Post on 28-May-2018
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SICKLE CELL DISEASE:
PREVENTING A CRISISRachel Dyke PharmD
PGY2 Pediatric ResidentThe University of Iowa Stead Family
Children’s Hospital
Rachel reports she has no actual or potential conflict of interest in relation to this presentation
Off label use of medications will not be discussed
DISCLAIMER
Hemoglobin
Disease state review Sickle cell
Thalassemias
Pathophysiology and treatment
Prophylaxis
Iron chelation
In the pipeline
PRESENTATION OVERVIEW
Goal: To appreciate the l imited treatment and prophylactic therapies available for sickle cell disease
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Pharmacists
Understand the pathophysiology of sickle cell disease
Compare thalassemiasand sickle cell diseases
Identify and differentiate between iron chelation therapies
Use the guidelines to direct evidenced based management of sickle cell disease
Technicians
Understand the pathophysiology of sickle cell disease
Compare thalassemia and sickle cell diseases
Communicate the role of specialty pharmacies for iron chelation medications
OBJECTIVES
BLOOD
https://upload.wikimedia.org/wikipedia/commons/6/69/Hematopoiesis_(human)_diagram.png
Metalloprotein tetramer located within erythrocytes that serves as an oxygen transporter 4 subunits
HEMOGLOBIN
http://higheredbcs.wiley.com/legacy/college/tortora/0470565101/hearthis_ill/pap13e_ch19_illustr_audio_mp3_am/simulations/figures/rbc.jpg
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Metalloprotein tetramer located within erythrocytes that serves as an oxygen transporter 4 ferrous iron (Fe2+) binding sites
HEMOGLOBIN
http://higheredbcs.wiley.com/legacy/college/tortora/0470565101/hearthis_ill/pap13e_ch19_illustr_audio_mp3_am/simulations/figures/rbc.jpg
Metalloprotein tetramer located within erythrocytes that serves as an oxygen transporter 4 heme sites to bind oxygen
HEMOGLOBIN
https://www.quora.com/How-is-the-heme-molecule-attached-to-the-globin-protein
Globins α, β, γ, δ, ε, ζ
Hemoglobin A 2 α, 2 β chains
Fetal hemoglobin 2 α, 2 γ chains
Hemoglobin A2
2 α, 2 δ chains
Other hemoglobin variants Hb D-Punjab, Hb G-Philadelphia, Hb Hasharon, etc.
HEMOGLOBIN TYPES AND COMPONENTS
Blood 2011 118:19-27. http://the-healthcare.org/wp-content/uploads/2014/06/Normal-Hemoglobin-Variants-and-Subunits1.png
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GLOBIN CHANGES
Blood. 2008; 112: 3927-3938.
Hereditary diseases of hemoglobin Sickle cell disease Variation in structure
Thalassemia Underproduction
Combination Sickle cell + thalassemia
HEMOGLOBINOPATHY
National Coalition for Health Professional Education in Genetics.. 2013.
Autosomal recessive mutation in the beta globin Hemoglobin S replacement
Iowa newborn screen
SICKLE CELL DISEASE
Iowa Newborn Screening Program. IDPH. http://ww.wefightwewin.org/wp-content/uploads/2013/08/Cells.png, http://evolution.berkeley.edu/evolibrary/article/mutat
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Sickle cell trait (HbαS) One abnormal gene, one abnormal chain
Sickle cell anemia (HbSS)
Two abnormal genes, two abnormal chains
AKA: sickle cell disease
Combination diseases One beta globin replace with hemoglobin S, one replaced with
abnormal variant
Hb SC, Hb SD, Hb SE
Thalassemia Decreased production of alpha or beta chains
TERMINOLOGY
CDC. Thalassemia. 2016; NHLBI. Health Topics: Sickle Cell Disease 2016.
Autosomal recessive or autosomal dominant mutation resulting in unusually low amounts of beta-globin
Beta Types Major (Cooley’s anemia)
Intermedia
β0 thalassemia: absence of beta-globin
β+ thalassemia: reduced amount of beta-globin Severity is not dictated by type “zero vs plus”
BETA THALASSEMIAS
CDC. Thalassemia. 2016; NIH. Genetics Home Reference: Beta Thalassemia 2017.
Autosomal recessive mutation resulting in unusually low amounts of alpha-globin Deletions of HBA1 or HBA2 genes
4 alleles
Alpha Types Silent carrier
Alpha thalassemia trait
HbH: milder form
Hb Bart syndrome Loss of all 4 alpha-globin alleles
ALPHA THALASSEMIAS
CDC. Thalassemia. 2016; NIH. Genetics Home Reference: Alpha Thalassemia 2017.
