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Hemoglobin  SC  Disease:  Updates  on  pathophysiology  and  treatment  

Sickle  Cell  Disease  Symposium    Toronto,  September  2014  

 By  Dr.  Veronique  Naessens,  MD,FRCPC  

Hematology,  McGill  University  Montreal,  Canada  

Disclosures:  None  relevant  

Outline  

•  IntroducLon  •  Historical  perspecLves  •  Natural  history  of  Hemoglobin  SC  Disease  •  Pathophysiology  •  Management  of  Hemoglobin  SC  Disease  in  2014  

•  Final  thoughts  

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IntroducLon  

 •  Hemoglobin  SC  Disease  is  an  inherited  sickling  disorder  

 •  Diagnosed  in  over  54  000  annual  births  worldwide1  

           

1Weatherall,  2010  

Historical  PerspecLve  

Historical  PerspecLve:  The  CSSCD  Trial  

Prospec(ve  data  of  3764  pa(ents  with  SCD  from  the  CSSCD  trial  in  the  USA  (1978-­‐88)    

Median  age  at  death:  60M,  68F  Median  age  at  death:  42M,  48F  

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The  evolving  percepLon  of  Hb  SC  Disease  

First  Case  Reports                  CSSCD  Trial                                                                1  AlloSCT  in  a  40M                                                    

1950s   1970s   1990s   2000   >2010  

«  HbSC  disease  should  not  be    considered  a  mild  form  of  SCA…  »2    

«  …milder  form  of  SCD  »1     1  www.cdc.gov  2Lionnet  et  al.,  2012    

What  is  the  natural  history  of  Hemoglobin  SC  disease?  

•  Recent  published  data  from  France  and  Brazil  aims  to  idenLfy  rates  of  complicaLons  of  Hemoglobin  SC  disease  

 •  Report  from  104  adults  (mean  age  34;  5  years  follow-­‐up)  with  Hemoglobin  SC  disease  followed  at  a  Toronto  academic  hospital  (University  Health  Network,  UHN)  

UHN  Hb  SC  Disease  Cohort  

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UHN  Hb  SC  Disease  Cohort  

Hb  SC  Disease:  a  different  comorbidity  profile  than  Hb  SS/  Hb  Sβ0  

In  Hb  SS/Hb  Sβ0   In  Hb  SC  

Painful  VOC  

Painful  VOC  

Thrombosis?  

Hearing  loss?  

Pathophysiology  of  SCD  

In  Hb  SC  Disease:          Hemolysis                            Hemoglobin  level                        ?  Viscosity  

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What  about  increased  blood  viscosity?  

•  Blood  viscosity  influenced  by:  •  Hemoglobin/Hematocrit  level  •  Red  Blood  Cell  deformability  and  aggregaLon  

•  Appears  to  correlate  with  severe  proliferaLve  reLnopathy  in  Hb  SC  paLents1  

•  Hemoglobin/hematocrit  level  unlikely  to  be  a  good  surrogate  for  blood  viscosity2  

1Lemaire  et  al.,  2013  2Lemonne  et  al.,  2014    

Why  does  sickling  occur  in  Hb  SC  Disease?  

RBC  dehydraLon  increases  HbS  polymerizaLon,  which  increases  RBC  sickling  

Water  export  out  of  the  cell      Via  KCl  transporters  

DeoxygenaLon  

TherapeuLc  ModaliLes  used  in  Hemoglobin  SC  Disease  

•  SupporLve    •  Hydroxyurea  (HU)  •  Phlebotomy  •  Chronic  transfusion  («  top-­‐up  »  or  exchange)  

•  Allo  Stem  Cell  TransplantaOon  

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Hydroxyurea:  Can  we  extrapolate  results  from  the  SCA  populaLon?  

•  No  trial  of  HU  in  the  Hb  SC  populaLon  alone.  

•  Benefit  of  raised  HbF  %  with  HU  seen  in  SCA  not  tradiLonally  seen  in  Hb  SC.  

•  PotenLal  mechanisLc  benefits  of  HU  in  Hb  SC:  –  Decreased  RBC  dehydraLon  

(KCl  transport)  –  Decreased  RBC  adhesion  –  Decreased  hemolysis  –  Decreased  polymerizaLon  of  

HbS  Voskaridou E et al. Blood 2010;115:2354-2363

Increased  survival  in  SCA  paLents  with  HU  

Absence  of  a  rise  of  HbF  in  Hb  SC  pa(ents  on  HU  does  not  equal  to  a  lack  of  efficacy!  

