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Pathoma Enhanced > CH5 - Red Blood Cell Disorders > Flashcards

CH5 - Red Blood Cell Disorders Flashcards

1
Q

What is Anemia?

A

Reduction in circulating red blood cell (RBC) mass

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2
Q

How does anemia present?

A

signs and symptoms of hypoxia

  1. Color: Pale conjunctiva and skin
  2. Low Energy: Weakness, fatigue, and dyspnea
  3. CNS low energy: Headache and lightheadedness
  4. Heart low energy: Angina, especially with preexisting coronary artery disease
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3
Q

How is RBC mass measured?

A

Hemoglobin (Hb) = [Hb] in blood

hematocrit (Hct) = Ratio of RBC volume to total blood volume

(Etymology: haemato- +‎ Ancient Greek krites (judge) - blood judge = way of assessing judge)

The percentage (by volume) of packed red blood cells in a centrifuged sample of blood

RBC count = #RBC’s/ volume of blood

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4
Q

Why would Hemoglobin, Hct, and RBC count be normal in a gun shot wound victim?

A

Heavy blood loss can still result in normal concentration test results because both RBC’s and plasma are lost proportionally. (won’t be reflected in tests until IV fluids given to patient and low RBC mass is diluted out)

All 3 are based on concentration and used as surrogates for RBC mass, which is difficult to measure

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5
Q

Why would Hb, Hct, and RBC count be abnormal in a healthy pregnant woman?

A

All 3 are based on concentration and used as surrogates for RBC mass, which is difficult to measure. Because they are concentration-based they can sometimes do a poor job of reflecting RBC mass

a woman’s blood volume (plasma) goes up during pregnancy, so her concentrations go down, but her RBC mass is normal.

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6
Q

Anemia is defined as what (in terms of Hb)?

A

Hb<12.5 g/dL in females - lower because of menstrual blood loss

Hb<13.5 g/dL in males

Normal: 12.5-16.0 g/dl. in females

Normal: 13.5-17.5 g/dL in males

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7
Q

What is the basis for anemia classification?

A

Based on mean corpuscular volume (MCV)

Normal MCV 80-100

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8
Q

What does the MCV measure?

A

Average volume of a red blood cell

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9
Q

Microcytic Anemia [Hb]

A

<80

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10
Q

Normocytic Anemia [Hb]

A

80-100

Normal size, but [Hb], RBC count are low

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11
Q

Macrocytic Anemia [Hb]

A

>100

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12
Q

Microcytic anemias are due to

A

decreased production of Hb

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13
Q

RBC progenitor cells in the bone marrow are?

A

large and normally divide multiple times to produce smaller mature cells (Normal MCV = 80-100)

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14
Q

Microcytosis is due to?

A

an “extra” division which occurs to maintain hemoglobin concentration in each RBC despite low [Hb]

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15
Q

Hemoglobin is made of

A

heme and globin (protein tetramer)

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16
Q

heme is composed of?

A

Fe

+

porphyrin ring

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17
Q

A decrease in what components leads to microcytic anemia?

A

1) Fe

2) Protoporphyrin

OR

3)Globin

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18
Q

Microcytic anemias include

A

(1) Fe deficiency anemia
(2) Anemia of chronic disease (Fe locked in response to chronic inflammatory state via Hepcidin)
(3) Sideroblastic anemia (failure in protoporphyrin synthesis)
(4) Thalassemia (failure in globin synthesis)

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19
Q

Iron deficiency anemia is due to?

A

↓ Fe -> ↓ heme -> ↓ hemoglobin —» microcytic anemia

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20
Q

What is the most common type of anemia?

A

iron deficiency anemia

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21
Q

What is the most common nutritional deficiency in the world?

A

Lack of iron, affecting roughly 1/3 of world’s population

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22
Q

Iron is consumed in what forms?

A

heme (meat-derived)

and

non-heme (vegetable-derived) forms

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23
Q

Absorption of iron occurs in the?

A

Duodenum

Enterocytes have heme and non-heme transporters

(DMT1 = Divalent metal transporter 1)

Heme = more readily absorbed

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24
Q

How do enterocytes transport iron?

A

via DMT1 (Divalent Metal Transporter) on luminal (aka apical)side and into blood via ferroportin on basolateral membrane (opposite of lumen))

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25
Q

Where does transferrin transports iron and where does it take it?

A

in the blood and delivers it to liver and bone marrow macrophages for storage

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26
Q

Stored intracellular iron is bound to what?

A

Ferritin = prevents iron from forming free radicals via the Fenton reaction

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27
Q

Followup Lab tests for anemic patient

A

1) serum iron
2) TIBC
3) % saturation
4) Serum Ferritin

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28
Q

What does the serum iron measure?

A

Serum iron is a measure of Fe in the blood

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29
Q

What does total iron-binding capacity (TIBC) measure?

A

How many transferrin molecules in the blood

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30
Q

What does % saturation of iron measure?

A

percentage of transferrin molecules that are bound by Fe (normal is 33%)

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31
Q

What does serum ferritin measure?

A

reflects iron stores in macrophages

of

Bone Marrow

and

Liver

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32
Q

What is iron deficiency is usually caused by?

A

Nutritional deficit

OR

blood loss

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33
Q

MCC of Fe deficiency in infants?

A

breast-feeding (human milk is low in Fe)

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34
Q

MCC of Fe deficiency in children?

A

poor diet

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35
Q

MCC of Fe deficiency in adults?

A

(20-50 years old)—peptic ulcer disease in males

and

menorrhagia or pregnancy in females

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36
Q

MCC of Fe deficiency in elderly?

A

colon polyps/carcinoma in the Western world;

hookworm (Ancylostoma duodenale and Nieator americanus) in the developing world

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37
Q

What are some other causes of iron deficiency?

A

1) malnutrition

2) malabsorption

3) gastrectomy - b/c acid aids iron absorption by maintaining the Fe2+ state, which is more readily absorbed

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38
Q

What are the stages of iron deficiency?

A
  1. Storage iron is depleted—> decreased serum ferritin> increased TIBC (transferrin)
  2. Serum iron is depleted— low serum iron; ↓ % saturation
  3. Normocytic anemia—Bone marrow makes fewer but normal-sized, RBCs
  4. Microcytic, hypochromic anemia—Bone marrow makes smaller and fewer RBC’s
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39
Q

The initial stage of iron deficiency results in what type of anemia?

A

normocytic anemia b/c the bone marrow’s initial response is to make as many normal RBC’s as possible, so RBC count goes down, but they are normocytic

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40
Q

what are the clinical features of iron deficiency

A

anemia

koilonychia = flat fingernails

pica = eating ice

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41
Q

Laboratory findings for iron deficiency include?

A
  1. microcytic, hypochromic RBCs with ↑ RDW (red cell distribution width)
  2. ↓ ferritin; ↑ TIBC; ↓ serum iron; ↓ % saturation
  3. ↑ Free erythrocyte protoporphyrin (FEP) because not enough Fe to bind up all protoporphyrin rings
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42
Q

What is FEP?

A

free erythrocyte protoporphoryin - ↓ Fe means less protoporphorin is bound

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43
Q

What is RDW?

A

red blood cell distribution width, measures the spectrum of size of the RBC’s

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44
Q

What does a low RDW mean?

A

all of the red blood cells have the same size

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45
Q

What does a high RDW mean?

A

RBC’s have different sizes

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46
Q

Why do you have increased RDW in iron deficiency?

A

Initial Bone Marrow response to lower Fe is to produce fewer normal sized RBC’s (normocytic)

After iron deficiency worsens, Bone Marrow starts producing small RBC’s with less Hb (microcytic)

Since RBC’s live 120 days, these varying sizes result in increased RDW

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47
Q

What is the treatment for iron deficiency anemia?

A

1) Determine underlying cause of Iron Deficiency,

DON’T JUST SUPPLEMENT

2) Supplemental iron (ferrous sulfate) - always

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48
Q

How does the size of the RBC compare to a lymphocyte on a blood smear?

