Pathoma Red Blood Cell Disorders Flashcards
What is the technical definition of anemia and what is one example which shows why Hb, Hct, and RBC count are not perfect surrogates?
Decrease in circulating RBC mass
I.e. after a gunshot wound, patient has lost RBC mass -> anemia. But until the fluid is replaced, the concentration of everything will be normal (these measure are concentration dependent).
What is the definition of anemia in males / females?
Males: Hb < 13.5 g/dL
Females: Hb < 12.5 g/dL
What is the normal range for MCV?
80-100 fL
Why does microcytosis happen?
To keep the hemoglobin concentration is constant
- > microcytosis is always caused by decreased production of hemoglobin
- > if hemoglobin is low, can divide to keep the concentration normal
What are the four general causes of microcytic anemia?
Low iron: 1. Iron deficiency anemia 2. Anemia of chronic disease Low heme: 3. Sideroblastic anemia Low globin: 4. Thalassemias
Where is iron absorbed and what is the key regulator of its movement into blood?
Absorbed by enterocytes in the Duodenum via DMT-1
Key regulator of transfer from enterocyte to transferrin in the “ferroportin” transporter. Ferroportin activity is modulated by hepcidin.
What is serum iron vs serum ferritin measuring?
Serum iron - amount of iron which is found to transferrin within the blood
Serum ferritin - amount of iron stored in liver / bone marrow macrophages
What are common causes of iron deficiency in infants and young adults?
Infants - breast feeding (poor iron ransfer)
Adult females - menorrhagia (uterine fibroids or hypothyroidism) or pregnancy
Adult males - peptic ulcer disease
What are common causes of iron deficiency of the elderly in the developing world vs in the west?
Developing world - hookworms (Necator and Ancylostoma)
West - Colorectal cancer / polyps
Why does gastrectomy predipose to IDA?
Fe2 goes in2 the body
Acid maintains iron in the Fe+2 state for better absorption
What is the first thing that happens in IDA?
Ferritin goes down -> bone marrow macrophages depleted of storage iron for making RBCs.
As serum ferritin drops, liver responds by increasing transferrin
Always: as ferritin decreases, TIBC rises
What is a normal value for % saturation and what happens to it as anemia progresses?
% saturation ~ 33%, or 1/3 TIBC
As serum iron decreases (used by the body) -> iron is taken off of transferrin -> saturation drops.
What is the first stage of anemia in iron deficiency?
It’s actually a normocytic anemia -> your body initially decides to just produce fewer, perfectly made RBCs before it starts churning out many mini ones.
What does iron deficiency anemia do to the RDW?
Increases the RDW, as there are some cells which are normal size and some the are small -> increased variability.
What value within RBCs will be characteristically increased in both IDA and ACD (anemia of chronic disease)?
Free erythrocyte protoporphyrin -> problem is lack of iron, so there will be free heme rings floating around ready for iron acceptance
What is a good marker to tell if RBCs are normal size?
Normal RBCs are about the size of a nucleus of a lymphocyte
What is the triad of Plummer Vinson syndrome? What happens to their tongue?
Dysphagia
Iron deficiency anemia
Esophageal WEBS - causes dysphagia
Tongue will have atrophic glossitis -> becomes beefy red
Give the two ways in which hepcidin causes anemia of chronic disease?
- Increases the degradation of ferroportin
- Decreases release of stored ferritin from bone marrow macrophages to erythroid precursors
- > ferritin stores will be up.
What factor, other than hepcidin, leads to ACD?
Decreased erythropoietin production occurs in ACD.
What happens to ferritin, TIBC, % saturation, and serum iron in ACD?
Ferritin - up, from macrophage sequestration
TIBC - down, since transferrin is always the opposite of ferritin
Serum iron - down, as bone marrow cannot get iron from ferritin, will pull from serum
% saturation - down
FEP will also be up
Is anemia of chronic disease a normocytic or a microcytic anemia?
Exactly like IDA, it starts normocytic and becomes microcytic overtime
-> some books classify it as normocytic.
Who might erythropoietin be used for in anemia of chronic disease?
