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Flashcards in Hem & Onc - Pathology (Normocytic anemia) Deck (71):

What defines normocytic anemia?

Anemia with blood cells of MCV of 80-100 fL


What are the divisions of normocytic, normochromic anemias?

Hemolytic and nonhemolytic


What are the divisions of hemolytic, normocytic anemias? What is the basis for this classification?

(1) Intrinsic vs. Extrinsic (2) Intravascular vs. Extravascular; According to cause of hemolysis (i.e., whether intrinsic or extrinsic to the RBC) & by location (i.e., intravascular vs. extrascular)


What are lab findings that characterize intravascular hemolysis?

(1) DECREASED HAPTOGLOBIN (2) Increased LDH (3) Blood smear - schistocytes & increased reticulocytes (4) Urobilinogen in urine (e.g., paroxysmal nocturnal hemoglobinuria, mechanical destruction [aortic stenosis, prosthetic valve], microangiopathic hemolytic anemias)


What happens in extravascular hemolysis? What are physical and lab findings that characterize this?

Macrophages in spleen clear RBCs; (1) Increased LDH (2) Increased LDH plus (3) INCREASED UCB (i.e., unconjugated bilirubin), which causes JAUNDICE (e.g., hereditary spherocytosis)


What are lab values that help you distinguish between intravascular and extravascular hemolysis?

Intravascular = decreased haptoglobin (& possibly Hb in urine); Extravascular = increased UCB (leading to jaundice)


What are examples of nonhemolytic, normocytic anemia?

(1) Anemia of chronic disease (ACD) (2) Aplastic anemia (3) Chronic kidney disease


By what process does anemia of chronic disease occur?

Inflammation --> Increased hepcidin (released by liver, binds ferroportin on intestinal mucosal cells and macrophages thus inhibiting iron transport) --> Decreased release of iron from macrophages


What are the lab findings (i.e., iron studies) of ACD?

(1) Decreased iron (2) Decreased TIBC (3) Increased ferritin


What is unique about ACD in terms of its classification?

Typically starts as a nonhemolytic, normocytic anemia but can become a microcytic, hypochromic anemia


In general, what event(s) cause(s) aplastic anemia? More specifically, what are examples of things that cause this event to occur, and consequently lead to aplastic anemia?

Caused by failure or destruction of myeloid stem cells; (1) Radiation and drugs (benzene, chloramphenicol, alkylating agents, antimetabolites) (2) Viral agents (parvovirus B19, EBV, HIV, HCV) (3) Fanconii's anemia (DNA repair defect) (4) Idiopathic (immune mediated, primary stem cell defect) - may follow acute hepatitis


What blood cell findings characterize aplastic anemia? What about bone marrow findings?

Pancytopenia characterized by severe anemia, leukopenia, & thrombocytopenia; Normal cell morphology but hypocellular bone marrow with fatty infiltration (dry bone marrow tap)


What are the symptoms of aplastic anemia?

(1) Fatigue (2) Malaise (3) Pallor (4) Purpura (5) Mucosal bleeding (6) Petechiae (7) Infection


What are the treatment options for aplastic anemia?

(1) Withdrawal of offending agent (2) Immunosuppressive regimen (antithymocyte globulin, cyclosporin) (3) Allogeneic bone marrow transplantation (4) RBC and platelet transfusion (5) G-CSF (6) GM-CSF


How does chronic kidney disease lead to nonhemolytic, normocytic anemia?

Decreased erythropoietin (EPO) --> Decreased hematopoiesis


What are examples of intrinsic hemolytic normocytic anemia? Which of these are extravascular versus intravascular?

(1) Hereditary spherocytosis = E (2) GP6D deficiency = I or E (3) Pyruvate kinase deficiency = E (4) HbC defect = E (5) Paroxysmal nocturnal hemoglobinuria = I (6) Sickle cell anemia = E


What is the defect in hereditary spherocytosis?

Defect in proteins interacting with RBC membrane skeleton & plasma membrane (e.g., ankyrin, band 3, protein 4.2, spectrin)


Describe and explain the morphology of RBCs seen in hereditary spherocytosis.

Less membrane causes small and round RBCs with no central pallor (increased MCHC, increased red cell distribution width)


How does hereditary spherocytosis often present?

(1) Splenomegaly (2) Aplastic crisis (parvovirus B19 infection)


What lab findings characterize hereditary spherocytosis?

Positive osmotic fragility test; Normal to decreased MCV with abundance of cells; masks microcytia


What is the treatment for hereditary spherocytosis, and why?

