Anemia Flashcards
Describe the basic shape of RBCs
Anucleate biconcave discs
Ratio of RBCs:WBCs in the peripheral blood
About 1000:1
What is the first stage of a RBC released from the marrow into peripheral blood? Describe its appearance
Reticulocyte
Cytoplasm may be blue-pink due to residual RNA (polychromasia)
What is the normal life span of a RBC?
120 days
What is the function of an RBC membrane skeleton?
Control biconcave shape and cell deformability
List some basic components of the RBC membrane
Phospholipid bilayer with glycolipids and cholesterol
Integral proteins span the bilayer
Describe the basic structure of heme
4 pyrrole groups joined into a large ring with a ferrous ion (Fe2+) in the center
Describe the basic structure of globin chains
~150 amino acids per chain
Heme binds to a specific region of each chain
Describe the basic structure of hemoglobin. What si the structure of the most common form of adult hemoglobin?
Two globin dimers and heme form hemoglobin
Hemoglobin A has 2 alpha and 2 beta globin chains
What organ removes aging RBCs from the circulation? How?
Spleen
Monouclear phagocytic engulfment
When hemoglobin is broken down, what are the elements it is broken into and how are they used?
Heme is divided into iron (gets recycled) and porphyrin rings (eliminated as bilirubin)
Globin is dismantled into amino acids
Accelerated RBC destruction is known as….
Hemolysis
Define anemia
Reduced O2 carrying capacity of the blood
Reduction below normal limits of total circulating RBC mass by either reducing volume of packed cells or reducing hemoglobin concentration
What are three general causes of anemia?
Blood loss
Hemolysis
Reduced RBC production
Some intrinsic abnormalities of RBCs that may lead to hemolysis are…
Membrane disorder
Enzyme deficiency
Hemoglobin synthesis disorder
Acquired disorder
Some extrinsic abnormalities of RBCs that may lead to hemolysis are…
Antibody mediated Mechanical trauma Infections Chemical injury Sequestration
Microcytic anemia may be seen in what diseases?
Iron deficiency
Thalassemias
Anemia of chronic disease
Macrocytic Anemia may be seen in what diseases?
Vitamin B12 or Folate deficiency (megaloblastic anemia)
What is the MCV in microcytic anemia? Macrocytic? Normocytic?
Normocytic - 80 - 100 fL
Microcytic - below 80 fL
Macrocytic - above 100 fL
List some general pathological characteristics of hemolytic anemias
Shortened RBC life span
Accumulation of hemoglobin catabolism products
Compensatory increase in erythropoiesis in marrow
Describe what intravascular hemolysis is and what it may lead to
RBCs are destroyed within the vascular compartment
May cause hemoglobinemia, hemoglobinuria, and hemosiderinuria
What should you look for in blood samples of anemic patients to detect potential hemolysis?
Haptoglobin
If haptoglobin levels are low, you know there is some kind of hemolysis occuring. Free hemoglobin will form complexes with haptoglobin and be removed by the liver.
Describe what extravascular hemolysis is and what is might lead to
RBCs are destroyed primarily by tissue macrophages
May cause splenomegaly
Hereditary Spherocytosis
What is the basic pathological problem?
Hereditary (autosomal dominant mostly) problem with intrinsic defect in RBC membrane
Results in spheroid RBCs that are less deformable and more vulnerable to splenic sequestration and destruction
Lower membrane stability and loss of membrane fragments
Hereditary Spherocytosis
Autosomal dominant form is primarily a defect in…
Ankyrin gene
Less synthesis of ankyrin leads to less synthesis of spectrin
Hereditary Spherocytosis
Autosomal recessive form is primarily a defect in…
alpha-Spectrin gene
Hereditary Spherocytosis
What will improve their symptoms?
Spenectomy
Spherocytes will persist, but the anemia will improve
Hereditary Spherocytosis
What is seen on the peripheral blood smear?
Spheroidal RBCs that are abnormally small and do not have a central zone of pallor
Hereditary Spherocytosis
Clinical Symptoms/Features
Anemia
Splenomegaly
Jaundice
May be asymptomatic in 20-30% of people
Hereditary Spherocytosis
How is it diagnosed?
Family history
Hematologic findings
Increased mean cell hemoglobin conc.
Lab evidence of increased osmotic fragility
G-6-PD Deficiency
What is the inheritance?
