Society for Pediatric Research Presidential Address 1998: The SPR and 1-800-NO-CLOTS: A Common Vision

Members and guests, it is needed an honor and pleasure to address you this morning as a spokesperson for pediatric research. I sincerely thank the Society for Pediatric Research (SPR) membership for bestowing upon me the honor of serving as President for the past year. As past presidents have recognized, one of the most daunting tasks for the person elected to the SPR presidency is to choose a topic for the presidential address that is important on a broad basis to the SPR membership, important to pediatric research in general, has not been presented in the recent past, and, perhaps most important, is a topic about which the president may, hopefully, have some knowledge. I have chosen to follow previous formats in which I will focus on an issue that I believe impacts on pediatric research and combine that with my own particular specialty: hemostatic disorders of the young. Upon reflecting on the issues that came before the SPR council, where I have been privileged to serve for the last nine years, none seemed as important as the central issue of the future of the SPR as we move into the 21st century. Specifically, should the SPR continue to exist as a separate academic pediatric organization, or has the need for the SPR been replaced by subspecialty societies? Has the SPR outlived its mandate? These questions can only be answered in the context of the role of academic pediatrics, which can be considered to focus on the creation, evaluation, dissemination, and utilization of knowledge. However, there are several pediatric organizations whose missions focus on one or more of these goals. What is the unique contribution that the SPR makes to the advancement of health in children? The SPR constitution defines the central purpose of the SPR as follows: "The Society's primary purpose shall be to encourage pediatric investigation by providing a forum for the interchange of ideas and providing opportunities for younger investigators to present work" (1). Regarding members, the constitution states, "Active members shall be limited to those individuals engaged actively in ongoing clinical or laboratory investigations in pediatrics" (1).

Clearly, the fundamental purposes of the SPR are dissemination of knowledge through the annual meeting and creation of knowledge through the SPR membership, which is actively engaged in pediatric research and are individuals under 45 years of age.

PART I

What Are the Unique Contributions That the SPR Has Made to the Advancement of Health in Children?

Since its inception, the membership of the SPR has consisted of young academics who have been a driving force for pediatric research. In the late 19th century, pediatrics was not recognized as a specialty and was usually considered under the umbrella of internal medicine or obstetrics. Only a few academic pediatricians were identifiable in the United States (1). The first convening of a small group of physicians who were dedicated to the permanent organization of a pediatric society occurred in Washington, D.C. September 7-9, 1887. Although the first name of the society was the American Pediatric Society (APS), one could argue that this was indeed the first meeting of the SPR, as 60% of the 43 founding members were less than 40 years of age, and only four were over 50 years old. Without argument, the establishment of the APS can be considered as one of the first accomplishments of young physicians focused on improving child health in North America. The leadership role of young academic pediatricians was perhaps next most evident when, in 1929, a group of "young radical" pediatricians decided to break away from the APS and form their own society, called the Eastern Society for Pediatric Research (ESPR), holding their own scientific meeting. The primary reason for this move was "to serve the younger members of university groups in Pediatrics" (1).

The practical objectives of the ESPR were to ensure that young pediatric researchers could present their work and influence the forum of their scientific meeting. In 1931, the ESPR became a national organization and was called the SPR. One of the founding criteria of the SPR was that active members must be under the age of 45. By 1938, the APS and SPR agreed to jointly sponsor an annual pediatric research meeting. In 1960, the Ambulatory Pediatric Association (APA) joined the APS and SPR in cosponsoring the annual meeting, a joint sponsorship that has continued to today. The pediatric annual meeting was the forum for ground-breaking research in pediatrics throughout most of the 20th century. The SPR was frequently the voice of change in the annual meetings, an example being the institution of overlap with the internal medicine societies to enhance content and the presentation of science important to both groups. The joint leadership role of the SPR in the annual meeting changed the character of the meetings, as noted at a 1961 business meeting where an APS member poignantly commented, "Do we need to be tied to the Junior Society? I love the Junior Society, but is it not possible to have a meeting in the old manner?" (1). I think that the answer to that question from the SPR point of view is "no."

