Anemias and Red Cell
Disorders
Jeffrey T. Reisert, DO
University of New England
Physician Assistant Program
25 FEB 2010
Contact Information
Jeffrey T. Reisert, DO
Tenney Mountain Internal Medicine, PLLC
16 Hospital Rd.
Plymouth, NH 03264
603-536-6355
603-536-6356 (fax)
Jeffrey.T.Reisert@Hitchcock.org
Case
You are referred a case from one of your
healthy patients. He was told the “Red
Cross didn’t want my blood.”
 You rarely see this healthy fellow
 You have no additional information

Case work up
Does he have anemia
 Does he have AIDS or something?
 What do you need to

– What tests are needed
– What is considered a reasonable work-up with
his story
Objectives
Participants will be able to analyze the CBC
(carry over from prior coursework on CBC)
 Develop an understanding of anemias and
polycythemias
 Given a hematologic case presentation,
students will define a common disorder and
its treatment.

Agenda
Analyzing the Complete Blood Count
(CBC)-A Quick Review
 Abnormalities of Hemoglobin synthesis
 Microcytic Anemias
 Normocytic Anemias
 Macrocytic Anemias
 Polycythemias
 Other disorders

The CBC
Complete Blood Count
 You have had this, right?
 First focus, the red blood cell

Red Blood Cell
Carries oxygen and nutrition to cells
 Survive about 120 days
 Contains hemoglobin molecule
 Requires erythropoietin for production
(kidneys)

Red Blood Cell synthesis
Pluripotential precursor (bone marrow)--->
Proerythroblasts--->Erythroblast
Normoblast--->Normocytes (Nucleated RBC)
--->Reticulocyte --->Erythrocyte (RBC)
Reticulocyte




Immature RBC
Usually less than 1.5% of total RBC’s
Seen in larger quantities after bleed, about 72 hours later
(Stress reticulocytosis)
Stains for reticulin
– New methylene blue stain, others
– Must be requested specifically by lab (not reported on normal
CBC)

Larger than mature RBC
– Will increase average cell size (MCV)
– If plentiful will increase RDW
Erythrocyte (RBC)
Normal, mature, red blood cell
 Biconcave disk

– Like a bagel (or donut…..Your choice!)

No nucleus
Hemoglobin molecule







Normal Hb (Hb A) 2 alpha chains, 2 beta chains
Hb F= 2 alpha, 2 gamma (Fetal Hb)
Hb A2= 2 alpha, 2 delta (Thalassemia)
Hb S= Single AA substitution on beta chain (Beta
s (βs) Sickle disease if in both beta globins)
Hb C=Beta c genotype (βc)
Hb Barts=γ 4. Seen in children
Hb H=β4 in adults
Example of geneticsHemoglobin C disease
If Hb C trait no symptoms
 If two Hb C traits, mild anemia
 If combined with Hb S, sickle variants with
sickling under stress

Hemoglobin electrophoresis
Adults 97% Hb A
 About 3% Hb A2


Handouts
CBC (See overhead, too)
Red Cell Count-Number
 Hemoglobin-Weight
 Hematocrit-Percentage of red cells
 MCV-Volume
 MCH-Hemoglobin
 MCHC-Hemoglobin concentration

Rule of 3’s
Hematocrit is generally 3x the Hemoglobin
 Eyeball for accuracy
 Is HCT better or Hb?

CBC continued

RDW-Distribution width


Variability of size
Reticulocyte count
– Increased in Hemolysis, Acute blood loss,
Treatment
Other tests-I

Iron
– Low in iron deficiency and chronic disease
– Test reduces Fe+3 and adds reagent that forms
color to measure

TIBC-iron binding
– High in iron deficiency

Body’s attempt to increase iron carrying capacity
– Low in chronic disease, Hemochromatosis,
sideroblastic
Other tests-II

Ferritin
– Reflective of iron stores
– Phase reactant protein (Goes up in acute illness)

% Transferrin sat. (Fe x TIBC x 100%).
Elevated in:
– Hemochromatosis
– Sideroblastic anemia
Other Acute Phase ReactantsFYI

Go up in face of acute illness
–
–
–
–
–
–
C reactive protein
Alpha 1 antitrypsin
Haptoglobin
Fibrinogen
Ceruloplasmin
C-3 Complement
Bone Marrow Biopsy



Perhaps most invasive hematologic test
Uses core needle to obtain aspirate and core
biopsy
Slides prepped at bedside
– Microscopic
– Iron assessment

Genetic tests
– I.e.: Philadelphia chromosome

See handouts for techniques
Pause here
Any questions so far?
 Diseases next…..