X linked, so mostly males are affected
G-6-PD Deficiency
What is the normal function of G-6-PD?
Converts NADP to NADPH, allowing for the conversion of GSSG (oxidized glutathione) to GSH (reduced glutathione)
G-6-PD Deficiency
What are the symptoms?
Usually asymptomatic until they have some infection, oxidative stress, exposure to certain drugs or toxins
G-6-PD Deficiency
What is the characteristic finding on histology?
Heinz bodies
G-6-PD Deficiency
How are Heinz bodies formed?
Due to H2O2 accumulating and oxidizing sulfhydryl groups of globin chains. This denatures the hemoglobin and forms Heinz bodies, which attach to the RBC memrbane and cause damage and decreasing deformability
G-6-PD Deficiency
What is a characteristic finding on peripheral blood smear? How are they formed?
Bite cells
Formed as the RBCs+Heinz bodies pass through spleen. Macrophages bite the Heinz bodies and lead to loss of membrane and formation of spherocytes
What are two problems with hemoglobin synthesis that may lead to hemolytic anemia?
Structually abnormal globin synthesis (sickle cell)
Deficient globin synthesis (thalassemia)
Sickle Cell Disease
What is the mutation that causes this disorder?
Mutation in 6th position of the beta-globin gene (substitute Val->Glu)
Sickle Cell Disease
What is the pathogenesis?
Hemoglobin S molecule is formed, which will aggregate and polymerize
RBC becomes distorted into the sickle shape
Sickle Cell Disease
What are some factors that may induce sickling in these patients?
More HbS synthesis
MHC increase
Fall in pH
Sickle Cell Disease
What are the two major clinical consequences of this disease?
Chronic hemolytic anemia
Occlusion of small blood vessels
Sickle Cell Disease
How is the spleen involved in the pathogenesis?
Spleen may play a role in the hemolysis (rigid sickled RBCs may become sequestered there)
Over time, hypoxic tissue damage may occur and the spleen may become small and fibrotic (“auto-splenectomy”)
Sickle Cell Disease
What is is the clinical outcome of occlusion of small blood vessels?
Widespread microvascular obstruction from rigid red cells may result in ischemic damage
Intermittent, sudden episodes are called vasoocclusive crises
Sickle Cell Disease
How may this be diagnosed?
Ordinary peripheral blood smear can show sickled cells
Blood sample may be induced to show sickling
Usually diagnosed by hemoglobin electrophoresis
Sickle Cell Disease
What group of people is this more commonly seen in?
African Americans
Thalassemia
What is the general pathological problem?
Genetic disorder characterized by decreased synthesis of either alpha or beta chains of hemoglobin A.
The consequences derive from diminished synthesis of one globin chain leading to low intracellular hemoglobin or excess of the other kind of chain
Alpha Thalassemia
Where are the alpha globin chain genes?
There are two alpha genes on chromosome 16.
Alpha Thalassemia
4 degrees of this disease may result. List them
Silent carrier -a/aa
Alpha thalassemia trait –/aa or -a/-a
HbH disease –/-a
Hydrops fetalis –/–
Beta Thalassemia
What causes the anemia?
Reduced synthesis of beta-globin, leading to inadequate Hgb A formation
Hemolysis is caused by excess alpha chains, which form insoluble aggregates
What is the major difference between Thalassemia major and Thalassemia minor?
Major - severe disease with reliance on transfusions
Minor - asymptomatic, mild, or absent anemia and some RBC abnormalities
Beta Thalassemia Major
What are some clinical observations?
Marrow space expanding into skull (hair on end appearance of the Xray)
Hepatosplenomegaly
Multiple transfusions necessary
Beta Thalassemia Minor
What are the clinical associations?
Minor microcytic hypochromic anemia
“Target” cell - central pallor with a dot in the middle
RBCs have “bell” shape
What is the only acquired defect in the RBC membrane?
PNH
Paraoxysmal Nocturnal Hemoglobinuria
PNH
What is the pathogenesis?
Stem cell disorder that results from a mutation in the PIGA gene
Leads to a deficiency of GPI anchor and lack of expression of GPI-linked proteins
List some important GPI-linked proteins.
CD55
CD59
C8 binding protein
PNH
Clinical Findings
Classic intravascular hemolysis
Infections and venous thrombosis
May occassionally evolve to aplastic anemia or leukemia
What are two causes of mechanical RBC hemolysis?
