r Bc Disorders

7/30/2019 r Bc Disorders

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Red Cell Disorders

Robert E. Richard, MD, PhD

Assistant Professor

Division of Hematology

University of Washington School of

Medicine

[email protected]

faculty.washington.edu/rrichard
mailto:[email protected]:[email protected]


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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).


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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

Definition:


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most accurately measured by obtaining a

RBC mass via isotopic dilution methods!

(Please dont order that test!)


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Review red blood cell disorders

Marrow Production


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Two main approaches that are

not mutually exclusive:

1. Biologic or kinetic approach.

2. Morphology.


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Anemia

Production? Survival/Destruction?

The key test is the ..

?


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The reticulocyte count

To be useful the reticulocyte count must be adjustedfor the patient's hematocrit. Also when the hematocritis 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 for25%, and 2.5 for 15%.)

Absolute reticulocyte count = retic x RBC number.


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Causes of Anemia (kinetic approach)

Decreased erythrocyte production

Decreased erythropoietin production

Inadequate marrow response to erythropoietin

Erythrocyte loss

Hemorrhage

Hemolysis


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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 signaldirectly 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/L)

Morphological Approach(big versus little)


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Underproduction

(morphological approach)MCV>115

B12, Folate

Drugs that impairDNA synthesis (AZT,

chemo)

MDS

MCV 100 - 115

Ditto

endocrinopathy(hypothyroidism)

Epo

reticulocytosis


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Underproduction

Normocytic

Anemia of chronic

disease Mixed deficiencies

Renal failure

Microcytic

Iron deficiency

Thal. trait

Anemia of chronic

disease (30-40%)

sideroblastic anemias


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Marrow production

Thalassemias

Myelodysplasia

Myelophthisic

Aplastic anemia

Nutritionaldeficiencies

Red cell destruction

Hemoglobinopathies

Enzymopathies

Membrane disorders

Autoimmune


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Acquired

Immunological

ToxinsBenzene Drugsmethotrexate, chloramphenicol

VirusesEBV, hepatitis

Hereditary Fanconi,

Diamond-Shwachman


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!).


Marrow Production - Aplastic Anemia


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Preleukemia, most commonly in the elderly.

Supportive care that involves transfusion

therapy is an option.

Poor response to growth factors


Marrow Production - Myelodysplasia


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Barosi G. Inadequate erythropoietin response to anemia:

definition and clinical relevance. Ann Hematol. 1994;68:215-223

(early review)


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Anemia associated with marrow infiltration

teardrops

Cancer, infections

Treatment is aimed at the underlying

disease

Supportive transfusions as needed.


Marrow Production - Myelophthisic


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Elevated reticulocyte count

Mechanical

Autoimmune

Drug

Congenital




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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 ahematocrit 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.


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Hereditary spherocytosis

Hereditary elliptocytosis

Hereditary pyropoikilocytosis

Southeast Asian ovalocytosis



membrane disorders


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membrane disorders


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G6PD deficiency

Pyruvate kinase deficiency

Other very rare deficiencies



enzymopathies


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Sickle Cell Anemia

Single base pair mutation results in a single

amino acid change.

Under low oxygen, Hgb becomes insolubleforming long polymers

This leads to membrane changes

(sickling) and vasoocclusion


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Red Blood Cells from Sickle Cell Anemia

OXY-STATE DEOXY-STATE

Deoxygenation of SS erythrocytes leads tointracellular hemoglobin polymerization, loss ofdeformability and changes in cell morphology.


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Deoxyhemoglobin S Polymer Structure

A) Deoxyhemoglobin S

14-stranded polymer

(electron micrograph)

D) Charge and size prevent

6b Glu from binding.

C) Hydrophobic pocket

for 6b ValB) Paired strands of

deoxyhemoglobin S

(crystal structure)

Dykes, Nature 1978; JMB 1979Crepeau, PNAS 1981 Wishner, JMB 1975


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Transfusion in Sickle Cell

(Controversy!)

Used correctly, transfusion can prevent

organ damage and save the lives ofsickle cell disease patients.

Used unwisely, transfusion therapy canresult in serious complications.

http://www.nhlbi.nih.gov/health/prof/blood/sickle/index.ht

m
http://www.nhlbi.nih.gov/health/prof/blood/sickle/index.htmhttp://www.nhlbi.nih.gov/health/prof/blood/sickle/index.htmhttp://www.nhlbi.nih.gov/health/prof/blood/sickle/index.htmhttp://www.nhlbi.nih.gov/health/prof/blood/sickle/index.htm


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Simpletransfusion give blood

Partial exchange transfusion - remove bloodand give blood

Erythrocytapheresis use apheresis tomaximize blood exchange

When to use each method?


(Controversy!)


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In severely anemic patients, simpletransfusionsshould 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) bedeferred.



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In general, patients should be

transfused if there is sufficient

physiological derangement to result inheart failure, dyspnea, hypotension, or

marked fatigue.

Tends to occur during an acute illnessorwhen hemoglobin falls under 5 g/dL.



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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.


(exchange transfusion)


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Exchange transfusion:

1. Bleed one unit (500 ml), infuse 500 ml of saline2. Bleed a second unit and infuse two units.

3. Repeat. If the patient has a large blood mass, do

it again.




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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.




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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




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Stroke

Chronic debilitating pain

Pulmonary hypertension

Setting of renal failure and heart failure


(chronic transfusion therapy)


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Controversial uses:

Prior to contast media exposure

Sub-clinical neurological damage

Priapism

Leg Ulcers

Pregnancy


(chronic transfusion therapy)


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Inappropriate uses of transfusion:

Chronic steady-state anemia

Uncomplicated pain episodes

Infection

Minor surgery

Uncomplicated pregnanciesAseptoic necrosis



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Thalassemias

Genetic defect in hemoglobin synthesis

synthesis of one of the 2 globin chains ( orb)

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


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Dx:

Smear: microcytic/hypochromic, misshapen RBCs

b-thal will have an abnormal Hgb electrophoresis(HbA2,HbF)

The more severe -thal syndromes can have HbHinclusions in RBCs

Fe stores are usually elevated

Thalassemias


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Thalassemias

The only treatments are stem cell transplant

and simple transfusion.

Chelation therapy to avoid iron overloadhas to be started early.


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Iron overload and chelation

Can occur in any patient requiring chronictransfusion therapy or in hemochromatosis.

Liver biopsy is the most accurate testthough MRI is being investigated.

Ferritin is a good starting test.

120 cc of red cells/kg of body weight is anapproximate point at which to think aboutiron overload


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Chelator, deferoxamine

25 mg/kg sq per day over 8 hours.

Supplementation with vitamin C may aidexcretion.

Otooxicity, eye toxicity, allergic reactions.

Discontinue during an infection. Oral chelators are in development.

Iron overload and chelation


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Conclusions

Transfuse for any severe anemia with

physiologic compromise.

Decide early whether transfusion will berare or part of therapy.

Avoid long-term complications by working

with your blood bank and using chelationtheraoy.


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SELF (9 frozen pints of

artists blood, frozen in

sculpture)

Mark Quinn

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