Week 2 Flashcards
HbH
B4 tetramer
HbBarts
y4 tetramer
Thalassemia
decreased (imbalanced) production of normal globin chains (quantitative disorder0
Thalassemias result in… (4)
- anemia
- Bone marrow expansion (to compensate for ineffective erythropoiesis),
- extramedullary hematopoiesis,
- increased intestinal iron absorption
Alpha globin present on chromosome ___
16
Beta globin present on chromosome ____
11
Microcytic anemias (4)
I. Iron deficiency
ii. Thalassemia syndromes:
1. A-thal, B-thal, sickle thal, HbE syndromes
iii. Severe lead poisoning (children)
iv. Chronic disease/inflammation
Explain the meaning of the terms thalassemia major, thalassemia intermedia, and thalassemia minor
Minor: mild anemia, asymptomatic trait state
Intermedia: moderate anemia, intermittent transfusions
Major: severe anemia, transfusion-dependent
HbE
B-globin gene mutation (glu → lys, at position 26)) → creates unstable mRNA → less production
A-thal trait
2 a gene deletion = thalassemia minor
Hbh disease
3 a gene deletion = thalassemia intermedia
Hydrops fatalis
4 a gene deletion = thalassemia major
Clinical manifestations of alpha thalassemias:
___ RBCs = ___ MCV
Small RBCs = ↓ MCV (mean corpuscular volume)
CM alpha thal:
____ MCHC and MCH
Low
CM alpha thal:
____ RBCs = ____ RDW
NORMAL
CM alpha thal:
___ in RBC production = ____ RBC
compensatory increase in RBC production = increased RBC
CM alpha thal:
____ red cell survival = ____ reticulocyte count
decreased
increased
CM alpha thal:
____ of intracellular RBC contents (such as: ____, _____, and ____)
increase
Indirect (unconjugated) bilirubin, Lactate dehydrogenase (LDH), and Aspartate aminotransferase (AST)
spleen in alpha thalassemia
splenomegaly
Peripheral smear of alpha thalassemia (3)
- Red cells much smaller (microcytosis, low MCV)
- Target cells
- Hypochromia
Diagnosis of alpha thal:
2 genes deleted->
microcytosis
Diagnosis of alpha thal:
3 genes deleted->
anemia, microcytosis
Diagnosis of exclusion for alpha thal (3)
microcytosis, without iron deficiency, and with normal electrophoresis
Clinical manifestations of Cooley’s anemia (6)
- dense skull (frontal bossing)
- Marrow expansion (hair on end finding)
- Splenomegaly
- Osteopenia/bone changes
- Iron overload (increased intestinal iron absorption, and dependent on blood transfusions to survive)
a. → Growth and endocrine failure (diabetes, thyroid problems, gonadal hormone issues)
b. ⅔ Cooley’s anemia pts have abnormal endocrine function
c. Hypothyroidism present in 40-60% of pts with B-thal major - Increased risk for pulmonary hypertension
Hemoglobin electrophoresis findings for B thal (2)
timing is important! (too soon, no B-chain being produced yet)
1.↑ HbA2, ↑ F in milder forms
2.No HbA in Cooley’s Anemia (no B-globin production)
**Must be sure person is NOT iron deficient
Thalassemia geographical distribution
Thalassemia most common in
- SE Asian,
- African
- Mediterranean descent.
SE Asians common alpha globulin genotype
(–/aa) → more likely to have child with hydrops fetalis
Africans common alpha globulin genotype
(a-/a-)
Treatment for alpha thalassemia
Most people require NO therapy
- HbH disease: may require intermittent transfusions
- May account for mild anemia, splenomegaly, bilirubin gallstones
- Iron should NOT be prescribed for microcytosis (can have iron overload due to increased iron absorption)
- Genetic counseling (avoid fetal hydrops via in utero bone marrow transplant)
Treatment for Cooley’s anemia (3)
- Transfusion therapy
- lnduction of fetal hemoglobin
- Bone marrow transplant
In transfusion therapy in the treatment of Cooley’s anemia, you want to maintain hemoglobin at ___ g/dL (transfusions every ____ weeks)
9-10 g/dL
3-5 weeks
Problem with transfusion therapy
Results in iron overload
a. Body has NO fixed method to lose iron (fixed at 1 mg/day)
b. 1 mL: of pure RBCs = 1 mg Fe, 1 unit RBC//month → 3-4 g Fe/yr
c. Can result in:
i. Hepatic fibrosis and cirrhosis
ii. Endocrinopathies (hypothyroidism, growth failure, DM)
iii. Cardiomyopathy and conduction disturbances (sudden death)
How do you prevent iron overload in transfusion therapy
- chelation therapy
- erythrocytapheresis
Common iron chelating agents (3)
- deferoxamine
- deferasirox
- deferiprone (only one that removes Fe from heart)
Treatment to induce fetal hemoglobin (2)
hydroxyurea and butyrate
Results newborn screen:
FBart’s
Genotype?
alpha thal
Results newborn screen:
F
Genotype?
