Transcript SICKLE CELL DISEASE - Oncology Hematology Associates

SICKLE CELL DISEASE
Michael L. Titzer, M.D.
Oncology/Hematology Associates
2015
SICKLE CELL DISEASE
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Molecular Biology
Epidemiology
Pathophysiology
Laboratory Evaluation and Diagnosis
Clinical Features
Management
Hydroxyurea
Transfusion Therapy
Surgical Considerations
Bone Marrow Transplantation
Prognosis
Molecular Biology
• RBC is a container for hemoglobin (Hb)
• Hb made of four globin chains and four heme
groups
• Each heme group binds an oxygen molecule
• Four types of globin chains (, , , )
•  globin encoded by two genes on chromosome 16
• Non- chains encoded by genes on chromosome 11
• Hb consists of two  chains and two non- chains
• Three types of Hb
Molecular Biology
• Three types of Hb
– Hb A (22) 97%
– Hb A2 (22) 2%
– Hb F (22) 1%
• RBC contains Hb F throughout fetal life
• After birth, -globin synthesis is
suppressed, and -globin and -globin
synthesis is activated
Molecular Biology
• Thalassemia – quantitative failure in globin
chain production due to gene mutation or
deletion
• Sickle cell disease – qualitative/structural defect
in globin involving single amino acid
substitution
Epidemiology
• Black Africans and Americans,
Mediterranean, East Indian, Latin America
• 70,000 cases in US
• 8% of Blacks carry trait
• 0.25% have SS disease
Pathophysiology
• Substitution of val  glu in -globin chain
• AR
• Sickle trait
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no sickling
40% Hb S and 60% Hb A
normal lifespan
no clinical disease
Pathophysiology
• Homozygotes present at age 6-12 months
• Oxygenated Hb S has normal shape
• Deoxygenation leads to distorted shape
• Sickling/unsickling leads to hemolysis
• Sxs result from hemolysis and vaso-occlusion
• Also see increased blood viscosity, release of
cytokines, changes in neutrophils, changes in
endothelial cells
Pathophysiology
• Can inherit two different abnormal -globin
genes
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Hb SC
Hb SDPunjab
Hb SOArab
Hb S-thal
Hb SE
• SC and S-thal have milder disease, although eye
disease is more common
Laboratory Evaluation and Diagnosis
• CBC
• MCV
• MCHC
• Peripheral smear
• Reticulocyte count
• Bilirubin and LDH
• Iron and Folate
• Hb electrophoresis
Clinical Features
• Vaso-occlusive complications
• Complications of hemolysis
• Infectious complications
• Psychosocial issues
Clinical Features
painful episodes
stroke
acute chest syndrome
priapism
liver disease
splenic sequestration
pregnancy
leg ulcers
osteonecrosis
proliferative retinopathy
renal insufficiency
pulmonary hypertension
sudden death
anemia
cholelithiasis
aplastic crises
fever
immunizations
antibiotic prophylaxis
psychosocial issues
Management – Painful Episodes
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90% of hospitalizations
Ischemic tissue injury from vascular obstruction
Ischemia → regional hypoxia and acidosis → ↑ sickling
Typically last 4-7 days
• Precipitants:
hypoxia, infection, dehydration,
acidosis, menses, OSA, cold, stress
• Treat underlying cause
• Usually no precipitating factors found
Management – Painful Episodes
• Frequency and severity are variable
• Survival correlates with frequency
• Chronic pain:
avascular necrosis, arthritis, LE ulcers,
vertebral body collapse
• Acute pain:
vaso-occlusion, acute chest syndrome,
RUQ syndrome, dactylitis, priapism,
splenic sequestration, gallstones
Management – Painful Episodes
• Immediate evaluation:
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Fever ≥ 101
Lethargy
Pallor
Persistent emesis
Acute pulmonary symptoms
Acute neurologic symptoms
Extremity weakness or loss of function
Acute joint swelling
Pain unrelieved with oral meds
Priapism
Acute flank or back pain
Management – Painful Episodes
• Labs nonspecific, can help determine underlying cause
• Worsening anemia, low retic → aplastic crisis
• Worsening anemia, low retic, low plts → splenic seques
• Elevated WBC and left shift → infection
Management – Painful Episodes
• Standard eval:
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CBC, retic count, UA, chemistry,
LFTs, CXR, oxygen saturation
Blood cultures if T ≥ 101
KUB for abdominal pain
Ultrasound if suspect RUQ syndrome
X-ray/bone scan/MRI/biopsy/culture for osteomyelitis
or septic joint
Management – Painful Episodes
• Five principles of treatment:
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Analgesics
Warmth
Rest
Hydration (3-4 liters/day)
Treat precipitating event
• Measure pain with verbal or visual analog scale
• Believe the patient
• Monitor for efficacy and side effects
Management – Painful Episodes
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Acetaminophen
NSAIDs
Ketorolac (Toradol)
Tramadol (Ultram)
Opiods
Long-acting morphine/oxycodone/fentanyl
Avoid meperidine (Demerol)
IV opiods with patient-controlled analgesia (PCA)
Taper dosing
Observe 12-24 hours on oral meds prior to discharge