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PATHOPHYSIOLOGY OF VASO-OCCLUSIVE EVENTS
AND TREATMENT
RBCs sickle with deoxygenation Increased adhesion
Decreased flexibility
Leads to microvascular occlusions & ischemia
Common sites of aggregation Lungs
Spleen
Kidneys
Liver
Bones
Brain
Penis
VASCULAR OCCLUSION
NEJM. 1999; 340 (13): 1021-1030. http://www.newsworks.org/images/stories/flexicontent/l_sickle-cell.jpg
Anemia
Fatigue
Pain
Dactylitis
Frequent infections
Stunted growth
End organ damage
Iron accumulation
COMPLICATIONS
Dactylitis
Bone infarcts
NEJM. 1999; 340 (13): 1021-1030. http://medical-photographs.com/images/infectious%20diseases/genetic-blood-dyscrasias/2.jpg. http://www.radiologyassistant.nl/data/bin/a509797a3920b8_Schermafbeelding-2010-02-23.jpg
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Acute chest syndrome
Splenic sequestration
Priapism
Stroke
SICKLE EMERGENCIES
APON. Sickle Cell Disease. 2012.
Mild-moderate pain: oral or parenteral NSAIDs
Severe pain: parenteral opioids NSAID adjuvant
Non-pharmacologic: Heating pad
Distraction
Hydration
Oxygen
ACUTE PAIN CRISIS TREATMENT
NHLBI: Sickle Cell Disease. Expert Panel Report 2014. https://cdn.sicklecellanemianews.com/wp-content/uploads/2015/02/shutterstock_89193115.jpg
Sickled cells become trapped inside the lung
Etiology: generally infection mediated Viral
Bacterial: chlamydia, mycoplasma
Post operative complication
Insidious
Treatment: supportive care, antibiotics! IV cephalosporin + oral macrolide
Oxygen, bronchodilators, analgesia, fluids
ACUTE CHEST SYNDROME
NHLBI: Sickle Cell Disease. Expert Panel Report 2014. Pediatr Rev. 2012; 33(5): 195-204. https://pedsinreview.aappublications.org/content/33/5/195
New pulmonary infiltrates
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Short & long acting opioids for pain not managed by non-opioids NSAID adjuvant
Bowel regimen
Encourage pain agreement 2-4 week prescriptions
Non-pharmacologic: Deep tissue/pressure massage
Muscle relaxation therapy
Self-hypnosis
Hydration
CHRONIC PAIN MANAGEMENT
NHLBI: Sickle Cell Disease. Expert Panel Report 2014
Counseling point:Patients should have a bowel regimen!
Clinical Pearl:Due to chronic pain and frequent exposure, patients may be on extremely high doses of opioids
TREATMENT
Bone marrow transplant Replace sickle erythrocyte progenitors with normal ones
Gene therapy Emerging
Blood transfusions Leukoreduced erythrocytes
THIS IS IT…
NHLBI: Sickle Cell Disease. Expert Panel Report 2014
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IRON CHELATION THERAPY
Transfusion dependent patients are exposed to large amounts of iron over their lifetime 1ml erythrocytes=1 mg iron
Deposits in target organs Liver, pancreas, heart especially vulnerable
Diagnostic gold standard Liver biopsy
Treatment: iron chelation
IRON ACCUMULATION
Clinical Pearl:All iron chelators are specialty medications with limited distribution
NHLBI: Sickle Cell Disease. Expert Panel Report 2014
Binds ferric iron (3:1 binding affinity) from thalassemic and sickle cell RBCs
Dosing (adult data) 25mg/kg PO TID Tablets: 500mg May take with food
Adverse ef fects [BBW] agranulocytosis Arthralgias Nausea Liver toxicity
Monitoring ANC, CBC LFTs
DEFERIPRONE (FERRIPROX®)
Counseling Point:Oral iron chelators should be separated from polyvalent cations
Deferiprone. TruvenHealth. 2017. Deferiprone. WoltersKluwer. 2016; Guidelines for the Management of Transfusion Dependent Thalassaemia. 3rd Ed. 2014.
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100mg deferoxamine binds 8.5mg elemental Fe Complexes ferric iron (Fe3+) in vascular space to form
ferrioxamine Chronic treatment dosing 20-40 mg/kg (max 1-2 g) SQ over 8 hrs 5-7 days/week
Adverse effects Infusion reaction Auditory toxicity Ocular toxicity
Monitoring Audiometry Funduscopy, slit-lamp examination
DEFEROXAMINE (DESFERAL®)
Deferoxamine. TruvenHealth. 2017; Deferoxamine. WoltersKluwer. 2016; Guidelines for the Management of Transfusion Dependent Thalassaemia. 3rd Ed. 2014.