A

RBC the size of a lymphocyte nucleus

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49
Q

What is Plummer-Vinson syndrome?

A

A questionable syndrome associated with iron deficiency anemia, esophageal webs, and atrophic glossitis

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50
Q

What is atrophic glossitis?

A

“Bald tongue” or “beefy tongue”

smooth glossy tongue that is often tender/painful, caused by complete atrophy of the lingual papillae

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51
Q

What is an esophogeal web?

A

some of the mucosa of the esophagous outfolds potentially creating a partial obstruction in the esophagus -> dysphagia

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52
Q

How Does Plummer-Vinson Syndrome Present?

A

presents with anemia, dysphagia (food stuck on esophageal webs), and beefy-red tongue (atrophic glossitis)

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53
Q

What is anemia of chronic disease?

A

Anemia associated with

chronic inflammation

(e.g., endocarditis or autoimmune conditions)

or

Cancer

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54
Q

What is the most common type of anemia in hospitalized patients?

A

anemia of chronic disease

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55
Q

How is hepcidin related to chronic disease?

A

chronic disease results in production of acute phase reactants from the liver including hepcidin

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56
Q

What does hepcidin do?

A

sequesters Fe in storage sites by:

(1) limiting iron transfer from macrophages to erythroblasts
(2) suppressing erythropoietin (EPO) production by kidney

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57
Q

Why did humans evolve to produce hepcidin in response to chronic inflammation?

A

Just in case, chronic inflammation is due to bacterial infection, to prevent bacteria from accessing Fe, b/c Fe necessary for bacterial survival.

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58
Q

How is anemia of chronic disease related to microcytic anemia?

A

↓ Fe —> ↓ heme -> ↓ Hb -> microcytic anemia

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59
Q

What are the laboratory findings for anemia of chronic disease?

Ferritin

TIBC

Serum Iron

% Sat

FEP (free erythrocyte protoporphyrin)

A

↑ Ferritin

↓ TIBC

(b/c High Ferritin causes ↓ transferrin)

↓ serum Fe

↓ % saturation (of transferrin)

↑ FEP

(floating around RBC, free, because not enough Fe to bind with it)

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60
Q

In anemia of chronic disease why is there increased ferritin?

A

in anemia of chronic disease hepcidin blocks the release of storage Fe from macrophages

  • storage Fe builds up meaning ↑ ferritin
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61
Q

Why is there a decrease in serum iron in anemia of chronic disease?

A

if the bone marrow cannot access the Fe in the macrophages it will deplete the serum Fe bound to transferrin->

↓ % saturation (transferrin)

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62
Q

Why is there increased FEP in anemia of chronic disease?

A

↓ Fe availability leads to free protoporphyrin since

Hb is composed of

HEME + PROTOPORPHYRIN

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63
Q

Is anemia of chronic classified as normocytic or microcytic?

A

in the early phase of anemia of chronic disease, the pt first develops a normocytic anemia (just like in Iron Deficiency Anemia) as RBC’s try to pump out fewer but normally sized RBC’s with proper [Hb],

As available Fe becomes severely depleted -> production of microcytic RBCs

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64
Q

What is the treatment of anemia of chronic disease?

A

Addressing the underlying cause,

exogenous EPO is useful in a subset of patients, especially cancer patients

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65
Q

What is sideroblastic anemia due to?

A

Defect in protoporphyrin synthesis

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66
Q

How does sideroblastic anemia lead to microcytic anemia?

A

↓ protoporphyrin -> ↓ Hb -> microcytic anemia

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67
Q

Where are the 7 reactions of the protoporphorin synthesis occuring?

A

Erythroblasts = RBC progenitor cells located in BM

In both the cytoplasm and Mitochondria

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68
Q

What is the first and rate-limiting step in the production of protoporphyrin?

A

Aminolevulinic acid synthetase (ALAS) converts

Succinyl CoA -> aminolevulinic acid (ALA)

vit B6 is cofactor for ALAS

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69
Q

What is the rate-limiting step in the synthesis of protoporphyrin?

A

SCoA -> ALA via ALAS with B6 as a cofactor

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70
Q

What happens after the rate-limiting step in the synthesis of protoporphyrin?

A

Aminolevulinic acid dehydrogenase (ALAD) converts

aminolevulinic acid (ALA) -> Porphobilinogen

(Additional rxns convert Porphobilinogen -> protoporphyrin)

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71
Q

In the synthesis of Protoporphyrin what happens in the final step?

A

Ferrochelatase attaches

Protoporphyrin + Fe -> HEME

(occurs in the mitochondria)

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72
Q

How is Heme formed?

A

Fe transferred from Bone Marrow Macrophages

Fe transferred to Bone Marrow Erythroid precursors (Erythroblasts)

Fe then transferred the Mitochondria to bind with Protoporphyrin to form HEME

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73
Q

What happens if protoporphyrin is deficient?

A

Fe remains trapped in Erythroblast mitochondria

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74
Q

What is seen when Fe gets trapped in the Mitochondria?

A

Fe-laden mitochondria form a ring around the nucleus of Erythroblasts (visualized using Prussian Blue Stain)

Erythroblasts with rings of Fe-laden Mitochondria surrounding the nucleus are called ringed sideroblasts

(hence, the term sideroblastic anemia)

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75
Q

Where does sideroblastic anemia get its name?

A

The ring around the nucleus of erythroid precursors of iron laden mitochondria is called ringed sideroblasts

Ancient greek = sídēros, “iron”

Latin = sideris “constellation”

Constellation fo Fe around nucleus

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76
Q

Is sideroblastic anemia congenital or acquired?

A

Can be BOTH:

congenital or acquired

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77
Q

Describe the Most Common Congenital form of Sideroblastic Anemia?

A

most commonly involves mutation in ALAS

(rate-limiting enzyme)

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78
Q

What are the acquired causes of sideroblastic anemia?

A

1) Alcoholism
2) Lead poisoning
3) Vitamin B6 deficiency

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79
Q

How can alcoholism lead to sideroblastic anemia?

A

EtOH = mitochondrial poison

  • >damages production of protoporphyrin
  • > sideroblastic anemia
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80
Q

How does lead poisoning lead to sideroblastic anemia?

A

Pb DENATURES

enzymes, including

ALAD (Protoporphyrin synthesis)

and

Ferrochelatase (binds Fe to Protoporphyrin)

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81
Q

How does Vitamin B6 deficiency lead to sideroblastic anemia? This is most commonly seen as a side effect of what treatment?

A

Required cofactor for ALAS

(first and rate-limiting step in Protoporphyrin synthesis)

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82
Q

What patients get Vit B6 deficiency, and what kind of anemia can they develop?

A

most commonly seen as a side effect of

isoniazid treatment for Tuberculosis

Sideroblastic anemia b/c Vit B6 is a cofactor for ALAS (rate limiting step in protoporphyrin synthesis)

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83
Q

In sideroblastic anemia why is there increased ferritin?

A

Fe builds up in the Bone Marrow Erythroid Precursor (Erythroblast)

A ton of Fe loaded in Erythroblast Mitochondria

Unbound Fe generates so many free radicals

Erythroblast damaged and dies

Fe leaks out of dead Erythroblast into BM and Serum

  • > leaked Fe consumed by Bone Marrow Macrophages
  • > high stores of Fe (increased ferritin)

Not enough Protoporphyrin to bind all of the Fe, so Fe accumulates

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84
Q

What are the laboratory findings for sideroblastic anemia?

Ferritin

TIBC

Serum Fe

% saturation

A

↑ Ferritin

(BM Macrophages store Fe leaked from dead Erythroblasts)

↓ TIBC

(in response to high Ferritin)

↑ serum Fe

(Fe leaked from dead Erythroblasts)

↑ % saturation

(Fe binds up transferrin at higher than normal 30% rate)

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85
Q

Why is there increased percent saturation in sideroblastic anemia?

