Red Cell Disorders

Shinta O Wardhani
Division of Hematology and Medical
Oncology
Department of Internal Medicine
Faculty of Medicine Brawijaya University
Saiful Anwar General Hospital
M a l a n g - 2016

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

Review red blood cell disorders

Marrow Production

Anemia
?
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/mm 3 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

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

Acquired

Immunological
Toxins Benzene
Drugs methotrexate, chloramphenicol
Viruses EBV, hepatitis

Hereditary

Fanconi,
Diamond-Shwachman

Review red blood cell disorders

Marrow Production - Aplastic Anemia

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

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

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

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

Thank You

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

Sickle Cell Mutation

Chromosome 16
5'
Chromosome 11
5'

Normal (HbA)
CCT GAG GAG

-Pro-Glu-Glu-

-O2
+O 2

3'
3'

Abnormal (HbS)
CCT GTG GAG

-Pro-Val -Glu-

-O 2
+O2

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 6 Val

D) Charge and size

prevent
6 Glu from binding.

Dykes,Nature1978;JMB1979
Crepeau,PNAS1981

Wishner,JMB1975

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/ind
ex.htm

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
patients 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)
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)

Stroke
Chronic debilitating pain
Pulmonary hypertension
Setting of renal failure and heart failure

Transfusion in Sickle Cell

(chronic transfusion therapy)
Controversial uses:

Prior to contast media exposure

Sub-clinical neurological damage
Priapism
Leg Ulcers
Pregnancy

Transfusion in Sickle Cell

Inappropriate uses of transfusion:

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 )
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
-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