• Deep venous thrombosis (DVT): involves large systemic veins outside the CNS.
• Dural sinus thrombosis: involves the intracranial venous sinuses often with extension into the cerebral veins.
• Superficial thrombophlebitis.
• Ischemic stroke: arterial occlusion or insufficiency with infarction of brain tissue.
• Hemorrhagic stroke: follows an ischemic event with reperfusion.
• Intracardiac thrombosis: mural, valvular, or hardware associated.
• Neonatal aortic thrombosis: can be spontaneous or catheter associated.
• Renal vein thrombosis: in the neonatal period or in children with nephrotic syndrome.
• Myocardial infarction: Kawasaki disease or with severe familial hypercholesterolemia.
• Budd-Chiari syndrome: thrombosis of the hepatic vein.
• Portal vein thrombosis.

• The incidence of venous thrombosis in children is approximately 0.7 per 100,000 per year. It is likely that the actual incidence is higher.
• Two-thirds of children with thromboembolic disease have a predisposing underlying condition, the most common being an indwelling catheter.

• Complications vary depending on the location and severity of the thrombosis.
• For deep venous thrombosis, pulmonary embolism is the most significant acute complication with recurrent thrombosis and post-phlebitic syndrome common chronic complications.
• For arterial thromboembolic disease the ischemic injury to the involved organ determines the acute and long-term complications.

• Factor V Leiden
• Protein C deficiency
• Protein S deficiency
• Anti-thrombin III deficiency
• Plasminogen deficiency
• Dysfibrinogenemia (30% will have thrombotic symptoms)
• Heparin cofactor II deficiency
• Tissue plasminogen activator deficiency
• Plasminogen activator inhibitor type 1 excess
• Homocysteinemia (mild to moderate) from minor defects in enzymes such as methylenetetrahydrofolate reductase (MTHFR)
• Factor XII deficiency
• Activated protein C resistance other than factor V Leiden (Factor V Cambridge, Factor V Hong Kong)

• Antiphospholipid antibody syndrome
• Post-infectious protein C or S deficiency
• Severe neonatal acquired protein C or S deficiency
• Lipoprotein(a) excess

• Birth trauma
• Prematurity
• Maternal diabetes
• Severe RDS
• Hypernatremic dehydration
• Umbilical catheters
• Sepsis
• Polycythemia
• Perinatal asphyxia

• Leukemia (hyperleukocyrosis, APML)
• Myeloproliferative disorders
• Paroxysmal nocturnal hemoglobinuria

• L-Asparaginase
• Oral contraceptives

• Indwelling catheters
• Cardiac catheterization
• Congenital heart disease
• Prosthetic heart valves
• Intracardiac baffles
• Tumor compression

• Nephrotic syndrome
• Inflammatory disorders
• Liver disease
• Heart failure/increased venous pressure
• Sickle cell disease
• Behçets disease
• Homocystinuria
• Diabetes mellitus

• Infection
• Trauma
• Orthopedic surgery (Hip)
• Strenuous exercise
• Prolonged immobilization or paralysis
• Prolonged sitting

• Kawasaki disease
• Takayasu arteritis
• Other vasculitides
• Hyperlipidemia
• Blalock-Taussig shunts
• Organ transplantation

• Thromboembolic disease is commonly overlooked.
• A familial and/or personal history of thrombosis is an important risk factor for thrombosis.
• Neonatal seizure is a common and often sole presenting sign for dural sinus thrombosis.
• Presenting signs and symptoms of pulmonary embolism can be subtle and include dyspnea and chest pain.

• Pain, decreased pulses and perfusion, color change.
• Superficial dilated cutaneous veins distal to the site of venous occlusion.
• Unilateral swelling/edema of a limb (may be bilateral if the IVC or SVC is extensively involved.
• Chronic discoloration (darkening) of the skin, ulcerations, pain, intermittent swelling.
• Unexplained hepatosplenomegaly may be the only sign of hepatic or portal vein thrombosis.
• Abdominal pain and ileus may be present with involvement of mesenteric, portal or hepatic vessels.

• Rapid evaluation of the hemostatic system prior to initiating therapy (CBC, PT/aPTT, fibrinogen).
• Therapy for thromboembolic disease should not be delayed.
• Whenever possible an antithrombin III level, a thrombin time and a screen for the lupus anticoagulant should be drawn before starting heparin. Protein C and S levels should be drawn before starting warfarin and plasminogen levels prior to any thrombolytic therapy.

• Serial imaging to assess response to treatment.
• Search for an etiology of the thrombosis and evaluate risk factors.
• Test for factor V Leiden and anticardiolipin antibodies if not done with initial blood work.

• Additional testing if a primary prothrombotic condition is strongly suspected.

