Pathoma Red Blood Cell Disorders Flashcards
1
Q
What is the technical definition of anemia and what is one example which shows why Hb, Hct, and RBC count are not perfect surrogates?
A
Decrease in circulating RBC mass
I.e. after a gunshot wound, patient has lost RBC mass -> anemia. But until the fluid is replaced, the concentration of everything will be normal (these measure are concentration dependent).
2
Q
What is the definition of anemia in males / females?
A
Males: Hb < 13.5 g/dL
Females: Hb < 12.5 g/dL
3
Q
What is the normal range for MCV?
A
80-100 fL
4
Q
Why does microcytosis happen?
A
To keep the hemoglobin concentration is constant
- > microcytosis is always caused by decreased production of hemoglobin
- > if hemoglobin is low, can divide to keep the concentration normal
5
Q
What are the four general causes of microcytic anemia?
A
Low iron: 1. Iron deficiency anemia 2. Anemia of chronic disease Low heme: 3. Sideroblastic anemia Low globin: 4. Thalassemias
6
Q
Where is iron absorbed and what is the key regulator of its movement into blood?
A
Absorbed by enterocytes in the Duodenum via DMT-1
Key regulator of transfer from enterocyte to transferrin in the “ferroportin” transporter. Ferroportin activity is modulated by hepcidin.
7
Q
What is serum iron vs serum ferritin measuring?
A
Serum iron - amount of iron which is found to transferrin within the blood
Serum ferritin - amount of iron stored in liver / bone marrow macrophages
8
Q
What are common causes of iron deficiency in infants and young adults?
A
Infants - breast feeding (poor iron ransfer)
Adult females - menorrhagia (uterine fibroids or hypothyroidism) or pregnancy
Adult males - peptic ulcer disease
9
Q
What are common causes of iron deficiency of the elderly in the developing world vs in the west?
A
Developing world - hookworms (Necator and Ancylostoma)
West - Colorectal cancer / polyps
10
Q
Why does gastrectomy predipose to IDA?
A
Fe2 goes in2 the body
Acid maintains iron in the Fe+2 state for better absorption
11
Q
What is the first thing that happens in IDA?
A
Ferritin goes down -> bone marrow macrophages depleted of storage iron for making RBCs.
As serum ferritin drops, liver responds by increasing transferrin
Always: as ferritin decreases, TIBC rises
12
Q
What is a normal value for % saturation and what happens to it as anemia progresses?
A
% saturation ~ 33%, or 1/3 TIBC
As serum iron decreases (used by the body) -> iron is taken off of transferrin -> saturation drops.
13
Q
What is the first stage of anemia in iron deficiency?
A
It’s actually a normocytic anemia -> your body initially decides to just produce fewer, perfectly made RBCs before it starts churning out many mini ones.
14
Q
What does iron deficiency anemia do to the RDW?
A
Increases the RDW, as there are some cells which are normal size and some the are small -> increased variability.
15
Q
What value within RBCs will be characteristically increased in both IDA and ACD (anemia of chronic disease)?
A
Free erythrocyte protoporphyrin -> problem is lack of iron, so there will be free heme rings floating around ready for iron acceptance
16
Q
What is a good marker to tell if RBCs are normal size?
A
Normal RBCs are about the size of a nucleus of a lymphocyte
17
Q
What is the triad of Plummer Vinson syndrome? What happens to their tongue?
A
Dysphagia
Iron deficiency anemia
Esophageal WEBS - causes dysphagia
Tongue will have atrophic glossitis -> becomes beefy red
18
Q
Give the two ways in which hepcidin causes anemia of chronic disease?
A
- Increases the degradation of ferroportin
- Decreases release of stored ferritin from bone marrow macrophages to erythroid precursors
- > ferritin stores will be up.
19
Q
What factor, other than hepcidin, leads to ACD?
A
Decreased erythropoietin production occurs in ACD.
