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Cerebral Infarcts in Patients with Sickle Cell Disease

Cerebral Infarcts in Patients with Sickle Cell Disease. Miguel R. Abboud , MD Professor of Pediatrics Hematology -Oncology Chairman, Department of Pediatrics and Adolescent Medicine American University of Beirut Medical Center Beirut , Lebanon. Definitions.

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Cerebral Infarcts in Patients with Sickle Cell Disease

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  1. Cerebral Infarcts in Patients with Sickle Cell Disease Miguel R. Abboud, MD Professor of PediatricsHematology-OncologyChairman, Department of Pediatrics and Adolescent MedicineAmerican University of Beirut Medical Center Beirut, Lebanon

  2. Definitions Adams RJ, et al. Hematology Am Soc HematolEduc Program. 2001:31-46.

  3. Ischaemic stroke1 54% of cerebrovascular accidents Highest in 1st decade and after 30 years Peak incidence at 2–5 years Haemorrhagic stroke1 Highest in 2nd decade Silent stroke/infarct Radiologic findings consistent with white matter disease1 10%–30% of patients with sickle cell disease (SCD)1 Associated with cognitive deficiencies1 and higher stroke risk2 Stroke Subtype by Age 1. Verduzco LA, et al. Blood. 2009;114:5117-5125. 2. Miller ST, et al. J Pediatr. 2001;139:385-390.

  4. Risk Factors for Infarctive Stroke • Multivariate predictors (P <.05 for each)1 • Prior transient ischaemic attack (TIA): Relative risk (RR) = 56 • Anaemia: RR = 1.85 per 1 g/dLHb decrease • Recent acute chest syndrome: RR = 7 • Acute chest syndrome rate: RR = 2.39 per event/year • Hypertension: RR = 1.31 per 10 mmHg increase • Additional predictors • Silent infarcts: RR = 142 • Nocturnal hypoxia: Hazard ratio (HR) = 0.85 per 1% increase in O2saturation3 1. Ohene-Frempong K, et al. Blood. 1998;91:288-294. 2. Miller ST, et al. J Pediatr. 2001;139:385-390. 3. Kirkham FJ, et al. Lancet. 2001;357:1656-1659.

  5. Stroke Recurrence Risk After Initial Simple vs Exchange Transfusion All children received scheduled chronic blood transfusion therapy for at least 5 years after the first stroke and initial therapy RR = 5.0 (1.3–18.6; P= .02) 8/14 8/38 Transfusion Type Hulbert ML, et al. J Pediatr. 2006;149:710-712.

  6. Management of Stroke and Prevention of Recurrence Study population with transfusion vs historical control subjects without transfusion2 • Ischaemic stroke is treated with emergent simple or exchange blood transfusion1 • Without transfusion, 70% will recur within 2–3 years1 • With chronic transfusion, risk of recurrence is reduced by 90%1 Cumulative observation time = 191.7 patient-years 8/60 10/15 1. Josephson CD, et al. Transfus Med Rev. 2007;21:118-133. 2. Pegelow CH, et al. J Pediatr. 1995;126:896-899. 3. Powars D, et al. Am J Med. 1978;65:461-471. Transfusion2 NoTransfusion3

  7. Hydroxyurea for Secondary Stroke Prevention—SWiTCH Aim of study: [hydroxyurea + phlebotomy = alternative arm] vs [transfusions + deferasirox = standard arm] for 30 months to prevent secondary stroke and reduce transfusional iron overload Alternative armHydroxyurea + phlebotomy n = 67 161 paediatric patients with SCD and documented stroke and iron overload enrolled in SWiTCH 133 patients randomized 1:1 Standard armTransfusions + deferasirox n = 66 Prediction: increased recurrence of stroke events in alternative arm but counterbalanced by better management of iron overload with phlebotomy Ware RE, et al. Blood. 2010;116:Abstract 844.

  8. SWiTCH—Stroke Recurrence Higher with Hydroxyurea than with Transfusions1 Study was terminated early2 due to the marked increase in secondary stroke risk with hydroxyurea compared with transfusion therapy and no benefit of phlebotomy over chelation in reducing iron overload 7/67 0/66 Hydroxyurea + Phlebotomy Transfusion + Deferasirox 1. Ware RE, et al. Blood. 2010;116:Abstract 844. 2. NIH. Press release. June 4, 2010. Accessed 11/21/11 at: http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2709.

