Where is EPO made?
Interstitial Fibroblast Cells of the Kidney near peritubular capillaries
Hypoxia shifts the O2 dissociation curve
Anemia shifts the O2 dissociation curve
Polycythemia vera has what effect on EPO production? O2 binding curve?
Decreases EPO due to high oxygen environment; Shifts O2 curve Right
Altitude has what effect on EPO production?
Low O2 conditions will cause a _________ in EPO production and shift the O2 curve ______
What 2 types of cancer may result in EPO production?
Renal Cell Carcinoma and to a lesser extent HCC
Clinical Features of Iron Deficiency Anemia
Microcytic Anemia, Koilonychia, Pica
Polycythemia vera is characterized by
bone marrow disease that results in an abnormal increased # of RBCs
Normal Reticulocyte count is
High Reticulocyte count is
Koilonychia is pathognomonic of
Iron deficient Anemia
4 Types of Microcytic Anemia
Iron deficiency, Anemia of Chronic Disease, Sideroblastic, and Thalassemia
Microcytic Anemia is a MCV value of
The following are features of iron deficiency anemia: _________ Serum Ferritin _________ TIBC _________ Serum Iron _________ % Saturation _________ FEP
1. Decreased serum ferritin (stored Fe)
Reticulocyte counts should be corrected for
Corrected Reticulocyte Count Equation =
HCT/45 X reticulocyte count (45=normal HCT)
1st Sign of increased EPO
Reticulocyte response/release from BM
How long before immature reticulocytes become mature?
An inadequate reticulocyte response implies the marrow is
not working well, dysplastic, or aplastic
The following are features of Anemia of Chronic Disease: _________ Serum Ferritin _________ TIBC _________ Serum Iron _________ % Saturation _________ FEP
Increased Serum Ferritin > 30 Decreased TIBC Decreased Serum Iron Decreased % Saturation
The following are features of Sideroblastic Anemia: _________ Serum Ferritin _________ TIBC _________ Serum Iron _________ % Saturation
Increased Serum Ferritin Decreased TIBC Increased Serum Iron Increased % Saturation
The following are features of Thalassemia: _________ Serum Ferritin _________ TIBC _________ Serum Iron _________ % Saturation
Increased Serum Ferritin Decreased TIBC Increased Serum Iron Increased % Saturation
Prussian Blue Stain is used to stain ______; It is diagnostic for __________ type of Anemia
Iron; Sideroblastic Anemia - Ringed Sideroblasts
Causes of Iron Deficient Anemia
Malnutrition, Malabsorption (Crohn's), Blood Loss (PUD, carcinoma, hookworms), Pregnancy, Menorrhagia, Gastrectomy
4 Stages of Iron Deficient Anemia
1. Iron Stores Depleted 2. Serum Iron Depleted 3. Normocytic Anemia 4. Microcytic Anemia
TIBC is a measure of
Transferrin in blood
% Saturation is a measure of
% of Iron-bound Transferrin molecules in blood
Serum Ferritin is a measure of
stored iron w/in bone marrow macrophages and liver
Treatment for Iron Deficient Anemia
Ferrous Sulfate, Address any underlying conditions
What is PLUMMER-VINSON SYNDROME?
a condition characterized by Iron Deficient Anemia + Esophageal webbing + Atrophic glossitis (anemia, dysphagia, beefy-red tongue)
Describe the mechanism involved in Anemia of Chronic Disease
Chronic Disease/Cancer -> chronic inflammation -> acute phase reactants - Hepcidin
What is Hepcidin's role?
sequesters Iron into BM macrophages and histiocytes of liver and prevents its transport out; also suppresses EPO (thought to help eliminate a bacterial infection)
Stages of Anemia of Chronic Disease
Begins as Normocytic Anemia and progresses to Microcytic Anemia
Treatment for Anemia of Chronic Disease
Address underlying cause of inflammation; Exogenous EPO for subset of cancer patients
Describe the mechanism involved in Sideroblastic Anemia
Decreased protoporphyrin synthesis -> reduced heme production -> reduced Hb
Describe the rate-limiting step of protoporphyrin synthesis
1st step: converts Succinyl-CoA to Aminolevulinic Acid (ALA); catalyzed by ALA synthase + required Cofactor Vitamin B6
ALA is converted to ____________ by __________
porphobilinogen by ALA Dehydrogenase
Final Step in protoporphyrin synthesis
Ferrochelatase links protoporphyrin and Iron to form HEME
Final Step in protoporphyrin synthesis occurs
erythroid precursor MITOCHONDRIA (surrounding nucleus)
What else is occurring during protoporphyrin synthesis
Iron transport to erythroid precursor MITOCHONDRIA
In Sideroblastic anemia where there is decreased protoporphyrin synthesis, what occurs in the erythroid precursor cell?