A

In iron-overloaded state there is also Fe leakage into serum

Leads to ↑ percent saturation (transferrin)

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86
Q

How are hemochromatosis patients similar to sideroblastic anemia patients?

A

Both are iron overloaded states

similar lab values

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87
Q

what is a characteristic of the carriers of thalassemia?

A

it is an inherited mutation

carriers protected against Plasmodium falciparum malaria

Sickle cell carriers also protected from severe malaria due to Plasmodium falciparum)

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88
Q

What are normal lab findings for

TIBC

Serum Iron

% Saturation

A

TIBC - 300pg/dL

Serum Iron - 100pg/dL (1/3 of TIBC)

% Saturation - 33% (1/3 of TIBC)

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89
Q

Regarding microcytic anemia what are the lab values for Iron Deficiency Anemia?

A

Ferritin - ↓

TIBC - ↑

Serum Iron - ↓

% Saturation- ↓

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90
Q

Regarding microcytic anemia what are the lab values for Anemia of Chronic Disease?

A

Ferritin- ↑

TIBC - ↓

Serum Iron- ↓

% Saturation- ↓

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91
Q

Regarding microcytic anemia what are the lab values for sideroblastic anemia?

A

Ferritin - ↑

TIBC - ↓

Serum Iron - ↑

% Saturation - ↑

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92
Q

What are lab values for

TIBC

% Saturation

seen with pregnancy and oral contraceptives?

A

TIBC- ↑

b/c liver ↑ production of transferrin

% Saturation- ↓ (because of ↑TIBC )

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93
Q

What is thalassemia?

A

Anemia due to decreased synthesis of the globin chains of hemoglobin

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94
Q

How is thalassemia divided?

A

Alpha

vs.

Beta

thalassemia

based on DECREASED production of

alpha vs beta globin chains

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95
Q

How is thalassemia related to microcytic anemia?

A

dec globin -> dec hemoglobin —> microcytic anemia

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96
Q

What are the normal types of hemoglobin?

A

HbF = Fetal Hemoglobin

(α2 and γ2)

HbA

(α2 and β2)

and

HbA2

(α2 and δ2)

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97
Q

What is alpha-Thalassemia usually due to?

A

Gene DELETION

Normally

4 αlpha alleles present

on chromosome 16

(2 on mom’s copy of Ch 16 and 2 on dad’s copy of Ch 16)

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98
Q

In alpha thalassemia what are the symptoms when one gene is deleted?

A

asymptomatic - 3 copies remain

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99
Q

In alpha thalassemia what are the symptoms when two genes are deleted?

A

mild anemia

with

slight ↑ RBC count

cis deletion - both copies knocked out on one chromosome

trans deletion - the 2 deleted alleles are on different copies of Ch 16

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100
Q

In alpha thalassemia what are the symptoms when cis deletion occurs?

A

it is when both deletions occur on the same chromosome; seen in Asians -

believed to be responsible for higher rate of spontaneous abortions in Asia

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101
Q

In alpha thalassemia what are the symptoms when trans deletion occurs?

A

mild anemia

with

slight ↑ RBC count

it is when one deletion occurs on each chromosome; seen in Africans, including African Americans (increased probability of carrier status in offspring-> protecting against Plasmodium falciparum)

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102
Q

Which is worse cis or trans deletion in alpha thalassemia?

A

Cis because it is associated with an increased risk of severe thalassemia in offspring, because 50% chance that offspring will get Ch 16 with both alpha globin alleles deleted.

If partner also has at least one defective copy, strong risk of severe thalassemia

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103
Q

In alpha thalassemia what are the symptoms when three genes are deleted?

A

No problem in utero. One copy enough to produce HbF.

Severe Anemia after birth

as HbA, and HbA2 production begins.

beta dimers (b/c low alpha dimers) combine to form tetramers (HbH) that damage RBCs

HbH is seen on electrophoresis

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104
Q

In alpha thalassemia what are the symptoms when four genes are deleted?

A

lethal in utero (hydrops fetalis = serious fetal condition defined as abnormal accumulation of fluid in two or more fetal compartments)

HbF not possible without alpha chains, so

gamma chains form tetramers (Hb Barts) that damage RBCs

Hb Barts seen on electrophoresis

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105
Q

What is Hb Barts?

A

it is a tetramer of gamma chains in Fetus

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106
Q

What is the difference between beta and alpha thalassemia?

A

Alpha is due to Alpha gene deletions

Beta is due to Beta gene mutations

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107
Q

Beta-Thalassemia is usually due what?

A

to gene mutations (point mutations in promoter or splicing sites); seen in individuals of African and Mediterranean descent

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108
Q

Where are beta genes present?

A

One beta allele present on each copy of Ch 11

Mutations result in either

complete knock out of Beta allele ( β0 - Beta Null)

or

Diminished ( β+) production of the β-globin chain

Results in spectrum of severity

β β+ - Beta Thalassemia Minor

β+/β+

β+β0

β0 β0

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109
Q

What is the difference between β0/ β+?

A

β0 is the complete inability to produce beta chain,

β+ is decreased production of beta chain

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110
Q

ß-thalassemia minor

A

(β/β+ - one normal beta and one decreased production of beta)

is the mildest form of disease

usually asymptomatic with an increased RBC count

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111
Q

In ß-thalassemia minor, what is seen on blood smear?

A

microcytic

hypochromic RBCs

target cells are seen on blood smear

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112
Q

In ß-thalassemia minor, what is seen on hemoglobin electrophoresis?

A

It shows slightly ↓ HbA

↑ HbA2 (5%, normal 2.5%)

↑ HbF (2%, normal 1%)

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113
Q

Why are target cells seen with Beta Thalassemia Minor?

A

Because Hb production is down, the RBC is not very densely packed, so some membrane forms a bleb in the middle where normally there is narrowing.

Hb accumulates in this bleb

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114
Q

ß-Thalassemia major

A

(ß0/ß0) is the most severe form of disease and

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115
Q

How does ß-Thalassemia major present?

A

with severe anemia a few months after birth;

high HbF (α2γ2) at birth is temporarily protective

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116
Q

In ß-Thalassemia major, why is there ineffective erythropoiesis?

A

alpha tetramers aggregate and damage RBCs as they are produced

removal by splenic macrophages of circulating RBCs by the spleen

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117
Q

In ß-Thalassemia major, why is there extravascular hemolysis?

A

removal by splenic macrophages of circulating RBCs by the spleen, as they recognize abnormal α-tetramers

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118
Q

What is ineffective erythropoesis in ß-Thalassemia major?

A

damage to the red blood cells as they are being generated by precipitated Hb caused by alpha tetramers

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119
Q

What is extravascular hemolysis in ß-Thalassemia major?

A

removal of circulating RBCs by the spleen

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120
Q

Why do the patients with ß-Thalassemia major develop massive erythroid hyperplasia?

A

Severe anemia causes massive EPO production by kidney

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121
Q

Why is there expansion of hematopoiesis into the skull in ß-Thalassemia major?

A

Severe anemia ->

massive EPO increase from kidney ->

BM hyperplasia

and

erythropoiesis expansion beyond axial skeleton and into skull and facial bones

and

Extramedullary hematopoesis

(Liver and Spleen)

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122
Q

What does expansion of hematopoiesis in ß-Thalassemia major present as?

A

reactive bone formation ->

skull with crewcut appearance on x-ray

and

facial bones giving chipmunk face

123
Q

In ß-Thalassemia major, what is seen in massive erythroid hyperplasia?

A

(1) expansion of hematopoiesis into bone marrow of skull and facial bones
(2) extramedullary hematopoiesis with hepatosplenomegaly
(3) risk of aplastic crisis with parvovirus B19 infection of erythroid precursors (Reticulocytes)

124
Q

What is Reticulocytopenia

or

Aplastic Crisis?

