Epidemiology

Studies have confirmed a significant increase in the diagnosis of venous thromboembolism (VTE) in pediatric tertiary hospitals across the United States. Although the overall incidence of thrombosis in the general pediatric population is quite low (0.07/100,000), the rate of VTE in hospitalized children is 60/10,000 admissions. Infants less than 1 yr old account for the largest proportion of pediatric VTEs, with a 2nd peak during adolescence.

The majority of children who develop a TE have multiple risk factors that may be acquired, inherited, and/or anatomic (Table 473-1). The presence of a central venous catheter (CVC) is the single most important risk factor for venous thromboembolism (VTE) in pediatric patients, associated with approximately 90% of neonatal VTE and 60% of childhood VTE. These catheters are often necessary for the care of premature neonates and children with acute and chronic diseases and are used for intravenous hyperalimentation, chemotherapy, dialysis, antibiotics, or supportive therapy. CVCs may damage the endothelial lining and/or cause blood flow disruption, increasing the risk of thrombosis. There are multiple other acquired risk factors that are associated with thrombosis, including trauma, infection, chronic medical illnesses, and medications. Cancer, congenital heart disease, and prematurity are the most common medical conditions associated with TEs.

Antiphospholipid antibody syndrome (APS) is a well-described syndrome in adults characterized by recurrent fetal loss and/or thrombosis. Antiphospholipid antibodies (APA) are associated with both venous and arterial thrombosis. The mechanism by which these antibodies cause thrombosis is not well understood. A diagnosis of APS requires the presence of both clinical and laboratory abnormalities (see under Laboratory Testing). The laboratory abnormalities must be persistent for 12 wk. Because of the high risk of recurrence, patients with APS often require long-term anticoagulation. It is important to note that healthy children may have a transient lupus anticoagulant, often diagnosed because of a prolonged PTT on routine preoperative testing. These antibodies may be associated with a recent viral infection and are not a risk factor for thrombosis.

Anatomic abnormalities that impede blood flow also predispose patients to thrombosis at an earlier age. Atresia of the inferior vena cava has been described in association with acute and chronic lower extremity deep venous thrombosis (DVT). May-Thurner syndrome (compression of the left iliac vein by the overlying right iliac artery) should be considered in patients who present spontaneously with left iliofemoral thrombosis, and thoracic outlet obstruction (Paget-Schroetter syndrome) frequently presents with effort-related axillary-subclavian vein thrombosis.

Clinical Manifestations

Extremity deep vein thrombosis (DVT): Children with acute DVT often present with extremity pain, swelling, and discoloration. A history of a current or recent CVC in that extremity should be very suggestive. Many times, symptoms of CVC-associated thrombosis are more subtle and chronic, including repeated CVC occlusion or sepsis, or prominent venous collaterals on the chest, face, and neck.

Pulmonary embolism (PE): Symptoms of PE include shortness of breath, pleuritic chest pain, cough, hemoptysis, fever, and, in the case of massive PE, hypotension and right heart failure. Based on autopsy studies, PEs are often not diagnosed, perhaps because young children are unable to accurately describe their symptoms and their respiratory deterioration may be masked by other conditions (Chapter 401.1).

Cerebral sinovenous thrombosis (CSVT): Symptoms may be subtle and may develop over many hours or days. Neonates often present with seizures, whereas older children often complain of headache, vomiting, seizures, and focal signs. They may also have papilledema and abducens palsy. Some patients may have a concurrent sinusitis or mastoiditis that has contributed to the thrombosis.

Renal vein thrombosis: Renal vein thrombosis is the most common spontaneous TE in neonates. Affected infants may present with hematuria, an abdominal mass, and/or thrombocytopenia. Infants of diabetic mothers are at increased risk, although the mechanism for this increased risk is unknown. Approximately 25% of cases are bilateral.

Peripheral arterial thrombosis: With the exception of stroke, the majority of arterial TEs in children are secondary to catheters, often in neonates related to umbilical artery lines or in patients with cardiac defects undergoing cardiac catheterization. Patients with an arterial thrombosis affecting blood flow to an extremity will present with a cold, pale, blue extremity with poor or absent pulses.

Stroke: Ischemic stroke commonly presents with hemiparesis, loss of consciousness, or seizures. This condition may occur secondary to pathology that affects the intracranial arteries (i.e., sickle cell disease, vasculopathy, or traumatic arterial dissection) or may be due to venous thrombi that embolize to the arterial circulation (placental thrombi, children with congenital heart disease or patent foramen ovale).

Diagnosis

Ultrasound with Doppler flow is the most commonly employed imaging study due for the diagnosis of upper or more often lower extremity VTE. Spiral CT is used most frequently for the diagnosis of PE (Fig. 473-1). Other diagnostic imaging options include CT and MR venography, which are noninvasive, although the sensitivity and specificity of these studies is not known. They may be particularly helpful in evaluating proximal thrombosis. For the diagnosis of cerebral sinovenous thrombosis and acute ischemic stroke, the most sensitive imaging study is brain magnetic resonance imaging with venography (MRV) or diffusion weighted imaging.

