Roll of Beta-Thalassemia Gene Discovered

Researchers from Weill Cornell Medical College may have discovered the precise role of a gene in beta-thalassemia,  The study, entitled “Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in B-thalassemia”  was published in the May 14, 2008 online issue of the journal Blood, the official publication of the American Society of Hematology (ASH).

Splenectomy (spleen removal) is not uncommon in individuals with thalassemia.  Unfortunately, after the spleen is removed, patients are at a  greater risk for stroke and infections.

Dr. Stefano Rivella, the study’s senior author and assistant professor of genetic medicine in pediatrics at Weill Cornell Medical College,  believes that he and his collaborators may have found a way around splenectomy. After giving mice with Cooley’s anemia a compound called JAK2 inhibitor, the researchers found that the mice’s spleens shrunk to normal sizes, and they began to produce normal red blood cells. The chemical blocks the activity of the JAK2 gene that is highly expressed in Cooley’s anemia, and is believed to play a crucial role in the malformation of red blood cells.

After splenectomy, patients are considered immunocompromised, and so should be placed on lifelong prophylactic oral antibiotics. Patients should also be vaccinated against common viral infections, and should receive annual influenza vaccinations.

Researchers disagree on the degree of risk associated with splenectomy. A study by Dr. M. Domenica Cappellini, a co-author of this research, found that 30 percent of splenectomized thalassemia intermedia patients developed clots. However, a recent study of 8,860 splenectomized patients with thalassemia major and thalassemia intermediate found that the rate of thrombolytic events was 1.75 percent.

Surgical technique has played a role in developing clots (thrombosis). A recent study found that patients who underwent open splenectomy had a 19 percent chance of developing life-threatening clots, whereas patients who had laparoscopic surgery had a 55 percent chance.

Researchers are only now discovering why splenectomy leads to clots. Injury of endothelial cells may lead to a coagulation cascade, involving the activation of endothelial adhesion proteins, monocytes, granulocytes and platelets. Alternatively, the splenectomy might result in an imbalance between coagulation factors and anticoagulation factors. Dr. Cappellini has recommended short-term anticoagulants such as heparin after surgery, and prophylactic anticoagulants any time thalassemic patients are exposed to thrombolytic risk factors such as surgery, prolonged immobilization or pregnancy. Oral contraceptives should be avoided because they carry their own risk of thrombosis.

This study was funded by grants from the National Institutes of Health (NIH), the Carlo and Micol Schejola Foundation, the Roche Foundation for Anemia Research (RoFAR), the Cooley’s Anemia Foundation (CAF), the Children’s Cancer and Blood Foundation (CCBF), the Associazione per la Lotta alla Talassemia di Rovigo (AVLT), and the American Portuguese Biomedical Fund.

Dr. Rivella’s co-authors and collaborators include Drs. Ilaria Libani, Ella Guy, Luca Melchiori, Raffaella Schiro, Pedro Ramos, Laura Breda, Amy Chadburn, YiFang Liu, Matteo Porotto, Patricia Giardina and Robert Grady (all of Weill Cornell Medical College in New York City); Dr. M. Domenica Cappellini, as well as Dr. Libani, of Centro Anemie Congenite, the University of Milan; Dr. Maria de Sousa, as well as Dr. Ramos, of Iron Genes and Immune System (IRIS) Lab, Oporto University, Portugal; Drs. Thomas Scholzen, Margrit Kernbach, Bettina Baron-Luehr and Johannes Gerdes, of Research Center Borstel, Germany; Dr. Eliezer Rachmilewitz, of E. Wolfson Medical Centre, Israel; and Dr. John Hood, of TargeGen, Inc., San Diego.


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