A

Abnormal cessation of RBC production due to

↓ Reticulocytes in the body

Viral Parvovirus B19 infection invades and destroys Reticulocytes (RBC precursors) and halts the RBC production

125
Q

Why do β-Thalassemia Major patients develop Aplastic Crisis when infected with Parvovirus B19

A

Infects and shuts down Reticulocytes (immature RBCs) - Normally self-limiting to 2 weeks

but in ß-Thalassemia major patients can’t afford to have Erythropoiesis shut down for even a day

126
Q

In ß-Thalassemia Major what is often necessary?

A

chronic transfusions to provide RBC’s often necessary RBC’s die after 120 days, but production of new RBC’s is very poor because globin Beta chain impossible.

leads to risk for secondary hemochromatosis

127
Q

In ß-Thalassemia Major, what does the blood smear show?

A

microcytic

hypochromic RBCs

with target cells

nucleated red blood cells (those abnormally produced extramedullary (spleen and liver) can escape before mature)

128
Q

Why does giving frequent blood transfusions lead to Secondary Hemochromatosis

A

Each transfusion is like a new bag of Iron

In Beta Thalassemia Major, patients can’t adequately replace RBC’s after they die (120 day lifecycle)

While normally people just recycle Fe from the old cells, These patients keep getting new Fe with each transfusion

129
Q

In ß-Thalassemia, what does electrophoresis show?

A

Little or No HbA

↑ HbA2 (α2 δ2)

and

↑ HbF (α2 γ2)

130
Q

What is Macrocytic Anemia?

A

Anemia with MCV > 100

MCC = folate or vitamin B12 deficiency (megaloblastic anemia)

One less division than normal of Erythroblasts (therefore bigger than normal) b/c

Disruption in DNA precursor synthesis

131
Q

What are folate and vitamin B12 are necessary for?

A

synthesis of DNA precursors

132
Q

What does folate circulates in the serum as?

A

methyltetrahydrofolate (methyl THF);

133
Q

What happens to methyl-THF?

A

removal of the Methyl group allows for participation in the synthesis of DNA precursors.

134
Q

What happens to the methyl group from methyl THF?

A

It is transferred to vitamin B12 (cobalamin),

135
Q

What does Vitamin B12 do with the methyl it receives from methyl THF?

A

B12 then transfers the methyl to homocysteine, producing methionine

136
Q

Lack of folate or vitamin B12 does what?

A

impairs synthesis of DNA precursors

THF without Methyl - necessary for synthesis DNA precursors

B12 necessary for removal of Methyl Group from Met-THF, so that THF can participate in synthesis of DNA precursors

137
Q

What does impaired division and enlargement of RBC precursors lead to?

A

Megaloblastic anemia

138
Q

What does impaired division of granulocytic precursors lead to?

A

hypersegmented neutrophils

=

Neutrophils that have > 5 lobes (Normal 3-5)

139
Q

Where is megaloblastic change also seen?

A

in rapidly-dividing (e.g., intestinal) epithelial cells

=

Enlargement of Epithelial cells in the Gut

140
Q

What are some other causes of Macrocytic anemia (Only called megaloblastic anemia if due to Folate or B12 deficiency)?

A

Alcoholism

Liver disease

Drugs (e.g., 5-FU)

Only affects RBC’s

You would see RBC MCV >100

but would NOT see

Hypersegmented Neutrophils

Megaloblastic change in Rapidly Dividing Cells

141
Q

Where is dietary folate obtained?

A

from green vegetables and some fruits

142
Q

Where is dietary folate absorbed?

A

in the jejunum

143
Q

How fast does folate deficiency develop?

A

within months

B/C body stores are minimal

144
Q

What are some causes of folate deficiency?

A

1) poor diet - Alcoholics and Elderly
2) increased demand for cell division - pregnancy, cancer, hemolytic anemia
3) folate antagonists - methotrexate - inhibits dihydrofolate reductase

145
Q

What are some examples of poor diet leading to folate deficiency?

A

Seen in alcoholics and elderly

146
Q

What are some examples of increased demand leading to folate deficiency?

A

Increase in DNA synthesis due to

Rapidly dividing cells:

Pregnancy

Cancer

OR need for replacing rapidly destroyed cells (rapid turnover)

Hemolytic anemia

147
Q

What are the clinical and laboratory findings for Megaloblastic anemia secondary to THF deficiency?

A
  1. Macrocytic RBCs and hypersegmented neutrophils (> 5 lobes.
  2. Glossitis b/c not enough DNA to sufficiently produce replacement cells for high turnover cells of tongue -> damage-> inflammation->pain
  3. decreased serum folate (obviously)
  4. increased serum homocysteine (because no THF, means no methyl transfer to cobalamine (b12), so no methyl transfer to ) (remember: homocysteine increases risk for thrombosis)
  5. Normal methylmalonic acid (This is a negative finding that rules out B12 as a culprit for the Megaloblastic anemia. Methylmalonic acid to Succinyl CoA requires B12 as a cofactor = if it is normal it means that B12 levels are normal)
148
Q

What is dietary vitamin B12 complexed to?

A

animal-derived proteins

149
Q

How is Vitamin B12 liberated from being complexed to animal-derived protein?

A

salivary gland enzymes (e.g., amylase) liberate vitamin B12 from animal-derived protein

150
Q

After Vit B12 reacts with salivary gland enzymes what happens?

A

R-binder (also produced by salivary glands) binds to B12 and they travel through the stomach and into the intestines

151
Q

What happens to Vit B12 after it reaches the Small Intestine?

A

Pancreatic proteases in the duodenum detach vitamin B12 from R-binder

152
Q

After Vitamin B12 is detached from R binder, what happens?

A

It binds intrinsic factor (made by gastric parietal cells) in the small bowel

153
Q

Where is the intrinsic factor-vitamin B12 complex absorbed?

A

in the ileum

154
Q

How common is vitamin B12 deficiency?

A

it is less common than folate deficiency and takes years to develop due to large hepatic stores of vitamin B12

155
Q

Why does it take years for Vitamin B12 deficiency to develop?

A

Due to large hepatic stores of Vitamin B12

156
Q

What is the MCC of vitamin B12 deficiency?

A

pernicious anemia

157
Q

What is pernicious anemia?

A

autoimmune destruction of parietal cells (found in body of stomach) -> Intrinsic Factor deficiency

158
Q

What are the 3 P’s of Parietal cells of the the Body of the stomach

A

1) Proton Pumps - They produce the Acid in the stomach
2) Pink (they are relatively pink compared to Bluish Chief Cells on Histology)
3) Pernicious Anemia - if destroyed by Autoimmune disease -> ↓Intrinsic Factor -> ↓B12

159
Q

What are some other causes of vitamin B12 deficiency?

A

Pancreatic insufficiency - b/c Pancreatic enzymes (proteases) NECESSARY to cleave Vit B12 from R-binder

Damage to the terminal ileum (by Crohn disease or Diphyllobothrium latum - fish tapeworm) b/c B12-IF is absorbed in Ileum

Dietary deficiency is rare, except in vegans

160
Q

What are the clinical and laboratory findings for Vitamin B12 deficiency?

A
  1. Macrocytic RBCs (MCV >100) with hypersegmented neutrophils
  2. Glossitis - Poor turnover of the cells of the tongue, because if B12 doesn’t remove Methyl group from THF, then THF not able to participate in DNA synthesis
  3. Subacute combined degeneration of the spinal cord (build up of methylmelonic acid in spinal cord myelin - positive finding that would not be seen wtih THF deficiency)
  4. ↓ serum vitamin B12
  5. ↑ serum homocysteine
  6. ↑ methylmalonic acid
161
Q

How does vitamin B12 relate to Subacure Combine Denegeneration of the Spinal Cord?

