IUHS Student-2-Student USMLE Step 1 Recall
Hematology
Normocytic/Normochromic Anemia
Microangiopathic Hemolytic Anemia
refers to mechanical destruction (hemolysis) of red cells caused by
narrowing within the microvasculature and is seen in patients with prosthetic heart vlaves or severe calcific aortic stenosis, or in patients having disseminated intravascular coagulopathy, thrombotic thrombocytopenic purpura, or hemolytic uremic syndrome...RBCs are normocytic and normochromic...
with two nucleated RBCs per 100 white cells...called
shistocytes...low MCV...fragmented RBCs
...Aplastic Anemia
aplastic anemia is characterized as pancytopenia by (1) anemia, (2) neutropenia, and (3) thrombocytopenia...
the basis for these changes is a failure or suppression of multipotent myeloid stem cells, with inadequate production or release of the differentiated cell lines
...normocytic anemia...
65% idiopathic...
most cases of aplastic anemia of so called known eitology follow exposure to chemicals and drugs...
with some agents, the marrow damage is predictable, dose related, and, in most instances, reversible when the use of the offending agent is stopped
...best documented as know myelotoxins are benzene, chloramphenicol, alkylating agents, and antimetabolites (6-mercaptopurine, vincristine, and busulfan)
...in most cases, the pancytopenia appears as an apparent idiosyncratic reaction to very small doses of known myelotoxins (chloramphenicol) or after the use of such drugs as phenylbutazone, methylphenylethylhydantoin, streptomycin, and chlorpromazine, which are generated without effect in other individuals...
whole body irradiation is an obvious mechanism for destruction of hematopoietic stem cells...
Parvoviridae Erythrovirus also will cause transient aplastic crisis...
splenomegaly is characteristically absent
...the red cells are typically normocytic and normochromic, although slight macrocytosis is occasionally present; reticulocytosis is absent...aplastic anemia may be inherited (Fanconi's anemia) or acquired...
fanconi's anemia is a rare familial form of aplastic anemia that is characterized by multple congenital anomalies
, including hypoplasia of the kidney and spleen and hypoplastic anomalies of the bones, particularly involving the thumbs or radii...due to defective DNA repair
...AutoImmuneHemolyicAnemias
Warm AutoImmune Hemolytic Anemia - the antibodies seen in warm-antibody autoimmune hemolytic anemias react at 37C in vitro, are composed of IgG, and do not fix complement...
instead, immunoglobulin coated
red blood cells are removed by splenic macrophages that recognize the Fc portion of the immunoglobulin...these warm IgG antiboides are found in patients with malignant tumors, especially leukemia-lymphoma
; they are associated with the use of such drugs as alpha-methlydopa; and they are also found in the autoimmune disease, especiallylupus erythematous
...sperocytes may result
...positive direct Coombs' test (direct antiglobulin test [DAT])
...Cold AutoImmune Hemolytic Anemia - cold agglutinins are monoclonal IgM antibodies that react at 4-6C...
they are called agglutinins b/c the IgM can agglutinate red cells due to its large size (pentamer)...
additionally, IgM can activate complement, which may result in IV hemolysis...
mycoplasma pneumonitis and infectious mononucleosis are classically associated with cold agglutinin formation...
in contrast, cold hemolysins are seen in patients with paroxysmal cold hemoglobinuria (PCH)..these cold hemolysins are unique b/c they are biphasic antierythrocyte autoantibodies...these antibodies are IgG that is directed against the P blood group antigen...they are called biphasic b/c they attach to red cells and bind complement at low temperatures, but activation of complement does nto occur until the temperature is increased
sperocytes may result
...Intravascular Hemolysis
occurs when normal erythrocytes are damaged by mechanical injury, complement fixation to red cells, or exogenous toxic factors...
whatever the mechanism, intravascular hemolysis is manifested by (1) hemoglobinemia, (2) hemoglobinuria, (3) methemalbuminemia, (4) jaundice, and (5) hemosiderinuria...
when hemoglobin escapes into the plasma, it is promptly bound by an alpha-2 globulin (haptoglobulin) to produce a complex that prevents excretion into the urine, since the complexes are rapidly cleared by the reticuloendothelial system...
a decrease in serum haptoglobulin level is characteristically seen in all cases of intravascular hemolysis...
schistocytes are red cell fragments that indicate hemolysis, and they occur in hemolytic anemias...
