Rbc Disorders Part I

Front 1

Where does iron absorption occur?

Back 1

duodenum

Front 2

Which form of iron is more readily absorbed

Back 2

heme (meat)

Front 3

Describe transport and storage of iron

Back 3

• enterocytes transport iron across cell membrane into blood via ferroportin
• transferrin transport iron in blood and delivers it to liver and bone marrow macrophages for storage
• stored intracellular iron is bound to ferritin (also prevents ROS formation via Fenton rxn)

Front 4

Causes of Microcytic Anemia

Back 4

Problem w/ Normal Hb production

1) Iron deficiency Anemia - Fe deficiency

2) Anemia of Chronic Disease - Fe locked up in Macrophages

3) Sideroblastic Anemia - protoporphyrin def.

4) Thalassemia - Globin defect

Front 5

Most important regulatory step in iron uptake?

Back 5

Ferroportin - transport of iron into blood (located on basolateral surface of enterocyte)

Front 6

TIBC

Back 6

measures amount of transferrin in blood

Front 7

Serum Iron

Back 7

Measure of iron in blood (this iron WILL be bound to transferrin)

Front 8

% Saturation

Back 8

percentage of transferrin bound to Fe

Front 9

Serum Ferritin

Back 9

amount of iron bound in liver and BM macrophages

Front 10

Lab findings in 1st stage of iron deficiency

Back 10

Storage iron is depleted 1st

↓ ferritin b/c stored Fe from hepatocytes/BM macrophage is exhausted

↑ TIBC b/c liver makes more transferrin to try and pick up more Fe

Front 11

Lab findings in 2nd stage of iron deficiency

Back 11

Serum iron is depleted next (2nd)

Serum Fe ↓(bound to transferrin)->

% Sat of transferrin ↓

Front 12

Lab findings in 3rd stage of Fe deficiency

Back 12

Normocytic anemia

Bone marrow makes fewer, but normal sized, RBCs

Front 13

Lab findings in 4th stage of iron deficiency

Back 13

Microcytic, hypochromic anemia

Erythroblasts divide extra time (Microcytic) in hopes of maintaining close to Normal [Hb]

Front 14

clinical features of iron deficiency

Back 14

1) Anemia

2) Koilonychia (spoon shaped nails)

3) Pica (chew on abnormal items->eat dirt or other things in search of Fe)

Front 15

Describe RDW & FEP in Iron deficiency anemia

Back 15

↑ RDW (RBC Distribution Width) ->spectrum of size of RBC's) due to initial normocytic RBC's mixing with microcytic, so the distribution of width is larger than Normal

↑FEP (Free Erythrocyte Protoporphyrin) - unbound due to the lack of Fe to bind to it

Front 16

Plummer-Vinson syndrome

Back 16

1) Fe deficiency Anemia presents w/

2) Esophageal webs

3) Atrophic glossitis (smooth tongue)

Front 17

Anemia of Chronic Disease pathophysiology

Back 17

chronic inflammation leads to

↑ acute phase reactant: Hepcidin

Hepcidin sequesters Fe in storage sites, preventing transfer of Fe from macrophages to erythroid precursors and suppressing EPO production

Front 18

Most common type of anemia in hospitalized patients

Back 18

Anemia of chronic disease (associated with chronic inflammation e.g. endocarditis or autoimmune conditions or cancer)

Front 19

Causes of Nutritional Deficiency of Fe

Back 19

1. Dietary insufficiency

2. Malabsorption

3. Gastrectomy - ↓Acid b/c part of stomach removed -> less Fe2+ (bioavailable b/c absorbable) since Acid necesary for reducing Fe3+ to Fe2+

Front 20

Populations suceptible to Fe Deficiency

Back 20

1) Infants - Breast feeding (milk is low in Fe)

2) Children - poor diet

3) Adults -

♀- menorrhagia (blood loss) & pregnancy (deficiency b/c fetus uses a lot of Fe)

♂- peptic ulcer dz. (blood loss)

4) Elderly -

Rich countries: colon polyps/carcinoma

Developing countries: hookworm (Necatur/Ancylostoma) due to blood loss

Front 21

Lab findings in anemia of chronic disease

Back 21

↑ ferritin (b/c all Fe is bound up to ferritin)

↓ TIBC - b/c Liver ↓Transferrin levels when Ferritin levels are HIGH

↓ serum Fe - b/c Erythroblasts use up a lot of Fe from blood

↓ %sat - b/c a lot of Fe removed from Transferrin

↑ FEP (Free Erythrocyte Protoporphyrin b/c ↓ heme due to low available Fe)

↑FEP b/c Heme = Fe+2 + Protoporphyrin
Since serum Fe is reduced, but protoporphyrin is Nrml, there is elevated protoporphyrin

Front 22

Sideroblastic Anemia pathophysiology

Back 22

defective protoporphyrin synthesis
Remember: Heme = Iron + Protoporphyrin

If protoporphyrin is bad, then problem making Heme->RBC's are going to be smaller (Microcytic Anemia)

Fe will be transferred from BM Macrophages to Erythroblast Mitochondria and get stuck there b/c Protoporphyrin Deficiency interferes w/ Heme production

Front 23

Rate limiting step in protoporphyrin synthesis?

