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Clinical Lab: Anemia


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Common presentation of anemia
-easy fatigability
-dyspnia on exertion
-ulcers of buccal mucosa
Physical signs of anemia
-rapid pulse
-low BP
-slight fever
-systolic murmor
Anemia definition
-reduced number of circulating erythroctes (RBCs)
-lowering of the concentration of hemoglobin
-reduction in hematocrit
Primary physical defect of anemia
-reduction in the oxygen carrying capacity of the blood resulting in hypoxia
Anemia may indicate underlying disease such as..
-chronic hemorrhage
-chronic infection
-renal failure
-composite function of all erythroid tissue in the body
-encompasses production of cells, release of cells, destruction of cells
Earliest red cell production occurs in...
-primative mesenchymal cells called blood islands
Blood islands
-primative mesenchymal cells where earliest RBC production occurs
-found in fetal yolk sac in 3rd or 4th week of embryonic life
-represent the earliest hemoglobin synthesizing cells
-migrate to liver, spleen, lymph nodes, and thymus in third month of life
RBC production in adults occurs in..
-medullary within the bone marrow
-mostly in flat bones (sternum, ribs, skull, vertebrae, epiphysial regions of long bones)
RBC production occurs in extra-medullary sites...
-before birth
-with pathological conditions after birth (reversion back to more primative cell production bc normal mechanisms are not functioning properly)
In times of increased cell demand, hematopoiesis may develop in..
-shafts of long bones
-e.g. individuals with chronic hemolytic disease like thalassemia or sickle cell
-may cause bone pain
Bone marrow consists of a mixture of...
-fat (yellow marrow)
-hematopoetic marrow (red marrow)
Red marrow is composed of..
-dense aggregates of cells lying alongside tiny, microscopic, open vascular spaces called sinusoids
Within the sinusoids, RBCs develop through a series of well defined stages:
-erythroblasts (rubriblasts)
Cell release at medullary sites
-release cells into blood stream when they are mature
Cell release at extramedullary sites:
-release cells in all stages (not just mature cells)
Presence of immature cells (RBC or WBC) in the peripheral blood indicates...
-hematoposiesis is taking place in extra-medullary sites
-disruption in bone marrow (leukemia, or space occupying lesions such as infection, cancer, granulomas, mylofibrosis)
Normal RBC life span
120 days
hemolytic anemia
-reduced life span of RBC
Causes of hemolytic anemia (extrinsic damage)
-immunological reactions (antigen antibody rxns)
-trauma (mechanical heart valves)
-physical stresses such as burns, pH changes, osmostic imbalance
-"march" (feet slamming against ground found in soldiers in WWII, marathoners)
Causes of hemolytic anemia
(instrinic causes)
-defects in hemoglobin synthesis (thalassemia, hemoglobinopathies such as sickle cell)
-invasion by animal parasites (malaria)
-enzyme defects that may lead to poor hemoglobin synthesis
Decrease in survival of RBC (hemolytic anemia) can effect other component of the erythron such as..
-increase in production
-alter normal release mechanism
Changes in the erythron due hemolytic anemia will manifest in...
peripheral blood smear
Types of anemias
1. hypochromic, microcytic
2. macrocytic
3. normocytic, normochromic
Hypochromic microcytic anemia
-erythrocytes do not posses sufficient hemoglobin
(tiny cells so they can't hold enough hemoglobin)
Common variants of hypochromic microcytic anemia
-iron deficiency
-thalassemia syndromes
-hemoglobinopathies (e.g. sickle cell)
-sideroblastic anemia
-iron-loading anemias
-refractory anemias
Most common form of anemia is...
iron deficiency anemia (type of hypochromic microcytic anemia)
macrocytic anemias
-MCV is too big
-may have oval macrocytes or round macrocytes
Macrocytic anemia with Oval macrocytes and tear drop poikilotosis (high MCV)
-commonly seen in megaloblastic anemias d/t vitamin B-12 or folate deficiency
-hypersegmentation or polymorphonuclear leukocytes is common feature
macrocytic anemia with round macrocytes
-seen in conditions causing increase in reticulocytes or in liver disease
Normocytic Normochromic Anemia: no poikilocytosis or polychromatophillic RBCs may indicate:
-chronic infections
-chronic renal failure
-endocrine dysfunction (hypethyroidism, hypopituitarism)
Normocytic Normochromic Anemia: poikilocytosis and occasional polychromatophillic macrocytes may indicate:
-disturbance of erythrocyte maturation
-leukemias (esp p drug therapy)
-carcinoma invading the bone marrow
Normocytic Normochromic Anemia: numerous polychromatophillic macrocytes may indicate:
-acute blood loss
In general, normocytic normochromic anemias typically indicate
chronic disease or bleeding
Microcytic hypochromic anemia with lack of reticulocytes may indicate:
-compensated blood loss
-lack of response to therapy
Microcytic hypochromic anemia with increased reticulocytes may indicate:
-bone marrow hyperplasia
-response to blood loss
-response to therapy
Msot common cause of microcytic anemia is...