Basic Definitions
Anemia-Low Red cell count
 Polycythemia-High Red cell count

Disorders of Hb synthesis

Sideroblastic anemias
–
–
–
–



A general term for failed synthesis
Also can be idiopathic (Idiopathic sideroblastic anemia)
Results in a delay……..Process is held up/stuck
As a result, abnormal red cell
Sickle cell anemia
Thalassemia
These change the O2 affinity of the molecule or
make molecule unstable
Sideroblastic anemias

Two categories conceptually
– Sideroblastic anemia-Idiopathic/Primary
– Sideroblastic anemias-A broad term incorporating
several different anemia types with key feature

Etiology: Problem with globin
synthesis/maturation
– Thalassemia, Sickle cell, Idiopathic


Also caused by alcohol, lead, INH (a treatment for
TB), chemotherapy
Increased ring sideroblasts in bone marrow
Sideroblastic anemias-II
Often dimorphic (two different populations
of cells)
 May be micro-, normo-, or macrocytic
 Iron Nl or Inc., % transferrin Sat high
 Abnormal amount of red cell precursors

– Immature cells that stain with Prussian blue
stain
Sickle cell disease

African Americans
– Trait 8%, 1/625 disease



Single amino acid substitution (valine for glutamic
acid at 6th AA in beta chain due to substitution of
thiamine for adenine in DNA)
Hemoglobin Beta s (βs )
Sickle disease if in both beta globins affected
Sickle cell disease-Symptoms
Sickling occurs at low oxygen tension
 Chronic anemia, abnormal smear
 Painful crises due to blood flow obstruction
 Typically die of infection
 SC variant (Hb S + Hb C), Hb S/Beta Thal

Sickle cell-Treatment






O2
IV fluids
Transfusion
Analgesia during crisis
Asplenic-Need Strep. pneumoniae vaccine
(Pneumovax®), meningococcal (N meningiditis)
vaccine, H. influenza vaccine- “Encapsulated
organisms.”
Hydroxyurea chronically
– Increases Hb F (Increases gamma chains)
– Resultant decrease crises and mortality
Thalassemias

Mediterranean's, N. Africans
– Thalassa (Greek for the sea)

Most common monogenic disease in humans
– Up to 3-10% of population in some regions

Develop ineffective erythropoeisis
– Expanded bone marrow
– Splenomegaly
– Extramedullary erythropoesis



Typically Microcytic, hypochromic anemias
Typically normal iron, TIBC, ferritin
Typically very microcytic, not very anemic
Thalassemia types
Minimal, Minor, Intermedia, or Major
 Alpha
 Beta

Alpha Thalassemia
Alpha globin is deficient
 Relative excess of beta chain
 Result is decreased Hb A (70-95%)

– If none at all, fatal (Hydrops fetalis)

May require splenectomy
Alpha thalassemias cont.
Deletion of 1 alpha chain in about 30% of
African descent-Asymptomatic
 Deletion of 2 called “alpha trait”
 Deletion of all but one, Hb H in adults or
Hb Barts in children
 Deletion of all 4 alpha incompatible with
life

Beta Thalassemia
200 different mutations can cause
 Beta (Can’t make beta globin)

–
–
–
–
Increased Hb A2 (> 4-5%) and Hb F
Excess of α-globin chains
Β0 thal-no beta globin
B+ thal-some beta globin
Beta thalassemia types

Major
–
–
–
–

No beta globin (B0 thal or alpha 4)
Diagnosed first year of life
Cooley’s anemia--->Hemolysis
Transfusion dependent
Intermedia
– Presents later
– Typically both parents are heterozygotes

Minor
– Common
– 1 mutant Beta gene

Minima
– Silent carrier
– 1 mutant Beta gene
Thalassemia treatments


Screening
Blood transfusion with iron chelation
– Iron overload is biggest problem
– Deferoxamine (Desferal®)-iron chelator IM or IV
– New one coming (NEJM 2006)



