Pediatric deep vein thrombosis is an increasingly recognized phenomenon, especially with advances in treatment and supportive care of critically ill children and with better diagnostic capabilities. High-quality evidence and uniform management guidelines for antithrombotic treatment, particularly thrombolytic therapy, remain limited. Optimal dosing, intensity and duration strategies for anticoagulation as well as thrombolytic regimens that maximize efficacy and safety need to be determined through well-designed clinical trials using use of a risk-stratified approach.
Key points
- •
Pediatric deep vein thrombosis (DVT) is an increasingly recognized phenomenon, especially with advances in treatment and supportive care of critically ill children and with better diagnostic capabilities.
- •
High-quality evidence and uniform management guidelines for antithrombotic treatment, particularly thrombolytic therapy, remain limited.
- •
Use of a thrombolytic approach is considered when rapid clot lysis could ameliorate limb/organ/life-threatening sequelae, reverse the inability to ambulate due to pain from occlusive DVT of the lower limb, or reduce the risk of clinically significant post-thrombotic syndrome in patients deemed to be at high risk for this adverse outcome.
- •
Optimal dosing, intensity and duration strategies for anticoagulation as well as thrombolytic regimens that maximize efficacy and safety need to be determined through well-designed clinical trials using use of a risk-stratified approach.
Objectives
This article aims to summarize the available evidence, guidelines, and practice considerations regarding conventional anticoagulation as well as less-conventional antithrombotic strategies in the treatment of venous thromboembolism (VTE) in children. Conventional agents are briefly overviewed to provide context (and are extensively reviewed elsewhere), whereas the latter approaches are discussed in detail, with main emphasis on thrombolysis and the new oral anticoagulants coming under study in pediatric trials.
Epidemiology of VTE
Although still rare in comparison with adults, pediatric VTE is being recognized with increasing frequency particularly in the tertiary care setting. In 2001, data from a prospective 2-year registry of children in Netherlands showed that in 85% of cases, thrombosis occurred in hospitalized patients. Although neonatal VTE was almost exclusively catheter related and located in the upper venous system, VTE was catheter related in only one-third of older children, more often located in the lower extremity. The Canadian Childhood Thrombophilia Registry reported significant long-term morbidity in pediatric DVT with 33/405 children (8.1%) having recurrent thrombosis, and 50/405 children (12.4%) having post-thrombotic syndrome (PTS) at about 3 years follow-up. Mortality directly attributable to DVT/pulmonary embolism (PE) occurred in 9/405 children (2.2%), all of whom had central venous line–associated thrombosis.
Data from the National Hospital Discharge Survey in 2004 identified an overall in-hospital incidence rate of 4.9 VTE/100,000 children/year in the United States, with bimodal distribution in which incidence peaked in neonates and adolescents. In a retrospective study, using the Pediatric Health Information System administrative database during the period from 2001 to 2007, Raffini and colleagues demonstrated that the annual rate of VTE in pediatric hospitals in the United States showed a dramatic increase of 70%, from 34 to 58 cases per 10,000 hospital admissions. The US Surgeon General’s Call-to-Action in 2008 on DVT and PE Prevention highlighted the growing incidence of VTE and the need to identify risk predictors and risk-stratified preventative and therapeutic strategies for this growing problem in adults as well as children.
Conventional anticoagulants
Conventional anticoagulants attenuate hypercoagulability, thus reducing the risk for thrombus progression and embolism. Nearly 50% of the VTE events treated with anticoagulant agents resolve over weeks to months. However, the evidence basis for the indication of anticoagulation in VTE (derived from early adult studies) is the reduction of life-threatening pulmonary embolism.
Conventional anticoagulants in pediatric VTE include unfractionated heparin (UFH), low molecular weight heparins (LMWHs, enoxaparin and dalteparin in the United States), and vitamin K antagonists (warfarin in the United States).
UFH has a shorter half-life than LMWH and is typically preferred in clinical situations with higher bleeding risk and/or higher acuity, due to rapid extinction of anticoagulant activity on discontinuing the drug. UFH is also preferred for acute VTE therapy in the setting of diminished renal function because of the relatively greater renal elimination of LMWH.