Counseling Point:All iron chelators can cause red-orange tinted urine
10mg/kg/day excretes 0.119 mg Fe/kg/day Binds ferric iron (2:1 binding affinity) Low affinity for zinc and copper Excreted through feces
Adverse Effects [BBW] Renal failure [BBW] Hepatic failure [BBW] GI hemorrhage Nausea
Monitoring Infusion reaction Audiometry Funduscopy, slit-lamp examination
Interactions 3A4 inducer, 1A2 & 2C8 inhibitor
DEFERASIROX
Deferasirox. TruvenHealth. 2017; Deferasirox. WoltersKluwer. 2016; Guidelines for the Management of Transfusion Dependent Thalassaemia. 3rd Ed. 2014.
20mg/kg PO QD Tablet for oral solution:
125mg, 250mg, 500mg Take on empty stomach
at least 30 minutes before meal
14mg/kg PO QD
Tablets: 90mg, 180mg, 390mg
Take on empty stomach or with l ight meal
DEFERASIROX
Deferasirox. TruvenHealth. 2017; Deferasirox. WoltersKluwer. 2016
http://www.exjade.com/images/caplets.jpg http://www.multivu.com/players/English/7440151-novartis-jadenu-fda-approval/gallery//image/761bfd65-adac-4f1c-a96a-8ca2873ef93f.jpg
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PROPHYLAXIS
Increases production of fetal hemoglobin
Increases water content of erythrocytes
Decreases circulating leukocytes and reticulocytes
HYDROXYUREA: PROPHYLAXIS AND TREATMENT
Evidence Lower annual rate of pain crises
Longer time to 1st & 2nd crisis
Lower incidence of ACS
Reduced need for transfusion
Increased total hemoglobin
Lower cost for pain hospitalization
No difference on mortality or stroke outcomes
Benefits limited to those with consistently increased fetal hemoglobin
HYDROXYUREA: THE DATA
Blood. 2008; 112: 3927-3938. NHLBI: Sickle Cell Disease. Expert Panel Report 2014.
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Indications All pediatric patients Adults 3+ pain crises per year, symptomatic anemia, interference with daily life
Dosing Infants/children: 20mg/kg/day Adults: 15mg/kg/day Maximum: 35mg/kg/day
Adverse effects: [BBW] Bone marrow suppression Secondary malignancies N/V/D/C
Monitoring CBC + differential Reticulocyte count Fetal hemoglobin
HYDROXYUREA
Blood. 2008; 112: 3927-3938. NHLBI: Sickle Cell Disease. Expert Panel Report 2014.
Counseling Point:Contraception is needed for all patients taking hydroxyurea. Continue for 1 year after therapy cessation
Penicillin VK Early infancy to at least age 5
Discontinue at 5 yrs unless splenectomy or invasive pneumococcal infection <3 years: 125mg PO BID
≥ 3 years: 250mg BID
ANTIBIOTICS
NHLBI: Sickle Cell Disease. Expert Panel Report 2014. http://www.pneumogen.net/gps/img/strep_sanger.jpg
Pneumococcus
H. influenzae (Hib)
Pneumococcal PCV13, PPSV23
Meningococcal
Influenza
IMMUNIZATIONS
NHLBI: Sickle Cell Disease. Expert Panel Report 2014.https://jnswire.s3.amazonaws.com/jns-media/67/be/67541/Child-Vaccination-Immunization.jpg
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WHAT’S COMING AROUND THE BEND?
THERE’S A “MAB” FOR THAT
Humanized monoclonal antibody against p-selectin blocking interaction with p-selectin glycoprotein ligand 1 (PSGL-1) Decreases adhesion of sickle erythrocytes and leukocytes to the
endothelium
NEJM. 3 Dec 2016. DOI: 10.1056/NEJMoa1611770
Primary end pointAnnual rate
of pain crises
1.63 vs 2.98
p=0.01
THE FUTURE OF PREVENTION?
All statistics cited as medians between high-dose and placeboNEJM. 3 Dec 2016. DOI: 10.1056/NEJMoa1611770
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Sickle cell disease and thalassemia are chronic disease with long term consequences including immunosuppression, pain, and iron overload
Prophylactic treatment is the most important aspect of managing sickle cell disease
Hydroxyurea is an effective option for most sickle cell patients
Multiple unique iron chelators are available but have many side effects and have a heavy administration burden
Additional treatment options are needed!
TAKE HOME POINTS: PREVENTING A CRISIS
Antibiotics!
Pain control!!
Supportive care!!!
TAKE HOME POINTS: BUT WHAT IF YOU ARE ALREADY IN A CRISIS?
http://www.medarcade.com/uploads/4/5/5/4/45547265/4460309_orig.jpg