Splenectomy
Give folic acid if deficient
Hydroxyurea
– Increases HbF


Bone marrow transplant
Gene therapy
G6PD deficiency








Most common red cell enzyme deficiency
Sex linked/X linked
400 different variations
12% African Americans, 20-30% Greeks
Increased risk of hemolysis under stress
Many drugs including sulfa drugs, nitrofurantoin
and others, fava beans
Diagnosis made by measurement of the RBC
enzyme
Treatment: Avoid these medications, stress
How to think about anemias

Two ways I suggest:
– By size
– By marrow activity
Anemia classification by size






Uses MCV off of the CBC
Small cell sized anemias-Microcytic
Normal cell size anemias-Normocytic
Large cell size anemias-Macrocytic
We will discuss these at length
One downfall is that some anemias can be two
– I.e.: anemia of chronic disease may be normo or
microcytic
– Thus, anemia is more of a spectrum of diseases, but still
helpful to use this categorization (I think)
Anemia by marrow activity

Hypoproliferative anemias
–
–
–
–

Sluggish marrow
Uses the reticulocyte as gauge
Low retic count, low bone marrow activity
Example: Aplastic anemia
Normoproliferative anemias
– Reticulocyte count is usually normal
– Example: Sickle cell anemia

I don’t use this one
– I don’t find as helpful
– Some do use the term, however
Anemias by size
“The diseases”
 Here we go……..

Microcytic anemias
Iron deficiency
 Anemia of chronic disease
 Sideroblastic anemias
 Lead-Children
 Thalassemia-As discussed previously

Iron deficiency
MC cause of anemia in world (tapeworm)
 MC in USA (menses)
 Low iron (<50), increased TIBC, Low
Ferritin
 Hypochromic
 GI vs. Gyn loss

– Must look for cause
Iron deficiency-treatment

325mg FeSO4 TID
– Contains 50mg elemental iron
– 3-4 days to respond
Also available as gluconate, IM, IV
 We use sodium ferric gluconate complex
(Ferrlecit®) 125mg IV weekly for 2-8
weeks. Others too.

Anemia of Chronic
disease/inflammation
Low iron (50-100), Low TIBC, Nl or Inc
Ferritin
 Often normocytic early
 Treatment: Treat cause

IDA-vs-ACD
FE
TIBC
Ferritin
Iron
deficiency
Low
High
Low
Anemia of
Chronic
Disease
Low
Low
High
Normocytic Anemias
Acute blood loss
 Pregnancy

– Dilutional
– Iron deficiency (though often microcytic)
Hemolysis (Include G6PD defic, PNH)
 Hypersplenism
 Spherocytosis, Myelophthesis, Aplasia

Normocytic Anemias-Part II

Renal failure
– Low erythropoietin
– Rarely is macrocytic
Myelophthesis (BM space occupying
lesion)
 Mixed (i.e.: Fe and Folate defic.)
 Others

Hemolytic anemia
Elevated LDH, serum bilirubin and urinary
bilinogen
 COOMBS test for circulating antibody to
red cell
 Haptoglobin low (used up)
 Causes multiple

Hemolytic anemia-Etiology

Congenital
– Spherocytosis, elliptocytosis, G6PD, Sickle cell
– A sort of chronic hemolysis
– Would these be hypo or normoproliferative?

Acquired
– Drugs, Infection (HIV, Ebstein Barr virus (EBV),
chlamydia),
– Immune, Splenomegaly, DIC,
– Paroxysmal Nocturnal Hemoglobinuria, Trauma (heart
valve)
Hemolytic anemia-Treatment
Supportive
 Immune suppression
 Intravenous immunoglobulin (IVIG)
 Folic acid (Folate)

– Helps as cofactor for BM production
– 1g per day po
Hypersplenism

Collection of different etiologies
– Infiltrative
– Malignancies
– Cirrhosis
Result in pancytopenias due to destruction
and engulfment of cells
 Not same a big spleen

Macrocytic Anemias









B12/Folate deficiency
Liver disease
Alcoholism
Aplastic anemia (lowers B12). IE: chemotherapy
Hypothyroidism
Myelophthistic diseases-Replacement of marrow with
fibrosis, infiltration (sarcoidosis), infection (TB)
Myelodysplastic diseases-Preleukemic state
Renal disease (Usually normocytic)
Pseudomacrocytosis
Folic acid (folate) deficiency
More common
 Seen perhaps most often in alcoholism
 Elevated LDH