Use  of  Phlebotomy  in  Hb  SC  Disease  

SICKLE CELL CHEST SYNDROME

0.3 A

L

B (I) p. 3 0.2 L Q)

B 8 6 g! 2 = 0.1

L

0.0

2-4

I I I I 6 8 10 12

Hemoglobin (g/dl)

Fig 3. Effect of blood Hb level on ACS incidence in SS patients as predicted by Poisson modeling. Age groups are as in Fig 2. The WBC variable also was set as in Fig 2. HbF level was assumed to be 6.8546, which was the overall mean for SS patients. ACS rate was plotted within the range of the observed Hb values for each age group.

discussed below, a high frequency of pain crises is also an indicator of disease severity (and a predictor of short sur- vival) in this patient population.

Other factors associated with a high ACS incidence were the SS genotype and a high steady-state leukocyte count. For SS patients, risk factors also included high Hb level and low Hb F concentration. In all age groups of patients with sickle cell anemia (SS), the incidence of ACS was inversely related to Hb F level. Our data may explain why previous analyses of the protective effect of Hb F on the prevalence of ACS have given equivocal results. The influence of age on ACS incidence is so strong that the protective effect of Hb F, which is only relative, can be detected only by examin- ing a narrow age range, particularly among younger patients. a Thalassemia did not affect ACS incidence in SS patients even though a thalassemia is known to lower these patients' hemolytic rate.*' The reasons for the association between high leukocyte count and ACS incidence are not clear. Pre- liminary analysis of the CSSCD patient survival data shows that higher leukocyte counts correlate with higher mortality rates. Therefore, the association of leukocytosis with ACS incidence could reflect the fact that both high WBC and high ACS rate are more frequent in patients with severe disease.

What do these risk factors suggest about the pathogenesis of ACS? The highest ACS incidence in young children is compatible with infection as an etiology because these pa-

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tients have not yet developed antibodies to a variety of bacte- rial and viral microorganisms. However, recent reports, in which careful bacteriologic and virologic studies were per- formed, excluded an infectious etiology of ACS in most adults and ~ h i l d r e n . ~ * ~ * ~ ~ The association of ACS with young age could also be explained by reasoning that the increased susceptibility to viral respiratory infection in young children could precipitate ACS if the latter had a vaso-occlusive pathogenesis. The within-patient decline in ACS incidence as these children age could then reflect a developing immu- nity to viral infections.

Sickle cell patients have a known predisposition to bacte- rid infection, particularly pneumococcal i n fe~ t ion .~~-*~ With- out invasive procedures it is very difficult to rule out conclu- sively a bacterial process as a cause of ACS. Bacteria could also superinfect an area of ischemic lung tissue. For these reasons, the ACS is almost always treated with antibiotics. On the other hand, reports of rapid resolution of severe ACS after exchange transfusions26-28 suggest that pulmonary vas- cular occlusion and ischemidinfarction play an important etiologic role in the syndrome. Indeed, vascular occlusion has been suggested by high resolution computerized tomog- r a p h ~ , ~ ~ and has been demonstrated in the isolated ACS cases in which pulmonary angiography was performed." The fre- quent finding of alveolar wall necrosis and marrow emboli3' at autopsy of sickle cell patients dying of various causes also suggests lung injury from vascular occlusion rather than infection. Other presumptive causes of ACS include viral infection, mycoplasma infection,32 thrombo-embolisrn~3 fat embolization syndrome,34 and hypoventilation-atelectasis due to rib infarction^.^^

It is interesting to compare the ACS risk factors with those of the most common sickle cell complication, the vaso- occlusive (pain) crisis. Platt et a136 recently analyzed the risk factors for pain crises using the same CSSCD database and multivariable analysis. As was the case with the ACS data reported above, pain crises in SS patients were associated with higher Hb levels and they were inversely related to Hb F concentration. Among SS adults, mortality risk was positively associated with pain crisis rate. In adult S S pa- tients, a high ACS incidence was an independent predictor of shorter survival, even after correcting for high pain crisis rate (data not shown but available on request). The similari- ties in the risk factors for ACS and painful events (crises) suggest, but do not prove, that vascular occlusion is the process underlying both of these complications. Additional insights may be gained after completing the analysis of the clinical presentation and clinical course of ACS in this large patient population (manuscript in preparation). In any case, our data indicate that therapeutic measures that increase Hb F should lower the risk for both pain and sickle cell chest syndrome.