20
Q
What happens to ferritin, TIBC, % saturation, and serum iron in ACD?
A
Ferritin - up, from macrophage sequestration
TIBC - down, since transferrin is always the opposite of ferritin
Serum iron - down, as bone marrow cannot get iron from ferritin, will pull from serum
% saturation - down
FEP will also be up
21
Q
Is anemia of chronic disease a normocytic or a microcytic anemia?
A
Exactly like IDA, it starts normocytic and becomes microcytic overtime
-> some books classify it as normocytic.
22
Q
Who might erythropoietin be used for in anemia of chronic disease?
A
- Chronic kidney disease - if due to reduced erythropoiein
- Malignancy / cancer
- HIV
23
Q
What two heme synthesis reactions occur in the mitochondria, and what are the relevant cofactors?
A
First and last steps:
1. Succinyl-CoA + glycine -> ALA, via ALA synthase, cofactor is B6. Rate-limiting step.
- Protoporphyrin 9 + iron -> heme, via ferrochelatase.
24
Q
What is responsible for the classical cell type of sideroblastic anemia and what is it?
A
Ringed sideroblast -> defective protoporphyrin synthesis -> accumulation of iron within mitochondria where ferrochelatase is supposed to use Fe for hemoglobin production.
25
What are the congenital and acquired causes of sideroblastic anemia? Pattern of inheritance?
Congenital - X-linked! ALA synthase mutation
Acquired:
1. Alcohol - mitochondrial poison
2. Lead - inhibits ALA dehydratase and ferrochelatase
3. B6 deficiency - usually due to isoniazid therapy - ALAS deficiency
4. Myelodysplastic syndromes - screws up synthesis
26
What happens to ferritin, TIBC, % saturation, and serum iron in sideroblastic anemia?
Iron-overloaded state (similar to hemochromatosis) -> iron within mitochondria will kill the erythroblasts and cause it to be leaked out into macrophages
Ferritin - high
TIBC - low (always opposite of ferritin)
% saturation - high
serum iron - high
27
What is seen on bone marrow vs peripheral smear in sideroblastic anemia / lead poisoning?
Bone marrow - ringed sideroBLAST (precursor cell) - as described previously
Peripheral smear - basophilic stippling - aggregation of residual ribosomes and denatured RNA
28
Why do thalassemias persist?
People with thalassemias (decreased globin SYNTHESIS) are relatively protected against Plasmodium FALCIPARUM malaria
29
What is the underlying cause of alpha thalassemia? What is seen in one allele loss?
A DELETION in the alpha globin chain on chromosome 16, causing decreased synthesis
1 allele lost - asymptomatic
30
Who gets cis vs trans two allele deletions of alpha thalassemia and what are the clinical consequences?
Cis - Asians -> accounts for higher risk of spontaneous abortion in offspring
Trans - Africans
Mild anemia seen in two allele deletion alone.
31
What is HbH disease and what is it caused by?
Only one functional copy of alpha gene, three knocked out (like a+ trait + a0 trait)
-> caused by buildup of beta4 tetramers which damage RBCs.
HbH = beta4 tetramers
32
What does four alpha genes deleted cause in alpha thalassemia? What abnormal hemoglobins are present?
Hydrops fetalis
In utero: Hemoglobin Barts (gamma 4) seen on electrophoresis
Later in life: HgH (beta 4), if they survive
33
What are the three possible states of each gene in beta thalassemia? What causes the abnormal globin synthesis and what chromosome is it on?
Chromosome 11 - Not due to deletions like alpha thalassemia, due to mutations in promoter sequences or splice sites
B0 = nearly complete suppression of synthesis
B+ = incomplete suppression
Bn = normal gene
34
What is thalassemia minor vs thalassemia major? Is minor symptomatic?
At least one normal beta allele - Bn / B+ or Bn / B0 = thalassemia minor. Usually asymptomatic.
Any thalassemia WITHOUT at least one Bn = thalassemia major. Worst is B0/B0.
