Transcript Anemia

Anemia
Robb Friedman, MD
Updated by Eyal Oren, MD
What is Anemia?
ANEMIA IS NEVER NORMAL
 Reduction below normal in the mass of
red blood cells in the circulation
 Hemoglobin concentration, hematocrit,
RBC count
 Men: HGB < 13.5 or HCT < 41%
 Women: HGB < 12.0 or HCT < 36%
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Anemia and Volume Status
HGB and HCT are CONCENTRATIONS
 Therefore dependent upon plasma volume
 Acute bleeds not reflected for 24-36 hrs
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– Due to volume deficit being slowly repaired via
movement of fluid from extravascular space to
intravascular
Anemic patients who are dehydrated will not
appear anemic
 Pregnant women expand RBCs 25% but plasma
volume increases 50%, producing “physiologic
anemia”
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Anemia: Special Cases
People who live at high altitude have
greater RBC volume
 Smokers have increased HCT
 African-American HGBs are 0.5 to 1.0g/dL
lower than Caucasians
 Athletes (increased plasma volume, Fe
deficiency, hemolysis, polycythemia, use
of performance enhancing agents)
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Anemia and the Elderly
Multiple studies support that the elderly
do not have a “lower normal range”
 Anemia, while common in the elderly, is
still abnormal
 HGB < 13 in males and < 12 in females
associated with an increased relative risk
of mortality (1.6 and 2.3 respectively)
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Anemia: History
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Is the patient bleeding?
– NSAIDs, ASA
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Past medical history of anemia? Family history?
Alcohol, nutritional questions
Liver, renal diseases
Menstrual history if applicable
Ethnicity
Environmental/work toxins (ie lead)
Symptoms of Anemia
Decreased O2 delivery
 Hypovolemia if acute loss
 Exertional dyspnea, fatigue, palpitations,
“bounding pulses”
 Severe: heart failure, angina, MI
 “Pica”– craving for clay or paper products
 Pagophagia– craving for ice
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Signs of Anemia
Tachycardia, tachypnea, orthostasis
 Pallor
 Jaundice
 Koilonychia or “Spoon nails”
 Splenomegaly, lymphadenopathy
 Petechiae, ecchymoses
 Atrophy of tongue papillae
 Guaiac
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The Three Causes of Anemia
 Decreased
red blood cell
production
 Increased red blood cell
destruction
 Red blood cell loss
Decreased RBC production
Lack of iron, B12, folate
 Marrow is dysfunctional from
myelodysplasia, tumor infiltration, aplastic
anemia, etc.
 Bone marrow is suppressed by
chemotherapy or radiation
 Low levels of erythropoeitin, thyroid
hormone, or androgens
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Increased RBC destruction
RBCs live about 100 days
 Acquired: autoimmune hemolytic anemia,
TTP-HUS, DIC, malaria
 Inherited: spherocytosis, sickle cell,
thalassemia
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RBC Loss
Bleeding!
 Obvious vs occult
 Iatrogenic: venesection e.g. daily CBC,
surgical, hemodialysis
 Retroperitoneal
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Approach to Anemia
LOOK AT THE
SMEAR!!!!
