Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
238 Cards in this Set
- Front
- Back
|
where does embryonic hematopoiesis take place? |
in the liver
starts in the third gestational month and continues until shortly before birth |
|
|
when does bone marrow hematopoiesis begin?
|
starts in the fourth month of development; all marrow stays red and active until puberty
the bone marrow is the major producer of blood cells at birth significant amounts of extramedullary hematopoiesis is abnormal in a full-term infant |
|
|
how does marrow change from childhood into adulthood?
|
until puberty, all marrow is red and active
in adults, about half is still active (ribs, sternum, pelvis, skull, vertebrae, proximal epiphyseal areas of the humerus and femur) |
|
|
what happens if the blood cell requirements exceed the capabilities of the axial skeleton?
|
fatty marrow can be transformed to red on increased demand
given adequate stimulation, marrow erythropoiesis can increase 8x after this increase, the liver, then the spleens, and then nodes can begin producing (extramedullary hematopoiesis) |
|
|
what cells give rise to rbcs, wbcs, and platelets?
|
pluripotent hematopoietic stem cells
first differentiation is into lymphoid stem cells or common myeloid (trilineage) stem cells |
|
|
lymphoid stem cells
|
arise from pluripotent hematopoietic stem cells
give rise to pro-T cells, pro-B cells, and pro-NK cells (there are no distinctive morphological changes, so differentiation antigens are found with monoclonal antibodies) |
|
|
common myeloid stem cells
|
arise from pluripotent hematopoietic stem cells
give rise to erythroid/megakaryocyte, granulocyte/macrophage, and eosinophilic colony forming units (CFUs) |
|
|
where do hematopoietic stem cells reside?
|
mostly in the bone marrow, but a subset resides in peripheral blood
environment in marrow fosters stem cell homing, survival, and differentiation |
|
|
why can bone marrow transplants be given in peripheral blood?
|
the stem cells given in the bone marrow will tend to home to the bone marrow
|
|
|
what happens if circulating marrow-derived stem cells seed tissues other than the marrow?
|
develops into non-hematopoietic cells
best characterized conversion is differentiation into endothelial cells precursors more controversial conversions are those into liver, myocardium, skeletal muscle glia, and neurons may be caused by fusion of the marrow stem cells with other mature cell types |
|
|
what is provided by bone marrow?
|
stem cells and the microenvironment in which they differentiate
|
|
|
morphology of bone marrow
|
network of thin-walled sinusoids lined with a single layer of endothelial cells and a discontinuous basement membrane
between sinusoids are clusters of hematopoietic and fat cells |
|
|
how do mature blood cells enter the bloodstream from the bone marrow? how does this differ from extramedullary hematopoiesis
|
enter sinusoids and undergo transcellular migration thru endothelial cells
in extramedullary hematopoiesis, cells in all stages of maturity are released |
|
|
how does the normal fat:cell ratio vary with age?
|
80:20 in infancy
50:50 in adulthood 30:70 at age 75 |
|
|
what is a normal myeloid:erythroid ratio in an adult?
|
ranges from 1.5:1 to 5:1
more mature forms dominate |
|
|
what is the normal blood cell differential in the bone marrow?
|
granulocytes: 65%
erythroid: 25% lymphocytes/monocytes: 10% |
|
|
anemia
|
technically, a reduction of total circulating red cell mass below normal limits
in practice, given as a reduction of rbcs, as measured by hemoglobin or hematocrit below normal limits |
|
|
besides loss of red blood cells, what can cause spurious abnormalities in hemoglobin or hematocrit?
|
abnormalities in plasma volume
|
|
|
signs/symptoms of significant anemia
|
- pallor, esp. of mucous membranes
- weakness/easy fatigue - dyspnea on mild exertion - brittle/concave nails (koilonychia) - fatty change in organs b/c of anoxia (only in long-standing anemia) - if severe, cardiac failure or angina can occur b/c of myocardial hypoxia - headache or faintness b/c of CNS hypoxia - shock/oliguria/anuria b/c of acute blood loss |
|
|
anemia caused by acute blood loss
|
clinical and morphologic changes depend on rate of loss and whether the loss is internal/external
alterations are more of a reflection of loss of blood volume than of hemoglobin |
|
|
why is hematocrit lowered in acute blood loss?
|
blood loss causes a compensatory shift of fluid from the interstitium to the circulation
hemodilution lowers the hematocrit |
|
|
how is erythropoietin synthesis stimulated in acute blood loss?
|
reduction in oxygenation of tissues stimulates erythropoietin, with subsequent erythropoiesis
|
|
|
after an acute hemorrhagic event, when do reticulocytes begin being released from bone marrow
|
5 days after the acute blood loss
|
|
|
how does anemia differ between internal and external acute blood loss?
|
if blood loss is internal, iron can be recycled
if blood loss is external, insufficient iron reserves can hamper recovery |
|
|
what should be suspected if a male or post-menopausal female with an iron deficiency?
|
GI bleed or cancer
|
|
|
morphology of acute blood loss anemia
|
immediate anemia is normochromic and normocytic
as the marrow responds, there is an increase in reticulocytes (reticulocytosis) up to 10-15% after a week (normal is 0.5-1.5) platelets and granulocytes are also released immediately after acute loss causing thrombocytosis and granulocytosis |
|
|
histologic appearance of reticulocytes
|
immature, non-nucleated rbcs containing RNA
polychromatophilic macrocytes dark blue network of granules (precipitates of RNA drawn out by new methylene blue) |
|
|
anemia due to chronic blood loss
|
in chronic blood loss, anemia is only present when the regenerative capacity or iron reserves are depleted
clinically, the picture is similar to an increased demand for reserves (i.e. pregnancy) |
|
|
what are the features of hemolytic anemia?
|
1) premature destruction of rbcs
2) accumulation of products of hemoglobin catabolism 3) increased erythropoiesis in attempt to compensate for rbc loss normally, old red blood cells are destroyed in the spleen via mononuclear phagocytes; in most hemolytic anemias there is also destruction in the spleen (extravascular hemolysis) and patients may have varying degrees of splenomegaly b/c of hyperplasia of phagocytes |
|
|
intravascular hemolysis
|
less common than extravascular hemolysis (destruction of rbcs via mononuclear phagocytes in the spleen)
red blood cells are damaged by mechanical injury (stress to rbcs as they navigate around prosthetic valves or thrombi in microcirculation), complement fixation to rbcs (transfusion of incompatible blood) or exogenous toxins (clostridial sepsis or malaria) pts DON'T have splenomegaly |
|
|
what are the manifestations of intravascular hemolysis?
|
1) hemoglobinemia
2) methalbuminemia 3) hemoglobinuria & methemoglobinuria 4) jaundice 5) hemosiderinuria |
|
|
why does intravascular hemolysis cause hemoglobinemia?
|
decreases haptoglobin, an alpha-2 globulin that binds free hemoglobin
the complex of haptoglobin and hemoglobin is cleared by the reticuloendothelial system the decrease in haptoglobin is characteristic of intravascular hemolysis |
|
|
why does intravascular hemolysis cause methalbuminemia?
|
when haptoglobin is depleted, hemoglobin is partially oxidized to methemoglobin resulting in hemoglobinuria and methemoglobinuria
|
|
|
why does urine turn red-brown in patients with intravascular hemolysis?
|
haptoglobin is destroyed, so free hemoglobin concentration is increased
hemoglobin is cleared by phagocytes where the heme is converted to unconjugated bilirubin in a normal liver the bilirubin is conjugated, but in a bad liver the bilirubin remains unconjugated and jaundice remains |
|
|
what type of hemoglobin is more toxic to tissues?
|
unconjugated (indirect) bilirubin is more toxic than conjugated (direct) bilirubin
|
|
|
why does intravascular hemolysis cause hemosiderinuria and hemosiderosis of the tubular epithelium?