35
What are the features of beta thalassemia anemia? What is seen on electrophoresis in minor / major?
Hypochromic, microcytic anemia with target cell formation
Minor: decreased HbA and mildly increased HbA2 (>4%) / HbF (>2%). >3.5% A2 is diagnostic.
Major: little to no HbA (20%), almost all HbA2 (4+%) / HbF (70+%)
36
Why do target cells form in Thalassemia? What else might be seen on peripheral smear which is abnormal?
Loss of hemoglobin mass within the RBC is like deflating the balloon (vs IDA where the amount of globin is normal)
-> relative excess of cytoplasm always membrane to collapse on itself -> bleb of membrane in the center = targetoid.
May also see nucleated RBCs on peripheral smear due to extramedullary hematopoiesis in liver / spleen leading to improper maturation of RBCs before release.
37
What happens when alpha chains accumulate in beta thalassemia major?
Alpha tetramers form (which are even more toxic than the beta tetramers of HbH disease / 3 allele alpha thalassemia)
1. Alpha chains are toxic to cell division and arrest hematopoiesis
2. Alpha chains make RBC deformed / damaged -> extramedullary hemolysis (splenic removal)
3. RBC damage causes K+ flux
These factors all lead to intramedullary death and short RBC survival -> hemolytic anemia
38
How long does it take for beta thalassemia major to present and why? What is seen on X-ray?
Takes several months after birth, for fetal hemoglobin production to drop off
First sign is facial changes, due to erythroid hyperplasia (extramedulary hematopoiesis)
Crew cut appearance on Xray due to expansion of diploid spaces of skull "hair standing on end"
39
What happens if beta thalassemia is left chronically untreated?
Splenomegaly due to work hypertrophy
Excessive erythropoietin -> increased iron absorption and extramedullary hematopoiesis
Extramedullary hematopoiesis -> hepatosplenomegaly, "crew cut" skull changes and facial bone changes "chipmunk facies"
Anemia -> High output cardiac failure, growth failure
40
What is the primary treatment of beta thalassemia major and the consequence?
Hypertransfusions - target is 9 to 10 gm/dL
Consequence - secondary hemochromatosis
41
What is the treatment for secondary hemochromatosis?
Iron chelators
Desferrioxamine - safest but cumbersome and painful - infused daily for 8-12 hours
Desferasirox and deferiprone - taken orally, have hepatic, renal and bone marrow side effects, but much easier
42
What is the key infection risk of beta thalassemia major?
Parvovirus B19 aplastic crisis -> need all of the RBCs we are trying to produce.
43
What is a macrocytic anemia vs a megaloblastic anemia?
Macrocytic anemia - any anemia where MCV > 100
Megaloblastic anemia - a subset of anemia where there is a problem with DNA synthesis, leads to formation of megaloblasts, which are large precursor blast cells of multiple cell lines. I.e. even gut epithelial cells will show megaloblastic change since they are rapidly dividing.
44
What is an example of a nonmegaloblastic macrocytic anemia? A couple more example causes?
Diamond-Blackfan anemia
A couple more:
1. Alcohol - can cause macrocytic (bone marrow suppression) or megaloblastic (folate deficiency)
2. Liver disease - mechanism uncertain
45
What are the characteristic cells of a megaloblastic anemia?
1. Macro-ovalocyte - large RBCs tend to take an oval shape
| 2. Hypersegmented neutrophils - >5 lobes
46
What role does the pancreas play in absorption of B12? Where does B12 come from?
Proteases are required to remove R-binder from B12
-> pancreatic insufficiency can cause B12 deficiency
it comes complexed with animal protein -> probably only deficient in vegans after years.
47
What are the three P's of parietal cells?
P - Pink = eosinophilic
P = Pernicious anemia - destroyed causing B12 deficiency
P = Proton pump - produce acid
48
How is B12 involved in fatty acid oxidation?