LMWH is increasingly being used as a first-line agent for anticoagulation in children due to (1) ease of subcutaneous over intravenous administration; (2) less frequent need for monitoring when compared with warfarin or UFH; and (3) decreased risk for the development of heparin-induced thrombocytopenia when compared with UFH. Raffini and colleagues reported that the proportion of children with VTE treated with enoxaparin increased from 29% to 49% during the time period from 2001 to 2007. Despite the widespread use of LMWH, the therapeutic and prophylactic guidelines for these agents in children are extrapolated from adult guidelines. The REVIVE trial aimed to assess the efficacy of another LMWH, reviparin sodium, compared with UFH and warfarin for the treatment of VTE in children. However, the trial was closed prematurely and thus not adequately powered to assess comparative efficacy. Hence, at present, the considerations for specific agents/regimens are largely guided by the considerations listed earlier, including the patient’s clinical status, bleeding risk, and renal function. Anticoagulant choices can also strongly be guided by patient preferences, particularly to achieve optimal adherence to a prescribed regimen in the outpatient settings.
Available studies regarding the pharmacokinetics, effectiveness, side effects profile, and optimum dosing for LMWH therapy in children suggest that a bolus (loading) dose is not necessary. The starting dose of enoxaparin in children (except neonates) should be 1.0 to 1.25 mg/kg subcutaneously Q12-hour. In term neonates, a higher dose of enoxaparin (1.5 mg/kg Q12 h) typically is necessary with even higher requirements in preterm infants. Bauman and colleagues also recently reported that age-based enoxaparin doses are required to achieve therapeutic levels in infants and children, observing an inverse relationship between dose/kg and age. These investigators found that increasing the starting dose of enoxaparin might result in faster acquisition of the therapeutic range with fewer venipunctures or dose adjustments and without an appreciable increase in bleeding events.
The FondaKIDS study recently reported prospective data on pharmacokinetics and safety of fondaparinux (a synthetic and specific inhibitor of activated Factor X) in children, with 0.1 mg/kg once daily dosing in children resulting in pharmacokinetic profiles comparable to adults, suggesting fondaparinux as a potential alternative to LMWH. Comparative efficacy studies are warranted.
Thrombolysis
Settings
Although conventional anticoagulation therapy continues to be the mainstay of VTE management, thrombolytic therapy represents a key treatment choice in select circumstances of pediatric DVT, with the aim of improving short-term outcomes and decreasing long-term morbidity and mortality. However, the current limited understanding of the risks and benefits results in limited use of thrombolysis in pediatric DVT. A recent survey among active and trainee members of ASPHO reveals a wide variability in the clinical practice and decision making pertaining to the use of thrombolytic agents in childhood VTE.
The latest evidence-based practice guidelines for antithrombotic therapy for VTE in the pediatric population vary with respect to recommendations for the use of thrombolytic therapy. Although American Heart Association guidelines suggest considering thrombolytic therapy in children in whom the “benefit may outweigh risk”, American College Chest Physicians (ACCP) guidelines discourage the “routine” use of thrombolytic therapy for pediatric DVT and recommend that thrombolysis be reserved for patients with life- or limb-threatening events.
Those VTE that have strong consensus for thrombolysis based on ACCP pediatric antithrombotic therapy guidelines include (1) massive PE with cardiovascular instability; (2) obstructive superior vena cava syndrome; (3) bilateral renal vein thrombosis; (4) cerebral sinus venous thrombosis with deteriorating neurologic status; (5) large atrial thrombi; and (6) VTE causing life-threatening shunt obstructions in patients with complex congenital heart disease status-post staged surgical repairs. Relatively weaker “indications” by consensus (which nevertheless remain important clinical considerations) include acute iliofemoral or inferior vena cava thrombosis and anatomic compressive syndromes, including May-Thurner ( Fig. 1 ) and Paget-Schroetter syndromes.
In adult patients, management guidelines from the American Heart Association recommended thrombolysis as a therapeutic modality in “young patients” with extensive and/or occlusive thrombus of recent onset and an anticipated long lifespan as well as low bleeding risk. Prospective studies and clinical trials aimed at reducing the risk of PTS are particularly important in children, given the sustained burden that PTS could have throughout a patient’s lifespan.
It has been suggested, and some evidence supports the notion, that prompt administration of thrombolysis can reduce venous obstruction and the risks of venous valvular insufficiency and PTS when compared with conventional anticoagulation alone. In a small cohort study in pediatric patients with complete veno-occlusive proximal lower-limb DVT who had up to an 80% risk of PTS at 1 year if managed by conventional anticoagulation alone, the use of acute thrombolysis (low-dose systemic tPA, followed by catheter-directed thrombolysis for any residual occlusion) significantly reduced the risk of PTS to 22% (odds ratio [OR], 0.02; 95% confidence interval [CI], <0.001–0.48). The findings of this study are preliminary, and the question would best be answered by a definitive prospective randomized clinical trial (RCT).