- Chronic kidney disease - if due to reduced erythropoiein
- Malignancy / cancer
- HIV
What two heme synthesis reactions occur in the mitochondria, and what are the relevant cofactors?
First and last steps:
1. Succinyl-CoA + glycine -> ALA, via ALA synthase, cofactor is B6. Rate-limiting step.
- Protoporphyrin 9 + iron -> heme, via ferrochelatase.
What is responsible for the classical cell type of sideroblastic anemia and what is it?
Ringed sideroblast -> defective protoporphyrin synthesis -> accumulation of iron within mitochondria where ferrochelatase is supposed to use Fe for hemoglobin production.
What are the congenital and acquired causes of sideroblastic anemia? Pattern of inheritance?
Congenital - X-linked! ALA synthase mutation
Acquired:
1. Alcohol - mitochondrial poison
2. Lead - inhibits ALA dehydratase and ferrochelatase
3. B6 deficiency - usually due to isoniazid therapy - ALAS deficiency
4. Myelodysplastic syndromes - screws up synthesis
What happens to ferritin, TIBC, % saturation, and serum iron in sideroblastic anemia?
Iron-overloaded state (similar to hemochromatosis) -> iron within mitochondria will kill the erythroblasts and cause it to be leaked out into macrophages
Ferritin - high
TIBC - low (always opposite of ferritin)
% saturation - high
serum iron - high
What is seen on bone marrow vs peripheral smear in sideroblastic anemia / lead poisoning?
Bone marrow - ringed sideroBLAST (precursor cell) - as described previously
Peripheral smear - basophilic stippling - aggregation of residual ribosomes and denatured RNA
Why do thalassemias persist?
People with thalassemias (decreased globin SYNTHESIS) are relatively protected against Plasmodium FALCIPARUM malaria
What is the underlying cause of alpha thalassemia? What is seen in one allele loss?
A DELETION in the alpha globin chain on chromosome 16, causing decreased synthesis
1 allele lost - asymptomatic
Who gets cis vs trans two allele deletions of alpha thalassemia and what are the clinical consequences?
Cis - Asians -> accounts for higher risk of spontaneous abortion in offspring
Trans - Africans
Mild anemia seen in two allele deletion alone.
What is HbH disease and what is it caused by?
Only one functional copy of alpha gene, three knocked out (like a+ trait + a0 trait)
-> caused by buildup of beta4 tetramers which damage RBCs.
HbH = beta4 tetramers
What does four alpha genes deleted cause in alpha thalassemia? What abnormal hemoglobins are present?
Hydrops fetalis
In utero: Hemoglobin Barts (gamma 4) seen on electrophoresis
Later in life: HgH (beta 4), if they survive
What are the three possible states of each gene in beta thalassemia? What causes the abnormal globin synthesis and what chromosome is it on?
Chromosome 11 - Not due to deletions like alpha thalassemia, due to mutations in promoter sequences or splice sites
B0 = nearly complete suppression of synthesis
B+ = incomplete suppression
Bn = normal gene
What is thalassemia minor vs thalassemia major? Is minor symptomatic?
At least one normal beta allele - Bn / B+ or Bn / B0 = thalassemia minor. Usually asymptomatic.
Any thalassemia WITHOUT at least one Bn = thalassemia major. Worst is B0/B0.
What are the features of beta thalassemia anemia? What is seen on electrophoresis in minor / major?
Hypochromic, microcytic anemia with target cell formation
Minor: decreased HbA and mildly increased HbA2 (>4%) / HbF (>2%). >3.5% A2 is diagnostic.
Major: little to no HbA (20%), almost all HbA2 (4+%) / HbF (70+%)
Why do target cells form in Thalassemia? What else might be seen on peripheral smear which is abnormal?
Loss of hemoglobin mass within the RBC is like deflating the balloon (vs IDA where the amount of globin is normal)
-> relative excess of cytoplasm always membrane to collapse on itself -> bleb of membrane in the center = targetoid.
May also see nucleated RBCs on peripheral smear due to extramedullary hematopoiesis in liver / spleen leading to improper maturation of RBCs before release.