Sickle Cell Disease
sickle cell disease results from a
point mutation that leads to substitution of valine for glutamic acid at the sixth position of the beta-globin chain...autosomal recessive
...
increased electrophoretic mobility at pH 7.0...
the resultant hemoglobin, HbS, has abnormal physiochemical properties that lead to sickle cell disease...
about 8% of black americans are heterozygous for HbS...
if an individual is homozygous, his/her hemoglobin in the erythrocyte is all HbS...
if an individual is heterozygous, then about 40% of hemoglobin is HbS...
sickle cell disease offers protection against falciparum malaria...
Howell-Jolly bodies
are remnants for nuclear chromatin and can be seen in the peripheral blood of individuals with severe anemia...Isolation of DNA from blood leukocytes followed by PCR amplification and allele specific oligonucleotide (ASO) hybridization
allows for detection of sickle cell diseae in the newborn...on deoxygenation, the HbS molecules undergo aggregation and polymerization
...this change converts hemoglobin from a freely flowing liquid to a viscous gel, leading to formation of HbS fibers and resultant distortion of the red cells, which acquire a sickle or holly-leaf shape...a
chronic hemolytic anemia and occlusion of small blood vessels, resulting in ischemic tissue damage...irreversibly sickled cells have rigid and nondeformable cell membranes and have difficulty in negotiating the splenic sinusoids...they become sequestered in the spleen, where they are destroyed by the mononuclear phagocyte system...
some
intravascular hemolysis may also occur because of increased mechanical fragility of the severely damaged cells...
the average red cell survival correlates with the percentage of irreversible sickled cells in circulation and is shortened to approximjately 20 days...
this finding supports the concept that the hemolysis results primarily from the lysis of irreversibly sickled cells...
chronic hemolytic anemia leads to chronic hyperbilirubinemia (jaundice), which leads to pigmented gallstones
...vascular occlusion results in leg ulcers, renal papillary necrosis, and multiple infarcts, which may cause severe bone pain...severe anemia, vaso-occlusive complications, and chronic hyperbilirubinemia...
the
spleen becomes small and shrunken due to multiple infarctions...increased susceptibility to infections is another threat, the basis of which is multifactorial: splenic function is impaired b/c erythrophagocytosis interferes with the ability of the spleen to clear bacteria, in later stages, total splenic fibrosis removes and important filter of blood borne microorganisms, and defects in the alternative complement pathway
impair opsonization of encapsulated bacteria such as pneumococci and haemophilus influenzae...septicemia and meningitis caused by these two organisms are the most common causes of death in children with sickle cell anemia...
Hemoglobin C has glutamic acid replaced by valine in the sixth position...
the metabisulfite test
is used to detect the presence of hemoglobin S, but it does not differentiate the herterozygous sickle cell trait from the homozygous sickle cell disease...the test is based on the fact that erythrocytes with a large proportion of hemoglobin S sickle in solutions of low oxygen content...metabisulfite is a reducing substance that enhances the process of deoxygenation...bone marrow becomes hyperplastic, with marked increases in the number of normoblasts (erythroblasts) and a
marked increase in RBC precursors and iron stores...G6PD_Deficiency
the erythrocyte and its membrane are vulnerable to injury by exogenous and endogenous oxidants...
abnormalities in the hexose monophosphate shunt or in glutathione metabolism resulting from
deficient or impaired enzyme function reduce the ability of red cells to protect themselves against oxidative injuries and lead to hemolytic disease...the most important of these enzyme derangements is a hereditary deficiency of glycose-6-phosphate dehydrogenase activity...
G6PD reduces NADP to NADPH while oxidizing glucose-6-phosphate...NADPH then provides the reducing power that converts oxidized glutathione to reduced glutathione...the reduced glutathione so generated of oxidant compounds like H2O2...Heinz bodies...
glutathione production is abnormal...
G6PD serves to protect the RBC from oxidative damage by maintaining high intracellular levels of NADPH...
the most common normal form is called G6PD B...
two variants, G6PD A- and G6PD mediterranean, lead to clinically significant hemolysis...
the A- type is present in about 10% of american blacks; G6PD mediterranean, as the name implies, is found largely in populations in the middle east...
Heinz bodies...
glutathione production is abnormal...
