Pathoma - Anemia (2) - Fundamentals Of Pathology

Front 1

Define normocytic anemia.

Back 1

Anemia with normal-sized RBCs. MCV is 80-100.

Front 2

The key differential diagnosis in most normocytic anemias is [...]

Back 2

Anemia due to increased peripheral destruction or underproduction.

Front 3

How can you differentiate between normocytic anemia due to increased peripheral destruction or underproduction?

Back 3

Reticulocyte count helps distinguish between these two etiologies.

Front 4

What are the strands in the cytoplasm of a reticulocyte?

Back 4

Thread-like RNA filaments (gives the cell its blue hue on smear and stain)

Front 5

Normal reticulocyte count in the blood is __ to __ %.

Back 5

1;2. Each day, 1-2% of cells are removed and replaced by reticulocytes.

Front 6

RBC lifespan is _________.

Back 6

~120 days

Front 7

If a healthy man acquires a normocytic anemia, how should the marrow respond?

Back 7

A properly functioning marrow should respond to anemia by increasing RC to > 3%.

Front 8

Percentage of RCs in anemia is ______________. Why?

Back 8

falsely elevated

A decrease in total RBCs, falsely elevates the percentage of reticulocytes.

Front 9

How do we correct a reticulocyte count for the degree of anemia?

Back 9

Correct it by multiplying reticulocyte count by Hct/45

Front 10

What can the corrected reticulocyte count be used for?

Back 10

To figure out what the etiology of RBC destruction is in normocytic anemia, i.e. are the RBCs being produced sufficiently or being destroyed outside the marrow. A corrected ret count > 3% indicates good marrow function, telling us it is being destroyed.

Front 11

A corrected reticulocyte count of > ____% indicates good marrow response, while < ___ % suggests underproduction.

Back 11

3;3

Front 12

Hemolysis can be divided into?

Back 12

(1) Intravascular
- Within blood vessels
(2) Extravascular
- Destroyed by reticuloendothelial system (macrophages of spleen, liver, lymph nodes)

Front 13

A normocytic anemia with hemolysis would result in a _________ (poor/good) marrow response.

Back 13

good, greater than 3% corrected reticulocyte count.

Front 14

Macrophages can consume _______ and break down the _______ (pigment).

Back 14

RBCs; hemoglobin

Front 15

Describe the breakdown of hemoglobin.

Back 15

Hemoglobin = Globin + Heme (iron + protoporphyrin)

Globin - amino acids
Heme - iron, protoporphyrin

Protoporphyrin - unconjugated bilirubin (indirect)

Front 16

After RBCs are broken down, macrophages spits out unconjugated bilirubin and it becomes bound to ____________. It is then delivered to the _________ for ____________ reactions and excreted in the ________.

Back 16

serum albumin; liver; conjugation; bile

Front 17

How would patients with extravascular hemolysis present? What are lab findings?

Back 17

(1) Anemia with splenomegaly (hypertrophy)
(2) Jaundice due to unconjugated bilirubin (more than capacity of liver to conjugate)
(3) Bilirubin gallstone risk
(4) Marrow hyperplasia with corrected reticulocyte count of > 3%.

Front 18

What is the initial phase in intravascular hemolysis of RBCs?

Back 18

Hemoglobin is released into the blood, subsequently complexing with haptoglobin. This is phagocytosed and degraded by macrophages. We see decrease in haptoglobin levels in intravascular hemolysis related anemias.

Front 19

After haptoglobin salvages some Hb, what is the next step in the evolution of an intravascular hemolysis?

Back 19

Haptoglobin is minimal, so after it is depleted, Hb builds up in blood, creating a hemoglobinemia. Reaches the urine, creating a hemoglobinuria. Some tubule cells absorb Hb, storing iron as hemosiderin. When tubule cells turn over, they slough off and this can be measured in urine as hemosiderinuria.

Front 20

What is hereditary spherocytosis? Be general, not specific.

Back 20

Inherited defect of RBC cytoskeleton-membrane tethering proteins.

Front 21

Hereditary spherocytosis most commonly involves these proteins.

Back 21

Spectrin, ankyrin, band 3.1

Front 22

Describe the pathophysiology of hereditary spherocytosis.

Back 22

Remember, because of the inherited defect, small blebs of cytoplasm falls off the cell, causing it to round off.

Front 23

Describe the makeup of parvovirus.

Back 23

Linear ssDNA. Naked icosahedral.

Front 24

Life span of spherocytes is _____ to _____ days.

