ to be transported by transferrin. RBC lifespan: 120 days (0.8-1% RBC/day)
Fe3+ must be reduced to Fe2+ by ferrireductase before it can 1 ml RBC = 1 mg elemental iron
be absorbed by intestinal mucosal cells. Daily iron requirements:
o Dietary iron: 10-20 mg/day (10-15% are absorbed)
NOTES: o Absorbed iron: Male: 1 mg; Female: 1.4 mg (2x in
Ferrireductase is vitamin C-mediated, so to enhance pregnancy; 1.5x in children and adolescents
absorption, take ascorbic acid (Vitamin C) or citrus drinks
together with iron. Values
Transferrin without iron is called apotransferrin. Hematocrit – proportion of total blood volume that is
Ferritin (storage form) decreases in iron deficiency anemia. composed of RBC
Transferrin (transporter) increases in iron deficiency o Male: 47% (±7)
anemia. o Female: 42% (±5)
o In IDA: low
Hemoglobin
o Male: 16 g/dL
o Female: 13 g/dL (menstruating); 14 g/dL (menopausal); 12
g/dL (pregnant)
o In IDA: low
Erythropoietin – 10-25 U/L
Mean Corpuscular Volume (MCV) – average volume of RBC;
determines size of RBC
90 ± 8 fL (HCT x 10/RBC) (normal: 80-100 fL)
Mean Corpuscular Hemoglobin (MCH) – average mass of
hemoglobin per RBC sample of blood
o 30 ± 3 pg (Hgb x 10/RBC)
Mean Corpuscular Hemoglobin Concentration (MCHC) –
concentration of hemoglobin in a given volume of packed RBC
o 33 ± 2% (MCH/MCV)
Serum iron – amount of circulating iron bound to transferrin;
can increase immediately on initiation of iron supplementation
o 9-27 umol/L (50-150 μg/dL)
o Children: 50-120 ug/dL, Newborn: 100-250 ug/dL (2019A)
Figure 3. Transferrin is the transporter in plasma and it binds to o In IDA: low
ferric (Fe3+) form of iron. Total iron binding capacity (TIBC) – the most specific
Iron is absorbed in the duodenum and proximal jejunum, indicator when levels are high
although the more distal small intestine can absorb iron if o 54-64 μmol/L (300-360 μg/dL)
necessary. Iron absorption increases in response to low iron stores o In IDA: elevated; this is a compensatory mechanism
or increased iron requirements. (implies an increased need for iron)
% transferrin saturation (SI x 100 / TIBC)
Regulatory Mechanisms o 25-50%
o In IDA: low
Ferritin
o Male: ~100 μg/L
o Female: 30 μg/L
o In IDA: low
2 of 8
| 3.04 Coagulants/Hematinics
MCV 80 – 100 fL
MCH 27 – 31 pg/cell Iron toxicity
MCHC 32 – 36 g/dL 19.9 – 22.3 mmol/L o Acute – exclusive in young children (10 tablets) necrotizing
gastroenteritis, vomiting, abdominal pain, blood diarrhea,
Treatment shock, lethargy, dyspnea, coma and death
Blood transfusion Whole bowel irrigation, deferoxamine (IV iron-chelating
Oral or parenteral iron therapy compound), supportive therapy
Mild to moderate IDA: oral iron; if not tolerated, give parenteral o Chronic – hemochromatosis (iron overload) results when
Severe IDA: blood transfusion + iron therapy excess iron deposits in heart, liver, pancreas etc; inherited
or acquired (treated with red cell transfusion)
Oral Iron Therapy Intermittent phlebotomy, deferasirox (oral iron chelator)
Goals of treatment: reverse anemia, replete iron stores
Outcome measures:
III. HYPOPROLIFERATIVE ANEMIA
o In 3-5 days: increased reticulocytes
Decrease in the overall RBC synthesis due to a chronic
o In 1 month: increased hemoglobin by 1g/dL
condition
Increased absorption with concurrent intake of ascorbic acid,
Usual observation of RBC: normocytic and normochromic
citrus drinks
Decreased absorption with intake of tea, dairy, fish, agents that Table 3. Diagnosis of Hypoproliferative Anemia.
