3.18.14* Hemolytic Anemia Flashcards
PPT* Lecture Notes* Reading (33-72, 88-108)* Powerpoint (98 cards)
1
Q
Possible causes of RBC loss?
A
a. Hemorrhage (chronic or acute)
b. Hemolysis ( many causes)
2
Q
What are the lab findings for hemolytic anemia?
A
molecules normally found only inside red cells are tested for in the serum:
a. LDH
b. uncojugated bilirubin
c. reduced haptoglobin (increased transport of iron)
d. increased red cell production (increased reticulocytes, nucleated RBCs)
e. hemoglobinuria
3
Q
increased LDH in serum due to
A
hemolytic anemia acute leukemia (lymphoblast lysis)
4
Q
increased unconjugated bilirubin seen in?
A
liver issues
hemolytic anemia
5
Q
bilirubin
A
end product of heme catabolism
6
Q
hemoglobinuria seen in
A
renal diseases
hemolytic anemia
7
Q
are haptoglobin levels increased or decreased in labs for hemolytic anemia?
A
decreased. Haptoglobin binds free hemoglobin in serum to prevent oxidative activity. If cells lyse, serum haptoglobin is taken up by binding to Hgb. haptoglobin:hepcidin is taken up by spleen macrophages
8
Q
What may cause masked haptoglobin levels in a patient with hemolytic anemia?
A
haptoglobin is increased in infectious/inflammatory states (it is an acute phase reactant)
9
Q
What is seen in a PBS with increased RBC production
A
polychromasia, nucleated RBC’s, increased reticulocytes
10
Q
Genetic etiologies of hemolytic anemia
A
a. defects in membrane anchors (Band 3) or cables (spectrin) or associated proteins (ankyrin)
b. Hemoglobinopathies
c. defect in glycolysis/ATP generation
d. defect in anti-oxidant system (PPP -> G6PD)
E. unblocked complement fixation (can also be neoplastic)
11
Q
osmotic fragility test
A
tests what fraction of RBCs survive after exposed to hypotonic environment for structural deficiencies that lead to hemolytic anemia
12
Q
Hemoglobinopathy
A
missence mutation in hemoblobin leading to unstable variants, often resulting in Hb precipitation and instability of RBC
13
Q
How to diagnose hemoglobinopathies
A
hb electrophoresis
14
Q
Defects in glycolysis; impact on RBC
A
(most common is pyruvate kinase deficiency)
leads to reduced ATP generation and inability to have active sodium potassium pump
15
Q
What is seen in PBS in patients with defects in RBC glycolysis -> hemolytic anemia
A
polychromasia (excess RBCs), many as reticulocytes, nRBCs
16
Q
reticulocyte
A
immature RBC with rRNA meshwork
17
Q
diagnostic test for defects in RBC glycolysis -> hemolytic anemia?
A
enzyme activity test
18
Q
What is the effect of oxidative damage to RBCs?
A
disulfide bonds are formed between Hb molecules, leading to unstable RBC.
19
Q
What molecules protects RBCs from oxidative damage?
A
glutathione
20
Q
G6PD deficiency
A
X-linked disorder. G6PD enzyme needed in PPP to make NADPH, needed to regenerate reduced glutathione. Without glutathione, Hb oxidation leads to unstable RBCs
21
Q
what is seen in a PBS in a patient with G6PD deficiency?
A
Heinz bodies
22
Q
Heinz bodies
A
small granular-like precipitates of Hb visualized by methylene blue stain
23
Q
What can be oxidized in an RBC?
A
Hb proteins heme iron (Fe 2+ -> Fe 3+)
24
Q
What happens if heme iron becomes oxidized (ferric form, 3+)
A
aka methemoglobinemia
The heme iron cannot carry oxygen. Needs to be reduced by cytochrome B5 reductase (unless deficiency).
25
What genetic mutations are favorable in malaria?
G6PD deficiency
| hemoglobinopathies (some heterozygotes)
26
What common condition results in hemolytic anemia due to deficiency in surface proteins that prevent complement fixation on RBCs?