Iron accumulates in the mitochondria creating an iron-laden ring around the nucleus --> eventually the toxic effects of iron cause cell death and Iron leaks into marrow (taken up by macrophages) and blood
The Iron-laden ring around the nucleus of erythroid precursors are characteristic of __________ cells
The most common congenital cause of Sideroblastic anemia is:
ALA S enzyme defect
Common causes of acquired Sideroblastic anemia are:
Alcoholism, Lead Poisoning, Vitamin B6 deficiency
How can Alcoholism lead to Sideroblastic anemia?
Direct Mitochondrial Poison
How can Lead Poisoning lead to Sideroblastic anemia?
Denatures the enzymes: ALA D and Ferrochelatase
How can Vitamin B6 deficiency lead to Sideroblastic anemia?
Necessary Cofactor for ALA S, inhibits the RATE-LIMITING Step of protoporphyrin synthesis
What Drug Therapy has been linked to Sideroblastic anemia due to its effect on Vitamin B6 depletion?
Isoniazid for TB Tx
Describe the mechanism involved in Thalassemia
Decreased production of globin chains
Anemia of Chronic Disease is common, occurring in ____% of Microcytic anemias
30%; usually accompanied by little to no morphological changes on peripheral smear
Anemia of Chronic Disease lasts
longer than 1-2 months
Causes of Anemia of Chronic Disease
Infection, Non-infectious inflammation, Malignancy
Hepcidin sequesters Iron and ALSO
In 25% of cases, the only chronic diseases present in a patient w/ Anemia of Chronic Disease
Diseases such as: congestive heart failure and diabetes mellitus
In Anemia of Chronic Disease, anemia is usually
mild-moderate w/ HCT > 25; mainly due to EPO repression by Hepcidin
Hb, HCT, WBC count, Platelet count, RBC count Calculate: MCV, MCH, RDW (NOT LAP)
Hemoglobin F shifts the O2 binding curve
LEFT - driving EPO production and Hb synthesis
Most common anemia in babies?
Iron deficiency since breast milk lacks Iron
HbF tetramer is composed of
2-alpha and 2-gamma
Extramedullary Hematopoiesis occurs where in fetuses and premature infants
yolk sac -> liver -> BM
What anemic condition results in Extramedullary Hematopoiesis in liver, spleen, face, and skull?
HbF is replaced by _____ ~ ____%
HbA ~97%; HbF may persist at ~1%
HbA2 may present at ~____%
HbF is broken down in the months following birth by
Splenic histiocytes thus “physiologic jaundice”
Explain how HbF/Fetal RBC breakdown may result in "physiologic jaundice"
RBC/HbF is broken down by splenic histiocytes. Hb is broken into heme (Fe and protoporphyrin) and globin. Protoporphyrin is then broken down into bilirubin, unconjugated bilirubin is fat-soluble (+serum albumin), enters the blood & is delivered to the liver for conjugation. If the concentration of unconjugated bilirubin exceeds the liver's ability to conjugate --> a build up of unconjugated bilirubin in blood results in "physiologic anemia"
Reticulocyte response to anemia would result in a CRC of > ___%
In anemia, a CRC
dysplastic or aplastic BM or failure to produce EPO
How can alcohol lead to macrocytic anemia?
DIRECT toxic effects causing macrocytic anemia
binds free Hb in blood and returns it to to the liver (saves a small amount of Hb)
Hb taken up by renal tubular cells, destroys Hb and binds as Hemosiderin in cell. Sloughing of renal tubular cells results in Hemosiderinuria
Hemosiderinuria is a common lab finding in
Intravascular Hemolytic Normocytic Anemia - PNH, G6PD def.,
HbA tetramer is composed of
alpha2, beta2 (97%)
HbA2 tetramer is composed of
alpha2, delta2 (~3%)
Children usually have lower Hb levels because they typically have higher _______ and ______
Phosphorus levels and 2,3-BPG
2,3-BPG shifts the O2 dissociation curve to the
Parvovirus B19 infects
Risk of aplastic crisis from a Parvovirus B19 infection occurs in
beta-thalassemia Major, Hereditary Spherocytosis, Sickle Cell Anemia
DNA fragments in RBCs - indicative of splenic dysfunction
What condition is likely to have Howell-Jolly bodies appear following Treatment?
The mechanism of Hereditary Spherocytosis is
defective RBC cytoskeletal proteins resulting in cell shape changes (biconcave to sphere) and membrane blebs that are cleaved by splenic histiocytes
Which hormone drives EPO production?
In what condition would you see a large number of nucleated RBCs?
beta-thalassemia Major - due to extra medullary erythropoiesis
What inherited genetic mutations may be selected for by their ability to protect against Plasmodium falciparum Malaria ?
Sickle Cell Anemia, Thalassemia, G6PD deficiency