Thrombosis, Pediatric

Basics

Description

Pathologic arterial or venous intravascular occlusion secondary to abnormal thrombus formation. ‚
The following are common thrombotic events: ‚

Deep venous thrombosis (DVT): involves large systemic veins outside the central nervous system (CNS)
Cerebral sinovenous thrombosis (CSVT): involves intracranial venous sinuses
Ischemic stroke: CNS arterial occlusion with infarction of brain tissue
Intracardiac thrombosis: mural, valvular, or foreign body associated
Femoral artery thrombosis: can be associated with vessel catheterization
Renal vein thrombosis: commonly in the neonatal period; may be unilateral or bilateral
Myocardial infarction: Kawasaki disease, antiphospholipid antibody syndrome or with severe familial hypercholesterolemia
Budd-Chiari syndrome: thrombosis of the hepatic vein
Portal vein thrombosis

Epidemiology

Incidence of venous thrombosis in children is estimated at 4.9 per 100,000 per year.
Age distribution is bimodal; peak rates are found in the neonatal and adolescent age groups.
Idiopathic thrombosis is rare in children.
>90% of pediatric venous thrombosis is associated with additional risk factors.
Central venous lines are the most common risk factor for venous thrombosis in children.

Risk Factors

Neonatal
- Prematurity
- Maternal diabetes
- Umbilical catheters or other central lines
- Sepsis
- Polycythemia
- Perinatal asphyxia
Malignancy/bone marrow disorders
- Leukemia (hyperleukocytosis, acute promyelocytic leukemia)
- Myeloproliferative disorders
- Paroxysmal nocturnal hemoglobinuria
Medications
- l-Asparaginase
- Oral contraceptives (with estrogen)
- Heparin-induced thrombocytopenia
- Steroids
Anatomic
- Indwelling catheters
- Congenital heart disease
- Prosthetic heart valves
- Intracardiac baffles
- Tumor compression
- Atresia of the inferior vena cava
- Thoracic outlet obstruction (Paget-Schroetter syndrome)
- May-Thurner syndrome (compression of the left iliac vein by the right iliac artery)
Miscellaneous
- Infection
- Trauma
- Surgery
- Obesity
- Prolonged immobilization or paralysis
- Dehydration
- Antiphospholipid syndrome
- Inherited prothrombotic state
Risk factors/conditions specific for arterial disease
- Kawasaki disease
- Takayasu arteritis
- Hyperlipidemia
- Antiphospholipid syndrome

Commonly Associated Conditions

Nephrotic syndrome
Inflammatory disorders
Liver disease
Sickle cell disease
Diabetes mellitus

Diagnosis

Differential Diagnosis

Other disorders that cause extremity swelling:
- Low albumin
- Obstruction of venous flow by a catheter without thrombus formation
- Hemihypertrophy
A high hematocrit in neonates can make the cerebral veins appear "dense " ¯ on a head CT and be misinterpreted as thrombosis.
Arterial stroke mimics: complex migraine, demyelinating disease, metabolic disease, tumor

Alert

Normal ranges for coagulation tests are age dependent: Diagnosing an inherited deficiency in any of the anticoagulant proteins can be difficult in the neonatal period. Repeat testing at 6 " “12 months of age is necessary.
Consumption can occur during acute thrombosis; therefore, low levels of the anticoagulant proteins must be repeated.
Warfarin will decrease the levels of protein C, protein S, and clotting factors II, VII, IX, and X.

Approach to the Patient

Phase 1
- Perform complete history and physical exam.
- Establish diagnosis using the appropriate radiographic study.
Phase 2
- Send initial laboratory studies (CBC, PT/aPTT, D-dimer, ˇ ²-hCG testing in postmenarchal females).
- If deemed safe, begin anticoagulation therapy with unfractionated heparin or low-molecular-weight heparin.
- Patients with life- or limb-threatening thrombosis may require thrombolysis.
Phase 3
- If appropriate, consider sending a complete lab workup for a hypercoagulable state; outpatient anticoagulation; follow thrombosis radiologically.

History

Presence of risk factors previously listed
Family history of thrombosis
Personal history of thrombosis
Neonatal seizure: common and often the only presenting sign for CSVT or arterial ischemic stroke in neonates

Physical Exam

Extremity DVT: unilateral swelling/edema of a limb
Thrombosis of the inferior vena cava: bilateral lower extremity edema of a limb
Superior vena cava syndrome: plethoric, swollen head and neck
Arterial thrombosis: pale extremity with decreased perfusion/pulses
Renal vein thrombosis: abdominal mass in neonate with hematuria
Pulmonary embolism: tachypnea, shallow respirations
Peripheral venous collateral formation: superficial dilated cutaneous veins
Postthrombotic syndrome: chronic discoloration (darkening) of the skin, ulcerations, pain, intermittent swelling

Diagnostic Tests & Interpretation

The following tests can be used to investigate for a prothrombotic state:
- Factor V Leiden mutation analysis
- Prothrombin 20210A mutation analysis
- Lupus anticoagulant screen (dilute Russell viper venom time, aPTT)
- Anticardiolipin antibodies (IgG, IgM)
- Anti " “ ˇ ²2-glycoprotein antibodies (IgG, IgM)
- Protein C activity
- Protein S activity
- Antithrombin activity
- Homocysteine
- Lipoprotein(a)
- Factor VIII activity

Imaging
Radiologists should be consulted for choosing the best imaging study for diagnosis and follow-up. ‚

Contrast angiography: gold standard, but invasive and sometimes technically difficult to perform in small children
Ultrasound: most commonly used imaging study because of noninvasiveness, absence of radiation, and ability to be performed at the bedside
In the diagnosis of upper extremity " “related DVT, often a combination of ultrasound and venography is necessary:
- Compression ultrasound of the upper central veins may be impeded by the distal end of the clavicle.
- Venography has poor sensitivity for diagnosing thrombosis of the internal jugular veins.
- Recommended approach for diagnosis of an upper extremity thrombosis is to start with ultrasound and proceed to venography if the ultrasound is normal and there is a high clinical suspicion for thrombosis.
Echocardiogram may be useful in evaluating atrial thrombi, which may result from central venous catheters.
Pulmonary angiography, ventilation " “perfusion scans, and spiral CT scans are the imaging studies used for the diagnosis of pulmonary embolism, although none of these have been studied in children.
In patients with a pulmonary embolism, it is important to look for a source of thrombosis in the upper and lower extremities.
Other diagnostic imaging options include CT or MRV:
- Noninvasive
- Sensitivity and specificity not known
- May be helpful in evaluating proximal thrombosis
For diagnosis of CSVT, the most sensitive imaging study is a brain MRI with venography.

Treatment

Unfractionated heparin:
- Given as a bolus followed by an infusion, adjusted to maintain the aPTT at 1.5 " “2.5 times baseline
- Younger children require higher doses of heparin to achieve a therapeutic level secondary to physiologically decreased antithrombin levels.
Low-molecular-weight heparin
- More predictable dose response
- Given subcutaneously twice a day
- Equivalent in efficacy to unfractionated heparin in the acute management of uncomplicated DVT
- Renal clearance
Thrombolytic therapy
- Recombinant tissue plasminogen activator
- May be given systemically or locally
- High risk of bleeding
Warfarin
- Oral anticoagulant
- Initially started when a patient is already receiving a form of heparin. The heparin is discontinued when the warfarin is in the therapeutic range.
- Warfarin is adjusted to maintain an international normalized ratio (INR) of 2 " “3 for treatment of DVT.
- Used for outpatient management
Aspirin
- Beneficial in stroke and other arterial events
- Irreversibly inhibits platelet function

General Measures

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

Ongoing Care

Complications

Inferior vena cava filters are used to prevent pulmonary embolism. There are limited pediatric studies. They should only be considered in the setting of a lower extremity DVT with a contraindication to anticoagulation (i.e., recent extensive surgery or active bleeding) or if a patient experiences a pulmonary embolism while on therapeutic anticoagulation. Temporary filters should be placed and removed as soon as possible, as they are a nidus for further thrombosis formation. The risk/benefit ratio needs to be considered individually.
Vary depending on the location and severity of the thrombosis
In acute DVT, pulmonary embolism is the most significant complication.
Recurrent thrombosis and postthrombotic syndrome are common chronic complications.
In arterial thromboembolic disease, the ischemic injury to the involved organ determines the acute and long-term complications.