Anemia Part II Flashcards
1
Q
Anemias due to increased destruction of red blood cells (hemolysis) consistently show what kind of reticulocyte count?
A
increased
2
Q
Bone marrow aspirates or biopsies from patients with hemolytic anemias show?
A
an increase in primitive nucleated red cell precursors such as normoblasts as well as more differentiated forms
3
Q
Many of the genetic (inherited) diseases which cause hemolytic anemia produce defects in ?
A
the red blood cell membrane or cytoskeleton
4
Q
The red cell membrane is associated with the outer cytoskeleton in which (1) dimers combine to form tetramers producing a head (further associating with (2) and a dimeric tail which associates with (3).
A
- alpha and beta spectrin
- ankyrin, band 4.2 and band 3.1
- band 4.1
5
Q
Mutations in the red cell membrane can cause the red cells to lose membrane which makes them more (1) instead of their usual (2) shape.
A
- spherical
2. biconcave disc
6
Q
Spherical cells increase the (1) and the red cells lose (2)
A
- MCHC
2. intracellular potassium, glucose, and water.
7
Q
Spherical cells are less deformable in the splenic cords so they are removed from circulation by the (1)
A
- spleen
8
Q
Splenectomy leaves the (1) but solves the (2) problem of hemolytic anemia
A
- spherocytes
2. shortened red cell life span
9
Q
The usual red cell life span is 120 days but these patients have life span closer to (1) days. This clinical disorder is known as (2) and can be due to a variety of mutations in genes encoding any of these genes.
A
- 10-20
2. hereditary spherocytosis
10
Q
The mutations arose most commonly in northern Europe and most commonly produce an autosomal (1) disorder with a frequency of 1/5000.
A
hereditary spherocytosis
1. dominant
11
Q
Individuals with two mutations will usually be (1) because of the tremendous heterogeneity of causative mutations.
A
- compound heterozygotes
refers to hereditary spherocytosis
12
Q
Extravascular hemolysis (in spleen and not within the blood) in patients with hereditary spherocytosis can lead to?
A
elevation of indirect (unconjugated) bilirubin, cholithiasis with calcium bilirubin stones, and increased lactate dehydrogenase (LDH) due to leakage of this enzyme from the damaged red cells.
13
Q
What test can identify these spherocytes and why?
A
An osmotic fragility test because they lyse more readily when incubated in hypotonic solutions.
14
Q
In contrast, glucose 6-phosphate dehydrogenase deficiency is (1) disorder which usually presents with (2) after patients have an (3) problem due to an infection or treatment with certain drugs.
A
- an X-linked
- intravascular hemolysis
- oxidative
15
Q
There are both (1) forms due to differing founder mutations and the (2) form is more sensitive to protein misfolding.
A
- Mediterranean and African-American
2. Mediterranean
16
Q
G6PD is a major source of (1) which is needed to restore (2) to eliminate (3)
A
- reduced NADPH
- reduced glutathione
- oxidative products like hydrogen peroxide (H202).
17
Q
Why is G6PD deficiency generally episodic and self-limiting?
A
Older red cells tend to be more suspectible to this type of damage so this disease is generally episodic and self-limiting once more new red cells have been produced (they have more glutathione and NADPH).
18
Q
The oxidative stress can be due to oxygen radicals from (1) (and leukocytes responding to infections), oxidant drugs including (2), and ingestion of (3) which contains oxidant substances.
A
- infections
- antimalarials, sulfonamides, and nitrofurantoin
- fava beans
19
Q
The excess oxidants cause the crosslinking of (1) groups in (2) proteins which denature and bind (3) proteins forming precipitates called (4) which can be stained with (5)
A
- reactive sulfhydryl
- globin
- membrane
- Heinz bodies
- crystal violet
20
Q
When the splenic cords deform these cells the (1) try to remove these inclusions by taking a “bite” out: so these cells with areas of membrane loss are called bite cells.
A
- macrophages
refers to G6PD deficiency
21
Q
Because there is intravascular hemoglobin outside of red cells, (1) binds the intravascular hemoglobin and is usually decreased in the serum relative to normal since it is consumed.
A
- haptoglobin
refers to G6PD deficiency
22
Q
Acute hemolysis results in?
A
hemoglobinemia (hemoglobin outside RBCs in plasma) and hemoglobinuria.
23
Q
Chronic hemolysis results in?
