RBC disorder

Question 1

anemia

Answer 1

reduction in red cell mass, with consequent decrease in oxygen transport capacity of the blood.

Question 2

what are the clinical parameters used in testing for anemia?

Answer 2

red cell count, hemoglobin concentration, and hematocrit, all of which reflect, but do not directly measure, the red cell mass. Accepted “normal” levels vary with age, sex, and geographic location.

Question 3

clinical manifestations of anemia

Answer 3

results in impaired tissue oxygenation as manifest by exertional shortness of breath, weakness, fatigue, and pallor. Polycythemia denotes an increase in red cell mass.

Question 4

how can anemias be classified?

Answer 4

Anemias can be classified into three broad categories based on the mechanism by which red cell mass is decreased: blood loss, decreased red cell production, and decreased red cell survival. Other classification systems based on red cell morphology are also in common use.
•RBC loss
–Hemorrhage (acute and chronic)
•Decreased RBC survival
–Hemolysis
•Decreased RBC production
–Nutritional deficiencies, aplastic anemia, myelophthistic processes

Question 5

what laboratory tests are done for anemia?

Answer 5

•CBC
–RBC count
–Hemoglobin
–Hematocrit
–Mean cell volume (MCV), Hb (MCH), and Hb concentration (MCHC)
–WBC
–Platelets
•Blood smear review
•Reticulocyte count

•Iron Indices
–serum Fe, iron-binding capacity, transferrin saturation, ferritin concentration
–Vitamin B12 and folate (serum and RBC concentrations)

Hemolysis work-up
•Bilirubin
–direct and indirect
•Haptoglobin
•LDH
•Coomb’s test
•Plasma hemoglobin
•Hemoglobin electrophoresis

Question 6

red blood cell loss

Answer 6

Young healthy subjects can tolerate rapid loss of 500-1000 mL (up to 15-20% of total blood volume) with few symptoms, but some will have a vasovagal response- sweating, weakness, nausea, slow heart rate, hypotension. If blood loss is controlled, interstitial fluid will redistribute (within 24 hours) into the vascular space in an attempt to re-expand the vascular volume. Loss of 1000-1500 mL produces lightheadedness, orthostatic hypotension; with loss of 1500-2000 mL, all patients are symptomatic- thirst, shortness of breath, loss of consciousness, sweating, rapid pulse, decreased blood pressure, clammy skin. Rapid loss of 2000-2500 mL produces shock. The loss of RBC stimulates increased production, mediated by erythropoietin, resulting in an increase in the reticulocyte count in the peripheral blood.

Question 7

chronic blood loss

Answer 7

causes anemia when the rate of loss exceeds the capacity for RBC regeneration or when iron reserves are depleted. Chronic GI hemorrhage due to ulcer or neoplasm, or GYN hemorrhage (menorrhagia) are important causes of iron deficiency.

Question 8

hemolytic anemias

Answer 8

characterized by shortened red cell survival and retention of products of red cell destruction (iron). Increased erythropoietin production results in increased red cell production with a reticulocytosis to compensate for the anemia. Red cell destruction can occur within the circulation (intravascular hemolysis) or in the reticuloendothelial system including spleen (extravascular hemolysis).

Question 9

what is intravascular hemolysis?

Answer 9

: destruction of RBC within the circulation. Examples: -mechanical trauma (e.g., from a defective heart valve), hemolytic transfusion reaction. Hemoglobin released from RBC into circulation (hemoglobinemia) is bound to haptoglobin, a binding protein, and cleared from the circulation by the liver. A decrease in serum haptoglobin is a key feature of intravascular hemolysis. When plasma hemoglobin levels exceed amount of available haptoglobin, free hemoglobin is excreted in the urine (hemoglobinuria); however hemoglobin is toxic to the kidney, and iron that accumulates in proximal tubular cells in the kidney as a breakdown product of hemoglobin is lost in the urine when these cells are shed (hemosiderinuria). Conversion of heme (derived from hemoglobin) to bilirubin leads to hyperbilirubinemia and jaundice. The degree of jaundice is dependent on the functional capacity of the liver and rate of hemolysis. Levels of haptoglobin are characteristically low.
•Immune-
–Transfusion reaction
•Non-immune-
–Mechanical trauma (defective heart valve)
•Decreased haptoglobin, hemoglobinemia, hemoglobinuria, hemosiderinuria, hyperbilirubinemia, reticulocytosis

Question 10

what is extravascular hemolysis?

Answer 10

destruction of RBC in reticuloendothelial system (spleen, liver). Examples: Hereditary spherocytosis, sickle cell anemia, erythroblastosis fetalis (antibody-mediated hemolytic disease of the newborn). Damaged or abnormal RBC are removed in spleen, where hemoglobin is broken down intracellularly. Free hemoglobin is not released directly into the blood and urine, but hemoglobin breakdown products are increased (hyperbilirubinemia) and jaundice may result. Spleen and liver may become enlarged since these are sites of removal of RBC from the circulation. Chronically elevated levels of bilirubin can promote formation of gallstones.

•Immune - Extrinsic defects
–Autoimmune
–Erythroblastosis fetalis
–Transfusion reaction

•Non-immune - Intrinsic defects
–RBC membrane defects
–Hemoglobinopathies
–Metabolic defects
•Decreased haptoglobin, hyperbilirubinemia, reticulocytosis
•May have hepatosplenomegaly

Question 11

how is hemolytic anemias classified?

Answer 11

Hemolytic anemias are classified by the mechanism of red cell destruction into intrinsic defects (hemoglobin production, membrane abnormality) which are usually inherited, and extrinsic defects (antibody, mechanical trauma) which are usually acquired abnormalities.

Question 12

what is hereditary spherocytosis?

Answer 12

membrane defect
intrinsic defect
– extravascular hemolysis.
An inherited defect in the red cell membrane results in less deformability of RBC, so that they are sequestered and destroyed in the spleen. The specific defect can be a qualitative or quantitative deficiency of spectrin, a structural protein of the cytoskeleton. Autosomal dominant inheritance in most cases. Manifest in adult life, severity is variable. Removal of spleen results in normal red cell survival but not normal red cell morphology. Production of spherocytes continues, but following splenectomy their destruction is decreased.
–Abnormality of spectrin, a structural protein of the red cell cytoskeleton
–RBC’s are less deformable – can’t squeeze through the splenic sinusoids, thus are sequestered and destroyed in the spleen
–Splenectomy helps symptoms and anemia
–Red cells remain abnormal (spheres)

Question 13

what is sickle cell anemia?

Answer 13

abnormal hemoglobin
intrinsic defect
extravascular hemolysis
An inherited defect (autosomal codominant) in the structure of globin chain causes hemoglobin to gel upon deoxygenation. The specific defect is a single base pair substitution in DNA that causes a single amino acid substitution (valine for glutamic acid) at position 6 in the beta chain of globin to produce sickle hemoglobin (HbS). Under low oxygen conditions the abnormal hemoglobin polymerizes, causing the RBC to assume a “sickle” shape. The sickled cells are rigid and vulnerable to splenic sequestration (decreased survival), and can also block the microcirculation causing ischemia and/or infarction. Sickle cell disease occurs in homozygotes for HbS, and is characterized by severe anemia, and vaso-occlusive crises, including acute chest syndrome and stroke. Complications may also include autosplenectomy, painful crises, leg ulcers, retinal and renal thromboses. About 8% of blacks in USA have sickle cell trait (heterozygotes), and are essentially asymptomatic because less than half of the hemoglobin is abnormal and the concentration of HbS within the RBC is insufficient to cause sickling. Small but significant resistance to malaria.

•Moderate to severe anemia 
•Hyperbilirubinemia, reticulocytosis
•“Autosplenectomy”
•Sickle Cell Trait 
–Heterozygotes; Hemoglobin AS
–Clinically asymptomatic
–Sickle cells are absent

Question 14

what is thalassemia?

Answer 14

lack of globin chains
intrinsic defect
extravascular hemolysis
. An inherited defect (autosomal codominant) that results in diminished or absent synthesis of either the alpha or beta globin chains of hemoglobin. The cause at the gene level can include whole or partial gene deletion, mutations in the coding sequence or promotor region, or mRNA instability. The type of thalassemia is named for the globin chain produced in reduced amounts. Decreased globin production results in decreased hemoglobin production, and anemia is the principal clinical manifestation. In addition, precipitation of the relative excess of the other globin chain within RBC causes membrane damage and premature destruction of RBC precursors in the marrow and spleen (ineffective erythropoiesis and extravascular hemolysis). Clinical manifestations vary from severe transfusion-dependent anemia and iron overload (thalassemia major) to mild anemia (thalassemia minor). In almost all cases there is a moderate to marked microcytosis (low MCV) with target cells and basophilic stippling of the red cells present on the blood smear. As the severity of the anemia increases there is increasing abnormalities of red cell shapes and sizes. Thalassemia is relatively common in persons of Mediterranean, African, and Southeast Asian descent. Reduces impact of malaria.

Question 15

what is Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency ?

Answer 15

metabolic defect
intrinsic defect
extravascular hemolysis. An inherited defect (X-linked) encountered primarily in blacks in which red cells are susceptible to oxidant injury by drugs or toxins (antimalarials, sulfonamides, etc.). The denaturation of oxidized hemoglobin causes it to precipitate within the cell and attach to the RBC membrane. The RBC membrane’s flexibility is reduced, leading to extravascular hemolysis. The condition is asymptomatic in the absence of the oxidant.

•“Bite” cells are the morphologic hallmark on cytologic exam

Question 16

what is erythroblastosis fetalis?

Answer 16

immune destruction
extrinsic defects
extravascular hemolysis
This disorder, also called hemolytic disease of the newborn (HDN), is caused by blood group incompatibility between the mother and fetus. This disease occurs in utero only when the fetal RBC express antigens inherited from the father that are not present in the mother. Fetal RBC that reach the maternal circulation during the third trimester of pregnancy or during childbirth can be recognized as foreign and stimulate an antibody response in the mother. When a sensitized mother is re-exposed to the foreign antigen during a subsequent pregnancy, the mother’s immune system makes antibodies (IgG) that cross the placenta and attach to the fetal RBC, resulting in extravascular hemolysis (antibody coated RBC are removed from circulation in liver and spleen) in the fetus. ABO and Rh antigens (especially anti-D) are most important in this disorder. Rh-negative mothers are given anti-D (Rhogam) within 72 hours of delivery of an Rh-positive fetus. The anti-D binds to the Rh-positive fetal cells and removes them from the maternal circulation before the mother can generate an antibody response and become sensitized. ABO hemolytic disease occurs in group A and B infants born to group O mothers. Certain group O mothers produce IgG anti-A or anti-B in addition to the usual IgM antibodies (which do not cross the placenta). Fortunately lysis of the fetal RBC is minimal, in part because fetal cells express A and B antigens weakly, and because other tissues also express A and B antigens and soak up the antibody.

Question 17

what is hemolytic transfusion reaction?

Answer 17

immune destruction
extrinsic defect
intravascular hemolysis
Here transfusion of incompatible red cells into a sensitized patient results in binding of antibody (in patient) to antigen (transfused RBC) with activation of complement (lyses antibody-coated RBC) and immediate intravascular hemolysis. Activation of coagulation cascade with bleeding, renal failure, shock, and death can occur. ABO antigens are most important, but other RBC antigens can produce a similar picture.

Question 18

what is autoimmune hemolysis?

