Thrombotic Thrombocytopenic Purpura - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

THROMBOTIC THROMBOCYTOPENIC PURPURA

A

3-in-1

Medical

Reference

A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers TO INTERNET REFERENCES

THROMBOTIC

THROMBOCYTOPENIC PURPURA A BIBLIOGRAPHY AND DICTIONARY FOR PHYSICIANS, PATIENTS, AND GENOME RESEARCHERS

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 7404 Trade Street San Diego, CA 92121 USA Copyright ©2007 by ICON Group International, Inc. Copyright ©2007 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher’s note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Thrombotic Thrombocytopenic Purpura: A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers/ James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-497-11387-2 1. Thrombotic Thrombocytopenic Purpura-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on thrombotic thrombocytopenic purpura. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Chaired Professor of Management Science at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 7404 Trade Street San Diego, CA 92121 USA Fax: 858-635-9414 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON THROMBOTIC THROMBOCYTOPENIC PURPURA ....................................... 3 Overview........................................................................................................................................ 3 Genetics Home Reference ............................................................................................................... 3 What Is Thrombotic Thrombocytopenic Purpura? ........................................................................ 3 How Common Is Thrombotic Thrombocytopenic Purpura?.......................................................... 4 What Genes Are Related to Thrombotic Thrombocytopenic Purpura?.......................................... 4 How Do People Inherit Thrombotic Thrombocytopenic Purpura? ................................................ 5 Where Can I Find Additional Information about Thrombotic Thrombocytopenic Purpura?........ 5 References....................................................................................................................................... 6 What Is the Official Name of the ADAMTS13 Gene?................................................................... 7 What Is the Normal Function of the ADAMTS13 Gene? ............................................................. 7 What Conditions Are Related to the ADAMTS13 Gene? ............................................................. 8 Where Is the ADAMTS13 Gene Located? ..................................................................................... 8 References....................................................................................................................................... 8 Federally Funded Research on Thrombotic Thrombocytopenic Purpura....................................... 9 The National Library of Medicine: PubMed ................................................................................ 22 CHAPTER 2. ALTERNATIVE MEDICINE AND THROMBOTIC THROMBOCYTOPENIC PURPURA ....... 69 Overview...................................................................................................................................... 69 National Center for Complementary and Alternative Medicine.................................................. 69 Additional Web Resources ........................................................................................................... 78 General References ....................................................................................................................... 79 Keeping Current .......................................................................................................................... 79 CHAPTER 3. BOOKS ON THROMBOTIC THROMBOCYTOPENIC PURPURA ....................................... 80 Overview...................................................................................................................................... 80 Book Summaries: Online Booksellers........................................................................................... 80 APPENDIX A. HELP ME UNDERSTAND GENETICS ......................................................................... 83 Overview...................................................................................................................................... 83 The Basics: Genes and How They Work....................................................................................... 83 Genetic Mutations and Health..................................................................................................... 94 Inheriting Genetic Conditions ................................................................................................... 100 Genetic Consultation ................................................................................................................. 108 Genetic Testing .......................................................................................................................... 110 Gene Therapy ............................................................................................................................. 116 The Human Genome Project and Genomic Research................................................................. 119 APPENDIX B. PHYSICIAN RESOURCES ........................................................................................... 122 Overview.................................................................................................................................... 122 NIH Guidelines.......................................................................................................................... 122 NIH Databases........................................................................................................................... 123 Other Commercial Databases..................................................................................................... 126 APPENDIX C. PATIENT RESOURCES .............................................................................................. 127 Overview.................................................................................................................................... 127 Patient Guideline Sources.......................................................................................................... 127 Finding Associations.................................................................................................................. 129 Resources for Patients and Families........................................................................................... 130 ONLINE GLOSSARIES................................................................................................................ 132 Online Dictionary Directories ................................................................................................... 135 THROMBOTIC THROMBOCYTOPENIC PURPURA DICTIONARY .............................. 137

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INDEX .............................................................................................................................................. 183

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FORWARD In March 2001, the National Institutes of Health issued the following warning: “The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading.”1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with thrombotic thrombocytopenic purpura is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about thrombotic thrombocytopenic purpura, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to thrombotic thrombocytopenic purpura, from the essentials to the most advanced areas of research. Special attention has been paid to present the genetic basis and pattern of inheritance of thrombotic thrombocytopenic purpura. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on thrombotic thrombocytopenic purpura. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to thrombotic thrombocytopenic purpura, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. We hope these resources will prove useful to the widest possible audience seeking information on thrombotic thrombocytopenic purpura. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/.