B0-thal
Results newborn screen:
FA
Genotype?
B+-thal
Results newborn screen:
FE
Genotype?
HbEE or HbEB0 thal
Results newborn screen:
FEA
Genotype?
HbEB+ thal
Diagnosis?
decreased MCV normal RBC >13 MCV/RBC increased RDW decreased ferritin Hb Electrophoresis normal Response to iron? yes
Fe deficiency
Diagnosis?
decreased MCV
increased RBC
a-thal
Diagnosis?
decreased MCV
increased RBC
B-thal
Molecular basis of sickle cell
AR - qualitative hgb disorder
-both B-globin genes mutated
Sickle Cell Disease B-globin genes vs. Sickle Cell Anemia B-globin genes vs. sickle cell trait
Disease: HbS
1 with single AA substitution (Beta6 glu→ val), 1 that is abnormal
Anemia: HbSS
Both genes have Sickle Cell AA substitution
Trait: 1 Sickle Cell gene, 1 NORMAL gene
HbC mutation
glu → lys (B gene position 6) = sickle cell disease (HbSC) or Hemolytic anemia (HbCC)
HbE mutation
glu → lys (B gene, position 26) = Thalassemia (HbE B-thal), Sickle cell disease (HbSE)
Lab findings for sickle cell:
Anemia? Retic count? WBC and platelet count? Chemistries? RDW? peripheral smear?
- Chronic anemia
- Retic count increased (compensatory)
- increased WBC and platelet count
- increased RDW
- abnormal peripheral smear
Peripheral smear in sickle cell (5)
1) Howell-Jolly bodies (evidence of splenic dysfunction - remnants of nuclear DNA)
- -> Purple dots in RBCs
2) Nucleated RBC (red cells that have not extruded nucleus)
3) Polychromasia (blue colored retics, larger in size)
4) Sickled RBC cells
5) Target cells: seen in Hb SBothal, Hb SB+thal, and a little in Hb SC
NOT seen in HbSS or Sickle trait
Target cells are seen in the peripheral smear for _______, _______, and ______ but NOT seen in _______ or _______
seen in Hb SBothal, Hb SB+thal, and a little in Hb SC
NOT seen in HbSS or Sickle trait
Sickle trait
genetic carrier state (Bnormal + Bsickle) - does NOT develop sickle cell disease
Normal CBC
Potential adverse effects or associations with sickle trait (6)
1) Microscopic hematuria
2) Renal papillary necrosis (gross hematuria)
3) Isosthenuria (mild urinary concentrating defect)
4) Increased risk of chronic kidney disease and blood clots
5) Splenic infarction (altitude of depressurized flight)
6) Exertional heat illness/rhabdomyolysis/death (sports-related)
Sickle cell anemia (HbSS)
B-globin genes? Hb levels? Retic count? Size of RBC (MCV)? Relative clinical severity?
B-globin genes - S + S
Hb levels - very low (6-9 g/dl)
Retic count - 5-30% (much higher)
Size of RBC (MCV)? normal
Relative clinical severity? 4+ (very severe)
Sickle-Bo thalassemia (HbS Bo)
B-globin genes? Hb levels? Retic count? Size of RBC (MCV)? Relative clinical severity?
B-globin genes - S + Bo (no normal B-globin)
Hb levels - very low (6-9 g/dl)
Retic count - 5-30% (much higher)
Size of RBC (MCV) - small
Relative clinical severity - 4+ (very severe)
Sickle-Hemoglobin C (HbSC)
B-globin genes? Hb levels? Retic count? Size of RBC (MCV)? Relative clinical severity?
B-globin genes - S + C
Hb levels - low (10-12 g/dl)
Retic count - 3-5% (higher)
Size of RBC (MCV) - normal
Relative clinical severity - 2+ (moderate severity)
Sickle-B+ Thalassemia (HbSB+)
B-globin genes? Hb levels? Retic count? Size of RBC (MCV)? Relative clinical severity?
B-globin genes - S + B+ (some normal B-globin)
Hb levels - slightly lower (11-13 g/dl)
Retic count - 3-5% (higher)
Size of RBC (MCV) - small
Relative clinical severity - 2+ (moderate)
Sickle cell trait
B-globin genes? Hb levels? Retic count? Size of RBC (MCV)? Relative clinical severity?
B-globin genes - normal + S
Hb levels - normal (14-16 g/dl)
Retic count - 1-2% (normal)
Size of RBC (MCV) - normal
Relative clinical severity - +0 (normal)
Pathophysiology of cell sickling:
Deoxygenation –> ?