Vitamin B12 deficiency

Pernicious anemia (MC)
– Lack of intrinsic factor or ileum

Malabsorption
– Alcoholism
– Diphyllobothrium latum (fish tapeworm)
– Dietary deficiency rare due to fortification of flour with


Elevated LDH
Treatment
– Oral supplement if able to absorb
– IM B12 if not (i.e.: PA) typically monthly
– Nasal spray (expensive) daily
Liver disease
Several reasons for anemias
 Include problems with synthesis,
destruction, loss

Alcohol affect on blood
Macrocytosis
 Anemia, leukopenia, thrombocytopenia
 Decreased synthesis in marrow
 Increased destruction

– Toxic effect
– Hypersplenism

Increased loss
– Hemorrhage (IE: varices)
Pancytopenias/Bicytopenias







Know this differential!
B12/Folate deficiency, Hypersplenism
Aplastic anemia, Alcohol, Lupus
Viral (HIV, others)
Myelophthesis
– Space occupying lesion of marrow
Myelodysplasia
– Unstable, unregulated growth of marrow
Paroxysmal nocturnal hemoglobinuria PNH-(next slide)
Myelodysplasia

Aged bone marrow
– Old people
– Pre-malignant state

Clue is abnormal counts
– Macrocytosis common

Treatment difficult
– Erythropoietin?
– Transfusion dependence?

See handouts for types
Paroxysmal Nocturnal
Hemoglobinuria (PNH)
Defect in production of Glycosylphosphatidyl-inositol (anchor protein)
 Hemolytic anemia

– Increased reticulocyte count
Pancytopenia
 Intermittent hemoglobinuria
 Increased risk of venous thrombosis

PNH Continued

Diagnosis
– Genetic test
– Ham’s test (lysis at pH 6.2)
– Sugar (sucrose) water test-lysis

Treatment
–
–
–
–
–
–
–
Supportive
Iron if needed
Folic acid (hemolysis)
Possibly steroids (debated)
Anticoagulation/Warfarin
Androgens?
Gene therapy?
Elevated iron
Not an anemia, but due to excess of metal,
iron. Never the less, cover here.
 Hemochromatosis

– 1% of Caucasians
– TIBC low, % saturation high
Aplastic anemia
 Myelodysplasia
 Myelophthesis

Iron deposition
Heart (Cardiomyopathy)
 Liver (Function affected, or even cirrhosis)
 Pituitary
 Pancreas (Diabetes can develop)
 Thyroid
 Parathyroid
 Adrenals

Polycythemias

Rubra Vera (Spurious or primary
polycythemia)
– Increased RBC mass, normal O2, splenomegaly
– Treatment: Phlebotomy

Secondary
– COPD
– Stress-Gaisböck's syndrome (tobacco)
– Treatment: Treat disease
Treatment of Anemias and
Coagulopathies
Transfusion
 Phlebotomy
 Others

–
–
–
–
Fix cause
Iron
B12
Etc.
Transfusion Therapy
Whole blood
 Packed red blood cells
 Platelets

– Derived from several donors
– Single phoresis donation
Require type and cross match
 Can request type and screen if may or may
not need transfusion

Transfusions cont.

Fresh frozen plasma
– Long storage
– Coagulopathies with factor deficiencies
– Volume expansion

Cryoprecipitate
– Contain extra Factor VIII and vWF
Transfusion Reactions
Immediate type immune mediated
hemolysis
 Delayed type
 Febrile non-hemolytic
 Graft vs. host disease (bone marrow
transplant)
 Fluid overload
 Infection (bacterial, viral)

Phlebotomy

To obtain blood products
– Whole blood
– Pheresis

Therapeutic
– Iron overload
– Polycythemias
Case study








What do you want to know?
Letter from Red Cross?
Serologies to r/o infection (Hepatitis, HIV)?
Repeat CBC-Most definitely
Iron levels? Other tests?
?GI work up (endoscopy?)
PA’s and PCP’s should all be able to do a work-up
for anemia…..doesn’t need a hematologist
Look for common things
Where to get more information
Harrison’s or Cecil’s textbooks of Internal
Medicine
 Any Hematology text (i.e...: Hoffman et al)
 The Beta-Thalassemias (NEJM Vol 341,
No. 2, July 8, 1999, pgs 99-109)
