Venous Thromboembolism in PediatricsShalu Narang, M.D.

Pediatric Hematology Newark Beth Israel Medical Center

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

DVT=63%CSVT=18%Isol PE=5%RVT=6%IAS=10%

DVT is the Most Common Blood Clot in Children (n=84)

Goldenberg et al. NEJM 2004;351:1081-8.

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Highest incidence of DVT in neonates and adolescents

Pathophysiology

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.

Coagulation Cascade

Pathophysiology

Hemostasis

Coagulation Fibrinolysis

Pathophysiology

HemostasisCoagulation

↓Thrombosis

Fibrinolysis

Signs, Symptoms and Diagnosis

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 mellitus• Sickle cell anemia• Infection• Surgery

Thrombophilia

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

Revel-Vilk. J Thromb Haemost 1 (2003), 915-921

Prevalence of inherited thrombophilia in children with DVT

Prevalence Test Affected/tested

Study Population

Factor V Leiden 8/171 4.7 % 4 %

Prothrombin G20210A 4/171 2.3 % 2 %

Protein S deficiency 2/171 1.2 % 0.3 %

Protein C deficiency 1/171 0.6 % 0.3 %

Antithrombin deficiency 0/171 0.0 % 0.02 %

Lipoprotein (a) >30mg/dl 8/107 7.5 % 7 %

Revel-Vilk. J Thromb Haemost 1 (2003), 915-921

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

7th ACCP evidence based guidelines

Why Screen?

Nowak-Gottl et al. Blood 2001;97:858-862.

Single Defect: OR 4.6, p<.0001Combined Defect: OR 24.0, p<.0001

Laboratory Studies

• DIC Screen:– CBC, PT, aPTT, 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:– 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

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– 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, CVL– Resolves within 6 weeks

• Standard Risk– FVIII <150U/dL– D-dimer <500ng/mL– < 3 thrombophilic factors– Non-occlusive thrombus

• High Risk– FVIII >150u/dL– D-dimer >500ng/mL– >3 thrombophilic factors– Occlusive thrombus

Manco-Johnson, Blood 2006*Studies in progress

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 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 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 courses may be completed with heparin, longer courses may benefit from transition to Warfarin

• Duration of anticoagulant therapy is individualized based on underlying co-morbidities

• 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 patients may benefit from additional screening

• Asymptomatic patients and family members not at increased risk for thrombosis should not routinely be screened

Thanks!