APPENDIX The Cooperative Study of Sickle Cell Disease is funded by the

Sickle Cell Disease Branch of the Blood Division of the National Heart, Lung, and Blood Institute, National Institutes of Health. The following are cooperating clinics and senior investigators in the study.

use only.For personal at GERSTEIN SCI INFO CENTRE on April 7, 2013. bloodjournal.hematologylibrary.orgFrom

From  the  CSSCD  trial      •  Raised  hemoglobin  was  

associated  with  an  increased  rate  of  ACS  

 •  Whether  this  finding  correlates  

with  increased  blood  viscosity  is  unknown  

Use  of  Phlebotomy  in  Hb  SC  Disease  

•  TheoreLcal  reducLon  of:  –  Blood  viscosity  – Hemoglobin  polymerizaLon  via  iron  deficiency  

•  No  randomized  trial  has  established  its  efficacy  •  Frequently  used  in  a  cohort  of  179  adult  Hb  SC  paLents  in  France  

•  Offered  to  all  paLents  with  acute  and/or  chronic  complicaLons  and  a  baseline  Hb>105  g/L  

•  Aim  Hb  95  g/L  •  Well  tolerated,  appeared  to  prevent  further  complicaLons  in  their  cohort  

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Treatment  consideraLons  in  Hemoglobin  SC  Disease  

•  Treatment  should  be  considered  in  all  paLents  with  acute  and/or  chronic  complicaLons  – No  known  survival  benefit  of  «  prophylacLc  »  treatment  of  adult  hemoglobin  SC  paLents  

•  Choice  of  therapy  should  be  guided  by:  –  IndicaLon  –  Baseline  laboratory  values  –  Side  effect  profile  and  paLent  consideraLon    

•  No  high-­‐quality  trial  has  been  performed  to  establish  the  ideal  therapy  for  Hemoglobin  SC  disease  

Towards  a  therapeuLc  algorithm…  

OpLmal  Care  of  Hemoglobin  SC  Disease  

•  DetecLon  and  early  referral  to  a  hemoglobinopathy  expert  

•  Preven(on  of  complicaLons  through:  –  Screening:  

•  Annual  ophtalmology  examinaLon  •  Imaging  of  painful  bones  at  steady  state  •  BMD,  renal  funcLon,  TTE,  +/-­‐  audiology  

–  PaLent  educaLon  –  Vaccines  

•  Annual  Influenza  •  Pneumococcus,  Hemophilus  Influenza  B,  Meningoccocus    

•  InstallaLon  of  therapy  when  required  

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Challenges  persist  in  the  care  of  Hemoglobin  SC  paLents  

•  MispercepLon  – Hb  SC  seen  as  a  «  mild  »  SCD  subset  

•  MisinformaLon    –  Some  paLents  are  told  they  do  not  have  sickle  cell  disease,  but  a  «  trait  »  

•  MisrecogniLon  – Delayed  diagnosis  and  referrals  in  adulthood    

•  Misunderstanding  – Detailed  pathophysiology  and  opLmal  treatment  of  Hb  SC  disease  yet  to  be  determined  

 

Conclusions  

•  Hemoglobin  SC  Disease  is  a  relaLvely  common  subset  of  SCD  

•  It  is  not  a  «  mild  »  SCD  subset,  but  rather  a  different  enLty  from  Hb  SS/Sβ0  with  a  different  distribuLon  of  complicaLons  

•  Therapy  has  mostly  been  guided  by  extrapolaLon  of  SCA  data  and  pathophysiology  principles  

 

Conclusions  •  Hydroxyurea,  phlebotomy  and  chronic  transfusions  have  been  used  as  disease-­‐modifying  therapies  

•  No  trial  has  established  a  therapeuLc  gold-­‐standard  

•  Choice  of  therapy  must  be  made  on  a  case-­‐by-­‐case  basis,  based  on  biochemical  and  paLent  factors  

•  Further  research  is  required  in  order  to  establish  dedicated  Hemoglobin  SC  Disease  management  guidelines.  

 

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