Microcytic and macrocytic anemias Flashcards
What is the unifying pathogenic mechanism for all microcytic anemias?
Defect in RBC hemoglobin synthesis at a cellular level
What can a large RDW indicate?
In respect to microcytic anemia
The presence of a population of mixed normo/microcytic RBC population
Dimorphic RBC populations
Classically associated w/ sideroblastic anemia (myelodysplastic variant)
Microcytic RBCs arise from the mutated clone and normal rbcs from the unmutated one
Can also be seen in Pt’s w/ iron deficiency anemia who are treated w/ iron - normal cells representing those produced in response to iron supplementation, and microcytic RBCs arising from the period of iron deficient erythropoiesis
Pathway abnormailities in microcytic anemia
Defect in cellular heme synthesis
Defect in globin chain synthesis
Defect in heme synthesis in microcytic anemia
Unavailability of iron:
-iron deficiency; anemia of inflammation/chronic disease
-Defect in cellular heme/protoporpyrin synthesis
Defect in globin chain synthesis in microcytic anemia
-Thalassemias
-Thalassemia-like hemoglobinopathies: :
HbC
HbE (both β globin);
Hb Constant Spring(HbCS (α globin))2
Decreased serum iron
Increased Tf/TIBC w/ decreased Tf/Fe saturation%
Iron deficiency anemia
In early stages, MCV might be normal but is typically low
Microcytic RBCs in in iron deficiency anemia are typically also hypochromic (decreased MCHC, expanded area of central pallor)
Causes of iron malabsorption
- Celiac disease
- Autoimmune gastritis
- Bariatric surgery
- Achlorhydria (acidic pH required for optimal iron apsorption)
- Resection duodenum/proximal ileum
- Iron-refractory iron deficiency anemia (IRIDA) TMPRSS6 mutation; congenital microcytic/hypochromic anemia
Gene mutation associated w/ iron-refractory iron deficiency anemia (IRIDA)
TMPRSS6 mutation; congential microcytic/hypochromic anemia
Qualitative defects of globin synthesis
Hemoglobinopathies - characterized by the production of abnormal hemoglobin w/ an abnormal α or (more commonly) β globin chain resulting from a mutation in the globin gene
Quantitative defects of globin synthesis
Thalassemias - . As a result of a mutation in a globin gene promoter, either α or β globin chains are not produced or are produced at a decreased level that leads to imbalance between α and β globin production. It is this imbalance that causes the anemia
Thalassemia associated w/ increased levels of HbF and/or HbA2
β thalassemia syndromes
Asymptomatic Pt who is not anemic, has normal iron studies, but has MCV in the 70s
Almost certainly has a thalassemia syndrome (thalassemia trait)
HbA2 and/or HbF are elevated
β thalassemia
Target cells
Thalassemia patients other than silent carriers have “target cells” (they look like targets).
infrequent in αα/-α thalassemia, β+/β thalassemia, more common in other phenotypes.
Nucleated RBCs in thalassemia
Indicates extramedullary hematopoiesis
HbH stained w/ new methylene blue or brilliant cresy blue
HbH cannot be quantified w/ HPLC
Thalassemia that requires molecular testing
Since the most common α thalassemia syndromes do not produce an abnormal hemoglobin, the vast majority of α thalassemia patients will have normal hemoglobin quantitation. The diagnosis can be inferred by patient and family history, but requires molecular studies to confirm it. Molecular studies are almost never needed in β thalassemia
Thalassemia major
Transfusion dependent throughout life
Risk for Fe overload and complications like myocardial iron deposition-related heart disease and endocrinopathy (massive splenomagaly and extramedullary hematopoiesis)
Thalassemia minor
almost never require transfusion, are typically only mildly anemic;
many have mild splenomegaly but do not have the other complications above; and have a low risk of iron overload.
Thalassemia intermedia
Require transfusion sometimes.
They have some risk of developing the same complications as thalassemia major patients, and if they start developing those problems, they are put on chronic transfusion programs to prevent excess ERFE production and suppression of hepcidin.
Thalassemia trait
are usually not anemic at all or just barely; they have microcytosis but nothing else.
HbH disease
Clinical phenotype of thalassemia major/TDT
Frequently also have a small abount of Hb Barts (present w/ hydrops fetalis, severe TDT, and short survival)
They mostly show HbA becuase HbH is unstable
A β thalassemia syndrome with no HbA
β0 thalassemia
A β thalassemia syndrome with HbA
β+ thalassemia
α-/αα
α THALASSEMIA
clinically silent carrier
–/αα or α-/α-
α THALASSEMIA
(α thalassemia trait type 1 (cis))
or
α-/α- (α thalassemia trait type 2 (trans)):thalassemia trait
Type 2 trait most common in Black/African ancestry
type 1 trait most common in Asian, rare with Black/African ancestry
α-/–
ααND/–
αND-/α-
Hb H disease (Three absent or mutant genes; ND – non-deletion mutation, of which the best known is HbCS)
-TDT/thalassemia major; target cells; nucleated red cells
-Non-deletional mutations like αCS are associated w/ more severe phenotype
αND-/–
αND-/αND-
Hb Barts/hydrops fetalis (Four absent or mutant alleles total- two or three absent alleles with one or two mutant alleles)
-Severe TDT; short lived
β/β+ or rarely β/β0
o Mild anemia, microcytosis, some targets
o β thalassemia minor
o Strictly speaking there is no “β thalassemia trait” but some β/β+ behave like it
β/β0, or mild β0/β+
o Definite anemia, microcytosis, targets but typically no or rare transfusions
o β thalassemia intermedia
β0/β+, β0/β0
o Severe anemia, transfusion dependent, microcytosis, target cells, nucleated red cells
o β thalassemia major
Mechanism of anemia in thalassemias
Hemolysis due to cell damage from unbound globin chains
Patients with concurrent α thalassemia trait 2 (α-/α-) and β thalassemia minor are less anemic and microcytic than patients with beta thalassemia minor alone because they have less imbalance in α and β globin chain production.