X-linked disorder...50% chance of mother passing the defect to offspring, if first child has already contracted the disease...
the enzyme activity is normal in reticulocytes, but older red cells are markedly deficient...exposure to oxidants, therefore, induces
hemolysis of older red cells but not of younger ones...the recent elucidation of the crystal structure of G6PD has provided insights into the basis of reduced stability...
the disease associated mutations result in a
loss of normal folding of the G6PD protein; b/c the unfolded forms are susceptible to proteolytic degradation, they have a shorter half-life...thus, G6PD deficiency, along with alpha-1 antitrypsin deficiency, belongs to a group of diseases in which
defective folding of the proteins lies at the heart of the disorder...the most common of which is
hemolysis after exposure to oxidant stress...this may occur after ingestion of certain drugs or even more commonly by exposure to oxidant free radicals generated by leukocytes in the course of infection...the oxidant drugs implicated in the causation of hemolysis are numerous...they include the
antimalarials primaquine and chloroquine, sulfonamides, nitrofurantions, and others...like Dapsone, treating leprosy...infections such as viral hepatitis, pneumonia, and typhoid fever...
patients with G6PDdeficiency may also present with
hemolysis after ingestion of fava beans...b/c the legumes generate oxidants, much in the same way as oxidant drugs do...infection or exposure to oxidants causes
oxidation of the sulfhydryl groups of the globin chains...this leads to denaturation of hemoglobin and formation of precipitates
(Heinz bodies) that can be seen within the red cells as dark inclusions when they are stained with crystal violet...these precipitates of denatured hemoglobin may damage the membrane sufficiently to
cause intravascular hemolysis...in addition, when attached to the cell membrane,
Heinz bodies decrease erythrocyte deformability...as the inclusion bearing red cells pass through the splenic cords,
macrophages pluck out the Heinz bodies, giving rise to red cells that appear to have a bite of cytoplasm removed ("bite cells")....indirect bilirubin is increased, direct bilirubin is normal, and urinary bilirubin is absent
...Hereditary Spherocytosis
this inherited disorder is
characterized by an intrinsic defect in the red cell membrane that renders erythrocytes spheroidal, less deformable, and vulnerable to splenic sequestration and destruction...
75% autosomal dominant
25% autosomal recessive (severe type)
spectrin
, the major protein of the membrane cytoskeleton, is a two dimensional spectrin cable meshwork so formed is tethered to the inner surface of the cell membrane by ankyrin and protein 4.1...ankyrin forms a bridge between spectrin and the transmembrane ion transported, called band 3, whereas protein 4.1 connects spectrin to glycophorin A...together these proteins are responsible for maintenance of the normal shape, strength, and flexibility of the red cell membrane...
a deficiency of spectrin seems to be the most common biochemical abnormality with all forms of HS...
mutations seen in HS act to diminish "vertical" interactions that serve to connect the membrane cytoskeleton to the overlying lipid bilayer...
the common autosomal dominant from of HS is caused most frequently by a mutation in the ankyrin gene...
regardless of the primary molecular defet, spectrin
deficiency is associated with reduced membrane stability and loss of membrane
fragments as the cells are exposed to shear stresses in the circulation...
lactic acid accumulates and the extracellular pH falls, which in turn inhibits glycolysis and generation of adenosine triphophate (ATP)...loss of ATP impairs the ability to extrude sodium, adding an element of osmotic injury...
stagnation in the cords also promotes contact with macrophages, which are plentiful, and eventually the hapless spherocytes fall prey to the appetite of phagocytic cells...
the cardinal role of the spleen in the premature demise of the spherocytes is proved by the invariably beneficial effect of splenectomy...
anemia,
splenomegaly, and jaundice...gallstones
, found in many patients, may also produce symptoms...the Osmotic fragility test is a diagnostic test for hereditary spherocytosis...spherocytes lyse at a higher concentration of salt than do normal cells, thus causing an increased osmotic fragility...
Paroxysmal Nocturnal Hemglobinuria (PNH)
PNH is an acquired clonal stem cell disorder that is characterized by
abnormal red cells, granulocytes, and platelets...the red blood cells (RBCs) are abnormally sensitive to the lytic activity of complement due to a
deficiency of glycosyl phosphatidyl inositol (GPI) linked proteins, namely decay accelerating factor (DAF, or CD55), membrane inhibitor of reactive lysis (CD55) or CD59 (a C8 binding protein)...complement is normally activated by acidotic states, such as occur with exercise or sleep...in patients with PNH, the acidotic condition that develops during sleep (which is usually at night) causes hemolysis of red blood cells and results in
red urine in the morning
...the erythrocytes of these patients lyse in vitro with acid (
Ham's Test) or sucrose (sucrose lysis test)...complications of PNH include the development of
frequent thromboses, particularly of the hepatic, portal, or cerebral veins...since PNH is a clonal stem cell disorder, patients are at an
increased risk of developing aplastic anemia or acute leukemia...elevated urine hemosiderin level.
..