|
proximal tubular cells resorb and catabolize some filtered hemoglobin
some of the catabolized iron gets into the urine (hemosiderinuria) and some accumulates within the tubular cells (causing the hemosiderosis) |
|
|
extravascular hemolysis
|
injured rbcs are rendered foreign or become less deformable (as in sickle cells or hereditary spherocytosis)
no hemoglobinemia/uria or associated changes anemia, jaundice, and splenomegaly dominate the clinical picture some hemoglobin does escape into the circulation from spleen, so that haptoglobin is decreased as it binds with the hemoglobin splenomegaly is the result of hypertrophy of the splenic mononuclear phagocytic system |
|
|
morphology of hemolytic anemias (intra- or extra-vascular)
|
increased number of normoblasts (normal sized nucleated red blood cells; erythroid precursors) in the marrow
anemia and hypoxia stimulate erythropoietin and if the anemia is severe enough, stimulates extramedullary hematopoiesis reticulocytosis in peripheral blood unconjugated hyperbilirubinemia if chronic, hemosiderosis of mononuclear phagocytic system is seen |
|
|
why do patients with hemolytic anemia commonly develop gallstones?
|
pts with hemolytic anemia commonly develop pigment-type gallstones (cholelithiasis) because the concentration of hemoglobin in the blood is increased, which can lead to the formation of gallstones
|
|
|
what are the classifications of hemolytic anemia?
|
intravascular hemolysis
extravascular hemolysis extrinsic hemolysis intrinsic hemolysis |
|
|
extrinsic hemolysis
|
subdivision of hemolytic anemia in which the red blood cell destruction is caused by an extracorpuscular mechanism, like trauma or antibodies
mostly caused by acquired defects |
|
|
intrinsic hemolysis
|
subdivision of hemolytic anemia in which the red blood cell destruction is caused by an intracorpuscular mechanism (a defect that is inherent in the rbcs)
mostly caused by inherited defects |
|
|
hereditary spherocytosis
|
intrinsic defect in rbc membrane caused by defects in the spectrin complex (spectrin is the major protein of the rbc membrane cytoskeleton), which causes the cells to be spheroidal, less deformable, and subject to splenic sequestration
more common in a northern european lineage (1 in 5000 ppl) 75% of cases are AD, but the AR form causes a much more severe anemia |
|
|
pathogenesis of hereditary spherocytosis
|
most common molecular abnormality in AD form is a mutation in the ankyrin gene
20% of the AD form has a mutation in the band 3 gene AR form has a mutation in alpha-spectrin (this causes a more severe anemia) compound heterozygosity for 2 defective alleles causes more severe membrane deficiency in all forms there is reduced membrane stability and loss of membrane fragments as cells are exposed to shear stress in the circulation; reduction in cell surface forces rbc to assume smallest possible diameter for a given volume (a sphere) spherocytes cannot deform properly to enter sinusoids in the spleen so they get trapped which causes sluggish circulation slowed circulation causes accumulation of lactic acid, causing pH to decrease and inhibition of glycolysis; lack of ATP production injures the Na pump; since the cell is in contact with splenic macrophages for so long, it gets phagocytosed |
|
|
what is the normal structure of the spectrin complex?
|
spectrin has alpha and beta chains intertwined into a flat, two-dimensional network; multiple spectrin tetramers bind to actin oligomers
the complexes connect to the cell membrane via: 1) ankyrin and band 4.2 proteins bind spectrin to the transmembrane ion transporter, band 3 2) protein 4.1 binds the tail of spectrin to the transmembrane protein, glycophorin A |
|
|
morphology/lab studies in hereditary spherocytosis
|
spherocytes (small rbcs with no central pallor) are a necessary finding, though they aren't pathognomonic
reticulocytosis to compensate for destroyed cells increased osmotic fragility (in 2/3 of pts, the spherocytes will lyse on exposure to hypotonic salt solution b/c the cell has little reserve to expand w/o rupturing) increased mean cell hemoglobin concentration (MCHC) more severe splenomegaly than that caused by other hemolytic anemias (caused by erythrophagocytosis in the congested cords) |
|
|
clinical features of hereditary spherocytosis
|
mild-moderate anemia, splenomegaly, jaundice
variable severity from needing transfusion at birth to asymptomatic (20-30%) if bone marrow is able to compensate usually pts have hypercellularity of bone marrow, but can have aplastic crisis b/c of marrow suppression (e.g. by parvovirus) can have hemolytic crisis from accelerated rbc destruction, but not as significant as aplastic crises splenectomy is beneficial, but not curative black/brown pigment-type gallstones found in 40-50% of affected pts |
|
|
why is parvovirus so dangerous to patients with hereditary spherocytosis?
|
parvovirus preferentially infects nucleated rbcs
infection decreases the life span of the rbcs from 120 days to 10-20 days so that even transient suppression is important causes aplastic crisis b/c of bone marrow suppression |
|
|
what is the most important of the enzyme deficiencies involving the hexose monophosphate shunt or of glutathione metabolism?
|
glucose-6-phosphate dehydrogenase deficiency
deficiencies render the rbc vulnerable to oxidative injuries leading to hemolytic anemia |
|
|
what are the normal functions of G-6-PDH?
|
secondary function is to reduce NADP to NADPH while oxidizing G6P
NADPH converts oxidized glutathione to the reduced form, which is protective against oxidative injury |
|
|
pathogenesis of G6P dehydrogenase deficiency
|
there are hundreds of G6PDH variants, most cousing no hemolysis (G6PDH B is most common normal variation)
variants G6PD- and G6PD Mediterranean have clinically significant hemolytic anemia (more severe in the latter) these mutations don't affect synthesis of G6PDH, but affect its stability (defective folding of protein makes it more susceptible to degradation), so activity in reticulocytes is normal but activity in older cells is markedly deficient drugs, fava beans, or generation of free radicals by wbcs in infection can cause intra- and extra-vascular hemolysis |
|
|
what is the most severe genetic abnormality in G6PDH deficiency?
|
G6PDH Mediterranean variant
|
|
|
what is the inheritance pattern of G6PDH deficiency?
|
X-linked inheritance
- in males, all rbcs are affected - in heterozygous females, there are two cell populations (normal and deficient b/c of random inactivation of X chromosome) |
|
|
what are the patterns of disease presentation for G6PDH deficiency?
|
most commonly presents as hemolysis after exposure to oxidant stress caused by:
- fava beans - antimalarials* - sulfonamides* - nitrofurantoin* - hepatitis - pneumonia - typhoid * = G6PDH- genotype may not be affected, but G6PDH Mediterranean genotype is affected |
|
|
what infections are especially notorious for causing hemolysis in G6PDH deficiency?
|
hepatitis
pneumonia typhoid |
|
|
describe the hemolysis in G6PDH deficiency
|
hemolysis is both intra- and extra-vascular
a trigger causes x-linking of sulfhydryl groups on global chains, leading to formation of precipitates called Heinz bodies that stain with crystal violet precipitates damage membrane enough to cause intravascular hemolysis; with less damage only a decrease in deformability is caused and as the cell goes through the spleen the area with the Heinz body is bitten out (extravascular hemolysis) "bite cells"=remainder of G6PDH deficient cells after splenic phagocytes have removed the portion that has a Heinz body; after removal of the Heinz body the cell turns into a spherocyte |
|
|
what is a Heinz body?
|
inclusions within red blood cells composed of denatured hemoglobin
seen in: - NADPH deficiency, which causes glutathione peroxidase dysfunction - G6PDH deficiency - chronic liver disease |
|
|
clinical features/lab findings of G6PDH deficiency
|
pt usually is not anemic until they are exposed to a trigger (e.g. fava beans, drugs, or infection)
after the trigger, there is a 2-3 day lag before there is acute intravenous hemolysis (leads to hemoglobinemia/uria and decreased hematocrit) the hemolytic episode is self-limited since it stops when old cells are destroyed and only young ones are left in the circulation in a blood smear you see spherocytes, bite cells, and Heinz bodies in the early par of the attack |
|
|
what is the prototype of the hereditary hemogobinopathies?
|
sickle cell disease (anemia and trait)
|
|
|
sickle cell disease (anemia and trait)
|
prototypical hereditary hemoglobinopathy, that results from production of a structurally abnormal hemoglobin, called HbS (caused by a point mutation that substitutes valine for glutamic acid at the 6th position on the beta-globin chain)
on deoxygenation, HbS undergoes aggregation and polymerization, converting hemoglobin from a liquid to a gel to HbS fibers; causes sickling of red blood cell shape which is initially reversible with oxygenation with repeated episodes of deoxygenation the membrane is damaged and the cell will irreversibly sickle despite the deaggregation of HbS |
|
|
what causes clinically significant hemoglobinopathies?
|
mutations in the beta-globin gene
|
|
|
normal hemoglobin
|
four globin chains, each with its own heme group
normal adult composition: - HbA - 96% - HbA2 - 3% - HbF - 1% (most adults do not have this) |
|
|
what genotypical abnormalities determine the rate and degree of sickling in patients with sickle cell anemia?