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CHAPTER 1. STUDIES ON THROMBOTIC THROMBOCYTOPENIC PURPURA Overview In this chapter, we will show you how to locate peer-reviewed references and studies on thrombotic thrombocytopenic purpura. For those interested in basic information about thrombotic thrombocytopenic purpura, we begin with a condition summary published by the National Library of Medicine.

Genetics Home Reference Genetics Home Reference (GHR) is the National Library of Medicine’s Web site for consumer information about genetic conditions and the genes or chromosomes responsible for those conditions. Here you can find a condition summary on thrombotic thrombocytopenic purpura that describes the major features of the condition, provides information about the condition’s genetic basis, and explains its pattern of inheritance. In addition, a summary of the gene or chromosome related to thrombotic thrombocytopenic purpura is provided.2 The Genetics Home Reference has recently published the following summary for thrombotic thrombocytopenic purpura:

What Is Thrombotic Thrombocytopenic Purpura?3 Thrombotic thrombocytopenic purpura is a rare disorder that causes blood clots (thrombi) to form in small blood vessels throughout the body. These clots can cause serious medical problems if they block vessels and restrict blood flow to organs such as the brain, kidneys, and heart. Resulting complications include neurological problems (such as personality

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This section has been adapted from the National Library of Medicine: http://ghr.nlm.nih.gov/.

Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/condition=thromboticthrombocytopenicpurpura.

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Thrombotic Thrombocytopenic Purpura

changes, headaches, confusion, and slurred speech), fever, abnormal kidney function, abdominal pain, and heart problems. In people with thrombotic thrombocytopenic purpura, clots in blood vessels are formed from clumps of platelets. Platelets are cell fragments that play a critical role in blood clotting. Because a large number of platelets are used to form clots in people with this disorder, fewer platelets are available to circulate in the bloodstream. A reduced level of circulating platelets is known as thrombocytopenia. Thrombocytopenia can lead to bleeding just under the surface of the skin, resulting in purplish spots called purpura. This disorder also causes red blood cells to break down (undergo hemolysis) prematurely. As blood squeezes past clots within blood vessels, red blood cells can break apart. A condition called hemolytic anemia occurs when red blood cells are destroyed faster than the body can replace them. This type of anemia leads to paleness, yellowing of the eyes and skin (jaundice), fatigue, shortness of breath, and a rapid heart rate. The two major forms of thrombotic thrombocytopenic purpura are an acquired (noninherited) form and a familial form. The acquired form usually appears in late childhood or adulthood. Affected individuals may have a single episode of signs and symptoms, or complications of the disorder may recur over time. The familial form of this disorder is much rarer and typically appears in infancy or early childhood. In people with the familial form, signs and symptoms often recur on a regular basis.

How Common Is Thrombotic Thrombocytopenic Purpura? The precise incidence of this condition is unknown, but researchers estimate that it affects 4 to 7 per million people each year in the United States. For unknown reasons, the disorder occurs more frequently in women than in men. The acquired form of thrombotic thrombocytopenic purpura is much more common than the familial form.

What Genes Are Related to Thrombotic Thrombocytopenic Purpura? Mutations in the ADAMTS13 (http://ghr.nlm.nih.gov/gene=adamts13) gene cause thrombotic thrombocytopenic purpura. The ADAMTS13 gene provides instructions for making an enzyme that is involved in the normal process of blood clotting. Both the familial form and the acquired form of thrombotic thrombocytopenic purpura result from a severe reduction in the activity of this enzyme. The familial form is caused by mutations in the ADAMTS13 gene that disrupt the enzyme's function. People with the acquired form do not have mutations in this gene; instead, their immune systems often produce specific proteins called antibodies that block the activity of the ADAMTS13 enzyme. A lack of ADAMTS13 enzyme activity disrupts the usual balance between bleeding and clotting. Normally, blood clots form at the site of an injury to seal off damaged blood vessels and prevent excess blood loss. In people with thrombotic thrombocytopenic purpura, clots form throughout the body as platelets bind together abnormally and stick to the walls of blood vessels. These clots can block small blood vessels unpredictably, causing organ damage and the other features of thrombotic thrombocytopenic purpura.