  9. Importance of Transcranial Doppler Screening in SCDAnnual Stroke Risk • Baseline risk from Cooperative Study of Sickle Cell Disease (CSSCD) is approximately 0.5%–1%1 • −If prior stroke, annual stroke risk is approximately 30%2 • Increased risk of infarctive stroke with TIA, lower baseline Hb, prior and recent acute chest syndrome (CSSCD study, no prior stroke), but yearly risk not quantitated1 • If abnormal transcranial Doppler (TCD), annual risk is 10%–13% per year3 • If MRI “silent lesions,” annual risk is approximately 2%–3%4 • Severe arterial lesions on angiography? • −Assumed to be bad,5 but yearly risk has not been quantitated 1. Ohene-Frempong K, et al. Blood. 1998;91:288-294. 2. Powars D, et al. Am J Med. 1978;65:461-471. 3. Adams RJ. Arch Neurol. 2007;64:1567-1574. 4. Miller ST, et al. J Pediatr. 2001;139:385-390. 5. Abboud MR, et al. Blood. 2011;118:894-898.

  10. Stroke-free Probability Is Increased with Long-Term Transfusions in Children with SCD Paediatric patients with SCD and abnormal TCD velocity were randomized to transfusion or standard care to prevent first stroke. Median follow-up = 21.1 months P <.001 11/67 12/130 1/63 *Includes 1 patient with intracerebral hematoma. Adams RJ, et al. N Engl J Med. 1998;339:5-11.

  11. Early TCD Screening and Intervention • Predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217, SS/Sβ0) • Screenedwith TCD early and yearly since 1992 • MRI/MRA every 2 years after age 5 years(or earlier in case of abnormal TCD) • Transfusions for abnormal TCD and/or stenoses • Hydroxyurea to symptomatic patients with no macrovasculopathy • Stem cell transplantation for those with HLA genoidentical donor • Mean follow-up 7.7 years (1609 patient-years) Bernaudin F, et al. Blood. 2011;117:1130-1140.

  12. Cumulative Risks in SCD Cohort with TCD Screening • Cumulative risks by 18 years of age • Stroke: 1.9% (95% CI 0.6%–5.9%) compared with 11% • Abnormal: TCD 29.6% (95% CI 22.8%–38%) plateau at age 9 years • Stenosis: 22.6% (95% CI 15.0%–33.2%) • SI: 37.1% (95% CI 26.3%–50.7%) age 14 years • All cerebral event risk by 14 years 49.9% (95% CI 40.5%–59.3%) • Independent predictive factors for cerebral risk • Baseline reticulocytescount: HR 1.003 per 1 x 109/L increase • Lactate dehydrogenase: HR 2.78 per 1 IU/mL increase • Conclusion: Early TCD screening and intensification therapy reduced risk of stroke by age 18 years from 11% to 1.9% • 50% cumulative cerebral risk suggests more preventive intervention is needed Bernaudin F, et al. Blood. 2011;117:1130-1140.

  13. TCD and Transfusions in Patients with Silent Infarcts—Conclusions • Early TCD and transfusions effective in preventing strokes • TCD does not screen for risk of silent infarcts • Most patients who develop silent infarcts have normal TCD • Different strategies needed BernaudinF, et al. Blood. 2011;117:1130-1140.

  14. STOP II Trial—Transfusion and Stroke Prevention • 79 subjectshavingnormalized TCD under transfusion wererandomized1 • 38 to continuecRCTtherapy • 41 to discontinuecRCTtherapy • No neurologic events in the cRCTgroup1 4.9% Patients with Neurologic Events (%) 34.1% STOP II trial terminated after 2 years and concluded that it is unsafe to stop blood transfusions in patients who are at high risk of stroke2 Abbreviations: cRCT, chronic red cell transfusion; TCD, transcranial Doppler.1. Adams RJ, et al. N Engl J Med. 2005;353:2769-2778. 2. NIH. Press release. December 5, 2004. Accessed 11/21/11 at: http://www.nhlbi.nih.gov/new/press/04-12-05.htm. Graphic courtesy of Dr. Miguel R. Abboud.

  15. STOP Trial—Transfusion Therapy vsStandard Care for Prevention ofSecondary Silent Brain Infarcts Outcome after observation for 36 months in patients who had silent infarcts at baseline and who were randomized to transfusion or standard care *Includes 1 patient with new or worse lesion prior to stroke. Pegelow CH, et al. Arch Neurol. 2001;58:2017-2021.

  16. STOP II Trial—Effect of Discontinuing Transfusion on Silent Brain Infarcts on MRI *1 patient had no follow-up MRI. †3 patients had lesion number decrease; 1 reverting to normal scan. Abboud MR, et al. Blood. 2011;118:894-898.

  17. STOP II Trial—Effect of Discontinuing Transfusion on Silent Brain Infarcts on MRI At study end, 3/37 (8.1%) patients in the continued-transfusion group developed new brain MRI lesions compared with 11/40 (27.5%) in the transfusion-halted group (P = .03) *1 patient had no follow-up MRI. †3 patients had lesion number decrease; 1 reverting to normal scan. Abboud MR, et al. Blood. 2011;118:894-898.

