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Transcript of Sickle’Cell’Diseases’ - · PDF fileSickle’Cell’Diseases ......
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Sickle Cell Diseases
Cage S. Johnson, M.D. Professor Emeritus of Medicine
Keck School of Medicine University of Southern California
Director, Sickle Cell Center Los Angeles County+USC Medical Center
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Acute & Chronic Manifestations of Sickle Cell Disease
• Pain : ischemic, neuropathic, collapsed bone • Brain: TIA, ischemic Stroke, hemorrhage • Eye: retinopathy • Bone: remodeling by marrow hyperplasia, bone infarct,
synovitis, osteonecrosis, collapse, osteomyelitis • Lung: ACS, chronic restrictive lung disease (hypoxia) • Heart : pulmonary hypertension • Liver : gallstones, hepatitis, iron overload, sequestration • Spleen : auto-infarction, sequestration, bacterial sepsis • GU: infection, proteinuria, renal insufficiency,
obstetrical, priapism • Skin: leg ulcers
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Manifestations of Sickle Cell Disease
1. Chronic Hemolysis 2. Intermittent “crises” 3. Frequent Infections 4. End organ dysfunction 5. Disorders unrelated to the Hbopathy
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Neurologic Complications • CVA: Acute neurological signs/symptoms lasting 24 h; ~ 1% per
year. Ct scan/MRI shows typical ischemic lesions. Rx with exchange transfusion immediately. Chronic transfusion therapy reduces recurrence by 90%; duration of therapy is unknown.
• TCD ultrasonography: Velocity > 200 cm/sec in MCA/ICA is predictive of CVA. Chronic transfusion reduces the incidence by 90%. Screening begins at age 2. Values > 170 cm/sec require frequent testing for increase.
• TIA: acute nuerological signs/symptoms lasting < 1 h with normal CT/MRI. Rx with chronic transfusion especially if there is an abnormal TCD.
• Silent CVA: Incidence 13% in children and up to 35% in adults. MRI shows infarctive lesions without neurological symptoms, but neuropsychometric testing shows deficits in “executive functioning”.
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Acute Chest Syndrome 1. Term recognizes the difficulty in
distinguishing among: a. Infection (bacterial, viral) b. Sickle vaso-occlusion (± infarction) c. Fat embolism d. Thromboembolism 2. Fails to distinguish between
uncomplicated acute pulmonary disease and progressive disease
Arch Intern Med 139:67, 1979
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Pulmonary Disease (CSSCD)
• N = 318, > 18 y of age (mean 31 ± 10), 41 % male • 90 % abnormal
Restrictive - 74 %
Obstructive - 1 %
Mixed O/R - 2 %
↓ DLCO - 13 %
• Association between lung & kidney disease
Am J Resp Crit Care Med epublished 23 Oct 2005
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Graphic: SL Johnson
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Pulmonary Hypertension
• Surveys with echocardiography reveal an incidence of ~10% in children and 35% in adults.
• Elevated pulmonary artery pressures are associated with shortened survival, pulmonary emboli/thrombosis, leg ulcers, priapism and increasing hemolysis
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Gall Bladder
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Br Med J 295:234, 1987
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J Clin Epidemiol 45:893, 1992
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Title
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Title
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Medicine 84:363, 2005
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Adult Health Care • Preventive Health Maintenance: • Psychosocial Assessment: school achievement,
occupational Hx, depression, anxiety, financial resources
• Education: tobacco, alcohol, recreational drugs, safe sex techniques, sickle cell related education – fever, dyspnea, pain management
• Surveillance for complications of SCDz, as well as for disorders of adulthood
• Referral network, early treatment of complications
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Surveillance: (repeated annually)
• H/O sickling related events: Pain-acute & chronic, CVA, PNA/ACS (ICU), Hepatitis, Cholelithiasis, Priapism, Retinopathy, Pregnancy, Leg Ulcer, Hematuria/Infection, Bone infections/AVN, Transfusion
• Lab: CBC, Bun/Creatinine, Urine protein, Iron/Ferritin, Hepatitis markers, B12, Folate, RBC phenotype, pulse oximetry, allo-antibodies, EKG (QTc), Brain naturetic peptide, & additional assays based upon Hx/Px
• X-ray: Chest, Hips, Shoulders, T/L Spines, etc.