Challenges to the SPR in the Last 20 Years of the 20th Century

The annual scientific meeting. One of the most significant challenges to face the SPR is the evolution of subspecialty pediatrics and their respective societies, which has resulted in an exodus of subspecialists, and their scientific contribution from the annual pediatric meeting. I believe that the evolution of subspecialty pediatrics in the last 25 years of the 20th century is easily as significant as the evolution of pediatrics as a specialty at the turn of the 19th century. What is the evidence for this statement? Figure 1 shows that in the 1980s a significant change occurred in the content of the submitted abstracts, with the contribution by neonatology increasing and that by subspecialty decreasing. Indeed, Figure 1 underestimates the contribution by neonatology in that many of the abstracts submitted to subspecialty areas were neonatal in content. The exitus of subspecialists was also occurring for internists, which had a profound impact on the attendance at their general meeting [American Federation for Clinical Research (AFCR), American Society for Clinical Research (ASCI), and the Association of American Physicians (AAP) informally called the Triple A Society (A/A/A)] (Fig. 2). One potential solution proposed by the SPR had been a simultaneous meeting with the A/A/A that had the potential to enhance the scientific presentations as well as provide a more secure base for the future for both organizations. However, for a variety of reasons, a concurrent/integrated meeting was not achieved, and the immediate future of the A/A/A meeting is currently in jeopardy (2).

Figure 1

The percent of abstracts submitted to the Pediatric Academic Society annual meeting. In 1986 (▴), the format was changed to recognize the increasing number of neonatal abstracts.

Figure 2

The attendance at the ASCI/AAP/AFMR (solid line) and the American Society of Human Genetics (dashed line) (Ref. 2).

Another solution to the decline in subspecialty participation in the annual pediatric meeting, spearheaded by the SPR, was a program committee. A program committee was introduced in 1992 with the mandate to 1) sustain the excellence of research presentation for the groups that currently meet at the annual meeting, 2) initiate educational programs to attract our trainees, 3) consider mechanisms by which subspecialists could be enticed to attend and contribute to the annual meeting, and 4) consider options by which the annual meeting could continue to grow and improve. The program committee was composed of members from the APS/SPR/APA and affiliated pediatric societies that met at the annual meeting. Indeed, in recognition of the multitude of pediatric societies that met together, the name of the annual meeting was officially changed to the Pediatric Academic Society's (PAS) annual meeting. The program committee introduced a very flexible format and a variety of educational programs, and numerous invited speakers were included throughout the scientific program (Fig. 3) (APS/SPR Central Office). The efforts of the program committee have, without question, enhanced the presentation of science and education at the PAS annual meeting. The composition of attendees shows an increasing number of trainees and a stable attendance by neonatologists and ambulatory care physicians (Fig. 4). However, the attendance of subspecialty pediatricians has continued to decline since 1993, the first meeting organized by the program committee (Fig. 4). The number of abstract submissions lead to the same conclusion as the information on attendees. The issue, in my opinion, is of central importance to the future of the SPR as well as other pediatric societies that jointly sponsor the annual meeting. Well, who are the subspecialists that attend the PAS annual meeting and why?

Figure 3

The educational components of the Pediatric Academic Societies. The number of speakers (◊) and educational programs (□) are indicated.

Figure 4

The attendance at the Pediatric Academic Societies annual meeting by neonatalogists (◊), subspecialists (□), and others (▵).

The three subspecialist groups with the largest attendance at the PAS meeting are endocrinology, infectious diseases, and nephrology (Fig. 5). These same three subspecialty groups, and only these three subspecialty groups, also have their subspecialty society meeting conjointly with the PAS meeting. Practically, this means that they have between 1 and 2 days of educational and scientific sessions sponsored by their society followed immediately by their subspecialty sessions in the PAS meeting. Despite this, we are seeing a decline in endocrinology, which is only partly explained, at least in 1997, by a conjoint meeting with their European colleagues. In contrast, the next three largest subspecialist groups that attend the PAS meeting are hematology/oncology, gastroenterology, and cardiology (Fig. 6). None of these societies meets with PAS, and the attendance of these subspecialists is reduced by approximately 75% compared with the three subspecialty societies that meet with PAS. The numbers of attendees from these subspecialties continue to decline despite the efforts of the program committee to enhance the scientific content of these subspecialties. These data suggest that one approach to enhance subspecialty attendance, and participation scientifically, is to approach pediatric subspecialty groups to consider meeting conjointly with the PAS annual meeting. Another approach is to identify new disciplines in pediatrics and attract them to our meeting. Emergency medicine provides an example (Fig. 7).

Figure 5

The attendance of the three largest groups attending the PAS annual meeting: endocrinology (◊), infectious disease (□), and nephrology (▵). All three groups have conjoint subspecialty meetings at the PAS annual meeting.

Figure 6

The three subspecialty groups who do not have conjoint subspecialty meetings at the PAS annual meeting: cardiology (♦), gastroenterology (▪), and hematology/oncology (▵).

Figure 7

The attendance of a new subspecialty (◊, emergency) to the PAS annual meeting.

Overall, the attendance and abstracts submitted to the PAS meeting are stable (Fig. 8). The program committee has had a significant role in securing the current health of our meeting. However, I believe that the PAS meeting is vulnerable and, therefore, so is the SPR. The exodus of neonatology and ambulatory pediatrics would, I believe, end the PAS meeting. This does raise the following question: Does the PAS meeting, compared with subspecialty meetings, offer a unique contribution outside of neonatology and ambulatory medicine? I personally believe that the answer is yes. Although we can never compete with the depth and breadth of basic and clinical science presented at subspecialty meetings, we can present the best of the basic and clinical research, and we can present it to pediatricians in all specialties. The PAS annual meeting could become the pediatric meeting that all academic pediatricians attend because of the breadth and excellence of the science as well as the meeting that provides outstanding educational sessions that nurtures our future pediatric clinician scientists.

Figure 8

The number of attendees (◊) and abstracts (□) at the PAS annual meeting.

Paucity of clinician scientists in pediatrics. Although the annual meeting is the primary activity of the SPR, the SPR has recognized other needs in pediatric research and initiated novel programs to address these issues. The problem of the paucity of clinician scientists was addressed in the mid 1980s by the Association of Medical Schools Pediatric Department Chairman (AMSPDC) and the Pediatric Scientist Development Program (PSDP) established by the AMPSPDC. Figure 9 summarizes the numbers of applicants and awardees. The quality of the applicants has been excellent, and they have achieved the desired outcome: functioning as outstanding, independent pediatric clinician scientists. However, one has to be concerned by the small number of applicants per year. The SPR initiated a summer medical student program in 1992 to encourage our brightest medical students to consider a career in pediatric research before their commitment to other areas of medicine. Medical students were placed in pediatric research laboratories of SPR members across North America and were given specific research projects. Figure 10 summarizes the numbers of applicants and those who received an award. Long-term tracking of the awardees is in place, and a link to the PSDP program is under consideration. Hopefully, the medical summer student project will increase the numbers of candidates for the PSDP.

Figure 9

The number of those applied (◊) and accepted (□) to the Pediatric Scientist Development Program.

Figure 10

The number of those applied (◊) and funded (□) by the Medical Student Research Program of the Society for Pediatric Research from 1991 to 1997.

Evolution of evidence-based research. The SPR recognized the evolution of the science of clinical research and the potential of the annual meeting becoming a forum for presentation of major clinical trials in pediatrics that cross all subspecialties. A small clinical trials program was initiated in 1996 to facilitate the initiation of multicenter clinical trials in pediatrics.

Declining SPR membership. The SPR recognized that its membership was declining (Fig. 11) and that the average age of its membership was increasing. At least one of the causes of the declining membership was the longer period of time required for young pediatric researchers to train and become independent, one of the most important criteria for membership. In 1996, the SPR increased its age restriction to 50, which has had an immediate positive impact on membership. Whether the growth in SPR active membership will be sustained remains to be seen.

Figure 11

The number of active (◊) and senior (□) members of the Society for Pediatric Research. In 1996, the Society for Pediatric Research (SPR) increased its age restriction to 50 (▴).

Other SPR contributions. Finally, the SPR is an active member on several councils that are concerned with pediatric research, education, clinical care, and political forums for children. Although these are wonderful programs and contributions, the future of the SPR needs to be carefully considered and not left unguided.

Unique contributions by the SPR. This brings me back to my original question: What is the unique contribution that the SPR makes to the advancement of health in children? My personal view is that the SPR has contributed to enormous advances in child health both through its membership and through the organization itself. The SPR has identified new problems in child health, pushed for changes in research, shown youthful impatience with the status quo, brought in novel ideas, started novel programs, and in general, insisted on change not for the sake of change alone but because change was needed and is the core of viability and the future. Change is not to be feared, only guided by thoughtful and knowledgeable women and men. The SPR, in collaboration with the APS, APA, and other organizations, has provided a forum for the evaluation and dissemination of the new knowledge that academic pediatricians create in their fundamental and clinical bedside laboratories. To achieve these accomplishments, the SPR has had to challenge our "facts" and, at times, the dogma of our leaders!

However, although all of this true, these facts do not in themselves ensure that the SPR membership will continue to represent the breadth of subspecialties in pediatrics in the future, nor that the PAS annual meeting will continue to present excellence in research from many subspecialty areas. Vision, long-term planning, and active initiation of change with specific goals are critically important. This now brings me to the second part: 1-800-NO-CLOTS.

PART II

1-800-NO-CLOTS

1-800-NO-CLOTS is a free consultative service for physicians world wide who are caring for children with complicated thromboembolic disease. 1-800-NO-CLOTS has also established a worldwide network of children's centers that are currently conducting international clinical trials that will change how we prevent and treat thromboembolic disease in children. Where did the concept of 1-800-NO-CLOTS come from, is its substance as superficial as the apparently light-hearted name, and what common visions could it share with the SPR? To answer these questions, we need to briefly examine the history of hemostasis in the infant and child over the last century.

Between 1880 and 1980, most of childhood hemostasis focused on bleeding disorders and not thrombotic disorders because thrombotic events were rare in children. At approximately the same time that the APS was forming in the 1880s, Townsend (3) defined the most common acquired bleeding disorder in children, hemorrhagic disease of the newborn (HDNB), as hemorrhage from multiple sites in otherwise healthy infants in the absence of trauma, asphyxia, or infection on days one through five of life. At the same time that the SPR was forming, Dam (4) discovered vitamin K, an absence of which caused HDNB, as an "... antihaemorrhagic factor responsible for the haemorrhagic disease in chicks. Vitamin K... K as Koagulation in German."

The discovery of vitamin K and its causal role in HDNB led to world wide prophylaxis programs with vitamin K at birth, which have nearly eliminated this previously frequent disease.

In the 1930s, one of the first schemas of coagulation was devised and consisted of only four components: prothrombinase, calcium, a tissue component, and fibrinogen. Discoveries of further components of hemostasis over the century, primarily in newborns with severe deficiencies, resulted in the dreaded schema of hemostasis that is presented in all books on the subject. There were numerous discoveries of proteins that regulated the hemostatic system (e.g. protein C, protein S) (5,6) and their characterization at a molecular level (7,8). One example of the impact of this burst of new knowledge on children was the link between homozygous protein C deficiency and purpura fulminans in affected neonates (9,10). Characterization of this disease has resulted in effective forms of therapy in the form of protein C concentrate (11,12) and, in some patients, the use of low molecular weight heparin (LMWH) (13). There were discoveries of other common prothrombotic genetic defects such as factor V leiden (14) and prothrombin gene A20210 (15) present in 5% and 2% of the population, respectively. Characterization of these prothrombotic defects permitted insight as to why some children develop thromboembolic disease and others do not (16–21).

During the 1980s, three large population studies of the hemostatic system during infancy and childhood (22–24) and a fourth study in healthy fetuses in the 1990s (25) were conducted. These four studies provided accurate age-dependent reference ranges and insight into the age dependency of thromboembolic disease and mechanisms that protect children from these events (22–25). To date, the described protective mechanisms have focused on enhanced regulation of thrombin in plasma (26–28) and by the vessel wall of the young (29,30). The capacity to generate thrombin in plasma from newborns and children is reduced by 50% and 20%, respectively, and is similar to adults receiving heparin (30). Both a decreased plasma concentration of prothrombin (22,23) and increased plasma concentrations of the inhibitor α₂macroglobulin (α₂M) are responsible for the enhanced regulation of thrombin in the young (31). Children who are heterozygous for antithrombin (AT) deficiency rarely develop thromboembolic events until after puberty. The increased plasma concentrations of α₂M throughout the first two decades is able to compensate, at least in part, for the decreased plasma concentrations of AT (32). Recent studies of the vessel wall in prepubertal animals have shown that there is an increased concentration of proteoglycans that have the capacity to enhance thrombin regulation by binding to either AT or heparin cofactor II (29).

The studies of the development of the hemostatic system also provided insight into anticipated differences in response to anticoagulants such as coumadin, heparin, and LMWH. Plasma concentrations of the vitamin K coagulant proteins are decreased throughout childhood, suggesting that the interaction with oral anticoagulants may differ (33). Plasma concentrations of AT, the main inhibitor of enzymes in the coagulation system, are decreased during the first weeks of life and may therefore alter the response to anticoagulants such as heparin and LMWH (34). Animal models that reflected the hemostatic system in the young were used to assess the influence of age on the pharmacokinetics of anticoagulants and showed that both heparin and LMWH are cleared more efficiently in the very young owing to an increased volume of distribution (35,36). The same animal model showed that decreased plasma concentrations of AT impaired the response to treatment doses of heparin and that increasing either the concentration of heparin or AT levels significantly improved the response to heparin (35,36).

During the 1980s, there were increasing numbers of reports in the literature of children who were developing thromboembolic complications (37,38). The reasons for the seemingly increasing numbers of children developing thromboembolic disease were not readily apparent. In the early 1990s, I accepted a part-time appointment at the Hospital for Sick Children (HSC) in Toronto, Canada to begin to determine whether there was a significant clinical population of children afflicted by thromboembolic disease. After numerous meetings with subspecialty physicians, I became convinced that there was a new field developing in pediatrics, "childhood thrombophilia." The term thrombophilia was chosen because it is a term that encompasses the diagnosis and management of children with, or at risk for, thromboembolic disease from acquired or inherited disorders. Childhood thrombophilia includes children receiving anticoagulants in a variety of situations such as extracorporeal membrane circulation, cardiac catheterization, cardiopulmonary bypass, and dialysis. There seemed to be several hundred children per year admitted to HSC whose diagnoses would be encompassed by the term thrombophilia. Numerous questions arose because we knew essentially nothing about this new field in pediatrics. How do you go about obtaining valid epidemiologic data for a new pediatric disease that is not widely recognized? How do you rapidly provide information to physicians caring for children with thromboembolic disease? What are the most important clinical questions to be addressed in clinical trials? How do you establish a network of children's hospitals that can conduct clinical trials in a relatively rare disorder in pediatrics?

The strategies adopted were as follows. 1) An institutional thrombophilia program was initiated at HSC, Toronto with the goals of providing excellence in care for children with thromboembolic disease and for conducting large prospective cohort studies that evaluated protocols for heparin, LMWH, coumadin, and thrombolytic therapy. These studies were the first large studies assessing antithrombotic therapy in the young, and the results have formed the rationale for recently initiated international interventional studies. 2) In the early 1990s, Canadian pediatric hematologists initiated national registries for thromboembolic diseases, including stroke. The Canadian health care system is ideally suited to population-based studies, as all children with serious diseases are admitted into one of 16 children's centers; they receive fairly uniform care, and long-term follow-up is feasible. The Canadian registries provided the first population-based epidemiologic studies in children with thromboembolic disease. 3) In 1994, an international registry/clinical service was initiated to respond to an enormous clinical need by physicians caring for children with thromboembolic disease and to identify individuals and centers who would be interested in participating in intervention trials in the future. This was the birth of 1-800-NO-CLOTS. 1-800-NO-CLOTS is a free consultative service for physicians caring for children with thromboembolic disease. The service is maintained 24 hours per day by four physicians who volunteer their time. Information is recorded on every consult, pertinent protocols are made available immediately to the caller, and the caller is linked into the network and its services.

Epidemiology of childhood thromboembolic disease. The epidemiologic studies have established that children less than one year of age and teenagers are at greatest risk for thromboembolic disease (Fig. 12) (39–41). Physiologic features of the hemostatic system in infants less than one year of age are very different from adults, suggesting that only limited extrapolations can be made from trials in adults assessing the prevention and treatment of venous thrombotic disease with anticoagulants. Over 95% of children with thrombotic complications have a serious underlying disorder compared with an incidence of idiopathic deep vein thrombosis (DVT) in 40% of adults (39,40). The most common underlying disorders include cancer, trauma/surgery, congenital heart disease (CHD), prematurity, systemic lupus erythematosus (SLE), and other disorders (Fig. 13). The vast majority of children have two or more risk factors for thromboembolic disease (42). The exact contribution of congenital prethrombotic disorders to thromboembolic disease in children remains uncertain because relevant testing is not routinely performed, and some prethrombotic disorders such as activated protein C resistance and the prothrombin gene defect A20210 have only recently been characterized (39,40). The German registry reports that as many as 20% of children with thrombotic complications related to acquired diseases also have a congenital risk factor (16). The Canadian registries have shown that DVT occurs in the central venous system in 90% of newborns and in the upper venous system in 55% of children compared with less than 2% of adults (43). The sole reason for the high frequency of DVT in the central and upper venous system is central venous lines (CVL) (39–41). CVLs are the single most important cause of thrombotic disease during childhood.

Figure 12

The age distribution of 884 children with thromboembolic events in the International Thrombophilia Network (1-800-NO-CLOTS).

Figure 13

The underlying diseases in 877 children with thromboembolic events.

CVL-related DVT. CVLs are, without question, a critical component of tertiary care pediatrics, without which many life-saving forms of therapy could not be consistently delivered. CVLs are placed for either short-term intensive care (as in the neonatal and pediatric intensive care units) or long-term supportive care for children requiring total parenteral nutrition (TPN) and/or therapy for cancer. The general perception has been that when CVLs provoke a clot, it is a small clot at the tip of the CVL, which interferes with function but is not otherwise usually clinically significant. Part of the reason that this misconception arose was that the radiographic tests commonly used in pediatric patients to evaluate for a large vessel thrombus (ultrasound, lineograms) were not adequate in the upper venous system, which is where most of the CVL-related thrombi occur. Figure 14 shows a normal venogram of the upper venous system (dye injected into an arm vein) and venograms of children with CVLs who were not thought to have large vessel clots. These venograms show the complete destruction of the upper venous system with collaterals draining the upper body through the azygous system into the heart.

Figure 14

Four bilateral venograms of patients receiving home total parenteral nutrition. The upper left venogram is normal, whereas the other three show varying degrees of venous occlusion with collateral circulation.

Incidence Of CVL-related DVT. The reported incidence in the literature of CVL-related DVT is variable and reflects the diagnostic tests used to detect a CVL-related DVT. For example, the reported frequency of CVL-related VTE in children receiving home TPN ranges from 1% to 80%, with the lowest frequencies reflecting clinical diagnosis of superior vena cava syndrome and highest frequencies reflecting venographic evidence of DVT.

Long-term clinical consequences of thromboembolic disease. The long-term consequences of thromboembolic disease in children include recurrent DVT, postphlebitic syndrome (PPS), long-term anticoagulation therapy with its risk of bleeding, and hemorrhage from ruptured collateral varices. There may well be other long-term complications that are not known at this time because of the relative newness of this particular secondary complication. These long-term complications of DVT are not minor. The risk of recurrent DVT will increase with age and is already at approximately 20% in the Canadian registry that has follow-up data for approximately 5 years. Recurrent DVT will likely mean the need for life-long anticoagulants and an increased risk of PPS. PPS is caused by incompetent perforating valves and blood flow directed from the deep system into the superficial system, leading to edema and impaired viability of s.c. tissues. Symptoms of PPS include swelling, pain, pigmentation, induration of the skin, and ulceration. Symptoms may occur early or can be delayed as long as 5 to 10 years after the initial thrombotic event. The incidence of PPS in children, with approximately 5 years of follow-up, is approximately 20%. At this time, we have no idea as to the incidence and severity of PPS in patients who develop a DVT in the first year of life. Physiologically, the relatively suppressed fibrinolytic system in the young may result in an incidence of PPS in children that exceeds that for adults. Finally, DVT during infancy will present a life-long risk of mortality. Only long-term programs following patients from infancy through adult life will determine the magnitude of the problem and therefore guide strategies focused on prevention and better treatment.

Clinical Trials Currently Underway to Alter the Short-Term and Long-Term Outcomes of Children with Thromboembolic Disease

In general, the levels of evidence supporting guidelines for anticoagulation in children are suboptimal. The reduced incidence of thromboembolic disease in children compared with adults limits the value of single institution studies, a problem that occurs for the majority of serious pediatric diseases. The rapid emergence of thromboembolic complications over the last decade and the facilitation of the 1-800-NO-CLOTS network in developing a network has led to the development of international collaborative clinical trial groups. Current and future multi-center trials will provide the best evidence upon which to formulate specific guidelines for the management of thromboembolic disease in children.

There are currently five ongoing multi-center, multi-national randomized controlled trials assessing the optimal use of anticoagulants in children with, or at risk for, specific thromboembolic complications. The following section briefly describes these trials.

