Initiative could result in paradigm shift in the care of sickle cell patients

Augusta, Ga. - The Medical College of Georgia is leading an initiative that could result in a paradigm shift in the care of patients with sickle cell disease.

Morehouse University School of Medicine and University of Florida are partners in the initiative that is enlisting primary care physicians across Georgia to serve as "medical homes" for patients, changing how patients are treated when a pain crisis sends them to the hospital and seeking better prevention and treatment strategies for the pain and organ damage caused by the genetic disease affecting 1 in 500 blacks in the United States.

"This is an exciting opportunity to really take on sickle cell disease from many angles: from ensuring that patients get regular medical care to improving hospital care to dissecting why patients respond to pain and analgesics differently," said Dr. Abdullah Kutlar, director of the MCG Sickle Cell Center.

Drs. Kutlar and Robert W. Gibson, an occupational therapist and medical anthropologist at MCG, are co-principal investigators for the $7 million, five-year grant from the National Center on Minority Health and Health Disparities of the National Institutes of Health to support the multifaceted strategy they believe will make a big difference in the lives of patients.

Major projects include:

• Establishing programs to ensure proper health care for pediatric patients as they grow into adults. The average life expectancy for patients with this chronic disease now reaches into the 50s. Such transitions are difficult, Dr. Gibson said, even in countries with publicly funded health care. "Are they seeing an adult physician for their health care? Have they made some kind of arrangement to have their health care reimbursed?" are questions that need answering, he said. Researchers will work with children age 12 to 17 to determine what they know, what they need to know and to identify the best way to teach them to prepare for care as adults. "We have a lot of significant legal change at age 18," Dr. Gibson said. "We will be looking at ways to measure independence. How do we know a kid is ready to go to adult medicine? We want to give patients more information and more control." Researchers will start with children and their families followed by MCG in Augusta, Albany, Waycross and other outreach sites across the state.

• Helping build medical homes that provide comprehensive care using family medicine physicians and residents across Georgia that have been given additional training in treating the disease. Hematologists, or blood specialists, that have historically been the front line physicians, are now "an endangered species," said Dr. Kutlar, a hematologist who has directed MCG's Sickle Cell Center for more than 15 years. The grant will establish ongoing education programs for physicians with an interest in treating these patients with lifelong needs. "This is a disease of red blood cells but it goes far beyond that in its implications," Dr. Kutlar said. "Abnormal red blood cells interact with the blood vessels and patients can have strokes, problems with the eyes, lungs, heart, spleen, kidneys, skeletal system." Improved care means longer lives but more potential for cumulative damage to body systems and serious health care problems. Dr. Richard Lottenberg, a hematologist at the University of Florida with expertise in outcomes in sickle cell disease, will lead the initiative to pilot studies focusing on family medicine physicians and residents at an MCG-affiliated program in Waycross and at Phoebe Putney Memorial Hospital in Albany. "The idea is to train family doctors and residents in some of the prevention measures hematologists would do and treatment of some of the major diseases these patients face," said Dr. Paul D. Forney, vice chairman of the MCG Department of Family Medicine who directs its resident educational programs.

• Creating a project to encourage primary care doctors to specialize in sickle cell disease and give young scientists the opportunity to work in established laboratories of veteran scientists. Primary care physicians in the project led by Dr. Thomas Adamkiewicz, a physician-scientist from Morehouse, will attend sickle cell clinics around the state to meet patients outside the hospital setting. "Most physicians will only see patients during a crisis, they may lack an understanding of the daily, chronic problems that these patients face," Dr. Kutlar said.

• Helping physicians and hospitals statewide set up observations centers that keep sickle cell patients experiencing a pain crisis out of busy emergency departments where they might not receive proper pain relief. Many patients undergo such pain episodes because of insufficient oxygen to tissue and bone and oddly shaped blood cells banging against vessel walls. About 40 percent of patients seek immediate medical attention, typically in an emergency department, with 5 percent of sickle cell patients averaging three to 10 of these pain episodes annually. In fact, pain crises are responsible for 90 percent of sickle cell patient hospitalizations. Dr. Matthew L. Lyon, an emergency physician who directs the Observation Unit at MCGHealth Medical Center, believes observation units – established at many hospitals for chest pain patients – are a better spot than busy emergency departments where patients might stay for hours receiving intravenous analgesics that may not be providing relief due to the patient's increased drug tolerance. In fact, patients at times becoming suspect as to whether they need or just want the drugs. "They have had lifelong pain so their tolerance is different," said Dr. Lyon. "They don't show pain the way you or I would." At MCGHealth Medical Center the standard has become patients going directly to the less- hectic observation unit where they receive pain pumps to self-administer drugs in small doses and pain pills that will get them through the crisis and back to their lives. "The PCA pump is to get you to a steady state and the oral meds are to keep you there," said Dr. Lyon who will be measuring outcomes for patients, including the need for a return visit, and working with physicians and hospitals across Georgia to set up similar systems.

• Better understanding the genetic modifications behind variations in the frequency, intensity and treatment of pain crises. Researchers believe their studies, which will include pain diaries kept by patients, will enable individualized pain treatment strategies that improve quality of life and avoid the mischaracterization of patients as drug seekers. Opioid pain relievers, such as morphine, are frequently used to treat pain crises by targeting the Mu opioid receptor gen. Variations of this receptor gene appear to affect response to pain relievers as well as the pain threshold. Studying these variations and the impact on pain perception will likely help explain the variations in pain response and drug need physicians see in patients, Dr. Kutlar said.

• Researching the body's natural switch from production of fetal hemoglobin – which cannot sickle – to adult hemoglobin during the first weeks of life. Because most adults have only miniscule amounts of fetal hemoglobin, understanding the switching process could lead to better drugs that selectively raise the levels and essentially eliminate the pain and organ damage resulting from sickle cell disease. Dr. Dorothy Y.H. Tuan, a molecular biologist at MCG who studies the switch, believes it has to do with the changing genetic expression from fetus to adult. She believes part of how hydroxyurea, the only FDA-approved drug for sickle cell, switches expression back to the fetal state is by activating the transcription factor, GATA-2, which binds to the promoter sequence of the fetal hemoglobin gene. "This is our hypothesis and we need to prove it," she said

• Developing a novel therapy for treating sickle cell disease by decoding signaling that enables fetal hemoglobin production in adults. "What is it and how can we tweak it?" said Dr. Steffen E. Meiler, an anesthesiologist and vice chair of research in Department of Anesthesiology and Perioperative Medicine. Some 70 known compounds raise fetal hemoglobin levels and he said there is common and disparate ground among them. Drs. Meiler and Tohru Ikuta, a molecular hematologist, suspect that with hydroxyurea, somewhere along the line where red blood cells are produced, the drug sends the message to keep on making fetal hemoglobin. The process begins when hematopoietic stem cells in the bone marrow differentiate into erythroid progenitor cells and, eventually, into red blood cells which contain hemoglobin, the oxygen carrying component of the cells. The grant will enable researchers to walk the line of red blood cell development in an animal model of sickle cell disease as well as human hematopoietic stem cells from healthy people and those with sickle cell disease. "We are looking for telephone lines. We need to know which ones are firing, which ones are silent and how do these drugs play into that," Dr. Ikuta said. They note that there is no known down side to continued high expression of fetal hemoglobin. In fact, some people have naturally high levels and those with sickle cell disease fortunate enough to have this aberration typically have few if any disease symptoms.

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