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VTE diagnosis and management: current challenges and issues

VTE diagnosis and management: current challenges and issues. Peyman Eshghi Prof. of Pediatric Hematology &Oncology Mofid Children`s Hospital,SBMU TEHRAN 12-09-2018. Incidence Risk factors Diagnostic imaging Laboratory investigation Anticoagulation treatment&prophylaxis.

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VTE diagnosis and management: current challenges and issues

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  1. VTE diagnosis and management:current challenges and issues Peyman Eshghi Prof. of Pediatric Hematology &Oncology Mofid Children`s Hospital,SBMU TEHRAN 12-09-2018

  2. Incidence • Risk factors • Diagnostic imaging • Laboratory investigation • Anticoagulation treatment&prophylaxis

  3. Incidence of VTE in children children Adults 5.6–16 per 10,000 adults per year • The incidence of hospital-acquired venous thromboembolism (VTE) in children is increasing • 58 cases per10,000 hospital admissions • Between 0.07 and 0.14 case per10,000 children • A bimodal distribution is evident.: • Early infancy accounting for up to 20% of pediatric VTE. • Adolescence (11–18 years old. )with about 50% of VTE events • TE in children is associated with a direct mortality rate of 1.5–2.2% Andrew M,et al. Blood 1994;83:1251–1257 van Ommen CH, et al. SeminThrombHemost 2003;29:391–404 Stein PD, Kayali F, Olson RE J Pediatr. 2004 Oct; 145(4):563-5.

  4. D-Dimer & VTE in children D-Dimer is not recommended to be used to excludeVTE in young children Brandao LR, et al. SeminThrombHemost 2011;37:772–785. Chalmers E, et al.: Guideline on the investigation, management and prevention of venous thrombosis in children. Br J Haematol2011;154:196– 207 • An elevated D-dimer plasma level at diagnosisand after 3–6 months of treatment has been • shown to be associated with: • persistent VTE, • recurrentVTE and/or • development of PTS Goldenberg NA: Hematology Am SocHematolEduc Program 2008;2008:236–244. PEYMAN ESHGHI IRSTH

  5. suggested diagnostic imaging tests in children`s VTE PEYMAN ESHGHI IRSTH Blanchette VS, Breakey VR, Revel-Vilk S (eds): SickKids Handbook of Pediatric Thrombosis and Hemostasis. Basel, Karger, 2013

  6. For clinically suspected lower limb DVT with a normal Doppler ultrasound: • consider performing venography as gold standard (if high index of suspicion) Or • repeating the Doppler ultrasound after a week to assess for proximal progression of a calf vein thrombus. • CTV or MRV should be considered in children with suspected proximal extension of femoral DVT Blanchette VS, Breakey VR, Revel-Vilk S (eds): SickKids Handbook of Pediatric Thrombosis and Hemostasis. Basel, Karger, 2013 PEYMAN ESHGHI IRSTH

  7. Disadvantages of imaging methods in children • DU: • small-diameter vessels, low pulse pressure and the presence of a CVC • Venography (gold standard in the diagnosis of VTE in children ) : • the need for good venous access, interventional radiologist and anesthesia support, exposure to contrast and ionizing radiation • Spiral CT: • anesthesia support ,exposure to contrast and ionizing radiation • MRV: • anesthesia support ,long time required to achieve adequate imaging PEYMAN ESHGHI IRSTH

  8. http://pchd.sbmu.ac.ir/uploads/Tehran_Thrombophilia_testing_Rosendaal.pdfhttp://pchd.sbmu.ac.ir/uploads/Tehran_Thrombophilia_testing_Rosendaal.pdf

  9. Why Test the Child with an Acute ThrombosisRaffini L. Thrombophilia in children: who to test, how, when, and why? ASH Education Program Book. 2008;2008(1):228-35 • Acute management: Almost never influence the acute management of a patient with venous thrombosis except in: • Purpura fulminant: replacement therapy with plasma-derived concentrate (protein C or antithrombin) in case of sever PC,PS,AT def. • APLA syndrome: especially in catastrophic APS which needs PEX,CPM,Rituximab. • SCA:simple or exchange transfusion or erythraphresis • Hyper-homocystinemia : adding folate,B12,B6 may be helpful in clinical course and preventive (Nathan &Oski 8th edit p.1070) • Duration of therapy : recurrence rate vs bleeding risk • Protein S deficiency, antithrombindeficiency, prothrombin gene mutation and combined defects associate with recurrent VTE • APLA with symptomatic thrombosis • Pathogenesis:particularlyin the case of unprovoked events • Thromboprophylaxis in high-risk situations (?): history of VTE alone is enough to warrant early thromboprophylaxis • Identification of other family members to receive Primary prophylaxis in the presence of transient risk factors: At present, there are no studies that demonstrate the benefit of such familial testing and counseling.

