Pathoma Chapter 5

Front 1

Iron absorption occurs in the?

Back 1

duodenum

Front 2

Iron consumed in two dietary forms

Back 2

Heme form(meat) and non-heme form(vegetables)

heme form more readily absorbed

Front 3

Describe transport and storage of iron

Back 3

1) Enterocytes take up Fe from gut lumen

2) Presence of ferroportin (transporter) on the basolateral side is the regulatory step that determines if Fe is absorbed into blood

3) Iron is then bound to transferrin in bloodstream where it is delivered to hepatocytes and bone marrow macrophages (MUST be bound to prevent ROS generation via Fenton rxn: Fe2+ + H2O2 ----> Fe3+ + ~OH + OH-)

4) Stored intracellular iron is bound to ferritin (also prevents ROS formation)

Front 4

Causes of Microcytic Anemia

Back 4

Problem w/ Nomral 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

Anemia of Chronic Disease - Iron locked away in macrophages during Chronic inflammatory states

Front 5

Most common nutritional deficiency in the world?

Back 5

Iron deficiency

Front 6

Most important regulatory step in iron uptake?

Back 6

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

Front 7

TIBC

Back 7

measures amount of transferrin in blood

Front 8

Serum Iron

Back 8

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

Front 9

% Saturation

Back 9

percentage of transferrin bound to Fe

Front 10

Serum Ferritin

Back 10

amount of iron bound in liver and BM macrophages

Front 11

Lab findings in 1st stage of iron deficiency

Back 11

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 12

Lab findings in 2nd stage of iron deficiency

Back 12

Serum iron is depleted next (2nd)

Serum Fe ↓(bound to transferrin)->

% Sat of transferrin ↓

Front 13

Lab findings in 3rd stage of Fe deficiency

Back 13

Normocytic anemia

Bone marrow tries to maintain Normal [Hb], but lacks Fe to make enough RBC's -> Anemia BUT they are normocytic!

Front 14

Lab findings in 4th stage of iron deficiency

Back 14

Microcytic, hypochromic anemia

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

Front 15

clinical features of iron deficiency

Back 15

1) Anemia

2) Koilonychia (spoon shaped nails)

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

Front 16

Describe RDW & FEP in Iron deficiency anemia...

Back 16

↑ 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 17

Plummer-Vinson syndrome

Back 17

1) Fe deficiency Anemia presents w/

2) Esophageal webs (obstruction in esophagus due to protrusions of mucosa-> poorly chewed foods can get stuck->dysphagia) &

3) Atrophic glossitis (smooth tongue)

Front 18

Patient presents with anemia, dysphagia, beefy red tongue

Back 18

Plummer-Vinson syndrome

esophageal webs
atrophic glossitis (smooth tongue)
iron deficiency anemia

Front 19

Anemia of Chronic Disease pathophys

Back 19

chronic disease --> chronic inflammation -->

↑ acute phase reactant: Hepcidin

Hepcidin sequesters Fe in storage sites, preventing transfer of Fe from macrophages to erythroid precursors

Chronic dz. also suppresses EPO production

Front 20

Iron deficiency occurs in cases of?

Back 20

1) Nutritional Deficiency

2) Blood loss

Front 21

Causes of Nutritional Deficiency of Fe

Back 21

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 22

Stages of Fe Deficiency

Back 22

1) Storage Fe depleted (b/c erythroblasts use up stores for Hb production) -> ↓ferritin BUT ↑TIBC (b/c liver senses low Fe stores and produces more transferrin to pick up any available Fe)

2) Serum Fe ↓ and % Saturation of Ferritin ↓ (18% instead of Nm: 33%) b/c serum Fe used

3) Normocytic Anemia - VERY EARLY STAGE OF Fe deficiency Anemia = Erythroblast can't make enough Hb, so just makes fewer cells, but they are normal in size/[Hb]

4) Microcytic/Hypochromic Anemia - As Fe defeciency becomes severe, much less Hb is made, so Erythroblasts divide extra times (forming smaller RBC's) in order to preserve minimum [Hb]. However, it will still be less than Nm -> Increased zone of central pallor due to ↓[Hb]

Front 23

Tx for Fe deficiency Anemia

Back 23

1) Find out cause (e.g. if Elderly Male: rule out carcinoma of colon)

2) Supplement Fe (Ferrous sulfate)

Front 24

Populations suceptible to Fe Deficiency

Back 24

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 25

Most common cause Anemia in Hospitalized Pts.

