Name two diseases associated with Heinz bodies.
-Thalassemia and glucose-6-phosphate dehydrogenase deficiency
What type of red blood cell morphology would you see in the peripheral blood that is associated with Heinz bodies?
Bite cells; the spleen bites off the precipitated hemoglobin in the cells
What is the role of the mean corpuscular volume in an anemia workup?
A mean corpuscular volume < 80 fL is a microcytic anemia; a volume > 100 fL is a macrocytic anemia; a volume between those values is a normocytic anemia
What are three etiologies of iron-deficiency anemia?
Loss (chronic bleeding), malnutrition or poor absorption, and increased demand (such as in pregnancy)
What biochemical pathway is interrupted in iron deficiency anemia?
The formation of heme (which requires iron)
You see a patient with tongue inflammation and atrophy, dysphagia for solids, and a hemoglobin of 9 g/dL; what is the cause of his anemia?
This patient has Plummer-Vinson syndrome, the triad of esophageal webs, atrophic glossitis, and iron deficiency anemia
What disease, common in Asia and Africa, is caused by deletions of the hemoglobin chain gene?
-thalassemia; gene deletions result in decreased globin synthesis
What would you see on hemoglobin electrophoresis in a fetus with deletions of all four globin genes?
Hemoglobin Barts (γ4); this is a lethal condition and will result in hydrops fetalis
A fetus undergoes amniocentesis and is found to have deletions of all four globin genes; what is the likely outcome?
Hydrops fetalis; deletion of four genes is incompatible with life
What condition would you expect to see in a patient with a deletion of three of the four globin genes?
Symptomatic microcytic anemia due to -thalassemia; known as hemoglobin H disease (4)
A mother is concerned that her child has deletions of two globin genes; what symptoms will likely manifest?
Deletion of one or two globin genes is not associated with symptomatic anemia
What disease, seen in people that live in the Mediterranean region, is caused by point mutations in hemoglobin chain genes?
-Thalassemia; typically these mutations are at splicing sites and in the promoter regions
What type of mutation is present in a patient with -thalassemia minor?
There is a mutation in one gene (heterozygote), causing underproduction of globin; the mutation is often in a promoter or splice site
What symptoms and laboratory findings are consistent with -thalassemia minor?
This condition is asymptomatic, and diagnosed by an hemoglobin A2 > 3.5% on electrophoresis
What treatment is indicated in a patient with -thalassemia major?
Because both genes are mutated, there is no chain production and the patient requires many blood transfusions
What is a long-term adverse effect of the treatment of -thalassemia major?
Iron overload (secondary hemochromotosis) due to repeated blood transfusions
What x-ray finding should raise your suspicion of -thalassemia major?
Bone marrow expansion, which can be seen as increased marrow space, bone deformities (chipmunk facies), and a crew-cut appearance of the skull x-ray
What should you see on hemoglobin electrophoresis in a patient with -thalassemia (major and minor) that, as in infants, increases the blood’s affinity for oxygen?
Increased fetal hemoglobin (2; γ2)
What disease do you expect to see in a child born to a father homozygous for hemoglobin S and a mother with -thalassemia major?
This child will be a hemoglobin S/-thalassemia heterozygote, which presents with mild or moderate sickle cell disease based on chain production
Lead poisoning disrupts which two enzymes involved in the formation of hemoglobin?
Lead blocks ferrochelatase and ALA dehydratase, which decreases the synthesis of heme
What is the cause of basophilic stippling associated with lead poisoning?
Lead disrupts the degradation of RNA, which builds up and stains with basic dyes
What is the cause of hereditary sideroblastic anemia?
A mutation in the δ-aminolevulinic acid gene
What is the inheritance pattern associated with a mutation in the δ-aminolevulinic acid gene?
This mutation, which causes a hereditary sideroblastic anemia, is found on the X chromosome
What is the treatment for sideroblastic anemia due to a mutation in δ-ALA synthase?
Pyridoxine (vitamin B6)
Name two reversible causes of sideroblastic anemia
Alcohol use and lead poisoning
A patient has an elevated serum iron and ferritin, and a normal total iron-binding capacity; what diagnosis should you suspect if a bone marrow aspirate shows blast forms of erythrocytes that have a dark ring around the nucleus?
