DN is a 26 yo man admitted for painful sickle

cell crisis for one and a half days . He

describes the pain as generalized, but
especially affecting his chest and legs. He
denied any fevers or chills, cough, or
shortness of breath.

PMH: Sickle cell anemia with frequent

admissions for pain. In the last year he has
been hospitalized for 143 days. ITP, treated
with prednisone, Cholecystectomy, Penile
prosthesis
Meds: prednisone, folate, MS Contin,
Dilaudid
PE: thin, african-american man in distress
VS: P 108 RR 18 BP 145/81 T 98
Lungs: clear
Cardiac: reg rhythm, flow murmur
Abd: soft, nontender, liver 8 cm
Neuro: intact

Labs:WBC 46 Hct 22.5 Plt 266

CXR: no effusions or infiltrates
He was admitted and treated with
morphine, IV hydration, and oxygen.
Pain service was contacted and the
patient was placed on a PCA pump. His
hematocrit decreased to 17 and he
received two units of PRBCs. He was
slowly weaned from the PCA device and
treated with oxycodone. He was
discharged after 13 days in the hospital.
Sickle Cell Anemia

Fall 2007
Bob Richard
rrichard@u.washington.edu
 James B. Herrick

American Heart Association

James B. Herrick Award
For Outstanding Achievement In
Clinical Cardiology

“Clinical Features of Sudden

Obstruction of the Coronary
Arteries” published in 1912.

(he also described sickle cell disease)

Pauling, L and colleagues, Science Vol. 110, 1949
 Internal Affections, Hippocrates
(460-377 B.C.E.)
“Another sickness of the spleen. It comes on mainly in the
springtime and is caused by the blood. The spleen
becomes engorged with blood, which evacuates into the
stomach. Shooting pains in the spleen, the breast, the
clavicle, the shoulder, and beneath the shoulder blade.
The body’s coloration resembles lead. Sores form on
the leg and become large ulcerations. The discharges
with the feces are bloody and bluish green. The belly
hardens and the spleen is like a stone. This one is more
murderous than the one before, and few survive it.”
Hemoglobins

• Single base pair mutation results in a

single amino acid change.
• Under low oxygen,
HbF
Hgb becomes insoluble
HbA HbS
forming long polymers HbA2
• This leads to membrane changes
s
(“sickling”) and vaso-occlusion
From Connie Noguchi, NIH
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 B) Paired strands of C) Hydrophobic pocket
14-stranded polymer deoxyhemoglobin S for 6b Val
(electron micrograph) (crystal structure)

D) Charge and size prevent

6b Glu from binding.

Dykes, Nature 1978; JMB 1979

Crepeau, PNAS 1981 Wishner, JMB 1975
 Schrier, S. ASH Image Bank 2001;2001:100248

Copyright ©2001 American Society of Hematology. Copyright restrictions may apply.

An intact RBC with an eccentrically placed hemoglobin C crystal is noted in the center of the
image

Lazarchick, J. ASH Image Bank 2005;2005:101384

Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.
Clinical Consequences of Sickle Disease
• Vaso-occlusion (pain)
• Stroke
• Proliferative retinopathy
• Acute Chest Syndrome/Pulmonary
Hypertension
• Gallstones
• Splenic
sequestration/infarcts/hyposplenis
m
• Renal insufficiency
• Avascular necrosis
• Spontaneous pregnancy loss
• Priapism
• Osteonecrosis
• Non-healing skin ulcer
 Hemoglobin polymerization is not
the whole story
• Wide spectrum of disease phenotypes
• Some patients have mild disease

• 24 yo AA man in the army presents to the infirmary

complaining of fatigue. CBC shows a Hgb of 8.5. Retic
of 4.5%. Total Bili of 3.0. He is transferred to Walter
Reed and sickle cell is diagnosed.

• NEJM 2007 Elderly Survivors with Homozygous Sickle

Cell Disease (letter)
 Clinical Variability!
• SS vs SC vs Sβ-thal
• Modifier genes (Epistasis)
• Hgb F (α2γ2)
• α – Thal ?