Mechanism for iron overload
ERFE production/hepcidin suppression. Subsequent iron overload leads to osteoporosis and endocrinopathy
Extramedullary hematopoiesis
manifestation of extreme ineffective erythropoiesis causing
reactivation of embryonic blood production sites.
Luspatercept
activin receptor ligand trap that drives late stage erythropoiesis, is approved for use in thalassemia
Triad of saturnine gout
Patients with lead poisoning may have neuropathic abdominal pain, hypertension, joint pain, and kidney disease
Causes sideroblastic anemia
Macrocytosis/macrocytic anemia vs megaloblastic anemia
Macrocytic anemia - increased MCV, usually reflects presence of large RBCs (macrocytes)
Megaloblastic anemia - defects of nucleic acid synthesis results in specific morphologic changes in nucleated cells (particularly erythroid and myeloid precursors)
In megaloblastic anemia where are megaloblastic changes present?
Bone marrow - macrocyte you see in peripheral blood is not a megaloblast
What you do see in the peripheral blood in megaloblastic anemia:
(macroovalocytes) and neutrophils with a greater than usual number of nuclear lobes (hypersegmented neutrophils; usually 5 or more lobes)
What anemia typically reflects an abnormality in B12 or folate metabolism?
Megaloblastic anemia
Megaloblastoid changes
Congenital dyserythropoietic anemia (CDA)
Multinucleate erythroid precursors - hallmark of CDA
Do not have hypersegmented neutrophils in peripheral blood - do not have macroovalocytes
B12 and folate are normal
Diamond-Blackfan anemia
Macrocytic
Congenital form of pure red cell aplasia that is associated w/ mutation in the ribosomal regulatory proteins
Chronic liver disease:
the lipid composition of the RBC membrane is abnormal, causing “extra” membrane that produces a higher surface-tovolume ratio.
These cells have the appearance of target cells except that the target cells of thalassemia and hemoglobinopathies are microcytic.
These cells are large and the “target” is not precipitated globin but rather a fold of cell membrane.
Artifactual macrocytosis
MCV is measured as large but RBCs are normal size
- Rouleaux/RBC clumping
- RBC agglutination
Pt’s w/ rouleaux typically have eleved erythrocyte sedimentation rate and CRP (common labs to ID inflammation)
Cryoglobulinemia type I
Associated w/ hematologic malignancies
Cryoglobulinemia type II
Associated w/ hepatitis C
Cryoglobulinemia type III
Nonspecific indicator of inflammation (mixed cyroglobulinemia)
What enhances folate/THF retention in cells?
Polyglutamation
MCV greater than 115 fL
Increases the likelihood that macrocytic anemia is due to B12
Although MCVs that high or
higher are routine in patients taking
hydroxyurea
Mutation associated w/ HbE syndrome
β26 Gln(Q) → Lys (K)
Reticulocyte index
Frontal bossing
Typical characteristic of thalassemias
Due to infeffective heamtopoeisis
Pathogenic mechanism of Hb constant spring (CS)
α142 STOP → Gln(Q)
(gives a long unstable α chain)
Pathogenic mechansim of HbC syndrome
β6 Gln(Q) → Lys (K)
B. Hemoglobin concentration
RBC# and red cell size (MCV) and hemoglobin concentration are only values that are measured directly
C. 36%
D. Polychromatophilic cytoplasm
Restless legs syndrome
PICA - is the most specific sx
C. Decreased cellular Hb synthesis
C. Low serum ferritin
D. 0%
HbE syndrome
Hb constant spring syndrome
C. SF3B1 mutation
Tx w/ rhEPO; transfusion/chelation; Luspatercept
D. Copper deficiency
Non-megaloblastic, macrocytic anemia causes
A. Hepatitis C (cryoglobulinemia type II)
B. Cubulin/amnion-less
Cubam, a multi-ligand receptor that absorbs vitamin B12 and reabsorbs proteins in the kidney, is made up of two proteins: cubilin and amnionless:
Cubilin: A cell receptor that recognizes the vitamin B12-intrinsic factor complex
Amnionless: A transmembrane protein that anchors the receptor to the membrane and helps with endocytosis
B. Binding to protein-coupled folate transporter
Dietary folic acid is polyglutamated and needs to be hydrolyzed by folypolyglutamate hydroxylase before binding to protein-coupled transporter
C. Both B12 and folate absorption (although folate is absorbed more broadly it will be impacted)
B. Hemodialysis
All answer choices are associated w/ folate deficiency - only hemodialysis is associated w/ loss (B12 does not dialyze)
Non-drug-related causes of folate deficiency
Methylene-THF DH (MTHFD1) - inborn defect of folate metabolism
Also; pregnancy, hemolytic anemia, exfoliative skin disease, leukemia, and hemodialysis
C. Thiamine-responsive megaloblastic anemia
Due to defect in SLC19A2 family gene (high-affinity thiamine recetor)
C. Serum anti-intrinsic factor antibodies
Serum methylmalonic acid accumulation just indicates B12 deficiency
D. Terminal ileum resection
“pernicious anemia is second best answer”