Answer 18

immune destruction
extrinsic defect
extravascular hemolysis 
Patient makes antibodies to his/her own RBCs. Antibody-coated cells can be lysed (complement activation) or removed by the reticuloendothelial system. Phagocytosis of antibody-coated RBC can lead to partial loss of red cell membrane (spherocytes). Spherocytes are sequestered by the spleen, further contributing to the anemia.
•Positive direct Coomb’s test

Question 19

what is cardiac valve prosthesis?

Answer 19

mechanical trauma
extrinsic defect
intravascular hemolysis
Red cells are disrupted by physical trauma as they pass through areas of turbulence and abnormal pressure related to abnormal valve function. Example: DIC (disseminated intravascular coagulation) where RBCs are lysed as they pass through fibrin clots/strands in the microcirculation. Loss of large portion of membrane produces schistocytes.

Question 20

what is malaria?

Answer 20

extrinsic defect
infections
intravascular hemolysis
Parasites infect RBC and cause lysis of RBC during maturation. Varying degrees of intravascular hemolysis are experienced by individual patients.

Question 21

what causes decreased red blood cell production?

Answer 21

Nutrient Deficiencies

A deficiency of a substance needed for erythropoiesis leads to diminished red blood cell production:

Question 22

what is iron deficiency anemia?

Answer 22

Iron deficiency is the most common cause of anemia worldwide. Iron is needed for hemoglobin, myoglobin, and a variety of enyzmes.  Red blood cells become smaller (microcytic) and contain less hemoglobin (hypochromic) than usual. This anemia occurs most commonly in infants (inadequate intake), adolescents (increased requirement), pregnancy, elderly, and alcoholics.  It is important to recognize that iron deficiency anemia may also be a sign of a more serious disorder associated with chronic blood loss (cancer).  Anemia develops insidiously, and remarkably low levels of hemoglobin can be tolerated with minimal symptoms. Diagnosis is usually established by laboratory tests (decreased serum iron, decreased serum ferritin, and increased serum iron-binding capacity). 
•Microcytic(low MCV) red cells
•Hypochromic (low MCHC) red cells
•Decreased serum ferritin
•Increased serum iron-binding capacity
•Decreased serum iron
•Absent reticulocyte response

Question 23

what is vitamin b12 and folate deficiency??

Answer 23

megaloblastic anemia
Both B12 and folate are involved either directly or as cofactors in the synthesis of thymidine, one of the purine bases in DNA. The impaired DNA synthesis causes a delay in mitotic division: nuclear size increases, but RNA synthesis and cytoplasmic maturation proceed normally. The end result is an abnormally large red cell precursor (megaloblast), decreased production of mature RBCs, and abnormally large red cells (macrocytes – high MCV). Hypersegmented neutrophils may be seen secondary to the delay in mitotic division. The megaloblasts accumulate in the bone marrow, releasing too few RBCs into the peripheral blood and causing anemia. The megaloblasts may undergo autohemolysis in the marrow or be destroyed by phagocytic cells in the marrow (ineffective erythropoiesis). The impairment of DNA synthesis is systemic, and affects other rapidly dividing cells in the body (granulocytes, megakaryocytes, epithelial cells).
•Abnormally large red & white cell precursors
–Increased MCV
–Hypersegmented neutrophils
•Decreased mature red cell production (absent reticulocyte response)
•If severe, white cell and platelet production can also be effected
•Marked intramedullary red cell death

Question 24

what causes folate deficiency

Answer 24

Folate deficiency-
•Present in fresh vegetables
•Body stores are small
•Increased requirements
–Pregnancy, hemolytic anemias, high cell turnover states
•Decreased dietary intake or malabsorption
Folate is found in fresh vegetables; deficiency can result from increased requirements (pregnancy, hemolytic anemia), decreased dietary intake (alcoholics), and malabsorption (intestinal disease, drugs). Body stores are relatively small. Folate is absorbed in the proximal small intestine.

