Red Cell Disorders
Robert E. Richard, MD, PhD
Assistant Professor
Division of Hematology
University of Washington School of
Medicine
rrichard@u.washington.edu
faculty.washington.edu/rrichard
Objectives
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Review red blood cell disorders for which
transfusions are therapeutic.
Discuss controversial areas of transfusion
therapy in red blood cell disorders.
Understand the risks related to long term
transfusion therapy (non-infectious).
Definition:
Anemia is operationally defined as a reduction in
one or more of the major RBC measurements:
hemoglobin concentration, hematocrit, or RBC
count
Keep in mind these are all concentration
measures
…most accurately measured by obtaining a
RBC mass via isotopic dilution methods!
(Please don’t order that test!)
Review red blood cell disorders
Marrow Production
Two main approaches that are
not mutually exclusive:
1. Biologic or kinetic approach.
2. Morphology.
Anemia
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Production?
Survival/Destruction?
The key test is the …..
The reticulocyte count
(kinetic approach)
• Increased reticulocytes (greater than 2-3% or
100,000/mm3 total) are seen in blood loss and
hemolytic processes, although up to 25% of
hemolytic anemias will present with a normal
reticulocyte count due to immune destruction of red
cell precursors.
• Retic counts are most helpful if extremely low
(<0.1%) or greater than 3% (100,000/mm3 total).
The reticulocyte count
• To be useful the reticulocyte count must be adjusted
for the patient's hematocrit. Also when the hematocrit
is lower reticulocytes are released earlier from the
marrow so one can adjust for this phenomenon.
Thus:
• Corrected retic. = Patients retic. x (Patients Hct/45)
• Reticulocyte index (RPI) = corrected retic.
count/Maturation time
(Maturation time = 1 for Hct=45%, 1.5 for 35%, 2 for
25%, and 2.5 for 15%.)
• Absolute reticulocyte count = retic x RBC number.
Causes of Anemia (kinetic approach)
Decreased erythrocyte production
•Decreased erythropoietin production
•Inadequate marrow response to erythropoietin
Erythrocyte loss
•Hemorrhage
•Hemolysis
Morphological Approach
(big versus little)
First, measure the size of the RBCs:
• Use of volume-sensitive automated blood cell
counters, such as the Coulter counter. The red cells
pass through a small aperture and generate a signal
directly proportional to their volume.
• Other automated counters measure red blood cell
volume by means of techniques that measure refracted,
diffracted, or scattered light
• By calculation from an independently-measured red
blood cell count and hematocrit:
MCV (femtoliters) = 10 x HCT(percent) ÷ RBC (millions/µL)
Underproduction
(morphological approach)
MCV>115
• B12, Folate
• Drugs that impair
DNA synthesis (AZT,
chemo)
• MDS
MCV 100 - 115
• Ditto
• endocrinopathy
(hypothyroidism)
• Epo
• reticulocytosis
Underproduction
Normocytic
• Anemia of chronic
disease
• Mixed deficiencies
• Renal failure
Microcytic
• Iron deficiency
• Thal. trait
• Anemia of chronic
disease (30-40%)
• sideroblastic anemias
Review red blood cell disorders
Marrow production
• Thalassemias
• Myelodysplasia
• Myelophthisic
• Aplastic anemia
• Nutritional
deficiencies
Red cell destruction
• Hemoglobinopathies
• Enzymopathies
• Membrane disorders
• Autoimmune
Review red blood cell disorders
Marrow Production - Aplastic Anemia
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Acquired
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Immunological
Toxins – Benzene
Drugs – methotrexate, chloramphenicol
Viruses – EBV, hepatitis
Hereditary
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Fanconi,
Diamond-Shwachman
Review red blood cell disorders
Marrow Production - Aplastic Anemia
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All lineages affected.
Most patients require red cell transfusions.
Transplant when possible.
Transfusions should be used selectively to
avoid sensitization (no family donors!).