Back 23

In Erythroblast Cytosol

Conversion of:

Succinyl-CoA -> Aminolevulinic Acid (ALA)

by the enzyme:

Aminolevulinic Acid Synthetase (ALAS)

Cofactor of ALAS: Vit B6 (pyridoxine)

Front 24

Classic histological finding in sideroblastic anemia? What causes them?

Back 24

Ringed Sideroblasts

-Accumulation of Fe in Mitoch. surrounding Nucleus of Erythroblasts

-Fe trapped b/c deficiency of functional Protoporphyrin

Front 25

What stain marks iron?

Back 25

Prussian Blue

Front 26

Congenital form of sideroblastic anemia caused by?

Back 26

Enzyme defect in ALAS (Aminolevulinic Acid Synthetase): the rate limiting step in Protoporphyrin/Heme Synthesis

Front 27

Acquired form of sideroblastic anemia caused by?

Back 27

1) Alcohol - Mitochondrial poison (dissolves mitochon. membranes) that damages production of Protoporphyrin

2) Lead poisoning - Denatures ALAD & Ferrochelatase

3) Vitamin B6 deficiency - ALAS cofactor

Front 28

What drug commonly causes vitamin B6 deficiency?

Back 28

Isoniazid treatment (used for TB)

Front 29

Lab findings in sideroblastic anemia

Back 29

Fe Overloaded state in Erythroblast Mitoch. Massive Fe stores generate ROS

ROS damages erythroblast->cell lysis

Fe leaks out

Fe picked up by BM MΦ's->

Results in ↑ Ferritin->

↓ TIBC

B/c some Fe leaks out into blood stream->

↑ serum Fe and ↑% sat

↑ ferritin, ↓ TIBC (ferritin & TIBC are always opposite b/c liver production of transferrin is stimulated by low ferritin levels)
↑ serum iron, ↑ % sat

Front 30

Another Fe Overloaded State w/ very similar lab findings to Sideroblastic Anemia

Back 30

Hemochromatosis (so much Fe that it is out of proportion to Normal levels of Protoporphyrin)

Front 31

What disease are people who are carriers for thalassemia protected against?

Back 31

Plasmodium falciparum malaria

Front 32

3 types of hemoglobin

Back 32

α2β2 - adult (HbA)
α2γ2 - fetal (HbF) (Fetus says "Gaga")
α2δ2 - (HbA2) (Normally small %)

Front 33

genetics of alpha thalassemia...

Back 33

4 total alpha globin alleles - 2 on each copy of chromosome 16

problem due to gene DELETION of at least 1 allele

Front 34

cis vs. trans deletion alpha thalassemia

Back 34

cis-both deletions occur on same chromosome; seen in Asians (higher risk for severe thalassemia in offspring)

trans-deletion seen in Africans (one deletion occurs on each chromosome)

Front 35

HbH

Back 35

Occurs when 3 genes are deleted in alpha thalassemia; B chains form tetramers (HbH) that damage RBCs; HbH is seen on electrophoresis

Front 36

HbBarts

Back 36

Gamma subunit tetramer (B/c insufficient copies of Alpha globin)

incompatible with life

can be seen on electrophoresis

Front 37

genetics of beta thalassemia

Back 37

• usually due to gene mutations (point mutations in promotor or splicing sites); seen in individuals of African and Mediterranean descent
• 2 β genes are present on chromosome 11; mutations result in absent (β⁰) or diminished (β⁺) production of β globin chain

Front 38

Beta thalassemia minor

Back 38

• (β/β⁺)
• mildest form of disease
• usually asymptomatic with increased RBC count

Front 39

What is seen on blood smear in beta thalassemia minor? Electrophoresis?