Back 25

Anemia of Chronic Disease

Front 26

Anemia of Chronic Dz. caused by:

Back 26

Chronic Inflammation - Can be chronic infection but often Autoimmune

Cancer - will also trigger Chronic Inflammation

Front 27

Why body evolved to release Hepcidin during Chronic inflammation

Back 27

B/c body lacks mechanism to differentiate Chronic Inflammation induced by Infection vs. Autoimmune/Cancer->

sequesters Fe that could be used by bacteria to grow/divide->

to limit spread of infection->

Consequence: Microcytic Anemia

Happens in chronic inflammatory states even if no actual infection exists

Front 28

Lab findings in anemia of chronic disease

Back 28

↑ 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 29

Tx for Anemia of Chronic Dz

Back 29

1) ↓ Inflammation-> ↓Hepcidin-> Erythroblasts can use stored Fe

2) EPO administration b/c Hepciding caused ↓EPO. This is particularly helpful for cancer pts. (probably b/c additional EPO downregulation mechanisms exist)

Front 30

Sideroblastic Anemia pathophys

Back 30

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 31

Rate limiting step in protoporphyrin synthesis?

Back 31

In Erythroblast Cytosol

Conversion of:

Succinyl-CoA -> Aminolevulinic Acid (ALA)

by the enzyme:

Aminolevulinic Acid Synthetase (ALAS)

Cofactor of ALAS: Vit B6 (pyridoxine)

Front 32

Second Major Step of Heme Synthesis

Back 32

In Erythroblast Cytosol

Conversion of:

Aminolevulinic Acid(ALA) -> Porphobilinogen

by the enzyme:

ALAD (ALA Dehydrogenase)

Front 33

Final step of protoporphyrin synthesis? Where does it occur?

Back 33

In Erythroblast Mitochondria

Attachment of:

Protoporphyrin + Fe -> Heme

by the enzyme:

Ferrochelatase

Front 34

Classic histological finding in sideroblastic anemia? What causes them?

Back 34

Ringed Sideroblasts

-Accumulation of Fe in Mitoch. surrounding Nucleus of Erythroblasts

-Fe trapped b/c deficiency of functional Protoporphyrin

Front 35

What stain marks iron?

Back 35

Prussian Blue

Front 36

Congenital form of sideroblastic anemia caused by?

Back 36

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

Front 37

Acquired form of sideroblastic anemia caused by?

Back 37

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

2) Lead poisoning - Denatures ALAD & Ferrochelatase

3) Vitamin B6 deficiency - ALAS cofactor

Front 38

What drug commonly causes vitamin B6 deficiency?

Back 38

Isoniazid treatment

(1. INH binds/inactivates pyridoxine

2. INH inhibits the enzyme that activates pyridoxine)

Front 39

Lab findings in sideroblastic anemia...

Back 39

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 40

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

Back 40

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

Front 41

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

Back 41

Plasmodium falciparum malaria

Front 42

3 types of hemoglobin

Back 42

Alpha 2, Beta 2 - adult (HbA)
Alpha 2, Gamma 2 - fetal (HbF) (Fetus says "Gaga")
Alpha 2, Delta 2 - A2 (HbA2) (Normally small %)

Front 43

genetics of alpha thalassemia...

Back 43

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

problem due to gene DELETION of at least 1 allele

Front 44

alpha thalassemia types common on what continents?

Back 44

cis-deletion of alpha alleles-Asia (DELETIONs on same Ch 16 copy (e.g. both on maternal Ch 16))->more likely to lead to Alpha Thalassemia Major->explains Higher incidence of miscarriage in Asia

trans-deletion seen in Africans (DELETIONs on opposite Ch 16 copies (1 on maternal Ch 16, and the other on paternal Ch 16)

Front 45

HbH

Back 45

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

can be seen on electrophoresis

Front 46

HbBarts

Back 46

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

incompatible with life

can be seen on electrophoresis

Front 47

genetics of beta thalassemia

Back 47

problem due to gene MUTATION of 1 of 2 alleles of Beta Globin (1 on each copy of Chromosome containing them)

Front 48

isolated increase in HbA2

Back 48

Beta Thalassemia Minor
(Beta-/Beta+) -> only 1 allele of Beta is mutated

Front 49

Hepatosplenomegaly with evidence of hematopoiesis in facial bones and skull

Back 49

Massive Erythroid Hyperplasia
Due to Beta Thalassemia Major(Beta0/Beta0)
Can also happen in Sickle Cell Anemia

"Crewcut appearance of skull"
Chipmunk like facial structure

Front 50

Aplastic crisis

Back 50

due to parvovirus B19 infection in Beta Thalassemia Major patients

parvovirus B19 invades and destroys RBC precursors and halts the red cell production. Since Beta Thallassemia Major already causes few functional RBC's, this additional destruction causes Aplastic Crisis (severe anemia)

Front 51

Target cells

Back 51

present in Beta Thalassemia Minor & Major

also post splenectomy b/c cells w/ extra cytoplasm are not removed/destroyed by Splenic MΦ's

Front 52

Target cells in thalassemia a result of...