Odd chain fatty acids end with a propionyl CoA
Propionyl-CoA made into methylmalonic acid via carboxylation (B7 dependent)
Methylmalonic acid needs to be made to succinyl-CoA (requires B12)
49
Why are reticulocytes slightly blue? What are the useful in the differential diagnosis of?
Due to residual RNA in the cytoplasm
Useful in the ddx of normocytic anemia:
Increased reticulocytes - anemia due to destruction
Decreased reticulocytes - anemia due to underproduction
50
What is the normal reticulocyte % and how do you correct it for anemia (i.e. the problem that loss of RBCs will artificially increase the reticulocyte % without a true increase in production)
Normal: 1-2%
Correct via multiplying reticulocyte % * hematocrit / 45
45 represents a normal hematocrit, so just normalizing the hematocrit for normal red cell mass.
>3% corrected = adequate response, peripheral destruction
<3% corrected = underproduction
51
What is hemosiderin and how is it made?
A pigment made from aggregation of ferritin micelles which are enveloped by lysosomes and degraded into low bioavailability substance
52
How does the presentation of intravascular vs extravascular hemolysis differ clinically?
Both can present with increased urobilinogen / urobilin due to increased bilirubin production
Intravascular - presents with decreased haptoglobin (binding hemoglobin), schistocytes, and hemoglobinuria / hemosiderinuria
Extravascular - presents with NO hemoglobinuria / hemosiderinuria since uptake is by RES system. Splenomegaly due to hypertrophy.
53
What causes hemosiderinuria?
Intravascular hemolysis - high exposure to hemoglobin in the tubules leads to increased iron uptake in kidney tubule cells
-> when the iron-saturated tubule cells are sloughed off, iron accumulates in the urine.
54
What happens to the RDW in hereditary spherocytosis and what causes hemolysis?
Blebbing of membrane leads to constant shrinking overtime (loss of structural proteins)
- > older RBCs will be smaller
- > high RDW due to age disparities
Hemolysis is extravascular by splenic removal because spherocytes cannot fit thru splenic sinusoids as they lose their disc shape
55
Will there be an aplastic crisis with Parvovirus B19 in hereditary spherocytosis?
Yes
56
What is the treatment for hereditary spherocytosis and what will appear on peripheral smear?
Splenectomy -> will resolve the anemia
Howell-Jolly bodies - remnants of nuclear material (DNA) in RBCs which the spleen normally removes, will appear on smear
-> happens in any asplenic patients, including sickle cell
57
What is the cause of sickling in sickle cell disease and what are the three risk factors? Whats the relevant mutation?
HbS (alpha2betaS2) polymerizes in certain conditions. BetaS -> glutamate to valine
1. Hypoxemia - i.e. high altitude
2. Dehydration
3. Acidosis
58
What causes hemolysis in sickle cell anemia?
Extravascular hemolysis - constant polymerization and depolymerization of HbS chains damage the cell membrane in microcirculation -> early splenic removal
Intravascular hemolysis - dehydrated RBCs easily lyse. Haptoglobin will thus actually be decreased in this condition.
59
Why do target cells form in sickle cell anemia?
Dehydration of the cytoplasm due to mechanical stressors -> loss of cytoplasm volume -> formation of target cell
60
What will happen in the skeleton in order to keep RBC production up in sickle cell anemia?
Massive erythroid hyperplasia -> same as thalassemia
| -> crew cut appearance on Xray, chipmunk facies, hepatomegaly.
61
What is the most common presenting symptom of sickle cell disease in infants?
Dactylitis - swollen hands and feet due to vasoocclusive infarcts in bones
62
What is the most common cause of death in children vs adults with sickle cell disease?
Children - infection with encapsulated organisms (i.e. S. pneumoniae, H. influenzae, Neisseria, Salmonella osteomyelitis)
Adults - acute chest syndrome
63
What is the pathogenesis of acute chest syndrome?