 Convenient to separate
into three classes based
on the size of the RBC
 MCV and RDW
 Microcytosis: < 80 fL
 Normocytosis: 80-100 fL
 Macrocytosis: >100 fL
 CBC, reticulocyte count,
Fe, Ferritin, TIBC, folate,
B12, LDH, CMP, ESR…
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Reticulocytes
Nucleated RBCs – form in marrow where they
mature for 3 days and then spend 1 day in
circulation (before maturing to RBC)
 Given avg life span of RBC of 100 days, 1% of
RBCs are destroyed each day
 Retics form 1% of circulating RBCs qd
 Nl RBC count is 5million/uL so marrow makes
50,000 reticulocytes/uL blood qd
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– With epo, can increase to 250,000 retics/uL blood qd
(given nl marrow and replete iron, folate, b12)
Reticulocyte Count
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Anemia with high retic # = appropriate response
Anemia with normal to low retic # = reduced marrow
response
Must adjust for anemia, use reticulocyte production index
Retic % x HCT/45 or x ½, nml is 1.0, less = inadeq. Retic
Or RI = retics x (Hct/45) / Correction Factor
– CF: Hct 41-50 (1), 30-40 (1.5), 20-29 (2), 10-19 (2.5)
– Reflects increased circulating time for retics as Epo pushes them out
of the marrow earlier
Microcytic Anemia
Iron Deficiency
Anemia
 Thalassemia
 Anemia of chronic
disease (esp. RA and
lymphoma)
 Sideroblastic anemia
(myelodysplastic
syndromes)
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Iron Deficiency Anemia
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The definitive test is serum
ferritin
Low serum ferritin is diagnostic
of iron deficiency
Although ferritin is an acute
phase reactant, it will still be
low in iron deficiency
Also, high TIBC
Low serum Fe is not in itself
diagnostic, neither is marrow
staining
Anisocytosis and poikilocytosis
Reactive thrombocytosis
Microcytic Anemia
Thalassemia
Decreased production of either α-globin or
β-globin chains
 Abnormal hemoglobin electrophoresis
 Polychromasia, basophilic stippling, target
cells
 Normal/increased RBC mass
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α-Thalassemia
α-Thalassemia: 4 genes
 ¼: silent carrier
 2/4: α-Thalassemia trait, microcytosis and
mild anemia
 ¾: excess β-chains form tetramers,
results in severe anemia and microcytosis
 4/4: hydrops fetalis
 Most common in SE Asian populations
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Basophilic stippling
β-Thalassemia
2 genes
 ½ mutation: β-Thal trait, increased Hgb
A2, rarely anemic, mild microcytosis
 2/2 mutation: β-Thalassemia disease, Hgb
F, microcytosis, anemia
 Usually found in people of African or
Mediterranean descent but has world-wide
distribution
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β-Thalassemia
Macrocytic Anemia (MCV>100)
Drug Induced (hydroxyurea, AZT, MTX,
chemotherapy)
 B12 / folate deficiency
 Myelodysplastic syndrome
 Liver disease, alcohol abuse
 Reticulocytes in the setting of hemolytic
anemia
 Spurious (i.e. cold agglutinins, etc)
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Folate and B12
Serum folate usually sufficient, but if folate level
is normal but folate deficiency is suspected,
check serum homocysteine (elevated because of
impaired folate dependent conversion of
homocysteine to methionine)
 B12 can be spuriously low– a more sensitive and
specific test is serum methylmalonic acid level,
will be increased if B12 is low.
 Schilling Test
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B12 and Folate Deficiency
Myelodysplastic Syndrome
Primary bone marrow
disorder, often found
in elderly
 Macrocytosis, anemia
 Pseudo-Pelger-Huet
abnormality– the
bilobed nucleus
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Normocytic Anemia
Large and complicated group of disorders!
 Hemolytic Anemias
 Anemia of chronic disease
 Bone marrow disorder
 Nutritional (Fe deficiency)
 Anemia of Renal Insufficiency
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Nutritional Anemias
Iron deficiency and B12/folate deficiency
can present with normocytic anemia– esp.
if both deficiencies are concurrent.
 Check iron studies and B12, folate levels.
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Anemia of Renal Insufficiency
Unremarkable peripheral blood smear
 Inappropriately normal erythropoietin level
 Anemia usually severe and symptomatic
when Cr > 3.0
 Mild to moderate anemia found in Cr 1.53.0
 Tx: Epogen or similar, Fe (oral, IV)
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Hemolytic Anemias
Hemolytic Anemia: Intrinsic causes
Spherocytosis, Sickle Cell
Evaluation of Hemolysis
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LDH: increases
Indirect bilirubin increases
(increased Hgb catabolism)
Haptoglobin decreases
Reticulocyte count increases
Urine hemosiderin test =
present for intravascular,
absent for extravascular
hemolysis!