|
amount of HbS and its interaction with other Hb chains
heterozygotes have only 40% HbS, which interacts only weakly with the remaining HbA, so that there is little sickling unless there is severe hypoxia (sickle cell trait) homozygotes have 100% HbS, so there is sickling with even a slight deoxygenation heterozygosity for HbS and HbC (HbSC) causes more severe aggregation of HbS than does HbA (more severe than HbSA) |
|
|
why does sickle cell anemia not present/manifest until 5-6 months of age?
|
HbF inhibits polymerization of HbS more than HbA does
disease manifests at 5-6 months when HbA replaces HbF |
|
|
what happens to deoxygenated cells with HbS present?
|
sickling
precipitation of HbS fibers, which damages the membrane in both sickled and normal-appearing cells these cells lose K+ and H2O but gain calcium; they lose volume and have increased intracellular hemoglobin conc. so they are dehydrated and dense |
|
|
what factors determine the rate and degree of sickling in patients with sickle cell anemia?
|
1) amount of HbS and its interaction with other Hb chains
2) Hb concentration per cell (MCHC) - higher the conc. the more apt to sickle 3) pH - decrease in pH reduces O2 affinity of Hb and enhances amt of deoxygenated HbS, augmenting sickling 4) duration of hypoxia |
|
|
what is the effect of MCHC on HbS polymerization?
|
the higher the MCHC, the more apt the cells are to sickle
dehydration favors sickling of cells combination of sickle cell and alpha-thalassemia gives milder disease, since there is reduced globin synthesis in thalassemia which limits Hb concentration/cell |
|
|
what is the effect of duration of hypoxia on HbS cell sickling?
|
sickling is usually confined to microvascular beds where the flow is sluggish (esp. in the spleen and marrow)
in other vascular beds, inflammation and inc. rbc adhesion to the endothelium causes longer transit time sickled cells also have increased expression of adhesion molecules so they're more likely to stick to the endothelium than are normal rbcs |
|
|
what are the consequences of sickle cell anemia?
|
chronic hemolytic anemia
- b/c the sickle cells are rigid, many are trapped/destroyed in the spleen - b/c of fragility of damaged cells, they are destroyed intravascularly - rbc survival correlates with % of irreversibly sickled cells - avg life of rbc dec. to 20 days occlusion of small vessels, with ischemic damage to tissue - unrelated to number of irreversibly sickled cells - related to membrane abnormalities that create increased expression of adhesion molecules on sickle cells - leukocytosis correlates with freq. of pain crises - vicious cycle of sickling, obstruction, hypoxia, more sickling |
|
|
why can NO be used as a Tx for sickle cell pain crises?
|
when the sickled cells finally lyse, they release hemoglobin which binds to and inactivates NO
|
|
|
what is seen in a peripheral blood smear of a pt with sickle cell anemia/trait?
|
normochromic, normocytic anemia
5-15% of rbcs will be irreversibly sickled target cells and Howell-Jolly bodies in older children/adults due to asplenia reticulocytosis |
|
|
what are Howell-Jolly bodies?
|
round remnants of chromatin (stain blue) inside of rbcs
found in: - sickle cell disease - megaloblastic anemias - hemolytic anemias - pts who have had splenectomy |
|
|
what is seen in the bone marrow of pts with sickle cell disease?
|
normoblastic hyperplasia of rbcs and increased iron stores in an attempt to compensate for the anemia
expansion of bone marrow with resorption of bone and secondary new bone formation creates a "crew-cut" appearance on Xray of the skull less often, see extramedullary hematopoiesis if marrow expansion is not sufficient |
|
|
what is seen in the spleen of pts with sickle cell disease?
|
enlarged in children up to 500gm with congestion of red pulp
by adulthood, spleen auto-infarcts caused by repeated congestion, stasis, and thrombotic episodes (auto-splenectomy) can have infarction of other organs secondary to vascular occlusion |
|
|
clinical problems associated with sickle cell disease
|
- anemia
- hyperbilirubinemia - increased susceptibility to infections - chronic tissue hypoxia - vaso-occlusive crises - aplastic crises - sequestration crises - priapism in males - pigment-type gallstones |
|
|
why do sickle cell pts. have increased susceptibility to infections?
|
auto-splenectomy caused by cycles of congestion, stasis, and thrombosis that lead to splenic infarcts
defects in alternate complement pathway impairs opsonization of encapsulated bacteria (pneumococcus and Haemophilus) |
|
|
what are the two most common causes of death in kids with sickle cell anemia?
|
septicemia
meningitis |
|
|
what are the most common sites of vaso-occlusive crises in pts with sickle cell anemia?
|
bone
lungs liver brain spleen penis |
|
|
in children with sickle cell anemia, what is often difficult to distinguish from the vaso-occlusive crises?
|
in children, vaso-occlusive crises often occur in bone
they may be difficult to distinguish from osteomyelitis (caused by salmonella), which is also a risk of pts with sickle cell disease |
|
|
what is hand-foot syndrome?
|
presentation of vaso-occlusive crises in sickle cell disease patients that are younger than 4
bilateral painful swelling of dorsa of hands and feet see periostitis on Xray (aka sickle dactylitis) |
|
|
acute chest syndrome
|
presentation of vaso-occlusive crises in sickle cell disease patients
sickling in pulmonary vasculature compromises pulmonary function with resultant systemic hypoxemia, sickling, and vaso-occlusion presents as a fever, cough, chest pain, pulmonary infiltrate, and potentially death may be triggered by infection |
|
|
what are the CNS complications of sickle cell vaso-occlusive crises?
|
seizures
strokes |
|
|
what are the skin complications of sickle cell vaso-occlusive crises?
|
leg ulcers
|
|
|
what are the complications of chronic tissue hypoxia caused by sickle cell vaso-occlusive crises?
|
impairment of growth and development
organ damage - renal medulla can't concentrate urine, so the pts are prone to dehydration |
|
|
what is a sickle cell aplastic crisis?
|
temporary cessation of bone marrow activity
usually caused by parvovirus presents as sudden, rapidly worsening anemia |
|
|
what is a sickle cell sequestration crisis?
|
acute, painful, rapid enlargements of the spleen in patients with sickle cell disease; can cause hypovolemia, and shock
seen in children with splenomegaly |
|
|
what is priapism?
|
erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours
|
|
|
how is diagnosis of sickle cell disease made?
|
clinical findings
peripheral smear Hb electrophoresis sickle cell test |
|
|
what is the sickle cell test?
|
mix blood with an oxygen-consuming agent (metabisulfite) which decreases the oxygen concentration and induces the sickling of rbcs
|
|
|
what is the prognosis for pts with sickle cell disease?
|
90% survive into their 20s
50% survive beyond their 40s Tx: hydroxyurea (inhibitor of DNA synthesis) - increases HbF, which causes fewer sickle crises - anti-inflammatory properties (inhibits wbc production) - increases mean cell volume (MCV), which decreases HbS conc. - oxidized to produce NO |
|
|
what are thalassemias?
|
lack of or decreased synthesis of one of the globin chains, which decreases synthesis of HbA
|
|
|
beta-thalassemia
|
lack of or decreased synthesis of beta-globin
beta^0 = total absence of beta-globin in homozygous state beta^+ = reduced synthesis of beta-globin in homozygous state |
|
|
what is the molecular pathogenesis of beta-thalassemia?
|
beta-globin gene is found on chromosome 11 (there are about 100 mutations cause beta-thalassemia, mostly point mutations)
- mutations in promoter regions reduce the transcription rate, which causes beta^+ - chain terminator mutations produce non-functional beta-globin fragments (beta^0) - mutations causing aberrant splicing are the most common (if in the normal splice junctions there is no splicing and all mRNA is abnormal and degraded in the nucleus - beta^0; if in introns away from the splice jcn there is a mix of normal and abnormal beta globin mRNA - beta^+) |
|
|
what is the macroscopic pathogenesis of beta-thalassemia?
|
lack of adequate HbA formation, so MCHC is low
cells are hypochromic and microcytic (O2 carrying capacity is decreased) relative excess of alpha-globin chains (unstable aggregates form that ppt into insoluble inclusions) inclusion-bearing cells that get out of marrow are at risk for splenic sequestration or destruction (extravascular hemolysis) |
|
|
what does microcytic mean? macrocytic? normocytic?