Back 52

Low levels of Hb in the RBC. This is like "taking the air out of a basketball" and allows the center to bleb out.

Front 53

Characteristic of Beta Thalassemia Major

Back 53

Nucleated RBC's - b/c RBC's are pushed out before completely mature b/c of Severe anemia

Front 54

Electrophoresis findings for Beta Thalassemia Major

Back 54

no HbA
Only see HbA2 and HbF

Front 55

Macrocytic Anemia

Back 55

due to folate or vitamin B12( cobalamin) deficiency (megaloblastic anemia)

THF-M --> VitB12-M --> Methionine (B/c Homocysteine picks up Methyl group)
(transfer of methyl groups)

Front 56

hypersegmented neutrophils

Back 56

neutrophils with greater than 5 lobes

a result of folate/B12 deficiency - b/c Organnelles growing, but not enough Nucleic Acids required for division

Front 57

Epithelial cell change in Folate/B12 deficiency

Back 57

Megaloblastic change in all rapidly dividing cells

Front 58

A drug that can cause macrocytic anemia

Clinical diseases that can cause it?

Back 58

5-Fluorauracil - Thymidylate synthase (TS) inhibitor

Interrupting the action of TS blocks synthesis of the pyrimidine thymidine, which is required for DNA replication

Alcohol and Liver disease can also cause macrocytic anemias but for completely different reasons

Alcohol - Directly damages BM

in Liver disease - Lecithin—cholesterol acyltransferase (LCAT) activity may be decreased (LCAT converts free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of a lipoproteinparticle-> HDL) -> increased cholesterol to phospholipid ratio, producing an absolute increase in surface area of RBC membranes

notably, would not see hypersegmented nuclei or megaloblastic change in other cells

Front 59

Where is folate absorbed?

Back 59

Jejunum

Front 60

Glossitis a/w?

Back 60

Folate deficiency and Vitamin B12 deficiency b/c cells can not divide properly b/c these are high turnover cells that require substantial nucleic acid synthesis that relies on Folate being available. Vit B12 contributes y removing CH3 from THF and transferring it to Homocysteine

Front 61

what kind of leukocyte is characteristic of macrocytic anemias?

Back 61

Hypersegmented neutrophils

folate deficiency lab findings:
macrocytic RBC's
Glossitis
decreased serum folate
increased serum homocysteine
Normal methylmalonic acid

Front 62

Methylmalonic Acid usefulness as a lab test?

Back 62

Differentiates Vit B12 deficiency vs. Folate deficiency

MMA Normal in Folate Deficiency b/c conversion of MMA -> Succinyl CoA relies on Vit B12 and this is not affected in folate deficiency

Front 63

Where is intrinsic factor made? Where are they located?

Back 63

gastric Parietal cells in body of stomach

Front 64

Describe path of Vitamin B12 Absorption

Back 64

1) Dietary form is bound to animal protein which is then cleaved by amylase from salivary glands

2) Salivary gland also secrete R-binder which stabilized Vit B12 until it reaches stomach

3) In Small Intestine, pancreastic proteases cleave R-binder

4) Vit B12 then binds IF from gastric parietal cells & together they are absorbed

4) IF-B12 complex then absorbed in ileum.

Front 65

Where is B12-IF complex absorbed?

Back 65

Ileum

Front 66

pernicious anemia arises from?

Back 66

autoimmune destruction of parietal cells, which can now not produce IF necessary for Vit B12 absorption

This is called Pernicious, b/c it takes a long time for Vit B12 stores to be exhausted

Front 67

Causes of vitamin B12 deficiency?

Back 67

1) Pancreatic insufficiency - inability to cleave Vit B12-R-binder complex

2) Absorption Problem due to Damage to terminal ileum due to Crohn's disease or Diphyllobothrium latum (tapeworm)

3) Dietary deficiency is RARE except for vegans

Front 68

deficiency in vegans

Back 68

Vitamin B12

Front 69

What causes Subacute combined degeneration of spinal cord. What is the presentation?

Back 69

Vitamin B12 deficiency-> Buildup of Methylmalonic Acid in Oligodendrocytes of Spinal Cord causing damage (B/C Vit B12 is a necessary co-factor in conversion of Methylmalonic Acid to Succinyl CoA)

Degeneration of dorsal and lateral columns leading to poor proprioception and vibratory sensation (dorsal column) as well as spastic paresis (lateral corticospinal tract)

Front 70

Spastic Paresis occurs due to damage where in the spinal cord?

Back 70

lateral corticospinal tract (CorticoMotor pathway)

Front 71

proprioception and vibratory sensation dysfunction is due to damage where in the spinal cord?