Coombs test + = autoimmune
hemolytic anemia, - consider
PNH (abnormal GPI protein,
send flow for CD55 and CD59)
More hemolytic anemias
Anemia of Chronic Disease
Thought to be a cytokine mediated
process which inhibits red blood cell
production or interferes with action of
erythropoietin
 Seen with diabetes, rheumatologic
diseases, chronic infections, malignancy
 Indices: Low Fe, Low TIBC, Nl/increased
Ferritin
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Anemia due to Primary Bone
Marrow Disorder
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Myelodysplastic syndrome
Bone marrow infiltration:
nucleated red blood cells
found in circulation
Might see “rouleaux”
formation in multiple
myeloma
WBC, plts often abnormal
Bone marrow biopsy
Anemia: Treatments
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“Transfusion triggers”
– CAD: Hgb > 10
– All pts: Hgb > 7.0
– Everyone else: usually Hgb > 8.5
Iron supplementation
 Erythropoietin analogs
 B12, folate
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What the hell is a Howell-Jolly
Body?
Acanthocytes vs Echinocytes
Acanthocytes: “spur cells” found in liver disease
 Echinocytes: “burr cells” found in renal disease
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Helmet vs. Teardrop Cells
Anemia: Summary
ANEMIA IS NEVER NORMAL
 CONSIDER THE THREE CAUSES
 LOOK AT THE SMEAR
 CONSIDER THE ETIOLOGY BASED ON
RBC MORPHOLOGY AND LABORATORY
STUDIES
 TREAT APPROPRIATELY
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MKSAP Questions
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An 80-year-old man who had a hemicolectomy for colon cancer is
evaluated because of a 4-month history of diarrhea, anorexia, and
fatigue. He had a remote history of alcoholism.
On physical examination, he is cachectic and mildly confused. His
pulse rate is 70/min, and blood pressure is 140/85 mm Hg. His
tongue is smooth. The abdomen is soft; there are no palpable
masses or hepatosplenomegaly. A stool specimen is negative for
occult blood. Neurologic examination shows loss of position sense in
the feet. He has a wide-based gait. The Romberg test is positive. His
hemoglobin is 9.4 g/dL, reticulocyte count is 2.5%, mean
corpuscular volume is 125 fL, and serum lactate dehydrogenase is
400 U/L.
Which of the following is the most likely cause for his
symptoms?
( A ) Alcoholic cerebellar degeneration
( B ) Vitamin B12 deficiency
( C ) Brain metastases
( D ) Folate deficiency
( E ) Liver metastases
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Critique (Correct Answer = B)
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The patient most likely has vitamin B12 deficiency, based on the degree of macrocytosis and neurologic
findings. An elevated serum lactate dehydrogenase level, due to intramarrow cell death from ineffective
erythropoiesis, is consistent with this diagnosis.
Severe macrocytosis (mean corpuscular volume > 120 fL) is often associated with vitamin B12 deficiency or
folate deficiency (megaloblastic anemia), usually seen in conjunction with “oval” macrocytes. The presence of
frequent hypersegmented neutrophils (> 5 segments) is strongly suggestive of vitamin B12 or folate
deficiency.
Bone marrow morphology in patients with vitamin B12 or folate deficiency is referred to as “megaloblastic”
and is characterized by the presence of large cells with immature nuclear chromatin but maturing erythrocyte
cytoplasm (nuclear-cytoplasmic dissociation). Anemia accompanies this process; hence the term “ineffective
erythropoiesis.” The intramarrow death of megaloblastic cells causes the serum lactate dehydrogenase level
to rise. If a patient has a low serum vitamin B12 or folate level, a bone marrow examination is probably
unnecessary. However, the physician should determine the cause of the deficiency. If a patient has a normal
serum vitamin B12 or folate level, a bone marrow examination is frequently helpful to exclude
myelodysplastic syndromes or other infiltrative marrow disorders.
Folate deficiency can induce megaloblastosis within weeks to months, whereas vitamin B12 deficiency
requires years to cause megaloblastosis since stores of vitamin B12 persist for years in the liver and other
tissues. In patients with vitamin B12 or folate deficiency, parenteral or oral repletion of vitamin B12 or folate
reverses some morphologic abnormalities within hours. Serum folate levels fluctuate quickly with changes in
dietary consumption. Low erythrocyte folate levels often reflect prior nutritional depletion. In patients who
are hospitalized and are begun on regular diets, the erythrocyte folate test may provide a better assessment
of tissue folate levels than determination of the serum folate level. The erythrocyte folate test often requires
a special laboratory, and results often are not quickly available.