• “Polymorphisms near a chromosome 6q QTL area are associated

with modulation of fetal hemoglobin levels in sickle cell anemia”.
Steinberg lab, Cell Mol Biol 2004 Feb;50(1):23-33.
• “Genetic dissection and prognostic modeling of overt stroke in sickle
cell anemia”. Steinberg Lab. Nat Genet 2005 Apr;37(4):435-40.
Senegal haplotype
was associated The best HbF response to HU were
with higher less likely to have their HbS gene
hemoglobin levels on a Bantu haplotype chromosome
 Different pathophysiology
Two subphenotypes?
Vaso-occlusion Hemolysis
(NO resistant state)

Pain, ACS, AVN Pulm HTN, ulcers

priapism, ?stroke

HbF, WBC LDH, Bili

HU more effective HU less effective

 Prevalence
• Sickle cell anemia affects 0.16% of
African-Americans (80,000 and increasing)
• 1000 births a year in the US
• 120,000 in Africa
• Sickle trait is present in 8%
• Sickle cell disease includes SS, SC, S-thal
• SS makes up 50% of sickle cell disease
Cooperative Study of Sickle Cell Disease, NEJM, Vol 330, No 23, 1994
 Adult Sickle Cell Mortality
Platt, et al, NEJM 1994

• Pain episodes (~1/2 ACS) 22%

• Unknown 18%
• Stroke 7%
• Trauma 6.7%
• Perioperative 6.7%
• Infection 6.2%
• CRF, CHF 15.8%
Autopsy study - BJH, 2004

• 306 autopsies from

1929 – 1996
• 56 0 – 2 years old
Autopsy study - BJH, 2004
Age 0-2 3-11 12-17 >18

Infection 80.4 60.6 62.1 35.1

Stroke 6.5 9.1 10.3 8.4

Therapy com. 0 0 13.8 9.9

Emboli 0 0 0 9.9

Sequestration 28.3 9.1 3.4 0.5

Chronic Organ Failure 0 3 10.3 13.1

Most deaths occurred outside of the hospital or within 24 hours of admission

 Mortality Studies
Good prognostic markers
1. Female
2. SC
3. Hgb > 7.1
4. HbF elevated
5. WBC < 15.1
 Pain in Sickle Cell Disease
Natural history study of 3578 patients (Platt et al., NEJM 325:11-16, 1991):
Average pain rate:
HbSS: 0.8 episode per patient year
HbSb0 thalassemia: 1.0 episode per patient year
HbSC and HbSb+ thalassemia: 0.4 episodes per year
Wide variation:
39% of patients with HbSS had no episodes of pain
Only 1% of patients had >6 episodes per year
5% of patients had 33% of episodes
Increased pain correlated with:
Higher hematocrit (increased viscosity)
Low fetal hemoglobin levels (pain rate inversely
proportional to [HbF]2
Early death
 Pain Management
BELIEVE THE PATIENT
IV Fluids (D5 1/4 NS)
Acute Pain Service
Patient Care Plan
Narcotic analgesics - AVOID meperidine
(demerol): Hydromorphone (Dilaudid), MSO4
NSAIDs – Ketorolac et al., Cox 2 inhibitors
O2 - for hypoxia
 Seamless Management of Pain in Adult Patients with
Sickle Cell Diseases
Donald Rucknagel1,2,3, Annette Lavender1,3, and Zahida Yasin1,3
Cincinnati Comprehensive Sickle Cell Center1, Divisions of Pediatric2 and Medical3 Hematology/Oncology, University of Cincinnati