Sideroblastic anemia; the aspirate describes the iron-laden mitochondria that create the appearance of a ringed sideroblast
Why is the mean corpuscular volume increased in megaloblastic macrocytic anemia?
There is a defect in DNA synthesis: the nucleus takes longer to mature than the cytosol and thus there is excess cytoplasm, creating a megaloblast; this is caused by B12 and folate deficiency
A patient has anemia with a mean corpuscular volume of 110 fL and glossitis and on the peripheral smear you note hypersegmented neutrophils; what are the two possible causes of this condition?
B12 or folate deficiency; both present with these features
What laboratory test (other than a vitamin level) will distinguish between B12 and folate deficiency as a cause of megaloblastic anemia?
Methylmalonic acid is elevated in B12 deficiency but normal in folate deficiency; homocysteine is elevated in both deficiencies
What is the homocysteine level in patients with B12 and folate deficiency?
Both B12 and folate deficiencies have elevated homocysteine levels
What kind of anemia is seen in a patient with poor dietary vitamin intake?
Macrocytic anemia, due to B12 or folate deficiency (remember that alcoholics are also often malnourished)
Why might a patient with Crohn’s disease have a macrocytic anemia?
Crohn’s disease often affects the terminal ileum, the site of vitamin B12 absorption; severe or extensive disease may cause malabsorption of folate as well
Name two drugs than can cause a folate deficiency and macrocytic anemia.
Methotrexate or trimethoprim, both of which interfere with folate metabolism
Name two conditions in which an increased demand for folate can result in a macrocytic anemia.
Pregnancy (folate is needed for fetal neural tube development) or hemolytic anemias (folate is needed to replenish hemolyzed blood)
What autoimmune disorder can result in a macrocytic anemia?
Pernicious anemia, which results in vitamin B12 deficiency and loss of intrinsic factor
Which parasite can cause vitamin B12 deficiency?
Diphyllobothrium latum, a tapeworm found in fish
What symptoms can distinguish macrocytic anemia caused by vitamin B12 deficiency and macrocytic anemia caused by folate deficiency?
Neurologic symptoms (combined subacute degeneration) are seen in vitamin B12 deficiency but not in folate deficiency because of the role B12 plays in fatty acid pathways
Name three ways that heavy alcohol use can cause macrocytic anemia.
As a result of vitamin B12 or folate deficiency (malnutrition), liver disease, or by directly affecting red blood cells and causing bone marrow suppression
What change in mean corpuscular volume would you expect in an otherwise healthy patient who has had moderate to severe blood loss?
Increased mean corpuscular volume, because the patient will compensate with reticulocytosis, which have slightly higher mean corpuscular volumes than mature red blood cells
What kind of anemia is associated with congenital deficiencies in purine or pyrimidine synthesis?
Macrocytic anemia (eg, orotic aciduria) because of the relative delay in nucleus maturation compared to cytoplasm
Name five medications that can cause macrocytic anemia.
Methotrexate, trimethoprim, fluorouracil, zidovudine, hydroxyurea
How are normocytic, normochromic hemolytic anemias further classified?
First by cause: intrinsic vs extrinsic to the red blood cell; and then by location: intravascular vs extravascular
Name three causes of normocytic, normochromic anemia that are not due to hemolysis.
Anemia of chronic disease, aplastic anemia (bone marrow failure), renal disease (decreased erythropoietin)
Name six causes of normocytic, normochromic hemolytic anemia that are intrinsic to the red blood cell.
Hereditary spherocytosis, glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, sickle cell anemia, hemoglobin C defect, and paroxysmal nocturnal hemoglobinuria
Name three causes of normocytic, normochromic hemolytic anemia that are extrinsic to the red blood cell.
Autoimmune hemolysis, microangiopathies like disseminated intravascular coagulation or thrombotic thrombocytopenic purpura–hemolytic uremic syndrome, or infections
What is a cause of normocytic, normochromic hemolytic anemia that is intrinsic to the red blood cell and occurs in the intravascular space?
Paroxysmal nocturnal hemoglobinuria
Name two causes of normocytic, normochromic hemolytic anemia that are extrinsic to the red blood cell and occur in the extravascular space.