|
microcytic: cells are smaller than normal
macrocytic: cells are larger than normal normocytic: cells are the same size as normal |
|
|
what does hypochromic mean? hyperchromic? normochromic?
|
hypochromic: color is more pale than normal
hyperchromic: color is darker than normal normochromic: color is normal |
|
|
why does beta-thalassemia cause ineffective erythropoiesis?
|
cell membrane is damaged with resultant apoptotic death of rbc precursors in the bone marrow
the fate of 70-80% of marrow normoblasts undergo apoptosis in severely affected pts |
|
|
what is caused by the marked anemia in patients with severe thalassemia?
|
erythropoietin secretion with erythroid hyperplasia in the marrow and extramedullary hematopoiesis (pts can develop skeletal problems due to the marrow expansion)
excessive absorption of dietary iron since ineffective erythropoiesis suppresses hepcidin (negative regulator of Fe absorption); in addition to iron accumulation from transfusions, pt gets iron overload & resultant organ damage , esp. to liver/heart RBC progenitors "steal" nutrients from other tissues, which can result in severe cachexia |
|
|
what are the syndromes associated with beta-thalassemia?
|
homozygous - beta^+,+ or beta^+,0 or beta^0,0 - have severe, transfusion-dependent anemia - aka beta-thalassemia major
heterozygous - beta^+,n or beta^0,n - have only mild anemia which may be asymptomatic - aka beta-thalassemia minor or trait beta-thalassemia intermedia - genetically heterogeneous milder variants of beta^+,+ or beta^+,0 - intermediate anemia, but doesn't require transfusions n= normal/nonmutated gene locus |
|
|
beta-thalassemia major
|
common in the Mediterranean, parts of Africa, and SE Asia; in U.S. the highest proportion are seen in immigrants from those areas
beta^+,+ or beta^0,0 or beta^+,0 manifests at 6-9 months when the infant stops producing HbF pts have severe, transfusion-dependent anemia |
|
|
morphology of beta-thalassemia major
|
Hb is 3-6gm/dL without transfusion
in peripheral smear, see marked anisocytosis (size variation) and poikilocytosis (shape variation), with many hypochromic and microcytic cells, target cells, schistocytes, basophilic stippled cells, reticulocytosis (though lower than expected for degree of anemia), and a variable number of normocytic rbcs with poor hemoglobinization little/no HbA with HbF markedly increased; HbA2 is variable expansion of bone marrow creates crew-cut skull x-ray marked hepatosplenomegaly (spleen may be 1500gm in adults) hemosiderosis or secondary hemochromatosis from Fe-overload |
|
|
clinical features of beta-thalassemia
|
transfusion is necessary to supply blood and suppress secondary effects of excess erythropoiesis (skeletal changes)
cardiac disease from Fe-overload is frequently a cause of death need to give iron chelators survive into 3rd decade with Tx only cure is bone marrow transplant from HLA identical sibling w/o severe thalassemia |
|
|
beta-thalassemia minor
|
heterozygous (beta^+,n or beta^0,n)
pt presents with mild, maybe asymptomatic anemia in the peripheral smear, see: - hypochromic, microcytic rbcs - basophilic stippling and target cells - can be confused with Fe-deficiency anemia, but giving iron can aggravate anemia in thalassemia mild marrow hyperplasia with increase in HbA2 (4-8%; normal is 2.5%) and variable change in HbF much more common than other types of beta-thalassemia common in the Mediterranean, in parts of Africa, and in SE Asia |
|
|
alpha-thalassemias
|
normally there are 4 alpha-globin genes, but pts with alpha-thalassemia have excess unpaired gamma-globin chains forming gamma4 tetramers (Hgb Barts)
in adult, excess beta-globin chains form tetramers of HbH non-alpha chains are more soluble, so diseases are not as severe as the corresponding beta-thalassemia most common cause is deletion of alpha-globin genes alpha-globin genes are in linked pairs on each of the copies of chromosome 16; each gene makes 25% of the chains - any one can be deleted independent of the others |
|
|
silent carrier of alpha-thalassemia
|
genotype: -a/aa
minimal decrease in synthesis no anemia slight microcytosis |
|
|
alpha-thalassemia trait
|
genotype: --/aa or -a/-a
(difference determines chances that offspring's chances of developing, but is indifferent to pt's symptoms) deletions on same chromosome (asian) or one on each chromosome (african) mild, maybe asymptomatic anemia or no anemia mild marrow hyperplasia peripheral smear: - hypochromic, microcytic rbcs - basophilic stippling and target cells - can be confused with Fe-deficiency anemia (giving Fe supplements can aggravate anemia in thalassemia) |
|
|
HbH disease
|
genotype: --/-a
mainly seen in Asians formation of beta tetramers (HbH) which has a very high affinity for O2 and is not very useful for O2 exchange anemia is disproportionately bad compared to level of Hb oxidized HbH forms precipitates, so older cells are destroyed in the spleen (these precipitates can be seen with brilliant cresyl blue) moderately severe anemia, resembling beta-thalassemia intermedia |
|
|
hydrops fetalis
|
genotype: --/--
in fetus, have Hb Barts which has an extremely high O2 affinity so there is no delivery to tissue fetus survives early intra-uterine life b/c of embryonic Hb, but fetal distress around the third trimester of pregnancy used to be lethal in utero, but now can do an intrauterine transfusion and bone marrow transplant after birth severe anemia, clinically like erythroblastosis fetalis |
|
|
paroxysmal nocturnal hemoglobinuria
|
rare clonal disorder of stem cells that usually presents in young adults
caused by acquired mutation in phosphatidylinositol glycan A (PIGA) gene not all cells have the defect, so pt has a mix of normal and abnormal cells only 25% of pts have nocturnal, paroxysmal attacks; most have chronic hemolysis w/o dramatic hemoglobinuria which eventually causes iron deficiency median survival is 10yrs can evolve into AML (5-10%) |
|
|
what is the mutation in paroxysmal nocturnal hemoglobinuria?
|
phosphatidylinositol glycan A (PIGA) gene
essential for the formation of glycosylphosphatidylinositol (GPI) that anchors some proteins to the cell membrane, including several (CD59) that inactivate complement (their absence in PNH makes blood cells sensitive to complement-mediated intravascular lysis) PIGA is X-linked and subject to lyonization, so only the active gene needs to be mutated to produce deficiency not all cells in a pt have the defect so a pt has a mix of normal & abnormal cells |
|
|
what cells are affected by a mutation in PIGA?
|
PIGA is mutated in paroxysmal nocturnal hemoglobinuria
affects pluripotent stem cells, so rbcs, wbcs, and platelets all have the defect |
|
|
what is noted in the blood cell count of pts with paroxysmal nocturnal hemoglobinuria?
|
normocytic anemia
neutropenia (60%) thrombocytopenia (67%) |
|
|
where are thrombotic episodes seen in pts with paroxysmal nocturnal hemoglobinuria?
|
hepatic, portal, and cerebral veins
thrombotic episodes are fatal in 50% of pts (median survival = 10yrs) - dysfunction of platelets favors thrombosis - absorption of NO by free Hb favors thrombosis |
|
|
what malignancy can can develop from paroxysmal nocturnal hemoglobinuria?
|
acute myelogenous leukemia (5-10% of pts)
|
|
|
if normal people have some bone marrow cells with PIGA mutations, why don't they all develop paroxysmal nocturnal hemoglobinuria?
|
disease only occurs if the mutant cells have a selective advantage over other cells
PNH often arises in the setting of aplastic anemia |
|
|
what is the treatment for paroxysmal nocturnal hemoglobinuria?
|
bone marrow transplant
|
|
|
immunohemolytic anemias (autoimmune hemolytic anemias)
|
extracorpuscular mechanisms
usually classified by nature of antibody involved major diagnostic criterion is the Coombs' antiglobulin test |
|
|
DAT (direct Coombs' antiglobulin test)
|
patient rbcs mixed with sera containing Abs for Ig or complement
if either Ig or complement is present on the rbcs, agglutination/clumping occur test for autoimmune hemolytic anemias |
|
|
indirect Coombs' antiglobulin test
|
test patient serum for ability to agglutinate commercial rbcs having particular defined antigens
characterizes the target antigen and temperature dependence of the antibody |
|
|
what is the most common form of immunohemolytic anemia?
