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Roland B. Scott Memorial Symposium Pharmacologic Treatment of Sickle Cell Disease. Kwaku Ohene-Frempong, MD Professor of Pediatrics, University of Pennsylvania Director Emeritus, Sickle Cell Center The Children’s Hospital of Philadelphia. Disclosure Nothing to disclose.

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roland b scott memorial symposium pharmacologic treatment of sickle cell disease

Roland B. Scott Memorial SymposiumPharmacologic Treatment of Sickle Cell Disease

Kwaku Ohene-Frempong, MD

Professor of Pediatrics, University of Pennsylvania

Director Emeritus, Sickle Cell Center

The Children’s Hospital of Philadelphia

disclosure nothing to disclose

DisclosureNothing to disclose

Kwaku Ohene-Frempong, MD

Professor of Pediatrics, University of Pennsylvania

Director Emeritus, Sickle Cell Center

The Children’s Hospital of Philadelphia

pathophysiology of scd

Sickle Cell Disease: Pharmacologic Treatment

When deoxygenated

When oxygenated…

- O2

+ O2

…Hb S molecules polymerize into long fibers; mishapen, dehydrated and adherent sickle cells.

…single Hb S molecules in free in solution;

allows red cell to be soft, round, and deformable

Pathophysiology of SCD

In a red blood cell containing mostly Hb S…

- O2

+ O2

pathophysiology of scd1

Sickle Cell Disease: Pharmacologic Treatment

Pathophysiology of SCD

1. Molecular pathology

2. Biochemical pathology

  • Cellular pathology
  • Vascular pathology
  • Clinical pathology
pathophysiology of scd consequences of hb s polymerization and rbc sickling

Sickle Cell Disease: Pharmacologic Treatment

Pathophysiology of SCDConsequences of Hb S polymerization and RBC sickling
  • Red cell injury
  • Hemolysis
  • RBC dehydration and dense cell formation
  • Adhesion of RBC to venule endothelium
  • Formation of heterocellular aggregates (WBC, ISC)
  • Vasooclusion
  • Local hypoxia, increased Hb S polymer formation
  • Propagation of vasooclusion in adjacent vasculature
  • Dysregulation of vasomotor tone by vasodilator mediators (NO)
molecular pathology of scd regular hemoglobin genes and products

Sickle Cell Disease: Pharmacologic Treatment

Gower 1: z2 e2

Gower 2: a2 e2

Portland: x2 g2

------------------

F: a2 g2

A2: a2 d2

A: a2 b2

< 2%

< 3%

96%

Hemoglobins by age > 1 yr

Molecular pathology of SCDRegular Hemoglobin Genes and Products
molecular pathology of scd hemoglobin genes and products in scd ss

Sickle Cell Disease: Pharmacologic Treatment

Gower 1: z2 e2

Gower 2: a2 e2

Portland: x2 g2

------------------

F: a2 g2

A2: a2 d2

S:a2 bs2

2-20%

3%

80-95%

Hemoglobins in SS by age > 1 yr

Molecular pathology of SCDHemoglobin Genes and Products in SCD-SS
molecular pathology of scd the sickle mutation

Sickle Cell Disease: Pharmacologic Treatment

GAG

GTG

Glutamic acid

Valine

Molecular pathology of SCDThe sickle mutation

The s Mutation

6th Codon of -Globin Gene

The same mutation found in all

s genes around the world

molecular pathology of scd normal versus sickle beta globin

Sickle Cell Disease: Pharmacologic Treatment

1

1

2

2

3

3

4

4

5

5

6

6

7

7

8

8

9

9

10

10

146

146

Normal

glu

A

- - - - - - - -

val

Sickle

S

- - - - - - - -

Molecular pathology of SCDNormal versus sickle beta globin
slide13

- O2

+ O2

deoxygenated

oxygenated

- O2

+ O2

+ O2

deoxygenated

oxygenated

RBC containing mostly normal Hb

RBC containing mostly Hb S

clinical pathology of scd

Sickle Cell Disease: Pharmacologic Treatment

Clinical Pathology of SCD

1. Anemia

2. Vasoocclusion

3. Chronic organ damage

clinical pathology of scd1

Sickle Cell Disease: Pharmacologic Treatment

Clinical Pathology of SCD

1. Anemia

  • Chronic intravascular hemolytic anemia
  • Acute episodes of severe anemia
    • Transient red cell aplasia (parvovirus B19)
    • Acute splenic sequestration
    • Acute hemolysis (“hyperhemolysis”)
clinical pathology of scd2

Sickle Cell Disease: Pharmacologic Treatment

Clinical Pathology of SCD
  • Vasoocclusive complications
    • Microvascular occlusion
      • clinically silent
    • Macrovascular occlusion
      • acute ischemic/infarctive damage
        • pain episodes
        • stroke
        • priapism
        • acute chest syndrome
        • renal papillary necrosis
        • splenic infarction
clinical pathology of scd3