A
hemosiderin in the urine
bilirubin stones in the gallbladder
splenomegaly
secondary hemosiderosis in liver
24
Q
Sickle cell anemia is an autosomal (1) disorder which produces microvascular occlusion due to a genetic defect which makes red cells occlude small blood vessels.
A
- recessive
25
The specific mutation within codon 6 of the adult beta globin gene from GAG to GTG produces an amino acid substitution of (1) (encoded by the triplet GTG) for the normal (2) (encoded by the triplet GAG) which results in Hb S or sickle hemoglobin.
1. valine
| 2. glutamic acid
26
(1) leads to aggregation of needle like fibers which lose (2) and have (3) pH which leads to more sickling of the hemoglobin.
1. Deoxygenated HbS
2. intracellular potassium and water
3. decreased
27
The continued dehydration leads to an increase in the
| (1) of the sickled cells which correlates well with the presence of crises and other disease.
1. MCHC
28
Reduction of the (1) of the sickle hemoglobin seems to decrease vascular obstruction
1. MCHC
29
Compound heterozygotes with (1) also have sickling in small blood vessels but this may be more a consequence of (2) than in the HbSS homozygous disorder.
1. HbC and HbS
| 2. dehydration
30
The sickled and dehydrated cells generally show (1) which contributes to the microvascular occlusion
1. increased adhesion of the red blood cells to vascular endothelium
31
Vessel occlusion occurs in the (1) at an early age in patients with sickle cell anemia so they often have (2)
1. spleen
| 2. splenic infarcts and damaged spleen with minimal splenic function.
32
These patients are said to be autosplenectomized and usually have (1) present due to the lack of splenic function.
1. Howell-Jolly bodies
sickle cell disease
33
During vessel occlusion there is sometimes (1) and the free hemoglobin in the circulation can locally bind and decrease (2) leading to (3)
1. intravascular hemolysis
2. nitrous oxide
3. more vasoconstriction and platelet aggregation.
refers to SCD
34
Heterozygotes with (1) (called sickle cell trait) usually only have crises or problems under what conditions?
1. HbA and HbS
| 2. at high altitudes or in low oxygen environments.
35
generally only seen in vascular beds with slow transit time
microvacular occlusion
36
Clinically sickling crises can lead to acute chest syndrome which is a sickling in the (1) which leads to (2), and continued sickling with microvascular occlusion.
1. pulmonary vasculature
| 2. pulmonary infiltrates, hypoxygenation
37
Manifestations of sickling crises
Acute chest syndrome, strokes, vascular necrosis of the femur, renal infarcts, skin ulcers, and retinopathy
38
(1) or other encapsulated organisms occurs as a consequence of inflection and autosplenectomy.
1. Osteomyelitis with salmonella
39
(1) occurs as a consequence of the multiple transfusions and hemolysis which can lead to (2)
1. Secondary hemosiderosis (iron overload)
| 2. calcium bilirubin stones and cholecystitis as well.
40
Bone marrow expansion occurs in uncommon skeletal areas such as the skull where there is intermittent bone resorption and secondary new bone formation which leads to a tower appearance clinically and a “crewcut” like appearance on X-ray.
sickle cell disease
41
There can also be erythroid hyperplasia in sites of extramedullary hematopoiesis including (1)
1. liver, spleen, and lymph nodes.
refers to Sickle cell disease thalassemia
42
How is sickle anemia identified?
1. Sickle cell test - mix blood with metabisulfite which deoxygenates blood leading to sickling
2. Hemoglobin electrophoresis
(more quantitative way to determine the percentage of HbA, HbC, HbS based on the differential electrophoresis of these different proteins)
43
How do you determine if there is a sickling crisis?
No blood test, apart from elevated WBC levels in inflammatory response; therefore, must be judged by clinical findings.
44
Pathophysiology of thalassemia
mutational problems with globin gene regulation or problems with splicing of pre-mRNA to mRNA which then encodes for protein
45
The thalassemias tend to have reduced (1) so they are more quantitative defects than qualitative defects in globin.
1. mRNA levels and less protein
46
Beta thalassemia (decreased (1) produces an excess of (2)
1. beta globin mRNA
| 2. alpha globin chains
47
Thalassemia with truncated non-functional globin proteins are caused by mutations in?
