THE DIAGNOSIS, TREATMENT, AND PREVENTION OF THROMBOSIS IN PAEDIATRIC AGE GROUPS
- Introduction
Thrombosis is increasingly recognized in the pediatric age group, especially venous thromboembolism (VTE). The annual incidence of childhood thrombosis was estimated to be 0.07-0.14/ 10,000 children in the 1990s10. However, recent studies showed increasing incidences of childhood thrombotic events due to improved diagnosis, increased survival of children with severe underlying diseases, and increased use of interventions such as central venous lines (CVL). Moreover, the diagnosis of VTE in hospitalized children increased from 34 to 58 cases /10,000 in the United States from year 2001 to 2007. Moreover, the true incidence could have been significantly higher as the majority of VTEs are clinically silent. The increased incidence of thrombosis was observed in all pediatric age categories, nevertheless, neonates, infants (< 2 years old), and adolescents have the greatest risk for VTE11. Egyptian children who have more than one heterozygous mutation even if weakly thrombophilic are prone to develop significant thrombotic events either spontaneously or when exposed to minor risk factors12.
Thrombosis is a serious disease, which leads to mortality and morbidity. The mortality rate is about 2%. Morbidity includes lack of thrombus resolution in 50% of the patients, the development of post-thrombotic syndrome (PTS)11, and recurrent thrombosis in 8.1% with an average follow-up period of 2.86 years 13.
Most of the venous thrombi in children are associated with clinical risk factors such as inheritance of prothrombotic defects, CVL insertion, cardiac disease, surgery, obesity, inflammatory conditions, immobility, medications such as asparaginase and estrogen-containing contraceptives, and cancer patients14. Also, there are some diseases with an increased tendency to thrombosis called acquired thrombophilia diseases as; antiphospholipid syndrome (APS), paroxysmal nocturnal hemoglobinuria (PNH), myeloproliferative neoplasms (MPN) and the presence of a Janase Kinase 2 (JAK2) mutation in the absence of an MPN phenotype2.
The inheritance of prothrombotic defects called inherited thrombophilia diseases which refers to genetic disorders of specific hemostatic proteins that include: the factor V Leiden (FVL) variant (F5 G1691A), the prothrombin gene variant (F2 G20210A), protein C (PC) deficiency, protein S (PS) deficiency, and antithrombin (AT) deficiency. Certainly, the inheritance of any of these prothrombotic genetic defects may lead to spontaneous VTE (unprovoked VTE), VTE with severity out of proportion to the stimulus (provoked VTE), recurrent thrombosis, or VTE at a young age. However, it is still a matter of debate whether it is useful to test for genetic thrombophilia defects in children with a first venous thrombotic event15.
Cancer-associated thrombosis is the second leading cause of death in patients with cancer and its prevalence is increasing. These patients are at high risk of recurrent VTE, io one side, and on the other side, they are at high risk for anticoagulant-related bleeding which is associated with high morbidity and resource use16.
The diagnosis and treatment of pediatric thrombosis are still debatable because children with thrombosis are a heterogeneous group, and it is unlikely that a single approach to testing and/or treatment is optimal or desirable.
The mainstay of treatment of acute pediatric thrombosis is anticoagulation with heparins and/or vitamin K antagonists. The immediate goals of anticoagulation are to prevent the propagation of acute thrombosis, prevent embolization, and prevent secondary VTE. Duration of therapy is therefore predicated on the time-dependent risk of recurrent VTE. Unfortunately, there is limited data by which to accurately define the frequency of VTE recurrence and anticoagulation-associated adverse events in pediatric VTE7. Bleeding is the primary complication of anticoagulant therapy, and is a risk of all anticoagulants, even when maintained within usual therapeutic ranges. Ironically, whereas unfractionated heparin and coumarin, the oldest and most widely used anticoagulants, have specific antidotes for their anticoagulant effect, many of the newer agents currently undergoing clinical evaluation do not have specific antidotes; thus, the best ways to reverse their actions remain to be determined17.
Thus, given that the field of pediatric thrombosis continues to evolve with the scarcity of evidence in the pediatric age group. Therefore, pediatricians dealing with this evolving and serious health problem are in great needof a guideline that may help them for best clinical decisions. Thus, this guideline will answer some of the health questions related to the prevention, diagnosis, and treatment of pediatric thrombosis.
The aim of this adapted clinical practice guideline (CPG) is to provide evidence-based recommendations for the Diagnosis, Treatment, and Prevention of Thrombosis in the Pediatric Age Groups.
These recommendations were adapted from the relevant six CPGs using a formal methodology for CPG adaptation: the Adapted-ADAPTE.