decrease gastric acidity (PPIs, H2 receptor blockers, antacids) Diagnosis of Hypoproliferative Anemia
Drug interaction: decreased absorption with quinolones, Test Iron- Inflammation Renal Hypometabolic
tetracyclines, levodopa, levothyroxine, mycophenolate mofetil Deficiency Disease
o Caution when giving iron to patients with hypothyroidism Anemia Mild-severe Mild Mild-severe Mild
(taking levothyroxine) MCV 60-90 80-90 90 90
Morphology N / micro N N N
Table 2. Oral Iron Preparations (Note: Values enclosed in parenthesis SI <30 <50 N N
TIBC >360 <300 N N
are elemental iron absorbed in mg.)
%sat <10 10-20 N N
Generic Name Tablet size (mg) Elixir (5 ml)
Ferritin <15 30-200 115-150 N
Ferrous sulfate 325 (65) 300 (60)
Iron Stores 0 2-4+ 1-4+ N
195 (39) 90 (18)
Extended release 525 (105) -
Ferrous fumarate 325 (107) - Causes
195 (64) 100 (33) Chronic Diseases
Renal Diseases
Ferrous gluconate 325 (39) 300 (35)
Metabolic Disease
Contents Bone Marrow Depression
Iron supplementation Anemia of Chronic Kidney Disease
o Pregnant women: 60 mg/day throughout pregnancy and up
Due to a decrease in erythropoietin production
to 6 months after pregnancy
Increased synthesis / release of hepcidin
o 6-24 months: 12.5 mg/day up to 12 months for infants with
normal body weight; up to 24 months for infants with low Leads to a decreased erythropoiesis (shortened erythrocyte
body weight life span)
o 2-5 years: 20-30 mg/d; 6-11: 30-60 mg/d; adolescents and
adults: 60 mg/d
Iron supplementation: with severe anemia
o <2 years: 25mg/day for 3 months
o 2-12 years: 60mg/day for 3 months
o >12 yrs (including pregnant women): 120mg/day for 3
months
Adverse reactions:
o Abdominal cramps (must not be given to pregnant women
who are in the first trimester)
o Nausea and vomiting
o Diarrhea or constipation
o Black stools
Parenteral Iron Therapy
o Indications: if the patient cannot tolerate oral iron,
condition is acute and severe, need iron continuously
o Iron dextran (anaphylaxis), ferric sucrose, ferric
carboxymaltose complex, sodium ferric gluconate complex,
ferumoxytol (paramagnetic ferric oxide)
o Used with recombinant Epo
o Risk of anaphylaxis
o Weight (kg) x 2.3 x (15-pt.’s hgb in g/dL) + 500 or 1000 Figure 5. Anemia of Chronic Disease
o Two ways:
1. Administer total dose required to correct deficit Endogenous Erythropoietin
and provide 500mg iron stores (infusion) Also called hematopoietin, hemopoietin.
2. Give repeated small doses over protracted period Produced in the kidney by interstitial fibroblasts (Fetus:
e.g. 100mg weekly x 10 weeks perisinusoidal cells of the liver)
Controls erythropoiesis; stimulates progenitor proliferation and
maturation
Normal level: 10-25 U/L
3 of 8
| 3.04 Coagulants/Hematinics
Increased when Hgb level <100-120g/L (10-12g/dL) d. Adenosylcobalamin
Clearance: 6-9 hours fuel B12
EPO release = 4-5x RBC production (1-2 weeks) not often given for patients with neurologic
deficit and megaloblastic anemia
Treatment: often in combination with Methylcobalamin
Blood transfusion - useful in DNA synthesis and mitochondrial
Recombinant erythropoietin cobalamin biochemical reaction
Stimulates proliferation and maturation of red cell 2. Supplementations:
progenitors; induces release of reticulocytes Cobalamin IM / IV
Indications: anemia observed in chronic kidney disease: Better absorption than oral