• PT/PTT/fibrinogen
• CBC with platelet count
• FSP/d-dimer
• Thrombin time

• Factor V Leiden mutation analysis by PCR
• Lupus anticoagulant screen
• Dilute Russell Viper Venom time
• Tissue thromboplastin inhibition test
• Anticardiolipin antibodies (IgG, IgM, IgA) by ELISA
• Protein C activity
• Protein S activity and/or free protein S antigen
• Antithrombin III activity
• Lipid profile for arterial disease

• Prothrombin 20210A allele by PCR
• Plasminogen
• Thrombin time or dysfibrinogenemia screen
• Protein S free antigen should be done if the activity was low
• Plasma homocysteine levels

• MTHFR-T by PCR
• Factor VIII activity
• Lipoprotein a
• Heparin Cofactor II
• Tissue plasminogen activator (post venoocclusion)
• Plasminogen activator inhibitor type 1
• Factor XII
• Activated protein C resistance clotting assay

• Ultrasound—least invasive but sensitivity for DVT in upper extremities variable.
• Magnetic resonance imaging with contrast (MRA/MRV)—expensive, time-consuming, and not adequately studied in children against the gold standard.
• Contrast angiography—is the gold standard but invasive and sometimes technically difficult to perform in small children.

• Normal ranges for coagulation tests are age dependent.
• Diagnosing an inherited deficiency in any of the anticoagulants can be difficult in the neonatal period. Repeat testing at 2 and 6 months of age.
• Consumption can occur during the acute thrombosii, therefore, low levels must be repeated.
• Warfarin will decrease the levels of protein C and protein S.

• Therapy for acute thrombosis and long-term management is individualized.
• Consult a pediatric hematologist or someone with expertise in pediatric anticoagulant therapy.

• Standard Heparin (SH): Standard therapy for acute thrombosis. Given as a bolus followed by an infusion, adjusted to maintain the aPTT at 60 to 85 seconds. The younger the child the more heparin per weight is required to achieve a therapeutic level.
• Low Molecular Weight Heparin (LMWH): More predictable dose response, which is given subcutaneously twice a day. Equivalent in efficacy to SH in the acute management of uncomplicated DVT.
• Urokinase: Thrombolytic agent of choice in pediatric patients. Given as a bolus followed by an infusion for 12 to 24 hours.
• Recombinant tissue plasminogen activator (tPA): a newer thrombolytic agent with theoretical advantages over urokinase.
• Warfarin: an oral anticoagulant given as a loading dose, adjusted to maintenance as the PT prolongs.
• Aspirin

• Growth of involved limbs, especially following an arterial event.
• Avoid acquired risk factors for vascular disease.
• Medical risk factors should be controlled: hyperlipidemia, hypertension, etc.

Q: What is the optimal strategy for preventing thrombosis associated with indwelling catheters?
A: Low-dose warfarin holds some promise in that the rate of thrombosis is decreased with minimal adverse effects. Using urokinase instead of heparin to flush the lines is an option, however, there is no strong evidence to suggest it is better than heparin.

Q: If an inherited prothrombotic condition is identified should family members be tested?
A: If they have other risk factors for thrombosis such as malignancy, major surgery, oral contraceptives, obesity, etc.

Q: When is it appropriate to use LMWH rather than standard heparin?
A: There are several potential advantages to LMWH. The pharmacokinetics are much more predictable and frequent monitoring is not necessary. It is administered subcutaneously, not intravenous. The risk of bleeding may be slightly lower.

Q: When is it appropriate to use thrombolytic therapy?
A: Studies do not clearly demonstrate a role for thrombolytic therapy in DVT. However, if a thrombus extends on heparin therapy, a pulmonary embolus is suspected, or if the disturbance in blood flow causes ischemia, thrombolytic therapy can be used. Intracranial bleeding is a contraindication. For arterial thrombotic events, thrombolytic therapy is often the treatment of choice because of the rapid resolution of the clot and restoration of blood flow.

Q: What precautions should be taken for invasive procedures and for athletics when a patient is on anticoagulant therapy?
A: Lumbar punctures, arterial punctures and surgical procedures should be avoided. If they are necessary then the child should have the anticoagulant partially or fully reversed prior to the procedure. The child should not participate in contact sports such as football, karate, and boxing. For baseball, a helmet should be worn at all times.

• Pediatric hematologists should be consulted to assist in evaluating for primary hypercoagulable states and assisting in the management of anticoagulant therapy.
• Interventional radiologists should be consulted for choosing the best imaging study for diagnosis and follow-up.
• Surgical thrombectomy or vascular reconstruction is rarely necessary and carries considerable risk.

• Heparin prophylaxis following surgery is not routinely done in pediatrics.
• Awareness of existing risk factors and avoidance of additional acquired risk factors.

Andrew M, Michelson AD, Bovill E, Leaker M, Massicotte MP. Guidelines for antithrombotic therapy in pediatric patients. J Pediatr 1998;132:575–588.

Manco-Johnson MJ. Diagnosis and management of thromboses in the perinatal period. Semin Perinatol 1990;14(5):393–402.

Manco-Johnson MJ. Disorders of hemostasis in childhood: risk factors for venous thromboembolism. Thromb Haemost 1997;78(1):710–714.