Sickle Cell Disease: Pharmacologic Treatment

Clinical Pathology of SCD

3. Chronic organ damage

  • Splenic dysfunction
    • high risk of bacterial infection
  • Progressive dysfunction of:
    • lungs - oxyhemoglobin desaturation, pulmonary hypertension
    • kidneys - proteinuria, renal failure
    • gallbladder - gallstones
    • eyes - proliferative retinopathy
    • joints - osteonecrosis, arthritis
    • heart - CHF
pharmacological therapy in scd potential targets

Sickle Cell Disease: Pharmacologic Treatment

Pharmacological therapy in SCDPotential targets
  • Intracellular Hb composition
  • Intracellular Hb concentration
  • RBC Transit time
    • circulatory factors
    • local tissue factors
    • systemic factors
  • O2 extraction from oxy-Hb S
  • Vascularity/ vascular pathology
  • Nitric oxide bioavailability
  • Multi-genetic and environmental factors
pathophysiology of scd vasoocclusion 1

Sickle Cell Disease: Pharmacologic Treatment

Pathophysiology of SCDVasoocclusion (1)

A. Prolongation of the RBC microvascular transit time caused by:

  • Enhanced red cell adhesion to endothelium and heterocellular aggregate formation
  • Abnormal cation homeostasis with cell dehydration, dense-cell formation, and
  • irreversibly sickled cell formation
  • Abnormal vasomotor tone favoring vasoconstriction (via NO, endothelin-1, and eicosanoid dysregulation)
pathophysiology of scd vasoocclusion 2

Sickle Cell Disease: Pharmacologic Treatment

Pathophysiology of SCDVasoocclusion (2)

B. Reduction in delay time to HbS polymer formation caused by:

  • Red-cell deoxygenation
  • Increase in intracellular HbS concentration
  • Low concentrations of protective Hb types (eg, HbF, HbA2)
  • Fall in pH

C. Miscellaneous potential modulators

  • Free-radical release and reperfusion injury
  • Coagulation activation with proadhesive thrombin formation
slide25

Hydroxyurea Therapy

in

Sickle Cell Disease

Kwaku Ohene-Frempong, M.D.

The Children’s Hospital of Philadelphia

slide26

Effect of Hb F on Polymerization of Deoxy-Hb S

A. 100% Hb S

Hb S

B. 75% Hb S / 25% Hb F

F/S Hybrid

Hb F

slide27

Hydroxyurea Therapy in Sickle Cell Disease

Effect of Hb F on SCD

1. In vitro gelation studies have shown that Hb F

is effective inhibitor of gelation.

2. Patients with high Hb F levels (> 20%) documented

to have mild clinical course.

3. Patients with S-HPFH produce 25-35% Hb F in every

RBC beyond infancy, and are clinically asymptomatic.

slide29

Hydroxyurea Therapy in Sickle Cell Disease

Beneficial RBC Effects of HU Treatment in SCD-SS

  • Increase in F-cell numbers and Hb F concentration per F cell
  • Inhibition of cation depletion and dense-cell formation
  • Reduction in stress reticulocytes and hemolytic rate
  • Increased deformability with improved rheology
  • Inhibition of sickle red cell-endothelium adhesion
  • Inhibition of sickle erythrocyte adhesion to extracellular

matrix components, including fibronectin,thrombospondin, and laminin

slide30

Hydroxyurea Therapy in Sickle Cell Disease

Beneficial non-RBC Effects of HU Treatment in SCD-SS

  • Quantitative reduction in leucocyte count
  • Qualitative changes in leucocytes, including reduction in leucocyte-free-radical production and activation marker L-selectin
  • Reduction in soluble VCAM-1 concentrations (indicative of decreased endothelial activation)
  • In-vivo NO release
slide31

Hydroxyurea Therapy in Sickle Cell Disease

Multicenter Study of Hydroxyurea

in Sickle Cell Anemia

(MSH Study)

EFFECT OF HYDROXYUREA

ON THE FREQUENCY OF PAINFUL CRISES

IN SICKLE CELL ANEMIA

Charache, et al.. NEJM, 1995

slide32

Multicenter Study of Hydroxyurea in SCA (MSH)

Effect of Hydroxyurea Therapy

on SCD Complications

PlaceboHUp value

Pain, episodes/yr. 4.5 2.5 < 0.001

Pain hospitalization 2.4 1.0 < 0.001

No. with acute chest 51 25 < 0.001

No. transfused 73 48 0.001

slide34

Hydroxyurea Therapy in Sickle Cell Disease

Effect of HU and Hb F on Mortality

Steinberg, et al: JAMA 2003: 280; 1645

slide35

Hydroxyurea Therapy in Sickle Cell Disease

Questions

So why is every adult with SCD-SS

NOT on hydroxyurea?