Autoimmune hemolysis due to warm agglutinins (not cold) or microangiopathies like disseminated intravascular coagulation or thrombotic thrombocytopenic purpura–hemolytic uremic syndrome
Generally, hemolysis that is intrinsic to the red blood cell occurs in the _____ (intravascular/extravascular) space, whereas hemolysis extrinsic to the red blood cell occurs in the _____ (intravascular/extravascular) space.
Extravascular; intravascular. Notable exceptions include paroxysmal nocturnal hemoglobinuria (intrinsic intravascular) and warm agglutinin autoimmune or microangiopathic hemolysis (extrinsic extravascular)
How do chronic inflammatory processes cause anemia?
The inflammation increases hepcidin levels, which cause macrophages to retain iron, preventing heme from forming
What are the iron, ferritin, and total iron-binding capacity levels in a patient with anemia of chronic disease?
Decreased iron and total iron-binding capacity, with increased ferritin
A patient with pancytopenia (anemia, neutropenia, and thrombocytopenia) has fatty infiltrates on bone marrow biopsy; what is the diagnosis?
Aplastic anemia; the marrow is depleted, but the cell morphology will be normal
What are four general etiologies of aplastic anemia?
Radiation or drugs, viral infections, Fanconi;s anemia, or idiopathic aplastic anemia
Name four drugs that can result in aplastic anemia.
Benzene, chloramphenicol (eg, gray baby syndrome), antimetabolites, and alkylating agents (chemotherapy)
What are four viral infections that can cause aplastic anemia?
Parvovirus B19 (especially in patients with sickle cell anemia), HIV, Epstein-Barr virus, and viral hepatitis
What mechanism of aplastic anemia is seen in patients with Fanconi’s anemia?
These patients have an inherited defect in DNA repair
What are two possible explanations for aplastic anemia that is considered idiopathic?
There may be an autoimmune etiology or a primary defect in the stem cell itself
A patient presents with petechiae and bleeding from the gums, fatigue and pallor, and has had several recent infections; a bone marrow aspirate is dry making you suspect what process?
Aplastic anemia; this patient has symptoms suggestive of thrombocytopenia, anemia, and neutropenia, which are confirmed by the hypocellular aspirate
You suspect that a patient has aplastic anemia due to an autoimmune process; what treatment can you pursue?
Immune suppression using antithymocyte globulin or cyclosporin
Name three treatments for aplastic anemia that can be tried when other interventions have failed.
Red blood cell and platelet transfusion, dosing with granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor, or allogeneic bone marrow transplantation
Why do patients with end-stage renal disease have normocytic, normochromic anemia?
The kidneys normally produce erythropoietin; in renal failure the loss of erythropoietin results in anemia, which is amenable to treatment with exogenous erythropoietin
What mutations are present in hereditary spherocytosis?
Ankyrin, band 3.1, or spectrin mutations; each normally interacts with the red blood cell skeleton and plasma membrane to preserve normal morphology
What organ is responsible for the anemia seen in hereditary spherocytosis?
The spleen; the small, inflexible membrane causes the spleen to remove affected red blood cells prematurely
What acute process should you suspect in a patient with red blood cells that have no central pallor, increased mean corpuscular hemoglobin concentration, and increased red blood cell distribution width if he contracts a parvovirus B19 infection?
Aplastic crisis; this patient likely has hereditary spherocytosis and is predisposed to aplastic anemia during parvovirus infection due to his increased reliance on erythropoiesis
You see a patient with hereditary spherocytosis but no splenomegaly on exam; if he had Howell-Jolly bodies on peripheral smear what is the reason for your exam and lab findings?
This patient has likely had a splenectomy; this treatment can be used if the anemia in hereditary spherocytosis is severe and refractory to treatment
What lab test should you order to confirm the diagnosis in a patient who has spherocytes on the peripheral smear and splenomegaly on exam?
Osmotic fragility test; in hereditary spherocytosis the red blood cells will lyse more easily because of decreased membrane flexibility
What is the inheritance pattern seen in glucose-6-phosphate dehydrogenase deficiency?