(neoplastic/acquired) paroxysmal nocturnal hemoglobinuria, X-linked defect in PIG-A enzyme needed for GPI anchor. Or neoplastic -> deficiency protease of complement/Ab in precursor RBC.
27
Diagnostic test for PNH
flow cytometry (for expression of relevant surface proteins)
28
Treatment for PNH
bone marrow trans
| Ecluzimab (anti-complement activation)
29
Neoplastic condition that causes hemolytic anemia
PNH
30
Infections that cause hemolytic anemia
a. malaria (plasmodium falciparum)
b. babesia
c. bartonella
d. C. perfringens
31
Pertinent positives for malaria
high fever
| dark urine
32
Babesia
protozoal intracellular parasite transmitted by ticks, mild
33
Bartonella bacilliformis
(aka carrion's disease, Oroya fever; transmitted by sand flies)
intracellular parasite endemic to N. Andes. Causes severe anemia in acute phase and cutaneous rash in chronic phase.
34
Bartonella baciliformis pertinent positives
present with fever, hemolytic anemia, and splenomegaly.
35
C. perfringens (welchii)
component of normal skin flora which can secrete a toxin (alpha toxin) that results in severe hemolysis. It can also cause the tissue destructive form of sepsis called gas gangrene. Trauma; septic abortions; Rare complication of Cholecystitis, or of various cancers.
36
Autoimmune hemolytic anemia
cause by antibodies for RBC antigens.
a. Complexes get cleared by tissue phagocytes in spleen/liver collectively caled the reticuloendothelial system (RES). Partial clearance by RES leads to characteristic microspherocytes in PBS.
b. antibodies fix complement
37
hemoglobin electrophoresis checks for
thalassemia
| will usually correlate with elevated MCV
38
First check in anemic patient with normal MCV that has not had blood loss
reticulocytes, LDH, haptocytes
39
Deficiency in what enzyme makes more susceptible to hemolysis
a. tetrahydrofolate reductase
b. methione synthase
c. cytochrome b5 reductase
d. pyruvate kinase
pyruvate kinase
40
What is the reticulocyte count in a patient with pyruvate kinase deficiency
elevated
41
increased reticulocyte count reveals that
there is not a problem in red cell production
42
what fraction of hospitalized patients have a positive DAT (direct coombs test)
80%
43
If a patient has a positive DAT, what do you want to check
```
LDH, haptoglobin, bilirubin
PBS
reticulocyte count
transfusion history
history of autoimmune disease
```
44
Low Hgb and low hematocrit, which number is inaccurate in patient with agglutination?
Hematocrit, because agglutination will cause it to be artifactually low.
45
can free hemoglobin be measured in plasma
yes
46
What is the normal relationship between Hct and Hb?
Hct is normally 3x the Hb
47
Low Hgb and low hematocrit, what could be the cause of the anemia?
hemagluttination, cold AIHA
| clumps form because antibody has low to moderate temperatures that causes them to clump before the smear is visualized
48
Patient has high LDH, low haptoglobin, and DAT is positive for IgG and C3. What are some likely causes?
a. lymphoma
b. mycoplasma pneumonia
c. concurrent autoimmune disease like SLE or RA
d. recent transfusion
e. acute leukemia
C, A, D
49
Man from Nigeria is being treated for p. ovale malaria with primaquine. His initial anmeia has worsened in spite of the lack of evident infected cells on his peripheral smear, what is the potenital cause for his anemia? (you see a blister cell)
G6PD deficiency
50
VWF function
...
51
If VWF gene encodes protein that is increased in susceptibility to cleavage by ADAMTS13. What is the expected clinical phenotype?
a. renal failure
b. frequent thromboses
c. frequent bleeding
d. hemolysis
e. thrombocytosis
increased susceptibility to bleeding
| if too long, susceptibility to clotting
52
What is the major cause of microcytic hypochromic anemia and what is the differential diagnosis?
iron deficiency
| thalassemia
53
How is iron stored in macrophages?
as ferritin and haemosiderin
54
What state is iron bound to:
a. transferrin
b. hemosiderin
c. ferritin
a. ferric
b. ferric
c. ferric
55
Iron overload leads to what effect on:
a. tissue ferritin
b. TfR1
c. DMT1
a. I
b. D (macrophages don't want to take up more iron by transferrin)
c. D (don't need to absorb dietary iron)
56
Iron deficiency leads to what effect on:
a. tissue ferritin
b. TfR1
c. DMT-1
d. ALA-S (aminolevulinic acid synthase)
a. D (don't want to store iron, need to get it to RBC)
b. I (want to transport iron)
c. I (want to absorb dietary iron)
d. D
57
DMT-1
protein involved in transfer of iron (ferrous) from lumen across the enterocyte microvilli.
