SickKids Handbook of Pediatric Thrombosis and Hemostasis

V. S. Blanchette, V. R. Breakey, S. Revel-Vilk

• Publisher: S. Karger
• Year: 2013
• ISBN:
  9783318021981
• Topic: Medicine
• Subtopic: Perinatology & Neonatology

This handbook takes the reader through the entire field of pediatric thrombosis and hemostasis. An introductory section concisely explains the complex pathophysiology of hemostasis and thrombosis. The chapters that follow include practical, evidence-based information on the diagnosis and management of inherited and acquired bleeding disorders and thrombotic events of the venous, arterial, cardiac and central nervous systems that affect children. Special features include practical clinical algorithms and appendices that cite normal laboratory reference ranges, as well as recommended dosages of blood products and major hemostatic agents. A stand-alone chapter is dedicated to developmental hemostasis and bleeding in the neonate. A chapter on antithrombotic therapy in children gives succinct information on the old and new anticoagulants, antiplatelet drugs and thrombolytic agents.

Blanchette VS, Breakey VR, Revel-Vilk S (eds): SickKids Handbook of Pediatric Thrombosis and Hemostasis.
Basel, Karger, 2013, pp 1–4 (DOI: 10.1159/000346901)

Chapter 1 Pediatric Thrombosis and Hemostasis: A Historical Perspective

Vicky R. Breakey
Victor S. Blanchette

Throughout medical school and residency, trainees frequently hear the old adage ‘kids are not just little adults’. Nowhere in pediatrics is this truer than in the physiology of coagulation. In fact, the coagulation system evolves in utero and continues to develop over the course of childhood. In the late 1980s, Maureen Andrew and her colleagues at McMaster University studied healthy newborns and subsequently preterm infants to better understand postnatal development of the human coagulation system and determine appropriate reference ranges [1, 2]. Additional work describing the maturation of the hemostatic system in children and adolescents was published by Andrew et al. [3] in 1992. These landmark studies confirmed significant and important differences in the physiology of coagulation and fibrinolysis in pediatric patients.

Thrombosis in Childhood

Unlike hemostatic disorders, thrombosis has long been considered a condition of adults. The first reported case of inherited coagulopathy described a Norwegian family and was published by Egeberg in 1965. Since then, mutations in numerous genes have been implicated in congenital thrombophilia. Some of the most severe presentations are homozygous mutations that manifest in infancy and childhood. Issues around who and when to test for inherited thrombophilias remain the source of much debate amongst experts in the field [4].

In addition to the clots that occur secondary to inherited mutations, acquired thromboembolic events also present in childhood. In the early 1990s, Dr. Andrew started the first surveillance program across Canada to determine the incidence and nature of thromboembolic diseases in childhood [5]. They found the incidence of DVT/PE to be 5.3/10,000 hospital admissions or 0.07/10,000 children. Follow-up data at a mean of 2.86 years gave additional insights, suggesting a heavy burden of mortality in this group of 16%. Death due to DVT/PE occurred in 2%, all of whom had central venous catheter-associated thrombosis. Morbidity was high with 8% having recurrent thrombosis, and 12% having post-phlebitic syndrome.

Following the initiation of the registry, Dr. Andrew led the development of two practical clinical treatment initiatives. The first was a telephone consultation service, called ‘1800-NO-CLOTS’ which logged well over 4,000 international physician pediatric thrombosis consults in the first 8 years and continues to be active today. The second initiative was the development of institutional pathways for thrombosis treatment. The latter, entitled ‘Thromboembolism and Stroke Protocols’ was published in 1997 [6]. This practical pocketbook is now in its third edition. These initiatives were well received internationally and continue to be utilized by physicians around the world.

Despite the perceived rarity of thrombosis in childhood, increasing complex medical interventions, central venous catheters and cancer therapies, in particular, have led to a much higher burden of disease. Improved awareness has elevated clinical suspicion, thus increasing the diagnosis of thromboembolic events. Pediatric guidelines for the management of clots were first included in the 5th edition of the American College of Chest Physicians Chest Guidelines for Antithrombotic and Thrombolytic Therapy in 1995. The 9th edition of the guideline was published in 2012 [7]. This document has become the preeminent resource for the management of pediatric thrombosis; however, many recommendations are still based on adult data.

Hemostatic Disorders in Children: The Evolution of Hemophilia Care

Historically, congenital bleeding disorders like hemophilia were considered to be pediatric conditions as patients’ life spans were limited due to bleeding. Over the course of the second half of the 20th century, hemophilia care saw considerable advancements, first with the discovery of cryoprecipitate in the 1960s and quickly thereafter with the development of easy to reconstitute and administer lyophilized FVIII and FIX plasma-derived clotting factor concentrates. Tragically, the tainted blood scandal of the 1980s resulted in the death of many young hemophilia patients who were infected with hepatitis virus and/or HIV. This devastating circumstance resulted in intense pressure to develop safe, virus-inactivated plasma-derived FVIII and FIX concentrates and subsequently to engineer synthetic, recombinant FVIII and FIX replacement products. Recombinant FVIII became available in 1988, followed by a recombinant FIX product in 1997. These synthetic products have become the mainstay of hemophilia treatment in much of the developed world.