In patients with megaloblastic anemias, erythrocyte production is diminished and a “corrected” reticulocyte
count is inappropriately low for the degree of anemia. This patient had a corrected reticulocyte count of 1%
(inappropriately low for a hemoglobin level of 9.4 g/dL).
In addition to changes in the blood, the epithelial cells in patients with megaloblastic anemias may become
atrophic and cause a smooth tongue and cheilosis. Posterior column dysfunction, particularly in patients with
vitamin B12 deficiency, may lead to changes in vibratory or position sense, causing ataxia. Signs of dementia
may appear. However, neurologic dysfunction is very uncommon in adults with folate deficiency.
Alcoholic cerebellar degeneration results in ataxia but not position loss. Although liver metastases are
possible in a patient with a history of colon cancer, their presence would not account for the neurological
findings in this patient. Brain metastases would most likely produce focal neurological findings and also would
not account for the blood findings.
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A 26-year-old man is evaluated because of progressive fatigue,
dyspnea on exertion, and orthostatic dizziness for the past 2 to 3
weeks. He takes no medications. Physical examination is normal
except for pallor.
Laboratory StudiesHematocrit 13%Leukocyte count 8300/μL;
normal differentialReticulocyte count 0Platelet count 320,000/μLA
routine biochemical profile, including liver function tests, is normal.
A chest radiograph shows normal lung fields and a widened
mediastinum, suggestive of an anterior mediastinal mass. Bone
marrow biopsy shows absent erythrocyte precursors, normal
megakaryocytes, and normal leukocyte numbers and maturation.
Which of the following is the most likely cause of the
mediastinal mass and anemia?
( A ) Hodgkin’s disease
( B ) Non-Hodgkin’s lymphoma
( C ) Thyroid carcinoma
( D ) Thymoma
( E ) Germ cell carcinoma
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Critique (Correct Answer = D)
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Each of the listed neoplasms may present as an anterior
mediastinal mass and may be associated with anemia of
chronic disease. However, pure red cell aplasia (which this
patient has) is often associated with a benign or invasive
thymoma. Approximately 5% to 15% of thymomas occur in
patients with pure red cell aplasia. Other thymoma-associated
autoimmune disorders include myasthenia gravis, systemic
lupus erythematosus, thrombocytopenia, and, rarely,
malabsorption states. A careful search by CT or MRI is always
warranted in patients with newly diagnosed or relapsing red cell
aplasia or myasthenia.
The other listed entities are also included in the differential
diagnosis for an anterior mediastinal mass. Germ cell tumors
have not been associated with pure red cell aplasia, and
Hodgkin’s disease, non-Hodgkin’s lymphoma, and thyroid
carcinoma are rarely associated with this disorder. Chronic
lymphocytic leukemia is also commonly associated with red cell
aplasia and may present with variable degrees of
lymphadenopathy but not with an isolated anterior mediastinal
mass, as in the patient discussed here.
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A 36-year-old black man with known sickle cell anemia is evaluated
because of a 2-week history of fever, a macular rash on his trunk,
and arthralgias. Subsequently, he developed weakness and dyspnea
on exertion. Several of his children had febrile illnesses with
associated rashes and fatigue over the past month. These illnesses
resolved spontaneously without sequelae.
On physical examination, his temperature is 38.8 °C (101.8 °F),
pulse rate is 100/min, and blood pressure is 160/70 mm Hg. A
maculopapular, truncal rash is noted. There is conjunctival pallor.
The remainder of his examination is unremarkable.
Laboratory StudiesHemoglobin 5.2 g/dLLeukocyte count
5000/μLReticulocyte count 0%Platelet count 130,000/μLSerum
lactate dehydrogenase 622 U/LWhich of the following is the
most likely diagnosis?