|
warm antibody hemolytic anemia
|
|
|
warm antibody hemolytic anemia
|
most common form of autoimmune hemolytic anemia (50% are idiopathic; 50% have an underlying condition or drug exposure, like lymphoma/leukemia/neoplasms/SLE)
most autoantibodies are IgG coated cells, partially phagocytized, form spherocytes and are removed in spleen (causes moderate splenomegaly) |
|
|
what is targeted by the autoantibodies in idiopathic warm antibody hemolytic anemia?
|
Rh blood group antigens
(autoantibodies are usually IgG) |
|
|
what are the targets of the autoantibodies in drug induced-warm antibody hemolytic anemia?
|
1) haptens - drugs (penicillin, cephalosporins, etc.) act as haptens by binding to rbc membrane to induce Abs against cell-bound drug or a complex of drug and a membrane protein - usually associated with large IV amts of drug, occurring 1-2 wks after therapy - rbc destruction may be intra- or extra-vascular
2) autoantibodies - drugs (methyldopa, etc.) initiate Ab production vs intrinsic rbc antigens (esp. Rh) via unknown mechanisms - 10% of users develop Abs, but only 1% have significant hemolysis |
|
|
what are the types of immunohemolytic anemias (autoimmune hemolytic anemias)?
|
- warm antibody hemolytic anemia (most common; IgG Abs against Rh or drugs)
- cold agglutinin immune hemolytic anemia (IgM Abs bind rbcs at 0-4C) - cold hemolysin hemolytic anemia (least common; IgG Abs against P blood group antigen) - hemolytic anemia due to rbc trauma |
|
|
cold agglutinin immune hemolytic anemia
|
IgM Abs bind to rbcs at 0-4degC
15-30% of autoimmune hemolytic anemias occurs acutely in recovery phases of some infections (M. pneumoniae, CMV, EBV, HIV, flu) and is self limited so it is rarely clinically significant chronic can be idiopathic or caused by lymphoproliferative diseases rbc agglutination and complement fixation in distal body parts, where temp is lower than 30C may cause IV hemolysis; dissociate at warmer temp, but leaves C3b attached to the cells which are destroyed in the liver and spleen pt has a variable severity of anemia and has Raynaud phenomenon |
|
|
cold hemolysin hemolytic anemia
|
aka Donath-Landsteiner syndrome
least common form of autoimmune hemolytic anemia IgG Abs against the P blood group antigen attach to rbcs at low temps and cause complement-mediated intravascular lysis when cells recirculate to warmer areas (since complement enzymes work better at 37C) paroxysmal cold hemoglobinuria caused by acute, intermittent massive hemolysis on exposure to cold usually seen in kids following viral infections (measles, mumps, flu, adeno-, VZV, CMV, EBV viruses especially |
|
|
hemolytic anemia due to rbc trauma
|
prosthetic cardiac valves (turbulent flow causes shear stresses and abnormal pressure gradients - mechanical valves cause more than bioprosthetic porcine valves)
narrowed/obstructed vasculature (microangiopathic HA; damage to rbc as it squeezes through narowed vessels often caused by by fibrin deposition in small vessels - DIC) other causes: malignant HTN, SLE, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, HUS, disseminated CA |
|
|
what is the most common cause of hemolytic anemia related to rbc trauma?
|
microangiopathic hemolytic anemia
damage to rbc as it squeezes through narrowed vessels often caused by fibrin deposition in small vessels (DIC) |
|
|
megaloblastic anemia
|
diverse group that all have impaired DNA synthesis, and distinctive changes in blood and bone marrow
cells are large due to defective cell maturation and division, but RNA synthesis is normal so there is asynchrony btwn nuclear and cytoplasmic maturation |
|
|
peripheral blood smear of megaloblastic anemias
|
- pancytopenia
- marked anisocytosis (variation in size) and poikilocytosis (variation in shape) - macrocytes - high MCV (>100um^3) - normal MCHC - lack central pallor (hyperchromic) - ovalocytes - multiple Howell-Jolly bodies in a single cell - reticulopenia - if severe anemia is present, see normocytic rbcs - neutrophils are large and HYPERSEGMENTED (>6 lobes or 5 in 5%) |
|
|
bone marrow of megaloblastic anemia
|
- hypercellular
- large rbcs - cytoplasm of both rbcs and granulocytes matures while nucleus retains fine chromatin - giant metamyelocytes and bands - megakaryocytes may be large w/ bizarre nuclei - megaloblasts accumulate in marrow, causing anemia |
|
|
what are the contributing factors to anemia in patients with megaloblastic anemia?
|
megaloblasts accumulate in the marrow
intramedullary destruction of megaloblasts (also of granulocyte and platelet precursors, so peripheral wbc and platelet counts are low b/c of apoptosis) increased hemolysis by unknown mechanism |
|
|
in what dietary products is B12 found?
|
animal products (vegetarians lack sufficient B12)
|
|
|
what is the daily requirement of B12?
|
2-3ug
with normal diet, a person has good reserves |
|
|
from where is intrinsic factor secreted? what is its function?
|
secreted by gastric parietal cells
necessary for absorption of vitamin B12 (cobalamin) |
|
|
what is the process by which vitamin B12 is absorbed in the diet?
|
it is released from animal proteins by pepsin in the acid environment of the stomach and then free B12 binds to salivary B12 binding proteins
the complex is broken down in the duodenum by pancreatic proteases and B12 attaches to intrinsic factor (released from gastric parietal cells) new complex travels to ileum and adheres to IF-specific receptors on mucosal ileal cells which B12 then enters B12 associates with transcobalamin II (a carrier protein) and is secreted into the plasma, which delivers it to tissue through the portal vein a small alternative non-IF pathway can take care of 1% |
|
|
pernicious anemia
|
B12 deficiency due to atrophic gastritis with failure to produce intrinsic factor
seen in all races (slightly more common in Scandinavian- and English-speaking groups median at Dx is in the 60s (presentation is rare < 30yo) |
|
|
B12 (cobalamin) deficiency
|
dietary deficiency takes years to develop
causes: 1) achlorhydria and/or loss of pepsin in some elderly people can cause deficiency 2) lack of intrinsic factor (pernicious anemia or gastrectomy) 3) loss of exocrine pancreatic function 4) ileal resection or diffuse ileal disease 5) tapeworms compete for B12 6) increase in requirement (pregnancy, hyperthyroidism, disseminated CA) |
|
|
functions of B12
|
1) essential cofactor for methionine synthetase, which is involved in conversion of homocysteine to methionine
- deficiency may trap folic acid in N5-methyl state, or may cause failure of synthesis of some other metabolically active forms of folate - lack of folate is the proximal cause of anemia in B12 deficincy 2) involved in isomerization of methylmalonyl CoA to succinyl CoA - deficiency causes inc. in levels of methylmalonate which leads to abnormal FAs incorporated into neuronal lipids, predisposing to myelin breakdown |
|
|
what happens if folic acid is given to a patient with pernicious anemia?
|
anemia improves because the proximal cause of anemia in B12 deficiency is lack of folate, but neurologic changes are unaffected because the neurologic changes are unrelated to folic acid
|
|
|
pathogenesis of pernicious anemia
|
immunologic mediated, maybe autoimmune, destruction of gastric mucosa resulting in chronic atrophic gastritis
- loss of parietal cells that secrete intrinsic factor - lymphoplasmacytic infiltrate - megaloblastic changes in mucosal cells 3 types of Abs (in many, but not all pts): 1) type I Ab - present in 75% of pts in the serum and gastric juice - blocks binding of B12 to IF 2) type II Ab - present in large number of pts - prevents binding of B12/IF complex to ileal receptors 3) type III Ab - present in 90% of pts - Abs against subunits of the gastric proton pump (present in 50% of pts with chronic atrophic gastritis w/o pernicious anemia) suspect that Abs may be secondary to T cell response which injures gastric mucosa and triggers autoAb formation; Abs cause further gastric damage |
|
|
GI morphology in pernicious anemia
|
tongue is shiny, glazed and beefy (atrophic glossitis)
stomach has diffuse chronic gastritis with atrophy of the fundic glands, the parietal cells (basically absent), and chief cells intestinal metaplasia, developing goblet cells cells and nuclei may double in size (megaloblastic change increased risk of gastric carcinoma autoimmune mediated (marrow responds to B12, but GI changes don't) |
|
|
CNS morphology in pernicious anemia
|
changes present in 75% of pts with pernicious anemia (rarely can have CNS changes w/o the anemia)
Changes: 1) myelin degeneration in dorsal & lateral tracts of spinal cord, maybe with loss of axons 2) spastic paraparesis, sensory ataxia, severe paresthesias of the legs |
|
|
clinical features of pernicious anemia
|
insidious onset, so pt usually has marked anemia when diagnosed
Dx dependent on: - megaloblastic anemia - leukopenia with hypersegmented neutrophils - mild-moderate thrombocytopenia - peripheral hemolysis causing mild jaundice - neurologic changes - achlorhydria (inability to make HCl) even after histamine stimulation - inability to absorb oral dose of B12 and low serum B12 - inc. in serum methylmalonic acid and homocysteine - parenteral B12 improves anemia and increases reticulocytes - serum Abs to intrinsic factor |
|
|
on what clinical features is a diagnosis of pernicious anemia dependent?
