Acute

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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,
  ostenecrosis, collapse
• Lung ACS, chronic restrictive lung disease
  (hypoxia)
• Heart pulmonary hypertension
• Liver gallstones, hepatitis, iron overload,
  sequestration
• Spleen auto-infarction, sequestration,
  bacterial sepsis
• Genito-Urinary proteinuria, renal
  insufficiency. obstetrical, priapism
• Skin leg ulcers

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Chronic Organ Damage in Hb SS
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Hb SS Additional End-Organ Damage
Medicine 84363, 2005
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Pulmonary Disease (CSSCD)

• N 318, gt 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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Comparison of Pediatric and Adult Inpatient
Statistics
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Day Hospital, Montefiore Medical Center
Blood 951130, 2000
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Hematology/Oncology Community Practice Patterns
(FL, NC)
Amer J Hematol 79107, 2005
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Options

• Stem Cell Transplantation
• Gene Therapy
• Hydroxyurea
• Transfusion/Chelation

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Challenges in Managementof Sickle Cell Disease

• 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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Acute Clinical Events in Hb SS
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Manifestations of Sickle Cell Disease

• Chronic Hemolysis
• Intermittent crises
• Frequent Infections
• End organ dysfunction
• Disorders unrelated to the Hbopathy

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Hb SS Additional End-Organ Damage
Medicine 84363, 2005
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Blood 1072279, 2006
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Outcome in Hb SS Mortality ()
Medicine 84363, 2005
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Outcome of Hb SC

• n 284 2,837 patient-yrs since 1964
• Males - 139, Females - 145

Follow-up started at
Am J Hematol 70206, 2002
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Acute Clinical Events in Hb SC
Am J Hematol 70206, 2002
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Chronic Organ Damage in Hb SC
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Outcome in Hb SC Mortality
Am J Hematol 70206, 2002
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Gene Therapy

• Clinical Trial in 5 Hb SS 5 ? Thal (Paris)
• Self-inactivating lentiviral vector
• ?A-T87Q

Ann NY Acad Sci 1054308, 2005
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Hydroxyurea End-Organ protection Secondary
prevention of stroke

• Transfusion overlapping with HU 3.6 events/year
• Transfusion alone 2.2 to 4.2 events/year
• (J Pediatr 145346, 2004)
• No recurrence in 5 pts treated for 3.5 to 9.5
  years
• (Am J Hematol 71161, 2002)

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Hydoxyurea End-Organ Protection

• No deleterious effect on growth (up to 8 yrs of
  Rx), weight, Tanner stage (J Pediatr 140225,
  2002 Blood 1032039, 2004 Blood 1062269, 2005
  - increased growth rate)
• Reduced incidence per 100 pt-yrs
• ACS 3.3 CVA 1.3 AVN 1.1 (Blood
  1052685, 2005 Blood 1062269, 2005)
• No apparent reduction in AVN (Pediatr Blood
  Cancer 21335, 2004)

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Mortality Hydroxyurea

• 40 reduction
• (JAMA 290756, 2003)
• Unclear
• (Blood 105545, 2005)

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Transfusion and Albuminuria

• Hb SS 15, Hb SC 4
• 3 of 20 on hydroxyurea
• 4 of 23 on chronic transfusion
• When analyzed by age, albuminuria was less common
  in those who started transfusion before age 8
  compared to those who started after age 12

Pediatr Blood Cancer epublished 31 Oct 2005
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Transfussion/Chelation

• Allo-immunization
• Reduced by extended phenotyping
• Iron overload
• DFO Exjade
• Viral Disease Transmission
• Current rates are extremely low
• Is it time to re-examine this issue??

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Blood Rheology in Sickle Cell Disease
Why is viscosity an issue? Tissue perfusion
depends not only on the oxygen-carrying capacity
of the blood, but also the rate at which the
blood can be delivered. Raising the hematocrit
increases both O2 capacity and viscosity. Above
a threshold of about 30, the reduction of flow
due to increased viscosity outweighs the
increased O2 capacity and O2 delivery
declines. Figure from K Jan, S Usami and JA
Smith. Transfusion 2217-20, 1982
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(mmHg)
(mmHg)
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pO
pO
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HEMATOCRIT ()
HEMATOCRIT ()
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Blood Flow in tubes (in vitro)

• Fåhraeus-Lindqvist Effect

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Poiseuille Equation (Jean Louis Poiseuille
1799-1869)
For flow in cylindrical tubes

Q flow rate ?P pressure drop
R radius of tube L length of
tube and ? (eta) viscosity of the fluid ?
Flow is proportional to the Pressure divided by
Viscosity
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