X-linked recessive; therefore, symptoms are usually seen in males
What molecule is depleted in the red blood cells of patients that have glucose-6-phosphate dehydrogenase deficiency, leading to anemia?
Glutathione; without glucose-6-phosphate dehydrogenase, there is a depletion of glutathione, which results in red blood cell susceptibility to oxidative stress
A patient develops anemia, indirect hyperbilirubinemia, and jaundice after eating fava beans; what condition should you suspect?
Glucose-6-phosphate dehydrogenase deficiency; fava beans, along with sulfa drugs and infections, are well-documented causes of oxidant stress
What is the diagnosis in a patient who has Heinz bodies on the peripheral smear and multiple bite cells?
Glucose-6-phosphate dehydrogenase deficiency
What is the inheritance pattern of pyruvate kinase deficiency?
Autosomal recessive
A newborn is born with hemolytic anemia and you determine that there is no blood group or Rh antigen difference between the baby and mother; what congenital error in metabolism may be the cause?
Pyruvate kinase deficiency, which causes low adenosine triphosphate in red blood cells and a resultant rigidity of the membranes
You see an African-American patient who has crescent-shaped cells on the peripheral smear; what is the cell and what is the prevalence of this disease?
This is a sickle cell; the trait (heterozygotes) occurs in 8% of African-Americans, whereas 0.2% have sickle cell disease (homozygotes)
What x-ray finding in sickle cell anemia may also be seen in thalassemia?
The crew cut skull radiograph, due to bone marrow expansion, is seen in both conditions
Why will a newborn with sickle cell disease initially be asymptomatic?
The newborn still has increased levels of hemoglobin F and will be asymptomatic until his hemoglobin F is replaced by hemoglobin S
What is the mutation that causes sickle cell disease?
Glutamic acid to valine in the globin chain
What happens to the hemoglobin in patients with sickle cell disease in the presence of low oxygen concentrations?
Without oxygen, the hemoglobin has an exposed charge that causes precipitation and formation of long polymers of hemoglobin that give the characteristic sickle shape to the red blood cell
What evolutionary advantage may explain the high prevalence of sickle cell trait in the population?
This mutation allows resistance to malaria, an intracellular parasite that infects erythrocytes
Name six complications seen in homozygotes for sickle cell disease.
Aplastic crisis (parvovirus infection), autosplenectomy, Salmonella osteomyelitis, painful vaso-occlusive crises, renal papillary necrosis, and splenic sequestration crisis
What vaccinations should be given to patients with sickle cell disease?
Vaccinations to encapsulated organisms because of the increased risk of sepsis after autosplenectomy: Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis
What treatment options are available for patients with sickle cell disease?
Patients can be treated with hydroxyurea, which increases hemoglobin F concentration, or may undergo allogeneic bone marrow transplantation
What kind of anemia is seen in patients with hemoglobin C disease?
Intrinsic normocytic hemolytic anemia; this condition is due to a mutation in the globin chain (different from hemoglobin S in sickle cell disease)
What is the significance of the hemoglobin C mutation?
Patients with hemoglobin S and C mutations have milder sickle cell disease than homozygotes for hemoglobin S
Why does the hemolysis seen in paroxysmal nocturnal hemoglobinuria occur in the intravascular space?
There is complement-mediated hemolysis, an intravascular process due to decreased levels of decay accelerating factor; decay accelerating factor normally prevents the membrane attack complex from destroying red blood cells
What laboratory test would be abnormal in a patient with paroxysmal nocturnal hemoglobinuria?
Increased urine hemosiderin; the hemolysis occurs all day, but urine accumulates overnight and thus appears darker the next day
What type of antibody is involved in autoimmune hemolytic anemia due to warm agglutinins?
Immunoglobulin G (remember: Warm weather is GGGreat)
Name three conditions that are associated with immunoglobulin G-mediated autoimmune hemolysis.
Systemic lupus erythematous, chronic lymphocytic leukemia, and drug reactions (for instance, -methyldopa)
What type of antibody is involved in autoimmune hemolytic anemia due to cold agglutinins?
Immunoglobulin M (remember: Cold ice cream is MMM); cold agglutinins trigger anemia when exposed to cold temperatures
What are two infections that can present with hemolytic anemia due to cold agglutinins?