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CHALLENGES in MANAGEMENT
of the ADULT PATIENT • Shorten the duration of acute complications
• Reduce the frequency of acute complications
• Reduce the frequency/severity of chronic complications
• Improve survival
• Enhance the Quality of Life
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Options
• Stem Cell Transplantation
• Gene Therapy
• Hydroxyurea
• Transfusion/Chelation
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Stem cell transplant in SCDz n ~ 600
• Mortality 5-7% • Engraftment >90%* • Event free survival >85% • Acute GVHD ~25%
Grade III-IV <5% Chronic GVHD ~20%
grade III-IV <10% * Some with partial chimerism
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Gene Therapy
• Clinical Trial in 5 Hb SS & 5 β Thal (Paris)
• Self-inactivating lentiviral vector
• βA-T87Q
Ann NY Acad Sci 1054:308, 2005
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New Agents
• GBT -440 • Small molecule attaches to Hb S and
increases oxygen afinity • In micromolar concentrations, n=8 for 28 days • Reduces circulating ISCs from a mean of
57% to 7% , Indirect bilirubin BY 25%, , LDH by 12%, retic cts by 30%
• Increases hgb by ~ 0.75 g/dL
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New Agents
• GMI-1070 • Pan selectin inhibitor, IV q 12 h • N = 43, placebo = 3 • Decreased VAS faster than control,
5-10-fold decrease in opioid dose, 28% decrease in LOS
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California Birth Rates (~600k per yr)
FS 79/yr
FSC 39/yr
FSA 13/yr
FS other 10/yr
FE 140/yr Eur J Hum Genet 1994;2:262
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6th position of Beta Chain Molecular Events in Hb S (Part 1)
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MEMBRANE DAMAGE SECONDARY TO SS TACTOID
Membrane Damage in Hb S (Part I)
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HEMOGLOBIN COMPOSITION IN VARIOUS CONDITIONS Hb A Hb A2 Hb F Hb S Hb C
Normal adult 96% 3% <2% -‐ -‐ Sickle cell trait (Hb AS) 58% 3% <2% 38% -‐ Sickle cell anemia -‐ 3% 2-‐15% 80-‐95% -‐ Hemoglobinopathy SC -‐ 3% 1-‐2% 48% 48% Sickle βO thalassemia -‐ 5% 5-‐20% 70-‐85% -‐ Sickle β+ thalassemia 10-‐30% 5% 5-‐20% 50-‐70% -‐
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Manifesta[ons of Sickle Cell Disease
1. Chronic Hemolysis 2. Intermi]ent “crises” 3. Frequent Infec[ons 4. End organ dysfunc[on 5. Disorders unrelated to the Hbopathy
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EXAMPLES OF TYPICAL BLOOD COUNTS IN VARIOUS SITUATIONS Condi[on Hb AA/AS Hb SS Hb SC Hb SβO thal Hb Sβ+ thal Hemoglobin (g/dl) 13-‐15 7-‐9 11-‐14 8-‐10 9-‐12 RBC volume (fl) 90±8 90±8 85±9 68±6 72±7 Re[culocyte count (%) 1.0 12.0 2.0 8.0 5.0
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Acute & Chronic Manifesta2ons of Sickle Cell Disease
• Pain : ischemic, neuropathic, collapsed bone • Brain: TIA, ischemic Stroke, hemorrhage • Eye: re[nopathy • Bone: remodeling by marrow hyperplasia, osteonecrosis,
collapse, osteomyeli[s • Lung: ACS, chronic restric[ve lung disease (hypoxia) • Heart : pulmonary hypertension, LV dysfunc[on • Liver : gallstones, hepa[[s, iron overload, sequestra[on • Spleen : auto-‐infarc[on, sequestra[on, bacterial sepsis • GU: infec[on, proteinuria, renal insufficiency,
obstetrical, priapism • Skin: leg ulcers