  10. Algorithm for Selecting Patients with a First Venous Thromboembolism (VTE) for Thrombophilia Testing. n engl j med 377;12 nejm.org September 21, 2017 PEYMAN ESHGHI IRSTH

  11. PEYMAN ESHGHI IRSTH

  12. Laboratory thrombophilia testing in the pediatric populationwith history of VTEs and ATEs Blanchette VS, Breakey VR, Revel-Vilk S (eds): SickKids Handbook of Pediatric Thrombosis and Hemostasis. Basel, Karger, 2013

  13. Laboratory thrombophilia testing in the pediatric populationwithout personal history of VTEs and ATEs Tests: protein C activity, protein S free antigen level, antithrombin activity, activated protein Cresistance, FVIII activity, Prothrombin gene mutation and FV Leiden gene mutation analysis, lupus anticoagulant test, anticardiolipinIgM and IgG antibodies,β2-GPI IgM and IgG antibodies, fasting homocysteine level and Lp(a) plasma level.

  14. WHY SHOULD WE HAVE A PREDICTIVE SCORING SYSTEM? • TO DECIDE: • ACUTE TREATMENT OR NOT : • mainly a clinical suspicion and decision IN CHILDREN • THROMBOPROPHYLAXIS OR NOT • DURATION OF PROPHYLAXIS • METHOD OF THROMBOPROPHYLAXIS

  15. ACUTE TREATMENT OR NOT IN CHILDREN SUSPECTED TO HAVE A VTE : • A CLINICAL DECISION

  16. ACUTE TREATMENT OR NOT IN CHILDREN

  17. EARLY RECOGNITION OF PEDIATRIC VENOUSTHROMBOEMBOLISM:A RISK-ASSESSMENT TOOL • Descriptive statistics show that the assessment tool displays strong reliability and validity. • Findings suggest that use of the assessment tool could significantly reduce adverse outcomes associated with venous thromboembolism in children Andrea S. Prentiss American Journal of Critical Care. 2012;21(3):178-184) PEYMAN ESHGHI IRSTH

  18. Risk factors Age Other special issues of children`s risk factors: Central venous/arterial catheter 85% of HA-VTEs occurring in patients with CVCs, more likely to require CVCs for vascular access The CVC-related VTE rate was 5.7% across all of the children, but 85% of the events occurred in children with peripherally inserted central catheter lines Congenital heart disease,Shunts(e.g. BT), surgical procedures (e.g. Fontan procedure) Anatomical thrombophilia:Paget-Schroettersyndrome,May-Thurner syndrome Congenital thrombophilia Newborn > infant/child < adolescent • Newborn-related risk factors: • Maternal conditions: diabetes mellitus, arterial hypertension, antiphospholipid syndrome • Perinatal/neonatal risk factors: prematurity, asphyxia (including meconium aspiration), sepsis, congenital heart disease, congenital diaphragmatic hernia, polycythemia • Adolesent: • Spontaneous (unprovoked) TEs occur more commonly in this age group • infant/child: • Spontaneous TE in this age group is unusual and should raise the possibility of an undiagnosed disorder PEYMAN ESHGHI IRSTH

  19. FAMILY /PERSONAL HISTORY OF THROMBOSIS? NEONATES? PEYMAN ESHGHI IRSTH F. Newallet al. Journal of Thrombosis and Haemostasis,2018 16: 196–208

  20. Thromboprophylaxis in children(according to ISTH Pediatric SSC) Mechanical prophylaxis Pharmacological prophylaxis in the absence of strong contraindications (active or potential bleeding, severe thrombocytopenia, hemodynamic instability, or imminent/urgent surgical procedure): Children in an ICU with a CVC and one other risk factor who fit a high-risk profile Children with either a CVC or admission to an ICU (but not both),who have two risk factors Children with neither a CVC nor ICU admission, who have at least three risk factors • Lower limb VTE: Sequential compression devices are preferred over compression stockings with the exception of a known thrombosis • Has not been well established for upper and central venous system VTE, particularly if CVC-associated. PEYMAN ESHGHI IRSTH

  21. PEYMAN ESHGHI IRSTH

  22. Pharmacological Management of DVT in children • In children with first DVT: • initial anticoagulation with UFH or LMWH is recommended for at least 5 days . For ongoing therapy, LMWH or VKA is recommended • beginning oral therapy as early as day 1 and discontinuing UFH/LMWH on day 6 or later than day 6 if the INR has not exceeded 2.0 compared with no therapy • Children with idiopathic DVT : • First VTE:should receive anticoagulant therapy for 6–12 months • Recurrent idiopathic DVT: indefinite therapeutic or prophylactic anticoagulation is recommended • Children with secondary DVT: • should continue in either therapeutic or prophylactic doses until the risk factor has resolved • Risk factor has resolved(eg, use of asparaginaseinALL,or removing CVAD) (Grade 2C): should be treated with therapeutic anticoagulation for 3 months PEYMAN ESHGHI IRSTH