Pulmonary vasculature vaso-occlusion, usually due to infection i.e. pneumonia
- > pneumonia causes hyperemia and slowed transit time thru vessels -> hypoxemia -> increased sickling
- > presents with chest pain, shortness of breath, and lung infiltrates
64
What is acute severe splenic sequestration? Why not just remove the spleen to prevent this?
Sudden pooling of blood in acutely enlarged spleen due to a viral infection, locks progress of blood thru spleen due to sickling
Can cause hypotensive shock if not treated with transfusions
We don't want to remove the spleen because early hyposplenism is associated with high mortality from bacterial sepsis in childhood
65
What are the clinical characteristics of Sickle cell trait? Is it common in the US?
Benign because HbA is made slightly more efficiently than HbS, and need >50% HbS for disease
- > hematuria, loss of urine concentration because hypertonicity/hypoxia of medulla causes sickling, causing microinfarctions
- > problems with high altitude (hypoxia)
->10% carrier rate in blacks in US
66
What test can be used to screen if patients have HbS of any amount?
Metabisulfite screen - positive in both disease and treat by inducing sickling
67
What is the inheritance pattern and cause of Hemoglobin C disease?
Autosomal recessive, mutation of glutamate to lysine
| -> not as severe as sickle cell since both amino acids are charged (Valine was hydrophobic, vs these are hydrophilic)
68
What type of hemolysis occurs in HbC disease and what will be seen on peripheral smear?
C = Crystals -> hemoglobin C crystals
| Will see target cells -> damage = dehydration
69
What is the cause of PNH?
Acquired defect in myeloid stem cell line leading to absent GPI anchor which is responsible for holding onto DAF (inhibitor of C3 convertase) and MIRL.
During the night, when there is mild respiratory acidosis, complement is fixed and cells of the myeloid lineage will lyse.
70
What is the main cause of death in patients with PNH?
Thombosis of hepatic, portal, and cerebral veins due to lysis and activation of platelets since they lack DAF as well.
71
What are the tests for PNH?
Sucrose test -> activate complement, screen for hemolysis
| Confirmed by urine acidification test or CD55- RBCs (CD55 = DAF)
72
What two conditions / diseases are patients with PNH at risk for?
1. Iron deficiency anemia - from loss of hemoglobin in urine (intravascular hemolysis)
2. AML - since mutation in GPI indicates the entire stem cell line is more vulnerable to mutations
73
What is the specific defect in G6PD deficiency? What are the two variants?
Defect in G6PDH where it has reduced halflife in the cell
African variant - less severe -> RBCs will last longer
-> protective against malaria
White / Mediterranean variant - more severe -> RBCs damaged earlier and have shorter halflives, really bad cuz you eat fava beans in the Mediterranean
74
What type of hemolysis is occurring in G6PD deficiency?
Predominantly INTRAvascular hemolysis
-> Heinz bodies are formed as Hb aggregations in response to oxidative stress. Although the spleen is removing the Heinz body, taking a "bite" out of the cells actually damages them -> causes them to lyse in the circulation
75
What are the presenting symptoms of G6PD deficiency? When should you test for it?
Hemoglobinuria and back pain a few days after oxidant stress -> hemoglobin is nephrotoxic
Screen for it with a Heinz prep -> see hemoglobin aggregates
Confirm via WAITING after acute attack until RBCs have had time to regenerate -> enzymatic studies will then show low G6PD levels
76
What antibody type causes a warm autoimmune hemolytic anemia? Is this intravascular or extravascular hemolysis? What is seen on peripheral smear?
IgG antibodies (just remember that cold is IgM)
Predominantly EXTRAVASCULAR hemolysis -> IgG antibodies bind which causes removal by splenic macrophages
Peripheral smear shows spherocytes -> membrane chunks are bitten off by splenic macrophages
77
What are some causes of IgG warm antibodies?