Studies

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Researchers believe that other genetic or environmental factors may contribute to the signs and symptoms of thrombotic thrombocytopenic purpura. In people with reduced ADAMTS13 enzyme activity, factors such as pregnancy, surgery, and infection may trigger abnormal blood clotting and its associated complications.

How Do People Inherit Thrombotic Thrombocytopenic Purpura? The familial form of thrombotic thrombocytopenic purpura is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder. The acquired form of thrombotic thrombocytopenic purpura is not inherited.

Where Can I Find Additional Information about Thrombotic Thrombocytopenic Purpura? You may find the following resources about thrombotic thrombocytopenic purpura helpful. These materials are written for the general public. MedlinePlus - Health Information •

Encyclopedia: Blood Clots: http://www.nlm.nih.gov/medlineplus/ency/article/001124.htm

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Encyclopedia: Hemolytic anemia: http://www.nlm.nih.gov/medlineplus/ency/article/000571.htm

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Encyclopedia: Purpura: http://www.nlm.nih.gov/medlineplus/ency/article/003232.htm

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Encyclopedia: Thrombocytopenia: http://www.nlm.nih.gov/medlineplus/ency/article/000586.htm

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Encyclopedia: Thrombotic thrombocytopenic purpura: http://www.nlm.nih.gov/medlineplus/ency/article/000552.htm

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Health Topic: Blood and Blood Disorders: http://www.nlm.nih.gov/medlineplus/bloodandblooddisorders.html Educational Resources - Information Pages

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Ask the Geneticist: Causes and inheritance of thrombotic thrombocytopenic purpura: http://www.genetics.emory.edu/ask/question.php?question_id=852

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Children's Hospital Boston: Thrombocytopenia: http://www.childrenshospital.org/az/Site1740/mainpageS1740P0.html

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Orphanet: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=54057

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The Merck Manual of Medical Information, Second Home Edition: http://www.merck.com/mmhe/sec14/ch173/ch173d.html

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Virtual Health Care Team, University of Missouri: http://www.vhct.org/case2300/index.htm Patient Support - for Patients and Families

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National Organization for Rare Disorders: http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Thrombotic+Th rombocytopenic+Purpura

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Platelet Disorder Support Association: http://www.pdsa.org/

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Rare Thrombotic Diseases Consortium: http://rarediseasesnetwork.epi.usf.edu/rtdc/learnmore/index.htm#ttp Professional Resources

You may also be interested in these resources, which are designed for healthcare professionals and researchers. •

Gene Tests - DNA tests ordered by healthcare professionals: http://www.genetests.org/query?testid=206849

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ClinicalTrials.gov - Linking patients to medical research: http://clinicaltrials.gov/search/condition=%22thrombotic+thrombocytopenic+purpura %22+OR+%22Purpura%2C+Thrombocytopenic%22?recruiting=false

•

OMIM - Genetic disorder catalog: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=274150

References These sources were used to develop the Genetics Home Reference condition summary on thrombotic thrombocytopenic purpura. •

George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med. 2006 May 4;354(18):1927-35. Review. No abstract available. PubMed citation

•

Kremer Hovinga JA, Studt JD, Lammle B. The von Willebrand factor-cleaving protease (ADAMTS-13) and the diagnosis of thrombotic thrombocytopenic purpura (TTP). Pathophysiol Haemost Thromb. 2003 Sep-2004 Dec;33(5-6):417-21. Review. PubMed citation

•

Kwaan HC, Boggio LN. The clinical spectrum of thrombotic thrombocytopenic purpura. Semin Thromb Hemost. 2005 Dec;31(6):673-80. Review. PubMed citation

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Lian EC. Pathogenesis of thrombotic thrombocytopenic purpura: ADAMTS13 deficiency and beyond. Semin Thromb Hemost. 2005 Dec;31(6):625-32. Review. PubMed citation

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Sadler JE, Moake JL, Miyata T, George JN. Recent advances in thrombotic thrombocytopenic purpura. Hematology (Am Soc Hematol Educ Program). 2004;:40723. Review. PubMed citation

Studies

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Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol. 2003 Apr;14(4):1072-81. Review. PubMed citation

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Tsai HM. Current concepts in thrombotic thrombocytopenic purpura. Annu Rev Med. 2006;57:419-36. Review. PubMed citation