Back 71

dorsal column (DCML-Dorsal Column Medial Lemniscus Pathway)

Front 72

What two reactions require Vitamin B12

Back 72

1) Conversion of Methylmalonic Acid to Succinyl CoA which is important for fatty acid synthesis (This is why Vit B12 deficiency leads to neuropathy-b/c MMA builds up/leads to damage in oligodendrocytes of spinal cord)

2) Transfer of CH3 (methyl group) from THF. B12-CH3 then transfers to Homocysteine which turns into Methionine

Front 73

Reasons for Folate Deficiency

Back 73

1) Dietary Deficiency due to poor diet- Elderly, Alcoholics

2) Increased Demand - Hemolytic Anemia, Pregnancy, Cancer

3) Methotrexate - Competitively Inhibits dihydrofolate reductase (DHFR- enzyme necessary for THF synthesis), with a one thousand-fold greater affinity for DHFR than that of folate

DHFR catalyses the conversion of dihydrofolate to the active tetrahydrofolate

B/C Folic acid is needed for the de novo synthesis of the nucleoside thymidine, and is essential for purine and pyrimidine base biosynthesis, Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins

Front 74

Lab findings of Vit B12 deficiency

Back 74

↓ Vit B12
↑ Methylmalonic acid
↑ Homocysteine

Front 75

The P's of Parietal Cells

Back 75

1) Proton Pumps

2) pH is lowered b/c secrete H+ (acid)

3) Pernicious Anemia - Autoimmune destruction of Parietal Cells b/c IF no longer produced-> Vit B12 def.

4) Pink - compared to more bluish Chief Cells

Front 76

MCV in Microcytic Anemia

Normal MCV Range

MCV in Macrocytic Anemia

Back 76

< 80

80-100

> 100

Front 77

Describe reticulocyte

Back 77

Slightly larger than normal RBC with a bluish hue due to residual RNA from protein synthesis

Front 78

Normocytic Anemia

Back 78

No deficiency in the lack of RBC components, therefore the RBC's are of Normal size, but the Anemia is due to

1) Destruction of RBC's outside of BM (Retic Count should Incr)

2) Decreased production in BM (Retic Count will be low)

Front 79

Reticulocyte correction in anemia

Back 79

Nml. Reticulocyte Percentage in Anemia should be >3% (this suggests that BM is responding properly to anemia by generating new RBC's). However, b/c in cases of anemia %Reticulocyte can be artificially high b/c of low RBC's (e.g. 2/100 now 2/50 ->the number of Reticulocytes has NOT Incr., but the % has artificially)

For this Reason, we take the Retic% and multiply it by (Hematocrit/45). B/c Nml. Hematocrit is 45, and in Anemia Hematocrit (or % of Blood VOlume taken by RBC's) will be low, therefore correcting the calculation

Front 80

Types of Hemolysis

Back 80

Intravascular Hemolysis - inside Blood Vessels

Extravascular Hemolysis - RBC's destroyed in Reticular Endothelial System by Macrophages in the Spleen/Liver/Lymph nodes

In both, Reticulocyte COunt will Incr., b/c BM functioning properly

Front 81

Describe digestion of RBC's by macrophages

Back 81

Macrophages of RES (Reticular Endothelial System digest RBC's and breakdown their components)

Globin --> Amino Acids
Heme ---> Fe (recycled) + protoporphyrin
protoporphyrin --> unconjugated bilirubin

unconjugated bilirubin binds albumin (b/c fat soluble) and is delivered to liver

In liver, unconjugated bilirubin is conjugated and excreted into bile

Front 82

Clinical presentation of extravascular hemolysis

Back 82

1) Anemia b/c RBC's are being destroyed in RES (Reticular Endothelial System)

2) Splenomegaly (hypertrophy due to excess digestion of RBC's by Macrophages)

3) Jaundice due to excess unconjugated bilirubin in blood (b/c overwhelms liver's processing ability to conjugate bilirubin, unconjugated bilirubin bound to albumin builds up in blood)

Increased risk of bilirubin gallstones ->b/c liver will be pumping bile into the gallbladder with VERY high [conjugatedbillirubin] -> the bile is super saturated with conjugated bilirubin that can form stones

Front 83

Lab findings for intravascular hemolysis

Back 83

RBC's lysed and Hb pours out into blood. The small amounts of Haptoglobinin blood bind up some of the Hb and complex with it-> low levels of free floating Haptoglobin. The rest of Hb accumulates in blood->Hemoglobinemia. It will ultimately make its way to kidneys/urine -> Hemoglobinuria.