Back 24

10;20

Front 25

How would spherocytes look like on smear?

Back 25

Loss of central pallor. May see a higher than normal RDW due to some cells being older and having lost more membrane.

Front 26

Spherocytes are less able to maneuver through the _________. What happens?

Back 26

splenic sinusoids

They are consumed by splenic macrophages.

Front 27

What are some clinical and lab findings in HS?

Back 27

(1) Spherocytes with loss of central pallor
(2) Increased RDW
(3) Increased MCHC (cell shrinks, Hb is more concentrated)
(4) Splenomegaly (macrophages hypertrophy), jaundice with indirect bilirubin, increased risk for gallstones
(5) Increased risk for aplastic crisis with parvovirus B19 infection of erythroid precursors.

Front 28

Diagnosis of HS occurs by?

Back 28

Osmotic fragility test (increased fragility in hypotonic solutions)

Front 29

Treatment of HS? What happens after this?

Back 29

Splenectomy.

(1) Anemia resolves
(2) Spherocytes PERSIST
(3) Howell-Jolly bodies emerge on blood smear

Front 30

What is a Holly-Jowell body?

Back 30

On occasion there might be a RBC where some nuclear material wasn't removed. It's the job of the spleen to remove it.

Front 31

In sickle cell anemia there is predominantly _______________ (intravascular/extravascular) hemolysis.

Back 31

extravascular

Front 32

In sickle cell anemia, patients have an ____ mutation in the _____ chain gene of hemoglobin.

Back 32

AR; beta

Front 33

What amino acids are replaced in sickle cell disease?

Back 33

Normal glutamic acid (hydrophilic) is replaced with valine (hydrophobic).

Front 34

The gene for sickle cell disease is carried by ____% of what ethnic group? What evolutionary significance does this have?

Back 34

10%; African americans

Likely due to protective role against falciparum malaria

Front 35

In intravascular hemolysis there is a risk for becoming _____ deficient.

Back 35

iron

Front 36

Sickle cell arises when ____ abnormal ______ (beta/alpha) genes are present.

Back 36

2; beta

Front 37

Sickle cell disease results in > _____% of Hb_ in RBCs.

Back 37

>90%; HbS

Front 38

What is the primary hemoglobin produced in patients with sickle cell disease?

Back 38

HbS (alpha2beta2[S])

Front 39

What's the issue with hemoglobin S?

Back 39

It polymerizes when deoxygenated. Polymers aggregate into needle-like structures resulting in sickle cells.

Front 40

What is this banan shaped cell?

Back 40

Sickle cell

Front 41

In sickle cell disease, there is an increased risk of sickling with these factors:

Back 41

(1) Hypoxemia
(2) Dehydration
(3) Acidosis

Front 42

This hemoglobin is protective against sickling.

Back 42

HbF

Front 43

Why don't patients with sickle cell anemia present until about 6 months of birth?

Back 43

High HbF at birth is protective for the first months of life.

Front 44

Treatment of sickle cell disease?

Back 44

Hydroxyurea increases HbF (we don't know why), this helps for sickle cell disease.

Front 45

Cells in sickle cell disease continuously ________ and ________ while passing through microcirculation.

Back 45

sickle; desickle

Front 46

Sickle cells passing through microcirculation leads to complications related to ________________. What happens?

Back 46

RBC damage.

(1) Less flexible over time, spleen removes them (extravascular hemolysis). Anemia.
(2) Jaundice with unconjugated hyperbilirubinemia.
(3) Increased risk for gallstones

Front 47

Is sickle cell anemia extravascular or intravascular mechanism of hemolysis? What is the result of intravascular hemolysis.

Back 47

Both, but extra is predominant.

(1) Intravascular happens and decreases haptoglobin.
(2) Cells dehydrate as they are damaged. Cytoplasm is going to be slowly decreased. Creating target cells.

Front 48

What is a consequence of extravascular and intravascular hemolysis in sickle cell disease?

Back 48

Massive erythroid hyperplasia.

(1) Expansion of hematopoiesis into skull and facial bones
(2) Extramedullary hematopoiesis with hepatomegaly
(3) Risk of aplastic crisis with parvovirus B19

Front 49

Outside of anemia as a major complication of sickle cell anemia, what is the second major complication?

Back 49

Irreversible sickling. Leads to vaso-occlusion.

Front 50

Give an example of vaso-occlusion in sickle cell disease. What is it? Who does it present in?

