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Venous Thromboembolism in Pediatrics Shalu Narang, M. D. Pediatric Hematology Newark Beth Israel Medical Venous Thromboembolism in Pediatrics Shalu Narang, M. D. Pediatric Hematology Newark Beth Israel Medical Center

Objectives • Epidemiology and pathophysiology of pediatric thrombotic disorders • Signs, symptoms and diagnosis Objectives • Epidemiology and pathophysiology of pediatric thrombotic disorders • Signs, symptoms and diagnosis of deep venous thrombosis (DVT) • Acquired vs. inherited thrombophilia • Diagnostic screening tests for thrombotic disorders • Role of anticoagulation in children with thrombotic disorders • Long-term sequelae of thrombosis

Epidemiology Epidemiology

DVT is the Most Common Blood Clot in Children (n=84) Goldenberg et al. NEJM DVT is the Most Common Blood Clot in Children (n=84) Goldenberg et al. NEJM 2004; 351: 1081 -8.

Highest incidence of DVT in neonates and adolescents Highest incidence of DVT in neonates and adolescents

Pathophysiology Pathophysiology

Pathophysiology • Virchow’s Triad • Endothelial Injury – Indwelling catheters • Abnormal Blood Flow Pathophysiology • Virchow’s Triad • Endothelial Injury – Indwelling catheters • Abnormal Blood Flow – – – Immobilization Dehydration Inflammation Nephrosis Cancer therapy Hyperviscosity • Hypercoagulability

Conceptual Model of Hemostasis Reprinted with permission from Sidney Harris. Conceptual Model of Hemostasis Reprinted with permission from Sidney Harris.

Coagulation Cascade Coagulation Cascade

Pathophysiology Fibrinolysis Coagulation Hemostasis Pathophysiology Fibrinolysis Coagulation Hemostasis

Pathophysiology Coagulation ↓ Thrombosis Hemostasis Fibrinolysis Pathophysiology Coagulation ↓ Thrombosis Hemostasis Fibrinolysis

Signs, Symptoms and Diagnosis Signs, Symptoms and Diagnosis

Signs & Symptoms • DVT: – Poorly Functioning Catheters – Edematous extremity – Plethoric Signs & Symptoms • DVT: – Poorly Functioning Catheters – Edematous extremity – Plethoric extremity – Warm extremity – Painful extremity • PE: – Cough, SOB, Hemoptysis – Tachycardia

Risk Factors • • • Indwelling catheters Thrombophilia Malignancy Chemotherapy Prosthetic cardiac valves Diabetes Risk Factors • • • Indwelling catheters Thrombophilia Malignancy Chemotherapy Prosthetic cardiac valves Diabetes mellitus Sickle cell anemia Infection Surgery

Thrombophilia Thrombophilia

Thrombophilia • Inherited: – – – Protein C deficiency Protein S deficiency Antithrombin deficiency Thrombophilia • Inherited: – – – Protein C deficiency Protein S deficiency Antithrombin deficiency Factor V leiden Prothrombin gene mutation Elevated Lipoprotein a, homocysteine • Acuired: – Antiphospholipid Syndrome – Nephrotic syndrome

Prevalence of inherited thrombophilia in children with DVT Revel-Vilk. J Thromb Haemost 1 (2003), Prevalence of inherited thrombophilia in children with DVT Revel-Vilk. J Thromb Haemost 1 (2003), 915 -921

Length of therapy remains the same regardless of thrombophilia First episode of DVT Length Length of therapy remains the same regardless of thrombophilia First episode of DVT Length of anticoagulation Transient risk factor 3 months Idiopathic TE 6 -12 months Thrombophilia 6 -12 months 7 th ACCP evidence based guidelines

Why Screen? Single Defect: OR 4. 6, p<. 0001 Combined Defect: OR 24. 0, Why Screen? Single Defect: OR 4. 6, p<. 0001 Combined Defect: OR 24. 0, p<. 0001 Nowak-Gottl et al. Blood 2001; 97: 858 -862.

