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THE DIAGNOSIS, TREATMENT, AND PREVENTION OF THROMBOSIS IN PAEDIATRIC AGE GROUPS

- Executive Summary

➡️Introduction

Pediatric thrombosis is a complex area of medicine covering a wide age range neonatal period to young adults. Compared to adult practice, there is a relative lack of high-quality research to inform evidence-based guidelines.

The aim of this adapted clinical practice guideline (CPG) is to provide evidence-based recommendations for the diagnosis and treatment  in the pediatric age group.

➡️Scope

This guideline focuses on the diagnosis and treatment of any venous thrombotic event in pediatric age group. It Provides an evidence-based document for the risk factors , diagnostic tools and manipulation of anticoagulation therapy with  defining the indications, dosing, and administration of these drugs and the indications and use of non-pharmacologic therapy.

➡️Guideline development process and methods

After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guidelines (CPGs):

  1. University of Wisconsin Venous Thromboembolism prophylaxis – Pediatric - Inpatient – Consensus care Guideline. UWHealth 2023
  2. Thrombophilia testing: A British Society for Hematology guideline. BSH 2022
  3. Guideline on the investigation, management, and prevention of venous thrombosis in children. BSH 2011 -addendum BSH 2021
  4. BSH Guideline: management of thrombotic and hemostatic issues in pediatric malignancy. BSH 2018
  5. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. ASH 2018
  6. Antithrombotic Therapy in Neonates and Children. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. ACCP 2012

Recommendations and Good Practice Statements (GPS)

This version of the CPG includes recommendations and good practice statements on the following four sub-sections:

➡️Diagnosis :

- The clinical presentation of VTE in children depends on several factors, including the patient's age, anatomic location of the thrombosis, affected organ system(s), characteristics of the thrombus (occlusive vs. nonocclusive), and chronicity. (GPS)

Laboratory diagnosis:

- full blood count, basal coagulation screen,liver and renal function to confirm safe base line.D dimer not required to exclude DVT.(Strong)

- Routine testing for heriditery thrombophilla not required with first episode. (Strong)

- Antiphospholipds antibodies should be screened in unprovoked venous thromboembolisms. (Strong)

- Neonates with purpura fulminant should screened for protein C and S deficiency . Antithrombin III should be screened for early childhood attaks. (Strong)

➡️Radiological diagnosis:

▪️ CVL and non-CVL related VTE in the upper limb (UL): With the use of US, MRV and multidetector CT venography.(Strong)

▪️ CVL and non-CVL related VTE in the lower limb (LL): Doppler US is recommended : where doppler and MRV are recommended(Conditional)

▪️ For blocked central venous lines:Chest X ray, Doppler US and contrast enhanced MRV are recommended. (Conditional)

▪️  For Diagnosis of cerebral sino-venous thrombosis:MRI including T2* imaging. (Strong)

·We recommend chest Xray, CT angiography if clinical symptoms are suggestive of pulmonary embolism. (Strong)

₋ We recommend testing for myeloproliferative neoplasms (MPN) panel (including JAK2 V617F, JAK2 exon 12, CALR, MPL mutation analysis) in patients with thrombosis at unusual sites and with full blood count abnormalities suggestive of a myeloproliferative neoplasm.           (Strong)

₋ Screening for antiphospholipid antibodies is recommended following unprovoked VTE because this may alter management including choice of antithrombotic therapy.         (Strong)

- We suggest to assess clues from history and physical examination.( GPS)

- Assessment of an individual’s VTE risk, based on the factors:Either patient related or disease related factors. (Conditional)

- Routine thrombophilia screening is not recommended. (Conditional)

-Testing for deficiencies of physiological anticoagulants should be performed only after 3 months of anticoagulation for acute thrombosis. (Conditional)


➡️Treatment

▪️ We recommend using anticoagulation in pediatric patients with symptomatic DVT or PE.(Strong)

▪️  We suggest no anticoagulation in pediatric patients with asymptomatic DVT or PE. (Conditional)

▪️  We suggest to use either low-molecular-weight heparin or vitamin K antagonists in pediatric patients with symptomatic DVT or PE. (Conditional)

▪️  Thrombolytic therapy is not indicated for the majority of children and considered only in the presence of extensive thrombosis and should be followed by anticoagulation in PE with hemodynamic compromise. (Conditional)