A

B12 is involved in 2 major rxns in body (picking up Methyl group from THF, and conversion of Methylmalonic acid to Succinyl CoA)

Vitamin B12 is a cofactor for the conversion of Methylmalonic acid to Succinyl CoA (important in fatty acid metabolism) –> toxic build up of methylmalonic acid builds up in oligodendrocytes of spinal cord (myelin cells of CNS) ->demyelination in spinal cord

162
Q

How does Vitamin B12 deficiency relate to spinal cord degeneration?

A

Vit B deficiency results in increased levels of methylmalonic acid, which impairs spinal cord myelination,

163
Q

What does damage to the spinal cord due to Vitamin B12 deficiency present?

A

poor proprioception and vibratory sensation

(Posterior column-medial lemniscus pathway = sensory pathway of the central nervous system that conveys localized sensations of fine touch, vibration, two-point discrimination, and proprioception (position sense) from the skin and joints)

and

spastic paresis = increased, involuntary muscle tone that causes resistance to movement. The condition is typically a result of insult to the CNS or motor neurons

(lateral corticospinal tract = controls fine movement of ipsilateral limbs (albeit contralateral to the corresponding motor cortex) as it lies distal to the pyramidal decussation.)

164
Q

How is Vitamin B12 deficiency similar to folate deficiency?

A

Increased serum homocysteine which is similar to folate deficiency and increases the risk for thrombosis

165
Q

What is normocytic anemia?

A

Anemia with normal-sized RBCs (MCV = 80-100 μm^3)

166
Q

What is normocytic anemia due to?

A

↑ Peripheral Destruction

or

Underproduction

167
Q

How do you distinguish between the two etiologies of normocytic anemia?

A

Reticulocyte count

if there is ↑Reticulocyte Count that means there is no Production problem, so it must me a RBC Destruction problem

168
Q

What are reticulocytes?

A

Young RBCs released from the Bone Marrow

169
Q

How are reticulocytes identified?

A

They appear on blood smear as larger cells with bluish cytoplasm (due too residual RNA)

170
Q

What is the normal reticulocyte count (RC)?

A

1-2%.

171
Q

What is the RBC lifespan?

A

120 days

172
Q

What is the turnover of RBC’s?

A

each day roughly 1-2% of RBCs removed from circulation and replaced by reticulocytes

that is why reticulocyte percentage is 1-2%

173
Q

How does a properly functioning marrow respond to anemia?

A

by increasing the Retic Count to >3%.

174
Q

Is Retic Count reliable in anemia?

A

Retic Count is falsely elevated in anemia

175
Q

Why is Retic Count falsely elevated in anemia?

A

It is measured as a percentage of total RBCs; decrease in total RBCs falsely elevates percentage of reticulocytes

176
Q

How is Retic Count corrected?

A

By multiplying reticulocyte count by Hct/45

45 because

Normal Hct = 45 µm³ of RBC’s for 100 µm³ of blood

therefore if Hct is below normal = anemia, this accounts for it

that way Retic Count won’t be Falsely Elevated in anemia

177
Q

What is the reticuloendothelial system?

A

An old term (now understood that endothelial cells not actually involced), now called

mononuclear phagocyte system (MPS)

consists of the phagocytic cells located in reticular connective tissue (connective tissue with a network of reticular fibers, made of type III collagen)

reticular cells are fibroblasts that produce the the type III collagen network

178
Q

What does a corrected Retic Count > 3% indicate?

A

good marrow response and suggests peripheral destruction

179
Q

What does a corrected RC count < 3% indicate?

A

poor marrow response and suggests underproduction

180
Q

What is peripheral vascular destruction divided into?

A

Extravascular

or

Intravascular

HEMOLYSIS

181
Q

What does peripheral vascular destruction result in?

A

Anemia with a good marrow response

182
Q

Extravascular hemolysis involves what?

A

RBC destruction by the reticuloendothelial system (macrophages of the spleen, liver, and lymph nodes)

183
Q

What is the role of macrophages in extravascular hemolysis?

A

consume RBCs and break down Hb

184
Q

What do macrophages break down globin into?

A

globin is broken down into amino acids

185
Q

What is heme broken down into?

A

Fe + Protoporphyrinn

Fe is recycled

186
Q

In the reticuloendothelial system what is protoporphyrin broken down into?

A

Protoporphyrin converted to Unconjugated bilirubin->

Unconjugated bilirubin binds to serum albumin ->

UB travels to liver for conjugation ->

Conjugatebilirubinn excreted into bile

187
Q

What is the clinical presentation

and

laboratory findings

for Extravascular Hemolysis?

A

Anemia - RBC’s destroyed

splenomegaly - 1) Splenic Macrophages actively destroying RBC’s by consuming parts of them-> work hypertrophy of splenic macrophages 2) Spherocytes have a hard time passing through the cords of Bilroth **, and they back up in the spleen, causing splenomegaly.

jaundice due to build up of unconjugated bilirubin (UC bilirubin produced at a higher rate than liver can conjugate)

increased risk for bilirubin gallstones (supersaturation of billirubin in the bile)

Marrow hyperplasia - In response to anemia

Retic count > 3% because BM pumping out as many as possible

** Cords of Billroth found in the red pulp of the spleen between the sinusoids, consisting of fibrils and connective tissue cells with a large population of monocytes and macrophages (Reticular Endothelial system)v

188
Q

When lab would be seen if marrow hyperplasia occurs in response extravascular hemolysis?

A

Corrected reticulocyte count > 3%

189
Q

What does intravascular hemolysis involve?

A

The destruction of RBCs within vessels

190
Q

What are the clinical and laboratory findings for intravascular hemolysis?

A

1) Hemoglobinemia ->Hb released into blood
2) Hemoglobinuria b/c Hb water soluble
3) Hemosiderinuria follows a few days later
4) Decreased serum haptoglobin - Haptoglobin doesn’t play big role, but valuable lab test

191
Q

what happens to small percentage of Hb that leaks out into blood due to intravascular hemolysis?

A

bound to Haptoglobin that takes Hb to spleen to be reprocessed, to save Fe.

Labs will show ↓ Free Haptoglobin, because most complexes with Hb

However, there is not a lot of Haptoglobin, so most Hb does not bind to Haptoglobin

192
Q

Why is there hemosiderinuria in intravascular hemolysis?

A

Renal tubular cells pick up some of the hemoglobin that is filtered into the urine and break it down into iron, which accumulates as hemosiderin; tubular cells are eventually shed resulting in hemosiderinuria.

193
Q

Why does Hemosiderinuria follow a few days later in Intravascular Hemolysis?

A

Hemosiderinuria follows a few days later - > some Hb taken up by Prox Convoluted tubule cells -> Fe piles up and binds together as Hemosiderin deposits -> b/c Fe is nephrotoxic, and these cells turn over, days later these cells die/shed -> Hemosiderin goes into urine

194
Q

What is a myelophthisic process?

A

Pathologic process (e.g., metastatic cancer) that replaces bone marrow; hematopoiesis is impaired, resulting in pancytopenia

myelo- bone marrow

-phthisis, from Ancient Greek φθίσις “waste away”

195
Q

What are the normocytic anemias with predominant extravascular hemolysis?

A

1) hereditary spherocytosis 2) Sickle cell anemia 3) Hemoglobin C

196
Q

What is hereditary spherocytosis?

A

Inherited defect of RBC cytoskeleton-membrane tethering proteins

197
Q

What is the underlying cause of hereditary spherocytosis?

A

RBC maintains shape because cytoskeleton is normally tethered to RBC membrane via (tethering molecules = spectrin, ankyrin, or band 3.1 )

An inherited defect in these tethering molecules causes blebs of membrane to pop out

The blebs are removed by splenic macrophages->

depletion of membrane, so no longer big enough to maintain biconcave disk shape

because anchoring molecules defective, and not enough membrane-> RBC’s turn into spherocytes

Spherocytes -> can’t effectively move through splenic sinusoids ->

consumed by splenic macrophages->

Anemia

198
Q

What happens with the RBC membrane in hereditary spherocytosis?