iron deficiency
Iron deficient can be ruled out if it deosn't meet the following criteria:
-low serum iron
-high iron binding capacity
-low ferritin
If iron deificiency is ruled out, consider..
-hemoglobinopathy (eg sickle cell)
If thalassemia and hemoglobinopathy are ruled out, consider..
-anemia of iron overload
-sideroblastic anemia
Amount of iron an normal adult body contains:
3.0-4.0 g of iron
Relative levels of iron in a normal adult body:
-hemoglobin: 66%
-tissure iron: 33%
-myoglobin and cytochromes: <1%
-plasma transferrin <0.1%
Normal plasma iron
100-125 ug/ml
Normal iron binding capacity
300-400 ug/ml
Normal saturation for circulating transferrin
1/3 saturated
RBCs in bone marrow can extract iron from....
Percentage of cardiac output received by erythroid marrow
5% of cariac output
Precentage of available iron extracted by erythroid marrow
85% of available iron (so it is very efficeint at picking up iron)
Iron deficiency definition
total body iron is less than normal
Sequential stages of Iron deficiency
1. iron depletion
2. iron deficiency without anemia
3. overt iron deficiency
Iron depletion
-normal serum iron and iron binding capacity
-low bone marrow iron stores
Iron deficiency without anemia
-low serum iron and low iron binding capacity
-low bone marrow irons stores
-normal hemoglobin and hematrocrit
Overt Iron deficiency
-low serum iron and binding capacity
-absent bone marrow iron stores
-low hemoglobin and hematocrit
-microcytosis and hypochromia
Amount of time needed to manifest anemia
2-4 months
Iron Deficiency Anemia: prevalence
-10-30% world population
-greater in woman, children, poor
Causes of Iron Deficiency Anemia in infants and childen
-milk anemia (prolonged breast feeding bc breast milk has low iron)
-rapid periods of growth (iron cannot meet increased needs)
-hookworm infections (parasites in intestines, chronic low grade bleeding in stool)
Causes of Iron deficiency anemia in adults:
-loss of blood (menstruation, pregnancy, etc)
Iron lost during menstruation:
0.7 mg/day
Iron lost during pregnancy in formation of placenta/fetus
4 mg/day
Iron lost during hemorrhage of devlivery
330 mg
Iron deficiency in adult males may inducate:
-colon cancer
-bladder cancer
Iron Deficiency Anemia: Sx
-easy fatiguability
-atrophic changes in tongue/corner of mouth
-atrophy of gastric mucosa (histamine-fast achlorydia)
-flattening/concavity of nails (spoon nails)
Lab results for iron deficency: peripheral smear
-target cells may be seen
-low reticulocyte count
-inc or norm platelets
-proliferation of erythroid cells in bone marrow (myeloid/erythroid ratio approaches 1:1)
Administration of iron should result in...
-immediate erythrocyte reponse
-gradual rise in hematocrit and hemoglobin
-retuculocytes in 10-15% (normally 0.5-1.5%)
-some normoblasts may be seen
presence of target cells in microcytic hypochromic anemia suggests..
-hemoglobin problem
Heme consist of..
-4 pyrrole rings surrounding a ferrous iron
Globin consists of..
-4 polypeptide chains
-for any type of hemoglobin, there are 2 pairs of chains
Chains for normal adult hemoglobin (Hemoglobin A1):
-2 alpha
-2 beta
Chains for Hemoglobin F (fetal hemoglobin)
-2 alpha
-2 gamma

<1% of normal adult hemoglobin
Chains for hemoglobin A2
-2 alpha
-2 delta

2% of total adult hemoglobin
Thalassemia definition
-group of disorders wherein one or more of the globin chains is diminished or absent
-may effect alpha or beta chains
Thalassemia: prevalance
-most common in Mediterranean Basin and Orient
Thalassemia is d/t..
