Hemostasis and Thrombosis in Pediatric Patients: Special Issues and Unique Concerns

 

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The coagulation system, evolving already in utero, is complex and keeps altering during infancy and childhood, a fact encapsulated in the term developmental hemostasis. Studies confirm the quantitative and qualitative differences between coagulation factors and inhibitors with age. Nevertheless, the magnitude of these changes as well as their implications on either thromboembolic or hemorrhagic events in various age groups, remain to be elucidated. In this special pediatric issue the editors have tried to sum up the current knowledge regarding topics associated with epidemiology, pathophysiology, and management of bleeding disorders as well as thrombosis in children.

Ignjatovic and colleagues review and discuss the most recent evidence with respect to age-related hemostatic changes and suggest possible strategies to further understand this complex and exciting field.

Indeed, the hemostatic system in the term infant has little reserve capacity and preterm infants are considerably predisposed to hemorrhagic complications. Intraventricular hemorrhage (IVH) occurs predominantly in very low birth weight premature infants and may lead to significant morbidity and mortality. Kuperman and coauthors present the epidemiology and pathogenesis of IVH and review studies targeted at coagulopathy and therapy.

Congenital bleeding disorders pose unique diagnostic and therapeutic challenges during infancy and childhood, thus, Kulkarni and Soucie share recent data and perspectives on hemophilia in children. Hemophilia is the most common X-linked inherited bleeding disorder, which if not properly managed can lead to chronic disease and lifelong disabilities. Awareness of clinical manifestations and complications of treatment such as inhibitors are crucial in instituting appropriate management and implementing preventive strategies.

As among commonest acquired pediatric bleeding disorders, immune thrombocytopenic purpura (ITP) prevails, Breakey and Blanchette supply a comprehensive overview of the approach for diagnosis and management of ITP in children, discussing new proposed definitions of ITP, summarizing recommendations from major ITP guidelines and commenting about newer therapeutic options of its treatment in children. Last but not the least, in the article concluding the hemostasis topics of our special issue, the clinical and laboratory assessment of the bleeding pediatric patient is discussed by Revel-Vilk. Combining bleeding history with the results of some screening tests is suggested to enable identification of children at higher risk of bleeding during relevant situations.

Thrombosis in children is increasingly being diagnosed, and the remaining articles of our special issue deal with this subject. As prospective, controlled trials for management of children with thrombosis are lacking, treatment guidelines are mainly extrapolated from adult data. Macartney and Chan focus on DVT diagnosis, management, and complications in pediatric populations. Brandão et al add a comprehensive review of epidemiology, diagnosis, therapy, and outcomes of pulmonary embolism in children, depicting most of the knowledge gaps in this field. Lyle and coauthors address childhood arterial ischemic stroke (AIS), a rare but serious, medical condition. In a narrative review, the current understanding of etiologies, consensus-based treatment recommendations, and prognostic factors in childhood AIS are presented and discussed.

As inherited thrombophilia undoubtedly contributes to the development of thromboembolic disease, pediatric hematologists are increasingly recommended to test patients with thrombosis or from thrombophilic families. Van Ommen and Middeldorp review the pros and cons of thrombophilia testing in pediatric populations. Kenet et al present a meta-analysis regarding the role of antiphospholipid antibodies in DVT and stroke epidemiology in children. The position of lipoprotein a in the pathogenesis of childhood thromboembolism and its age dependency is summarized by Langer and coworkers.

Four articles compact aspects related to therapy of childhood thrombosis. Within the past two decades low molecular weight heparins (LMWH) have gained increasingly widespread use as anticoagulants in children. The use of LMWH has been implemented into clinical care even though there is a lack of firm evidence on its efficacy and safety in pediatric populations due to the absence of sufficiently powered randomized controlled trials. Bidlingmaier and colleagues perform a meta-analysis of available single-arm studies using LMWH in children.

A special subgroup of pediatric patients, requiring prolonged anticoagulant therapy is composed of children undergoing cardiac surgery. Advances in medical and surgical care have resulted in improved survival of patients with congenital heart disease (CHD), yet one important complication in CHD is the development of thrombosis. There is insufficient evidence and no consensus for optimal anticoagulant prophylaxis or treatment in children with CHD. This specific topic is discussed in the article by Thom et al. Quality of life research is increasingly recognized as an add-on instrument to evaluate therapy in patients with bleeding or thrombotic disorders. Bruce et al present current concepts regarding quality of life measurements to be applied in children receiving anticoagulant care.

Finally, establishment of standardized definitions of outcomes of pediatric anticoagulation clinical trials is critically important as these outcomes reflect the safety and efficacy of the trial intervention. The topic of outcomes in pediatric anticoagulation clinical trials is the subject of Mitchell and Male's article, including a summary of the literature on clinical trial outcomes, discussing various outcomes in pediatric anticoagulation trials and the relationship of outcomes to clinical trial design.

Future research perspectives regarding genome-wide associations (GWA) and pediatric thrombosis conclude this special issue with the article of Preuss and Stoll. As a result of technological advances in the field of high-throughput genomics, there has been a remarkable transition in studying the nature of complex genetic disorders. The genetic analysis of prothrombotic risk factors has shifted from candidate gene to genome-wide association studies (GWAS). The study reviews the current knowledge regarding genetic factors affecting prothrombotic risk in children and adults. Advantages and pitfalls of the GWA approach are discussed.

In summary, this special issue encompasses knowledge and gaps regarding pediatric hemostasis. Intelligently designed and well-powered studies incorporating stringent assessments and validated definitions will contribute to decipher the etiology and lead to proper therapy of bleeding as well as thrombosis in children.

Gili KenetM.D. 

Professor - Hematology, Thrombosis Unit, National Hemophilia Center

Sheba Medical Center, Tel Hashomer 52621, Israel

Email: Gili.kenet@sheba.health.gov.il