-- Hemoglobinuria
-- Hemoglobinemia
-- Hemosiderinuria - renal tubular cells pick up some hemoblobin and digest the Globin/Heme, leaving Fe to accumulate in Renal Tubular cells (PCT) as hemosiderin. When the renal cells turn over, hemosiderin shows up in the urine.
-- Decreased serum haptoglobin - b/c free haptoglobin complexes with some of the Hb in blood

Front 84

Most common protein defects causing hereditary spherocytosis

Back 84

spectrin, ankyrin, band 3.1 - Anchoring proteins connecting RBC cytoskeleton to its PM (Plasma Membrane)

These cause cytoskeletal defects that result in the formation of blebs that portrude from plasma membrane.

These Blebs are removed by MPhages, leading to loss of membrane.

B/c cytoplasm stays normal, but PM is progressively disappearing, the RBC loses its biconcave disks shape, in favor of a sphere.

These spherocytes, also become smaller with time as blebs form/removed by Mphages.

These Spherocytic RBC's function normally but lose their flexibility/ability to maneuver within the spleen with time as they move through the RES (Reticular Endothelial System) -> they get stuck and are destroyed by Macrophages. The spleen will hypertrophy due to hypertrophy of Macrophages digesting these RBC's (splenomegaly)

Front 85

Describe RDW in Hereditary spherocytosis

Back 85

SINCE the cause of the spherocytosis is destruction of blebs of membrane from the RBC's by the spleen, this means that older cells will be smaller due to loss of membrane compared with newer cells -> increased variability in RBC size

Causes increased RDW

Front 86

What is MCHC? How does it change in hereditary spherocytosis?

Back 86

Mean Corpuscular Hemoglobin Concentration. It is INCREASED in hereditary spherocytosis due to the relative increase in [Hb] per size of RBC since the spleen is picking off blebs of the RBC making RBC volume smaller, but Hb amount stays constant

Front 87

Clinical features of Hereditary Spherocytosis

Back 87

1) Splenomegaly (increased RBC destruction results in hypertrophy of splenic Macrophages),

2) Jaundice with unconjugated bilirubin (b/c amount of unconjugated bilirubin overwhelms processing ability of liver),

3) Increased risk for bilirubin gallstones-> b/c liver makes so much conjugated bilirubin

4) Increased risk of aplastic crisis with parvovirus B19 -> b/c already anemic, and Parvovirus B19 BM supression would cause Extremely Severe anemia

5) Increased RDW & Mean Corpuscular Hemoglobin Concentration (MCHC)

Front 88

How do you diagnose w?

Back 88

Osmotic fragility test - place RBC's in osmotic solution

Normal cell fairly resistant to hypotonic solution b/c is biconcave - has lots of S.A. (surface area) to spare when it swells w/ H20

Spherocyte will easily lyse in osmotic solution (fragile), b/c it has already lost a lot of PM due to cytoskeletal defects, and will burst if more fluid enters

Front 89

What is the Tx for Hereditary Spherocytosis?

Back 89

The Tx is Splenectomy b/c

The problem is not having spherocytes, but rather that they get stuck in Spleen and get destroyed by Macrophages

Removing Spleen, allows Spherocytes to survive

Front 90

What kind of cell will you see on peripheral blood smear post-splenectomy?

Back 90

Howell-Jolly bodies (fragments of nuclear material in RBCs).

An example of when you might see this is Hereditary Spherocytosis treated with a splenectomy. Due to lack of a spleen w/Macrophages that would remove these nucleic acids or destroy the RBC's with Howell-Jolly bodies altogether

Front 91

Profile of Hereditary Spherocytosis post-splenectomy

Back 91

1) Spherocytes (b/c not destroyed in spleen)

2) Howell-Jolly Bodies (b/c not removed in spleen)

3) Anemia resolves - b/c Spherocytes not destroyed

Front 92

Sickle Cell Anemia protects against?

Back 92

protects against Plasmodium Falciparum

Front 93

What drug will increase levels of HbF?

Back 93

hydroxyurea, MOA unknown

Front 94

HbS

Back 94

when both Beta alleles have substitution of Valine (non-polar) in place of glutamic acid (polar) ->Resulting in hydrophobic polymerization when this HbS gives up O2

Front 95

How do HbS cells sickle, what happens?

Back 95

HbS polymerizes (NOT Covalent bonds. It is reversible) in response to loss of O2 induced by:

1) Hypoxemia

2) Dehydration

3) Acidosis

This HbS polymerization causes the RBC's to become needle-like/sickle shaped

RBC's Sickle and Unsickle repeatedly depending on [O2]. Repeated sickling/unsickling -> membrane damage (due to HbS polymer damaging PM) -> Hemolysis

Front 96

Clinical manifestations of Sickle Cell Disease

Back 96

A result of RBC membrane damage. Leads to...