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Tsai HM. Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes. J Thromb Haemost. 2003 Apr;1(4):625-31. Review. No abstract available. PubMed citation

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Tsai HM. Molecular mechanisms in thrombotic thrombocytopenic purpura. Semin Thromb Hemost. 2004 Oct;30(5):549-57. Review. PubMed citation

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Tsai HM. The molecular biology of thrombotic microangiopathy. Kidney Int. 2006 Jul;70(1):16-23. Epub 2006 May 31. Review. PubMed citation

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Yarranton H, Machin SJ. An update on the pathogenesis and management of acquired thrombotic thrombocytopenic purpura. Curr Opin Neurol. 2003 Jun;16(3):367-73. Review. PubMed citation

A summary of the gene related to thrombotic thrombocytopenic purpura is provided below:

What Is the Official Name of the ADAMTS13 Gene?4 The official name of this gene is “ADAM metallopeptidase with thrombospondin type 1 motif, 13.” ADAMTS13 is the gene's official symbol. The ADAMTS13 gene is also known by other names, listed below.

What Is the Normal Function of the ADAMTS13 Gene? The ADAMTS13 gene provides instructions for making an enzyme that is involved in blood clotting. After an injury, blood clots normally protect the body by sealing off damaged blood vessels and preventing further blood loss. The ADAMTS13 enzyme processes a large protein called von Willebrand factor, which also plays a role in clot formation. In the bloodstream, the enzyme cuts von Willebrand factor into smaller pieces. Von Willebrand factor normally interacts with cell fragments called platelets, which are essential for blood clotting. The factor helps platelets stick together and adhere to the walls of blood vessels at the site of a wound. These groups of platelets form temporary clots, plugging holes in blood vessel walls to help stop bleeding.

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Adapted from the Genetics Home Reference of the National Library of Medicine: http://ghr.nlm.nih.gov/gene=adamts13.

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Thrombotic Thrombocytopenic Purpura

What Conditions Are Related to the ADAMTS13 Gene? Thrombotic Thrombocytopenic Purpura - Caused by Mutations in the ADAMTS13 Gene More than 70 mutations in the ADAMTS13 gene have been reported in people with the familial form of thrombotic thrombocytopenic purpura. Most of these mutations change a single building block (amino acid) in the ADAMTS13 enzyme. Other mutations lead to the production of an abnormally small version of the enzyme that cannot function properly.

Where Is the ADAMTS13 Gene Located? Cytogenetic Location: 9q34 Molecular Location on chromosome 9: base pairs 135,276,940 to 135,314,327

The ADAMTS13 gene is located on the long (q) arm of chromosome 9 at position 34. More precisely, the ADAMTS13 gene is located from base pair 135,276,940 to base pair 135,314,327 on chromosome 9.

References These sources were used to develop the Genetics Home Reference gene summary on the ADAMTS13 gene. •

Bowen DJ, Collins PW. Insights into von Willebrand factor proteolysis: clinical implications. Br J Haematol. 2006 Jun;133(5):457-67. Review. PubMed citation

•

Dong JF. Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions. J Thromb Haemost. 2005 Aug;3(8):1710-6. Review. PubMed citation

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Kremer Hovinga JA, Studt JD, Lammle B. The von Willebrand factor-cleaving protease (ADAMTS-13) and the diagnosis of thrombotic thrombocytopenic purpura (TTP). Pathophysiol Haemost Thromb. 2003 Sep-2004 Dec;33(5-6):417-21. Review. PubMed citation

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Levy GG, Motto DG, Ginsburg D. ADAMTS13 turns 3. Blood. 2005 Jul 1;106(1):11-7. Epub 2005 Mar 17. Review. PubMed citation

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Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, Yang AY, Siemieniak DR, Stark KR, Gruppo R, Sarode R, Shurin SB, Chandrasekaran V, Stabler SP, Sabio H, Bouhassira EE, Upshaw JD Jr, Ginsburg D, Tsai HM. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001 Oct 4;413(6855):488-94. PubMed citation

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Sadler JE, Moake JL, Miyata T, George JN. Recent advances in thrombotic thrombocytopenic purpura. Hematology (Am Soc Hematol Educ Program). 2004;:40723. Review. PubMed citation

•

Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol. 2003 Apr;14(4):1072-81. Review. PubMed citation