Splenectomy; Because premature removal of RBCs (spherocytes) by spleen due to augmented RBC morphology (Recall specifics: less membrane causes small and round RBCs with no central pallor [increased MCHC, increased red cell distribution width] --> premature removal of RBCs by spleen)


What is the hereditary nature of G6PD deficiency?



What effect does a defect in G6PD have?

Defect in GP6D --> Decrease Glutathione --> Increase RBC susecptibility to oxidant stress


What are 4 causes of oxidant stress? With what hematologic disorder is oxidant stress associated?

(1) Sulfa drugs (2) Infections (3) Fava Beans (4) Antimalarials; G6PD deficiency


In G6PD deficiency, where are RBCs primarily destroyed?

Extravascular (but also minimal intravascular)


What are signs/symptoms associated with G6PD deficiency? What do lab results classically show?

Back pain, hemoglobinuria a few days after oxidant stress; Blood smear shows RBCs with Heinz bodies and bite cells; Think: "STRESS makes me eat BITES of FAVA BEANS with HEINZ ketchup."


What is the hereditary nature of pyruvate kinase deficiency?

Autosomal recessive


What effect does a defect in pyruvate kinase have?

Decreased ATP --> rigid RBCs


In pyruvate deficiency, where are RBCs destroyed?

Extravascular hemolysis


What condition can pyruvate kinase deficiency cause at early stages of life?

Hemolytic anemia of newborn


What causes HbC defect?

Glutamic acid-to-lysine mutation at residue 6 in Beta-globin


What is important to know about HbC and sickle cell patients?

Patients with HbSC (1 of each mutant gene) have milder disease than HbSS patients


In HbC defect, where are RBCs destroyed?

Extravascular hemolysis


What mechanism causes paroxysmal nocturnal hemoglobinuria?

Increased complement-mediated RBC lysis (impaired synthesis of GPI anchor or decay-accelerating factor that protect RBC membrane from complement)


How does the mutation arise in paroxysmal nocturnal hemoglobinuria, and where?

Acquired mutation in hematopoietic stem cell


What are the symptoms most associated with paroxysmal nocturnal hemoglobinuria?

PNH triad: Coombs (-) hemolytic anemia, pancytopenia, & venous thrombosis


What do the labs for PNH show?

CD55/59 (-) RBCs (i.e., RBCs lack proteins protecting them from complement attack) on flow cytometry


In PNH, where are RBCs destroyed, and how in general?

Intravascular hemolysis; Complement-mediated RBC lysis


How do you treat paroxysmal nocturnal hemoglobinuria?



What exactly causes the HbS phenotype characteristic of sickle cell anemia?

HbS point mutation causes a single amino acid replacement in Beta chain (substitution of glutamic acid with valine) at position 6


Explain the pathogenesis of sickle cell disease.

Low O2 or dehydration precipitates sickling (deoxygenated HbS polymerizes) --> Anemia & Vaso-occlusive diease


What is seen in newborns with sickle cell anemia, and why?

Initially asymptomatic, because of high HbF and low HbS (i.e., HbF is protective early in life)


What advantage do HbS heterozygotes (sickle cell trait) have? Give the ethnic population most associated with carrying this trait, and the percentage of this population that carries it.

Resistance to malaria; African Americans - 8%


What lab result(s) characterize sickle cell disease?

Sickled cells (crescent-shaped RBCs) seen on blood smear


What is seen on x-ray in sickle cell anemia patients, and why? What other condition shares this finding?

"Crew cut" on skull x-ray, due to marrow expansion from increased erythropoiesis (also the case in thalassemias)


What are 6 complications seen in homozygotes with sickle cell disease?

(1) Aplastic crisis (due to parvovirus B19) (2) Autosplenetomy (Howell-Jolly bodies) --> Increased risk with encapsulated organisms; functional splenic dysfunction occurs in early childhood (3) Splenic sequestration crisis (4) Salmonella osteomyelitis (5) Painful crisis (vaso-occlusive): dactylitis (painful hand swelling), acute chest syndrome (most common cause of death in adults), avascular necrosis, stroke (6) Renal papillary necrosis (due to low O2 in papilla) and microhematuria (medullary infarcts)


What is/are the treatment(s) for sickle cell anemia?

Hydroxyurea (increased HbF) & bone marrow transplantation


In sickle cell anemia, where are RBCs destroyed?

Extravascular hemolysis


What infections are complications of sickle cell disease?