1) Extravascular Hemolysis -- b/c will become less flexible w/ time and get stuck in spleen/hemolyzed by Macrophages, Anemia, jaundice (unconjugated hyperbilirubinemia), bilirubin stones risk in gallbladder

2) Intravascular Hemolysis (minor) -- decreases free haptoglobin (Hb scavanger in blood) as it binds to Hb

3) Target Cells seen in Sickle Cell due to dehydration of RBC's as they get damaged (air out of basketball)

Front 97

Seen in both Extravascular & Intravascular Hemolysis due to Sickle Cell Anemia

Back 97

Massive Erythroid Hyperplasia due to Anemia ->

1) Expansion of hematopoeisis to Skull & Facial bones-> Crew cut appearance on X-ray/Chipmunk faces in response

2) Hepatomegaly - due to Extramedullary Hematopoesis (Normally in Liver/Spleen, but here only Liver b/c Spleen destroyed)- this is part of expansion of hematopoesis due to anemia

3) Risk of Aplastic Crisis w/ Parvovirus B19

Front 98

Tx for Sickle Cell Anemia

Back 98

Hydroxyurea to elevate HbF

Front 99

When does Sickle Cell Anemia first present?

Back 99

6 months after birth b/c for the first 6 months levels of HbF are still pretty high, therefore RBC'S are not likely to sickle

Front 100

Extravascular Hemolysis can be caused by?

Back 100

1) Hereditary Spherocytosis

2) Sickle Cell Anemia

Front 101

Haptoglobin

Back 101

Circulates in serum and scavanges Hb in intravascular hemolysis

Front 102

Irreversible Sickling leads to...

Back 102

Vaso-occlusion of Sickled RBC's leading to Infarction of Tissues

Front 103

Consequences of Vaso-occlusion in Sickle Cell Anemia

Back 103

1) Dactylitis - Swollen hands and feet due to vaso-occlusive infarcts of bones - Common presenting sign in children at >6 m.o.

2) Autosplenectomy - Infarction of Spleen leading to shrunkedn/fibrotic spleen due to Vaso-occlusive Crisis

Front 104

Consequences of Autosplenectomy?

Back 104

1) Increased risk of infection w/ encapsulated organisms (MCC of death in children) - B/c most Plasma cells secrete Ab in Spleen, but will now be missing (ex. H. Influenza, Strep Pneumo,..therefore you must vaccinate sickle cell child against these organisms)

2) Osteomyelitis MC (most commonly) due to Salmonella paratyphi (Normally MCC of osteomyelitis is Staph Aureus)

3) Howell-Jolly bodies on blood mear b/c not removed by splenic Macrophages

Front 105

Most common cause of death in adults with sickle cell disease?

Back 105

Acute Chest Syndrome -- vasoocclusion in pulmonary microcirculation. Presents with chest pain, shortness of breath and lung infiltrates. Can be precipitated by pneumonia (pneumonia infection->inflamamtion->vasodilation->slows RBC transit time->slow moving RBC's give up more O2 from Hb due to hypoxia/vasodilation->sickling->occlusion)

Front 106

Acute Chest Syndrome

Back 106

Usually follows pneumonia b/c

Inflammation-> Vasodilation -> slowed RBC transit-> More time for HbS to release O2 in hypoxic/acidemia->sickling of RBC's->Vaso-occlusion in pulmonary microcirculation-> Chest PAIN!!!, SOB, lung infiltrates

Front 107

Vaso-occlusion in Sickle Cell Anemia causing pain in various organs

Back 107

Pain Crisis

Front 108

Renal Papillary Necrosis

Back 108

Hematuria & proteinurea due to vaso-occlusion in kidney blood vessels due to Sickle Cell Disease

Front 109

Sickle cell train - clinical presnetation

Back 109

Heterozygous pt. makes 45% HbS & 55% HbA (b/c production of functional alpha2Beta2 is more efficient). Since >50% HbS is necessary for an RBC to sickle, these pts generally do not exhibit sickling, with 1 Exception

Front 110

What organ is most susceptible to damage in sickle cell TRAIT individuals? What is the classic finding of long term complications related to this fact?

Back 110

renal medulla- b/c highly hypoxic (due to little blood flow) & hypertonic -> leading to Sickling ->leading to vaso-occlusion in medullary Vasa Recta-> microinfarctions->microscopic hematuria->Eventually Decreased ability to concentrate urine

Front 111

What chemical induces sickling even if small amount of HbS?

Back 111

Metabisulfite
Will cause sickling in both trait and disease b/c can cause sickling even at very low % of HbS (helps identify heterozygotic individuals)

Front 112

Name the types of hemoglobin present in sickle cell disease and trait

Back 112

Sickle Cell Disease -

HbS= 90%,

HbF=8% HbA2 = 2%

HbA= 0% (No HbA present!!)

Sickle Cell Trait -

HbA = 55%

HbS = 43%

HbA2 = 2%

Front 113

Hemoglobin C high yield association?

