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Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome

Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome
Authors:
Manuela Albisetti, MD
Anthony KC Chan, MBBS, FRCPC, FRCPath
Section Editor:
Sarah O'Brien, MD, MSc
Deputy Editor:
Carrie Armsby, MD, MPH
Literature review current through: Feb 2022. | This topic last updated: Feb 01, 2022.

INTRODUCTION — Venous thromboembolism (VTE; which includes venous thrombosis and/or pulmonary embolism [PE]) is increasingly recognized in the pediatric population as a complication of contemporary health care. Timely diagnosis, treatment, and optimal prophylactic strategies for VTE in children are critical to avoid long-term complications.

The treatment, prevention, and outcome of noncerebral VTE in infants and children will be discussed here. Other aspects of VTE are discussed in separate topic reviews:

Risk factors, clinical manifestations, and diagnosis of VTE in infants and children (see "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis")

VTE in the newborn (see "Neonatal thrombosis: Clinical features and diagnosis" and "Neonatal thrombosis: Management and outcome")

VTE in children with cancer (see "Thromboembolism in children with cancer")

Cerebral venous thrombosis (see "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis" and "Cerebral venous thrombosis: Treatment and prognosis")

APPROACH TO VTE TREATMENT

Overview — The goals of treating VTE are to:

Prevent local extension and embolization of the thrombus

Aid in resolving the existing thrombus

Prevent VTE recurrence

Minimize long-term complications (eg, post-thrombotic syndrome [PTS]) (see 'Post-thrombotic syndrome' below)

Commonly used anticoagulant agents for treatment of VTE include low molecular weight heparin (LMWH), unfractionated heparin (UFH), direct oral anticoagulants (DOAC), and vitamin K antagonist (VKA; eg, warfarin). Data on the use of these therapies in children are limited, as described below. (See 'Anticoagulant agents' below.)

Despite the lack of definitive data, LMWH is generally preferred over UFH for acute management for reasons summarized in the table and detailed below (table 1) (see 'Choice of agent' below). LMWH also is generally preferred over VKA because the response to VKAs in children tends to be unpredictable and requires frequent monitoring and dose adjustment. Nonetheless, VKAs may be preferred by patients requiring long-term therapy because they are administered orally. DOACs are a relatively new group of agents that, compared with VKAs, have the advantage of having a more predictable dose response and therefore do not require lab monitoring. As experience is gained with using DOACs in children and as long-term data become available, these agents are likely to play an important role in managing and preventing VTE in pediatric patients. (See 'Direct oral anticoagulants' below.)

Thrombolytic therapy (eg, recombinant tissue plasminogen activator [tPA]) is rarely used in the management of pediatric VTE; its use is limited to cases in which thrombosis causes major vessel occlusion with compromise of organs or limbs. (See 'Thrombolytic therapy' below.)

Our suggested approach to treating VTE in children is based on the available evidence (both direct evidence from studies in pediatric patients and indirect evidence from adult studies), expert opinion, and clinical experience. Our approach is generally consistent with the guidelines of the American College of Chest Physicians and the American Society of Hematology; however, both guidelines were published prior to the availability of pediatric DOAC formulations [1,2].

Indications and duration of anticoagulant therapy

Provoked VTE — The vast majority of thromboembolic events in pediatric patients are "provoked," meaning that they develop due to identifiable underlying conditions and risk factors. Of these risk factors, the most common is an indwelling central venous catheter (CVC). Other common risk factors include surgery, trauma, infection, immobilization, malignancy, and use of estrogen-containing oral contraceptive pills (table 2) [3]. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Risk factors'.)

Children with provoked VTE who meet all of the following criteria are at low risk of experiencing VTE recurrence and other complications:

Patient has no prior history of VTE

VTE is not severe or life threatening (eg, not causing hemodynamic compromise, not requiring thrombolytic therapy)

Provoking risk factor is transient (CVC, recent surgery, trauma) and has resolved within six weeks (eg, CVC has been removed)

Thrombus has resolved or is nonocclusive within six weeks

For these low-risk patients, we suggest six weeks of anticoagulant therapy rather than the conventional three-month duration.

For most other children, including those with persistent provoking risk factors (eg, malignancy, systemic lupus erythematosus [SLE]) and those with severe or life-threatening VTE, we suggest at least three months of anticoagulant therapy.

In both scenarios, initial treatment consists of a parenteral agent (ie, either LMWH or UFH) for the first few days, followed by either parenteral or oral therapy (ie, LMWH, a DOAC, or VKA) [1,2,4]. Choice of agent and guidance for transitioning from parenteral to oral therapy are discussed below. (See 'Choice of agent' below and 'Transitioning from parenteral to oral therapy' below.)

The practice of using a six-week duration of therapy in select low-risk patients is supported by a randomized trial that compared six weeks versus three months of anticoagulant therapy in 417 children with low-risk provoked VTE (CVC-associated in 50 percent, infection-related in 30 percent, surgery- or trauma-related in 20 percent) [5]. Rates of symptomatic VTE recurrence within one year were similarly low in both groups (1.1 and 1.6 percent, respectively). There were fewer episodes of clinically relevant bleeding in the six-week group (1.1 versus 2.4 percent); however, the difference was not statistically significant.

