The fibrinolytic system is a dynamic system that continues to develop following birth (14), and is regulated by various cofactors and inhibitors (18). During fibrinolysis, the zymogen plasminogen is activated by two main serine proteases, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). tPA binds to fibrin at lysine binding sites and converts plasminogen into plasmin. uPA has no fibrin specificity and can activate both fibrin-bound and circulating plasminogen (14). Both activators have a short half-life of 4–8 min due to the actions of circulating inhibitors: plasminogen activator inhibitor (PAI-1), thrombin-activatable fibrinolysis inhibitor (TAFI), and alpha-2 antiplasmin, which inactivate plasmin or impair plasmin formation (18).

Neonates and infants have qualitative and quantitative differences in plasminogen compared with older children and adults (19). Plasminogen levels increases to adult levels by 6 months of age (20). TPA is also decreased at birth while PAI-1 levels are normal or increased; levels of tPA and PAI-1 do not reach adult levels until late adolescence. Thus, fibrinolysis throughout childhood may be downregulated. Low levels of plasminogen have been shown to impact the actions of pharmacologic thrombolytics (21), but there are insufficient data to demonstrate what effect, if any, high levels of PAI-1 or other fibrinolysis inhibitors may have on the activity of thrombolytic therapy throughout childhood.

To improve the safety of and optimize outcomes in patients receiving thrombolysis, a multidisciplinary approach is needed (27). The ability to quickly obtain coagulation testing results for ongoing adjustments in therapy is critical for managing patients receiving thrombolysis and concomitant anticoagulation. Thrombolysis should occur in the critical care setting to allow for rapid intervention should bleeding occur. Access to imaging modalities such as duplex ultrasound, computed tomography, and magnetic resonance imaging also allows for the necessary surveillance of thrombolysis. For endovascular thrombolysis, experienced interventional radiologists or interventional cardiologists familiar with techniques in young patients must be available.

Whether systemic or endovascular thrombolysis is used, concomitant use of anticoagulation is recommended to prevent new thrombus formation during thrombolysis, as clot lysis releases active thrombin which was bound to thrombi (28). Reported dosing of concomitant anticoagulation has ranged from therapeutic UFH to UFH at a set dose of 5–10 units/kg/h (29–31). While UFH therapy alone can be monitored using either aPTT or anti-Xa levels, anti-Xa levels should be monitored during thrombolysis when possible. Fibrin split products can prolong the activated thromboplastin time (aPTT), thus aiming for a specific aPTT is of unclear utility during thrombolysis. Infants or any child with suspected acquired plasminogen deficiency should receive fresh frozen plasma prior to initiation of thrombolysis. Careful laboratory monitoring during thrombolysis is required, with hemoglobin/hematocrit, platelet count, fibrinogen, fibrin degradation products, d-dimer, aPTT, prothrombin time, and UFH anti-Xa levels done every 6–12 h. d-Dimer levels can help direct systemic thrombolysis therapy, as a normal or low d-dimer indicates a lack of thrombolysis and can be used to guide dose increases, while an elevated d-dimer indicates that chemical activation of fibrinolysis has been achieved. A current blood type and screen is also recommended for any patient receiving thrombolysis, as is a renal panel for patients requiring contrast for venography or undergoing mechanical thrombolysis, due to a risk of hemolysis with the latter.

In general, thrombolysis is used in acute thrombosis of less than 14 days duration of vessel occlusion. In one study assessing efficacy of systemic thrombolysis, 83% of patients with thrombus less than 2 weeks had full or partial response to rtPA compared with 25% in those patients where the thrombus was older (32). For endovascular pharmacomechanical thrombolysis, though, some investigators suggest that more than 60 days from the onset of symptoms is a contraindication (33), although recent attempts to revascularize chronic venous occlusions are proving promising and can be considered for high-risk thrombi (34, 35).

Several precautions should be taken during thrombolysis:

No arterial punctures or line placements.

While the decision to use thrombolysis should be made on a case-by-case basis, weighing pertinent risks, and benefits, there are general contraindications to thrombolysis that should be considered (27, 36).

Active bleeding.