Agents
Major thrombolytic agents include streptokinase, urokinase, recombinant tPA (rt-tPA), tenecteplase, and reteplase; published use of the latter two agents in pediatric VTE is limited to case reports/series. These thrombolytic agents are plasminogen activators, which promote fibrinolysis by converting plasminogen to plasmin. The thrombolytic agent used most frequently in children over more than the past 10 years is rt-tPA. This agent is produced in Chinese hamster cell lines using recombinant DNA technology. It is rapidly cleared through the liver, with an intravascular half-life of approximately 5 minutes.
Modalities
Systemic thrombolysis
In a pooled analysis of adult RCT’s of systemic thrombolysis using streptokinase compared with heparin, greater than 50% clot lysis was seen more often in proximal DVT patients treated with streptokinase (62% vs 17%, P <.0001), albeit at the cost of substantively increased bleeding risk. In small RCTs with substantial methodological limitations, the use of thrombolytic therapy with streptokinase showed a trend toward PTS prevention. RCTs in adults comparing dosing regimens of systemic intravenous rt-PA plus heparin compared with heparin alone in the treatment of acute proximal DVT have provided evidence that rt-PA and rt-PA plus heparin result in more clot lysis than heparin alone. The addition of heparin to rt-PA does not improve the lysis rate. This study also found a trend toward PTS reduction with rt-tPA use. A recent Cochrane database systematic review of RCTs of thrombolysis (systemic thrombolysis or catheter-directed thrombolytic infusion) versus standard anticoagulation alone in adult VTE concluded that the acute rate of achieving complete patency is significantly increased (RR = 4.14, 95% CI = 1.22–14.01) with thrombolysis, and the risk of PTS is correspondingly decreased (RR = 0.66, 95% CI = 0.47–0.94). However, mortality and the risk of recurrent VTE were not reduced by thrombolysis and a slight increase in acute major bleeding risk was attributed to thrombolysis as compared with standard anticoagulation (RR, 1.73; 95% CI, 1.04–2.88).
There are several reports available citing the use of tPA in infancy and childhood in various clinical settings. Systemic thrombolytic therapy in children typically follows one of two dose-based regimens: (1) so-called “standard-dose” tPA (0.1–0.5 mg/kg per hour) and (2) low-dose tPA with a dose of 0.03 mg/kg to 0.06 mg/kg per hour. Wang and colleagues reported on 35 pediatric subjects of which 29 had acute thrombi and 6 had chronic thrombi. In this analysis, low-dose tPA was used at 0.01 to 0.06 mg/kg per hour (a higher dose of 0.06 mg/kg/hr was used in neonates) in 17 subjects and standard dose tPA at 0.1 to 0.5 mg/kg per hour in 12 subjects. In approximately half of the study population, tPA dosing regimens used concomitant antithrombotic therapy with UFH (5–10 U/kg per hour) or LMWH (enoxaparin 0.5 mg/kg twice daily). Systemic therapy was used in 25 of 35 cases, whereas catheter-directed infusion of tPA was administered in the remaining patients. Major bleeding occurred in only 1 subject (a preterm infant). Complete thrombolysis was observed in 28 of 29 (97%) cases of acute thrombi. Partial clot resolution was seen in each of 6 chronic thrombi. Low-dose systemic tPA has since been used effectively, with seemingly lower bleeding risk than with standard/high-dose regimens. In 2007, Goldenberg and colleagues also reported favorable by the responses and safety for low-dose systemic tPA, albeit requiring salvage local lytic therapy in some cases.
Catheter-directed thrombolysis/thrombolytic infusion
In the CaVenT multicenter RCT, adults with proximal lower extremity DVT and symptoms less than 21 days were randomized to receive additional CDT or standard treatment alone. The trial showed that the use of additional CDT was associated with a 26% relative reduction in the risk of PTS at 2 years follow-up and a major bleeding rate of 3.3%. There were no intracranial bleeds or fatal bleeds. Other reported bleeds were time-limited events that did not ultimately affect the patients’ long-term health.
In 2000, Manco-Johnson and colleagues reported retrospective data in 32 children with VTE using urokinase for CDTI with concurrent low-dose UFH at 10 U/kg/h. At 48 hours, 50% of the children showed substantial clot lysis, and at 1-year follow-up, these children had continued complete resolution. There was one thrombotic death, one thrombus progression, and one pulmonary embolism. Three children with poor early clot lysis had recurrent VTE.