58
What factors decrease hepcidin expression so that ferroportion can be expressed for iron mobilization and absorption?
hypoxia
erythropoietin
erthyroblasts (twsg1, gdf15)
59
Leading causes of iron deficiency anemia
a. chronic blood loss (GI, menses)
| b.
60
koilonychia
spoon nails
61
angular cheilosis
fissuring of corner of the mouth
62
What is seen on a PBS with iron deficiency anemia? CBC?
a. hypochromic microcytic cells with occasional target cells and pencil-shaped poikilocytes
b. low reticulocyte count
c. platelets often moderately raised (bleeding).
d. low serum iron
e. increased TIBC so that it is less than 20% saturated.
63
What does a dimorphic PBS on a patient with iron defiicency anemia mean?
they are responding to iron therapy.
64
What would values be a in a patient with anemia of chronic disorders?
a. low serum iron
b. low TIBC
c. ferritin normal/raised
d. normochromic, normocytic
e. bone marrow storage iron is normal, erythroblast iron is reduced
65
What does normal iron storage look like in the bone marrow?
will stain blue (hemosiderin)
66
Why are serum ferritin levels normal or increased in anemia of chronic disorders?
because chronic diseases make hepcidin, which decreases iron mobilization, but it is still in storage and bound as ferritin.
67
What is seen in a PBS in sideroblastic anemia
ring of iron granulates around a nucleated RBC (sideroblasts)
68
What are the types of sideroblastic anemia?
a. hereditary: X-linked defect in ALA-s gene
b. acquired: malignant diseases of bone marrow, antituberculous drugs, alcohol, lead, hemolytic anemia, malabsorption, RA.
69
How can lead poisoning cause anemia?
inhibits heme and globin sythesis. Inhibits degredation of RNA is RBCs which causes appearance of basophilic stippling.
Anemia will be hypochromic or hemolytic, bone marrow may show ring sideroblasts.
70
Differential diagnosis of hypochromic anaemia
```
(if not iron deficiency, bleeding)
thalassemia
chronic inflammatory disease
sideroblastic anemia
lead poisoning
```
71
megaloblastic anemia
maturation of the nucleus in bone marrow RBCs is delayed relative to the cytoplasm due to defective DNA synthesis (usually B12/folate deficiency)
72
pernicious anemia
caused by autoimmune attack of gastric mucosa leading to atrophy of stomach and reduced/absent IF production causing B12 deficiency. H. pylori can initiate the autoimmune gastritis which presents in young as iron deficiency ans elderly as pernicious anemia
73
why do patients with megaloblastic anemia often have mild jaundice?
because of excess breakdown of hemoglobin resulting from ineffective erythropoiesis in bone maroow.
74
Vitamin B12 neuropathy
(subacute combined degeneration of the spinal cord) neuropathy especially for lower limbs probably due to accumulation of homocysteine.
75
Lab findings in macrocytic anemia
a. macrocytes typically oval
b. low reticulocyte count
c. WBC and platelets may be reduced
d. hypersegmented neutrophils
e. hypercellular bone marrow
f. normal Hgb
g, raised serum unconjugated bilirubin and LDH due to marrow cell breakdown.