•

Tsai HM. Current concepts in thrombotic thrombocytopenic purpura. Annu Rev Med. 2006;57:419-36. Review. PubMed citation

•

Tsai HM. Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes. J Thromb Haemost. 2003 Apr;1(4):625-31. Review. No abstract available. PubMed citation

•

Tsai HM. Molecular mechanisms in thrombotic thrombocytopenic purpura. Semin Thromb Hemost. 2004 Oct;30(5):549-57. Review. PubMed citation

•

Tsai HM. The molecular biology of thrombotic microangiopathy. Kidney Int. 2006 Jul;70(1):16-23. Epub 2006 May 31. Review. PubMed citation

•

Wolf G. Not known from ADAM(TS-13)--novel insights into the pathophysiology of thrombotic microangiopathies. Nephrol Dial Transplant. 2004 Jul;19(7):1687-93. Epub 2004 May 5. Review. No abstract available. PubMed citation

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Yarranton H, Machin SJ. An update on the pathogenesis and management of acquired thrombotic thrombocytopenic purpura. Curr Opin Neurol. 2003 Jun;16(3):367-73. Review. PubMed citation

Federally Funded Research on Thrombotic Thrombocytopenic Purpura The U.S. Government supports a variety of research studies relating to thrombotic thrombocytopenic purpura. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.5 CRISP (Computerized Retrieval of Information on Scientific Projects) CRISP is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to thrombotic thrombocytopenic purpura.

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore thrombotic thrombocytopenic purpura. The following is typical of the type of information found when searching the CRISP database for thrombotic thrombocytopenic purpura: •

Project Title: A PLATELET LIGAND MIMETIC FOR NEUROTHROMBOTIC DISORDERS Principal Investigator & Institution: Woods, Catherine; Targeted Molecules Corporation Suite 318 San Diego, Ca 921092253 Timing: Fiscal Year 2006; Project Start 30-SEP-2006; Project End 31-AUG-2007 Summary: (provided by applicant): The role of the blood brain barrier in regulating immune surveillance and hemostasis and the deregulation at this site during inflammatory and pro-thrombotic disorders are poorly understood. There is an urgent medical need for improved therapies for diseases such as stroke, cerebral hemorrhage and cerebral thrombotic complications in disorders such as thrombotic thrombocytopenic purpura (TTP), cerebral malaria, meningitis vascular dementia and Alzheimer's Disease (AD) where localized recruitment of activated platelets within the CNS vasculature is a key aspect of the disease process. Antagonists of the platelet (II(3 integrin have been clinically validated for acute coronary syndromes but not thus far for neuro-thrombotic disorders, suggesting that the pivotal interactions regulating thrombotic responses at the blood brain barrier have yet to be defined. Using in vivo phage display, we have identified a novel ligand (TMC-0A3) that targets the brain vasculature with high selectivity and prevents platelet adhesion to brain vasculature under severe inflammatory conditions. Based on our preliminary data, TMC-0A3 is a novel ligand mimetic of the platelet GPIb-( that functions as an antagonist of plateletvWF interactions. In this Phase I application we propose to map the basic pharmacophore structure using the Company's kSARTM technology and optimize the molecule. The optimized molecule will then be used for proof of concept efficacy studies in murine models of arterial thrombosis, cerebral hemorrhage and botrocetin-induced thrombocytopenia to establish whether this mechanism of action can offer an improved therapeutic profile compared to current anti-platelet strategies. This will pave the way for efficacy studies in defined animal models of neuro-thrombotic diseases with the preclinical development candidate to support the pre-clinical and phase I clinical development plan that is planned for Phase II of this grant. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ADAMTS13 DEFICIENCY IN TTP Principal Investigator & Institution: Tsai, Han-Mou M.; Associate Professor of Medicine; Montefiore Medical Center (Bronx, Ny) 111 East 210Th St Bronx, Ny 104672490 Timing: Fiscal Year 2005; Project Start 01-JAN-1999; Project End 30-JUN-2009 Summary: (provided by applicant): Thrombotic thrombocytopenic purpura (TIP), a disease characterized by von Willebrand factor (VWF)- and platelet-rich thrombi in the arterioles and capillaries, typically presents with thrombocytopenia and microangiopathic hemolysis, accompanied by neurological dysfunction, renal abnormalities and other organ dysfunctions in the advanced cases. The use of plasma exchange has improved the survival rate of the disease from