▪️   We suggest anticoagulation for < 3 months for  patients with provoked DVT or PE. (Conditional)

▪️ We suggest anticoagulation for 6 to 12 months for patients with unprovoked DVT or PE and recurrent idiopathic VTE and children with antiphospholipid syndrome with life-long anticoagulation. (Conditional)

▪️  We recommend anticoagulation should be initiated with low molecular weight heparin (LWMH) followed by warfarin (INR 2.5) or continuing LMWH. (Strong)

▪️ Unfractionated heparin (UFH) may be used for initial therapy where rapid reversal of anticoagulation may be required. (Conditional)

▪️We recommend using anticoagulation in pediatric patients with CSVT without hemorrhage. (Strong)

▪️  We recommend removal of a functioning CVAD in pediatric patients for  symptomatic CVAD-related thrombosis with worsening signs or symptoms, despite anticoagulation, and who continue to require venous access. (Strong)

For neonates with RVT:

▪️ In unilateral renal vein thrombosis (RVT) we suggest supportive care with radiologic monitoring for extension of thrombosis and  anticoagulation with UFH/LMWH or LMWH in therapeutic doses in a time range of 6 weeks-3 months. (Conditional)

▪️ In bilateral RVT with evidence of renal impairment we suggest anticoagulation with UFH/LMWH or initial thrombolytic therapy with tissue plasminogen activator (tPA) followed by anticoagulation with UFH/LMWH for a time range 6 weeks-3 months. (Conditional)

▪️  For portal vein thrombosis we suggest using anticoagulation in patients with PVT with occlusive thrombus, post liver transplant, and idiopathic PVT. (Conditional)

▪️ Children with VTE unrelated to CVLs should receive anticoagulation for an initial period of 3 months.(Strong)

▪️We suggest continuation of treatment beyond 3 months in patients with active cancer or other ongoing risk factors. (Conditional)

▪️  In children with cancer with incidental VTE we suggest systemic anticoagulation as per protocols for symptomatic disease. (Conditional)

▪️  We suggest LMWH as an anticoagulant of choice for VTE in children with malignancy. Unfractionated  heparin can be used initialy when LMWH or direct oral anticoagulants are contraindicated, or not available for at least 3 months or as long as active cancer or cancer therapy.                ( Conditional)

▪️  Routine measurement of peak anti-Xa activity, with a target range of 0.5–1.0 units/mL, is suggested for children receiving LMWH.( Conditional)

▪️ For children on warfarin, the last dose should be given 4– 5 days prior to an invasive procedure. Bridging anticoagulation with LMWH when the International Normalised Ratio (INR) becomes sub-therapeutic will be required for individuals within 1 month of a VTE.       ( Conditional)

▪️  Symptomatic CVL-related VTE should be treated with anticoagulation for a minimum of 3 months. (Conditional)

▪️ For cancer patients: Doses of asparaginase may be administered following an asparaginase-related VTE covered by prophylactic or therapeutic anticoagulation and continued for 3 weeks following each dose of pegylated asparaginase(Conditional)

➡️Prevention

▪️   Hematology  consultation is required if the patient is considered at high risk for VTE. (Strong)

Non-pharmacological (Physical) methods for thromboprophylaxis

▪️ We suggest maintenance of good hydration, early mobilisation whenever possible to reduce the risk of VTE. (Conditional)

▪️ Physical methods may be useful for high risk patients. (Strong)

Pharmacological thromboprophylaxis (LMWH, VKA) 

▪️  We recommend not to use of aspirin for VTE prophylaxis in children. (Strong)

▪️ Children, particularly adolescents, with multiple risk factors for VTE should be considered for thromboprophylaxis with LMWH. (Strong)

▪️  Enoxaparin is the preferred pharmacologic prophylaxis agent for pediatric patient. (strong)

Recommendations for patients with special risk factors

▪️ We recommend anticoagulation or protein C replacement in pediatric patients with congenital purpura fulminans due to homozygous protein C deficiency. (Strong)

▪️ We recommend against thromboprophylaxis for primary prevention of CVL related thrombosis. (Strong)

▪️  Routine thromboprophylaxis in children with cancer is not recommended, but should be considered in adolescents with multiple risk factors. (Strong)

 

➡️Guideline Registration

PREPARE (Practice guideline REgistration for transPAREncy), WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: (PREPARE-2022CN444). Link: http://www.guidelines-registry.org/