Frameshift mutations which create internal stop codons
48
Frameshift mutations leads to (1)
1. reduced levels of mRNA
49
Alpha thalassemia (decreased (2) produces an excess of (3)
2. alpha globin mRNA
| 3. Beta globin chains.
50
Thalassemia which produce no functional beta globin protein are caused by mutations in?
splice donor or acceptor sites; these are B0 mutations
51
B+ mutations are caused by mutations in (1) and therefore leads to decreased mRNA levels levels, or by mutations that create (2) that create (3) which competes with the normally spliced pre-mRNA
1. gene promoters
2. cryptic splices
3. dysfunctional pre-mRNA
refers to thalassemia
52
The resulting deficits in (1) synthesis lead to (2) red cells which have what characteristics?
1. HbA
2. hypochromic, microcytic
target cells, basophilic stippling, reduced red cell survival.
53
What happens to excess alpha chains in beta-thalassemia?What complications does this lead to?
precipitate forming insoluble inclusions and membrane damage which lead to splenic sequestration and extravascular hemolysis
54
Hemoglobin electrophoresis in beta-thalassemia generally has an increase in the (1)
1. HbA2; two alpha chains and two delta chains (the other adult beta hemoglobin).
55
The more severely affected homozygous mutant disorder is called (1), affects patients more than the heterozygous disorder which is often called (2)
1. thalassemia major
| 2. thalassemia minor
56
Usually compound heterozygotes of two different mutations; can have a B0 and a B+
thalassemia major
57
Paroxysmal nocturnal hemoglobinuria is a disease which can present with (1)
1. episodes of hemolysis at night but more frequently has intermittent intravascular hemolysis at other times.
58
PNH is caused by (1) mutations in (2) genes which affects (3) which are attached to the cell membrane through (4)
1. acquired (not inherited)
2. phosphatidylinositol glycan group (PIGA)
3. non-transmembrane proteins
4. GPI glycosylphosphatidylinositol
59
PIGA is (1) so the gene can be randomly inactivated in females by the process of (2)
1. X-linked
| 2. lionization
60
Which cells are affected in PNH?
all progeny of hematopoietic stem cells - RBCs, WBCs, and platelets
61
Two key GPI anchored proteins which are defective due to PIGA gene mutation are (1) and (2)
1. decay-accelerating factor (CD55)
| 2. CD59
62
Deficiency of these key complement inhibitors disrupts
the balance between complement activation and complement inhibition which can lead to hemolysis of red blood cells by complement.
CD55 and CD59 - refers to PNH
63
The nocturnal nature of hemolysis in PNH is explained by ?
There is a lower pH at night when we sleep leading to an increase in complement activity
64
Although the hemolysis is what generally leads to diagnosis, the (1) of PNH is the most likely cause of death in these patients
1. increased clotting
65
inhibitor of complement cell lysis
CD55 decay accelerating factor
| defective due to PIGA gene mutation in PNH
66
inhibits the C3 convertase and activation of the alternative complement pathway.
CD59
| defective due to PIGA gene mutation in PNH
67
Warm autoimmune hemolytic anemias tend to have (1) antibodies directed against red cells in the serum (2) which are present on the red cells (3).
1. IgG or IgA
2. indirect Coombs or indirect antiglobulin test
3. direct Coombs or direct antiglobulin test
68
direct antiglobulin test
Incubate anti- human immunoglobulin antibodies, wash red cells, and then using agglutination to detect the antibodies stuck to the red cells
69
indirect antiglobulin test
looking for antibodies present in the serum or plasma
Use commercially available red cells with specific antibodies already present on them
70
In summary, the direct Coombs detects (1) and the indirect detects (2)
1. antibodies on red cells
| 2. antibodies in serum or plasma.
71
The antibodies are actually bound to the red cells in the patient which can activate (1) and lead to (2)
1. complement
2. extravascular hemolysis most likely in the spleen.
refers to warm and cold autoimmune hemolytic anemia
72
Cold autoimmune hemolytic anemia tends to involve (1) which bind red cells easily and (2)
1. IgM antibodies
| 2. activate complement.
73
S/S of cold autoimmune hemolytic anemia
pallor and cyanosis of extremities at low temperatures
| Raynaud’s
74
Cold agglutinins are associated with certain infections such as?
mycoplasm pneumonia, EBV, CMV, and HIV.
75
The (1) is less commonly positive in the cold autoimmune hemolytic anemias but there can be (2) present on the red cells.