Figure 473-1 Chest CT from a 15 yr old male with a large pulmonary embolism. There are large filling defects in both the right and left main pulmonary arteries.

Laboratory Testing

All children with a TE should have a complete blood count and a baseline PT and aPTT to assess their coagulation status. In adults suspected to have a DVT, the D-dimer level has a high negative predictive value. The D-dimer is a fragment produced when fibrin is degraded by plasmin and is a measure of fibrinolysis. Based on the clinical scenario, other laboratory studies such as renal and hepatic function may be indicated. Testing for APS includes evaluation for the lupus anticoagulant as well as anticardiolipin and antiβ2-glycoprotein antibodies.

There is some debate regarding which patients should have testing for inherited risk factors. Thrombophilia testing rarely influences the acute management of a child with a thrombotic event. Identification of an inherited thrombophilia may influence the duration of treatment, particularly for those with combined defects, and may aid in counseling the patient about their risk of recurrence.

The evaluation of coagulation studies in pediatric patients is often complicated due to the differences in normal ranges that have been established for infants and for older children/adults. In addition, there is often significant variation in the laboratory assays used to test anticoagulant levels. It is critical to refer to the age-related normal ranges when interpreting pediatric coagulation studies. One limitation of these normal ranges is that they were performed many years ago, using assays that may not be equivalent to those used today. Molecular assays are not age dependent.

Treatment

Therapeutic options for children with thrombosis include anticoagulation, thrombolysis, surgery, and observation. The goal of anticoagulation is to reduce the risk of embolism, halt clot extension, and prevent recurrence. In premature neonates and critically ill children who may have an increased risk of bleeding, the potential benefits must be weighed against the risks. Options for acute anticoagulation include unfractionated heparin (uFH) or low molecular weight heparin (LMWH), though LMWH is more frequently used because of the ease of dosing and need for less monitoring (Table 473-2). Both drugs act by catalyzing the action of antithrombin. Thrombolytic therapy, using a plasminogen activator, will hasten thrombus resolution but at the risk of increased bleeding. Surgery may be necessary for life- or limb-threatening thrombosis when there is a contraindication to thrombolysis. The optimal treatment for a child with acute ischemic stroke depends on the likely etiology and the size of the infarct. Children with sickle cell disease who develop stroke are treated with chronic red blood cell transfusions to reduce recurrence.

Complications

Complications of VTE include recurrent thrombosis (either local or distant), and development of post-thrombotic syndrome (PTS). A thrombosed blood vessel may partially or fully recanalize or may remain occluded. Over time, an occluded deep vein may cause venous hypertension, resulting in blood flow being directed from the deep system into the superficial veins and potentially producing pain, swelling, edema, discoloration, and ulceration. This clinical picture is known as post-thrombotic syndrome (PTS) and may be chronically disabling. Several prospective studies in adults have shown PTS to be present in 17-50% of patients with a history of thrombosis. The likelihood of developing PTS is highest in the 1st 2 yr but continues to increase over time. Graduated compression stockings reduce the risk of PTS in adults and can be used in children.

Unfractionated (Standard) Heparin

Heparin enhances the rate by which antithrombin III neutralizes the activity of several activated clotting proteins, especially factor Xa and thrombin. The average half-life of heparin administered IV is approximately 60 min in adults and can be as short as 30 min in the newborn. Heparin does not cross the placenta. The half-life of heparin is dose-dependent; the higher the dose, the longer the circulating half-life. In thrombotic disease, the half-life may be shorter than normal in patients with significant thromboembolism (pulmonary embolism) and longer than normal in patients with cirrhosis and uremia.

Anticoagulation with heparin is contraindicated in the following circumstances: a recent central nervous system hemorrhage; bleeding from inaccessible sites; malignant hypertension; bacterial endocarditis; recent surgery of the eye, brain, or spinal cord; and current administration of regional or lumbar block anesthesia. A pre-existing coagulation defect or bleeding abnormality is a relative contraindication. Despite these precautions, the frequency of bleeding in patients given heparin anticoagulation is 0.2-1.0%.

Guidelines for therapy using unfractionated heparin are shown in Table 473-1. In newborns with low levels of clotting factors, in patients with a lupus inhibitor, or in patients with elevated levels of factor VIII (as a result of stress or surgery), PTT may not reflect the correct degree of anticoagulation, and specific heparin levels should be obtained so that the heparin level is 0.35-0.70 U/mL by anti–factor Xa assay or 0.2-0.4 U/mL by protamine sulfate assay.

