Transcript The Management of Sickle Cell Disease

The Management of
Sickle Cell Disease
Susan E. Kirk, MSPAS, PA-C
Instructor, Baylor College of Medicine
Texas Children’s Hematology Center
April 15, 2016
Texas Children’s Hospital Advanced Practice Provider Conference
Disclosures
• No relevant financial disclosures
• Discussion of off-label use of hydroxyurea
Objectives
• Discuss diagnosis and pathophysiology of sickle cell disease
• Review types of sickle cell disease and general preventative care
recommendations
• Discuss common acute complications of sickle cell disease and
management
• Discuss chronic complications of sickle cell disease and management
• Discuss therapy options
Genetics
Genetics
• Autosomal recessive disorder
• Both parents must be carriers of a trait
• About 1:12 black Americans have sickle cell trait, 1:40 have C trait
• By comparison, cystic fibrosis trait is about 1:29 for white Americans
• About 1:100 South/Central Americans have sickle cell trait
• Beta thalassemia trait: African, Mediterranean, Asian, Middle Eastern descent
• Incidence of sickle cell disease is 1:400 black Americans
• About 2000 children are born with sickle cell disease each year in the US
Genetics
• “Normal” genotype: AA
• Trait: A/notA (AS, AC, Aβ0, Aβ+, etc)
• Disease: notA/notA (SS, SC, Sβ0, Sβ+, etc)
https://www.stjude.org/treatment/disease/sickle-cell-disease/diagnosing-sickle-cell/sickle-cell-trait.html?vgnextoid=9454db6324d6f110VgnVCM1000001e0215acRCRD
Diagnosis
Diagnosis
• In the US, typically identified on newborn screen
• Hemoglobinopathy screening in all 50 US states
• Normal: F,A
• Sickle Cell Trait: F,A,S
• Sickle Cell Disease: F,S or F,S,C or F,S,A
http://www.meandmyobg.com/2014/05/newborn-screening-advisory-committee-announcement/
Texas Newborn Screen
Results
Initial Report
Follow up DNA
Report
Diagnosis
Outside of the newborn period
Hemoglobin profile >3 months from any transfusions
• Sickle Cell Disease: >50% hemoglobin S
• Hemoglobin SS: Majority hemoglobin S, normal A2, no hemoglobin A
• Hemoglobin Sβ0: Majority hemoglobin S with elevated A2, no hemoglobin A
• Hemoglobin Sβ+: Majority hemoglobin S with elevated A2, some hemoglobin
A
• Hemoglobin SC: Majority hemoglobin S (~60%) and hemoglobin C (~40%),
no hemoglobin A
Hemoglobin profile
Hemoglobin A
Latest Ref Range: 90-100 % 0.0 (L)
Hemoglobin A2 Latest Ref Range: <4.0 % 3.3
Hemoglobin F
Latest Ref Range: 0-3 %
4.1 (H)
Hemoglobin S
Latest Units: %
46.7
Hemoglobin C
Latest Units: %
45.9
Hemoglobin OtherUnknown
0.0
Hemoglobin A
Latest Ref
Hemoglobin A2 Latest Ref
Hemoglobin F
Latest Ref
Hemoglobin S
Latest Ref
Hemoglobin C
Latest Ref
Hemoglobin OtherLatest Ref
Range: 90-100 % 0.0 (L)
Range: <4.0 % 3.2
Range: 0-3 %
2.1
Range: . %
94.7
Range: . %
0.0
Range: .