Other contraindications to thrombolysis have included pregnancy or puerperium; presence of intracranial vascular malformations, aneurysms or neoplasms; uncontrolled hypertension; infective endocarditis; and any contraindication to the use of unfractionated heparin or radiographic contrast media (if needed for assessment of thrombosis) (27).

In the past decade, there have been reports of the use of thrombolysis in children for indications beyond acute limb- or life-threatening situations (31, 33, 38, 39). The goal of therapy in these cases is often to improve long-term outcomes or to maintain venous patency in children dependent on central venous access (17). Small prospective and retrospective case series suggest that the use of thrombolysis may be indicated for occlusive, symptomatic iliofemoral or inferior vena cava DVT to acutely decrease pain and improve function and, long-term, to potentially decrease the risk of (PTS) (31, 33, 38). Thrombolysis has been shown to decrease PTS in adults (40). Venous compression syndromes such as May-Thurner (41, 42) and Paget Schroetter (43) (effort thrombosis) have also been treated with combined thrombolysis and endovascular or surgical techniques. Table 1 shows the results of published case series or cohort studies and demonstrates convergent results in thrombolysis efficacy, and rates of recurrence, PTS, and major bleeding.

Systemic thrombolysis is the intravenous administration of thrombolytics distant from the site of thrombosis. Case series using rtPA in children have used various dosing regimens with differing rates of success (29, 48, 49). A low-dose rtPA infusion and a high-dose (previously referred to as “standard dose”) rtPA regimen have been described, with low-dose therapy showing equivalent efficacy to a high-dose regimens (29, 30). High-dose rtPA can be used for 6 h at a time and may be repeated over a 72-h period if imaging suggests no response. Low-dose rtPA can be a continuous infusion over 6–72 h, with close laboratory monitoring and imaging at a minimum of daily. Table 2 describes dosing regimens.

In a review of pediatric thrombolysis, the reported overall number of patients with complete or partial resolution of thrombosis with systemic thrombolysis was 79%, with an incidence of major bleeding in 15% (47). Major bleeding is most often defined as fatal bleeding, bleeding resulting in a drop in hemoglobin of 2 g/dL or more within 24 h, retroperitoneal, pulmonary or intracranial, and bleeding requiring surgical intervention (50). Major bleeding events in children receiving systemic thrombolysis are often associated with longer tPA infusion times and a lower fibrinogen level immediately after thrombolysis (48).

No studies have compared endovascular to systemic thrombolysis in children. Advantages of directed therapy are lower doses of rtPA, with potentially less risk of bleeding, and the ability to instill the thrombolytic agent directly into or near the thrombus. Endovascular thrombolysis is invasive, and is more costly than systemic thrombolysis due to the need for pediatric intensive care for up to 4 days, requirement of general anesthesia, use of interventional radiology expertise and suite for up to three sessions. In a systematic review of pediatric thrombosis, endovascular thrombolysis resulted in complete resolution in 76%, partial resolution in 17%, and no resolution in 7% of cases (47). Endovascular thrombolysis can be done over 12–96 h and can include several interventions (51):

Infusion-only, catheter-directed thrombolysis (CDT): This is the placement of a catheter under radiologic imaging directly into the thrombus to deliver thrombolytic agent.

There is no standard protocol or preferred device in pediatrics, and use of any of these modalities is often physician-dependent. By allowing direct access to the occluded vessel, endovascular therapy can allow for additional techniques such as angioplasty and stent placement to improve vessel patency. Retrievable IVC filters may be placed at the time of endovascular thrombolysis to prevent embolization (53) but are not always necessary and are placed at the discretion of the interventionalist. If placed, IVC filters can be removed at the end of the procedure or within 3 months of placement. Pulmonary embolism is a known complication of endovascular thrombolysis and has been reported in 1–3% (44, 54). Major bleeding in children undergoing endovascular thrombolysis has been reported to be 0–3% (31, 33, 39, 55). Surgical thrombectomy has been reported in severe pediatric thrombosis where anticoagulation and thrombolysis have failed (56), cardiac ventricular thrombosis (57), and IVC thrombosis associated with abdominal tumors (58). Surgical thrombectomy should be reserved for the direst cases.