Treatment of

Hemolytic Anemias
Felicia L. Wilson, M.D.
Professor of Pediatrics
Director, Division of Hematology/Oncology

Normal Red Blood Cells

(RBCs)

Normal RBCs

Normal RBCs maintain themselves in

physiological state by metabolizing
glucose through the glycolytic &
pentose-phosphate shunt pathways.

In this way they generate the energy

needed for maintaining

Shape & flexibility

Cation and water content through action of

sodium and calcium pumps

Reducing power is also generated as

NADH, NADPH & reduced glutathione
(GSH) protect the membrane,
hemoglobin and other cell structures
from oxidant damage

Red Cell Metabolism

2,3-DPG is the most

abundant RBC phosphate

Important in maintaining the

position of the O2
dissociation curve.

The higher the content in

RBCs, the more easily
oxygen is liberated from
hemoglobin.

Hemolytic Anemias
Increased

RBC destruction

shortened

survival

Hereditary (intracorpuscular) defects of

membrane

enzymes
globin

Acquired

(extracorpuscular) causes

Immune
Nonimmune

Physical Features
Pallor
Jaundice

Tachycardia
Heart

murmur
Splenomegaly

Laboratory Features

Reticulocytosis

Increased
Bilirubin
LDH
AST

Hemoglobinuria
Hemoglobinemia
Hemosiderinuria

Case # 1

A 18 month old African-American male

presents to the emergency room with
low-grade fever, decreased appetite and
painful swelling of his hands. He
received a dose of Tylenol at home but
did not get any relief.

On physical examination, he is fussy,

but consolable and is tachycardic with a
III/VI systolic ejection murmur. The
spleen is palpable 2 cm below the left
costal margin.

The CBC reveals a hemoglobin of 8.3

gm/dl, hematocrit 24%, MCV 78, RBC of
3.2 MIL/l and a retic count of 8%.

100,000 cases

RBC Function

One RBC contains ~ 250 million hemoglobin molecules and each

hemoglobin can bind 4 molecules of oxygen. During each circuit of
the body, a single RBC carries ~ one billion molecules of oxygen.

Polymerization of HbS

Deoxygenated Sickle
Hemoglobin

Sickling and Membrane Injury

Manifestations of Sickle Cell Disease

normal
RBC
vessel
occlusion

vessel
occlusion

Vaso-occlusion

Sickled Erythrocytes
Endothelial Cells

Vascular injury
Hemolytic anemia

Complications in Sickle Cell Disease

Organ

Complication
(%)

Bones

Vasoocclusive
Episodes

Pain/Infarcts (1-2 events/yr

> 70%)

Spleen

Infarction (90)
Sequestration (11)
Infection (15)

Lungs

Acute chest syndrome (40)

Liver

Gallstones (42)
Sequestration

CNS/Eyes

Strokes (10)
Proliferative retinopathy (12)

GU

Hypostenuria (50)
Renal failure (3)

Dactylitis

Often the 1st

manifestation of SCD

Jaundice 35%
HSM 50-75%

Ischemic necrosis of
small tubular bones
of the hands &/or
feet

Often bilateral

Dactylitis
Hand-foot
Syndrome
Characterized by
soft tissue swelling,
heat & tenderness
Peak age 2 years
(6 months 8 years)

Destructive Bone Lesions of

Dactylitis

Unequal Growth of Digits

Pain is an indication of tissue damage.

Most common reason for hospitalization and ER visits.
Recurrent pain is known to be associated with early death.
Pain crisis is a diagnosis of exclusion!

World Health Organization

3-Step Ladder

Cooperative Study of
Sickle Cell Disease

Initiated in 1978 by NIH to gather data

prospectively on the natural history of
SCD

Cohort of 2824 patients registered,

followed, and managed (4007
registered)

23 clinical centers in the US

CSSCD Mortality Data

Infection - major cause of morbidity & mortality

S. pneumoniae - most common during early childhood
Enteric organisms emerge as important pathogens in older patients
Leinken et al. Pediatrics. 1989;84:500.