Revive. Revive (reviparin in venous thromboembolism) is a randomized controlled trial comparing LMWH (Reviparin) to standard heparin and warfarin for the treatment of DVT in children. The principal investigator is Dr. Patricia Massicotte, with 48 participating centers from Canada, the United States, Netherlands, Germany, and the United Kingdom.

Protekt. Protekt (prophylaxis of thromboembolism in kids trial) is a randomized controlled trial comparing LMWH (Reviparin) to standard of care primary prophylaxis for the prevention of DVT in children with CVLs. The principal investigator is Dr. Patricia Massicotte, with 20 participating centers from Canada, Netherlands, Germany, and the United Kingdom.

Fontan. The Fontan study is a randomized controlled trial comparing aspirin with heparin/warfarin as primary prophylaxis against thromboembolic complications following Fontan surgery. The principal investigator is Dr. Paul Monagle, with 11 participating centers from Canada, the United States, and Australia.

SLE. The SLE study is a randomized placebo-controlled trial of warfarin anticoagulation for primary thromboembolic prophylaxis in children with SLE and antiphospholipid antibodies. Leslie Mitchell is the principal investigator, with nine participating centers from Canada and the United States.

Parka. Parka (prophylactic antithrombin replacement in kids with acute lymphoblastic leukemia treated with asparaginase) is a randomized controlled trial of AT replacement as thromboembolic prophylaxis for children with acute lymphoblastic leukemia during L-asparaginase therapy. Lesley Mitchell is the principle investigator, with nine participating centers from Canada and the United States.

The Canadian registries and 1-800-NO-CLOTS have identified critical questions in the prevention and management of childhood thrombophilia. These questions can only be answered through well designed, clinical trials with several hundred patients.

PART III

The SPR and 1-800-NO-CLOTS: a common vision?. One may fairly ask, "What could the 1-800-NO-CLOTS network and the SPR share as a common vision?" Part of the mandate of the SPR is to identify new frontiers in pediatric research and to develop them through the SPR membership and at the PAS annual meeting.

1-800-NO-CLOTS is an example of a clinical/research approach to a new disease in pediatrics. Figure 15 shows the increasing number of calls to this service since its inception. Thromboembolic disease in children is a secondary complication of the successful treatment of primary life-threatening diseases, a disease that will evolve and extend throughout adult life, a disease that confers considerable morbidity and mortality, and a disease that took over 20 years to recognize. This disease can be regarded as an example of a whole new area in pediatrics that already exists but is barely recognized from the point of view of both basic and clinical research, as well as clinical care. With rare exception, neither internal medicine or pediatrics is actively organizing clinical and research programs for these patients. I have unsuccessfully struggled with a name for this new field of pediatrics and only describe the field as "adult survivors of pediatric diseases" (Fig. 16). Other examples besides thromboembolic disease are children with CHD, organ transplantation, cancer, cystic fibrosis, cancer, SLE, and numerous others. Although one cannot necessarily predict the face of these new, life-long pediatric diseases, one can predict that they will likely parallel the rapid pace of change in successful treatments for life-threatening pediatric diseases in children. This population of patients needs to be formally recognized with clinical/research programs put in place, both with a basic and clinical research focus that tracks these patients throughout their life-time. The SPR and the PAS annual meeting have a unique opportunity to promote the presentation of new diseases, secondary diseases, and particularly the results of clinical trials in those diseases that cross subspecialists. For example, the results of the clinical trials on childhood thromboembolic disease will be presented at a "clotters" meeting. However, their primary presentation should be at the PAS annual meeting because the results will be of interest to most attendees.

Figure 15

The number of calls (n = 949) to the 1-800-NO-CLOTS international network.

Figure 16

The newly evolving areas in pediatrics: fetal medicine and adult survivors of previously lethal pediatric diseases.

The evolution of evidence-based research and particularly large randomized controlled trials will, I predict, become a major part of pediatric research within the next decade in almost every specialty. This step has already occurred in neonatology and ambulatory medicine, with results presented at the annual PAS meeting. At this time, there is no natural home for the presentation of these large, important clinical trials that will generate interest in the pediatric academic world for essentially all specialists. Many of the trials will begin to focus on the prevention and treatment of secondary complications, which, by their nature, tend to cross subspecialty boundaries.