Macro/normocytic Anemia II Flashcards
What are the most common causes of macrocytic anemia?
Folate or B12 deficiency (megaloblastic anemia with hypersegmented neutrophils)
–> there is not enough DNA material to divide, so cells do one less division and end up larger than normal
What are causes of macrocytic anemias?
(MCV > 100)
Vitamin or B12 deficiency (most common)
Alcoholism
Liver disease
Certain drugs
What is characteristic of a megaloblastic anemia?
Hypersegmented neutrophils (>5 nucleus segments)
Megaloblastic change in rapidly dividing cells (i.e. RBCs and intestinal epithelium, etc)
Where is folate absorbed in the intestine?
In the jejunum
What are characteristics of folate deficiency?
Caused by poor diet (i.e. alcoholics, elderly), increased folate demand (i.e. pregnancy, cancer), or folate antagonists (i.e. methotrexate)
Develops in months
Macrocytic RBCs and hypersegmented neutrophils
Glossitis
Decreased serum folate
Increased serum homocysteine
Normal methylmalonic acid
What are characteristics of Vitamin B12 deficiency?
Takes years to develop due to large hepatic stores
Macrocytic anemia (MCV > 100) with hypersegmented neutrophils
Glossitis
Subacute combined degeneration of spinal cord (produces neurological findings)
Decreased serum vitamin B12
Increased serum homocysteine
Increased Methylmalonic Acid
What is the most common cause of B12 deficiency? What is the mechanism of action that leads to this?
Pernicious anemia
- Autoimmune destruction of parietal cells leads to intrinsic factor deficiency.
- without intrinsic factor, B12 (which is first bound to R-binder in the saliva, then cleaved by pancreatic enzymes) needs to be bound to Intrinsic Factor to be absorbed in the Ileum
If parietal cells are destroyed, they no longer produce intrinsic factor and B12 cannot be absorbed
What are causes of Vitamin B12 deficiency?
- Pernicious anemia (destruction of parietal cells)
- Pancreatic insufficiency
- Damage to terminal ileum due to Crohn’s disease or Diphyllobothrium latum (fish tapeworm)
Dietary deficiency (rare, except in vegans)
How do you calculate a corrected reticulocyte count? Why is this necessary?
Corrected retic count = (reticulocyte count)*Hct/45
- This is necessary to determine if a normocytic anemia is due to peripheral loss of RBCs or due to lack of production of RBCs
- An increased retic count in a normocytic anemia means the bone marrow is working correctly and the anemia is due to damage outside of the BM
What is the RE system composed of?
Spleen
Liver
Lymph nodes
What is the source of extravascular hemolysis?
Found in a normocytic anemia, extravascular hemolysis occurs due to the RE system
- Macrophages consume RBCs and break down the hemoglobin:
Globin –> amino acids
Heme –> Iron + protoporphyrin
Protoporphyrin –> unconjugated bilirubin
What are the clinical and laboratory findings of extravascular hemolysis?
Anemia with splenomegaly (hypertrophy due to destruction of RBCs by macrophages)
Jaundice (due to unconjugated bilirubin)
Increased risk for bilirubin gallstones
Marrow hyperplasia with corrected reticulocyte count >3%
What are the clinical and laboratory finding of intravascular hemolysis?
Hemoglobinemia
Hemoglobinuria
Hemosiderinuria
Decreased serum haptoglobin (free haptoglobin has been bound to free iron in the blood)
What defect results in hereditary spherocytosis?
Mutations in cytoskeleton-membrane tethering proteins:
Ankyrin
Spectrin
or Band 3.1
What are clinical and laboratory features of hereditary spherocytosis?
Spherocytes with loss of central pallor
Increased RDW and MCHC
Splenomegaly (hypertrohpy due to macrophage ingestion of RBCs)
Jaundice with unconj. bilirubin
Increased risk for bilirubin gallstones
Increased risk for aplastic crisis with parvovirus B19 infection of erythroid precursors
What is used to treat hereditary spherocytosis?
Splenectomy
- Anemia resolves
- Spherocytosis persists
- Howell-Jolly bodies emerge in blood smears
What is used to diagnose hereditary spherocytosis?
Osmotic Fragility test
- Spherocytes membranes are much more fragile than normal
What causes sickle cell anemia?
Autosomal Recessive mutation in beta chain of hemoglobin
Glu > Val
–> Sickle cell disease arises only when patient is homozygous for Bs
Under what stressors due sickle cells present in blood?
HbS polymerizes when deoxygenated
Increased risk of sickling occurs with:
Hypoxemia
Dehydration
Acidosis
–> polymers agggregate into needle-like structures resulting in sickle cells
(this is reversible)
What molecule in the blood protects patient with sickle cell anemia from sickling? Why is this clinically relevant?
