sickle cell disease martin h. steinberg department of medicine, boston university school of...
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Sickle Cell Disease
Martin H. Steinberg
Department of Medicine, Boston University School of Medicine, Boston, MA
(07/18/13)
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Sickle Cell Disease: General PointsA 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
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Globin Gene Mutations are Autosomal Co-dominant (Recessive) Traits
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Pathophysiology of Sickle Cell Disease, 2013
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A
B
C
Laboratory Diagnosis
family study, clinical symptoms, exam, blood morphology
separation of hemoglobin proteins by HPLC
DNA-based Dx by PCR and sequencing
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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
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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
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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
Pathophysiology
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Irreversibly Sickled Cells (ISCs)
Result of membrane damage
Hemoglobin may be in solution
Do NOT signify acute sickle cell-related events
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Leg ulcersCholelithiasisPriapism↓Renal function/albuminuriaStroke, ↑TCD, silent cerebral infarctionTRV and pulmonary hypertension
Vascular Complications
Little affected by HbF concentration; less prevalent with co-incident α thalassemia; sometimes a mortality risk
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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
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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
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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.
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Pain in Sickle Cell Disease
Acute painful episode-most frequent
Acute chest syndrome-often presents as acute pain
Others
Osteonecrosis
Leg ulcers
(
Acute
Chronic
Neuropathicopioid induced, secondary to acute pain
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Prerequisites of EffectiveAcute 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
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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
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Diagnosis of the Acute Painful Episode
(Ballas and Smith, Blood, 1992)
History
Hematological changes are not diagnostic
Other laboratory not useful
RBC deformability and density change but measurement not clinically practical
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Acute Sickle Cell Pain: Management
Short-acting Parenteral Opioids
Morphine
Hydromorphone (Dilaudid)
Fentanyl
Avoid Meperidine (Demerol)
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Acute Sickle Cell Pain: Management
Assessment
Analgesic choice; type, dose, route, PCA vs. bolus dosing
Titration
Adjuvants; antidepressants, NSAIDs, antihistamines
Maintenance
Manage side-effects
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Acute Sickle Cell Pain: Management
Adjustment for tolerance/rotation
Tapering
Switch to oral agents
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Neuropathic Pain
• Burning
• Tingling
• Shooting
• Lancinating
• Numb• Paroxysmal• Emotional distress• Behavioral dysfunction
Damage or dysfunction of the nervous systemAssociated with dysesthesia and allodynia Continuous and/or episodic
Rx: antidepressants, anticonvulsants, opioids, others
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Causes of Persistent Severe Pain
Progressive tissue damage
Inadequate treatment
Tolerance
Hyperalgesia
Changes at receptors
Maladaptive behavior
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"Difficult" Patients
Often alienate the entire health care team
No single causesevere sickle cell diseasesevere psychosocial diseasepoor treatmentexcessive or ineffective opioid use
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Complications of the Acute Painful Episode: Days 1-5
Acute chest syndromeAcute multiorgan failureSudden deathRelapse/hospital readmission
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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
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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
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Benefits of Hydroxyurea
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)
Reduced pain and ACS
Mortality reduced 40%
Less hemolysis (improved anemia)
Fewer hospitalizations
Reduced medical costs
Improved physical capacity
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Transfusion
Beneficial Severe anemia Prevention of CVA Preoperative Some acute chest syndrome
Sometimes Needed Pregnancy Renal failure
Major problems: iron storage, alloimmunization, venous access
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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)
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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