( A ) Paroxysmal nocturnal hemoglobinuria
( B ) Parvovirus infection
( C ) Glucose-6-phosphate dehydrogenase deficiency
( D ) Aplastic anemia
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Critique (Correct Answer = B)
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Patients with hemolytic disorders may occasionally present with reticulocytopenia and an “aplastic crisis.” This
patient has sickle cell anemia with parvovirus infection, which is causing an aplastic crisis. Parvovirus may
infect patients with hemolytic anemias (for example, patients with hereditary spherocytosis, sickle cell
disease, or thalassemia). In children with sickle cell anemia, over 80% of aplastic crises may be attributed to
parvovirus infections. In adults, the usual presenting features are rash, arthritis, and anemia. The “slapped
cheek” syndrome is rarely a presenting feature. There is usually a complete suppression of erythropoiesis to
a reticulocyte level of 0%. The bone marrow shows giant dysplastic (megaloblastoid) erythroblasts,
occasionally with viral inclusions. The diagnosis is usually made by demonstrating IgM antibodies to the virus.
IgG antibodies appear later during the course of the infection and persist. Parvovirus in the blood may be
detected by the polymerase chain reaction, which is the definitive diagnostic method. Occasionally, other
blood components such as leukocytes and platelets are affected and result in mild to moderate pancytopenia.
The diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) should be considered in patients with bone
marrow failure or aplasia, unusual location of thromboses, and unexplained hemolysis. The anemia may be
severe, and patients with PNH typically have reticulocytopenia. There is no characteristic finding on bone
marrow examination, although the bone marrow of patients with PNH may demonstrate myelodysplastic
changes. The diagnosis is based on demonstration of exquisite sensitivity to complement-mediated lysis by
the sucrose lysis test or the acidified serum lysis test (Ham’s test).
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is another cause of hemolysis that occasionally is
associated with reticulocytopenia. In patients with G6PD deficiency, erythrocytes are subject to oxidative
stresses. Hemoglobin becomes oxidized and precipitates within the erythrocytes, which then undergo
destruction by the reticuloendothelial system. G6PD deficiency is an autosomal recessive disorder that
predominantly affects males. After a hemolytic episode, qualitative assays may be normal because only
erythrocytes that are resistant to G6PD remain. The African variant of G6PD is associated with a mild form of
hemolysis, whereas the Mediterranean variant is usually severe. Causes include infectious stresses, drugs
such as quinidine and sulfonamides, or, in the Mediterranean variant, favism (consumption of fava beans).
Therapy requires avoiding certain medications and supportive care in crisis situations.
In contrast to this patient’s presentation, patients with aplastic anemia have pancytopenia with severe
anemia, reticulocytopenia, thrombocytopenia, and granulocytopenia. In patients with severe aplastic anemia,
the bone marrow examination shows less than 5% cellularity with only residual lymphocytes and plasma
cells. The abnormal cells described above that are attributable to parvovirus infection are not seen.
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A 36-year-old man is evaluated because of fatigue. He has had two
episodes of acute gouty arthritis over the past 6 months. He has a 10-year
history of significant alcohol use, but he quit drinking 4 months ago. He
works in a factory making battery products. A complete blood count
obtained prior to elective hernia repair surgery 4 years ago was normal. He
takes no medications.
On physical examination, his temperature is 37.3 °C (99.1 °F), pulse is
60/min, and blood pressure is 135/70 mm Hg. His skin is normal. There is
slight scleral icterus. There is a blue line at the edge of his gums.
The remainder of the examination is normal. Stool specimens are negative
for blood on three occasions.
Laboratory StudiesHemoglobin 7.5 g/dLMean corpuscular volume 71
flLeukocyte count 9400/µLReticulocyte count 5.3%Platelet count
435,000/µLSerum lactate dehydrogenase 553 U/LSerum uric acid 11
mg/dLA peripheral blood smear is shown.
Which of the following diagnostic studies is most useful for
determining the cause of this patient’s anemia?
( A ) Serum iron, total iron-binding capacity, and ferritin levels
( B ) Serum lead levels
( C ) Direct and indirect antiglobulin tests
( D ) Hemoglobin A2 quantitation
( E ) Serum ethanol and folic acid levels
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Critique (Correct Answer = B)
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The patient has chronic lead intoxication that can be confirmed by measuring serum lead levels.
He has a hypochromic, microcytic anemia with coarse basophilic stippling and reticulocytosis.