Management – Painful Episodes
• Adjuvant medications:
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Antihistamines (pruritus, nausea)
Antiemetics (nausea)
Laxatives (constipation)
Benzodiazepines (anxiety)
Tricyclic antidepressants (depression, pain, insomnia)
Selective serotonin reuptake inhibitors (depression, pain)
Anticonvulsants (pain)
• Supplemental oxygen controversial
• Transfusion controversial
Management – Stroke
• 10-15% of patients
• Highest in ages 2-9 years
• Sxs: seizure, somnolence, disorientation, HA, aphasia,
sensory or motor loss, speech or vision disturbance
• Risk of recurrence 50%
• Risk decreases to 10% with transfusion
• Can be hemorrhagic or thrombotic
• Acutely treat with exchange transfusion to Hb S < 30%
• Maintain for 3-5 years with simple transfusion
Management – Stroke
• Clinical trial of prophylactic transfusion
• Those with flow velocity > 200 cm/sec randomized
• Decreased risk of stroke from 16% to 2%
• Screen with transcranial doppler q6mos ages 2-16 years
• Simple transfusion to keep Hb S < 30%
Management – Acute Chest Syndrome
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30% of patients
50% recurrence, 5-10% mortality
Pleuritic CP, fever, cough, hypoxia, infiltrates on CXR
Precipitated by infxn, fat embolism, pulmonary infarct
Admit and monitor for rapid deterioration
IVF, abx, oxygen, bronchodilators, analgesia
Exchange transfusion for hypoxia, respiratory distress,
or multi-lobar involvement
• Steroids controversial – generally not used
Management – Priapism
• 10-40% of patients
• Persistent painful erection
• Pain medications
• IV fluids
• Nifedipine as vasodilator
• Aspiration and epinephrine irrigation if > 24 hours
Management – Liver Disease
• Less than 2% of patients
• Multiple etiologies:
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Iron overload from transfusions
Hepatitis B and Hepatitis C
Acute chest syndrome
Multi-organ failure
• Treat underlying cause
Management – Splenic Sequestration
• Seen in children under age 6 years
• Acute onset of severe anemia and thrombocytopenia
• Hypotension from pooling of blood in spleen
• May be fatal
• IV fluids
• Transfusion
• Splenectomy if recurs
Management – Pregnancy
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Prenatal counseling
6% spontaneous abortion
Folic acid supplementation
Follow every 2 weeks until 36th week, then weekly
Monitor fetal growth
Transfuse prior to c-section – Hct 30% and Hb S < 50%
• Most acute sickle cell problems treated the same as in
the nonpregnant patient
Management – Leg Ulcers
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20% of adults
Small nonhealing sores on lower extremities
Debridement
Wet-to-dry dressings TID
Skin graft or compression dressing (Unnaboot)
Topical antibiotics
Regranex gel BID
Transfusion controversial, keep Hb S < 50%
May take months or years to heal
Management – Osteonecrosis
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10-50% of adults
Chronic hip or shoulder pain
MRI best diagnostic test
Rest
Analgesics
Osteotomy for children
Core decompression may decrease pain in adults
Joint replacement
Management – Retinopathy
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3% in SS disease, 30-50% in SC disease
Sickling in vascular bed of eye
Retina exquisitely sensitive to oxygen deprivation
Usually asymptomatic
Visual field defects and eventually blindness
Dilated fundoscopic exam yearly
Laser photocoagulation
Vitrectomy if hemorrhage does not clear spontaneously
Surgery for retinal detachments
Management – Renal Insufficiency
• 5-20% of adults
• Renal medulla is hypoxic, acidic, and hyperosmotic
• Series of events:
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 medullary blood flow / hyposthenuria / hyperfiltration
papillary necrosis / RTA / proteinuria / hematuria
glomerulonephritis /  renal blood flow/nephrotic syndrome
chronic renal failure
• At age 3 years, monitor BP, UA, creatinine annually
• Avoid diuretics
• Hematuria – UA, coags, culture, US, IVP, cystoscopy
Management – Pulmonary HTN
• Most common cause of death in adulthood
• Secondary to microvascular obstruction, acute chest
syndrome, pneumonia, infarction, and fat emboli
• Cor pulmonale and restrictive lung disease
• Chronic hypoxia worsens sickling
• Supplemental oxygen
Management – Sudden Death
• Reported in military recruits
• Associated with extreme exertion
Management – Anemia
• Hemolysis from repeated sickling and unsickling
• Hb 6-9 common baseline
• Patients well-adapted
• Folic acid 1-2 mg PO QD
Management – Cholelithiasis
• Seen in most adults
• Many asymptomatic
• Increased bilirubin from hemolysis
• Ultrasound for diagnosis
• Cholecystectomy if symptomatic
Management – Aplastic Crises
• Rapidly occurring, severe anemia
• 85% associated with Parvovirus B-19
• Also seen with EBV, Streptococcus, and loss of
erythropoietin in renal disease
• Fatigue, DOE, pallor, anemia below baseline, low retic
• Spontaneously resolves in 1-2 weeks