other indications: AIDS, cancer chemotherapy, surgery, 1mg/week for 8weeks
prematurity, chronic inflammation 1mg/month for life
Recombinant human erythropoietin (epoietin alfa) 2,000- Cochrane review:
40,000 units/ml IV / SQ; HL 4-8hrs (once dosing) 1-2mg/d orally for 90-120days has similar
Darbepoietin alfa extends half-life 24-36 hours serum improvement compared to IM
Complications: IDA – start iron supplementation; injections regardless of etiology
thromboembolic events-start with anticoagulants See appendix (A1 and A2)
4 of 8
| 3.04 Coagulants/Hematinics
o Circumvent inhibition of DHF reductase by o 100g/kg as single dose/chemotherapy cycle
methotrexate o cannot be mobilized if patient is being given stem
o Used for toxicity to anti-folates cell transplantation
o Not used for supplementation Filgrastim – short acting
For most cases: no advantage over folic acid, more PEG-filgrastim – long acting
expensive
Both should not be used for treatment of pernicious Growth Factors / Mobilizers
anemia because you only treat the megaloblastic Lenograstim
anemia, not the the deficiency in cobalamin (it masks o Produced by hamster
signs and symptoms of cobalamin deficiency) o Recombinant human glycosylated G-CSF
Avoid multivitamin preparations unless there is clear o reverses neutrophil count by 30% compared to
deficiency of other vitamins filgrastim; mobilizes granulocytes (after PBSCT),
Well tolerated (even at 15mg/d) 150g/kg/d SQ or IV drip
Counteract effects of Phenobarbital, Phenytoin, and Sargramostim
Primidone o Produced by yeast
o Recombinant human glycosylated GM-CSF
V. IMPAIRED HEMATOPOIESIS o 250g/kg/d SQ given 1-4 days after chemotherapy;
Granulopoiesis – neutropenia, leukopenia mobilizes granulocytes (after PBSCT)
Thrombopoiesis – thrombocytopenia o Half-life: 2-3hrs
Causes o Slow infusion: 3-6 hours
o Immunosuppressive cancer chemotherapy (incl. o Adverse Effects:
those used in autoimmune diseases) Bone pain
o Autologous stem cell transplantation – decreases Malaise
blood cell lines Flu-like symptoms
o Medication / immune related Fever
Zidovudine induced bone marrow Diarrhea
suppression in AIDS patients Dyspnea
Kidney disease, chronic infection and inflammation, Hypersensitivity reactions
malignancy, hypometabolic Cutaneous necrotizing vasculitis
Hematopoietic Growth factors Splenomegaly
o Glycoprotein hormones that regulate the
proliferation and differentiation of hematopoietic GM-CSF can cause more severe side effects, particularly at
progenitor cells in the bone marrow high doses
o Known hematopoietic growth factors:
Erythropoietin (epoetin alfa and epoetin Recombinant Interleukin 11
beta) Interleukin 11 - growth factor that stimulates megakaryocyte
Granulocyte Colony Stimulating Factor (G- maturation; produced by fibroblasts and stromal cells in the
CSF) bone marrow
Granulocyte-Macrophage Colony
Stimulating Factor (GM-CSF) Oprelvekin
Interleukin-11 (IL-11) Produced by Escherichia coli
Recombinant human Interleukin 11
Colony Stimulating Factors (CSF) Bacterially derived 19,000-Da polypeptide
Glycoproteins that stimulate the proliferation and Used in chemotherapy-related thrombocytopenia (<20,000
differentiation of blood cell lines
cells/l) - Goal is to reach at least to 100,000 cells/l
First growth factors to be identified
25-50g/kg/d SQ 5-9 days
Produced naturally by fibroblasts, endothelial cells,
Half-life: 7 hours