  23. Heparin therapy in children & neonate • UFH: • Titration to achieve: • target anti-Xa range of 0.35 to 0.7 units/mL (for the first 24 Hr and for infants <12 months is advocated)or • an activated partial thromboplastin time range that correlates to this anti-Xarange ( aPTR of 1.5-2 times)or • protamine titration range of 0.2 to 0.4 units/mL (Grade 2C). • A loading dose should be avoided or reduced in: • neonates, children with stroke or if the risk of bleeding is high • Monitoring: • 6 h after commencing a heparin infusion • 4 h after any change in infusion rate, • every 24 h once therapeutic levels are achieved • Avoid dead space during sampling from catheter • Either daily or bid therapeutic low-molecular-weight heparin: • to a target range of 0.5 to 1.0 units/mL in a sample taken 4 to 6 h after subcutaneous injection or, • 0.5 to 0.8 units/mL in a sample taken 2 to 6 h after subcutaneous injection(Grade 2C). PEYMAN ESHGHI IRSTH

  24. UFH

  25. UFH special notes for children • Infants required a greater number of APTT tests a;more dose escalation ;and longer time to achieve target APTT as compared with older children Al Obary,et al. Asian CardiovascThoracAnn 2012; 20: 153–9. Schechter T. J ThrombHaemost 2012; 10: 368–74. • May need AT concentrate or FFP to achieve the target APTT Ryerson et al.PediatrCrit Care Med 2014; 15: e340–6. • Poor correlation between UFH dose and measures of UFH effect (APTT, anti-FXa, anti-FIIa, and TCT):the use of weight-based UFH dosing achieves outcomes that may be safe and efficacious despite the lack of certainty regarding optimal laboratory management strategies. Newallet al. Journal of Thrombosis and Haemostasis,2018 16: 196–208 PEYMAN ESHGHI IRSTH

  26. LMWH

  27. LMWH special notes for children • multiple studies that have failed to confirm any association between achievement of a laboratory-confirmed target range and either thrombosis resolution or bleeding rates Newallet al. Journal of Thrombosis and Haemostasis,2018 16: 196–208 • Weight based, unmonitored LMWH therapy may achieve outcomes comparable to those of laboratory-monitoring therapy • Greene L, et al. J ThrombHaemost 2014; 12:1554–7 PEYMAN ESHGHI IRSTH

  28. WARFARIN

  29. DOACS • we are not yet ready to use the DOACs inchildren in clinical routine. • It is expected pediatric market authorizations for some of the DOACs by the early 2020s.

  30. VTE&CVAD IN CHILDREN • In children with a CVAD in place who have a VTE: • CVAD is no longer required or is nonfunctioning : • we recommend it be removed(Grade 1B) after at least 3 to 5 days of anticoagulation therapy (Grade 2C) . • CVAD access is required and the CVAD is still functioning: • CVAD remain in situ and the patient be given anticoagulants(Grade 2C) • First CVAD-related VTE:initial management as for secondary VTE • Recurrent CVAD-related VTE: continuing therapeutic doses until the CVAD is removed and for a minimum of 3 months following the VTE (Grade 2C) .

  31. THROMBOLYSIS IN CHILDREN WITH VTE • only for life- or limb-threatening thrombosis (Grade 2C) . • If thrombolysis is used in the presence of physiologically low levels or pathologic deficiencies of plasminogen, we suggest supplementation with plasminogen(Grade 2C)or FFP. • Systemic thrombolysis vscatheter-directed thrombolysis:dependingon institutional experience and, in the latter case, technical feasibility • In children with life-threatening VTE, we suggest thrombectomy(Grade 2C)

  32. IVC FILTER & VTE IN CHILDREN • In children >10 kg & lower-extremity VTE & a contraindication to anticoagulation, we suggest placement of a retrievable IVC filter (Grade 2C) . • Appropriate anticoagulation should be added for VTE as soon as the contraindication to anticoagulation is resolved (Grade 1C) .

  33. Special clinical situation &VTE in children • For children with VTE in the setting of antiphospholipid antibodies (APLAs), we suggest management as per general recommendations for VTE management in children • For children with VTE, independent of the presence or absence of inherited thrombophilic risk factors, we suggest that the duration and intensity of anticoagulant therapy • VTE secondary to structural venous abnormalities: • First VTE: as spontaneous VTE • Recurrent VTE: indefinite anticoagulation unless successful percutaneous or surgical interventions can be performed (Grade 2C) .

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