NHLBI Comprehensive Sickle Cell Centers: Northern California Comprehensive Sickle Cell Center

About Nothern California CSCC

The Northern California Comprehensive Sickle Cell Center is a longstanding collaborative effort between Children's Hospital & Research Center at Oakland and the University of California, San Francisco. It is in its 28th year of grant funding by the National Heart, Lung and Blood Institute as one of ten comprehensive sickle cell centers in the United States. The NCCSCC provides comprehensive care to over 1000 children and adults with sickle cell disease and other hemoglobinopathies in the San Francisco Bay area.

Advisory Boards: An external advisory board of scientists and clinicians review the scientific progress annually of the NCCSCC projects. A community advisory board, presently coordinated by Samuel Wallace and Wanda Williams, works with the center in implementing outreach, patient education, and review of center activities.

East Bay Program

Comprehensive care for children with sickle cell disease is provided at Children's Hospital & Research Center at Oakland and occurs within the hospital and outpatient clinic. This care includes an ambulatory center, day hospital, pheresis unit, inpatient unit and regional satellite clinics in Sacramento, Stockton, and Reno. Specialized care clinics include stroke, pulmonary disease, chronic pain and avascular necrosis. A psychopharmacology clinic is held in conjunction with the Department of Psychiatry. In the outpatient setting, children are evaluated and enrolled in clinical studies as part of their visits to the outpatient clinic. Inpatient care for children with sickle cell disease occurs on the Hematology/Oncology ward of CHRCO and is overseen by members of the pediatric sickle cell team.

Sickle cell patients undergoing bone marrow transplantation are cared for within the new pediatric Bone Marrow Transplant Unit under the direction of Mark Walters, MD. The Bone Marrow Transplant Program coordinates a national cord blood registry focusing on sickle cell disease and the national multi-center sickle cell transplant study and research in nonmyeloblative bone marrow transplants.

The East Bay pediatric clinical core program is coordinated by Dr. Lori Styles, Dr. Keith Quirolo and Dr. Carolyn Hoppe. The adult clinical program is supervised by Ward Hagar, MD.

Services Provided

The core program monitors clinical and translational research. Selected aspects are listed below.

Clinical and research databases : An integrated sickle cell clinical and research database interfaces with the hospital information system to incorporate sickle cell patient clinical data and organize medical and adverse event history for use by clinical staff and to and facilitate patient participation in and extraction of data for clinical research studies.

Pulmonary research and clinical care : A new pulmonary database has been developed, and a pediatric research team tracks pulmonary function, hospital events, pulmonary hypertension and biologic markers of lung disease. Patients are monitored and treated for early detection of broncho-reactive disease and pulmonary hypertension. New therapies for acute chest syndrome are studied, including arginine, nitric oxide, and transfusions.

Neurocognitive Disease and Stroke Prevention : The center is home to the only certified transcranial doppler screening program on the West Coast for early detection of patients at risk for stroke, and provides screening for patients throughout Northern California. Volumetric MRI and neurocognitive testing are part of a comprehensive program that includes assessment of school performance and home functioning.

Pediatric-Adult Transition Clinic . Two separate staffs collaborate and work in parallel in the same clinical space to improve the transitioning from pediatric care to the adult sickle cell service.

Adult Comprehensive Center . Within Children’s Hospital and Research Center at Oakland, a comprehensive adult center offers a multidisciplinary approach to pain management, rehabilitation, renal failure, and chronic lung disease to the center’s adult sickle cell population.

Transfusion Pheresis Services . A 20-bed day unit adjacent to the sickle cell center provides red cell pheresis, transfusion therapy, and pain management for adults and children.

Iron Overload Program. A multidisciplinary iron overload program monitors patients with SQUID measurements of liver iron and T2* MRI measurements of heart iron. Access to new iron chelators is available in clinical trials undertaken by the center.