Re-oxygenation –> ?
glu → val (hydrophobic → charged AA)
- Deoxygenated sickle Hgb polymerizes into 14 strand helical fibers → Hgb precipitates out of solution, distorted sickle form of RBC
- Reoxygenation → polymers dissolve, RBC returns to normal shape
-After several deox-ox cycles → permanently sickled → lysed (Destroyed)
→ Increased vaso-occlusion
→ Decreased NO bioactivity
-Presence of some normal Hgbs or HbC interferes with polymerization, lessens severity
Normal vs. Sickle RBCs
Normal: biconcave disc-shaped, pliable, easily flow through small blood vessels, lives for 120 days
Sickle: sickle-shaped, rigid, stick (even when not sickled), lives
Acute complications of SCD (4)
1) Acute chest syndrome
2) Infections
3) Spleen sequestration –> infarction
4) Stroke
Chronic complications of SCD (6)
1) Sickle Lung Disease
2) Sickle Nephropathy
3) Retinopathy
4) Skin ulcers (legs)
5) Avascular necrosis - femoral/humeral heads
6) Splenic infarction
Acute Chest Syndrome in SCD occurs because…
Diagnosis? (2 criteria)
Treatment?
sickle RBCs trapped in lung circulation → damage vessel endothelium → fluid leak into lungs → compromise ability to oxygenate blood
-Most common acute cause of death in SCD
Diagnosis: new pulmonary infiltrate on CXR AND evidence of lower airway disease (cough, SOB, retractions, rales, CP)
Treatment: rapid transfusions
Risk for infections in SCD due to…
Treatment?
- Increased risk for encapsulated bacteria due to splenic dysfunction
- Preventable cause of death in children with penicillin prophylaxis
Aplastic crisis signs/symptoms (2)
1) retic count very low
2) severe anemia, pallor (transient)
Aplastic Crisis and Parvovirus B19 connection
- Aplastic crisis = sudden drop in hemoglobin
- Parvovirus B19: infects RBC precursors, arresting RBC development into mature cells
(Transient, Common in children)
Sickle cell disease patients rely on increased retics to compensate for increased RBC destruction anything that compromises bone marrow’s ability to rapidly produce RBCs → aplastic crisis
Splenic sequestration
prior to splenic infarction, blood can flow into sinusoids, but can’t flow out → spleen engorged and precipitous drop in Hgb → can lead to death
Sickle Lung Disease
- Present in 25-40% of sickle cell patients
- Severe pulmonary HTN in up to 28%
-Progressive obliteration of pulmonary vasculature
Intimal hyperplasia, micro interstitial fibrosis, plexiform lesions
-Most common cause of death in adults with sickle cell disease.
Sickle Nephropathy
occurs in 10-15% of sickle cell patients
Results from adhesion of sickle red cells in afferent/efferent arterioles
→ Mesangial cells phagocytose RBC fragments → get deposited on basement membrane
Findings:
- initial hyperfiltration and enlarged glomeruli (creatinine NOT a good measure)
- Microalbuminuria/proteinuria (protein loss in urine)
- Focal segmental glomerulosclerosis (FSGS)
Retinopathy in SCD
11-45% of sickle cell patients
retinal vessel damage→ retinal detachment, hemorrhage, and blindness
Skin ulcers in SCD due to…
decreased peripheral blood flow
Treatments of sickle cell disease (5)
1) Folic acid
2) Prohylactic penicillin
3) bone marrow transplantation
4) hydroxyurea therapy
5) transfusion therapy
Folic acid used in SCD to treat…
developmental delays caused by anemia
Bone marrow transplantation in SCD
transplantation done with HLA-matched full sibling unaffected by sickle cell disease with a greater than 90% disease free survival.
- Only 20% of eligible patients have such a donor available.
- “The cure”
Hydroxyurea therapy
1) oral chemotherapy agent that induces production of HbF
2) Interferes with sickle hemoglobin polymerization
3) Improves anemia, increases MCV, decreases WBC count (decreased adhesion molecules)
4) Reduces frequency of acute pain crises and reduces mortality
5) No evidence of reduction in chronic organ injury
6) Only FDA approved drug for sickle cell disease
Transfusion therapy
two types
“Dilutes out” sickle RBCs (keep sickle
Risks of transfusion
Increased hyperviscosity if transfused to a hemoglobin >10 g/dL
Associated with transmission of infection, allo-immunization (antibody formation to donor blood), iron overload
Exchange vs. Simple transfusion therapy
- Exchange transfusion: remove pts sickle RBCs, replace with normal RBCs
- Simple transfusion: dilution by transfusion of normal RBCs