Back 50

Dactylitis.

Swollen hands and feet due to vaso-occlusive infarcts of bones. Common presenting sign in infants.

Front 51

What is this?

Back 51

Autoinfarcted spleen in sickle cell disease

Front 52

What happens to the spleen in sickle cell anemia?

Back 52

It gets repeatedly infarcted, and eventually leading to a shrunken fibrotic spleen.

Front 53

If the spleen is lost, the primary source of what is lost? This creates an opportunity for infection with ____________.

Back 53

primary source of antibodies is lost.

Encapsulated organisms

Front 54

This is the MC cause of death in children with sickle cell disease.

Back 54

Infection with encapsulated organisms

Front 55

Sickle cell disease increases the risk for osteomyelitis with this organism.

Back 55

Salmonella paratyphi

Front 56

Eventually, in sickle cell anemia, the RBCs show _________ bodies.

Back 56

Howell-Jolly

Front 57

What is acute chest syndrome? How does it present?

Back 57

In the context of sickle cell anemia, there is vaso-occlusion in pulmonary microvasculature.

Presents with chest pain, dyspnea, lung infiltrates.

Front 58

Acute chest syndrome in sickle cell disease is often precipitated by ____________. Why?

Back 58

pneumonia

Infection, inflammation, vasodilation, increased transit time, increased sickling.

Front 59

MCC of death in adults with sickle cell anemia.

Back 59

Acute chest syndrome

Front 60

Vaso-occlusion in sickle cell anemia can lead to _________ crisis.

Back 60

Pain crisis

Front 61

A vaso-occlusive crisis in the kidney in the context of sickle cell disease may lead to? This results in?

Back 61

Renal papillary necrosis. Results in gross hematuria and proteinuria.

Front 62

You need about ____% of HbS for it to start to sickle.

Back 62

50%

Front 63

Sickle cell trait results in < _____% HbS in RBCs.

Back 63

50%

Front 64

Patients with sickle cell trait are generally ______________. There is one exception however, what is it?

Back 64

Asymptomatic

Renal medulla (they tend to sickle here). In the medulla there is extreme hypoxia and hypertonicity (mimicking sickling)

Front 65

A patient with sickle cell trait has sickling in her kidneys. What happens there? What does it lead to?

Back 65

Hypoxic and hypertronic environment sickles cells. Causes microinfarctions. Initially presents with microscopic hematuria, and, eventually, decreased ability to concentrate urine.

Front 66

True or false: Sickle cells and target cells are seen on smear in sickle cell trait.

Back 66

False. They are seen in sickle cell disease, but not the trait.

Front 67

What is a screening test for sickle cell anemia? Is it positive in trait or disease?

Back 67

Metabisulfite screen, induces cell to sickle. It is positive in both.

Front 68

How could you confirm the presence of HbS?

Back 68

Hb electrophoresis

Front 69

What are the relative percentages of different hemoglobins in sickle cell disease?

Back 69

(1) 90% HbS
(2) 8% HbF
(3) 2% HbA2 (no HbA; no beta chains)

Front 70

What are the relative percentages of different hemoglobins in sickle cell trait?

Back 70

(1) 55% HbA
(2) 43% HbS
(3) 2% HbA2

Front 71

What is Hemoglobin C?

Back 71

A hemoglobinopathy. AR mutation in beta chain of hemoglobin. Normal glutamic acid is replaced by lysine.

"Hemoglobin C has lyCIIIIIIIIINE"

Front 72

Hemoglobin C is __________ (more/less) common than sickle cell disease.

Back 72

less

Front 73

How does Hemoglobin C present?

Back 73

Mild anemia due to extravascular hemolysis.

Front 74

What is this?

Back 74

Characteristic HbC crystals (lysine and hemoglobin C crystals) are seen in RBCs of patients with Hemoglobin C.

Front 75

What is paroxysmal nocturnal hemoglobinuria?

Back 75

Intravascular hemolysis. ACQUIRED defect in myeloid stem cells resulting in absent GPI. Renders cells susceptible to complement (which is more active in more acidic conditions, as when you sleep).

Front 76

What is the molecule(s) used by RBCs (and other cells) to protect themselves against their deadly neighbour?

Back 76

(1) Decay accelerating factor (DAF)
(2) MIRL - Membrane inhibitor of reactive lysis

Front 77

DAF accelerates the degradation of ___________________.

Back 77

C3 convertase

Front 78

DAF and MIRL are both connected to the RBC membrane by a protein called a __________.