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Pain Management
• Hydra[on: D5+0.5 NS @ 1.5 x maintenance • Analgesia: IV q 10-‐15 min un[l pain score is 5 or less or
respiratory is < 14 per minute (SQ if no venous access) <50 kg: morphine 0.1 to 0.15 mg/kg or hydromorphone 0.015 to 0.2 mg/kg
> 50 kg: morphine 5 to 10 mg or hydromorphone 1.5 mg
Con[nue 50% of loading dose q 3-‐4 h ATC Provide a rescue dose
Add a NSAID, especially if there is bony tenderness
• When pain is controlled, begin oral analgesic with rescue dose in prepara[on for discharge
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Pain Management
• Incen[ve spirometry q 2h ATC to prevent atelectasis and acute chest syndrome
• Monitor pulse oximetry for progressive decrease
• Periodic assessment of respiratory effort, cough, sputum produc[on
• DVT prophylaxis
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PiSCES FINDINGS Pain, Crises, And U.liza.on
• 55% of pa2ents had pain on more than half of their diary days
• 30% had pain essen2ally daily • 4,429 crisis days (14.8%) • In contrast, pa2ents reported only 1,057 u2liza2on days (3.5%)
Wally Smith et al. Virginia Commonwealth University
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MULTICENTER HYDROXYUREA TRIAL
Group Hydroxyurea Placebo p value*
Pain Episodes 2.5 / year 4.5 / year p < 0.001Pain Admits 1.0 / year 2.4 / year p < 0.001Acute Chest 25 episodes 51 episodes p < 0.001Transfused 48 73 p < 0.001Total Units 336 586 p = 0.004
*Van der Waerden’s test.
Charache et al. N Engl J Med 322:1317, 1995.
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Sickle Cell Diseases
The Acute Chest Syndrome: A new chest x-‐ray infiltrate plus One or more pulmonary signs/symptoms:
fever, cough, sputum produc[on, tachypnea, dyspnea, new onset hypoxia
In contrast to the general popula[on, mul[ple lobe involvement and delayed clearance of infiltrates (12 d) is more common is SCDz.
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Acute Chest Syndrome 1. Term recognizes the difficulty in dis[nguishing
among:
a. Infec[on (bacterial, viral)
b. Sickle vaso-‐occlusion (± infarc[on) c. Fat embolism
d. Thromboembolism
2. Fails to dis[nguish between uncomplicated acute pulmonary disease and progressive disease
Arch Intern Med 139:67, 1979
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NACSSG (NEJM 342:1855, 2000)
• 671 episodes in 538 pa[ents • 27 pathogens iden[fied Chlamydia -‐ 7.2% Mycoplasma -‐ 6.6% Viral -‐ 6.4% Infarc[on -‐ 16.1% Fat embolism -‐ 8.8% (most common cause of death)
S. pneumonia -‐1.7% (11 of 671) • 48% developed ACS as inpa[ent with acute pain • Physical examina[on was normal in 35% of cases
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Graphic: SL Johnson
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Treatment
• Cephalosporin (3 or 4th genera[on) plus a macrolide
• Alterna[ve – quinolone or macrolide plus a betalactam
• Hydra[on – 0.5 ns @ 1.5-‐2.0 [mes maintenance
• Incen[ve spirometry • Bronchodilator if needed
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Treatment, Goals
• Preven[on of alveolar collapse • Maintenance of gas exchange
• Preven[on of further pulmonary injury (ARDS)
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Treatment, transfusion
• Simple transfusion aimed at raising the oxygen carrying capacity and reducing cardiac workload.