Background Methodolog Discussion

y
The pain of sickle cell diseases may be:
Integral to the preceding is excellent communication and
1. Acute
Of variable severity. Pain cooperation with the emergency department. A spreadsheet there
appraises them of each patient’s special needs and contains
Localized
recommendations for initial analgesia, based upon tolerance of
Migratory
each
Generalized
patient evident during prior hospitalizations.
Duration may be minutes, hours, days or weeks
2. Chronic
The visits to the emergency department appear to have
decreased with the implementation of this process, as have the
We have developed a methodology over a period of years based upon
number of hospitalizations.
the following observations:
1. Good analgesia requires utilizing equianalgesic principles;
In our experience, “drug seeking behavior” has five causes:
2. If analgesia is not adequate patients will manipulate, thereby
1. Inadequate analgesia;
creating mistrust and conflict with medial staff;
2. Pain avoidance, due in large measure, to the
3. Emergency department visits for moderate pain may occur
psychological association of pain with mortality;
simply because they lack analgesics at night and have
3. Self-medication of psychological illness--anxiety or
no recourse.
Mild Moderate Severe depression--with narcotics;
4. Selling or trading their medications;
Our methodology , summarized in the algorithm, is based upon the
5. Psychological dependency.
following goals:
1. To assist the patient to have as normal a life style as
Should the pattern of usage and opioid screening establish one
possible;
of the above diagnoses, appropriate remedies are applied. Those
2. To safely minimize the number of emergency department
deemed to be psychologically dependent must be evaluated, and
visits and hospital admissions; In-patient if necessary, treated in a dependency treatment program. Written
3. To aggressively manage pain in a socially responsible Out-patient Emergency Admission consent must be given to communicate with this program around
manner. Department
Clinic the issue of compliance. Failure to comply results in restrictions
Patients are scheduled in the out-patient clinic at weekly to quarterly
intervals, depending upon their needs. They are told never to allow placed on prescribing narcotics outside the hospital, thresholds
themselves run out of analgesics for moderate pain. They can request for admission to the emergency department and to the hospital
prescriptions for small amounts of analgesics that are left at the 5-15 mg IV MS+ 30-60 mg (or more) SR-MS are increased.
information desk in the lobby of the University Hospital at their NSAID and/or every 12 hrs + 5-15 mg IV- MS
convenience
30-60 mg (or more)
acetaminophen /codeine SR-MS every 4 hrs prn
#3 (40 tabs) Increase SR-MS* daily until
Because of this manner with which we manage pain, we also are
Repeat IV MS every EQUIANALGESIC DOSES*
mindful of our obligation to administer the program in a socially and/or breakthrough use is minimal
responsible manner. When the pattern of use increases we first look for 45-60 minutes until or
acetaminophen/oxycodon
inter-current medical complications, such as infection or psychological
e (30 tabs)
comfortable. 20-40 mg SR-oxycodone* (or IV/IM PO
stress.
or more) every 12 hours + 1-3 mg
and
Patients are told that it may be necessary for us to screen urines or IV- hydromorphone every 4 hrs MORPHINE 10 mg 30 mg
measure blood levels for opioids in order to better manage their pain.
SR- MS (30 tabs) 1-3 mg IV prn
hydromorphone + MEPERIDINE 70 280
or until breakthrough use is minimal
20-40 mg SR- HYDROMORPHONE 2 10
SR-oxycodone (30tabs)
oxycodone (or If patient is very ill or has ileus, SR-MS 30
more) convert to IV, either bolus or SR-oxycodone 20
Repeat IV PCA, and later back to SR
medication SR = sustained release
hydromorphone
every 45-60 minutes
until comfortable Convert from IV to oral .
breakthrough
Send home or admit using po MS or oxycodone in 1-
Leave 2 days
prescriptions for Discharge when stable and
patients at the improving on SR-MS or SR-
information desk oxycodone
of the University
Hospital

Home
 Pain

Mild Moderate Severe

Emergency In-patient
Out-patient
Department Admission
Clinic
30-60 mg (or more) SR-MS every 12 hrs + 5-
NSAID and/or 5-15 mg IV MS+ 30-60 mg 15 mg IV- MS every 4 hrs prn
(or more) SR-MS Increase SR-MS* daily until breakthrough use
acetaminophen /codeine #3 (40 tabs)
and/or Repeat IV MS every 45-60 is minimal
minutes until comfortable. or
acetaminophen/oxycodone (30 tabs) 20-40 mg SR-oxycodone* (or more) every 12
and or hours + 1-3 mg IV- hydromorphone every 4
SR- MS (30 tabs) 1-3 mg IV hydromorphone hrs prn
+ 20-40 mg SR-oxycodone until breakthrough use is minimal
or
(or more)
SR-oxycodone (30tabs) If patient is very ill or has ileus, convert to
Repeat IV hydromorphone IV, either bolus or PCA, and later back to SR
every 45-60 minutes until medication
comfortable
Send home or admit Convert from IV to oral breakthrough
using po MS or oxycodone in 1-2 days
Discharge when stable and improving on SR-
Home MS or SR-oxycodone
 Chest syndrome
• New or progressive pulmonary infiltrate in
a patient with sickle cell disease.
– Admit and treat
• At least one of the following additional
features is required for the diagnosis: the
onset of chest pain, a temperature higher
than 38.5°C, tachypnea, wheezing, or
cough.
Causes and Outcomes of the Acute Chest Syndrome in
Sickle Cell Disease
NEJM, Volume 342:1855-1865 June 22, 2000
 Infarction of the Femoral Head

