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Sickle Cell Disease
Martin H. Steinberg
Department of Medicine, Boston University School of Medicine,
Boston, MA
(07/18/13)
Sickle Cell Disease: General Points
A single point mutation in HBB causes sickle hemoglobin
(HbS)
Sickle cell trait is innocuous
HbS homozygotes and some compound heterozygotes, like
HbSC disease and HbS-β thalassemia have a severe
disease
Pathophysiology is complex and suggests multiple Rx
targets
The clinical features are heterogeneous; life is shortened
Acute painful episodes are the major clinical issue and their
treatment can be very difficult
Globin Gene Mutations are Autosomal
Co-dominant (Recessive) Traits
Pathophysiology of Sickle Cell Disease, 2013
Laboratory Diagnosis
A
B
C
family study,
clinical
symptoms,
exam, blood
morphology
separation of
hemoglobin
proteins by
HPLC
DNA-based
Dx by PCR
and
sequencing
Many Genotypes Comprise the
Phenotype of Sickle Cell Disease
Sickle cell anemia: HbS homozygote (1/600 African
Americans)
HbSC: compound heterozygote (1/800)
HbS-β thalassemia: β+, β0 thalassemia compound
heterozygotes (1/1600)
HbSE: compound heterozygote, Asian ancestry
Many rarer compound heterozygotes; e.g., HbSD,
HbSOArab
Sickle Cell Trait
Sickle cell trait is not a disease
•Normal blood counts (PCV, MCV, reticulocytes)
•Normal blood film
•60% HbA, 40% HbS, normal HbA2 and HbF
•Normal lifespan; few medical problems
hyposthenuria; hematuria; ? increased UTI in
pregnancy; 2x increased risk of thromboembolic
disease and pulmonary embolism(4x);
increased risk of death from exertional heat
illness
Pathophysiology
HbS polymerization
Sickle cell membrane damage
Hemolysis of sickle cells (anemia)
Intracellular adherence
Reperfusion injury, NO scavenging,
oxidant injury, inflammation
Complexity suggests sites for intervention
Irreversibly Sickled Cells (ISCs)
Result of membrane damage
Hemoglobin may be in solution
Do NOT signify acute sickle cell-related events
Vascular Complications
Leg ulcers
Cholelithiasis
Priapism
↓Renal function/albuminuria
Stroke, ↑TCD, silent cerebral infarction
TRV and pulmonary hypertension
Little affected by HbF concentration;
less prevalent with co-incident α thalassemia;
sometimes a mortality risk
Other Complications
Clinical manifestations are very heterogeneous
Acute painful episode-most patients, most frequent
Acute chest syndrome- ~½ of patients; can be lethal
Osteonecrosis-crippling, painful
Retinopathy; splenomegaly in HbSC disease
Multiorgan failure
HbF affects the incidence of many of these
complications
HbSC Disease
Proliferative retinopathy
Splenomegaly: infarction, sequestration
Acute chest syndrome: half the rate of HbSS
Stroke: age-adjusted prevalence 0.84% (4% in HbSS)
Osteonecrosis: ~1/2 the prevalence as HbSS
Leg ulcers: rare
Renal failure: 2.4% (4.2% in HbSS)
Pain: 0.4 episodes/patient y (0.8 in HbSS)
Priapism: uncommon
Necrotic Bone Marrow Embolization and ACS
46 y.o. man,HbSC disease, chest and leg pain,
weakness, SOB. Acute severe anemia,
leukocytosis, hypoxia, obtundation, liver and
renal failure, death.
