Erythroid disorders Flashcards
How do we call high RBC production?
polycythemia
How do we call low RBC production?
anemia
What are 2 possible causes of anemia?
decreased production or decreased lifespan of RBCs
What is Counter principle?
Method to count RBCs.
Cells suspended in cuvette; in which there is another cuvette. Communication between the 2 is made through a small aperture
There is an electrode in both cuvettes and a vacuum
Cells will enter the smaller chamber in the middle causes change in current resistance between 2 chambers
Change in current is proportional to the number of cells passing through
Particles, liquid and electric current are pumped through an orifice of an exact diameter
The particles cause changes in the electric current and these changes are monitored to count and size particles
Why do males have a higher Hct?
Androgens have a direct effect on RBC production in the bone marrow thus males have a higher Hct
How is a reticulocyte count performed?
Young RBCs that still contain a lot of mRNA; stains blue under microscope because of RNA
They are larger than RBCs thus will increase the MCV.
What is anemia?
Hgb low
What is polycythemia?
Hct > normal
What is erythrocytosis?
count > normal
What is macrocytosis?
MCV > normal
What is microcytosis?
MCV < normal
What is MCV? What types of conditions can be determined with it?
MCV = hematocrit/RBC count (mean volume)
Normocytic, microcytic, macrocytic, anisocytosis
*Anisocytosis = medical term meaning that a patient’s red blood cells are of unequal size
What is mean corpuscular hgb?
MCH = mean mass of hemoglobin in RBC
what is mean corpuscular hemoglobin concentration? What types of conditions can be determined with it?
MCHC= mean concentration of hemoglobin in rbc
- Normochromic, hyperchromic, hypochromic
What is bilirubin? how is it made? what are its types?
Pigment produced by macrophages through heme degradation
Made by reduction of biliverdin IXalpha by NADPH and biliverdin reductase
2 forms = conjugated and unconjugated
- Conjugated: done by liver
- Unconjugated: means increased RBC destruction, produced by macrophages
Is bilirubin water-soluble? How is it transported ?
No
It is transported by albumin to the liver where it is made soluble by the 2 UDP-glucuronic acid enzyme
Then goes to the intestines as bile
Urobilinogen formed by bacteria –> either stercobilin in feces or reabsorbed and excreted as urobilin in urine
What is an increase in RBC concentration and what are the types?
Polycythemia
2 major categories:
Primary polycythemia
Secondary polycythemia
Describe primary polycythemia
intrinsic to red blood cell precursor
Acquired (often with increased age): Polycythemia vera (PCV)
Acquired somatic mutations and bone marrow stem cells
What is polycythemia vera?
a stem cell disorder characterized as a panhyperplastic, malignant, and neoplastic marrow disorder
Often mutation in JAK2 kinase (V617F) (most common; 99% of cases; downstream of EPO receptor), common
V617F is the autoinhibitory domain of the Jak2 kinase
Constitutively active jak2 kinase tricks cells into thinking there is plenty of EPO around
Describe secondary polycythemia
Acquired
- high altitude (hypoxic environment)
- renal artery stenosis (local hypoxia)
- renal cell carcinoma (inappropriate EPO production)
- drug associated (EPO, androgen administration)
- Genetic
- Mutations in EPO-R or O2 sensing pathways (VHL)
Your body tricks your kidney into thinking there is a lack of oxygen in the body = high epo production
Name 7 abnormalities in cell types
Target cells Acanthocytes Echinocytes Spherocytes Poikilocytes/fragments Elliptocytes Stomatocytes
What are target cells?
increased surface of membrane due to decreased volume
Absolute increased SA d/t increased phospholipid and cholesteron (obstructive liver disease)
Relative increased SA d/™ decreased volume (iron deficiency, thalassemia, HGB E, HGB C)
What are acanthocytes?
Accumulation of cholesterol in outer lipid bilayer (liver disease)
Accumulation of sphingomyelin in outer lipid bilayer (abetalipoproteinemia)
What are echinocytes?
Expansion of outer lipid bilayer relative to inner surface (uremia, PK deficiency, artifact)
What are spherocytes?
o Spectrin, ankyrin, and/or band 3 deficiency –> membrane instability –> loss of membrane lipid –> increased surface area (higher MCV)
o Hereditary spherocytosis
o R-E removal of antibody and RBC membrane fragments (autoimmune hemolysis)
What are Poikilocytes/fragments?
Severely impaired horisontal protein interactions (hemolytic HE, HPP)
What are elliptocytes?
Deformation due to altered horizontal membrane protein (spectrin-dimer) interactions (common HE)
What are stomatocytes?
Expansion of inner surface bilayer relative to outer aspect (vinca alkaloids, alcoholism, cation permeability disorders)
what type of anemia does defective hemoglobinisation lead to? Name examples of problems that may cause it.