Mental Health and Psychosocial Support Services. . Mental health, child life, genetic counseling, community outreach, social services are provided under the direction of Marsha Treadwell, PhD. This program includes summer camp, desferal camp, teen activities and employment counseling.

Reference Laboratory and Newborn Screening . Children’s Hospital and Research Center at Oakland is the reference hemoglobin laboratory for the State of California, under the direction of Carolyn Hoppe MD and in collaboration with the federal Maternal and Child Health Bureau. The program has been expanded to provide services nationwide. Clinical interpretation is a key component of the program, along with rapid cost-effective genotyping. In-depth diagnosis includes instruments such as mass-spectrometry, HPLC and functional studies. Henry Ehrlich collaborates with Roche Molecular Systems in developing rapid DNA diagnosis. Services are available to all CSSC programs nationwide. A research laboratory studying red cell biology under the supervision of Dr. Frans Kuypers is available to all research projects.

West Bay Adult and Pediatric Programs

University of California, San Francisco Children’s Hospital : The pediatric program, directed by William Mentzer, MD, was relocated from San Francisco General Hospital in 2003 to UCSF Children’s Hospital in order to take better advantage of pediatric specialist services available at UCSF and to provide a more comprehensive infrastructure for comprehensive clinical management. Comprehensive care is provided by a multidisciplinary team and includes a special pediatric ambulatory transfusion center for outpatient transfusions, as well as a pediatric bone marrow transplant team.

San Francisco General Hospital : The UCSF Adult Sickle Cell Program at San Francisco General Hospital, directed by Dr. Brad Lewis, offers comprehensive services to patients from all parts of Northern California. In addition to providing primary care, the center works closely with providers outside the system to coordinate care for sickle cell patients who may not live in San Francisco. Sickle cell clinics for adult patients are held weekly. Patients have access to a day hospital for treatment as well as an infusion center in the hospital for transfusions. Fellows, residents and medical students participate in the clinical activities of the center. Integration of the clinical program into the UCSF academic environment provides a dynamic intellectual atmosphere and promotes useful collaborations.

Community Outreach and Education

The multidisciplinary approach towards research and clinical care for sickle cell disease has been strengthened through the integration of community groups, outreach programs, clinicians and basic scientists.

The support of community groups includes the sickle cell advisory group, sickle cell health network, and the African-American wellness project. Community and patient education has been a significant highlight of the past year. Ongoing team sickle cell workshops, serial radio broadcasts, along with publication of the NCCSCC Sickle Cell Resource Kit (American Academy of Pediatrics) and A Parents Handbook for Sickle Cell Disease (California Genetic Disease Branch) have increased the awareness of sickle cell disease for the entire community.

A major priority of the NCCSCC is to increase the number of scientists interested in sickle cell disease. These efforts include high school, college and junior faculty mentoring programs. During the past year, five sickle cell investigators have submitted or received clinical research training/mentoring awards:

Ellen Fung PhD (Zinc metabolism and hemoglobinopathies)
Titi Singer MD (Thrombosis pulmonary hypertension)
Lori Styles MD (Mentoring award in sickle cell disease)
Marsha Treadwell PhD (Mental health in sickle cell disease)
Carolyn Hoppe MD (Genetic modifiers of sickle cell disease; center applicant for the Junior Faculty Research Development Award).

Since 1994, the NCCSCC has conducted the Sickle Cell Summer High School Internship Program. The curriculum includes preparation of a two-page grant application including hypothesis, goals for the summer project, significance of the work proposed, and the research plan. At the end of the summer program, students present their work at a special research symposium. During this past year, several of the high-school students enrolled in the program have been informed of early undergraduate admission to Brown, MIT, Princeton and Stanford University.

