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Blood Disorders

Description
Blood disorders include a wide range of medical problems that lead to poor blood clotting and continuous bleeding. When someone has a blood disorder they have a tendency to bleed longer. The disorders can result from defects in the blood vessels or from abnormalities in the blood itself. The abnormalities may be in blood clotting factors or in platelets. In many blood disorders, symptoms include anemia, fatigue, shortness of breath, pale skin, weakness, general malaise, and degeneration of the nervous system. Many blood disorders are hard to diagnose, but they are sometimes easily treated if diagnosed correctly.

Who is at Risk?
In some cases, drugs used to damage DNA, and to treat cancers, such as breast and ovarian, may cause a blood disorder. In some cases, people with a weakened immune system may be at increased risk for a blood disorder.

Sources: Health Insite, Seattle Cancer Care Alliance

Blood Flow Beneath a Microscope
TSRI Professor Zaverio Ruggeri, M.D., studies the movement of blood cells, particularly platelets - the flat molecule-filled cytoplasmic disks in the blood that are necessary for clotting. He uses the microscopic stage to look at the interaction of platelets with various surfaces encountered in the circulation, and to study the interaction of individual platelets with the endothelial cells and wounds. Ruggeri is interested in the molecular mechanisms that govern clotting because many individuals suffer from diseases relating to these mechanisms, such as bleeding disorders. Another reason scientists are interested in clotting is its potential for therapeutic intervention in vasculature disease. Clotting is an essential physiological process, but at the same time, the blood components that heroically stop bleeding, also nefariously cause diseases such as heart attacks and stroke, which are the most common causes of death in the United States today.

Ruggeri is conducting basic research to address the main disease-causing mechanisms responsible for arterial and venous thrombosis, the clotting of veins and arteries, and is laying the foundation for novel and more efficient therapeutic approaches. Ruggeri and his team study the interaction between vessels and blood platelets, the cell fragments that carry the chemicals the body uses in hemostasis, in which blood clots at a site of injury. Members of the Ruggeri lab are particularly interested in the structures of the adhesion proteins that mediate the formation of blood clots and the receptors on the platelets. Lab members have been solving the structures of these interacting molecules and piecing together how they work. Such detailed knowledge of the three-dimensional structure of these adhesion proteins is indispensable for understanding the differences between normal hemostasis, where bleeding is stopped after a cut, and pathological thrombosis, in which a clot of platelets occludes blood flow and causes cardiovascular disease.

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Preventing Blood Coagulation
Blood clots in veins may travel to the lungs and kill swiftly or strangle the blood supply to vital organs. TSRI Professor John Griffin, Ph.D., and Associate Professor Mary Jo Heeb, Ph.D., and their colleagues have long been studying the specialized proteins in the blood that prevent its coagulation. The studies of proteins designated as protein C, protein S, and protein Z are gradually being translated into tests that can identify persons at risk for clotting disease and can help treat those in whom clots have developed.

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Scripps Research Scientist Receives $98,000 Grant from Factor Foundation to Study Hemophilia
A TSRI Assistant Professor Andrew Gale, Ph.D., has received a grant of $98,769 from the Factor Foundation of America to study hemophilia A, a bleeding disease that strikes some 17,000 Americans. Gale and his colleagues have already made an important discovery that they hope will lead to an improved therapy for hemophilia A. They engineered a stable form of the protein Factor VIII, which is a coagulatory blood protein that hemophiliacs have little or no ability to produce themselves. Hemophilia A is often treated with infusions of pre-activated Factor VIII, and several forms of the treatment are already on the market. These infusions provide patients with the normal inactive form of the protein, and when that person gets cut, other proteins in the body can then process the inactive Factor VIII into its active form, called "Factor Villa" However, once activated, Factor Villa is highly unstable and tends to fall apart in the bloodstream. This instability is an important feature of normal coagulation because it prevents the clotting process from getting out of control. In hemophiliacs being treated with Factor Villa, however, its instability is a problem because, as its pieces disassociate, the protein infusion loses its potency.

Gale and his colleagues made a more stable form of Factor Villa by engineering the protein so that its individual pieces are linked together with what are known as "disulfide bonds." These prevent the subunits from falling apart - sort of like handcuffing them together on the molecular level. The Factor Villa is very stable. As a therapy, this increased stability could improve the effectiveness of Factor VIII infusions by reducing the number and amount of such infusions a hemophiliac would need. But Gale and his colleagues' initial discovery a few years ago left open the question of the effect of the new stabilized form of Factor Villa on the body. The scientists have looked at its stability in the test tube, but further studies are needed to determine whether the body could handle the new form of the protein. The Factor Foundation grant will pay for some of the preliminary pre-clinical experiments aimed at testing how effective the new form of Factor Villa is in laboratory rodents. If data from these experiments looks promising, then the next step would be to consider human trials. The grant will allow Gale and his colleagues to see how well the engineered, stabilized Factor VIII works.

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Scripps Research Team Sheds New Light On How Blood Clots Form – Findings Could Lead To Novel Ways To Prevent Heart Attack And Stroke
Scripps Research Institute scientists have discovered new elements of the blood clot-formation process. The findings could lead to better drugs for preventing heart attacks and other clot-related conditions. The work helps to establish a new model of clot formation.

According to the old model, an injury to the wall of blood vessels causes smooth muscle cells to expose a clot-organizing protein called tissue factor. In the emerging new model, tissue factor exists on the surfaces of these smooth muscle cells, as well as on circulating immune cells, but in an inactive state. Scripps Research Professor Wolfram Ruf, M.D., led the study.  Ruf and his colleagues showed that cell-surface receptor P2X7, which was known to promote inflammation when stimulated, also plays a major role in the clot-forming process by activating tissue factor.

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