A

membrane blebs are formed and lost over time

loss of central pallor as biconcave shape is replaced with one homogeneous ball

199
Q

In hereditary spherocytosis what happens due to loss of the membrane?

A

It renders cells round (spherocytes) instead of disc-shaped-> spherocytes get stuck in Splenic sinusoids -> consumed by splenic macrophages-> Anemia

200
Q

How does hereditary spherocytosis lead to anemia?

A

Spherocytes are less able to maneuver through splenic sinusoids and are consumed by splenic macrophages, resulting in anemia

201
Q

What do the clinical and laboratory findings for hereditary spherocytosis include?

A

Blood Smear

1) Spherocytes with loss of central pallor
2) ↑ RDW (the older the RBC the smaller it becomes because more and more membrane blebs removed)
3) ↑mean corpuscular hemoglobin concentration (MCHC) - as cells lose membrane, the volume of the cell goes down, but the Hb content of the cell remains the same, therefor MCHC goes UP

Clinical Presentation

1) Splenomegaly (work hypertrophy = macrophages eating up spherocytes, becoming bigger)
2) jaundice with unconjugated bilirubin - b/c so much Hb released that it overwhelms liver’s capacity to conjugate bilirubin
3) ↑ risk for bilirubin gallstones (extravascular hemolysis)- once all bilirubin conjugated it will get dumped into gallbladder at very high concentrations.
4) Increased risk for aplastic crisis with parvovirus B19 infection of erythroid precursors, because already limited reserve of RBC’s due to spherocyte destruction, so blocking production -> aplastic crisis

202
Q

What lab test is used to diagnose hereditary spherocytosis?

A

Osmotic fragility test,

which reveals increased spherocyte fragility in hypotonic solution (because as water rushes in, membrane is so tight b/c now shere instead of biconcave, so it has no room for expansion-> RBC ruptures))

203
Q

What is the treatment for hereditary spherocytosis?

A

splenectomy b/c no problem with having spherocytes. The problem is that the splenic macrophages eat the spherocytes-> Anemia

  • Anemia resolves (because macrophages don’t destroy spherocytes)
  • Spherocytes persist because membrane blebbing still occurs, and macrophages in other reticuloendothelial system organs - lymph nodes and liver - still remove blebbing membrane
  • Howell Jolly bodies (fragments of nuclear material left over from erythropoeisis) emerge on blood smear because no spleen around to remove them
204
Q

What are Howell Jolly bodies?

A

fragments of nuclear material in RBCs – appears on blood smear

205
Q

What is sickle cell anemia?

A

Autosomal recessive mutation in β-chain of hemoglobin; a single amino acid change Valine (hydrophobic) instead of glutamic acid (hydrophilic)

206
Q

Who carries the gene for sickle cell anemia?

A

it is carried by 10% of individuals of African descent, likely due to protective role for carriers against falciparum malaria

207
Q

When does sickle cell disease arise?

A

When two abnormal beta genes are present;

Results in α2 β2S = Hb S ->

>90% HbS in RBCs

208
Q

What causes the formation of the sickle cell structure?

A

HbS reversibly polymerizes when (hypoxemia, dehydration, acidosis) - anything that causes HbS to come together (in deoxygenation Hb expands, as it expands they are more likely to interact, same is true in dehydration. Acidosis causes Hb to expand and release oxygen (because usually means high carbonic acid - from high Co2))

polymers aggregate into needle-like structures, resulting in sickle cells

209
Q

When is there increased risk of sickling?

A

3 driving factors for sickling

Hypoxemia - Hb is deoxygenated

Dehydration

Acidosis

210
Q

Is sickle cell seen at birth?

A

HbF protects against sickling; high HbF at birth is protective for the first few months of life

211
Q

What is the treatment for sickle cell anemia?

A

hydroxyurea b/c it causes ↑ levels of HbF

mechanisms unknown

212
Q

In sickle cell anemia, what happens to cells as it passes through microcirculation?

A

The cells sickle and de-sickle depending on O2 saturation while passing through the microcirculation

-> the crystal polymers of HbS in sickling phase prick and damage the RBC membrane

213
Q

How does sickle cell anemia interact with the reticuloendothelial system?

A

RBC’s with HbS get membrane damage ->

become less flexible ->

get stuck in splenic sinusoids ->

Extravascular Hemolysis b/c

macrophages of reticuloendothelial system remove RBCs with damaged membranes->

1) anemia
2) jaundice with unconjugated hyperbilirubinemia
3) increased risk for bilirubin gallstones

214
Q

How does sickle cell anemia lead to decreased haptoglobin and target cells on blood smear?

A

In addition to mostly Extravascular Hemolysis in Spleen, there is also a small amount of

Intravascular hemolysis where RBCs with damaged membranes lyse -> lab show ↓ haptoglobin as it binds up released Hb in blood

Target cells on blood smear - b/c RBC membrane damage -> dehydration-> decreased cytoplasm in those cells -> now blebs form in the middle, as cytoplasm volume increases but membrane Surface Area remains constant -> bleb in the middle, which gets full of Hb

215
Q

Massive erythroid hyperplasia ensues in sickle cell anemia resulting in what?

A

1) Expansion of hematopoiesis into the skull (‘crewcut’ appearance on x-ray) and facial bones (‘chipmunk faces’) (just like in β-thalassemia major)
2) Extramedullar hematopoiesis with hepatomegaly (b/c once BM is producing at the max, but EPO continues to be high hematopoeisis moves to liver (and spleen of they still have one)
3) Risk of aplastic crisis with parvovirus B19 infection of erythroid precursors

216
Q

What does irreversible sickling lead to?

A

complications of vaso-occlusion

217
Q

Besides Membrane damages from sickling leading to anemia, what is the other major problem in sickle cell disease?

A

Irreversible sickling

218
Q

What are the complications of vaso-occlusion resulting from irreversible sickling?

A

1) Dactylitis
2) Autosplenectomy
3) Acute chest syndrome
4) Pain crisis
5) Renal papillary necrosis

219
Q

What is dactylitis?

A

swollen hands and feet due to vaso-occlusive infarcts in bones

Very common presenting sign in 6 month old infants once HbF runs out

220
Q

What is autosplenectomy, and what are the consequences?

A

vaso-occlusive crises in spleen -> infarction-> shrunken, fibrotic spleen

Consequences include:

1) Increased risk of infection with encapsulated organisms (b/c spleen is primary source of Ab production - but now gone) such as Streptococcus pneumoniae

and

Haemophilus influenzae (most common cause of death in children with Sickle Cell disease) affected children should be vaccinated by 5 years of age

2) Increased risk of Salmonella paratyphi osteomyelitis (in normal population Staph aureus is MCC of osteomyelitis, but in Sickle Cell Disease pts it is Salmonella paratyphi)
3) Howell-Jolly bodies on blood smear - on rare occasion that RBC exits BM with nucleus, spleen normally removes it. However, non-functioning, fibrotic spleen (autosplenectomy) can’t do this

221
Q

What is the most common cause of death in children sickle cell patients?

A

Infection from encapsulated organisms secondary to autosplenectomy

222
Q

What is acute chest syndrome?

A

vaso-occlusion in pulmonary microcirculation

223
Q

What does acute chest syndrome present with?

A

Presentation

chest pain

Shortness of breath

Lung infiltrates

224
Q

Acute chest syndrome is often precipitated by?

A

Often precipitated by pneumonia

Lung infection-> inflammation-> vasodilation-> slowing down of blood flow in pulmonary microcirculation-> ↑transit time for RBC’s with HbS -> increased transit time can result in incr chance of dehydration, acedemia, and deoxygenation of RBC’s (all cause HbS to interact with each other ->promoting sickling)

225
Q

What is the most common cause of death in adult sickle cell patients?

A

Acute chest syndrome

226
Q

Renal papillary necrosis results in what?