McMahon, L. E.C. et. al. N Engl J Med 1997;337:1293-1301

 Phospholipase A2 levels as a means to
diagnose Chest syndrome
• Styles, LA, et al Blood 2000
• Transfusion prevents acute chest syndrome predicted by
elevated secretory phospholipase A2 (BJH 2007)
– 9 of the 13 patients who did not receive a transfusion developed
ACS during hospitalisation versus none of those who were
transfused
• Can blocking phospholipase A2 prevent chest
syndrome?
Can we use CRP instead?
 Treatments
• Supportive care
– Hydration, O2, incentive spirometry
• Hydroxyurea
• Transfusion
• Stem Cell Transplant
• “New” agents
– Clotrimazole (ICA-17043)
– Chromatin modifiers (turn on fetal
hemoglobin)
 Sickle Cell Treatment
• Pediatric care
• Long standing funding of the
Comprehensive Sickle Cell Centers
• Milestones
– PROS I and II
– PED HUG
– STOP
 Sickle Cell Treatment - Adults
“An Evidence-Based Approach to the Treatment of Adults with Sickle Cell
Disease”
ASH Education Book 2005

Multicenter Study of Hydroxyurea in Sickle Cell Anemia - Hydroxyurea reduces

the frequency of painful episodes, acute chest syndrome, transfusions,
hospitalizations
Preoperative Transfusion in Sickle Cell Disease - Simple blood transfusion to
increase the Hb level to 10 g/dL is as effective as exchange transfusion to
reduce Hb S to 30%
Prophylactic Transfusion in Pregnancy - Prophylactic blood transfusion to
increase the Hb level to 10 g/dL compared to transfusion for Hb < 6 g/dL or
for emergent indications did not improve obstetrical or perinatal outcomes
but reduced the incidence of painful episodes
Captopril for Albuminuria in Sickle Cell Anemia - Captopril reduces albuminuria
in normotensive patients (22 patients)
Poloxamer 188* for Treatment of Acute Vaso-occlusive Crisis - Poloxamer 188
reduces the duration of acute painful episodes
 Hydroxyurea can prevent
painful episodes
• Randomized, double-blinded, placebo controlled
trial
• Hydroxurea treatment resulted in a 44%
reduction in the median annual rate of painful
crises
• There was also a significant decrease in the
frequency of acute chest syndrome and the
number of transfusions
• HU was stopped for a short time in almost all
cases for transient marrow depression
NEJM, Vol 332, No 20, 1995
 How does hydroxyurea work?

Steinberg, MH, NEJM, 340:1021-1030, 1999

 Effect of Hydroxyurea on Mortality and
Morbidity in Adult Sickle Cell Anemia

• JAMA. 2003;289:1645-1651.
• 1.5 (5.8) deaths per 3-month period on HU
vs 2.6 (7.9) deaths per 3 months for
people off HU; (P = .04)
• Increased Hgb F correlated with improved
survival
 What effect has HU had on sickle
patients?
• In clinical trials, 44% decrease in
hospitalizations, 40% decrease in mortality.
• But a review of records in MD before and
after HU approval for sickle, no change in
hospitalization rates or costs
• Lanzkron et al., Am J Heme, 2006
• Same group at JHU have surveyed care
givers and found less than half prescribed HU
to all eligible patients
 Transfusion in Sickle Cell

• 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
 Transfusion in Sickle Cell

• 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 30 to 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)

• 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
– Aseptic necrosis
 Other therapies:
Potential treatment with ICA-17043

or
ICA-17043
The Process of Vaso-Occlusion in Patients with Sickle Cell Disease

Hebbel, R. P. N Engl J Med 2000;342:1910-1912

 Other therapies:
5-aza-2'-deoxycytidine

•Hypomethylating agent: results in reactivation of

fetal hemoglobin

Blood, Vol. 102, Issue 12, 3865-3870, December 1, 2003

 Survival of sickle cell patients with
pulmonary hypertension

BMJ. 2003 Nov 15;327(7424):1151-5.