• Exchange transfusion when there are signs of worsening pulmonary func[on, (i.e., considering mechanical ven[la[on)
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Exchange Transfusion, indica[ons
• Physical examina[on: a. Altered mental status
b. Persistent tachycardia > 125/min
c. Respiratory rate > 30/min or increased work of breathing
d. Fever > 400 C
e. Hypotension compared to baseline
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Exchange Transfusion, indica[ons
• Laboratory/Radiologic findings a. Arterial pH < 7.35 b. Oxygen satura[on < 88% despite aggressive ven[latory support c. Serial decline in sPo2 or increasing A-‐a gradient
d. Hemoglobin falling by 2 g/dl or more e. Platelet count < 200k/µl f. Evidene for mul[organ failure
g. Pleural effusion h. Progression with addi[onal lobar infiltrates
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Pulmonary Disease (CSSCD)
• N = 318, > 18 y of age (mean 31 ± 10), 41 % male
• 90 % abnormal
Restric[ve -‐ 74 %
Obstruc[ve -‐ 1 %
Mixed O/R -‐ 2 %
↓ DLCO -‐ 13 %
• Associa[on between lung & kidney disease
Am J Resp Crit Care Med epublished 23 Oct 2005
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Chronic Organ Damage in Hb SS: n = 1,056; 11,427 pa[ent-‐yrs since 1959
Organ # of pts % pts Age at Dx (median)
Gallbladder 297 28.1 28
AVN 224 21.2 30
Lung 165 15.6 32
Leg ulcer 152 14.4 30
Priapism 71 13.5 29
Renal 122 11.6 37
CVA 116 11.0 20
Re2na (III,IV) 92 8.7 30
Non-‐sickle 30 2.8 24
Composite 540 48.5 24
Mortality 232 22.0 31
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Chronic Organ Damage in Hb SC
Organ # of pts % pts Age at Dx (median)
Re[na (III, IV) 65 23 28
AVN 42 15 34
Gall bladder 22 8 32
CVA 13 4.6 33
Osteomyeli[s 12 4 29
CLD 12 4 32
Renal 8 3 52
Priapism 7 2.5 26
Leg ulcer 6 3 33
Composite 112 39 28
Mortality 25 9 37
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Medicine 84:363, 2005
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CHALLENGES in MANAGEMENT of the ADULT PATIENT
• Shorten the dura[on of acute complica[ons
• Reduce the frequency of acute complica[ons
• Reduce the frequency/severity of chronic complica[ons
• Improve survival
• Enhance the Quality of Life
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Op[ons
• Stem Cell Transplanta[on
• Gene Therapy
• Hydroxyurea -‐ not supported by Baby HUG
• Transfusion/Chela[on
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Stem cell transplant in SCDz n ~ 600
• Mortality 5-‐7% • Engrayment >90%* • Event free survival >85% • Acute GVHD ~25%
Grade III-‐IV <5% Chronic GVHD ~20% grade III-‐IV <10%
* Some with par[al chimerism
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Gene Therapy
• Clinical Trial in 5 Hb SS & 5 β Thal (Paris)
• Self-‐inac[va[ng len[viral vector
• βA-‐T87Q
• N = 7 to date
Ann NY Acad Sci 1054:308, 2005
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M Cavazzana-Calvo et al. Nature 467, 318-322 (2010) doi:10.1038/nature09328
Conversion to transfusion independence.
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Gene Edi[ng
• Cluster Regularly Interspaced Short Palindromic Repeats (CRISPR-‐CAS-‐9)
• CAS-‐9 splits DNA for repair • Has corrected the defect in the sickle mouse
• Human embryo experiments showed mul[ple sites edited
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Transfusion/Chela[on • Allo-‐immuniza[on:
Reduced by extended phenotyping
• Iron overload: DFO & Exjade® /Jadenu ® & Deferipone
• Viral Disease Transmission:
Current rates are extremely rare
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Transfusion Hemosiderosis
• Liver fibrosis/cirrhosis • Diabetes via pancrea[c fibrosis • Endocrine organ dysfunc[on Growth retarda[on Gonadal failure
• Cardiac fibrosis/cardiomyopathy
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Hb SS (n=43) Thal (n=30)
Cardiac 0 % 20 %
Endocrine 0 % 37 %
Gonadal failure 0 % 33 %
Viral hepa22s 2 % 33 %
Hepa2c fibrosis 39 % 81 %
Transfusion Hemosiderosis
Am J Hematol 80:70, 2005
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New Agents
• GBT -‐440 • Small molecule a]aches to Hb S and increases oxygen afinity
• In micromolar concentra[ons, n=8 for 28 days • Reduces circula[ng ISCs from a mean of 57% to 7% , Indirect bilirubin BY 25%, , LDH by 12%, re[c cts by 30%
• Increases hgb by 0.75 g/dL
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New Agents
• GMI-‐1070 • Pan selec[n inhibitor, IV q 12 h • N = 43, placebo = 3 • Decreased VAS faster than control, 5 rp10-‐fold decrease in opioid dose, 28% decrease in LOS
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New Agents
• SEL-‐G1 humanized monoclonal an[body: (SUSTAIN-‐phase II/III)
• P-‐selec[n inhibitor; sickle RBCs have a PSGL-‐1 receptor
• IV q 4 wks for 50 weeks, • N = 174 • Hi dose, low dose, placebo
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Clincal Issues in Hb AS (sickle cell trait)
• Hyposthenuria due to renal medullary damage • Hematuria due to renal papillary necrosis • Splenic infarction at altitude • Increased susceptibility to heat stroke • Sudden death due to myo-necrosis with extreme exertion • Importance of education regarding genetic transmission
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Summary: Goal of reducing morbidity & mortality
• More aggressive use of Hydroxyurea: www.ahrq.gov/clinic/tp/hydscdtp.htm
• Regular Surveillance • Prompt referral
• Individualize therapy to the pa[ent
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Graphic: SL Johnson
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Days in Pain
≤5
6-10
11-2526-50
51-75
76-95
96-100
0
5
10
15
20
25
30
35Pe
rcen
t of P
atie
nts
Percent of Days in Pain
30% of subjects had pain nearly every day Only 13% of subjects almost never had pain
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Neurologic Complica[ons • CVA: Acute neurological signs/symptoms las[ng 24 h; ~ 1% per year.