SLE - typically the autoantibodies of lupus are IgG
CLL - Chronic Lymphocytic Leukemia -> can also result in cold agglutinins
Drugs
78
What are the two mechanisms by which drugs can induce autoantibodies and give an example of each?
1. Attachment to drug membrane and forming a drug-membrane complex - antibody is formed against that
i. e. Penicillin
2. Drug may induce production of autoantibodies which bind self antigens on RBCs
i. e. alpha-methyldopa
79
What is the treatment for IgG-mediated AIHA?
High dose steroids - reduce Ab production
IVIg - distract macrophages
Plasmapheresis
Splenectomy if refractory - removes source of antibody and removal
Remove offending drug if that's the cause
80
What are two common causes of IgM-mediated AIHA and where does hemolysis occur?
IgM agglutinates RBCs in relatively cold temps of extremities -> fixes complement (IgM good at fixing complement) -> INTRAVASCULAR hemolysis
1. Mycoplasmia pneumonia
2. Mononucleosis (infectious)
81
What is the most important test for AIHA? How does this work?
Direct Coombs test
- > add patient's RBCs in a vial with Coombs reagent (anti-human Ig antibodies)
- > If patient has autoantibodies already bound to their own RBCs, Coombs reagent will bind these antibodies and agglutinate the RBCs
82
What is the indirect Coombs test?
Tests to see if patient has autoantibodies in their serum to general Type O blood
- > add patient's serum to donor RBCs
- > If Coombs reagent agglutinates these, they are indirect Coombs positive.
83
Give an example of a cause of microangiopathic hemolytic anemia which is not TTP, HUS, or DIC.
HELLP - hemolysis, elevated liver enzymes, and low platelets
84
Give two causes of macroangiopathic hemolytic anemia?
Due to smashing forces
1. Aortic stenosis - calcified valve
2. Prosthetic heart vales
3. March hemoglobinuria - in the feet of people who walk all day
85
What is a myelophthisic process? Give two examples of causes.
A process in which something replaces the bone marrow, leading to atrophy and pancytopenia
1. Metastatic cancer -> takes over the bone marrow
2. Osteopetrosis - thickening of bone so nothing can escape.
86
What is the treatment for aplastic anemia?
1. Immunosuppression if idiopathic - often autoimmune mediated with abnormal T cell activation adn release of cytokines
2. Treatment based on putative causation i.e. lack of EPO, removal of offending drug, treatment of virus.
Use EPO, GM-CSF, or G-CSF
3. Bone marrow transplant as last resort.
87
What enzyme is defective in acute intermittent porphyria and what is the inheritance pattern? What builds up?
```
Porphobilinogen deAminase (deAminase for Acute)
-> build up of porphobilinogen and ALA
```
Inherited via autosomal dominant mechanism
88
What are the symptoms of acute intermittent porphyria?
NEUROVISCERAL SYMPTOMS
5 P's of porphyria
Painful abdomen
Port-wine urine - which oxidizes when exposed to air for long periods
Polyneuropathy - tingling of limbs, respiratory failure
Psychological disturbances - insomnia, agitation
Precipitated by drugs, alcohol, puberty (increased hormones) and starvation -> inducers of CYP
Treat with glucose and heme to inhibit ALA synthase
89
What enzyme is defective in porphyria cutanea tarda (PCT) and what is the inheritance pattern? What builds up?
Uroporphyrinogen deCarboxylase (Carboxylase for cutaneous)
Uroporphyrin builds up (tea-colored urine)
Autosomal dominant, but usually acquired
90
What conditions is PCT associated with?
Cutaneous symptoms and iron overload (chronic)
- > blistering photosensitivity, hypertrichosis, iron overload, and chronic liver disease (associated with alcohol consumption)
- > makes you look like a werewolf
- > associated with HIV, HFE, and Hep C
Porphyrins make you photosensitive
91
How is PCT treated?
Avoid ETOH consumption (hepatic toxin), avoid sun exposure (werewolf), phlebotomy to reduce iron levels