Cell mediated immunity and humoral immunity

Immune Dysfunction

Penicillin Prophylaxis Study

PROPS - I

13/110
Infections,
3 deaths

2/105
Infections,
No deaths

NEJM, 1986 314:1593-9

Study was
terminated
8 months
early

IMMUNIZATION

as recommended by the AAP

PCV13 (conjugated pneumococcal vaccine)

pneumococcal vaccine

23-valent polysaccharide vaccine

Age 2 years

Booster age 5 years

meningococcal vaccine

influenza vaccine

HPV (human papilloma virus) vaccine

STREPTOCOCCUS PNEUMONIAE

Deaths continue to occur

despite PCN prophylaxis

Non-compliance

Inappropriate outpatient
management

400 fold above normal

population

Septicemia

Meningitis

Pneumonia

Septic Arthritis

Resistance

22-25% - penicillin

15% - cephalosporin

50% - macrolide

Transfusion Therapy in SCD

Episodic Transfusions

Symptomatic Anemia
ASSC
Aplastic crisis
Stroke or acute neurological event
ACS
Multiorgan failure
Preoperative management

Chronic Transfusions

Primary and secondary stroke prevention

Recurrent ACS not improved by hydroxyurea
Progressive organ failure
Recurrent ASSC
Complicated Pregnancy

Modulators of SCD
Severity
Fetal

Hemoglobin

1948

SCD babies rarely have problems in 1st yr of life

High Hb F levels protects the infant

1975

Dr. Janet Watson

Stamatoyannopoulos et al.

HPFH > 20% F in all cells

Fetal Hb disrupts polymerization
Few pts with SCD have F > 10% in some cells

Multicenter National Trial 1991

FDA

approved 1995
50% reduction in pain crises, ACS and need for transfusion
40% reduction in deaths

The Cure
To date, > 300
Bone Marrow
Transplants have been
performed around the
world for
Sickle Cell Disease.

Outcome After Transplantation

BMT Patient with SCD & AML

Case #2

One of your friends went on a

mission trip in the Mediterranean

She adopted this little boy from

an orphanage and doesnt know
anything about his PMH or FH

Since arriving in America he

seems tired and depressed and
doesnt want to do much

She wants you to be his primary

care provider and recommend a
good dentist

Peripheral Smear

Abnormal shapes, red cell rigidity

& fragmentation

 Thalassemia Major

Results from inheritance of two impaired globin

genes

Profound anemia secondary to ineffective

erythropoiesis with impaired production of Hb A

Presents in early infancy with anemia, paleness,

weakness, failure to thrive, splenomegaly

Transfusions are necessary for survival

Oliveri,N. NEJM 1999;341(18):1407

200 Mutations Causing Thalassemia

Adult Hemoglobin

Globin chains
- alpha
- delta
Hemoglobin
A1 - 2 2
A2 - 2 2
F - 2 2

- beta
- gamma

 - Thalassemia
Decreased synthesis of chains

Relative excess of chains

chains
Increased Synthesis

2 2 (Hb A2)

chains 2 2

(Hb F)

Age 4 low transfusion

Age 11 high transfusion

Treatment for
-Thalassemia Major

Transfusions are the mainstay of therapy

Goal is to maintain Hg >9.5g/dl

Requires transfusions every 2 to 4 weeks

Advantages include:

Improved physical and psychologic well being

Decreased cardiomegaly
Decreased hepatosplenomegaly
Fewer bony changes and orthodontic problems
Normal or near normal growth until adolescence

However, patients become severely iron overloaded

Case # 3
18 month old
Fever
Stuffy nose
Decreased activity
Sleeping more
Rash

Peripheral Smear

Hereditary Spherocytosis

Most common cause of non-immune hemolytic anemia

Autosomal dominant transmission

25-30% sporadic mutations

Loss of membrane surface area relative to intracellular

volume spheres and decreased deformability

Extravascular hemolysis in the spleen

HS

Abnormalities of spectrin and/or ankyrin, and

less commonly Protein 4.2 or Band 3

Clinical Manifestions of HS

Hemolytic anemia
Degree of anemia varies with different mutations
25% with compensated hemolysis and no anemia

Pallor, fatigue
Jaundice
Neonatal jaundice in first 24 hours of life
Splenomegaly

Gallstones
Positive family history
May present with parvovirus associated aplasia

Laboratory Manifestations of HS
Spherocytes on
peripheral blood smear
Reticulocytosis
Increased incubated
osmotic fragility
Negative DAT
Increased MCHC > 36%
due to relative cellular
dehydration
Increased bilirubin, LDH

Incubated Osmotic Fragility

Testing

Normal Osmotic Fragility

Red cells are incubated in varying

concentrations of saline (0
0.9%) for up to 48 hours
As concentration of saline
decreases, cells take on water and
are hemolyzed

Increased Sensitivity to Lysis

Normal cells around 0.5%

HS cells at higher NaCl concentrations

Degree of hemolysis is detected by

spectrophotometry
Not reliable < 6-12 months of age

Treatment
Folic

acid supplementation

Transfusion

if anemia is severe

Splenectomy

Indications for Splenectomy

Controversy re: need for and timing of splenectomy

Splenectomy typically leads to marked improvement in RBC
survival and laboratory parameters
Risk of gallstones is reduced (but not gone)
Complications include local infection, bleeding,
postsplenectomy sepsis, thrombosis, cardiovascular disease,
pulmonary HTN
Pneumococcal, meningococcal vaccines preop
Indications: growth failure, skeletal changes, transfusion
dependence, massive splenomegaly

Case #4

3 yo WM

Playing hide and seek

with the baby sitters
grandson

Mom noticed peculiar

smell, dark urine and
found these in his pocket

Hemoglobinuria

G-6-Phosphate Dehydrogenase

Regenerates NADPH, allowing

regeneration of glutathione

Protects against oxidative

stress

Oxidative stress leads to Heinz

body formation &
extravascular hemolysis

G6PD Deficiency

Most common red cell enzymopathy

X linked inheritance
Decreased production of NADPH with inability to
maintain reduced glutathione levels
Hemolysis occurs in response to oxidative stresses such
as infections, drugs, fava beans (favism), naphthalene
(moth balls)
Anemia may be low grade and chronic (CNSHA) or acute
after exposure to oxidant
Denatured hemoglobin seen as Heinz bodies on blood
smear; also with blister cells on smear
Reticulocytes have 5X higher G6PD, so assay after
resolution of hemolytic crisis

Treatment for G-6-PD

Avoid precipitating
factors

Infections
severe stress
certain foods (such
as fava beans) and
certain drugs

Rest during episodes

Transfuse if
necessary

Antimalarial drugs
Aspirin
Nitrofurantoin
Nonsteroidal antiinflammatory drugs
(NSAIDs)
Quinidine
Quinine
Sulfa drugs

RBC Enzyme Disorders

RBC enzymes are important

for:

Energy production through

glycolysis and the pentose
phosphate shunt
Maintaining cation gradient
Protecting from oxidative damage
Production of 2,3 DPG
Maintenance of ferrous 2+ iron
Nucleotide salvage

Abnormalities result in diverse

phenotypes

Pyruvate Kinase Deficiency

Autosomal

recessive enzyme
dysfunction leading to anemia that is
chronic rather than episodic

Transfusion

is the mainstay of therapy

Case #5
14

yo WF at UMS track meet Wednesday

night

It

was the first day of spring so she

thought it would be warm, instead she
was freezing

Yesterday

she noticed tea colored urine

and got concerned

Autoimmune Hemolytic Anemia

Treatment Cold AIHA

Treat underlying cause
Causes: Mycoplasma, EBV, HIV, CLL

Avoid cold triggers react at 28-31 degrees C

Steroids/splenectomy/IVIG
Rituximab

Try to avoid transfusions

Treatment for Warm AIHA

Causes: Lupus, Rheumatoid Arthritis, CLL,
methyldopa
IgG reacts at 37 degrees C

Steroids & folic acid, IVIG - frontline

Splenectomy, rituximab 2nd line
Immunosuppression cyclophosphamide,
imuran, MMF

Try to avoid transfusions

Treatment for PCH

Causes:

Measles, Mumps, EBV, CMV,

Mycoplasma, syphilis, HIV

Self

limited

Treat

underlying cause

Case #6

15 yo WM

Vomiting, bloody diarrhea started 1 week ago

Now 1 week later c/o weakness

Hemoglobin is 9 and pt referred to USACWH EC

Treament of
Hemolytic Uremic Syndrome
E.

coli bacteria O157:H7 toxin

Also

linked to shigella & salmonella

Dialysis

Steroids
Transfusion

of pRBCs and platelets