Back 78

GPI (Anchoring protein)

Front 79

What cell types can become lysed in PNH?

Back 79

(1) RBCs
(2) WBCs
(3) PLTs

Front 80

Why does PNH occur during the night?

Back 80

When we sleep we breathe shallow. Mild respiratory acidosis ensues, activating complement more readily.

Front 81

What laboratory indices are seen with PNH?

Back 81

(1) Hemoglobinemia
(2) Hemoglobinuria
(3) Hemosiderinuria is seen days after hemolysis

Front 82

How do you screen for PNH?

Back 82

Sucrose test is used to screen for disease. It activates complement in the blood.

Front 83

What is a confirmatory test of PNH?

Back 83

Confirmatory test is acidified serum or flow cytometry to detect lack of CD55 (DAF).

Front 84

DAF is also known as cluster of differentiation ____.

Back 84

55 (CD55)

Front 85

What is the main cause of death in patients with PNH?

Back 85

Thrombosis of hepatic, portal or cerebral veins. Since PLTs are destroyed, cytoplasmic contents are released into circulation inducing thrombosis.

Front 86

Complications of PNH include?

Back 86

(1) Iron deficiency anemia
- Hemoglobinuria
(2) AML (develops in ~10% of patients)
- Remember, this dx is a mutation in myeloid stem cell.

Front 87

G6PD is a predominantly _____________ (intravascular/extravascular) disorder.

Back 87

intravascular

Front 88

What is the inheritance pattern of G6PD? What happens to the enzyme?

Back 88

X-linked recessive

It has a reduced half life

Front 89

G6PD renders cells susceptible to what?

Back 89

Oxidative stress

Front 90

RBCs live in an environment of ___________.

Back 90

oxidative stress

Front 91

Why are RBCs more susceptible to oxidative stress in G6PD deficiency?

Back 91

G6PD participates in making NADPH, needed to reduce GS-SG back to GSH such that it can neutralize H2O2.

Front 92

G6PD has two major variants. What are they?

Back 92

(1) African-variant with mildly reduced half life
(2) Mediterranean variant with markedly reduced half life

Front 93

Why is there a high frequency of G6PD in african americans and people of mediterranean descent?

Back 93

Likely due to protective role against falciparum malaria.

Front 94

Causes of oxidative stress to RBCs include?

Back 94

(1) Infections
(2) Drugs (primaquine, sulfa drugs, dapsone)
(3) Fava beans

Front 95

When hemoglobin hits an oxidative stress, what happens?

Back 95

It causes Hb to precipitate as a Heinz body. It is removed by splenic macrophages, resulting in bite cells, leading to intravascular hemolysis.

Front 96

How does G6PD deficiency present?

Back 96

Hemoglobinuria and back pain (hemoglobin is nephrotoxic). Occurs hours after exposure to an oxidative stress.

Front 97

If you want to see the precipitated hemoglobin (Heinz), you won't be able to see it on a smear. You must do something first, what is it?

Back 97

Heinz preparation. Used to screen for disease.

Front 98

How do you confirm G6PD disease after screening?

Back 98

Confirm it by enzymatic studies.

Front 99

A patient with G6PD has an acute hemolytic episode. You want to confirm this disease by doing enzyme studies. It comes back negative. Why might it be falsely negative?

Back 99

You have to perform the test in between hemolytic episodes. All cells present in the blood sample will lack the enzyme (others being lysed).

Front 100

Immune hemolytic anemia is an ____________mediated destruction of RBCs.

Back 100

Antibody (IgG or IgM)

Front 101

IgG-mediated disease usually involves __________________ (intravascular/extravascular) disease.

Back 101

extravascular

Front 102

IgG in the context of immune hemolytic anemia is also called _________________.

Back 102

warm agglutinin because it binds RBCs in the relatively warm central body

Front 103

What is the resulting shape of RBCs in IgG-mediated hemolytic disease?

Back 103

Spherocytes. Membrane of antibody-coated RBCs is consumed by splenic macrophages.

Front 104

IgG-mediated hemolytic disease is associated with what?

Back 104

(1) SLE
(2) CLL (neoplastic B-cells here do not have a desire to do anything beneficial, not only do they not produce Abs, but when they do so, they do a poor job)
(3) Certain drugs (like penicillin, which could adhere to RBC membrane which removes pieces of membrane). The drug could also induce production of Ab itself (methyldopa).

Front 105

Treatment of IgG-mediated hemolysis?