  18. Consequence of Stroke Prevention with Blood Transfusions Paediatric patients with SCD and abnormal TCD velocity were randomized to transfusion or standard care to prevent first stroke. IRON OVERLOAD is an inevitable consequence of chronic transfusions in patients with SCD Median follow-up = 21.1 months Initial serumferritin 164 ± 155ng/L P <.001 1-year serumferritin 1804 ± 773ng/L 2-year serumferritin 2509 ± 974ng/L 11/67 12/130 1/63 *Includes 1 patient with intracerebral hematoma. Adams RJ, et al. N Engl J Med. 1998;339:5-11.

  19. Organ Dysfunction inSickle Cell Disease and β-Thalassaemia SCD n = 43 β-Thal n = 30 *P-value = not significant; P-value significant for all other comparisons.Vichinsky E, et al. Am J Hematol. 2005;80:70-74.

  20. Why Do SCD Patients Demonstrate Less Organ Injury than β-Thalassaemia Patients? • Organ injury may require a critical iron level with prolonged exposure • SCD biology and its secondary inflammatory state may be protective factors • Inflammation may decreaseorgan injury by restricting iron to shielded sites within the reticuloendothelial system (RES) and delaying the release of iron from the RES system • The 2 diseases may have different transport and storage proteins Vichinsky E, et al. Am J Hematol. 2005;80:70-74.

  21. Possible Explanations for Absence of Cardiac Iron Overload in SCD • Nontransferrin-bound iron higher in thalassaemia major than SCD • Other factors • Splenic tissue • Ineffective erythropoiesis • Gastrointestinal iron metabolism • Urinary iron loss Vichinsky E, et al. Am J Hematol. 2005;80:70-74.

  22. KupfferCellSiderosis HepatocyteSiderosis With permission from Pierre Brissot, MD.

  23. How to Monitor Iron Status • Serum ferritin • Noninvasive, available, inexpensive • Confounded by several parameters • Use long-term trends and avoid using acute-phase values • Liver biopsy • Gold standard • Reveals pathology • Invasive • Sampling error • Magnetic resonance • Accurate • Expensive

  24. How to Manage Iron Overload • Chelating agents • Desferrioxamine • Deferasirox • Deferiprone • Licensed for thalassaemia major only1 • Nonpharmacologic techniques • Erythrocytapheresis • Phlebotomy 1. Ferriprox (deferiprone). Summary of product characteristics. Leiden, Netherlands: Apotex; 1999.

  25. Chronic Transfusion Methods 1. Sickle Cell Society. Standards for the clinical care of adults with sickle cell disease in the UK. 2008.Accessed 11/29/11 at: http://www.sicklecellsociety.org/app/webroot/files/files/CareBook.pdf. 2. Kim HC, et al. Blood. 1994;83:1136-1142.

  26. Iron Chelation Therapy is Needed to Treat Iron Overload 1. Desferal (desferrioxamine). Summary of product characteristics. Camberly, UK: Novartis; 2010. 2. Exjade (deferasirox). Summary of product characteristics. Nuremberg, Germany: Novartis; 2006. 3. Ferriprox (deferiprone). Summary of product characteristics. Leiden, Netherlands: Apotex; 1999. Graphic courtesy of Dr. Miguel R. Abboud.

  27. Deferasirox vs Desferrioxamine—Measures of Iron Overload LIC Reduction (SQUID) Serum Ferritin Reduction Deferasirox(n = 117) Desferrioxamine(n = 56) Deferasirox(n = 83) Desferrioxamine(n = 33) P = NS P = NS Data from Cochrane review of randomized-controlled trials that compared deferasirox with desferrioxamine. Abbreviations: LIC, liver iron concentration; SQUID, superconduction quantum interference device. Meerpohl JJ, et al. Cochrane Database Syst Rev. 2010;8:CD007477.

  28. Deferasirox vs Desferrioxamine—Measures of Satisfaction and Adherence Data from Cochrane review of randomized-controlled trials that compared deferasirox with desferrioxamine. Meerpohl JJ, et al. Cochrane Database Syst Rev. 2010;8:CD007477.

  29. Conclusions • Infarctive strokes are a devastating complication of SCD • Chronic transfusion regimens are very effective in preventing stroke recurrence as well as new strokes in patients with abnormal transcranial Doppler • Early transfusions seem effective in preventing development and progression of silent infarcts • Iron accumulation in sickle cell disease is different compared with thalassaemia • Iron chelators are effective in preventing iron overload in these patients

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