What to do about the children?

slide36

Hydroxyurea Therapy in Sickle Cell Disease

Effects of Hydroxyurea on SCD

slide37

Hydroxyurea Therapy in Sickle Cell Disease

Effects of Hydroxyurea on SCD

Zimmerman, et al. 2004

slide38

Hydroxyurea Therapy in Sickle Cell Disease

Effects of Hydroxyurea on SCD

Zimmerman, et al. 2004

slide39

Hydroxyurea Therapy in Sickle Cell Disease

Effects of Hydroxyurea on SCD

Hankins, et al. 2005

slide40

Hydroxyurea Therapy in Sickle Cell Disease

Effects of Hydroxyurea on SCD

Hankins, et al. 2005

slide41

Hydroxyurea Therapy in Sickle Cell Disease

Effects of Hydroxyurea on SCD

Hankins, et al. 2005

slide42

Hydroxyurea Therapy in Sickle Cell Disease

Effects of Hydroxyurea on SCD

Hankins, et al. 2005

slide43

Hydroxyurea Therapy in Sickle Cell Disease

What are the treatment goals?

  • Hematologic
    • Hb F (> 20%)
    • Hb concentration (9 - 10 g/dL)
  • 2. Clinical
    • pain episodes
    • acute chest episodes
  • 3. Therapeutic dose
    • dose adjustments to maintain goals

4. Period of observation

slide44

Hydroxyurea Therapy in Sickle Cell Disease

Effects of Hydroxyurea on SCD

Zimmerman, et al. 2004

slide45

NIH

Consensus Development Conference on

Hydroxyurea Treatment

for

Sickle Cell Disease

February 25-27, 2008

slide46

Hydroxyurea Therapy in Sickle Cell Disease

Short- and Long-Term Side Effects

slide47

Hydroxyurea Therapy in Sickle Cell Disease

Barriers to Treatment

1. Patient Level

• Fears - cancer, birth defects, infertility, uncertainty of

other potential long-term risks

• Concern - non-FDA-approved status for children means

HU an experimental drug

• Lack of knowledge about HU as a therapeutic option

• Lack of perception that HU is currently the only therapy

that directly modifies disease process

• Lack of adherence to treatment regimen

• Need for frequent monitoring of hydroxyurea response

slide48

Hydroxyurea Therapy in Sickle Cell Disease

Barriers to Treatment

2. Parent / Family / Caregiver Level

• Fears - cancer, birth defects, infertility, uncertainty of

other potential long-term risks

• Concern - non-FDA-approved status for children means

HU an experimental drug

• Lack of knowledge about HU as a therapeutic option

• Lack of perception that HU is currently the only therapy

that directly modifies disease process

• Difficulty in communication between patients and caregivers regarding the use of HU and other therapeutic options

slide49

Hydroxyurea Therapy in Sickle Cell Disease

Barriers to Treatment

  • 3. Provider Level
  • • Lack of knowledge about HU as a therapeutic option
  • Concerns - cancer, birth defects, infertility, uncertainty of other potential long-term risks
  • Provider bias and negative attitudes toward SCD patients and their treatment
  • • Lack of clarity in HU treatment regimens and undertreatment in adults
  • • Limited number of physicians with expertise in use of HU for SCD
  • • Failure to engage patients/caregivers in treatment decision making in a developmentally appropriate manner
  • Lack of perception that hydroxyurea is currently the only therapy that directly modifies the disease process
slide50

Hydroxyurea Therapy in Sickle Cell Disease

Barriers to Treatment

  • 4. Systems Level (a)
  • Financing (lack of insurance, type of insurance, underinsurance,
  • scope of coverage, copays, reimbursement, payment structures)
  • • Geographic isolation
  • • Lack of coordination between academic centers and community-based
  • clinicians
  • • Limited access to comprehensive care centers and comprehensive
  • care models
  • • Problems in transitioning from pediatric to adult care
slide51

Hydroxyurea Therapy in Sickle Cell Disease

Barriers to Treatment

  • 4. Systems Level (b)
  • • Limited access (e.g., geographic distribution, recruitment, and retention
  • of clinicians competent in provision of comprehensive care to SCD patients)
  • Inadequate Government, industry, and philanthropic support for the
  • care of patients who have sickle cell disease
  • • Development and promotion of hydroxyurea are hindered by lack of
  • commercial interest in the development and promotion of hydroxyurea
  • • Lack of visibility and empowerment of SCD advocacy groups
  • • Cultural and language barriers to the provision of appropriate care
  • • Inadequate information technology systems to support the long-term
  • care of patients who have sickle cell disease
slide52

Hydroxyurea Therapy in Sickle Cell Disease

Final Question

So why are we not using hydroxyurea for many more patients with

sickle cell disease?