76
differential diagnosis of macrocytic anemia
alcoholism (raises MCV without anemia) and liver disease
hemolytic anemia (due to high reticulocyte count)
hypothyroidism
bone marrow malignancy
77
protoporphyrin is broken down into
bilirubin
78
haptoglobin
binds free hemoglobin in serum and takes to macrophages
79
clinical features of hemolytic anemia
The patient may show pallor of the mucous membranes, mild fluctuating jaundice and splenomegaly. May have dark urine due to increased urobilinogen
80
lab features of hemolytic anemia
a. reticulocytes 5-20%
| b. microspherocytes
81
What can cause episodes of hemolytic anemia
Acute haemolytic anaemia in response to oxidant stress, e.g. drugs, fava beans or infections
82
What is seen in G6PD deficiency?
a. ‘bite’ cells and ‘blister’ cells which have had Heinz bodies removed by the spleen. Heinz bodies (oxidized, denatured haemoglobin) may be seen in the reticulocyte preparation, particularly if the spleen is absent.
83
pyruvate kinase deficiency
autosomal recessive causes red cells to be rigid because of reduced ATP production.
84
lab findings in warm autoimmune hemolytic anemia
a. microspherocytes and reticulocytes
| b. DAT positive for IgG, IgA, or complement
85
treatment options for immune hemolytic anemia
a. remove underlying cause
b. corticosteroids (not very effective if complement is involved.
c. splenectomy
d. immunosupression or monoclonal antibodies
86
what can cause cold autoimmune hemolytic anemia?
a. monoclonal: idiopathic cold hemagglutinin syndrome or lymphoproliferative disorders
b. polyclonal: infection (mononucleosis or mycoplasma)
87
lab findings in cold autoimmune hemolytic anemia
a. agglutination
| b. positive DAT for C3d (this is caused by IgM fixing complement on RBCs)
88
Paroxysmal cold haemoglobinuria
is a rare syndrome of acute intravascular haemolysis after exposure to the cold. It is caused
by the Donath – Landsteiner antibody, an IgG antibody with specificity for the P blood group antigens, which binds to red cells in the
cold but causes lysis with complement in warm conditions. Viral infections and syphilis are predisposing causes and the condition is
usually self-limiting
89
Alloimmune hemolytic anemia
during transfusion when donor Ab react to recipient RBCs due to ABO-incompatible blood or Rh disease of the newborn.
90
Paroxysmal nocturnal hemaglobinuria
defect in PIG-A gene which leads to defect in production of GPI anchor which is needed to present DAF and CD59 on the surface of RBCs to prevent complement binding. RBCs are prone to lysis resulting in hemosiderinuria and recurrent thromboses.
91
What are features of extravascular hemolysis
```
jaundice
gallstone
splenomegaly
increased reticulocytes
increase unconjugated bilirubin
absent haptoglobins
```
intravascular hemolysis
hemaglobinuria/
hemosiderinuria
92
A patient’s VWF gene encodes a form of VWF that shows increased susceptibility to cleavage by ADAMTS13. What would you expect the clinical effect of this to be?
a. Renal failure
b. Frequent thromboses
c. Frequent bleeding (“coagulopathy”)
d. hemolysis
e. thrombocytosis
...
93
AdamTS13
a. cleaves vWF to optimal size
94
vWF function and role in TTP (thrombotic thrombocytopenic purpura
multimeric cable that hangs off the surface of damaged vascular surfaces (it binds collagen) for the purpose of providing platelets a place to adhere when necessary. The system is finely tuned; if the cables are too long, too much platelet adherence takes place, resulting in thromboses in small and medium sized vessels. That in turn results in a type of hemolysis we call “microangiopathic”. One can think of it as red cell lysis resulting from cords of fibrin strung across the small vessels, slicing the red cells into bits as they come flying by (although it is not clear whether that’s exactly how it works).
95
What causes thrombotic thrombocytopenic purpura (TTP)
Autoimmune anti-AdamTS13 Ab binds up AdameTS13 leading to longer vWF and causes thromboses, thrombocytopenia, hemorrhage, 'microangiopathic hemolytic anemia
96
What is the characteristic red cell morphology of microangiopathic hemolytic anemia
schistocytes
97
What is the clinical triad of microangiopathic hemolytic anemia
fever (w/ absense of sepsis)
renal failure
fluctuating CNS symptoms
98
How do you treat microangiopathic hemolytic anemia?
plasmapheresis to removed anti-Adam TS13