Microcytosis
E.g. IDA
Thalassemia
Sideroblastic anemia
what type of anemia does defective DNA synthesis lead to? Name examples of problems that may cause it.
Macrocytosis E.g. Low folate Low B12 Cytotoxic drugs Myelodysplasia
OR macrocytosis may be caused by elevated plasma lipids…
- Liver disease
- Hypothyroidism
- Alcohol
- Hyperlipidemia
- Pregnancy
Explain why and how abnormal size of RBC results from problems of DNA synthesis or hgb synthesis
RBC production is a balance between nucleic acid production and Hgb production
- Problem with hgb production will decrease rbc size
- Problem with nucleic acid production will be larger
Name non-megaloblasti macrocytic anemia causes.
- Liver disease
- Hypothyroidism
- Alcohol
- Hyperlipidemia
Name 3 drugs that may cause macrocytic megaloblastic anemia
Methotrexate
Zidovudine (AZT)
Metformin (decreases B12 absorption)
How do neutrophils look in cases of B12 deficiency
B12 deficiency: hyper segmented neutrophils
In sickle cell disease, how is..
MCV?
Reticulocyte count?
Hgb?
MCV? Low
Reticulocyte count? High
Hgb? Low
What is sickle cell disease?
- Inherited genetic disorder more common in south countries (Africa)
- Problems in hgb gene; only 1 AA change leads to polymerization
Name the significant comorbidities of sickle cell disease
- microvascular complications
- Several organs affected
- painful episodes
- decreased life expectancy
What are the treatments of sickle cell anemia?
- O2 transfusions
- Pain management
- Antibiotics
- Inducers of Hgb F (hydroxyurea, epigenetic Rx)
Approx how much iron is in the plasma?
4 mg
In thalassemia, how is.. MCV? Reticulocyte count? Hgb? The shape of the cell?
Have target cells
Low MCV
N reticulocyte
low hgb
What is thalassemia?
Inherited mutation in the hgb gene
Can be alpha or beta
Alpha globin genes (2 copies of the gene per chromosome; so 4 in total. in chromosome 16); can have a mutation on one, two, three or all 4
Large part of treatment is genetic counselling
A mutation for which disease can be protective against malaria?
Only 1 mutation of thalassemia has a protective effect against malaria
What happens in thalassemia?
- Anemia (relative high globin alpha vs beta (example))
- Skeletal deformities due to bone marrow expansion (compensation mechanism for + hemolysis)
- Systemic iron overload
Name possible Beta-thalassemia therapies
Mostly supportive treatments
- Transfusion therapy
- Chelation therapy (to avoid iron overload)
- Inducers of fetal hgb
- Antioxidants
- Splenectomy
- Bone marrow transplantation
Explain possible chelation therapies for thalassemia
o IV infusion
o Oral
o Combinations and new agents
Deferoxamine (Desferal) efficient, inexpensive, subcuteanous, pump 8-12/day
Deferiprone (L1), oral, 3x/day, variable efficiency, side effects
Exjade (ICL670) Deferasirox, oral, 1x/day, promising, side effects, high costs, not available North America
What happens in people who have elliptocytosis and spherocytosis?
Problems in structural proteins in RBC membranes
RBCs need to be able to squeeze between narrow capillaries and others so structure is important
Decreased deformability and shortened lifespan due to acquired genetic mutations / heredity reasons
What is warm autoimmune hemolytic anemia?
Warm antibody hemolytic anemia is the most common form of autoimmune hemolytic anemia. It is defined by the presence of autoantibodies that attach to and destroy red blood cells at temperatures equal to or greater than normal body temperature
Homolytic anemia –> jaundice; destruction of RBCs
Immune system attacks organs in the body –> RBC destruction
Autoimmune –> antibody -mediated process; can activate complement and cause complement-mediated hemolysis
In malaria, how is.. MCV? Reticulocyte count? Hgb? Skin color?
jaundice, low hgb, dark urine, normal MCV
What is malaria caused by and where are the majority of the cases?
Parasites in RBCs Plasmodium falciparum
Sub-saharan africa
What are RBC enzymopathies?
Rbcs do not have mitochondria and thus generate their energy by relying on glycolysis and pentose phosphate pathway
Heinz bodies; “bite cells”, “blister cells”
- Glucose 6-phosphate dehydrogenase deficiency; impaired production of NADPH (major antioxidant for RBCs)
- G6PD is a X-linked enzymes (females are carrier, males are affected)
- Mutations affecting other enzymes of the glycolytic pathway also lead to hemolysis due to impaired ATP production
- i.e. Pyruvate kinase deficiency
- Normal RBC do not have mitochondriae!
- So they rely on G6PD…
Name 7 things that can cause oxidative stress
- Infection
- Drugs (dose related)
- Antimalarials (Primaquine, chloroquine)
- Aspirin (<1g/day normally ok)
- Antibiotics (Quinolones, nitrofurantoin, sulphonamides eg septra)
- Dapsone
- Fava beans