Two pediatric studies have reported on experience with CDTI using tPA. In the retrospective study by Wang and colleagues, of the 35 subjects, 10 received tPA through a local catheter; no difference in outcome was detected when systemic administration was compared with local tPA administration. Major bleeding occurred in only one premature infant, and minor bleeds (mostly oozing at IV sites) occurred in 27% of infants during TPA infusion. In 2007, Goldenberg and colleagues reported the use of tPA in a dose of 0.5 to 1.0 mg/h using CDTI, as part of a thrombolytic regimen that directly followed pharmacomechanical thrombectomy (PMT, see later discussion) as salvage therapy for suboptimal response to initial systemic tPA. No major bleeds were attributed to CDTI.
Percutaneous mechanical/pharmaco-mechanical thrombectomy
PMT refers to the use of a catheter-based device that contributes to mechanical clot lysis by causing clot fragmentation, maceration, and/or subsequent aspiration. Pharmacomechanical CDT or percutaneous pharmacomechanical thrombectomy (PPMT) are used interchangeably and refer to clot dissolution using a combined approach with CDT and PMT. In adults, there are retrospective data providing evidence of equivalent outcomes with clot lysis with PMT/PMMT than CDT alone but with (1) significant reductions in the thrombolytic agent dose and (2) drug infusion time, thus being more resource efficient. However, there are very limited prospective data supporting the evidence, and the data were generated in the setting of few reported cases of PMT/PMMT in the context of studies essentially focused on CDT. In the retrospective adult data, although the initial results have been very promising with rapid response, data on PTS risk are as yet lacking, and data on long-term vessel patency are limited.
In small neonates and children, the needed technical expertise and limited manufacturing of age-adapted devices limit the wide availability for mechanical thrombectomy. Goldenberg and colleagues recently provided prospective evidence of efficacy as well as safety of PMT/PPMT in a cohort of adolescents with VTE ( a priori judged to be at high risk for PTS because of complete vaso-occlusion and dual elevation of factor VIII and D-dimer) who underwent PMT/PPMT, with adjunctive catheter-directed thrombolytic infusion of tPA post-procedure. The investigators reported a technical initial success rate of 94% with no periprocedural major hemorrhage events and one symptomatic pulmonary embolism. They further reported an early local DVT recurrence of 40% with successful clot relysis in 83% cases and a late DVT recurrence rate at median follow-up of 14 months (range: 1–42 months) of 27% with a cumulative PTS incidence of 13%. Previously, Goldenberg and colleagues had reported that thrombolysis with systemic tPA by low-dose continuous intravenous infusion with salvage PMT/PPMT intervention (for persistent thrombi) led to a significant reduction in the risk of PTS (OR, 0.02; 95% CI, <0.001–0.48). Interestingly, ASPHO physician members and trainees identified PMT/PPMT as the most common preferred approach to thrombolysis in DVT.
Contraindications/Safety Issues
Standards of safety and efficacy in treatment of pediatric and neonatal DVT with thrombolytic therapy are evolving. Recently, standards for safety and efficacy endpoint reporting and definitions in pediatric VTE studies were published from the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Bleeding definitions were standardized.
The main complication of thrombolytic therapy, much like for other antithrombotic therapies such as conventional anticoagulation, is bleeding. “Major bleeding” complications include CNS hemorrhage, retroperitoneal hemorrhage, any bleeding significant enough to require a surgical intervention and/or cause a decline in hemoglobin by greater than or equal to 2 g/dL in a 24 hour period. Reported bleeding complications following thrombolysis in the pediatric population range from 0% to up to 40%. Zenz and colleagues reported on a review of 30 years of reported literature that the risk of intracerebral hemorrhage (ICH) from thrombolytic therapy in the pediatric age group was lower in children than in neonates, and lower in term infants than preterm infants.
Contraindications to systemic and local tPA use are largely modeled after those used in adult studies, but have been suggested and used in several pediatric studies. Some of the well-recognized contraindications for thrombolytic therapy adapted from adult literature include (1) active bleeding, (2) recent major surgery or invasive procedure (in past 7–14 days), (3) central nervous system (CNS) surgery, trauma, or hemorrhage with in the last 30 days, (4) seizures in the last 48 hours, (5) uncontrolled hypertension, (6) severe and uncontrolled coagulopathy with inability to maintain platelet count greater than 75,000/μL and/or fibrinogen greater than 100 mg/dL, (7) sepsis, and (8) serum creatinine greater than 2mg/dL.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