Clinical and Basic Science Research

The NCCSCC directs and participates in several key pilot and national research projects. In addition to the CSCC multi-center projects, the NCCSCC is the coordinating center at the national level for studies involving:

Chlamydia infection as a risk factor for cerebral vascular disease
Decompression coring study of avascular necrosis of the hip
Multi-center study of iron overload in sickle cell disease
Sibling cord blood
Allogenic bone marrow transplantation and mixed chimerism
Secondary hemochromatosis in beta thalassemia and sickle cell disease
Genetic modifiers of sickle cell disease

NCCSCC participation in national projects has recently included:

Stroke prevention trial in sickle cell disease (“STOP II”)
Multi-center study of hydroxyurea
Icagen trial with gardos channel inhibitor in sickle cell disease
Biofrontiers starch desferal phase I/II trial in sickle cell
Novartis ICL670 pediatric and adult oral chelators in sickle cell
Multi-center nitric oxide trial for acute chest syndrome
Parvovirus study
Allogeneic bone marrow transplantation for the treatment of symptomatic sickle cell anemia

CSSC multi-center projects which originate from the NCCSCC include:

“Arginine Supplementation in Sickle Cell Anemia: Physiological and Prophylactic Effects” (Lori Styles, M.D., R. Nagel, M.D., M. Fabry, Ph.D.). This study will test whether daily oral arginine results in an increase in nitric oxide and other beneficial effects in patients with sickle cell disease. Its primary and secondary objectives are to assess the physiological effects of the administration of oral and to evaluate the effect of daily oral arginine on clinical vaso-occlusive events in patients with sickle cell disease.

“Neuropsychological Dysfunction and Neuroimaging Abnormalities in Neurologically Intact Adult Patients with Sickle Cell Disease” (P.I. Elliott Vichinsky, M.D.). The purpose of this study is to determine the extent of neurocognitive/neuro-imaging dysfunction in neurologically asymptomatic adult patients. A secondary aim is to determine if transfusion therapy can improve neurocognitive functioning.

Sickle cell studies at the local level:

Pulmonary hypertension in sickle cell disease and arginine and nitric oxide metabolism
Stroke risk and genetic modifiers
T2*MRI and SQUID in sickle cell patients with iron overload
Psychobiological reactivity
Osteoporosis and bone density in children with sickle cell disease
Zinc metabolism
Analysis of causes of death in sickle cell disease: autopsy and clinical study
Factors affecting compliance to chronic therapy
Oxidative injury and anti-oxidant therapy in sickle cell disease
Prevalence of cocaine use and its effect on lung injury and sickle cell disease
Anti-adhesion markers in sickle cell disease
Dysregulard arginine metabolism Hemolysis-Associated Endothelia dysfunction.

Specific NCCSCC funded projects:

“Regulation of sickle cell phospholipid organization (Frans Kuypers, PhD)”. The long-term goal of this project is to understand the dynamic regulatory mechanisms that are involved in plasma membrane phospholipid organization, and the physiological consequences. The study hypothesizes inflammatory lipid mediators affecting calcium homeostasis, signal transduction pathways, and leads to phosphatidylserine exposure affecting red blood cell endothelial cells and macrophage interaction.

Scholar Award (Kitty De Jong, PhD). The scholar project aims to determine alterations in sickle cells that lead to enhanced formation of red cells that expose phosphatidylserine.

Phospholipase A2 inhibitor trial (Lori Styles, MD). The first phase of these studies demonstrated phospholipase elevation predicts patients who will develop acute chest syndrome. The second phase demonstrated acute chest syndrome can be prevented by transfusion therapy in high-risk patients. In the 3 rd phase, drugs which inhibit phospholipase A2 will be studied to see if their use can prevent acute chest syndrome.

“Construction of sickle cell anemia mice carrying chromosomes from the 4 human sickle cell anemia haplotypes” (Y.W. Kan, MD). The aim of this proposal is to construct mouse models of sickle cell anemia that represent the major haplotypes of sickle cell genes in the human populations using BAC vectors and to study their phenotype in response to hemoglobin F drugs. Aim 1 is to clone DNA in BAC vector and create transgenic mice that carry these sequences. Aim 2 is to study its phenotype, and Aim 3 is its response to intervention.

Program Staff

East Bay Physicians: