• Transfusion-Related Acute Lung Injury
• The Future of Hematology: Good News – Bad News
• Therapy for Sickle Cell Disease: Making Promise a Reality
• Senate Approves Sickle Cell Disease Legislation
• ASH Launches State-of-the-Art Symposium
• Second Edition of ASH-SAP Will Feature Latest Advances in Hematology
• Online Early Bird Registration
• A Change in the Abstract Deadline
• Denise Graves to Perform at 2004 ASH Annual Meeting

Transfusion-Related Acute Lung Injury

Toronto Consensus Conference

By John Fisk, M.D., Edward Snyder, M.D., and Morris Blajchman, M.D.
Dr. Fisk is currently a Transfusion Medicine Fellow at Yale University.
Dr. Snyder is currently a Professor of Laboratory Medicine and the Associate Chair for Clinical Affairs at Yale University.
Dr. Blajchman is currently a Professor and Head of Transfusion Medicine at McMaster University and the Medical Director of the Hamilton Centre of Canadian Blood Services.

On April 1-2, 2004, Canadian Blood Services (CBS) and Héma-Québec (HQ), with support from the International Society of Blood Transfusion's (ISBT) Biomedical Excellence for Safer Transfusion (BEST) subcommittee, hosted a Consensus Conference in Toronto, Ontario, entitled "Towards an Understanding of TRALI." The conference drew over 200 delegates worldwide, bringing together 19 internationally-recognized experts to review the latest findings on the etiology, pathogenesis, diagnosis, epidemiology, treatment, and prevention of Transfusion-Related Acute Lung Injury (TRALI).

Transfusion-Related Acute Lung Injury

TRALI is a syndrome within the larger syndrome set of Acute Lung Injury (ALI) or the Adult Respiratory Distress Syndrome (ARDS). The current generally accepted definition of TRALI is the development of mild to severe lung injury, generally during or within two to six hours of a transfusion, characterized by respiratory distress, hypoxemia, bilateral pulmonary infiltrates, hypotension, and fever. Nearly all blood components have been implicated in TRALI including fresh frozen plasma, red blood cells, platelets, cryoprecipitated AHF, and even hematopoietic progenitor cells.

In its severest form, a diagnosis of TRALI mandates ventilatory support in nearly three-quarters of affected patients. With intensive care, resolution of the pulmonary embarrassment occurs within 72 to 96 hours of onset. Mortality is reportedly from 6 to 14 percent. According to data presented at the Consensus Conference from the Food and Drug Administration's (FDA) Office of Blood Research and Review, TRALI is the leading cause of the approximately 100 transfusion-associated deaths reported annually to the FDA over the last three years (2001 through 2003): TRALI, 16.3 percent; ABO/hemolytic transfusion reactions, 14.3 percent; and bacterial contamination, 14.1 percent.

Donor alloantibodies to HLA Class I and II antigens and/or granulocyte-specific antigens, frequently found in multiparous donors (~20 percent), have been strongly implicated in the pathogenesis of TRALI. Antibody binding to recipient leukocyte antigens appears to trigger a cascade of immunologic events, ultimately resulting in pulmonary capillary leak and tissue injury, frequently leading to an ARDS-like clinical picture. Recent studies by Silliman and colleagues have identified non-immune biologic response modifiers that develop during blood component storage. These have been shown both in vitro and in vivo (in mice) to possess potent granulocyte priming capabilities. Additionally, compelling clinical evidence suggests that host factors, such as recent surgery, sepsis, or massive transfusion, play a significant role in defining the severity of the clinical TRALI picture in the blood product recipient. The interplay between host factors and biologic agents in transfused blood components has been elaborated in a proposed "two-hit mechanism" of TRALI pathogenesis.

Consensus Panel Questions

TRALI remains a poorly understood and under-recognized clinical syndrome. Guiding the discussion at the Consensus Conference were six questions posed by members of the Steering Committee. These fundamental questions were: What is the true prevalence of TRALI; how should TRALI be defined; what pathophysiologic mechanisms are responsible for its development; how to manage donors involved in TRALI episodes; what donor screening procedures are warranted given our present understanding of TRALI; and what research endeavors are likely to be the most fruitful to better understand the epidemiology and pathophysiology of TRALI?

Consensus Findings

The Consensus Conference Panel arrived at several conclusions that will be more fully elaborated in forthcoming publications. The panel's preliminary conclusions included the following statements:

• The risk of TRALI is estimated at between 1:5,000 and 1:100,000 depending on the definition of TRALI that is used
• The pathophysiology of TRALI appears to involve an interplay between white blood cell antibodies in plasma-containing blood components, predisposing recipient conditions, and biologic response modifiers that are elaborated during blood component storage
• TRALI should be diagnosed if new acute lung injury (ALI) occurs during or within six hours of transfusion when other risk factors for ALI are absent
• Possible TRALI should be diagnosed when ALI develops within six hours of transfusion and one or more other ALI risk factors - which include multiple trauma, sepsis, shock, pneumonia, or lung contusion - are coexistent
• At present, there is insufficient evidence to support instituting a program of laboratory screening or other donor deferral measures in order to reduce the risk of TRALI
• Removal of multiparous females from the blood donor pool remains controversial
• Several immediate avenues have been proposed that include the creation of a major educational initiative aimed at healthcare providers; adoption of the proposed Consensus TRALI definition by established national surveillance systems; and the organization of broad-based, multi-institutional collaboration to provide "denominator data" in order to better clarify the true prevalence of TRALI

As TRALI may be a final common pathway of various pathogenic mechanisms, the definition of the epidemiology and mechanisms will doubtless require a multidisciplinary research approach involving individuals from the fields of basic sciences, pulmonary medicine, hematology, and transfusion medicine. Funded clinical and basic research protocols are urgently needed to further elucidate the pathophysiology and epidemiology of the clinical syndrome known as TRALI.

References:

1. Canadian Blood Services.
   TRALI Consensus Conference. http://www.bloodservices.ca/CentreApps/Internet/UW_V502_MainEngine.nsf/resources/Trali/$file/TRALI+-+Web+report+-+final2.pdf. Last accessed Tuesday, May 18, 2004.
2. Silliman CC, Bjornsen AJ, Wyman TH, Kelher M, Allard J, Bieber S, Voelkel NF. Plasma and lipids from stored platelets cause acute lung injury in an animal model. Transfusion 2003; 43:633-40.
3. Popovsky MA. Breathlessness and blood: A combustible combination. Vox Sang 2002; 83 (Suppl 1):147-50.
4. Silliman CC, Boshkov LK, Mehdizadehkashi Z, Elzi DJ, Dickey WO, Podlosky L, Clarke G, Ambruso DR. Transfusion-related acute lung injury: epidemiology and a prospective analysis of etiologic factors. Blood 2003;101: 454-62.
5. Kopko PM, Marshall CS, MacKenzie MR, Holland PV, Popovsky MA. Transfusion-related acute lung injury: Report of a clinical look-back investigation. JAMA 2002; 287:1968-71.
6. Engelfriet CP, Reesink HW, Brand A, Palfi M, Popovsky MA, Martin-Vega C, Ribera A, Rouger P, Goldman M, Decary F, Freedman J, Lucas G, Navarette C, Neppert J, von Witzleben-Schurholz E, Lin M, Zupanska B. Transfusion-related acute lung injury (TRALI). Vox Sang 2001; 81:269-83.

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The Future of Hematology: Good News - Bad News

H. Franklin Bunn, M.D.
Dr. Bunn is currently the Research Director of the Hematology Division at Brigham and Women's Hospital, Harvard Medical School.

In pondering the future of hematology and the role of ASH, both in the United States and abroad, we face a "good news - bad news" situation. By a number of readily documented objective criteria, hematology has never been healthier. The growth of our annual meeting and the content of presentations, both scientific and clinical, attest to the continuing creativity and impact of our discipline. Our Society has benefited greatly from continuing growth in membership, particularly from industry and abroad. Likewise our journal Blood has grown impressively in both quality and impact. On the other hand, the future of hematology as a clinical discipline is threatened by a marked decline in the number of qualified trainees who are entering our specialty as well as angst about the fragmentation of hematology into "sub-subspecialties" that are at risk of being assimilated into other medical disciplines. Clinical hematology is on the verge of losing recognition as a viable and freestanding entity.

My mixed feelings of pride and worry came into focus during the past month when I served as attending physician on our inpatient hematology service. I had the privilege of working with a superb first-year fellow from the DFCI-BWH-MGH Hematology/Oncology Training Program. The following thumbnail descriptions of four of the patients who were under our care illustrate some of the problems and challenges that hematologists face.

• A 27-year-old woman with recurrent thrombotic thrombocytopenic purpura responded promptly to plasma exchange. However, owing to rapid recurrences, it was difficult to wean her from this cumbersome, somewhat risky, and expensive form of therapy. This patient illustrates how transfusion medicine has evolved into a challenging interventional clinical discipline, offering an opportunity for young trainees to enter a field which is science-oriented, fast-moving, and high impact.
  
  
• A 42-year-old woman with severe aplastic anemia developed a severe bilateral aspergillus pneumonia accompanied by liver failure of uncertain cause and metabolic acidosis. Our fellow's meticulous care of this challenging patient resonated with a recurrent theme encountered during my 30 years on our medical residency selection committee. Many applicants through the years have stated that although they want to enter a medical subspecialty, they also have a strong interest in maintaining competence in the care of critically ill patients. Hematology is an ideal subspecialty for trainees who want to remain broadly-based clinicians.
  
  
• A 45-year-old man with classic hemophilia and a high titer anti-Factor VIII inhibitor was admitted twice during the month with a huge hemarthrosis in his shoulder complicated by a staphylococcal abscess. This case brought into focus the rapid pace of development of new agents for coagulation and thrombotic disorders which have become such an important part of the hematologist s therapeutic armamentarium. It is virtually incumbent for any large medical center to have an in-house expert in this important domain of clinical hematology. Hematology/oncology trainees should be enticed to populate this important niche.
  
  
• A 30-year-old primagravida was admitted to our obstetrical service late in the last trimester with thrombocytopenia, hemolytic anemia, and liver dysfunction (HELLP syndrome). Even though her hemolysis was only moderate, her blood film revealed approximately equal numbers of nucleated red blood cells and white blood cells. There is no evidence that the patient had ever undergone splenectomy. There was no apparent explanation for this remarkable peripheral blood finding. Unfortunately, our fellow was so busy that he was unable to devote the time he would have liked to further investigate this patient with me. So often, fascinating problems that arise in hematology are given short shrift because of the pressures of a busy clinical service.

The experience of taking care of these four patients brought into focus thoughts about what we might do to encourage trainees to enter hematology. First, we should emulate our colleagues in oncology and take more initiative in the design of relevant cutting-edge clinical research studies. The first three cases presented above underscore the need for development and testing of improved immunosuppressive therapy for TTP, aplastic anemia, and hemophilia with high titer inhibitor. Second, we must be proactive in recruiting residents and fellows. Many are undecided as to their choice of subspecialty. It is important for us to "sell" hematology to those who have an inquiring mind and a strong interest in biomedical science and mechanism of disease, as well as to those who, as mentioned above, want to remain broadly based in the many aspects of clinical medicine that interface with hematology. We need to show by primary example how much fun it is to be a hematologist.

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Therapy for Sickle Cell Disease: Making Promise a Reality

George Buchanan, M.D.

Over 500 physicians, nurses, social workers, and investigators in basic laboratory, clinical, and psychosocial arenas came together in Los Angeles on April 19-21, 2004, to present and hear the latest research developments in sickle cell disease at the 27th Annual Meeting of the Sickle Cell Disease Program. The theme of this year's meeting, sponsored jointly by the Comprehensive Sickle Cell Center at Keck School of Medicine at the University of Southern California, its affiliated hospitals, and NHLBI, was "Therapy for Sickle Cell Disease: Making Promise a Reality." The meeting commenced with the Roland Scott Lecture by Dr. Alan Guttmacher, Deputy Director of the National Human Genome Research Institute at NIH. He summarized the results of a spectacular meeting held at NIH last November aimed at extending discoveries of the human genome project to understanding the phenotypic variability of sickle cell disease and improving the therapy for affected persons from around the world. Instrumental steps will include development of a clinical research network that goes beyond the ten existing NIH-funded comprehensive sickle cell centers and better characterizing the various subphenotypes of the disease so as to allow for more effective targeted therapy that is risk-based. At this year's meeting, particular focus was on the lung, especially the identification, risk factors, and potential therapy for pulmonary hypertension, a major cause of morbidity and mortality in adult patients with sickle cell disease. Other areas of research emphasis where substantial progress was described include improvements in chronic transfusion approaches (using novel central venous access strategies and several means to reduce iron overload) and enhanced understanding of the early development and progression of cerebrovascular disease and its sequelae in affected children. Preventive and therapeutic measures, including several new transfusion and hydroxyurea strategies, were presented and vigorously debated. Further information about the Comprehensive Sickle Cell Centers can be obtained on its Web site: www.rhofed.com/sickle.

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Senate Approves Sickle Cell Disease Legislation

On May 11, 2004, the Senate passed the Sickle Cell Treatment Act of 2003 (S 874). Championed by Senators Jim Talent (R-MO) and Charles Schumer (D-NY), the amendment would enhance prevention and treatment services for patients with sickle cell disease (SCD).

For the past two months, Senator Talent has been working with Senate leadership to attach the sickle cell bill to another piece of legislation as an amendment. ASH has been actively supporting this legislation since its inception in April 2003 by advocating in House and Senate offices with the Government Affairs Committee and launching an ASH Grassroots Network campaign to try to get more co-sponsors of the legislation. Several ASH Grassroots Network members were directly responsible for securing Senate co-sponsors of the bill.

"This is great news for the tens of thousands of Americans with sickle cell disease," said Senator Talent. "I want to thank Senator Charles Schumer who has been my bipartisan partner in this effort." This legislation provides federal matching funds for SCD services. Right now, Medicaid covers physician and laboratory services for all states. This bill allows any state that spends money on new SCD prevention and treatment services specified in this bill to receive a federal match.

In addition, this legislation provides federal reimbursement for education and other services related to the prevention and treatment of SCD. Moreover, the bill would create grant programs for 40 health centers nationwide. Grants could be used for the education, treatment, genetic counseling and testing, and continuity of care for individuals with SCD, for training health professionals, and to identify and secure additional federal funds to continue SCD treatment. The legislation also establishes a national coordinating center to collect, monitor, and distribute information on best practices for the prevention and treatment of SCD and to develop educational materials regarding the prevention and treatment of SCD.

Although the Sickle Cell Treatment Act passed the Senate as an amendment to the JOBS Act, it still has not cleared the House of Representatives. In order to be enacted into law, legislation must pass both Houses of Congress and be signed by the President. Therefore, it will be important to continue to build support for this legislation in the House of Representatives.

Additional action may be required by the ASH Grassroots Network to recruit more House co-sponsors of the sickle cell bill. At press time there were 49 House co-sponsors. For more information, visit the online ASH Advocacy Center.