(1) Encapsulated organisms (increased risk due to autosplenectomy complicated) (2) Salmonella osteomyelitis


What kidney complications are associated with sickle cell disease, and why?

Renal papillary necrosis (due to low O2 in papilla) and microhematuria (medullary infarcts)


What is the general mechanism behind painful crisis complication in sickle cell disease? What are examples of painful crisis seen in sickle cell disease patients?

Low O2 or dehydration precipitates sickling (deoxygenated HbS polymerizes) --> vaso-occlusive; (1) Dactylitis (painful hand swelling) (2) Acute chest syndrome (3) Avascular necrosis


What complication may parvovirus B19 cause in patients with sickle cell disease?

Aplastic crisis


In what complication of sickle cell disease are Howell-Jolly bodies seen?

Autosplenectomy (Note: Howell-Jolly bodies = basophilic nuclear remnants [clusters of DNA] in circulating erythrocytes, typically cleared by spleen)


What are the spleen-related complications of sickle cell disease?

(1) Splenic sequestration crisis (2) Autosplenetomy (which is associated with Howell-Jolly bodies in RBCs on blood semar & increases risk of infection with encapsulated organisms), note: functional splenic dysfunction occurs in early childhood


What are examples of extrinsic hemolytic, normocytic anemias?

(1) Autoimmune hemolytic anemia (2) Microangiopathic anemia (3) Macroangiopathic anemia (4) Infections


In cases of autoimmune hemolytic anemia, which antibodies are warm versus cold agglutinin? What is a good way to remember this?

Warm agglutinin (IgG), Cold agglutinin (IgM); "WARM weather is GGGreat" & "COLD ice cream is yuMMM"


In cases of autoimmune hemolytic anemia, where are warm versus cold agglutinin seen? Which agglutinin(s) cause(s) acute versus chronic anemia?

Warm agglutinin (IgG) - CHRONIC anemia seen in SLE, CLL, or with certain drugs (e.g., alpha-methyldopa) ; Cold agglutinin (IgM) - ACUTE anemia triggered by cold, seen in CLL, Mycoplasma pneumonia infections, or infectious mononucleosis


What is important to know about the etiology of many warm and cold AIHA?

Many warm and cold AIHA are idiopathic in etiology


What is the primary lab finding associated with AIHA?

Coombs test positive


What is the difference between Direct and Indirect Coomb's tests?

(1) DIRECT COOMB'S TEST - anti-Ig antibody added to patient's blood, RBCs agglutinate if RBCs are coated with Ig (2) INDIRECT COOMB'S TEST - normal RBCs added to patient's serum. If serum has anti-RBC surface Ig, RBCs agglutinate when anti-Ig antibodies (Combs reagent) added (i.e., need Coomb's reagent to trigger reaction).


What is the pathogenesis of microangiopathic anemia?

RBCs damaged when passing through obstructed or narrowed vessel lumina


In what conditions is microangiopathic anemia seen?

DIC, TTP-HUS, SLE, & malignant hypertension


What is the characteristic lab finding in microangiopathic anemia, and why?

Schistocytes (helmet cells) are seen on blood smear, due to mechanical destruction of RBCs


What is the pathogenesis of macroangiopathic anemia?

Prosthetic heart valves and aortic stenosis may cause hemolytic anemia secondary to mechanical destruction


What is/are the lab finding(s) in macroangiopathic anemia?

Schistocytes seen on peripheral blood smear


What are examples of infections that cause extrinsic hemolytic normocytic anemia, and how do they cause it in general?

E.g., malaria, babesia; Increase destruction of RBCs


What what kind of anemia is urobilinogen in urine associated? Give 3 examples of conditions causing this.

Normocytic, normochromic, intravascular hemolysis; Urobilinogen in urine (e.g., paroxysmal nocturnal hemoglobinuria, mechanical destruction [aortic stenosis, prosthetic valve], microangiopathic hemolytic anemias).


What test (not osmotic fragility test) is useful in screening for Hereditary spherocytosis?

Eosin-5-maleimide binding test useful for screening.


What disease has increased incidence in paroxysmal noctural hemoglobinuria patients?

Increased incidence of acute leukemias


What are 4 symptoms/components of painful crisis in sickle cell patients? Which of these is the most common cause of death?

Painful crisis (vaso-occlusive): (1) dactylitis (painful hand swelling) (2) acute chest syndrome (most common cause of death in adults) (3) avascular necrosis (4) stroke


How is sickle cell anemia diagnosed?

Diagnosis: Hemoglobin electrophoresis