• Support with simple transfusion
• Recurrence of Parvovirus B-19 is rare
Management – Fever
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Infection most common cause of death in children
Splenic dysfunction
Panculture and start antibiotics immediately
Lumbar puncture if signs/symptoms of meningitis
Generally admit to hospital
Streptococcus pneumoniae
Hemophilus influenzae
Staphylococcus aureus
Escherichia coli
Neisseria
Salmonella
Mycoplasma
Management – Immunizations
• Usual childhood immunizations:
– HBV, DPT, Hib, IPV, MMR, OPV, Varicella
• Age 2 years:
– Pneumovax every 5 years
– Flu shot yearly
– Meningovax
• Prior to surgical splenectomy:
– Hib, Pneumovax, Meningovax
Management – Antibiotic Prophylaxis
• Oral Penicillin VK 125mg BID ages 3 months – 3 years
• Oral Penicillin VK 250mg BID to age 18 years
• Erythromycin if allergic to PCN
Management – Psychosocial Issues
• Growth retardation
• Absenteeism from school or work
• Frequent hospitalizations
• Medical expenses
• Fear of death
Hydroxyurea (HU) Therapy
• Mechanism of action
• Indications
• Side effects
• Dosing
Hydroxyurea – Mechanism of Action
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Exact mechanism unknown
High Hb F associated with milder disease
Hb F increases with sudden erythroid regeneration
Cytotoxic agents trigger erythroid regeneration
HU is oral and less toxic than other chemotherapeutics
HU increases Hb F levels by 2-20%
Randomized study stopped early due to benefit
Decreased pain, transfusions, acute chest syndrome
Hydroxyurea – Indications
• Patients with end-organ damage
• History of stroke
• History of acute chest syndrome
• Frequent pain episodes
Hydroxyurea – Side Effects
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Mutagen and teratogen (no birth defects yet reported)
Myelosuppression
Thrombocytopenia
Macrocytosis (elevated MCV)
Increases Hb F and total Hb
GI upset and diarrhea
Rash
Long-term adverse effects still unknown
– Increased risk of leukemia, possible growth delay
Hydroxyurea – Dosing
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No correlation between dose and clinical benefit
Responses variable and may take several months
Not all patients respond
Proper contraception for women and men
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500-1500 mg PO QD
Titrate dose q6-8 weeks based on response/tolerance
Monitor CBC every 2 weeks initially
Keep ANC > 2000 and platelets > 80,000
Look for elevation in MCV, Hb F, total Hb
Transfusion Therapy
• Simple transfusion
– Can increase viscosity
• Partial exchange transfusion
– Manual phlebotomy before or during transfusion
• Automated exchange transfusion (pheresis)
– Rapid exchange without increasing viscosity or total Hb
Transfusion Therapy
• Indications for exchange transfusion
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Acute stroke or transient ischemic attack
Acute chest syndrome with hypoxia
Severe RUQ syndrome
Unresponsive priapism
Cardiac failure or angina
• Goal is to reduce Hb S < 30%
Transfusion Therapy
• Indications for acute simple transfusion:
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Acute anemia (aplastic crisis/splenic sequestration/blood loss)
Prior to surgery requiring general anesthesia
Prior to any eye surgery
Before injection of contrast materials
Intractable acute pain syndromes
• Goal is hematocrit of 30%
Transfusion Therapy
• Indications for chronic simple transfusion:
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Primary prevention of stroke (16%  2%)
Secondary prevention of stroke (50%  10%)
Chronic organ failure
Complicated pregnancy
Refractory leg ulcers
Symptoms related to chronic anemia
• Goal is Hb S < 30% (Hb S < 50% for leg ulcers)
• Generally done every 2-4 weeks
Transfusion Therapy
• Transfusion generally NOT indicated for:
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Routine pain episodes
Compensated anemia
Uncomplicated pregnancy
Local anesthesia/conscious sedation
Minor infections
Aseptic necrosis
Risks of Transfusion Therapy
• Alloimmunization
– Hard to find compatible blood
– Delayed hemolytic reactions
– All blood products should be leukocyte depleted
• Infections
– HIV, HCV, HBV
• Iron overload
– Start iron chelation when ferritin > 2000 ng/ml
– Deferoxamine prolonged SQ infusion daily
Surgical Considerations
• Pre-operative:
– Admit 12-24 hours before surgery, IV fluids, bronchodilators,
transfuse to hematocrit 30%
• Intra-operative:
– Monitor pulse oximetry, IV fluids, prevent hypothermia,
replace blood loss
• Post-operative:
– Monitor pulse oximetry, IV fluids, incentive spirometry,
observe 24-48 hours for acute chest syndrome
Bone Marrow Transplantation
• For children with severe complications
• Need HLA-matched sibling donor
• Only 1% of patients meet the above criteria
• 10% treatment-related mortality
• Full extent of toxicity is still unknown
Prognosis
• Hb SS median lifespan:
– Female 48 years
– Male 42 years
• Those with sickle trait have normal lifespan