macrophages and T cells
Adverse Effects:
GM-CSF stimulates the proliferation, differentiation and
o Rash
function of a number of the myeloid cell lineages
o Paresthesias
G-CSF is limited to neutrophils and their progenitors, o Fluid retention
stimulating their proliferation, differentiation and function o Dyspnea
o Tachycardia
Recombinant CSF o Palpitation
Indications: o Blurred vision
o After immunosuppressive non-myeloid cancer
chemotherapy Recombinant Thrombopoietin
High risk for post-chemo febrile Thrombopoietin - growth factor that stimulates megakaryocyte
neutropenia (FN; >20%) production
Prior episodes of FN
For chronic thrombocytopenia
Those that will not survive from FN
o After peripheral blood autologous stem cell
Romiplostim and Elthrombopag
transplantation
Immediate mobilization of PBSCs resulting Romiplostim - SQ, shorter T1/2; Elthrombopag - oral, longer
to reversal of granulocyte count T1/2
Thrombopoietin agonists
Filgrastim, PEG-filgrastim High affinity to human antibody Mpl receptor
Produced by Escheichia coli Used in chronic immune thrombocytopenia (ITP, TTP)
Non-glycosylated recombinant human G-CSFs Adverse Effects:
o 5g/kg/d SQ 1-3 days after chemotherapy until o Headache
o Dizziness
neutrophil count reaches 10,000cells/l (5-7days)
5 of 8
| 3.04 Coagulants/Hematinics
o Dyspnea
o Arrhythmias
o Hypokalemia
o Hepatotoxicity
o Marrow fibrosis
Hemostasis
Step 1- Vascular spasm
o Contraction of the smooth muscle produces the
vasoconstriction
Step 2- Formation of the platelet plug
o Lesion of the endothelium exposes the collagen
fibers, platelet adhesion is triggered
o Platelets release mediators which further
favorize platelet aggregation; the platelet plug is
formed
Step 3- The coagulation
o Fibrin filaments polymerize; red and white blood
cells get trapped and the blood clot is formed
Impaired Hemostasis
Test Value Normal
Platelet count <50,000 cells/µL 150,000-450,000
cells/µL)
Vitamin K Supplementation
Natural forms:
o K1 (Phytonadione; found in food)-
6 of 8
| 3.04 Coagulants/Hematinics
Available clinically in oral and o In practice: 500-1000 mg qid for 4-5 days
parenteral AE: clotting problems (thrombosis, retinal occlusion,
Used for vitamin K deficiency or embolism, infarct, seizures), hypotension, myopathy, GI
depressed prothrombin observed in discomfort, nausea, diarrhea, hypersensitivity reactions
excess warfarin (nasal stuffiness, rash)
o K2 (Menaquinone; found in tissues) CI: DIC, upper GU bleeding (potential for excessive
o K3 (Menadione) clotting)
Not used as therapy
Synthetic : TPA activates your plasminogen to produce plasmin which
Toxic increases fibrinolysis of a stable fibrin clot. Para siyang blood
RDI: Males- 120 µg/day; Females- 90 µg/day; infants- 10 thinners. So if you inhibit it (TPA inhibitors), it acts as
µg/day procaogulant.
To prevent newborn vitamin K deficiency bleeding:
Vitamin K1- 0.5-1mg IV/IM ( most common is 0.5 mg) Off label indications of TPA inhibitors:
Vitamin K1 is currently administered to all newborns Patients with trauma in which you can’t control
to prevent the hemorrhagic diseases of vitamin K bleeding
deficiency, which is common in premature infants After operation or surgical procedure in which there
IV administration of vitamin K1 should be slow, is still profuse bleeding
because rapid infusion can produce dyspnea, chest and
back pain, and even death.