Back 113

HbC Crystals seen on blood smear- b/c Beta chain of HbC has LySIne in place of glutamic acid->mild anemia due to Extravascular Hemolysis

Front 114

Paroxysmal Nocturnal Hemoglobinurea (PNH)

Back 114

ACQUIRED defect (mutaiton w/ age) in myeloid stem cell in the gene for GPI (GPI anchors DAF (Decay Accelerating Factor= accelerates decay of C3 Convertase) and MIRL (Membrane INhibitor of Reactive Lysis) to RBC) ->

DAF and MIRL are not present on RBC (DAF & MIRL protect RBC from complement in the blood)-> complement can lyse the RBC's

When you sleep, your respiratory drive decreases causing a transient respiratory acidosis (as CO2 accumulates) which can activate complement leading to destruction of RBC. DAMMIT DAF AND MIRL WHERE WERE YOU??-> Missing b/c GPI was not anchoring them

Front 115

What cells will be missing GPI in PNH?

( Paroxysmal = sudden recurrence or onset of symptoms)

Back 115

All descendentsts of myeloid precursor w/ acquired mutation in GPI - RBC's Granulocytes, Platelets-> No DAF/MIRL->these cells are suceptible to complement destruction-> on some nights (paroxysmal) they have RBC destruction-> Dark urine due to Hb in Urine-> Additionally Platelets & Granulocytes are lysed

Front 116

Intravascular Hemolysis

Back 116

Hemoglobinemia

Hemoglobinuria

Hemosiderinuria - days after hemolysis b/c some Hb absorbed by PCT cells, they accumulate Fe (siderin) and when they slogh off, hte hemosiderin ends up in urinecreen S

Front 117

Screen for PNH

Back 117

Sucrose test-> Sucrose activates compliment in pts serum sample -> hemolysis

Confirmatory Test - Acidified Serum Test - Acidification activates Compliment

New Confirmatory Test - Flow Cytometry detects absence of CD55 (DAF) -> confrims absence of GPI

Front 118

Main Cause of Death in PNH

Back 118

Thrombosis in Cerebral, hepatic, portal veins b/c lysis of platelets causes fragments of platelets to activate Coagulation Cascade

Front 119

Complications of PNH

Back 119

Fe deficiency Anemia - due to loss of Fe w/ Hbinuria

AML in 10% of pts, simply b/c if PNH pts have mutation in GPI, they are likely to have other mutations that can lead to Leukemia

Front 120

Glutathione Reductase Pathway

Back 120

G6PD reduces oxidized glutothione so that it can continue to reduce H2O2 that would normally cause oxidative damage to RBC

Front 121

Variants of G6PD?

Back 121

African variant -- mildly reduced t1/2 of G6PD leading to mild intravascular hemolysis with oxidative stress (b/c only very old RBC's lose G6PD and lyse)

Mediterranean Variant - markedly reduced half life of G6PD leading to marked intravascular hemolysis.

Front 122

What does oxidative stress do to Hb?

Back 122

Precipitates Hb as Heinz bodies

Front 123

Causes of Oxidative stress?

Back 123

Infections, Drugs (sulfa, nitryl, primaquine), and Fava beans (Mediterranean diet)

Front 124

Classic sign in G6PD?

Back 124

Heinz bodies -- precipitated Hb due to oxidative stress. These precipitates are bitten out of the RBC in the spleen leading to 'bite cells'

Front 125

G6PD Clinical signs?

Back 125

Intravascular hemolysis causing hematuria. This causes back pain since Hb is nephrotoxic in PCT. Hemoglobinuria seen w/in hours of oxidative stress

Front 126

Normocytic anemias with Predominantly Intravascular hemolysis

Back 126

PNH, G6PD, IHA(Immune Hemolytic Anemia), Microangiopathic Hemolytic Anemia, Malaria

Front 127

Heinz Preparation?

Back 127

Test for G6PD

Front 128

Immune Hemolytic Anemia

Back 128

IgG or IgM mediated destruction of RBC's

IgG is usually EXTRAvascular
IgM is usually INTRAvascular

Front 129

IgG type Immune Hemolytic Anemia Clinical Signs

Back 129

IgG will present with spherocytes since antibody coating of RBC will cause splenic Macrophages to pick off bits and pieces of cytoplasm->Spherocytes

IgG mediated is therefore ->Extravascular Hemolysis b/c Spherocytes will get stuck/destroyed in Spleen with time

Front 130

IgG type Immune Hemolytic Anemia associated with...?