|
- megaloblastic anemia
- leukopenia with hypersegmented neutrophils - mild-moderate thrombocytopenia - peripheral hemolysis causing mild jaundice - neurologic changes - achlorhydria (inability to make HCl) even after histamine stimulation - inability to absorb oral dose of B12 and low serum B12 - inc. in serum methylmalonic acid and homocysteine - parenteral B12 improves anemia and increases reticulocytes - serum Abs to intrinsic factor |
|
|
why are pts with pernicious anemia at an increased risk for atherosclerosis and thrombosis?
|
[homocysteine] is increased in pernicious anemia and homocysteine is a risk factor for atherosclerosis and thrombosis
|
|
|
in what dietary elements is folate found?
|
green, leafy vegetables
livers - need 50-200ug daily - cooking destroys 95% of the folate - liver has modest reserves (enough to supply for wks-mos) |
|
|
how are folate and B12 deficiencies similar? how do they differ?
|
they are similar because they both cause a very similar megaloblastic anemia
B12 deficiency also causes neurological changes (myelin degeneration with subsequent spastic paraparesis, sensory ataxia, and severe leg paresthesias) but folate deficiency doesn't |
|
|
what is the function of folate?
|
folate is essential for 1C transfers
needed for: 1) purine synthesis 2) synthesis of methionine from homocysteine 3) synthesis of deoxythymidylate monophosphate |
|
|
what is important about the synthesis of deoxythymidylate monophosphate?
|
dTMP is important for DNA synthesis
in the pathway of its synthesis, a reductase is necessary to get FH4 back into the donor pool this enzyme can be inhibited by various drugs |
|
|
what are the causes of folate deficiency?
|
decreased intake
- alcoholics (cirrhosis can trap folate, with excess urinary loss) - elderly - poor malabsorption - sprue (folate absorbed in proximal jejunum) - infiltrative diseases of small intestine (lymphomas) - some drugs (BCPs, dilantin, phenytoin) increased demand - pregnancy - infancy - hemolytic anemias - cancer antagonists - methotrexate (inhibits DHFR) |
|
|
what cells are affected by folic acid deficiency?
|
all rapidly growing cells (particularly those of the GI and bone marrow)
main presentations: anemia + GI ulcers |
|
|
what are the requirements to diagnose folate deficiency?
|
dec folate levels in serum and in rbcs (rbc level is more sensitive
NO neurological changes |
|
|
what is the most common nutritional disorder globally?
|
iron deficiency anemia
|
|
|
how much iron is in the normal western diet?
|
10-20mg Fe/day
- most from animal products (20% is absorbed) - non-heme iron (1-2% absorbed) |
|
|
how much total iron is in a male? in a female?
|
6gm in a male
2gm in a female 80% is functional iron in Hb there is efficient recycling from functional and storage pools |
|
|
transferrin
|
protein made in liver that transports iron in the plasma and delivers the iron to cells (including erythroid precursors which have high-affinity receptors for transferrin)
usually about 1/3 of plasma protein is saturated, causing serum Fe of 100ug in women and 120ug in men |
|
|
where is the storage pool for iron?
|
free Fe is highly toxic, so it is bound to hemosiderin and ferritin to make it safer
storage pool is 15-20% of the total body iron (with less storage in women than in men) |
|
|
ferritin
|
protein-iron complex that is present in all tissue, but especially in the liver, spleen, marrow, and skeletal muscle
in the liver, it is mostly found in hepatocytes and is derived from transferrin in the spleen and marrow, it is mostly found in macrophages and is derived from rbc breakdown partially degraded shells of ferritin aggregate as hemosiderin granules which stain for prussian blue b/c iron in hemosiderin is chemically reactive |
|
|
plasma ferritin
|
correlates with adequacy of body iron stores
<12 ug/L in iron deficiency up to 5000 ug/L in iron overload |
|
|
how much Fe is lost daily?
|
fixed daily loss is 1-2 mg
since only 10-15% of ingested iron is absorbed, the daily requirement is 5-10mg in men and 15-20mg in women average diet contains about 15-20mg, so women get just enough to maintain a marginal balance |
|
|
where is iron mostly absorbed in the gut?
|
duodenum
|
|
|
what is the process of absorption of non-heme iron?
|
1) converted from Fe3+ to Fe2+
2) divalent metal transporter 1 moves Fe2+ across apical membrane of duodenal cells 3) Fe2+ can remain in enterocyte in storage form or is transported across basolateral membrane by ferriportin 1 4) ceruloplasmin & hephaestin convert Fe2+ to Fe3+ so that it can be carried by transferrin 5) DMT1 mediates uptake of Fe across membranes in rbc precursors 6) most Fe is stored as mucosal ferritin, and either transferred to transferrin more slowly or lost when mucosal cell sheds off into the lumen 7) Fe absorption is regulated by hepcidin (inhibits Fe transfer from enterocyte to plasma) |
|
|
divalent metal transporter 1 (DMT1)
|
1) moves iron across apical membrane of duodenal cells
2) mediates uptake of Fe across membranes in rbc precursors |
|
|
ferriportin 1
|
1) transports Fe across the basolateral membrane of enterocytes
2) plays a role in the release of storage Fe from macrophages |
|
|
ceruloplasmin
|
protein made in the liver
functions: 1) carries about 70% of the total copper in human plasma while albumin carries about 15% (rest is macroglobulins) 2) oxidation of Fe2+ (ferrous iron) into Fe3+ (ferric iron), (transferrin can carry iron only in the ferric state) |
|
|
hephaestin
|
protein found in highest conc. on the basolateral membrane of cells in the small intestine (esp. the duodenum)
oxidizes Fe2+ (ferrous iron) to Fe3+ (ferric iron), therefore assisting in its transport in the plasma in association with transferrin (can carry iron only in the ferric state) |
|
|
how is most iron stored?
|
as mucosal ferritin
either transferred to transferrin more slowly, or lost when mucosal cell sheds off into the lumen in iron deficiency, more iron goes to transferrin |
|
|
hepcidin
|
protein that is made in the liver and released in response to elevated intra-hepatic Fe
inhibits Fe transfer from enterocyte to plasma by binding to ferriportin, causing the ferriportin to be degraded (causes trapping of Fe in enterocytes which are eventually sloughed off into intestinal lumen) when Fe stores are high, hepcidin increases; when Fe stores are low, hepcidin decreases since it binds to ferriportin, it also suppresses Fe release from macrophages |
|
|
dietary deficiency of iron
|
should be rare in countries with abundant food, including meat
seen in: - elderly - poor people - infants (breast milk contains little Fe; cow milk has more but bioavailability is low) - children, especially young (blood volume is expanding) |
|
|
impaired absorption of iron
|
- sprue
- chronic diarrhea - gastrectomy (impairs Fe absorption by decreasing both HCl and duodenal transit time) - some elements in diet (ex. tannate in tea) inhibit absorption |
|
|
what is the most important cause of Fe deficiency in the west?
|
chronic blood loss
external/GI/urinary/genital hemorrhage - urinary is not as severe if blood loss is internal, the iron can be recycled |
|
|
in adult men and postmenopausal women, iron deficiency is due to what until proven otherwise?