To prevent osteoporosis in menopausal women: Serine Protease Inhibitors
Vitamin K2- 45 mg/day Aprotinin
To reverse warfarin effect prior to operation: Vitamin o Inhibits fibrinolysis by free plasmin and may
K1 1-2.5 mg have other antihemorrhagic effects
o Inhibits plasmin-streptokinase complex
Hemophilia A and B o Reduce bleeding especially involving
Plasma Fractions extracorporeal circulation for open heart
Bleeding occurs in setting with deficient coagulation procedures and liver transplantation
factors (<5-10%) o Associated with increased risk of renal failure,
Most common are VIII (Classic hemophilia or Hemophilia heart attack, and stroke
A) and IX (Christmas or Hemophilia B)
Concentrated plasma fractions are given. Risk of VII. SUMMARY
transmission of infection diminished by pasteurization Anemia
o Iron- elemental iron
Combined factor treatment are recommended:
o Cobalamin- supplementation and biochemical
o Prothrombin complex concentrates-
reactions
when most of the clotting factors are o Folic acid- supplementation and biochemical
deficient, more expensive reactions
o Factor VIII plasma fractions-for Hemophilia A o Supportive therapy- for anemia of chronic disease
o Factor IX plasma fractions- for Hemophilia B Erythropenia (Erythopoietin)
o Humate P ( von Willebrand factor and VIII o Erythopoeitin alfa- short acting
concentrate)- for von Willebrand disease o Darbepoietin- long acting
Desmopressin acetate increases the factor VIII activity Neutropenia/ Leukopenia
of patients with mild hemophilia A or von Willebrand disease. It o rHu G CSF- more frequently used
FIlgastrim
can be used in preparation for minor surgery such as tooth
Pegfilgrastim- long acting
extraction without any requirement for infusion of clotting
Lenograstim- mobilizer
factors if the patien has documented adequate response. o rHu GM CSF
Sagramostim
Recombinant Factor VIIa is approved for treatment of Thrombocytopenia
inherited or acquired hemophilia A or B with inhibitors, o Interleukin 11 (oprelvekin)- for thrombocytopenia
treatment of bleeding associated with invasive procedures in due to chemotherapy
congenital or acquired hemophilia, or factor VII deficiency. In o Thrombopoietin agonists (romiplostim,
the European Union, the drug is approved for treatment of elthrombopag)- for chronic thrombocytopenia (ITP
Glanzmann’s thrombasthenia. and TTP)
Hemolysis
o Vitamin K supplementation- phytonadione for
Bleeding due to Trauma and Surgical Procedure newborns
Fibrinolysis/ TPA Inhibitors o Plasma fractions (VIII, IX)- for hemophilia A, B
Indications: o TPA inhibitors (aminocaproic acid, tranexamic
o Minimize or prevent post-surgical bleeding acid)- for patients with excessive bleeding
(prostatic and orthopedic surgery)
o Minimize bleeding after tooth extraction III. REFERENCES
(especially hemophiliacs) 1. Katzung
Aminocaproic acid- inhibitor of fibrinolysis (similar to 2. 2019 A and C trans
lysine) 3. Lecture Notes
o Inhibits plasminogen activation by competing 4. Recordings
for lysine binding sites in plasminogen 5. Powerpoint
o Blocks interaction of plasmin with fibrin
o IV 5g LD for 30 mins; 1-1.25 g/hr PO for 8 hrs IV. QUIZ
Tranexamic acid- analog of ACA; same indication 1. TRUE or FALSE: DMT1 cotransporter carries ferric iron in the
o Administered orally/IV 15 mg/kg LD followed by gut.
30 mgkg q6
7 of 8
| 3.04 Coagulants/Hematinics
2. TRUE or FALSE: Hepcidin levels increase when iron levels
are adequate.
3. Which of the following medications will help normalize low
leukocyte levels (neutropenia)?
a. Iron
b. Darbepoietin
c. Folic acid
d. Filgrastim
4. Which of the following medications is a recombinant
interleukin-11 used to prevent thrombocytopenia?
a. Oprelvekin
b. Sargramostim
c. Darbepoietin
d. Filgrastim
3. What distinct morphological appearance can be seen on
developing RBCs of a patient with megaloblastic anemia?
a. Microcytic
b. Hypochromic
c. Macrocytic
d. Hyperchromic
4. What form of vitamin K is administered to newborns to
prevent vitamin K deficiency bleeding?
a. K1
b. K2
c. K3
d. K4
8 of 8
| 3.04 Coagulants/Hematinics
APPENDIX
Figure A1. Cobalamin (blue square) and Folic Acid (red square) Biochemical Reaction. Cobalamin is needed to convert Homocysteine to Methionine,
which leads to DNA Methylation/Synthesis. If there is no cobalamin, there would be a decrease in production of methionine and decrease in DNA
synthesis.
Figure A2. Cobalamin Biochemical Reaction. Two bioactive forms of cobalamin – (1) Methylcobalamin and (2) Adenosylcobalamin. Contributes to
energy in the mitochondria and health in myelin sheath. But most neurologic problems are because of methylcobalamin.
Table A1. Clinical Uses of Hematopoietic Growth Factors and Agents that mimic their actions.
9 of 8
| 3.04 Coagulants/Hematinics
10 of 8