Pain in Sickle Cell Disease
Acute painful episode-most frequent
Acute
Acute chest syndrome-often
presents as acute pain
Others
Osteonecrosis
Chronic
Neuropathic
Leg ulcers
opioid induced, secondary to
acute pain
(
Prerequisites of Effective
Acute Pain Management
Know & understand the patient
Know the types and patterns of pain
Know the pharmacology of a few
analgesics
Patient education
Non-pharmacological, alternative and
complementary therapeutics
Acute Painful Episodes
Most common complication: some patients always in pain;
others rarely have pain; most have 2-3 episodes/year
Most pain is managed at home
Etiology unclear: unrelated to "sickling," blood film is not
diagnostic
Pain distribution variable
Physical findings limited
Duration variable
High incidence of pain is a bad prognostic sign
Directly related to PCV/indirectly related to HbF
Diagnosis of the Acute Painful Episode
History
Hematological changes are not diagnostic
Other laboratory not useful
RBC deformability and density change but
measurement not clinically practical
(Ballas and Smith, Blood, 1992)
Acute Sickle Cell Pain: Management
Short-acting Parenteral Opioids
Morphine
Hydromorphone (Dilaudid)
Fentanyl
Avoid Meperidine (Demerol)
Acute Sickle Cell Pain: Management
Assessment
Analgesic choice; type, dose, route, PCA vs. bolus
dosing
Titration
Adjuvants; antidepressants, NSAIDs, antihistamines
Maintenance
Manage side-effects
Acute Sickle Cell Pain: Management
Adjustment for tolerance/rotation
Tapering
Switch to oral agents
Neuropathic Pain
Damage or dysfunction of the nervous system
Associated with dysesthesia and allodynia
Continuous and/or episodic
•
•
•
•
Burning
Tingling
Shooting
Lancinating
•
•
•
•
Numb
Paroxysmal
Emotional distress
Behavioral dysfunction
Rx: antidepressants, anticonvulsants, opioids, others
Causes of Persistent Severe Pain
Progressive tissue damage
Inadequate treatment
Tolerance
Hyperalgesia
Changes at receptors
Maladaptive behavior
"Difficult" Patients
Often alienate the entire health care
team
No single cause
severe sickle cell disease
severe psychosocial disease
poor treatment
excessive or ineffective opioid use
Complications of the Acute Painful Episode:
Days 1-5
Acute chest syndrome
Acute multiorgan failure
Sudden death
Relapse/hospital readmission
Chronic Opioid Treatment
Develop a formal Rx plan and prescribe
judiciously
Use an opioid contract and evaluate often
Be careful of dose escalation
Use a single long- and short-acting agent
Interruption of Rx can mimic acute pain
episode
High doses make acute pain Rx difficult
Hydroxyurea in Sickle Cell Disease
Almost all patients should take HU
Dose must be titrated for maximum effect
HbF, blood counts and MCH and MCV should be
followed
Benefits of Hydroxyurea
Reduced pain and ACS
Mortality reduced 40%
Less hemolysis (improved anemia)
Fewer hospitalizations
Reduced medical costs
Improved physical capacity
After 17.5 years, ↓deaths; 87% of deaths occurred in
patients who never took hydroxyurea or took it for <5
years. Long-term use of hydroxyurea in adults is safe.
(Steinberg et al, 2003, Steinberg et al, 2010,
Voskaridou et all, 2009)
Transfusion
Beneficial
Severe anemia
Prevention of CVA
Preoperative
Some acute chest syndrome
Sometimes Needed
Pregnancy
Renal failure
Major problems: iron storage,
alloimmunization, venous access
Stem Cell Transplantation
Myeloablative transplantation in children:
~85% disease free survival (Lucarelli, 2012)
Nonmyeloablative HLA matched transplants in
10 adults: stable mixed chimerism and "cure"
in 9 of 10 cases (Hsieh, 2009)
Related haploidentical transplants in adults
and children (Bolanos-Meade, 2012; Dallas, 2013)
Summary
Correct diagnosis important
especially for genetic counseling
Disease phenotype is very variable
HU in adults reduces pain, prolongs life and
should be used in nearly all patients
Pain management often difficult
Transfusions should be used cautiously
Transplantation can help some patients