0.0
Hemoglobin SC
Hemoglobin SS
Texas Newborn Screen
Hemoglobin Sβ+
Peripheral Smears
http://imagebank.hematology.org/image/3666/nor
mal-peripheral-blood-smear--1?type=upload
Normal
http://dx.doi.org/10.1016/S0140-6736(10)61029-X
Hemoglobin SS
Hemoglobin SC
Pathophysiology
• Gene mutation
• Beta globin gene is on chromosome 11
• Point mutation: substitution of valine for
normal glutamic acid
• Hemolysis
https://www.mun.ca/biology/scarr/Hb_Val_substitution.html
• Polymerization of hemoglobin S leads to membrane rigidity
• Intravascular and extravascular hemolysis (↑LDH and ↑bilirubin)
• Sickle RBC lives 8-21 days vs ~120 days: ↑reticulocyte count
• Inflammation
• ↑WBC, ↑platelets, ↑inflammatory markers
Labs
Untreated
• Hemoglobin 6-9 gm/dL, depending on type
• MCV is normal in SS, decreased in Sβ and SC
• WBC typically elevated
• Platelets normal or elevated
• Reticulocyte count elevated
Management
General Preventative Care
• SS and Sβ0
• Start prophylactic penicillin by 6 weeks of age
• 125 mg BID <3 years
• 250 mg BID ≥3 years
• Transcranial Doppler Ultrasound (TCD) by age 2 years and at least annually until unable
to obtain values
• All types
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•
•
•
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Fever precautions: 101F is a medical emergency
Pneumococcal and meningococcal vaccines, annual influenza vaccine
Annual retinopathy screening beginning at age 10 years
Annual screening for proteinuria beginning at age 10 years
Genetic counseling for parents and adolescents
• Folic acid not typically necessary
Acute Complications of SCD
•
Infections
•
Vaso-occlusive crisis
•
Acute Chest Syndrome
•
Splenic Sequestration
•
Priapism
•
Aplastic Crisis
•
Stroke
Infections
• Most common cause of death in children with SCD
• Functional asplenia
• Increased risk of encapsulated bacterial infections
• Fever treated as medical emergency
• CBC, blood cultures, CXR, ± UA/urine cultures, ± LP
• Empiric antibiotics
• Decision to admit based on clinical or social indications
• Osteomyelitis can be difficult to discern from VOC pain on imaging
• Prevention: prophylactic penicillin, immunizations, education
• 84% of pneumococcal infections in children <5 years could be prevented with
prophylactic oral penicillin
Vaso-occlusive Pain Crisis
• Most common complication
• “Dactylitis” in younger children
• In older children and adults, typically in long bones
• Lack of abnormal physical findings
• Pain is ischemic in nature due to tissue infarction
• May be precipitated by dehydration, temperature extremes
• Treatment:
•
•
•
•
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Faster treatment may decrease overall length of VOC pain
Fluids – oral or IV
NSAIDs, opiates
Local heat
RBC transfusion not typically indicated
Oxygen not typically indicated unless O2 sats decreased
Acute Chest Syndrome
• Significant cause of mortality in SCD
• Defined as a new lung infiltrate, chest pain or respiratory sx ± fever
• Any fever in SCD requires blood cultures and antibiotics ± CXR
• Typically requires admission and treatment for pneumonia
• Monitoring for sepsis which is a life threatening complication
• Supplemental oxygen if decreased O2 saturations
• RBC transfusion if hemoglobin decreased from baseline or other clinical
indication
• Bronchodilators, incentive spirometry
Splenic Sequestration
• Life threatening and requires emergent attention and admission
• Typically occurs in patients <5 years but can happen at any age
• Vascular flow out of spleen blocked due to occlusion
• Spleen starts blowing up like a balloon
• Acute painful splenomegaly, irritability, pallor, ± fever
• Hemoglobin below baseline ± thrombocytopenia
• Small aliquots of RBC transfusions, even though hemoglobin may be dramatically
low
• Non-sickled blood helps to release trapped native RBCs in spleen
• Recurrence is common
• All caregivers should be educated regarding spleen palpation and recognizing
signs/symptoms
Priapism
• Occurs in males of all ages, education is extremely important
• Early intervention may prevent irreversible penile fibrosis or impotence
• Sexual dysfunction reported in 46% of patients with a history of priapism
• Treatment
• Short episodes may be managed at home: increase fluids, warm bath, frequent
urination, analgesics ± pseudoephedrine
• If >2 hours, call hematologist or go to ED
• Potential urinary catheterization
• Consult urology
Aplastic Crisis
• Definition: hemoglobin severely below baseline with reticulocytopenia