Heparin can be neutralized immediately by using protamine sulfate. Because of the rapid clearance rate of heparin, however, stopping the infusion is adequate treatment for most patients. One milligram of protamine sulfate neutralizes 90-110 U of heparin. Because heparin has rapid in vivo metabolic decay, only one half of the total dose of protamine should be administered. A clotting test is performed to determine whether adequate neutralization has occurred; if not, the additional protamine can be given. Protamine itself is an anticoagulant; thus, if too much is given, clotting time may be prolonged. Although excess protamine has an anticoagulant effect, it rarely (if ever) is a cause of clinical bleeding. Once heparin is neutralized, the patient is returned to the original “prothrombotic” state.

Low Molecular Weight Heparin

LMWH is an effective, convenient alternative to standard heparin therapy, and its use is described in Table 473-1. Several heparins and heparinoids are undergoing clinical trials. Most pediatric experience is with enoxaparin. Adult patients receiving LMW heparin rarely need to have their heparin levels monitored, but in pediatric patients, there is more diversity of response. Monitoring is critical to ensure that a therapeutic level is achieved. PTT cannot be used to monitor LMW heparin; a specific assay should be used. Once a therapeutic range is achieved, routine monitoring is not required or is required only infrequently. When LMW heparin is used for prophylaxis against thrombosis, the dose is 0.5 mg/kg q12hr subcutaneously, with the goal of achieving a level of 0.3 U/mL 4 hr after injection.

Warfarin

Coumarin derivatives are oral anticoagulant drugs that act by decreasing the functional levels of the vitamin K–dependent coagulation factors: II, VII, IX, and X, as well as protein C and protein S (vitamin K–dependent anticoagulants). These drugs inhibit vitamin K–dependent carboxylation of the precursor coagulation proteins. Warfarin probably acts by competitively inhibiting vitamin K metabolism. After the administration of warfarin, levels of factors II, VII, IX, and X decrease gradually, according to each factor’s plasma half-life. Because factor VII has the shortest half-life, its level is the 1st to decrease, followed by factors IX and X, and finally, factor II. It generally takes 4-5 days to reduce the levels of all 4 coagulation factors consistent with effective anticoagulation.

Prothrombin time (PT) is the clotting test used to assess warfarin anticoagulation. Current recommendations are based on the International Normalized Ratio (INR), which permits comparison of PT using a wide variety of reagents or instruments. The INR for standard treatment of thrombosis is 2.0-3.0. Table 473-1 provides guidelines for the administration of warfarin to children. For patients with mechanical heart valves and those with homozygous protein C deficiency, the INR should be 3.0-4.0.

The most serious side effect of warfarin is hemorrhage. This is often related to changes in the dose or metabolism of the drug. The addition or removal of certain drugs in the patient’s therapeutic regimen can have significant effects on oral anticoagulation. The effect of warfarin can be enhanced by the administration of antibiotics, salicylates, anabolic steroids, chloral hydrate, laxatives, allopurinol, vitamin E, and methylphenidate hydrochloride; its effect can be diminished by barbiturates, vitamin K, oral contraceptives, phenytoin, and other agents. Warfarin-induced bleeding is treated by discontinuation of the drug and oral administration of vitamin K. Generally, the amount of vitamin K given is equal to the amount of the daily warfarin dose. Vitamin K can be administered orally, subcutaneously, or IV (not IM), but the parenteral forms have a much longer half-life and may overshoot the correction. Correction of coagulopathy begins within 6-8 hr and should be complete in 24-48 hr. If the patient is having a significant or life-threatening hemorrhage, fresh frozen plasma (15 mL/kg) should be given when the vitamin K is administered.

Contraindications to coumarin anticoagulants are essentially the same as those for heparin therapy. The oral anticoagulants are teratogenic, cross the placenta, and should not be given during pregnancy, particularly during the 1st trimester. Although breast milk contains warfarin, the quantity is insignificant and the drug can be used to treat the lactating mother without a significant effect on the infant.

Thrombolytic Therapy

Thrombolytic agents, such as recombinant tissue-type plasminogen activator (rTPA), activate plasminogen to lyse blood clots by enzymatic digestion; rTPA is most often used in pediatrics for thrombolytic therapy, as described in Table 473-1. For this therapy to be effective, the patient should have a relatively fresh clot (<3-5 days old), the clot must be accessible to the lytic agent, and there must be an adequate amount of plasminogen. Once plasmin has been formed, it lyses fibrin. Relatively more fibrin-specific than the older thrombolytic agents urokinase and streptokinase, rTPA activates plasminogen within or on a fibrin clot. Clinical trials with rTPA suggest that it rarely produces a systemic hyperfibrinolytic state. The initial dose of rTPA is 0.1 mg/kg/hr. It may be useful to monitor for a therapeutic effect by looking for an increase in the concentration of D-dimers or fibrin degradation products. Higher doses or more prolonged courses of thrombolytic therapy are likely to be associated with an increased risk of bleeding complications. Low doses of rTPA have been efficacious in restoring patency in occluded vascular access catheters.