A

vaso-occlusive crisis in kidney -> gross hematuria and proteinuria

The hypoxic, acidotic, and hyperosmolar environment of the inner medulla (vasa recta) ->

sickling of red blood cells (RBCs)->

occlusion/congestion->

impairment in renal medullary blood flow, ischemia, microinfarction, and papillary necrosis ->

Hematuria due to vascular obstruction and RBC extravasation into the collecting system or due to papillary necrosis

227
Q

What is the sickle cell trait?

A

Only 1 mutated copy of beta chain gene

and 1 normal copy

228
Q

What is result of sickle cell trait ?

A

<50% HbS in RBCs ~45%

and >50% HbA (HbA is slightly more efficiently produced than HbS) - ~55%

Important because you need > 50% HbS for sickling to happen

∴

GENERALLY ASYMPTOMATIC

with only 1 EXCEPTION:

Renal Medulla

229
Q

How does the sickle cell trait present?

A

Generally asymptomatic with no anemia; RBCs with < 50%, HbS do not sickle in vivo except in the renal medulla

230
Q

When would sickling occur in the sickle cell trait?

A

Extreme hypoxia and hypertonicity in the Vasa Recta of the medulla cause sickling

231
Q

In the sickling trait what happens?

A

microinfarctions in renal medulla ->

microscopic hematuria and, eventually…

decreased ability to concentrate urine

because of medullary infarction (urine concentrated in renal medulla)

232
Q

What are the laboratory findings for the sickle cell trait?

A

1) Blood smear shows no sickle cells and target cells (unlike sickle cell disease)
2) Metabisulfite screen causes cells with any amount of HbS to sickle; positive in both disease and trait
3) Hb electrophoresis confirms the presence and amount of HbS.

233
Q

What does Hb electrophoresis show in sickle cell disease?

A

90% HbS

8% HbF

2% HbA2

0% HbA - b/c no normal β chains exist

234
Q

What does Hb electrophoresis show in sickle cell trait?

A

55% HbA

43% HbS

2% HbA2

235
Q

What is hemoglobin C?

A

Autosomal recessive mutation in β chain of Hb

236
Q

What amino acid is affected in hemoglobin C?

A

AA lysine instead of glutamic acid

237
Q

How common is Hemoglobin C?

A

It is less common than sickle cell disease

238
Q

What does hemoglobin C present with?

A

presents with mild anemia due to extravascular hemolysis

239
Q

In Hemoglobin C what is seen on blood smear?

A

Characteristic HbC crystals are seen in RBCs on blood smear

240
Q

What are the normocytic anemias with predominant intravascular hemolysis?

A

1) Paroxysmal Nocturnal Hemoglobinuria (PNH)
2) G6PD deficiency
3) Immune Hemolytic Anemia (IHA)
4) Microangiopathic hemolytic anemia
5) Malaria

241
Q

What is paroxysmal nocturnal hemoglobinuria?

A

Acquired mutation in myeloid stem cells ->

Loss of GPI (glycosylphosphatidylinositol ) expression->

Loss of RBC surface molecules that inactivated complement b/c GPI was their anchoring molecule->

Renders RBCs susceptible to destruction by complement

242
Q

What is the relationship between blood cells and complement?

A

Blood cells coexist with complement in circulation

In order to survive and not be destroyed by complement, blood cells have membrane surface proteins that inactivate complement

243
Q

What are DAF and MIRL?

A

Blood cell (RBC’s, leukocytes, platelets) surface proteins that inactivate complement

DAF (Decay-Accelerating Fact) is on the surface of blood cells

protects against complement-mediated damage by inhibiting C3 convertase.

MIRL (Membrane Inhibitor of Reactive Lysis)

244
Q

How is DAF secured to the cell membrane?

A

By GPI (an anchoring protein)

245
Q

What is the consequence of the absence of GPI on the RBC membrane?

A

Absence of DAF ->

RBCs rendered susceptible to complement-mediated lysis

246
Q

How is intravascular hemolysis related to paroxysmal nocturnal hemoglobinuria?

A

Intravascular hemolysis occurs episodically, often at night during sleep

b/c

shallow breathing at night->

↑CO2 ->

↑carbonic acid->

↑Mild Respiratory Acidosis in blood->

Acidosis activates complement->

RBC’s without complement deactivators on surface get attacked->

RBC Lysis->

Hb leaks out into blood (Hemoglobinemia)->

FIltered by kidneys ->

Hemoglobinuria

247
Q

What develops in paroxysmal nocturnal hemoglobinuria?

A

Mild respiratory acidosis

develops with shallow breathing during sleep and activates complement

The CO2 mixes with water in the body to form carbonic acid. The body’s main response is an increase in excretion of carbonic acid and retention of bicarbonate base in the kidneys, so when person wakes up, and breathes normally, everything resolves.

248
Q

In paroxysmal nocturnal hemoglobinuria what is lysed?

A

RBCs, WBCs, and platelets are lysed

249
Q

What test is used to screen for paroxysmal nocturnal hemoglobinuria?

A

Sucrose test b/c it activates complement -> Lysis of RBC’s without complement inhibitors

250
Q

What is a confirmatory test for paroxysmal nocturnal hemoglobinuria?

A

Acidified serum test (b/c acid activates complement)

or

flow cytometry to detect the lack of CD55 (DAF) on blood cells (confirms absence of GPI and of course absence of DAF)

251
Q

What is the main cause of death in paroxysmal nocturnal hemoglobinuria?

A

Thrombosis of

Hepatic

Portal

or

Cerebral veins

252
Q

In paroxysmal nocturnal hemoglobinuria what induces thrombosis?

A

Destroyed platelets release cytoplasmic contents into circulation->

inducing thrombosis

253
Q

In paroxysmal nocturnal hemoglobinuria what are the complications?

A

Fe deficiency anemia due to chronic loss of Hb in the urine

Thrombosis of Hepatic, Portal, Cerebral Veins

and

Association w/ Acute Myeloid Leukemia (AML) = develops in 10% of patients, (Since 1 mutation led to loss of DAF or MIRL in myeloid stem cell, likelihood of another mutation is high

254
Q

What is G6PD deficiency?

A

X-linked recessive disorder ->

reduced half-life of G6PD in RBCs->

RBCs susceptible to oxidative stress

255
Q

How does G6PD deficiency lead to intravascular hemolysis?

A

↓ G6PD ->

↓ NADPH ->

↓ Glutathione (enzyme that inactivates radicals) ->

oxidative injury to RBCs by H202 ->

intravascular hemolysis

256
Q

What is the relationship between G6PD and RBCs?

A

RBCs are normally exposed to oxidant stresses in circulation

Particularly H2O2

257
Q

What neutralizes H2O2?

A

Glutathione (an antioxidant) neutralizes H2O2, but becomes oxidized in the process

H2O2 + GSH (Glutothione) -> GS-SG

NADPH picks up the electron and reduces GS-SG back to GSH

Without G6PD ->

NADPH not produced in Pentose Phosphate Pathway->

GSH (Glutothione) not regenerated->

H2O2 NOT Neutralized by GSH->

Oxidative damage to RBC’S

258
Q

What is needed to regenerate glutathione?

A

NADPH (by-product of G6PD in Pentose phosphate pathway)

259
Q

How many variants are there for G6PD deficiency?

A

2 major variants

African variant

and

Mediterranean variant

260
Q

What is seen with the African variant of G6PD deficiency?

A

mildly reduced half-life of G6PD (RBC’s survive ~90/120 days) ->

Mild intravascular hemolysis (b/c only RBC’s >90 days old are G6PD Deficient) with oxidative stress

261
Q

What is seen in the Mediterranean variant of G6PD deficiency?

A

Markedly reduced half-life of G6PD (RBC only survives ~30/120 days) ->

marked intravascular hemolysis with oxidative stress

262
Q

Why is there a high carrier frequency for both variants of G6PD deficiency?

A

High carrier frequency in both populations is likely due to protective role against Plasmodium falciparum malaria

263
Q

What is the relationship between G6PD deficiency and Heinz bodies?