1. direct Coombs test
| 2. C3 breakdown products such as 3b (an opsinin) and 3d
76
Abs in warm versus cold autoimmune hemolytic anemias
Warm - IgG or IgA
Cold - IgM
77
INHERITED defect in RBC membrane (specifically cytoskeleton-membrane tethering proteins)
Hereditary Spherocytosis
78
RBC membrane "head" vs "tail"
(a) Head: Red cell membrane is associated w/ the outer cytoskeleton in which 1) combine to form tetaramers; these further associate w/ 2)
(b) Tail: dimeric tail which is associated w/ 3) and 4) molecules
Mutation in head or tail associated with Hereditary Spher.
1) alpha and beta spectrin dimers
2) ankyrin, band 4.2 and band 3.1
3) band 4.1
4) actin
79
Hereditary Spherocytosis: genetics
Autosomal Dominant (Northern Europe); compound heterozygotes (i.e. two different mutations) are more severe
80
treat Hereditary Spherocytosis; what should you do after this treatment?
Splenectomy (form of treatment)--> spherocytes persist but anemia is corrected;
*recall spleen protects against encapsulated organisms -->VACCINATE patient
81
Spleen makes Hereditary Spherocytosis red cells lose: 1)
| depletes red cell 2) and diminishes red cell 3)
1) membrane, K+ ions and H2O
2) glucose
3) pH
82
Hereditary Spherocytosis:
| what happens to pH of RBCs affected?
DECREASED; becomes acidic
83
Hereditary spherocytosis
| Compare histo of pt with spleen and without
Splenectomized --> Spherocytes w/ Howell-jolly bodies
Unsplenctomized --> spherocytes w/o Howell-jolly bodies.
84
diagnose Hereditary sphero:
1) test: Red cells are abnormally sensitive to osmotic lysis when incubated in 2) (H2O influxes into spherocytes w/ little margin for expansion)
Osmotic fragility test: Red cells are abnormally sensitive to osmotic lysis when incubated in hypotonic salt solutions (H2O influxes into spherocytes w/ little margin for expansion)
85
Hereditary spherocytosis
Clinical findings:
If untreated --> 1), marrow erythroid hyperplasia, 2), jaundice,
1) reticulocytosis
| 2) hemosiderosis
86
Hereditary spherocytosis:
| 1) occurs in 40-50% of adults with HS
cholelithiasis (pigment calcium bilirubin stones)
87
Hereditary spherocytosis:
| pts are at increased risk of:
↑risk of aplastic crisis w/ parvovirus B19 infection of erythroid precursors—until immune response in 1-2 weeks.
88
↑risk of aplastic crisis w/ parvovirus B19 infection of erythroid precursors—until immune response in 1-2 weeks.
Hereditary spherocytosis:
89
Compound heterozygotes present at birth w/ marked jaundice and require exchange transfusions
Hereditary spherocytosis:
90
Desc. Hereditary spherocytosis peripheral smear:
- anisocytosis and dark-appearing spherocytes with no 1)
- also see 2)
1) central pallor
| 2) Howell-Jolly bodies in asplenic pts.
91
how is anemia caused Hered. spherocytosis
Spherocytes are less deformable by the spleen and thus trapped in the splenic cords --> consumed/phagocytosed by macrophages --> anemia
92
G6PD
| 1) disorder that results in a glycolytic enzyme deficiency
1) X-linked recessive
93
G6PD
| Causes 1) due to oxidative stress
1) INTRAVASCULAR HEMOLYSIS
94
Two types of G6PD; ID type, enzyme, and where are they predominantly found
African variant in blacks; G6PD(-) enzyme
| Mediterranean variant in Middle Easterns; G6PD MED enzyme
95
G6PD
| compare half life of RBCs in the two variants:
1) African variant: Mildly reduced ½ life of G6PD;
| 2) Mediterranean variant: More severe. Markedly reduced ½ life (reduction in protein stability
96
marked intravascular hemolysis w/ oxidative stress. Seen in Middle Eastern ppl;
2) Mediterranean variant G6PD
97
why are OLDER RBCs more affected in G6PD
B/c mature RBCs do not synthesize new proteins (lack nucleus and organelles) --> G6PD(-) and G6PD-Med enzyme activities fall to low for oxidant stress
98
how is H2O2 disposed
G6PD leads to production of NADPH which makes gluthatione which then disposes H2O2
99
How is recovery phase of G6PD identifed
RETICULOCYTOSIS
100
Clinical Findings: Acute intravascular hemolysis *even if spleen deforms cells*--> anemia, Hbemia, and Hburia 2-3 days following exposure to oxidants
G6PD
101
```
The offspring of two heterozygotes
has a ______ chance of being
homozygous for the sickle mutation,
a state that produces symptomatic
sickle cell disease
```
1 in 4
102
Sickle Cell Anemia
- 1) mutation in β-chain of Hb
- single point mutation in the 6th codon --> 2) mutation.
