Normal red blood cells are disc-shaped and resemble doughnuts; they travel through the small blood tubes in the body called blood vessels to deliver needed oxygen. When sickle red blood cells release their oxygen they became hard and sickle-shaped. Sickle cells are also abnormally sticky. The combination of rigid and sticky red blood cells causes generalized bone pain, as well strokes, and failure of the lungs, liver, and kidneys. The only approved treatments for this disorder are pain relief, adequate hydration, oxygenation, bone marrow stimulation, and blood transfusion. But the results of a new study may lead to the development of additional therapies that stop or inhibit the deadly coagulation.
The Study
“Heparin Inhibits the Adhesion of Sickle Red Blood Cells to Endothelial Cell P-selectin,” is the subject of a new study conducted by the research team of Neil M. Matsui, Ph.D. of the University of California, San Francisco and of the Northern California Comprehensive Sickle Cell Center, Stephen H. Embury, M.D. of the University of California, San Francisco, and Lubor Borsig, Ph.D. and Ajit Varki, M.D. of the University of California, San Diego. The researchers will present their findings in full during the American Physiological Society’s (APS) annual meeting, part of the "Experimental Biology 2002” conference. More than 12,000 attendees will attend the conference being held at the Ernest N. Morial Convention Center, New Orleans, LA from April 20-24, 2002.
Methodology
This experiment was accomplished observing the adhesion-enhancing effects of thrombin on human umbilical vein endothelial cells (HUVEC). Treatment of HUVEC with 0.1 U/ml thrombin for five minutes causes a rapid increase in the ability of HUVEC to bind sickle red blood cells.
Results
The findings demonstrated that the flow adhesion of sickle red blood cells to HUVEC is enhanced by thrombin (flow adhesion in all these experiments were measured by both the number of erythrocytes that are rolling and their rolling velocities). The thrombin-enhanced adhesion is inhibited by adhesion-neutralizing P-selectin mAb as well as by unfractionated heparin, but not by non-blocking P-selectin mAb.
Low molecular weight heparin has less of an inhibitory effect than that of unfractionated heparin. The researchers also discovered that sickle erythrocytes (red blood cells) had increased flow adhere to immobilized P-selectin specifically as compared to immobilize Siglec or immobilized bovine serum albumin (BSA). This adhesion to immobilized P-selectin was also inhibited by unfractionated heparin. Finally, the research found that both laboratory and clinical grade heparins at a concentration of 0.5 U/ml, which corresponds to the levels in plasma during clinical therapy, reduced the adhesion of sickle erythrocytes to immobilized P-selectin.
Conclusions
The findings from this research demonstrate that sickle red cells traveling through the blood stream may adhere to a protein called P-selectin on the surface of the cells that form inner lining of the blood vessels. It is this P-selectin to which the sickle red cells stick to eventually cause a blockage to flow of blood. The results are recurrent pain and organ damage.
The second finding from this research shows that that the adhesion of sickle cells to the P-selectin protein is prevented by the anticoagulant heparin. This observation on heparin is of great significance in that it offers hope that heparin might be used to prevent blockage of blood vessels in patients with sickle cell disease. The development of heparin preparations that can be taken by mouth may provide promise for a novel treatment of sickle cell disease that is effective, convenient, and safe.
The American Physiological Society (APS) is one of the world’s most prestigious organizations for physiological scientists. These researchers specialize in understanding the processes and functions underlying human health and disease. Founded in 1887 the Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals each year.
APS Newsroom: April 20-24, 2002
Morial Convention Center, New Orleans
Room: Level 2, Room B211
Telephone: 504.670.6534