 Distribution (Panel A) and Frequency Distribution (Panel B) of Tricuspid Regurgitant Jet
Velocity in 195 Patients with Sickle Cell Disease and 41 Black Control Subjects and the
Association between Right Ventricular Systolic Pressure Measured by Doppler
Echocardiography and Pulmonary-Artery Systolic Pressure, Measured during Catheterization
(Panel C)

Gladwin, M. T. et. al. N Engl J Med 2004;350:886-895

 Survival after matched sibling allogeneic transplant
for sickle cell

BMJ. 2003 Nov 15;327(7424):1151-5.

 Long-term results of related myeloablative stem-cell
transplantation to cure sickle cell disease

Bernaudin, F. et al. Blood 2007;110:2749-2756

Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.

 Protocol 03-DK-0170: Mini-allo stem cell
transplant for sickle cell disease
Eligibility: Hb SS, SC, or Sb0-thal
• Severe end-organ damage
– stroke or abnormal CNS vessel
– pulmonary hypertension (TRV ≥2.5 m/s)
– renal damage
• Or modifiable complication, not ameliorated by
hydroxyurea
– > 2 hospital admissions per year for pain crises
– previous acute chest syndromes
– red cell alloimmunization
– osteonecrosis of multiple joints
 Transplant conditioning regimen
• Campath (alemtuzumab, anti-CD52 monoclonal
antibody) total 1 mg/kg
• TBI 300 cGy
• Sirolimus (rapamycin) targeting trough level of
15 ng/mL
• Stem cell infusion
• Monitor for blood count recovery
 Hospital course during and after
transplant
• Tolerated conditioning (radiation and
Campath infusion) without serious
adverse events
• No significant need for parenteral
antibiotics or nutritional support
• No sickle cell related events
 Transplant outcome
Pt CD34 and CD3 Months (%) Donor (%) Donor (%) Donor Hgb
(per kg of recipient wt) post BMT CD3 CD14/15 RBC

1 5.72 x 10 6 / (3.21 36 13 53 100 12.9

x 108)

2 7.56 / (2.27) 15 60 37 100 11.9

3 10 / (3.42) 22 44 98 100 13.3

4 8.3 / (5.35) 10 0 0 0 12.4

5 5.51 / (3.71) 12 23 98 100 12.1

6 23.8 / (2.81) 10 21 98 100 13.2

7 18.8 / (3.32) 8 39 100 100 10.9

8 20.1 / (3.04) 7 26 94 100 11.4

 Gene Therapy?
• Many different approaches
• Stable transduction of the stem cell with
expression in the red cells
• Manipulating the expression of the various
globin genes may be easier than replacing
the sickle b-globin gene
• Gene correction strategies are in the early
stages
 Management Summary
• New therapy offers patients with sickle cell disease
a prolonged life span, with the potential to prevent or
minimize complications that impair quality of life
• Multi-organ screening can now detect early injury
and allow corrective intervention.
• Advances in transfusion therapy has resulted in
improved safety.
• Advances in clinical therapy include prophylactic
antibiotics, red cell pheresis, and hydroxyurea.
• Bone marrow transplantation has become accepted
therapy for severely affected patients, but is only
available for a minority of patients.
 Sickle Cell Disease 2007

• The first molecular disease, yet far from

cured
• Sickling is more complicated than Hgb
polymerization
• Understanding the biology of the red cell
has led to possible treatment approaches
Treatment Guidelines

http://www.nhlbi.nih.gov/health/prof/blood/s
ickle/sc_mngt.pdf

2002 – tweaked in 2004