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ASH Launches State-of-the-Art Symposia in September

Michael Williams, M.D., Chair, Committee on Educational Affairs

ASH will present the first in an ongoing series of State-of-the-Art Symposia (SAS) on September 11-12, 2004, at the Mayflower Hotel in Washington, D.C. This CME-based symposium will focus on hematologic malignancies and will feature internationally-recognized experts to lead didactic and interactive sessions.

The aim of the SAS meetings is to provide cutting-edge updates in key areas of hematology, emphasizing the clinical relevance of recent advances and the ways in which new data alters current practice. Attendance will be limited to 500 participants; fellows and trainees are encouraged to attend.

The speakers and topics for the September meeting include:

These symposia are offered in response to ASH membership requests for smaller-format, clinically-based meetings that supplement the annual meeting and summarize the many rapid advances in clinical hematology. Currently two symposia are planned per year; the second will focus on hemostasis/thrombosis and will be held in April 2005.

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Second Edition of ASH-SAP Will Feature Latest Advances in Hematology

The ASH Self-Assessment Program (ASH-SAP) is a high-quality educational product offering the latest advances in the field of pediatric and adult hematology for hematologists, oncologists, hematology-oncology fellows, internists, and pediatricians. The ASH-SAP is the premier review resource in hematology, providing board preparation, recertification preparation, and 50 category 1 CME credits.

The second edition of the SAP, available December 2004, will again include both an updated syllabus and a self-assessment test composed of case-based, multiple-choice questions and critiques. In addition, the following enhancements are available in the second edition:

• A new chapter covering myelodysplastic syndromes
• The addition of pediatric co-authors to provide even more pediatric content
• Color images included in both the text and question book
• More than 200 all-new case-based, multiple-choice questions, and critiques

A companion Web site adds an interactive element to the self-assessment, allowing users to move back and forth between questions and critiques, chapter text, and illustrative slides with just a few mouse clicks. In addition, the ASH-SAP will integrate cutting-edge information with resources from other ASH educational products, such as the Image Bank, Education Program Book, and Blood. Full access to the interactive Web site is included in the SAP package price. Users can work through the case-based questions on the Web site, as well as claim the 50 category 1 CME credits online.

For more details about the SAP second edition launch, visit the ASH Web site or stop by the ASH booth in the exhibit hall during the 2004 ASH Annual Meeting.

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For ASH Members Only!

Online Early-bird Registration (July 20 to August 9)

Book your hotel room ahead of the pack through online early-bird registration! ASH members who have paid their dues for 2004 are eligible for online early-bird registration beginning July 20, 2004. This benefit allows members to register for the 2004 ASH Annual Meeting and make hotel reservations online via the ASH Web site before the general public. Note that members must register for the annual meeting before making a hotel reservation.

This early-bird registration is available online only. Beginning August 10th, members and non-members can register and make hotel reservations online, by fax, or by mail. For the most up-to-date information on the annual meeting, visit the ASH Web site.

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A Change in the Abstract Deadline

The electronic abstract submission deadline for the 46th ASH Annual Meeting has been set for August 10th, 2004. Please note that this deadline is earlier than in previous years. To take advantage of the convenient online submission program, visit www.call4abstracts.com/hem.

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Denyce Graves to Perform at 2004 ASH Annual Meeting

At this year's Scholar Awards program fundraising evening, ASH is proud to present an extraordinary performance by Denyce Graves. The performance will begin at 8:00 p.m. on December 6, 2004, at the Copley Symphony Hall. All proceeds from tickets sales will be contributed to the ASH Scholar Awards program

Ms. Graves is recognized worldwide as one of today's most exciting vocal stars. The combination of her expressive, rich vocalism, elegant stage presence, and exciting theatrical abilities allows her to pursue a wide breadth of operatic portrayals as well as delight audiences in concert and recital appearances. She continues to gather unparalleled popular and critical acclaim in performances on four continents.

Tickets can be purchased online when registering for the annual meeting.

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