-defect in the genes leading to a decrease in the production of mRNA reponsible for the synthesis of specific polypeptide chains
Heterozygous beta chain thalassemia
-only involved 1 beta chain gene
-mild hypochromia and microsytosis occur
Homozygous beta chain thalassemia
-Cooley's anemia
-involves both genes controlling beta chain
-no hemoglobin A1 is produced
-hemoglobin F and A2 are increased (these have no beta chains)
Heterozygous alpha thalassemia
-homoglobin alpha chains are minimally compromised
Homozygous alpha thalassemia
-no alpha chains are made
-no hemoglobin A1, A2, F
Thalassemis: Dx
-hx of mild anemia since childhood
-microcytic hyprochromic RBCs
-target cells
-normal iron
-increase in hemoglobin A2 and F
Suspect Hemoglobinopathies when...
-hypochromic microcytic
-normal iron
-target cells present
-normal hemoglobin A2 and F
Most common types on hemoglobinopathies:
-hemoglobin S (sickle cell)
-hemoglobin C
Hemoglobin S
-glutamic acid is replaced by valine on the beta-chain of hemoglobin
(in normal, healthy person, glutamic acid is found on single locus on beta chain)
-2 mutant beta chains and 2 alpha chains form hemoglobin S, which polymerises under low oxygen conditions causing a distoration of RBC
Hemoglobin C
-abnormal hemoglobin with substitution of lysine for glutamic acid on the beta chain
-reduced plasticity of etythrocytes
Homozygous for Sickle Cell
-produce all hemoglobin S
Heterzygous for Sickle Cell
-produce some hemoglobin S and some regular hemoglobin
Consider sideroblastic anemia if..
-cells are hypochromic/microcytic
-normal iron
-no thalassemia
-no hemoglinopahthy
Sideroblastic anemia
-anemia d/t abnormal production of RBC
-caused by toxins (lead/zinc), drugs (thanol, isoniazid), nutritonal (copper or pyrodoxine deficiency)
Causes of sideroblastic anemia
-vitamin deficiency
-mineral deficiency
3 categories for normocytic normochromic anemia:
1. anemias d/t bone marrow failure
2. hemolytic anemia
3. refractory anemias (myelodysplastic syndrome)
Causes of Normocytic normochromic anemia:
-exposure to drugs or chemicals (benzene derivatives, chloramphenicol)
-exposure to radiation
-consistitutional factors
-idiopathic causes
Examples of anemias due to bone marrow failure
-pure red cell aplasia
-anemia of chronic renal failure
-anemia of endocrine disorders
Pure red cell aplasia (anemia due to bone marrow failure)
Examples of anemia of endocrine disorders (anemia d/t bone marrow failure)
-pituitary disease
-thyroid disease
-adrenal disease
-gonadal disease
Clincal Mainfestations of hemolytic anemias:
-increased hemoglobin catabolsim/breakdown
-decreased plasma haptoglobin
-hemoglobinemia (free hemoglobin in plasma)
Increased hemglobin catablism from hemolytic anemia lead to..
-elevation of unconjugated bilirubin
-increase in urine and fecal urobilinogen
Hemoglobinurea in hemolytic anemia
-occurs when hemoglobin in plasma exceeds 30 mg/dl
-at this concentration, the capacity of the proximal tubular cells to reabsorb free hemoglobin is exceeded so free, unbound hemoglobin is excreted in the urine (this is abnormal)
Methalbuminemia in hemolytic anemia
-free hemoglobin is catablized into methemoglobin
-some is transfered into albumin
Congenital hemolytic jaundice is characterized by..
-mild elevation of indirect bilirubin
-high-normal MCHC
-increased urobilinogen (colourless product of bilirubin reduction; part is resorbed and the rest is excreted in feces; trace amounts can be detected in urine)
-no bilirubin in urine
-negative direct antiglobulin test
-peripheral smear shows spheroctyes
-increase osmotic fragility of RBCs
-increase in reticuloctyes and erythroid hyperplasia
Congential hemolytic jaundice
-"hereditary spherocytosis"
-defect in membrane
-autosomal dominant
Congeintial hemolytic jaundice: Tx
Other conditions associated with spherocyte include:
-acquired immunohemolytic anemia
-thermal injury
-chemical poisons
-certain septicemias
Osmotic fragility test will prove...