|
GI loss (occult cancer or other bleeding lesion)
|
|
|
morphology of Fe-deficiency anemia
|
as reserves decrease serum iron, transferrin saturation, and ferritin decrease (iron binding capacity increases)
when reserves are exhausted pt gets hypochromic, microcytic anemia with poikilocytosis in form of pencil cells reduced heme synthesis causes elevation of free rbc protoporphyrin in the marrow, initially see inc. in erythropoiesis in attempt to compensate - increased normoblasts - decreased stainable iron as it is being used up - don't collect bone marrow to diagnose |
|
|
clinical features of Fe-deficiency anemia
|
- alopecia (loss of hair on head/body)
- tongue atrophy - gastric mucosa atrophy with malabsorption if severe kids with iron-deficiency tend to crave ice |
|
|
what chronic diseases can cause anemia?
|
- chronic infections (b/c of impaired rbc production)
- chronic immune disorders - neoplasms (carcinomas of lung/breast or Hodgkin Lymphoma) - renal insufficiency/failure |
|
|
anemia of chronic disease
|
associated with low serum iron, reduced iron-binding capacity, and abundant iron stores
suggested defect in reuse of iron due to some block in transfer of iron from storage pool to erythroid precursors marrow hypoproliferation inflammatory mediators, esp. IL6, stimulate liver production of hepcidin, so Fe is not released from macrophages to rbc precursors erythroid precursors do not proliferate normally since erythropoietin is low for the degree of anemia (might be an effect of hepcidin) |
|
|
morphology of anemia of chronic disease
|
anemia is usually mild - may be hypochromic and microcytic or normochromic and normocytic
inc serum ferritin, dec iron binding capacity rules out Fe-deficiency anemia transferrin is usually normal or low inc. iron stores in marrow |
|
|
aplastic anemia
|
chronic primary hematopoietic failure
really a pancytopenia (dec levels of rbcs, wbcs, and platelets) caused by failure or suppression of multipotent myeloid stem cells |
|
|
drug-induced aplastic anemia
|
some are predictable, dose-related, and reversible on stopping the causative agent
most are idiosyncratic reactions to very small doses of the drug that may be severe and irreversible |
|
|
causes of aplastic anemia
|
drug/chemical-induced
whole body radiation infection fanconi anemia 65% are idiopathic inherited defect in telomerase or abnormally short telomeres |
|
|
what infections most commonly cause aplastic anemia?
|
most commonly hepatitis (non-A,B,C,G)
|
|
|
fanconi anemia
|
rare disease with AR inheritance
mutations result in defective DNA repair pts generally have congenital defects and marrow hypofunction early in life pts commonly develop aplastic anemia and cancer (most commonly AML) |
|
|
what inherited defects can cause aplastic anemia?
|
inherited defects in telomerase (in 5-10% of adult-onset aplastic anemia)
abnormally short telomeres (50% of pts) |
|
|
T-cell mediated pathogenesis of aplastic anemia
|
stem cells antigenically altered by offending agent which evokes a T cell-mediated immune response
TNF and IFN-gamma produced by activated T cells suppress and kill heme progenitor cells (inhibits stem cell proliferation/differentiation) antithymocyte globulin and cyclosporine therapy helps in 60-70% of pts by killing autoreactive T cell clones present in up to 70% of pts |
|
|
stem cell abnormality mediated pathogenesis of aplastic anemia
|
some insult causes genetic damage, with generation of stem cells with poor proliferative/differentiation ability
if these clonal cells dominate aplastic anemia is caused occasionally aplastic anemia transforms to acute leukemia (supporting this hypothesis) |
|
|
what are the two major mechanisms that lead to aplastic anemia?
|
1) inhibition of stem cell proliferation/differentiation by activated T cells (70%)
2) fundamental stem cell abnormality that causes generation of stem cells with poor proliferative/differentiation ability occurs b/c of some insult that causes genetic damage |
|
|
bone marrow of aplastic anemia
|
- markedly hypocellular
- fat & fibrous stroma with clusters of scattered lymphocytes and plasma cells - normochromic, normocytic anemia with reticulocytes - dec. wbc count (risk for infection) - dec. platelets (bleeding) |
|
|
morphology of aplastic anemia
|
- pancytopenia
- rbcs are usually slightly macrocytic and normochromic - hypocellular marrow with fat/fibrous stroma with clusters of scattered lymphs and plasma cells |
|
|
clinical features of aplastic anemia
|
usually a gradual onset, but can be quite sudden
pancytopenia spleen is not enlarged (if there is splenomegaly, question the dx) if pt doesnt respond to anti-thymocyte globulin and cyclosporine, some respond to marrow transplant |
|
|
DDx for aplastic anemia
|
other causes of pancytopenia
need bone marrow biopsy to rule out aleukemic leukemia and myelodysplasias |
|
|
pure red cell aplasia
|
rare form of marrow failure where only erythroid progenitors are suppressed
can be primary can be secondary to: - neoplasms, especially thymoma or leukemia of lg granular lymphs - drugs - autoimmune in thymoma, 1/2 improve after tumor resection parvovirus likes nucleated rbc precursors - normally infection clears in 1-2 wks, so aplasia is transient - much more problematic if superimposed on a hemolytic anemia |
|
|
myelophthisic anemia
|
displacement of hemopoietic bone-marrow tissue into the peripheral blood, either by fibrosis, tumors or granulomas
space-occupying lesions destroy significant amts of marrow and microenvironment and replaces marrow elements see tear drops in peripheral blood commonest cause is metastatic cancer from lung, breast, and prostate carcinomas can be caused by infitrative granulomatous diseases in bone marrow (feature of the spent phase of myeloproliferative disorders) |
|
|
marrow failure caused by diffuse liver disease
|
usually more rbc depression than wbc or platelets
may be macrocytic anemia due to lipid abnormalities of liver failure |
|
|
marrow failure caused by chronic renal failure
|
anemia is usually proportional to severity of uremia
dominantly caused by lack of erythropoietin production by kidneys pts often have superimposed Fe deficiency |
|
|
erythrocytosis (polycythemia)
|
increased conc. of rbcs, usually with corresponding inc in Hb
can be caused by relative hemoconcentration (dehydration due to various causes) can be primary (polycythemia vera) or secondary, but there is an absolute increase in total red cell mass |
|
|
Gaisbock syndrome
|
aka stress polycythemia
relative polycythemia associated with HTN, obesity, anxiety, and males there is not enough plasma, so the rbcs are concentrated |
|
|
polycythemia vera
|
primary increase in red cell mass
caused by abnormality of stem cells - clonal neoplastic proliferation - mutation in EPO receptors (much less common) |
|
|
secondary polycythemia
|
normal stem cells, but excess rbc proliferation due to increased EPO
appropriate secondary polycythemia is seen in high altitude, lung disease, and cyanotic heart disease inappropriate secondary polycythemia is seen in EPO-secreting tumors in the kidney |
|
|
what are the general causes of excessive bleeding?
|
1) increased fragility of vessels
2) platelet deficiency or dysfunction 3) derangement of coagulation **all can be alone or in combination** |
|
|
prothrombin time (PT)
|
assesses the extrinsic and common coagulation pathways
clotting of plasma after an exogenous source of tissue thromboplastin and calcium ions is measured in seconds prolonged PT results from deficiency/defect in factor V, VII, X, prothrombin, or fibrinogen |
|
|
partial thromboplastin time (PTT)
|
assesses the intrinsic and common clotting pathways
clotting of plasma after addition of kaolin (activates factor XII), cephalin (substitute for platelet phospholipids), and calcium ions is measured in seconds prolonged PTT results from deficiency/defect in factor V, VIII, IX, X, XI, XII, prothrombin, or fibrinogen |
|
|
platelet count
|
reference range: 150,000-300,000/uL
thrombocytopenia: <100,000/uL spontaneous bleeding: <20,000/uL spurious low counts could be caused by clumping of platelets high counts could indicated myeloproliferative disorder |
|
|
what are nonthrombocytopenic purpuras?
|
bleeding disorders caused by vessel wall abnormalities
- relatively common - rarely cause serious bleeding problems (usually just induces petechiae/purpura in skin or mucous membranes, esp. gingivae) |
|
|
what form do more significant hemorrhages take in bleeding disorders caused by vessel wall abnormalities?
|
bleeding into joints, muscles and subperiosteal locations
menorrhagia nosebleeds GI bleeding hematuria |
|
|
what are the results of PT, and PTT in bleeding disorders caused by vessel wall abnormalities?
|
usually results are normal
|
|
|
what are the causes of bleeding disorders caused by vessel wall abnormalities?