Prosthetic cardiac valves
Narrowing of small vessels and fibrin deposition (Microangiopathic hemolytic anemia)
List some forms of Microangiopathic hemolytic anemia
TTP
HUS
DIC
How can you confirm Microangiopathic hemolytic anemia with a blood smear?
See schistocytes
In anemias from impaired RBC production, what are some general problems that can halt RBC production?
Deficient heme synthesis
Deficient DNA synthesis
Multiple mechanisms
Disordered proliferation and maturation of the stem cells
What is the most common cause of iron deficient anemia?
Chronic blood loss, usually in the GI tract
Describe the pathogenesis of iron deficient anemia (what happens first, etc)
Stored iron (ferritin) is depleted first, the circulating iron goes low
Hemoglobin eventually goes low and the RBCs become microcytic with reduced hemoglobin concentration
Symptoms of iron deficient anemia
Nails develop ridges, get spoon shape
Tongue may become smooth
Intestinal malabsorption
Esophageal webs (rare)
What would the blood smear of iron deficient anemia look like?
RBCs have a larger central pallor than usual
What is the general problem in megaloblastic anemia?
Deficient DNA synthesis from a Vit B12 or Folate deficiency
Megaloblastic Anemia
What is seen in the proliferating cells?
Enlarged RBC precursors (megaloblasts)
Enlarged red cells (macrocytes)
Megaloblastic Anemia
How does impaired DNA synthesis cause enlargement?
Abnormal cell maturation and division
What could potentially cause a B12 deficiency?
Intrinsic Factor (IF) deficiency Pancreatitis Gastrectomy Ileal resection Parasites (Fish tapeworm)
What is pernicious anemia?
Vit B12 deficiency secondary to gastritis with underproduction of IF
What is the role of IF in B12 absorption?
Intrinsic Factor (IF) from the stomach needs to bind B12 for its absorption in the distal ileum
Why is Vitamin B12 necessary for humans?
Necessary cofactor in methionine synthesis (deficiency of B12 leads to less THF for the reaction)
Isomerization of methylmalonyl CoA to succinyl CoA
What may be seen on peripheral blood smear in B12 deficiency?
Megaloblastic anemia
Leukopenia with hypersegmented granulocytes
Describe the problems Megaloblastic Anemia may cause in the CNS
Subacute combined degeneration
-affects sensory and motor tracts
What are some symptoms of Megaloblastic Anemia from folate deficiency?
Megaloblastic anemia is identical to B12 deficiency, but there are no CNS symptoms in folate deficiency.
Anemia of Chronic Disease
You may see high plasma levels of….
What does this compound do?
Hepcidin
High levels of hepcidin may block transfer of iron from macrophages to RBC precursors
List the pathological consequences of Anemia of Chronic Disease
Microcytic anemia with low serum iron
High ferritin
Decreased total iron binding capacity
Increased bone marrow iron stores
Aplastic Anemia
What will you find in the peripheral blood?
“Pancytopenia”
Anemia
Granulocytopenia
Thrombocytopenia
Aplastic Anemia
What is the pathologic problem?
Failure or suppression of stem cells leading to a hypocellular marrow
May be caused by defect in HSCs, bone marrow stroma, or suppression by T cell mediated immunity
Aplastic Anemia
What would you see in the bone marrow?
Hypocellular bone marrow
Increased fat
Aplastic Anemia
How should you treat?
Could use HSC transplant, but this is difficult and the morbidity/mortality is high
What is the MCH? How is it calculated?
Mean Corpuscular Hemoglobin
MCH = (Hemoglobin x 10)/RBC
What is the MCHC? How is it calculated?
Mean corpuscular hemoglobin concentration
Hemoglobin/Hematocrit = MCHC
In hypochromic anemias, how are the MHC and MCHC affected?
Both are decreased in hypochromic anemias (like iron deficiency or thalassemia)
Give an example of a hyperchromic anemia.
How are the MCH and MCHC affected?
Hereditary spherocytosis
MCHC will be increased
In macrocytic anemias, how is the MCHC affected?
It is normal.
MCH is high (hemoglobin is increased), but the cells themselves are also large.
What is RDW a measure of?
Red Cell Distribution
Measure of the variability in RBC size
What is anisocytosis?
Variation in RBC size, measured by RDW
What is poikocytosis?
Variation in RBC shape
