Red Cell Disorders

1
Red Cell Disorders

• Robert E. Richard, MD, PhD
• Assistant Professor
• Division of Hematology
• University of Washington School of Medicine
• rrichard_at_u.washington.edu
• faculty.washington.edu/rrichard

2
Objectives

• 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).

3
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
4
most accurately measured by obtaining a RBC mass
via isotopic dilution methods! (Please dont
order that test!)
5
Review red blood cell disordersMarrow Production
6
Two main approaches that are not mutually
exclusive
1. Biologic or kinetic approach.
2. Morphology.
7
Anemia
?
Production?
Survival/Destruction?
The key test is the ..
8
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
  (lt0.1) or greater than 3 (100,000/mm3 total).

9
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 Hct45, 1.5 for
  35, 2 for 25, and 2.5 for 15.)
• Absolute reticulocyte count retic x RBC number.

10

• Causes of Anemia (kinetic approach)
• Decreased erythrocyte production
• Decreased erythropoietin production
• Inadequate marrow response to erythropoietin
• Erythrocyte loss
• Hemorrhage
• Hemolysis

11
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)

12
Underproduction (morphological approach)

• MCVgt115
• B12, Folate
• Drugs that impair DNA synthesis (AZT, chemo)
• MDS

• MCV 100 - 115
• Ditto
• endocrinopathy (hypothyroidism)
• Epo
• reticulocytosis

13
Underproduction

• Normocytic
• Anemia of chronic disease
• Mixed deficiencies
• Renal failure

• Microcytic
• Iron deficiency
• Thal. trait
• Anemia of chronic disease (30-40)
• sideroblastic anemias

14
Review red blood cell disorders

• Marrow production
• Thalassemias
• Myelodysplasia
• Myelophthisic
• Aplastic anemia
• Nutritional deficiencies

• Red cell destruction
• Hemoglobinopathies
• Enzymopathies
• Membrane disorders
• Autoimmune

15
(No Transcript)
16
Review red blood cell disordersMarrow Production
- Aplastic Anemia

• Acquired
• Immunological
• Toxins Benzene
• Drugs methotrexate, chloramphenicol
• Viruses EBV, hepatitis
• Hereditary
• Fanconi,
• Diamond-Shwachman

17
Review red blood cell disordersMarrow 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!).

18
Review red blood cell disordersMarrow Production
- Myelodysplasia

• Preleukemia, most commonly in the elderly.
• Supportive care that involves transfusion therapy
  is an option.
• Poor response to growth factors

19
Barosi G. Inadequate erythropoietin response to
anemia definition and clinical relevance. Ann
Hematol. 199468215-223 (early review)
20
Review red blood cell disordersMarrow Production
- Myelophthisic

• Anemia associated with marrow infiltration
• teardrops
• Cancer, infections
• Treatment is aimed at the underlying disease
• Supportive transfusions as needed.

21
Review red blood cell disordersRed cell
destruction

• Elevated reticulocyte count
• Mechanical
• Autoimmune
• Drug
• Congenital

22
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.
23
Review red blood cell disordersRed cell
destruction membrane disorders

• Hereditary spherocytosis
• Hereditary elliptocytosis
• Hereditary pyropoikilocytosis
• Southeast Asian ovalocytosis

24
Review red blood cell disordersRed cell
destruction membrane disorders
25
Review red blood cell disordersRed cell
destruction enzymopathies

• G6PD deficiency
• Pyruvate kinase deficiency
• Other very rare deficiencies

26
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

27
(No Transcript)
28
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
29
Deoxyhemoglobin S Polymer Structure
A) Deoxyhemoglobin S 14-stranded polymer
(electron micrograph)
C) Hydrophobic pocket for 6b Val
B) Paired strands of deoxyhemoglobin S
(crystal structure)
D) Charge and size prevent 6b Glu from
binding.
Dykes, Nature 1978 JMB 1979 Crepeau, PNAS 1981
Wishner, JMB 1975
30
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.htm

31
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?

32
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.

33
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.

34
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.

35
Transfusion in Sickle Cell(exchange transfusion)

• Exchange transfusion
• Bleed one unit (500 ml), infuse 500 ml of saline
• Bleed a second unit and infuse two units.
• Repeat. If the patient has a large blood mass,
  do it again.

36
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
  oxygen-carrying capacity of blood and decrease
  the proportion of sickle red cells.

37
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.

38
Transfusion in Sickle Cell(exchange transfusion)

• episodic, acute transfusions to stabilize or
  reverse complications.
• Limited studies have shown that aggressive
  transfusion (get Hgb S lt 30) may help in sudden
  severe illness.
• May be useful before general anesthesia.
• Vichinsky et al., NEJM 1995

39
Transfusion in Sickle Cell(chronic transfusion
therapy)

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

40
Transfusion in Sickle Cell(chronic transfusion
therapy)

• Controversial uses
• Prior to contast media exposure
• Sub-clinical neurological damage
• Priapism
• Leg Ulcers
• Pregnancy

41
Transfusion in Sickle Cell

• Inappropriate uses of transfusion
• Chronic steady-state anemia
• Uncomplicated pain episodes
• Infection
• Minor surgery
• Uncomplicated pregnancies
• Aseptoic necrosis

42
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

43
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

44
Thalassemias

• The only treatments are stem cell transplant and
  simple transfusion.
• Chelation therapy to avoid iron overload has to
  be started early.

45
(No Transcript)
46
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

47
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.

48
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.

49
SELF (9 frozen pints of artists blood, frozen in
sculpture) Mark Quinn