|
infections (particularly meningococcemia)
drug reactions scurvy & Ehlers-Danlos Henoch-Schonlein purpura hereditary hemorrhagic telangiectasia perivascular amyloidosis |
|
|
how do drug reactions cause vascular damage, leading to nonthrombocytopenic purpuras?
|
vascular injury mediated by drug-induced immune complexes in vessel walls
leads to hypersensitivity (leukocytoclastic) vasculitis |
|
|
how do infections cause vascular damage, leading to nonthrombocytopenic purpuras?
|
via microbial damage to microvasculature or via DIC
|
|
|
what are the results of a PT and PTT in pts with thrombocytopenia?
|
usually normal
|
|
|
what sites commonly bleed spontaneously in thrombocytopenia?
|
skin and mucous membranes of the GI and GU tracts
worst place to get spontaneous bleeding is intracranially |
|
|
what are the four major categories of causes of thrombocytopenia?
|
decreased platelet production
decreased platelet survival splenic sequestration dilution (massive transfutions) |
|
|
what are the most important non-immunological causes of decreased platelet survival?
|
disseminated intravascular coagulation (DIC)
thrombotic microangiopathies **unbridled, often systemic, platelet activation reduces platelet life span** |
|
|
why do pts with prosthetic heart valves develop thrombocytopenia?
|
mechanical injury to the platelets can cause nonimmunological destruction of the platelets
|
|
|
chronic immune thrombocytopenic purpura (ITP)
|
destruction of platelets caused by autoantibodies to platelets (usually IgG and most often against gpIIb-IIIa, or gpIb-IX)
can be primary (idiopathic) or secondary (HIV, SLE, CLL) |
|
|
pathogenesis of chronic immune thrombocytopenic purpura (ITP)
|
autoantibodies (most often IgG and against gpIIb-IIIa or gpIb-IX) can be demonstrated in plasma and bound to platelet surface in 80% of pts
Abs act as opsonins for Fc receptors on phagocytes causing platelet destruction, mainly in the spleen in some cases Abs bind to and damage megakaryocytes leading to decrease in production of platelets |
|
|
morphology of chronic immune thrombocytopenic purpura (ITP)
|
principal changes in spleen, marrow, and blood
spleen is normal size, with congestion of sinusoids and enlargement of follicles marrow has modestly increased number of megakaryocytes peripheral blood usually has abnormally large platelets |
|
|
clinical features of chronic immune thrombocytopenic purpura (ITP)
|
most common in women <40yo
- insidious in onset - characterized by bleeding into skin and mucosal surfaces (pinpoint hemorrhages) - pt hx of easy bruising, nosebleeds, bleeding from gums, and hemorrhages w/ minor trauma - may present with melena, hematuria, or excessive menstrual flow Tx: glucocorticoids (inhibit phagocyte fcn) |
|
|
acute immune thrombocytopenic purpura (ITP)
|
destruction of platelets caused by autoantibodies to platelets
childhood disease that appears abruptly about two weeks after a viral illness and usually spontaneously resolves in 6 mos |
|
|
drug-induced thrombocytopenia
|
drugs induce thrombocytopenia through direct effects or secondary to immunologically mediated effects
commonly caused by: - quinine, quinidine, vancomycin - gold salts - drugs that bind gpIIb/IIIa - heparin |
|
|
what drugs are commonly implicated in drug-induced thrombocytopenia?
|
quinine*
quinidine* vancomycin* gold salts** *= bind platelet glycoproteins and in one way or another create antigenic determinants that are recognized by Abs **=induce true Abs by unknown mechanism |
|
|
heparin-induced thrombocytopenia (HIT)
|
subset of drug-induced thrombocytopenia caused by heparin
type I - common, but clinically unimportant - occurs rapidly after starting Tx - caused by direct platelet aggregating effect type II - rare, but more clinically important - occurs 5-14 days after Tx begins - caused by Abs that recognize complexes of heparin w/ platelet factor 4 (a normal component of platelet granules) |
|
|
HIV-associated thrombocytopenia
|
one of the most common hematologic manifestations of HIV infection
CD4 & CXCR4 are found on megakaryocytes, so they can be infected by HIV; infected megakaryocytes are prone to apoptosis and their ability to produce platelets is impaired HIV-mediated B cell hyperplasia predisposes to development of anti-platelet autoAbs |
|
|
what are the thrombotic microangiopathies?
|
thrombotic thrombocytopenic purpura (TTP)
hemolytic-uremic syndrome (HUS) |
|
|
thrombotic thrombocytopenic purpura (TTP)
|
caused by a deficiency in ADAMTS13 (plasma enzyme which degrades high molecular weight multimers of vWF) which causes accumulation of vWF and promotes platelet activation/aggregation
deficiency can be inherited - inactivating mutation in ADAMTS13 gene - onset in adolescence - episodic Sxs deficiency can be acquired - autoAbs inhibit metalloprotease activity |
|
|
hemolytic-uremic syndrome (HUS)
|
epidemic/typical HUS - strongly associated w/ gastroenteritis caused by E. coli O157:H7 (elaborates a shiga-like toxin) - mostly children & elderly - present with bloody diarrhea and then HUS a few days later
nonepidemic/atypical HUS - associated with defects in factor H, CD46, or factor I (proteins that prevent excessive alternative complement activation) |
|
|
what are the three pathogenically distinct groups of inherited disorders of platelet fcn?
|
defects of adhesion
defects of aggregation disorders of platelet secretion |
|
|
bernard-soulier syndrome
|
AR inherited disorder caused by inherited deficiency of gpIb/IX (receptor for vWF)
results in bleeding from defective platelet adhesion to subendothelial matrix |
|
|
glanzmann thrombasthenia
|
AR inherited disorder caused by inherited deficiency of gpIIb/IIIa (binds fibrinogen to form bridges btwn platelets)
platelets fail to aggregate in response to ADP, collagen, epi, or thrombin |
|
|
what are the two clinically significant acquired defects of platelet function?
|
ingestion of aspirin/NSAIDs
uremia |
|
|
how does the bleeding due to isolated coagulation factor deficiencies most commonly present?
|
large post-traumatic ecchymoses or hematomas or prolonged bleeding after a laceration/surgical procedure of any kind
bleeding into GI and GU tracts and into weight-bearing joints is common |
|
|
how do hereditary deficiencies of clotting factors differ from acquired deficiencies?
|
hereditary deficiencies affect a single clotting factor
acquired deficiencies usually involve multiple coagulation factors simultaneously and can be based on decreased protein synthesis or shortened half life |
|
|
what are the most common inherited deficiencies of coagulation factors?
|
1) vWF (von Willebrand disease)
2) factor VIII (hemophilia A) 3) factor IX (hemophilia B) |
|
|
factor VIII
|
essential cofactor of factor IX, which converts factor X to factor Xa
made in sinusoidal endothelial cells and Kupffer cells in the liver, as well as tubular epithelium in kidney when it reaches the circulation, it binds to vWF (produced by endothelial cells and megakaryocytes) to increase its half-life from 2.4hrs to 12hrs |
|
|
vWF
|
produced by endothelial cells and, to a lesser degree, megakaryocytes (vWF in platelet alpha-granules)
binds and stabilizes factor VIII to increase half-life from 2.4 to 12 hours promotes adhesion of platelets to subendothelial matrix through bridging interactions btwn platelet gpIb/IX, vWF, and collagen - some is secreted by endothelial cells and lies in wait in the subendothelial matrix in case endothelial lining is disrupted - some is secreted into circulation to bind collagen in the subendothelial matrix to augment adhesion |
|
|
ristocetin agglutination test
|
assay of vWF function performed by mixing pt's plasma with formalin-fixed plateles and ristocetin (a small molecule that binds and activates vWF)
ristocetin induces multivalent vWF multimers to bind gpIb-IX and form bridges, thereby causing aggregation |
|
|
what is the most common inherited bleeding disorder of humans?
|
von Willebrand disease
affects about 1% of adults in US in most, bleeding tendency is mild and goes unnoticed until some hemostatic stress reveals its presence |
|
|
von Willebrand disease
|
AD inherited disorder caused by deficiency in vWF
in most, bleeding tendency is mild and goes unnoticed until some hemostatic stress reveals its presence Sx: spontaneous bleeding from mucous membranes, excessive wound bleeding, menorrhagia prolonged bleeding time in presence of a normal platelet count (defect is in platelet function - aggregation) |