Ct scan/MRI shows typical ischemic lesions. Rx with exchange transfusion immediately. Chronic transfusion therapy reduces recurrence by 90%; dura[on of therapy is unknown.
• TCD ultrasonography: Velocity > 200 cm/sec in MCA/ICA is predic[ve of CVA. Chronic transfusion reduces the incidence by 90%. Screening begins at age 2. Values > 170 cm/sec require frequent tes[ng for increase.
• TIA: acute neurological signs/symptoms las[ng < 1 h with normal CT/MRI. Rx with chronic transfusion especially if there is an abnormal TCD.
• Silent CVA: Incidence 13% in children and up to 35% in adults. MRI shows infarc[ve lesions without neurological symptoms, but neuropsychometric tes[ng shows deficits in “execu[ve func[oning”.
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ACUTE Clinical Syndromes in SS (and Sickling Disorders) Due to Microvascular
Occlusion
Acute Pain
Hand-foot syndrome
Acute chest syndrome
Ischemic stroke
Splenic sequestration crisis
Acute priapism
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Acute Clinical Events in Hb SC
Event # of pts % of pts Incidence per 100 pt-‐yrs
(mean)
Hospitaliza2ons 202 71 47
Sickle related 187 66 38
Uncomplicated pain 157 55 30
20 sickle pain 95 33 18
ACS 91 32 7
Bone infarct 27 9.5 1.6
Am J Hematol 70:206, 2002
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J Clin Epidemiol 45:893, 1992
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Causes of Tendini[s/Bursi[s
• Trauma
• Overuse
• Abnormal biomechanics
• Differing leg lengths
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Treatment
Lidocaine 5 mg
Bupivacaine 1.25 mg
Methylprednisolone 10 mg
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Diagnos[c Criteria
H. Li]le: CMAJ 120:456, 1979
• Localized tenderness (pinpoint) • Aggravated by ac[ve mo[on
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Response
1) immediate relief of pain
2) resump[on of range of mo[on
3) con[nuing relief for 6 months or more
4) failure = recurrence of symptoms within 1 month
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Causes of Worsening Anemia in Patients with SS Disease
• Aplastic crisis secondary to infection
• Renal failure with erythropoietin deficiency
• Hepatic or splenic sequestration crisis
• Decreased folic acid (i.e. during pregnancy)
• Iron deficiency in growing children or during pregnancy
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Conclusions
• Tendini[s/Bursi[s syndromes are common in the general popula[on, age 25 to 50 with a female preponderance
• Diagnosis requires clinical suspicion and specific maneuvers on physical examina[on
• Local anesthe[c + steroid injec[on is both diagnos[c and therapeu[c
• T/B is present in the sickle cell pa[ent popula[on, but the incidence is unknown
• Response to anesthe[c + steroid injec[on in SCD is similar to the 60-‐70% ini[al response rate in the general popula[on
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Br Med J 295:234, 1987
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Pulmonary Hypertension
• Surveys with echocardiography reveal an incidence of ~10% in children and 35% in adults.
• Elevated pulmonary artery pressures are associated with shortened survival, pulmonary emboli/thrombosis, leg ulcers, priapism and increasing hemolysis
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Int J Artif Organs 13:231, 1990
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