Mycoplasma pneumoniae infection or infectious mononucleosis
What type of hemolytic process causes erythroblastosis fetalis?
Warm agglutinin-mediated immune reaction; remember that this is caused by maternal immunoglobulin G antibodies against the fetal Rh group
What does a positive direct Coombs’ test represent?
A direct Coombs; test adds anti-immunoglobulin G antibodies to the patient;s red blood cells; if agglutination occurs, it indicates that the patient;s red blood cells are covered with immunoglobulin G antibodies
What does a positive indirect Coombs’ test represent?
An indirect Coombs’ test adds normal red blood cells to the patient;s serum; if agglutination occurs, it indicates that the patient has anti-red blood cell antibodies in serum
You note schistocytes or helmet cells on the peripheral smear of a patient; what mechanism causes this deformity?
This red blood cell morphology is seen in microangiopathic hemolytic anemias, thought to be due to damage as red blood cells pass through a narrow or obstructed vessel lumen
What are four conditions that may be the cause of helmet cells or schistocytes on a patient’s peripheral blood smear?
Disseminated intravascular coagulation, thrombotic thrombocytopenic purpura–hemolytic uremic syndrome, systemic lupus erythematous, or malignant hypertension
What are two cardiac pathologies that can cause hemolytic anemia?
Severe aortic stenosis, or any mechanical valve, due to the shearing and mechanical destruction of red blood cells
Name two infections that cause hemolysis but are not associated with agglutinins.
Intracellular pathogens, like malaria and babesia, can lyse the erythrocyte and cause hemolytic anemia
What are the relevant lab values in a patient with anemia of chronic disease?
The serum iron and total iron-binding capacity are low, whereas the ferritin is elevated; the percent transferrin saturation is normal
What are the relevant lab values in a patient with iron-deficiency anemia?
The serum iron and ferritin are low, whereas the total iron-binding capacity is elevated; the percent transferrin saturation is very low
What are the relevant lab values for a patient with hemochromatosis?
The serum iron and ferritin are high and the total iron-binding capacity is low; the percent transferrin saturation is very high
What changes are seen in serum iron studies for a patient who is either pregnant or using oral contraceptive pills?
The serum iron and ferritin are normal; the total iron-binding capacity is elevated due to estrogen exposure (increased binding proteins); the percent transferrin saturation is low
What is the role of ferritin in the body?
It is the primary iron storage protein of the body
What is the relationship between transferrin and total iron-binding capacity?
Total iron-binding capacity is an indirect measure of transferrin, which transports iron in the blood
What is the evolutionary theory behind the etiology of anemia of chronic disease?
Pathogens need iron to thrive; sequestration of iron in macrophages may prevent pathogens from reproducing
What pathologic process occurs if there is a defect in one of the steps of heme synthesis?
Porphyria, in which heme precursors accumulate and enter various bodily fluids
Lead poisoning affects which two enzymes in the heme synthesis pathway?
Ferrochelatase and ALA dehydratase are inhibited by lead
What substrate of heme synthesis accumulates in the blood in lead poisoning?
Protoporphyrin
A child presents with a microcytic anemia, gastrointestinal distress, and renal disease; she has developmental regression and basophilic stippling on red blood cells; what is the diagnosis?
These are the symptoms of lead poisoning, commonly seen when children are exposed to lead paint
What are the differences in neurologic outcomes between adults and children with lead poisoning?
Adults typically have headaches, memory loss, and demyelination, whereas children typically have developmental delays
What environmental exposures are common sources of lead poisoning in adults? In children?
Adults are exposed to lead in the workplace, such as a battery/ammunition/radiator factories, whereas children are exposed via lead paint
A patient who recently started phenobarbital presents after a day at the beach where she had multiple alcoholic drinks with abdominal pain, polyneuropathy, an altered mental status. Her urine turns pink on standing. What is the diagnosis?
Acute intermittent porphyria (remember the five P’s: Painful abdomen, Pink urine, Polyneuropathy, Psychological disturbances, Precipitated by drugs [eg, phenobarbital or ethanol])
What enzymatic defect is present in acute intermittent porphyria?
Porphobilinogen deaminase (also called uroporphyrinogen-I-synthase)