Laboratory Studies • DIC Screen: – CBC, PT, a. PTT, Thrombin Time, Fibrinogen, D-dimer Laboratory Studies • DIC Screen: – CBC, PT, a. PTT, Thrombin Time, Fibrinogen, D-dimer • • Protein C Activity Protein S Activity Antithrombin III Activity Lupus Anticoagulant Anticardiolipin antibody Prothrombin gene mutation Factor V leiden

Healthy Children w/ Family History of DVT or Thrombophilia • Screening is rarely indicated: Healthy Children w/ Family History of DVT or Thrombophilia • Screening is rarely indicated: – Risk assessment limited by heterogeneity of genotype and phenotype – No guidelines for management – Potential risk of anticoagulation outweighs benefit – May inhibit ability to obtain life/disability insurance – Ethical concerns: autonomy, assent, consent – Appropriate age for screening unknown – Unnecessary anxiety Courtesy: Bryce A. Kerlin, M. D.

Anticoagulation Therapy Anticoagulation Therapy

Therapeutic Goals • Prevent thrombus propagation and/or embolization • Restore blood flow (rapidly, when Therapeutic Goals • Prevent thrombus propagation and/or embolization • Restore blood flow (rapidly, when necessary) • Minimize long-term sequelae

Anticoagulants • Heparin – Un-fractionated vs. low molecular weight – IV or SQ – Anticoagulants • Heparin – Un-fractionated vs. low molecular weight – IV or SQ – Monitoring with PTT or anti-Factor Xa – Reversible with protamine • Warfarin – – Vitamin K antagonist Only oral anticoagulant Monitor with PT Reversible with vitamin K – Very long T½

Risk Stratification* (for persistence or recurrence) • Low Risk – Thrombus post surgery, trauma, Risk Stratification* (for persistence or recurrence) • Low Risk – Thrombus post surgery, trauma, CVL – Resolves within 6 weeks • Standard Risk – – FVIII <150 U/d. L D-dimer <500 ng/m. L < 3 thrombophilic factors Non-occlusive thrombus • High Risk – – FVIII >150 u/d. L D-dimer >500 ng/m. L >3 thrombophilic factors Occlusive thrombus Manco-Johnson, Blood 2006 *Studies in progress

Anticoagulant Duration • Ongoing Studies: no guidelines! – Low/Standard Risk: • 6 wks (Thrombus Anticoagulant Duration • Ongoing Studies: no guidelines! – Low/Standard Risk: • 6 wks (Thrombus Resolution and no thrombophilia) • 3 months (Residual Thrombus or thrombophilia) – High Risk: • Early thrombolysis AND • 6 months vs. 12 months Multi-institutional studies in progress.

Long-term Sequelae • Post-thrombotic Syndrome (PTS) – Pain, swelling, visible collateral vain formation, skin Long-term Sequelae • Post-thrombotic Syndrome (PTS) – Pain, swelling, visible collateral vain formation, skin abnormalities – 10 -60% children • Recurrent TE – Life-Threatening Embolic Disease – 7 -8% children

Summary • Pediatric thrombosis is most common in infants and adolescents • DVT is Summary • Pediatric thrombosis is most common in infants and adolescents • DVT is most common form of VTE • The upper extremity circulation is most commonly affected • Diagnosis should be confirmed with: – D-dimer – Venous Doppler Ultrasonography – CT Angiogram

Summary • Initial treatment should be standard or low molecular weight heparinization • Short Summary • Initial treatment should be standard or low molecular weight heparinization • Short courses may be completed with heparin, longer courses may benefit from transition to Warfarin • Duration of anticoagulant therapy is individualized based on underlying comorbidities • Patients should be followed closely for recurrent disease and/or post-phlebitic syndrome

Summary • All thrombosis patients should be screened for treatable molecular thrombophilias • Some Summary • All thrombosis patients should be screened for treatable molecular thrombophilias • Some patients may benefit from additional screening • Asymptomatic patients and family members not at increased risk for thrombosis should not routinely be screened

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