Review red blood cell disorders
Marrow Production - Myelodysplasia
• Preleukemia, most commonly in the elderly.
• Supportive care that involves transfusion
therapy is an option.
• Poor response to growth factors
Barosi G. Inadequate erythropoietin response to anemia:
definition and clinical relevance. Ann Hematol. 1994;68:215-223
(early review)
Review red blood cell disorders
Marrow Production - Myelophthisic
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Anemia associated with marrow infiltration
“teardrops”
Cancer, infections
Treatment is aimed at the underlying
disease
• Supportive transfusions as needed.
Review red blood cell disorders
Red cell destruction
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Elevated reticulocyte count
Mechanical
Autoimmune
Drug
Congenital
Hemolytic Anemias
Hemolytic anemias are either acquired or congenital. The laboratory
signs of hemolytic anemias include:
1. Increased LDH (LDH1) - sensitive but not specific.
2. Increased indirect bilirubin - sensitive but not specific.
3. Increased reticulocyte count - specific but not sensitive
4. Decreased haptoglobin - specific but not sensitive.
5. Urine hemosiderin - specific but not sensitive.
The indirect bilirubin is proportional to the hematocrit, so with a
hematocrit of 45% the upper limit of normal is 1.00 mg/dl and with a
hematocrit of 22.5% the upper limit of normal for the indirect bilirubin is
0.5mg/dl. Since tests for hemolysis suffer from a lack of sensitivity and
specificity, one needs a high index of suspicion for this type of anemia.
Review red blood cell disorders
Red cell destruction – membrane disorders
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Hereditary spherocytosis
Hereditary elliptocytosis
Hereditary pyropoikilocytosis
Southeast Asian ovalocytosis
Review red blood cell disorders
Red cell destruction – membrane disorders
Review red blood cell disorders
Red cell destruction – enzymopathies
• G6PD deficiency
• Pyruvate kinase deficiency
• Other very rare deficiencies
Sickle Cell Anemia
• Single base pair mutation results in a single
amino acid change.
• Under low oxygen, Hgb becomes insoluble
forming long polymers
• This leads to membrane changes
(“sickling”) and vasoocclusion
Red Blood Cells from Sickle Cell Anemia
• Deoxygenation of SS erythrocytes leads to
intracellular hemoglobin polymerization, loss of
deformability and changes in cell morphology.
OXY-STATE
DEOXY-STATE
Deoxyhemoglobin S Polymer Structure
A) Deoxyhemoglobin S
14-stranded polymer
(electron micrograph)
B) Paired strands of
deoxyhemoglobin S
(crystal structure)
C) Hydrophobic pocket
for 6b Val
D) Charge and size prevent
6b Glu from binding.
Dykes, Nature 1978; JMB 1979
Crepeau, PNAS 1981
Wishner, JMB 1975
Transfusion in Sickle Cell
(Controversy!)
• Used correctly, transfusion can prevent
organ damage and save the lives of
sickle cell disease patients.
• Used unwisely, transfusion therapy can
result in serious complications.
http://www.nhlbi.nih.gov/health/prof/blood/sickle/index.ht
m
Transfusion in Sickle Cell
(Controversy!)
• Simple transfusion – give blood
• Partial exchange transfusion - remove blood
and give blood
• Erythrocytapheresis – use apheresis to
maximize blood exchange
• When to use each method?
Transfusion in Sickle Cell
• In severely anemic patients, simple
transfusions should be used.
• Common causes of acute anemia:
• acute splenic sequestration
• transient red cell aplasia
• Hyperhemolysis (infection, acute chest
syndrome, malaria).
• If the patient is stable and the reticulocyte
count high, transfusions can (and should) be
deferred.
Transfusion in Sickle Cell
• In general, patients should be
transfused if there is sufficient
physiological derangement to result in
heart failure, dyspnea, hypotension, or
marked fatigue.
• Tends to occur during an acute illness
or when hemoglobin falls under 5 g/dL.