HbF protects against sickling
- High HbF is protective from birth to first few months of life
- This explains why treatment with hydroxyurea (which increases levels of HbF) works as treatment
What is a consequence of the eventual irreversible sickling of RBCs in Sickle cell anemia?
–> leads to complications of vaso-occlusion
Causes infarction of tissues:
- Dactylitis (common presenting sign in infants): swollen hands and feet due to infarcts of bones
- Autosplenectomy: shrunken, fibrotic spleen and increased risk of infection with encapsulated organisms
- Acute Chest Syndrome: chest pain, SOB, lung infiltrates due to vaso-occlusion of pulmonary microcirculation
- Pain crisis
- Renal Papillary necrosis: gross hematuria and proteinuria
What is a metabisulfite screen useful for?
Causes cells with any amount of HbS to sickle (even in sickle trait carriers with <50% HbS)
–> positive in both disease and trait
What is the cause of Hemoglobin C?
Autosomal recessive mutation in beta chain of hemoglobin
–> Glu >Lys
(less common than sickle cell disease)
Which normocytic anemias are predominantly extravascular hemolysis?
Hereditary Spherocystosis
Sickle Cell Anemia
Hemoglobin C
What is paroxysmal nocturnal hemoglobinuria?
An acquired defect in myeloid stem cells resulting in absent GPI (no GPI = no MIRL or DAF = no protection from Complement)
–> leads to intravascular hemolysis often at night (due to shallow breathing and a respiratory acidosis)
What are laboratory findings of intravascular hemolysis?
Hemoglobinemia
Hemoglobinuria
Hemosiderinuria (days after hemolysis)
What is used to diagnose PNH?
Sucrose test is used to screen for PNH
Confirmation test is to:
Acidify serum (to activate complement) Or Use flow cytometry to detect CD55 (CD55, which is DAF, uses GPI to anchor to the plasma membrane)
What is the main cause of death in PNH?
Thrombosis of hepatic, portal, or cerebral veins
–> Destroyed platelets release cytoplasmic contents into circulation, inducing thrombosis
What are complications of PNH?
Iron deficiency anemia (due to loss of Hgb in urine)
AML develops in 10% of patients
What is the cause symptoms of G6PD deficiency?
Without G6PD, there is decreased NADPH produced in cells, NADPH is used by glutathione reductase to reduce glutathione after it has stabilized ROSs
–> causes increase in ROS in cells (especially RBCs) and results in:
primarily intravascular hemolytic, normocytic anemia
What can increase the oxidative stress of RBCs, thus exacerbating G6PD deficiency?
Infection
Drugs (Primaquine, sulfa drugs, dapsone)
fava beans
–> leads to precipitation of Heinz bodies and bite cells (splenic macrophages remove precipitated Hgb, resulting in bite cells)
What are symptoms of G6PD deficiency?
Hemoglobinuria
Back pain (Hgb is nephrotoxic, leading to pain)
Heinz preparation shows heinz bodies
What is immune hemolytic anemia?
Antibody mediated hemolysis of RBCs
- -> IgG mediated:
- results in spherocytes due to loss of membrane from splenic macrophage
- warm agglutinin
- Associated with SLE, CLL and certain drugs
- -> IgM mediated:
- Fixes comoplement in extremeties (cold agglutinin)
- Associated with Mycoplasma pneumoniae and infectious mononucleosis
What is treatment for IgG immune hemolytic anemia?
Cessation of offending drug
Steroids
IVIG (macrophages eat IVIG, not RBC bound Ig)
Splenectomy (removes source of Ab and source of damage)
What produces schistocytes in a peripheral blood smear?
microangiopathic hemolytic anemia
(as seen in TTP, HUS, and Hemolysis elevated liver enzymes and platelets (HELP) of pregnancy)
Prosthetic heart valves
Aortic stenosis
What can lead to low reticulocyte counts?
- Causes of microcytic or macrocytic anemias
- Renal failure (no EPO)
- Damage to bone marrow precursor cells
What is aplastic anemia?
- Damage to Hemotopoietic Stem Cell
- Results in pancytopenia with low reticulocyte count
–> due to:
Drugs or chemicals
Viral infections
Autoimmune damage
What is a myelophthisic process?
Pathologic process that replaces bone marrow (i.e. metastatic cancer)
- Hematopoiesis is impaired, resulting in pancytopenia
Which normocytic anemias are predominantly intravascular hemolysis?
PNH
G6PD deficiency
Immune Hemolytic anemia
Microangiopathic hemolytic anemia (as seen in TTP, HUS, etc)