Back 130

extravascular hemolysis
SLE(most common), CLL, and drugs(penicillin, cephalosporin, alpha-methyldopa)

penicillin can bind to RBC yielding Ab complexes or alpa-methyldopa can induce production of Ab's that happen to be also reactive against RBC antigens (self-antigens)

Front 131

Treatment of IgG type Immune Hemolytic Anemia

Back 131

1) Cessation of offending Drug if it exists

2) Steroids

3) IVIG -- eat IVIG instead of RBCs

4) Splenectomy - (Last Resort) removes source of Ab & source of RBC destruction (Splenic Macrophages)

Front 132

IgM type Immune Hemolytic Anemia Associations

Back 132

INTRAvascular hemolysis due to IgM binding in relative cold temp of extremities.

A/w Mycoplasma pneumonia (cold agluttinins) that cause complement activation->MAC Complex formation->Intravascular Hemolysis

Also associated with infectious mononucleosis

Front 133

Overview of Coombs Test

Back 133

Done to identify IHA

Direct Coombs Test- Confirms presnce of Ab coated RBC's --- Do I have RBC's already bound to IgG?
---> add Anti-IgG Ab to solution of patient RBC. If IgG already attached to RBC's, these Anti-IgG Ab's will cause agglutination of RBC's

Indirect Coombs Test -- Do I have Ab to RBC's in my serum?
---> Anti-IgG and test RBC's are added to patient serum. If pt's serum already had Anti-RBC Ab's, then agglutination of test-RBC's will occur

Front 134

Microangiopathic Hemolytic Anemia

Back 134

Formation of Schistocytes due to creation of thrombi in microcirculation.

Occurs in A/w TTP(defective ADAMTS13- necessary for cutting up vWF complex->platelet thrombi), HUS(ETEC O157->verotoxin that damages endothelial cells & inactivates ADAMTS13), DIC ->platelet/fibrin thrombi, HELLP (Hemolysis Elevated Liver ENZYMES and Low Platelets - pregnant woman in liver due to thrombi), Prosthetic heart valves and aortic stenosis. Calcified valves shear RBCs

Front 135

'helmet' shaped RBC

Back 135

Schistocyte

Front 136

Malaria transmitted by?

Back 136

Anopheles mosquito transmits the Plasmodium species of bug, infects RBC's & Hepatocytes

Front 137

Plasmodium falciparum vs vivax/ovale?

Back 137

Plasmodium falciparum -- daily fever
Plasmodium vivax/ovale -- fever every other day

Fever happens every time RBC's rupture

RBC rupture happens every time Plasmodium reproduces & starts new life cycle

Front 138

Intravascular Hemolysis can be caused by?

Back 138

G6PD
Paroxysmal Nocturnal Hemoglobinuria
Microangiopathic Hemolytic Anemia
Immune Hemolytic Anemia
Malaria

Front 139

Extravascular Hemolysis in Malaria

Back 139

A little bit b/c some RBC's are destroyed by Splenic Macrophages ->Hypertrophy of these Macropahges causes Splenomegaly

Front 140

Anemia's Due to Underproduction

Back 140

Decreased production of RBC's by defective BM

Lab findings - Anemia w/ low Retic COunt b/c BM not capable of compensating for low RBC levels

Front 141

Causes of BM UNderproduction

Back 141

1) Anything that would cause Macrocytic or Microcytic anemia b/c low Fe or B12/ Folate deficiency will also interfere w/ Reticulocyte production

2) Renal failure - b/c EPO will be low and EPO extends RBC precursor lifespan

3)Damage to BM precursor cells (e.g. Parvovirus B19)

Front 142

Parvovirus B19 effect on Progenitor Red cells

Back 142

1) Temporarily halts Erythropoeisis b/c infects progenitor Red cells

2)Significant Anemia in pts already struggling to produce enough RBC's - in healthy pts it is not a problem b/c enough RBC reserves

3)Infection is self-limited - resolves in 7-10 days

Front 143

Aplastic Anemia

Back 143

Damage to HSC

Results in Pancytopenia (Platelets/RBC's/WBC LOWV) w/ low Retic Count

Front 144

Causes of Aplastic Anemia

Back 144

Drugs or Chemicals

Viral INFECTION

AUTOIMMUNE DAMAGE

Front 145

Aplastic Anemia Histology

Back 145

ADIPOSE TISSUE REPLACES HEMATOPOEITIC ELEMENTS IN BM

Front 146

Tx of Aplastic Anemia

Back 146

1) Cessation of Causative Dx

2) Transfusions

3) Marrow Stimulating Factors (EPO for RBC's, GM-CSF & G-CSF for Granulocytes) of whatever HSC's remain

4) Immunosupression b/c one of Etiolgies of Aplastic Anemia is Auto-immune

5) BMT (last resort)

Front 147

Myeophthisic Process

Back 147

Pathologic Process that replaces BM->

Hematopoesis is impaired->pancytopenia

e.g. metastatic cancer replacing BM would interfere w/ Hematopoesis->pancytopenia