Other anemias due to membrane defects:
-hereditary elliptocytosis
-hereditary stomatocytosis
-microangiopathic anemia
-paroxysmal nocternal hemogobinurea
Hereditary Elliptocytosis
-cigar shaped elliptical cells
-membrance defect unknown
-mild anemia
hereditary stomatocytosis
-"fish mouth" RBCs
-membrane defects caused by hyperpermeability to sodium
-potassium is forced out
-hemolysis is usually mild
-no improvement following splenectomy
-found inceidentally following consumption of large amts of ETOH
Microangiopathic Anemias
-damaged RBC appear as fragments
-helmet cells
-traingular pieces or other distorred images
Causes of microangiopathic anemias
-prosthetic heart valve replacements
-long distance runners (march hemoglobinurea)
-following extensive burns
Paroxysmal Nocternal Hemoglobinurea
-acquired disorder wherein the RBC membrane is hypersensitive to complement
-cause is unknown, perisists for life with no cure
-platelets and WBCs may be effected
-pt presents c fatigue and low grade anemia
-reticulocytes present
-spherocytes do NOT occur
-mild respiratoty acidosis with sleep
-hemoglobinurea in a.m.
hemolytic anemias d/t extracorpuscular defects:
-caused by antibodies destroying the integrity of the RBCs
-acquired disorders
-positive direct antiglobin test (direct Coombs test) d/t warm or cold autoantibodies
-hemolysis is secondary to sequestration of cells in liver
Hemolytic anemias (extracorp. defect) caused by warm antibodies
-idiopathic acquired autoimmune hemlytic anemia
-secondary immunohemolytic anemia
Idiopathic acquired autoimmune hemolytic anemia
-mild to severe
-positive DAT of unknown cause
-pt shows splenomegaly, marked spherocytosis, reticulocytosis
Secondary immunohemolytic anemia
-develops with other disorder like neoplasma, leukemia, lupus
Hemolytic anemias with cold antibodies
-in association with viral disorders (esp pneumonia and mononucleosis)
-in association with lymphoproliferative disease
-idopathic cold agglutinin disease
-mild to severe anemia
Paraxysmal Cold hemoglobinurea
-associated with syphilis
-produced intravascular hemolysis due to exposure to cold
-antibody is known as Donath-Landsteiner antibody
-immature red blood cells
-develop in mature in bone marrow
Number of reticulocytes is a good indicator of...
-red bone marrow activity

-can be used to monitor the progress of the treatment of anemia
Increased reticulocytes (reticulocytosis) may indicate..
-hemolytic anemia
-sickle cell anemia
Decresed reticulocytes may indicate...
-aplastic anemia
-pernicious anemia
-bone marrow malignancies
-problems with erythropoitin production
-other casues of poor RBC production
Megaloblastic anemia
anemia resulting from deficiceny in vitamin B12 and folilc acid
Magaloblastic anemia hematologic findings:
-dec RBC
-dec hemoglobin
-increased MCV
-normal reticulocyte
-platelet dec or norm
-macrocytes are present (large RBC)
-ovalocytes may be present (oval shaped RBCs)
-bone marrow shows megaloblastic hyperplasia
increased varitaion in RBC size
abnormally shaped RBC
Pernicious anemia
-autoimmune anemia
-antibodies are directed against intrinsic factor or parietal cells that make intrinsic factor (intrinsic factor is required fo vitamin B12 absorption)
-macrocytic anemia with low vita,in B12
Where are RBC cleared out of circulation?
Hemolytic anemia hematologic findings:
-spherocytes (RBCs smaller and rounder than normal)
-increased reticulocytes
-inc bilirubin levels
-dec haptoglobin
-yellow breakdown of normal heme catabolism
-responsible for th yellow color of bruises
-formed when RBC die and their hemoglibin is broken down within the macrophages to heme and globins
-can lead to juandice
-a protein in the blood plasma the binds free hemoglobin released from erythrocytes
-once bound, the haptoglobin-hemoglobin complex is removed via the spleen
-decreased with hemolytic anemia
Aplastic anemia
-bone marrow does not produce enough, or any, new cells to replenish the blood cells
-low RBC, low WBC, loe platelets
Sideroblastic anemia hemotologic findings:
-inc ferritin
-dec total iron binding capacity
Sickle Cell disease
-RBC change shape upon deixygenation bc of polymerization of the abnormal sickle hemoglobin (Hgb S or Hb S)
-damaged RBC can casue RBC to become stuck in blood vessels and cause obstructions (infarction, ischemia)
Sickle cell hemotologic findings:
-microcytic, hypochromic
-inc reticulocytes (reflecting new RBC replacing the rapidly destroyed older RBCs)
-inc WBC and platelet (often)
-genetic defect results in synthesis of abnormal hemoglobin molecules
-as a result, blood cells are vulnerable to mechanical injury and early death

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