With improved accessibility to factor replacement and decreased risk of transmission of infectious diseases, the opportunities for regular replacement therapy (prophylaxis) increased. The first FVIII prophylaxis was given in the late 1950s by Inga Marie Nilsson in Sweden [8]. Early studies of prophylaxis were optimistic, suggesting that infusing factor regularly could dramatically improve outcomes. The Swedish group devised the Malmo protocol, which aimed to keep factor levels at >1%, essentially converting severe hemophiliacs to the moderate phenotype with a substantial reduction in the frequency of spontaneous bleeding. Factor was given at a dose of 25-40 IU/kg for a minimum of 3 times weekly for FVIII deficiency, and twice weekly for FIX deficiency. Data showed that early institution of prophylaxis before bleeding is optimal for preventing joint disease. Investigators reported that anything less than full-dose prophylaxis, or prophylaxis started at an older age (>3 years), did not completely prevent significant hemophilic arthropathy in boys with severe hemophilia A [9]. Manco-Johnson et al. [10] were the first to prospectively study prophylaxis in severe hemophilia. The USA Joint Outcome Study randomized 63 boys (<30 months of age) with severe hemophilia to one of two treatment regimens, either primary prophylaxis using the Malmo regimen, or an on-demand regimen in which they received 40 IU/kg of factor with each joint bleed, followed by 25 IU/kg the next day and 2 days later. The primary outcome was preservation of normal joint structure in ankles, knees and elbows as seen with plain-film radiography and MRI at 6 years of age. The results of this prospective randomized controlled trial demonstrated that prophylaxis was significantly better than on-demand therapy for preventing hemarthroses and preserving joint structure and function in boys with hemophilia. With prophylaxis, severe hemophilia patients have far less joint disease. Their lifespan in developed countries approaches that of the general population.

Despite dramatic improvements in hemophilia care, there is still much work to be done. Research into the development and management of inhibitors is ongoing. Although there are excellent clinical outcomes in high-income countries, 80% of the world's hemophilia patients live in places where the cost of safe factor concentrates prohibits its routine usage. It should be noted that hemophilia is only one example of a multitude of hemostatic disorders that affect children. The more rare disorders receive less research funding and are in general less well studied.

The Future of Pediatric Thrombosis and Hemostasis

As we move forward, two essential things must be considered to further develop and advance the field of pediatric thrombosis and hemostasis. The first is continued research in this field. In this small patient population of uncommon disorders, physicians and researchers must continue to form alliances and collaborations. We must continue to pursue representation on committees of large organizations, such as the subcommittee for perinatal and pediatric issues in the ISTH and work together with those who provide adult hematology care. In addition, research collaborations at national and international levels will increase patient enrollment numbers and promote the success of prospective clinical studies. We must find creative ways to overcome additional barriers beyond small numbers of patients, which include practical limitations to the number and volume of blood samples needed and financial constraints on funding for pediatric research [11]. In providing improved evidence, we will promote the best care for our patients.

Secondly, we must support trainee education and sub-specialization. In pediatrics, we face an ongoing struggle to ensure that non-malignant hematology receives sufficient attention in intensive combined pediatric hematology/oncology training curricula. If hematology is taught well by enthusiastic teachers, more trainees will opt to focus in this area. An editorial in the Journal of Thrombosis and Hemostasis suggested a dramatic decline in the number of physicians interested in careers in the area of bleeding disorders [12]. There was a call for additional fellowship programs to support the education of a new generation of specialists in this area, and it was suggested that training should not be concentrated in one area alone, but should embrace both thrombosis and hemostasis, at least for young academic physicians entering the field [13]. Since that time, many additional fellowships have been started, most funded by industry sponsors. There is no data to show the number of trainees pursuing those fellowships, but human resources continue to be an important issue.

In summary, the history of the study and care of disorders of pediatric thrombosis and hemo-stasis is a tale of innovative thought, hard work and dedication. Our predecessors were talented and driven to build the science that supports our clinical practice. The story continues to evolve and much is left to be discovered. International research collaborations and focused efforts to mentor young academically oriented physicians will ensure that new gains continue to be made in the coming years.

Acknowledgment

The authors would like to express their appreciation for the thoughtful comments provided by Drs. Anthony K.C. Chan (Hamilton, Ont., Canada), Gabrielle DeVeber (Toronto, Ont., Canada), M. Patricia Massicotte (Edmonton, Alta., Canada) and Paul Monagle (Melbourne, Vic., Australia) who reviewed this chapter.

References

1 Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, et al: Development of the human coagulation system in the full-term infant. Blood 1987;70:165-172.

2 Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, et al: Development of the human coagulation system in the healthy premature infant. Blood 1988;72:1651-1657.

3 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L: Maturation of the hemostatic system during childhood. Blood 1992;80:1998-2005.

4 Heleen van Ommen C, Midd...