Back 39

Smear: Microcytic, hypochromic RBCs and target cells

Electrophoresis: slightly decreased HbA with increased HbA2 (5%, normal 2.5%) and HbF (2%, normal 1%)

Front 40

Pathophysiology beta thalassemia major

Back 40

• Unpaired alpha chains precipitate and damage RBC membrane, resulting in ineffective erythropoiesis and extravascular hemolysis (removal of circulating RBCs by spleen)
• Massive erythroid hyperplasia

Front 41

Consequences of massive erythroid hyperplasia

Back 41

• Expansion of hematopoiesis into skull (reactive bone formation leads to 'crewcut' appearance on x-ray) and facial bones ('chipmunk facies')
• Extramedullary hematopoiesis with hepatosplenomegaly
• risk of aplastic crisis with parvovirus B19 infection of erythroid precursors

Front 42

What does blood smear show in beta thalassemia major

Back 42

microcytic, hypochromic RBCs with target cells and nucleated red blood cells

Front 43

What does electrophoresis show in beta thalassemia major?

Back 43

HbA2 and HbF with little or no HbA

Front 44

When does beta thalassemia major present?

Back 44

presents with severe anemia a few months after birth (high HbF is temporarily protective)

Front 45

Most common cause of macrocytic anemia

Back 45

• folate or vitamin B12 deficiency (megaloblastic anemia), which impairs synthesis of DNA precursors
• other causes (without megaloblastic change) include alcoholism, liver disease, and drugs (e.g. 5-FU)

Front 46

Where is folate absorbed?

Back 46

Jejunum

Front 47

Causes of folate deficiency

Back 47

• Poor diet (alcoholics, elderly)
• Increased demand (pregnancy, cancer, hemolytic anemia)
• Folate antagonists (methotrexate, which inhibits dihydrofolate reductase)

Front 48

Clinical/lab findings in folate deficiency

Back 48

• Macrocytic RBCs and hyper segmented neutrophils (>5 lobes)
• Glossitis
• decreased serum folate
• increased serum homocysteine
• normal methylmalonic acid

Front 49

Where is vitamin B12 absorbed?

Back 49

Ileum

Front 50

Most common cause of B12 deficiency?

Back 50

• Pernicious anemia (autoimmune destruction of parietal cells) leads to IF deficiency
• other causes include pancreatic insufficiency and damage to terminal ileum (e.g. Crohn disease or fish tapeworm)
• dietary deficiency rare except in vegans

Front 51

Clinical/lab findings in B12 deficiency

Back 51

• Macrocytic RBCs and hyper segmented neutrophils (>5 lobes)
• Glossitis
• increased serum homocysteine
• increased methylmalonic acid (leads to subacute combine degeneration of spinal cord due to impairment of spinal cord myelinization - poor proprioception and vibratory sensation, spastic paresis)
• decreased serum B12

Front 52

Causes of normocytic anemia

Back 52

Increased peripheral destruction or underproduction (reticulocyte count helps to distinguish between these)

Front 53

How are young RBCs identified on blood smear?

Back 53

Larger cells with bluish cytoplasm (due to residual RNA)

Front 54

Normal reticulocyte count (RC)

Back 54

• 1-2%
• properly functioning marrow responds to anemia by increasing RC to >3% (indicating peripheral destruction); <3% indicates underproduction

Front 55

Extravascular hemolysis

Back 55

destruction of RBCs by RES (macrophages of spleen, liver, and lymph nodes)

Front 56

Clinical/lab findings in extravascular hemolysis

Back 56

• Anemia with splenomegaly
• jaundice due to unconjugated bilirubin
• increased risk for bilirubin gallstones
• marrow hyperplasia with corrected RC >3%

Front 57

Clinical/lab findings in intravascular hemolysis

Back 57

• Hemoglobinemia
• Hemoglobinuria
• Hemosiderinuria (renal tubular cells pick up some of the Hb that is filtered into urine and break it down into Fe, which accumulates as hemosiderin; tubular cells eventually shed resulting in hemosiderinuria)
• Decreased serum haptoglobin

Front 58

Hereditary spherocytosis

Back 58

• Inherited defect of RBC cytoskeleton-membrane tethering proteins (most commonly involves ankyrin, spectrin, or band 3)
• Membrane blebs are formed and lost over time
• Loss of membrane renders cell round instead of disc-shaped
• Spherocytes are less able to maneuver through splenic sinusoids and are consumed by splenic macrophages, resulting in anemia

Front 59

Clinical/lab findings in hereditary spherocytosis

Back 59

• Spherocytes with loss of central pallor
• increased RDW
• increased MCHC (because size decreases but Hb concentration stays the same)
• Splenomegaly, jaundice with unconjugated bilirubin, and increased risk of bilirubin gallstones (extravascular hemolysis)
• Increased risk for aplastic crisis with parvovirus B19 infection of erythroid precursors

Front 60

How is hereditary spherocytosis diagnosed?

Back 60

Osmotic fragility test, which reveals increased spherocyte fragility in hypotonic solution