Back 105

(1) Remove offending drug
(2) Steroids (slow down production of Ab)
(3) IV Ig (splenic macrophages eat IgG instead; or Fc receptors are blocked)
(4) Splenectomy

Front 106

IgM-mediated hemolysis usually involves ________________ (intravascular/extravascular) hemolysis.

Back 106

intravascular

Front 107

In IgM-mediated hemolysis, IgM binds and fixes complement on RBCs where?

Back 107

Usually in the colder temperature of the extremities (called cold agglutinins).

Front 108

IgM-mediated hemolysis is associated with what other diseases or infections?

Back 108

(1) Mycoplasma pneumoniae
(2) Infectious mononucleosis

Front 109

What is used to diagnose immune hemolytic anemias?

Back 109

Coombs test. Can be direct or indirect.

Front 110

What is the "Question" behind the use of Direct Coombs test. How does it work?

Back 110

"Do I have RBC bound to IgG".

Anti-IgG is added to patients RBCs. Agglutination occurs if patients RBCs are already coated by IgG.

Front 111

What is the most important test for IHA?

Back 111

Coombs

Front 112

What is the "Question" behind the use of indirect Coombs test. How does it work?

Back 112

"Does the patient have antibodies in their serum?"

You take test RBCs, put it in the patients serum, add anti-IgG. Agglutination occurs if there is antibodies.

Front 113

What is the HELLP syndrome?

Back 113

HELLP syndrome
(1) Hemolytic anemia with schistocytes
(2) ELevated serum transaminases
(3) Low Platelets
• Due to disseminated intravascular coagulation

Front 114

Microangiopathic hemolytic anemia can occur with what conditions of the heart?

Back 114

(1) Prosthetic heart valves
(2) Calcific aortic stenosis

Front 115

Microangiopathic hemolytic anemia can occur with conditions that produce microthrombi. What are they?

Back 115

(1) TTP-HUS
(2) DIC
(3) HELLP

Front 116

Microthrombo produce ___________ on blood smear.

Back 116

schistocytes

Front 117

Malaria results in infection of __________ and _________ with __________ (species).

Back 117

RBCs; liver; plasmodium

Front 118

Malaria is transmitted by ________________.

Back 118

female Anopheles mosquito (moskito, mygg)

Front 119

Regarding malaria. RBCs rupture as part of what?

Back 119

Plasmodium life cycle.

Front 120

Each time Plasmodium undergoes its life cycle in RBCs, what happens? Describe fever patterns in each spp.

Back 120

Results in intravascular hemolysis and cyclical fever

P. falciparum - daily fever
P. vivax, P.ovale - fever every other day

Front 121

Where else than intravascularly does hemolysis occur in malaria? What is the result?

Back 121

Spleen. It consumes some infected RBCs. Results in mild extravascular hemolysis with splenomegaly.

Front 122

What type of anemia is characterized by a low corrected reticulocyte count?

Back 122

Anemias due to underproduction. It can't compensate.

Front 123

What are the etiologies of anemia due to underproduction?

Back 123

(1) Causes of microcytic and macrocytic anemias
(2) Renal failure (less EPO produced)
(3) Dmg to bone marrow precursor cells
- Parvovirus B19

Front 124

What is aplastic anemia?

Back 124

When you have damage to hematopoietic stem cells. Results in a pancytopenia with low reticulocyte count.

Front 125

What are etiologies of aplastic anemia?

Back 125

(1) Drugs or chemicals
(2) Viral infections
(3) Autoimmune damage

Front 126

What do you see?

Back 126

A spicule of bone, and fat. This is an empty marrow. Can be seen in aplastic anemia.

Front 127

Treatment of aplastic anemia involves?

Back 127

(1) Cessation of any drug that may be involved
(2) Transfusions to support the patient
(3) Marrow-stimulating factors (EPO, GM-CSF, G-CSF)
(4) Immunosuppression (remember, one etiology is autoimmune)
(5) Bone marrow transplant is last resort

Front 128

What is myelophtisic process?

Back 128

A pathologic process that replaces the bone marrow. Hematopoiesis is impaired, resulting in pancytopenia. E.g. metastatic cancer.

Front 129

What cancers most often cause a myelophtisic process?

Back 129

Breast, lung, prostate

Front 130

What shape of RBCs would you expect on a smear in myelophtisic process?

Back 130

Tear-drop shaped RBCs called dacrocytes.

Believed to be deformed during their tortuous escape from the fibrotic marrow.