A

Oxidative stress precipitates Hb as Heinz bodies (Oxidation causes cross-linking of sulfhydryl groups on globin chains ->precipitation of Hb)

264
Q

What are some causes of oxidative stress?

A

Infections

Drugs

(e.g., primaquine (malaria), sulfa drugs and dapsone (antibiotics))

Fava beans - think Mediterranean variant

265
Q

What happens to Heinz bodies?

A

Removed from RBCs by splenic macrophages->

Bite cells

266
Q

Hb precipitating as Heinz bodies leads to what?

A

After Splenic Macrophages “Bite” the Heinz bodies->

Predominantly Intravascular hemolysis as contents leak out of RBC in blood

Rarely Extravascular hemolysis where splenic macrophages consume entire RBC is rare

267
Q

What does G6PD deficiency present with?

A

hemoglobinuria

and

back pain hours after exposure to oxidative stress (b/c Hb toxic to kidneys)

268
Q

What is used to screen G6PD deficiency?

A

Heinz preparation stains precipitated Hb (Heinz body)

pink on microscopy

269
Q

How can precipitated Hb be seen?

A

precipitated Hb can only be seen with a special

Heinz stain

270
Q

What is used to confirm G6PD deficiency? When is it performed?

A

Enzyme studies confirm deficiency (performed weeks after hemolytic episode resolves b/c immediately after oxidative stress, all old RBC’s with malfunctioning G6PD have been lysed and destroyed leaving only young RBC’s with functioning G6PD)

271
Q

What is immune hemolytic anemia?

A

Antibody-mediated (IgG or IgM) destruction of RBCs

272
Q

In IHA what does the IgG-mediated disease usually involve?

A

Extravascular Hemolysis

first turned into spherocytes by splenic macrophages, and as more IgG binds, ultimately lysed by splenic macrophages

273
Q

In IgG mediated IHA why do spherocyte form?

A

IgG binds RBCs in the relatively warm temperature of the central body (warm agglutinin)

portions of RBC membrane coated with antibodies consumed by SPLENIC macrophages->

spherocytes

274
Q

What is the most common cause of IgG-mediated IHA?

A

SLE

275
Q

What is IgG mediated IHA associated with?

A

1) SLE (most common cause)
2) CLL
3) Drugs (classically, penicillin and cephalosporins)

276
Q

How do certain drugs relate to IgG mediated IHA?

A

1) Drug may attach to RBC membrane (e.g. penicillin) ->

Binding of Ab specific to drug-membrane complex

2) Drug induces production of autoantibodies (e.g. methyldopa) that bind self-antigens on RBCs

277
Q

What does the treatment of IgG mediated IHA involve?

A

1) Cessation of the offending drug - underlying cause
2) Steroids - immunosupressants
3) IVIG - temporary relief because IVIG overwhelms splenic macrophages, so RBC’s allowed to temporarily survive
4) If necessary: Splenectomy

278
Q

What happens in IgM mediated IHA?

A

IgM binds RBCs

and

Fixes Complement

in the relatively cold temperature of the extremities (cold agglutinin)

279
Q

What is the IgM mediated IHA associated with?

A

Mycoplasma pneumoniae

and

Infectious Mononucleosis

280
Q

What test is used to diagnose IHA?

A

Coombs test

Direct

vs

Indirect

281
Q

What does IgM-mediated IHA disease involve?

A

Intravascular Hemolysis

282
Q

What is the Direct Coombs test?

A

Confirms presence of antibody-coated RBCs

Anti-IgG added to patient RBCs; agglutination occurs if RBCs are already coated with antibodies, therefore Anti-IgG Ab’s cross-link multiple RBC’s

283
Q

What is the most important test for IHA?

A

Direct Coombs test

284
Q

What is the indirect Coombs test?

A

Confirms presence of Ab in patient serum

Anti-IgG and test RBCs are mixed with the patient serum

agglutination only occurs if serum antibodies are also present

b/c

Serum Ab’s bind test RBC’s

and Anti-IgG Ab’s cross-link test RBCs now covered with serum Ab’s

285
Q

What is microangiopathic hemolytic anemia?

A

Intravascular hemolysis that results from vascular pathology->

RBC destruction as they pass through microthrombi (platelet or platelet-fibrin thrombi) in circulation

1) Thrombotic Thrombocytopenic Purpura: due to Anti- ADAMTS13 Ab, which normally cleaves vWF -> vWF multimers
2) HUS due to toxin produced by E. coli O157:H7
3) DIC = platelet + Fibrin thrombi -> schistocytes
4) HELLP (Hemolysis Elevated Low Liver Enzymes and Platelets) Syndrome - Pregnant woman can develop Microangiopathic Hemolytic Anemia in Liver due to these thrombi as well

286
Q

What occurs with chronic hemolysis?

A

Iron deficiency anemia b/c -> hemoglobineuria -> Fe loss

287
Q

Intravascular Hemolytic anemia occurs with what?

A

Microthrombi (TTP, HUS, DIC, HELLP)

Prosthetic heart valves (RBC’s crushed)

Aortic stenosis (calcified degenerative valve-> turbulent flow - RBC’s crushed)

(Microthrombi -> schistocytes on blood smear)

288
Q

What is malaria?

A

Infection of RBCs and liver with Plasmodium

transmitted by the female Anopheles mosquito

289
Q

How does malaria affect RBCs?

A

RBCs rupture as a part of the Plasmodium life cycle->

intravascular hemolysis and cyclical fever

290
Q

How does patient with Plasmodium falciparum classically present?

A

daily fever

291
Q

Hoq do Plasmodium vivax and Plasmodium ovale present?

A

fever every other day

292
Q

What is the role of spleen in malaria?

A

Spleen consumes some infected RBCs->

mild extravascular hemolysis with splenomegaly

293
Q

What is anemia due to underproduction?

A

Decreased production of RBCs by bone marrow

characterized by low corrected reticulocyte count

294
Q

What are the etiologies for anemia due to underproduction?

A

1) Microcytic and Macrocytic Anemias
2) Renal failure (b/c ↓ EPO)
3) Damage to bone marrow precursor cells (may result in anemia or pancytopenia)

295
Q

What is pancytopenia?

A

Medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets

296
Q

How does renal failure lead to anemia due to underproduction?

A

Decreased production of EPO by peritubular interstitial cells

297
Q

What is parvovirus B19?

A

Infects progenitor red cells and temporarily halts erythropoiesis->

significant anemia in the setting of preexisting marrow demand (i.e. RBC numbers already low) e.g. sickle cell anemia

298
Q

What is aplastic anemia?

A

Damage to hematopoietic stem cells->

pancytopenia (anemia, thrombocytopenia, and leukopenia) with low reticulocyte count

299
Q

What are the Aplastic etiologies for pancytopenia?

A

1) Drugs or chemicals

2) Viral infections

3) Autoimmune damage

300
Q

In aplastic anemia, what does biopsy reveal?

A

Reveals an empty, fatty marrow

b/c adipose tissue has replaced hematopoietic elements

301
Q

What does treatment of aplastic anemia include?

A

#1 Cessation of any causative drugs

supportive care with

Transfusions

and

Marrow-stimulating factors

(e.g., erythropoietin (RBC’s), GM-CSE and G-CSE for granulocytes)

302
Q

Aside from cessation of causative drugs what may be helpful in the treatment of apalstic anemia?

A

Immunosuppression may be helpful as some idiopathic cases are due to abnormal T-cell activation with release of cytokines

303
Q

What may be helpful in the treatment of aplastic anemia as a last resort?

A

bone marrow transplantation as a last resort

304
Q

What is Myelophthisic Process?

A

Pathologic Process that replaces the bone marrow ->

Hematopoiesis impaired->

Pancytopenia

(e.g. metastatic cancer that diffusely replaces Bone Marrow)

Pathoma Enhanced (19 decks)

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