Transfusion in Sickle Cell
(exchange transfusion)
• Except in severe anemia, exchange
transfusion offers many benefits and is our
first choice
• Phenotypically matched, leukodepleted
packed cells are the blood product of choice.
• A posttransfusion hematocrit of 36 percent or
less is recommended.
• Avoid hyperviscosity, which is dangerous to
sickle cell patients.
Transfusion in Sickle Cell
(exchange transfusion)
Exchange transfusion:
1. Bleed one unit (500 ml), infuse 500 ml of saline
2. Bleed a second unit and infuse two units.
3. Repeat. If the patient has a large blood mass, do
it again.
Transfusion in Sickle Cell
(exchange transfusion)
• A comprehensive transfusion protocol should
include accurate records of the patient’s red
cell phenotype, alloimmunization history,
number of units received, serial Hb S
percentages, and results of monitoring for
infectious diseases and iron overload.
• Transfusions are used to raise the oxygencarrying capacity of blood and decrease the
proportion of sickle red cells.
Transfusion in Sickle Cell
(exchange transfusion)
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Transfusions usually fall into two
categories:
 episodic, acute transfusions to stabilize or
reverse complications.
 long-term, prophylactic transfusions to
prevent future complications.
Transfusion in Sickle Cell
(exchange transfusion)
•
episodic, acute transfusions to stabilize or
reverse complications.
 Limited studies have shown that aggressive
transfusion (get Hgb S < 30%) may help in
sudden severe illness.
 May be useful before general anesthesia.
Vichinsky et al., NEJM 1995
Transfusion in Sickle Cell
(chronic transfusion therapy)
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Stroke
Chronic debilitating pain
Pulmonary hypertension
Setting of renal failure and heart failure
Transfusion in Sickle Cell
(chronic transfusion therapy)
Controversial uses:
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Prior to contast media exposure
Sub-clinical neurological damage
Priapism
Leg Ulcers
Pregnancy
Transfusion in Sickle Cell
Inappropriate uses of transfusion:
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Chronic steady-state anemia
Uncomplicated pain episodes
Infection
Minor surgery
Uncomplicated pregnancies
Aseptoic necrosis
Thalassemias
• Genetic defect in hemoglobin synthesis
–  synthesis of one of the 2 globin chains ( or b)
– Imbalance of globin chain synthesis leads to depression of
hemoglobin production and precipitation of excess globin (toxic)
– “Ineffective erythropoiesis”
– Ranges in severity from asymptomatic to incompatible with life
(hydrops fetalis)
– Found in people of African, Asian, and Mediterranean heritage
Thalassemias
• Dx:
– Smear: microcytic/hypochromic, misshapen RBCs
– b-thal will have an abnormal Hgb electrophoresis
(HbA2, HbF)
– The more severe -thal syndromes can have HbH
inclusions in RBCs
– Fe stores are usually elevated
Thalassemias
• The only treatments are stem cell transplant
and simple transfusion.
• Chelation therapy to avoid iron overload
has to be started early.
Iron overload and chelation
• Can occur in any patient requiring chronic
transfusion therapy or in hemochromatosis.
• Liver biopsy is the most accurate test
though MRI is being investigated.
• Ferritin is a good starting test.
• 120 cc of red cells/kg of body weight is an
approximate point at which to think about
iron overload
Iron overload and chelation
• Chelator, deferoxamine
– 25 mg/kg sq per day over 8 hours.
– Supplementation with vitamin C may aid
excretion.
– Otooxicity, eye toxicity, allergic reactions.
– Discontinue during an infection.
• Oral chelators are in development.
Conclusions
• Transfuse for any severe anemia with
physiologic compromise.
• Decide early whether transfusion will be
rare or part of therapy.
• Avoid long-term complications by working
with your blood bank and using chelation
theraoy.
SELF (9 frozen pints of
artists blood, frozen in
sculpture)
Mark Quinn