extravascular normocytic anemias and general principles

Question 1

reticulocyte count

Answer 1

reticulocytes are young RBCs, and look blue-ish compared with normal RBCs because of retained residual RNA.
normal reticulocytes are 1-2% of RBCs, but this number should go up in anemia to compensate for low numbers. In properly functioning bone marrow, it may be as high as 3%. We must correct for potential blood loss using the reticulocyte index: retic count X (hematocrit/45). low retic counts in anemia suggest underproduction

Question 2

extravascular vs. intravascular hemolysis

Answer 2

extravascular hemolysis: RBCs broken down in the reticuloendothelial system. macrophages consume RBCs and break down hemoglobin: globin to aas, heme to Fe (recycled) and protoporphyrin. protoporphyrin made into unconjugated bilirubin, which is bound to albumin and carried to the liver for conjugation and excretion. Findings: Anemia with splenomegaly, jaundice from unconjugated bilirubin (you overwhelm conjugating ability of liver), risk of bilirubin gallstones, marrow hyperplasia.
Intravascular hemolysis: breakdown of RBCs within blood vessels. hemoglobinemia, hemoglobinuria, decreased serum haptoglobin (which binds Fe), high LDH, and hemosiderinuria: renal tubular cells pick up the Hb that is filtered into the urine and break it into iron, which accumulates as hemosiderin. tubular cells are eventually shed –> hemosidurinuria.

Question 3

hereditary spherocytosis

Answer 3

predominantly extravascular hemolysis
inherited defect of RBC cytoskeleton membrane tethering proteins- ankyrin, spectrin, or band 3.
membrane blebs are formed and lost over time. causes spherocyte shape. spherocytes are also less able to maneuver through splenic sinusoids and are consumed by splenic macrophages. incr. risk of aplastic crisis with parvovirus B19.
dx: osmotic fragility test- incr. spherocyte fragility
Tx: splenectomy. anemia resovles but then Howell Jolly bodies will emerge on blood smear.

Question 4

sickle cell anemia: what causes disease, basic pathophysiology, labs, tx

Answer 4

AR mutation of B chain of hemoglobin (glutamic acid to valine).
2 defective genes causes >90% HbS. HbS polymerizes when deoxygenated. polymers aggregate in needle-like structures, causing a sickle cell deformity. incr. risk of sickling with hypoxemia, acidosis, dehydration.
HbF protects against sickling. Tx with hydroxyurea (inhibits ribonuclease reductase) also prevents sickling

Question 5

consequences of sickle cell anemia in terms of RBCs

Answer 5

constant sickling and desickling while passing thru microvasculature causes complications related to RBC membrane damage:

1. extravascular hemolysis: reticuloendothelial system removes RBCs with damaged membranes. causes anemia, jaundice, hyperbilirubinemia.
2. intravascular hemolysis: RBCs with damaged membranes dehydrate. see decr. haptoglobin and target cells on blood smear.
3. massive erythroid hyperplasia: expansion of erythropoeisis into the skull (crew cut on X ray) and face (chipmonk face); extramedullary hematopoiesis with hepatomegaly; susceptibility to parvovirus B19

Question 6

sickle cell complications

Answer 6

vaso-occlusion:

1. dactylitis. swollen hands and feet. presenting sign in infants.
2. autosplenectomy- shunken, fibrotic spleen. incr risk of infection with strep pneumo, H flu, salmonella paratyphi osteomyelitis, howell-jolly bodies.
3. acute chest syndrome: vaso-occlusion in pulmonary microcirc. chest pain, SOB, lung infiltrate. often precipitated by pneumonia. common cause of death in adult pts.
4. pain crisis
5. renal papillary necrosis- gross hematuria and proteinuria

Question 7

sickle trait

Answer 7

usually asymptomatic. less than 50% HbS on blood smear. HbS do not sickle except in the renal medulla. microinfarctions leading to microscopic hematuria and decr. ability to concentrate urine.

Question 8

sickle cell and sickle trait labs

Answer 8

sickle cells and target cells only seen in disease
metabisulfite screen causes cells with any amt of HbS to sickle- positive in disease and trait.
Hb electrophoresis.

Question 9

hemoglobin C

Answer 9

AR mutation in beta chain of hemoglobin. glutamic acid replaced by lysine. less common than sickle disease. causes mild anemia from extravascular hemolysis. HbC crystals seen on RBCs in blood smear.

Question 10

megaloblastic macrocytic anemia

Answer 10

impaired DNA synthesis –> maturation of nucleus of precursor cells in bone marrow delayed relative to maturation of cytoplasm. abnormal cell division causes pancytopenia.
impaired division and enlargement of RBC precursors leads to megaloblastic anemia. impaired division of granulocytic precursors leads to hypersegmented neutrophils. megaloblastic change also seen in other rapidly dividing tissues like intestinal epithelial cells.

Question 11

causes of nonmegaloblastic macrocytic anemia

Answer 11

macrocytic anemia without DNA synthesis impairment.
caused by liver disease, alcoholism, or reticulocytosis.
drugs like 5-FU, zidovudine, and hydroxyrurea can also do it.

Question 12

orotic aciduria

Answer 12

inability to convert orotic acid to UMP (de novo pyrimidine synthesis) becasue of defect in UMP synthase. autosomal recessive.
presents in kids as megaloblastic anemia that can’t be cured by B12 or folate. no hyperammonemia (vs. orinthin transcarbamylase deficiency- incr. orotic acid with hyperammonemia).
see hypersegmentedneutrophils, glossitis, and orotic acid in urine.
tx: uridine monophosphate to bypass mutated enzyme

Question 13

folate deficiency

Answer 13

folate absorbed in the jejunum. causes include poor diet, incr. demand (pregnancy, cancer, hemolytic anemia,_ and folate antagonists.
macrocytic RBCs, hypersegmented neutrophils, glossitis, decr. folate, incr. homocysteine. normal methymalonic acid

Question 14

vitamin B12 absorption

Answer 14

salivary enzymes liberate vitamin B12, which is then bound by R binder and carried to the stomach. pancreatic proteases in the duodenum detach vitamin B12 from R- binder; it instead binds intrinsic factor made by gastric parietal cells. intrinsic factor-B12 complex absorbed in the ileum.

Question 15

vitamin B12 deficiency

Answer 15

rare- takes years to develop. pernitcious anemia is most common cause; can also be casued by pancreatic insufficiency, damage to the terminal ileum from Crohn’s disease or diphyllobothrium latum (fish tapeworm)
see macrocytic RBCs with hypersegmented neutrophils, glossitis, subacute combined degeneration of the spinal cord (cofactor for converstion of methylmalonic acid to succinyl coA. methylmalonic acid impairs spinal cord myleination). see incr. homocystein (incr. risk of thrombosis) and increased methylmalonic acid.