Question 25

what causes b12 deficiency

Answer 25

•Present in animal foods
•Body stores are large
•Increased requirements
•Decreased dietary intake or malabsorption
•In addition to hematologic abnormalities can be associated with neurologic symptoms
Vitamin B12 is found in animal foods; deficiency can result from decreased intake (strict vegans without vitamin supplementation), or malabsorption (lack of intrinsic factor, intestinal disease).

Question 26

what is pernicious anemia?

Answer 26

Patients with pernicious anemia have autoantibodies directed against intrinsic factor. A deficiency of B12 also causes a demyelinating disorder. Absorption of Vitamin B12 requires intrinsic factor (IF), a protein produced by parietal cells of the gastric mucosa. The IF-B12 complex passes to the distal ileum where it attaches to receptors on epithelial cells and is absorbed. The absorbed B12 is bound to transcobalamins (transport protein) in plasma which deliver it to the liver and other cells via the bloodstream.

• Caused by autoantibodies to parietal cells and intrinsic factor
• B12 deficiency associated with atrophic gastritis
• Associated with loss of gastric parietal cells, achlorhydria and deficient IF

Question 27

how is b12 and folate anemia differentiated?

Answer 27

Since the megaloblastic features are indistinguishable morphologically in folate and B12 deficiencies, diagnosis is established by laboratory tests (serum B12 level, serum and RBC folate levels, presence of antibodies directed against intrinsic factor); treatment involves replenishing body stores and defining how the anemia developed.

Question 28

what causes decreased red cell production?

Answer 28

aplastic anemia

A stem cell abnormality results in marked diminution of hematopoiesis:

Question 29

what is aplastic anemia?

Answer 29

: Production of all cellular elements of the blood (red cells, white cells, and platelets) is markedly decreased (pancytopenia). Over half of the cases have no known predisposing cause (idiopathic), but viruses (hepatitis), drugs (chloramphenicol) and toxins (benzene, radiation) have been implicated. Two major pathogenetic theories exist: an acquired defect in stem cell production or suppression of stem cells by T lymphocytes. Aplastic anemia must be distinguished from other causes of marrow failure. Clinical problems result from anemia (weakness, fatigue), leukopenia (infections), and decreased platelets (bleeding). Bone marrow transplantation has been successful, especially in patients less than 40 years old.

Question 30

what else cause decreased red cell production?

Answer 30

Myelophthisic Anemia

Decreased production of red cells due to replacement of marrow elements:

Question 31

what is myelophthisic anemia?

Answer 31

The normal hematopoietic cells in the marrow are crowded out by tumor (usually multiple myeloma or metastatic cancer) or fibrosis.
•Often see misshapen RBCs resembling “teardrops” on blood smear
•Platelets are often also decreased

Question 32

what is polycythemia?

Answer 32

The opposite of anemia is polycythemia, an increase in red cell mass. Relative polycythemia occurs with hemoconcentration from dehydration, vomiting, diarrhea, or excessive use of diuretics. Absolute polycythemia can be a primary or secondary phenomenon.
Stimuli which increase erythropoietin (a growth and differentiation factor for red cell precursors) can produce secondary absolute polycythemia (these include cyanotic heart disease, pulmonary disease, living at high altitude, abnormal hemoglobin, erythropoietin-producing tumor).
Primary absolute polycythemia occurs when a non-regulated (neoplastic) proliferation of red cells and myeloid cells is called polycythemia vera. This condition is a stem cell disorder and is associated with normal or low levels of erythropoietin. Polycythemia vera can cause neurologic and visual abnormalities due to sludging of red cells in capillaries. Treatment is removal of excess RBC by phlebotomy.
Erythropoietin levels are helpful in distinguishing primary from secondary cases of absolute polycythemia. Cases of secondary absolute polycythemia have increased levels of erythropoietin., where as primary absolute polycythemia has normal or suppressed levels of erythropoietin.