• Typically associated with illness, especially parvovirus B19
• Recovery is spontaneous within 7-10 days
• May need transfusion support until recovery
Stroke
• Occurs in ~7% of patients with SCD
• Can be isolated event, with illness or other SCD complication
• May have underlying abnormality in intracranial vessels
• Acute on chronic vasculopathy
• Hemiparesis, seizures, gait dysfunction and speech defects are common
• Initial non-contrast CT, then MRI ± MRA
• Emergent exchange transfusion
• Untreated: 20% mortality and 70% with permanent motor/cognitive defects
• Screening for increased risk with TCD
After Stroke
• 70% will experience recurrence within three years without treatment
• Patients are transfused every 3-4 weeks to achieve a hemoglobin S <30%
• Eventually require chelation for iron overload
• Side effects from chelators: rash, decreased hearing, ocular changes, cytopenias,
hepatotoxicity, renal toxicity, GI complaints
• May have exchange transfusions
• Transfusions are indefinite, no safe endpoint has been established
• SWiTCH trial explored if patients with stroke could be transitioned to
hydroxyurea
• Concluded that chronic transfusion therapy and chelation remains the best therapy
Abnormal TCD
• TCD is a screening tool to determine children at increased risk of stroke
• Abnormal values are >200 cm/s
• Screening begins at age 2 years until at least 16 years old
• Confirmed abnormal values are indication to start chronic transfusion
therapy to prevent stroke
• Recent TWiTCH trial indicates switching to hydroxyurea after one year of
transfusion therapy is effective at preventing stroke in patients with
abnormal TCDs
Chronic Complications of
SCD
• Neurocognitive abnormalities
• Cognitive function and fine motor skills are often affected
• Neuropsychological evaluations for delays or declining school performance
• Retinopathy
• Annual eye exams at age 10 years
• Lung disease
• PFTs for those with pulmonary symptoms
• Cholelithiasis
• Bilirubin stones in childhood or early adolescence
• Leg ulcers
• More common in tropical climates
Chronic Complications of SCD
Avascular Necrosis
Growth delay
• SCD is the most common cause of
AVN of the femoral head in
children
• Delayed linear growth
• Close to normal range postadolescence
• Weight below normal range and does
not normalize with age
• Delayed puberty
• Best assessed with MRI
• May have chronic pain or be
asymptomatic
• Progression may result in need for
total hip replacement
• Not entirely effective at eliminating
pain or discomfort
Chronic Complications of SCD
Cardiovascular
• Systolic ejection murmur
• Cardiomegaly with LVH
• Pulmonary hypertension
• 20-40%
renal
• Hyposthenuria
• Enuresis
• Proteinuria and nephrotic syndrome
• Annual urine microalbumin
• Increasing creatinine can be significant,
even if within normal limits
• Avoid nephrotoxic agents, contrast dye
when possible
Treatments
Curative
• Bone marrow transplant
• Typically only for patients with severe disease or stroke
• Best prognosis with HLA matched sibling donors
• Gene therapy
• Trials are ongoing
Treatments
• Transfusions
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Transfusion calculations
Quick and dirty: weight (kg) x (goal hgb-current hgb) x 3.75 = mL of PRBCs
mL PRBC = [TBV (goal hgb – current hgb)] /22 * 100
Total Blood Volume = (weight (kg) x 75)/100
Leukoreduced
Sickle negative units
C, E, Kell matched units
Increased risk of alloimmunization, autoantibodies
Avoid overtransfusion – no need to achieve a ‘normal’ hemoglobin
• Avoid target hemoglobins >10 gm/dL in non-chronically transfused patients
• Awareness of delayed hemolytic transfusion reactions
• 1-4 weeks post transfusion, can be life threatening
• Guidelines available on need for preoperative/perioperative transfusion needs
based on procedure, genotype and baseline labs
Treatments
Hydroxyurea
• FDA approved use in adults with sickle cell disease in 1998
• Not approved for pediatric use but widely used
• Reduces
•
•
•
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frequency of sickle cell pain events
Incidence of acute chest syndrome
Hospitalizations
Need for transfusion
• Increases
• Hemoglobin
• Hemoglobin F
Hydroxyurea
• Ribonucleotide reductase inhibitor
• Oral, once daily dosing
• Capsule or compounded liquid
• Old – used for myeloproliferative neoplasms for decades
• Cheap, generic
• Generally well tolerated
• Side effects: myelosuppression (reversible)
Hydroxyurea – Who should
take it?