Substitution of 3) (hydrophilic) for 4) (hydrophobic).
1) Autosomal recessive
2) missense
3) glutamic acid
4) valine
103
40% of HbS and the other 60% is HbA is 1); they are 2) (genetics)
Sickle Cell Trait --> heterozygous; asymptomatic—only sickle on profound hypoxia
104
Sickle Cell Disease pathogenesis:
HbS polymerizes when 1), which causes 2)
cytosol is initially 3) --> polymers aggregate into long needle-like structures—which lose 4) and have ↓pH --> result in sickle cells.
1) deoxygenated
2) membrane damage
3) viscous
4) intracellular K+ and h2O
105
Sickle Cell Disease
HbF inhibits 1) --> infants do not become symptomatic until they reach 5-6 months of age (when levels ↓),
Hereditary persistence of HbF pts tend to do better
1) HbS polymerization
106
HbC Defect
Autosomal recessive mutation in βchain of Hb,
1) is replaced by 2) and also see sickling
1) Glutamic acid
| 2) LYSINE (*think C for Ly’seen’*)
107
Sickle Cell Disease
Intracellular dehydration leads to 1) which also facilitates sickling;
However, pts Homozygous for HbS with alpha-thalassemia has milder disease b/c
1) ↑ MCHC
| 2) Hb synthesis is reduced and MCHC decreases
108
Increased risk of sickling occurs w/ 1), dehydration and 2) ↑fraction of deoxygenated HbS at any O2 levls
1) hypoxemia
| 2) acidosis (↓pH; Bohr effect (reduced Hb O2 affinity)
109
```
Sickle Cell Disease
. A decrease in pH
reduces the 1) , thereby increasing the
fraction of deoxygenated HbS at any
oxygen level increasing sickling
```
oxygen affinity of
| hemoglobin
110
Aplastic crises: RBC progenitors w/ parvovirus B19
Sickle Cell Disease
111
Sickle Cell Disease
| Osteomyelitis w/ salmonella or other encapsulated organisms (1)—vaccinate)—due to infection and autosplenectomy
1) P. pneumoniae and H. influenzae
112
Sickle Cell Disease
1) as a consequence of multiple transfusions and hemolysis, which can lead to calcium bilirubin stones and cholecystitis
1) Secondary hemosiderosis (iron overload)
113
Sickle Cell Disease
| HbS polymers herniate thru 1) which leads to 2) ultimately resulting in Sickled cells
1) cytoskeleton which leads to Intracellular dehydration*
114
β+-thalassemia
Due to: (1) --> reduce transcription 75-89% (i.e. affects pre-mRNA).
(2) mutations --> create an “ectopic” cryptic splice site within the intron, so have abnormal and normal splicing that occurs
1) Promotor mutations
| 2) Splicing
115
β-Thalassemia minor vs major;
| genetics; severity;
β-Thalassemia minor: Heterozygous; mild symptoms
β-Thalassemia major: Homozygous (usually compound heterozygous); severe anemia --> requires blood transfusion
116
β-Thalassemia Hb electrophoresis:
↑in HbA2 (α2δ2).
| Major--> INC. HbA2, HbF and little to no HbA.
117
PNH leading cause of death
thrombosis esp. venous
118
Occurs w/ microthrombi, prosthetic heart valves, and aortic stenosis; narrowing of BVs trap RBCs;
Microangiopathic Hemolytic Anemia
119
due to sheer force cardiac trauma and in sheer forces that occur in luminal narrowing (such as TTP or hemolytic uremic syndrome)
Microangiopathic Hemolytic Anemia
120
Microangiopathic Hemolytic Anemia histo:
shistocytes (narrowed BVs squeeze RBCs out) + reticulocytes