He also has evidence of hemolytic anemia with increased serum lactate dehydrogenase and
indirect bilirubin levels. His physical examination is remarkable for gingival “lead lines.” Bone
marrow examination shows erythroid hyperplasia and ringed sideroblasts. The anemia of lead
poisoning fits this description. Sideroblastic anemia with hypochromic indices is typical.
Hemolysis is common, and basophilic stippling, blue staining polyribosomal aggregates with
mitochondrial fragments in the erythrocytes, is frequently seen. Lead inhibits pyrimidine 5′nucleotidase which normally clears ribosomal fragments. Occupational exposures to lead are
relatively uncommon today. However, workers who produce batteries or are exposed to paint,
particularly those who remove leaded paint from old buildings, are at greatest risk if they are
not protected from inhalation of paint particles during the sanding process. Other
manifestations of lead toxicity in adults include peripheral neuropathy, abdominal colic, and
saturnine gout (effects of lead on renal tubules that prevent the excretion of uric acid).
Chelation therapy is indicated for patients with serum lead levels exceeding 70 µg/dL and
should be continued until lead levels fall below 40 µg/dL. Agents such as EDTA or dimercaprol
may also be effective.
This patient is unlikely to have iron deficiency since his reticulocytes are increased. In addition,
basophilic stippling usually is not seen in patients with iron deficiency.
Thalassemia is associated with a microcytic anemia, reticulocytosis, and basophilic stippling.
However, a normal complete blood count 4 years ago rules out this possibility. Therefore,
quantitative studies to measure hemoglobin A2 are not necessary.
Autoimmune hemolytic anemia should be excluded by performing a direct antiglobulin test in
any patient who has evidence of hemolysis on a peripheral blood smear. However, the “lead
lines” on this patient’s gingivae are classic for lead poisoning, and autoimmune hemolytic
anemia therefore is less likely.
Alcoholism may cause a transient sideroblastic anemia, which resolves with cessation of alcohol
intake. Folic acid deficiency may complicate alcoholism but usually presents with macrocytosis.
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A 22-year-old man is evaluated in the intensive care unit because of
bleeding immediately after scoliosis surgery. During surgery, 12
units of packed red blood cells and 12 units of fresh frozen plasma
were transfused. There is no history of a bleeding disorder or of
drug administration that could affect platelet function.
On physical examination, the patient is afebrile. His pulse rate is
100/min, and blood pressure is 110/72 mm Hg. Petechiae are
present on his arms, and blood is oozing from the drains.
Laboratory StudiesHemoglobin 9.0 g/dLPlatelet count
43,000/µLProthrombin time 12 sActivated partial thromboplastin
time 32 sPlasma fibrinogen 400 g/dLd-Dimers NegativeWhich of
the following is the most likely cause of the
thrombocytopenia and bleeding?
( A ) Dilutional thrombocytopenia
( B ) Incompatible blood transfusion
( C ) Posttransfusion purpura
( D ) Septic transfusion reaction
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Critique (Correct Answer = A)
Approximately a 50% reduction in the platelet count occurs when
transfusions of 1.5 to 2 times the blood volume are given over 4 to 8 hours.
Blood stored for more that 2 to 3 days has essentially no platelets, which
explains the thrombocytopenia. Fresh frozen plasma contains all of the
clotting proteins in normal concentrations. This patient received one unit of
fresh frozen plasma for each unit of transfused red blood cells, which
resulted in no measurable alteration in the prothrombin time or activated
partial thromboplastin time. Incompatible red blood cell transfusions can
lead to the development of disseminated intravascular coagulation, which is
characterized by thrombocytopenia. The other hallmarks of disseminated
intravascular coagulation are absent in this patient, namely, he has a
normal fibrinogen, prothrombin time, activated partial thromboplastin time,
and negative d-dimers. Posttransfusion purpura is characterized by
profound thrombocytopenia that develops 5 to 7 days after a transfusion. It
occurs in patients who are negative for the PLA-1 human platelet antigen
and have been transfused or pregnant in the past. Posttransfusion purpura
almost always occurs in women.
 Septic transfusion reactions can be associated with thrombocytopenia when
either bacteremia or endotoxemia causes disseminated intravascular
coagulation. This patient has no indication of either sepsis or disseminated
intravascular coagulation.
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