HU should be offered to all patients with SS or
Sβ0 who are 9 months of age or older
Hydroxyurea
• Baseline CBC, retic, CMP, hemoglobin profile
• Starting dose
• Adults: 15 mg/kg/day
• Children: 20 mg/kg/day
• Maximum dose 35 mg/kg/day
• Monitor CBC w/ diff and retic
• Monthly if escalating dose, every 2-3 months on stable dose
• Goals: hemoglobin >8.0 gm/dL, Platelets >80K, ANC 2000-4000
• MCV typically increases, hemoglobin F should increase
• Hold for myelosuppression, CBC/retic weekly until cytopenias improve
• Resume HU at decreased dose
• Caution in pregnancy
Hemoglobin A
Latest Ref Range: 90-100 % 0.0 (L)
Hemoglobin A2 Latest Ref Range: <4.0 % 3.9
Hemoglobin F
Latest Ref Range: 0-3 %
32.3 (H)
Hemoglobin S
Latest Units: %
63.8
Hemoglobin C
Latest Units: %
0.0
Hemoglobin OtherUnknown
0.0
http://www.bloodjournal.org/content/115/26/5300?sso-checked=true
S Trait
Hemoglobin Traits – Why do
we have them?
http://www.britannica.com/place/South-Asia/images-videos
A Few Words about Sickle
Cell Trait
• No expected symptoms or complications, labs are normal
• Rare form of cancer, renal medullary carcinoma, is associated with S trait
• Under extreme physiologic conditions, sickling can occur
• High altitude, severe dehydration, high intensity exercise
• 2007: NFL player with S trait experiences splenic infarction while playing in Denver
• NCAA requires sickle cell trait testing in all Division I and II athletes or a signed
statement declining testing
• American Society of Hematology opposes mandatory trait testing
• Instead recommending universal precautions to protect all athletes from exertion-related
illness and death
Resources
• National Heart, Lung and Blood Institute Evidence Based Management of
Sickle Cell Disease, Expert Panel Report
• https://www.nhlbi.nih.gov/sites/www.nhlbi.nih.gov/files/sickle-cell-diseasereport.pdf
• Penn State University Gene Server
• Main page: http://globin.cse.psu.edu/
• Variant search: http://globin.cse.psu.edu/cgi-bin/hbvar/query_vars3
Questions?
References
Abboud, MR, et al. Discontinuing prophylactic transfusion increases the risk of silent brain infarction in children with sickle cell disease: data from
STOP II. Blood. 2011;118(4):894-8.
Adams, RJ, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler
ultrasonography. N Engl J Med. 1998;339(1):5-11.
Adams, RJ, et al. The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med. 1992 Feb 27; 326(9):605-10.
Ataga, KI, et al. Pulmonary hypertension in sickle cell disease. Am J Med. 2004;117:665-669.
Emond, AM, et al. Priapism and impotence in homozygous sickle cell disease. Arch Intern Med. 1980; 140:1434-143
Gaston, MH et al, Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. N Engl J Med. 1986; 314:1593-1599.
Health Supervision for Children with Sickle Cell Disease. http://pediatrics.aappublications.org/content/109/3/526
Orkin, S, et al (2009). Hematology of Infancy and Childhood (7th ed). Philadelphia: Saunders Elsevier.
Rees, D. et al, The Lancet. 2010;9757:2018–2031. http://dx.doi.org/10.1016/S0140-6736(10)61029-X
Sickle Cell Trait. American Society of Hematology. http://www.hematology.org/Patients/Anemia/Sickle-Cell-Trait.aspx
Sutton, LL, et al. Pulmonary hypertension in sickle cell disease. Am J Cardiol. 1994;74;626-628.
Ware, RE. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood. 2010;115(26).
Ware, RE, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial Doppler flow velocities in children with sickle cell
anaemia-TCD with transfusions changing to hydroxyurea (TWiTCH): a multicenter, open-label, phase 3, non-inferiority trial. Lancet.
2016:387(10019):661-70.
Ware, RE, et al. Stroke with transfusions changing to hydroxyurea (SWiTCH). Blood. 2012;119(17):3925-32.