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Thrombomodulin Mutations in Atypical Hemolytic–Uremic Syndrome
New England Journal of Medicine, 07/23/09

Delvaeye M et al. – Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic–uremic syndrome.

Exclusive Author Commentary
Dr. Conway, 07/23/09

Atypical hemolytic uremic syndrome, or aHUS, is a rare but serious condition. The major cause of the disorder is vascular endothelial cell damage, which leads to arteriolar and microvascular thrombosis, microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. Approximately 25% of patients with aHUS die, and about 50% end up requiring dialysis. aHUS is most frequently seen in individuals who have excess activation of complement via the alternative pathway. The complement system comprises a complex set of proteins, a major component of innate immunity, to rapidly destroy any invading pathogens (eg. bacteria or viruses), but without damaging any of the “host” cells, particularly the endothelial cells. When the system is too active and without adequate normal protective mechanisms, the endothelial cells become more easily damaged, and this places individuals at increased risk of developing aHUS. Mutations in different complement proteins that cause excess activation of the system and cause loss of protection to the host cells, have been identified in about 50% of the patients. For the rest, the etiology has remained a mystery. We studied over 150 patients with aHUS, and in 7 patients, we identified 6 different mutations in a protein that is predominantly expressed on the surface of endothelial cells. This protein, called thrombomodulin, is recognized as a cofactor in a major natural anticoagulant pathway. Using a variety of biochemical techniques, we found that thrombomodulin not only protects blood from excess clotting, but that it has the added property of preventing complement activation. In those patients with aHUS and thrombomodulin mutations, the mutated thrombomodulin was less effective at interfering with complement activation. Thus, the endothelial cells in these patients would be more likely to become damaged, increasing the risk of these individuals developing aHUS. Although we found that thrombomodulin mutations only explain an additional 5-6% of cases with aHUS, the findings are very important. First, identification of all of the mechanisms leading to aHUS will hopefully lead to earlier diagnosis, and new treatments that are currently lacking and urgently needed. It is reasonable to consider that administration of thrombomodulin might be effective as a treatment, at least for some patients with aHUS. Further studies, however, would be necessary to show that. Second, the findings point us in new directions to look for ways that complement is controlled. There are several anticoagulant proteins on endothleial cells and in the blood. Further study will determine whether these also regulate complement, and whether mutations in some of them may predispose to aHUS. Such findings would again, provide opportunities for new effective therapies. Third, they identify a new biochemical pathway in the circulatory system that controls complement. Many other common diseases are associated with excess complement activation, including, for example, some types of arthritis and atherosclerosis. It is reasonable to consider that thrombomodulin mutations may contribute to increasing the risk of patients developing these diseases. If that is the case, new forms of therapy might be designed for these diseases.

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