There are few pediatric data to support the three-month treatment duration for children who do not meet low-risk criteria. This practice is largely based upon indirect evidence from adult studies, which are described separately. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Duration of treatment'.)

Special considerations and/or modifications of this regimen are warranted in the following circumstances:

CVC-associated VTE – In addition to providing anticoagulant therapy, removal of the CVC may be warranted. The decision depends on whether the CVC is functioning, whether the VTE is symptomatic, how critical central venous access is in the child's management, and the potential difficulty of obtaining new venous access [1,2]. If the CVC is not functioning or no longer necessary, it should be removed. However, if the VTE is asymptomatic and the child has an ongoing need for central venous access, it is reasonable to keep the CVC in place while treating with an anticoagulant and monitoring for symptom development. If the child develops signs of symptoms associated with the VTE, we suggest removal of the CVC if feasible. When the decision is made to remove the CVC, we typically remove it after three to five days of initial anticoagulation; however, there are scant data to support this approach and it is reasonable to remove the CVC sooner. For children with CVC-related VTE who continue to have their CVC in place at the end of the planned treatment period, we suggest providing ongoing VTE prophylaxis until the CVC is removed [1].

Management of a blocked CVC without a definite thrombus typically involves instilling recombinant tPA into the lumen of the catheter, as described below (see 'Blocked central venous catheter' below). Otherwise, thrombolytic therapy is generally not necessary in the management of uncomplicated CVC-related VTE; its use is limited to major vessel occlusion causing compromise of organs or limbs. (See 'Thrombolytic therapy' below.)

Malignancy – Management of thromboembolism in children with cancer requires special consideration because these patients typically have CVCs, are undergoing treatment with drugs that may affect anticoagulation decisions, and often need surgical procedures. The evaluation and management of VTE in children with cancer are discussed in a separate topic review. (See "Thromboembolism in children with cancer".)

Patients using estrogen-containing contraceptives – The additional consideration in this patient population is how to best manage ongoing contraception during anticoagulation therapy. Though the optimal practice has not been established, we favor changing to a progesterone-only oral contraceptive or implant or a levonorgestrel-releasing intrauterine device since these are not associated with increased VTE risk and have the advantage of reducing uterine bleeding. Others prefer to avoid all hormonal contraceptive therapy during anticoagulation therapy to minimize the risk of recurrent VTE. However, this practice may also exacerbate heavy, prolonged, or irregular menstrual bleeding, which is common in women receiving anticoagulant therapy. If hormonal contraception is discontinued in a patient who is sexually active, counselling should be provided on alternative methods of birth control and those receiving warfarin should be advised of the risk of congenital anomalies should pregnancy occur. The risks of continuing an estrogen-containing contraceptive during antithrombotic therapy are not established but are probably low.

The risk of thrombosis associated with estrogen-containing contraceptives and the risk of heavy menstrual bleeding in patients receiving anticoagulant therapy are discussed in greater detail separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Thrombophilia and thrombosis' and "Abnormal uterine bleeding: Management in premenopausal patients", section on 'Anticoagulant therapy'.)

SLE and antiphospholipid syndrome (APS) – Some patients with SLE may require prolonged or even lifelong anticoagulant therapy. The duration of therapy depends upon the persistent presence of antiphospholipid antibodies (aPL) and, to a lesser extent, the location of the thrombus. The most common approach in children with a first VTE is indefinite anticoagulant therapy as long as aPL are present. (See "Systemic lupus erythematosus (SLE) in children: Treatment, complications, and prognosis".)

APS is a condition that can occur in patients with or without SLE. It is characterized by recurrent VTE and persistent aPL. For patients with APS, lifelong anticoagulant therapy is suggested (typically with VKA [warfarin]). Management of APS is discussed in detail separately. (See "Management of antiphospholipid syndrome".)

Of note, the presence of aPL in plasma may interfere with the coagulation tests used to monitor heparin and VKA. If aPL interfere with the activated partial thromboplastin time (aPTT), either an insensitive aPTT reagent or a heparin assay should be used to monitor heparin therapy. If the aPL interfere with the prothrombin time (PT), plasma concentration of prothrombin can be used to monitor VKA therapy [6].

Unprovoked VTE — VTE is considered unprovoked if it is not attributable to an underlying risk factor (eg, CVC, trauma, surgery, estrogen) that predisposes the patient to thrombosis. Unprovoked thrombosis is rare in children. Treatment of unprovoked VTE consists of therapeutic anticoagulation for 6 to 12 months [1,2]. Children with recurrent unprovoked VTE are treated indefinitely [1,2].

In addition, children with unprovoked VTE should be tested for inherited thrombophilia, as summarized in the algorithm and table (algorithm 1 and table 3). This issue is discussed in detail separately. (See "Thrombophilia testing in children and adolescents".)

Blocked central venous catheter — When a CVC is blocked but no definite thrombus is identified, recombinant tPA (alteplase) may be used to lyse intraluminal thrombus and restore catheter patency. For this purpose, acceptable dosing regimens of recombinant tPA include:

Children ≤10 kg – Alteplase 0.5 mg/mL; instill a volume equal to the internal volume of the lumen catheter (maximum 1 mL/lumen)

Children >10 kg – Alteplase 1 mg/mL; instill a volume equal to the internal volume of the lumen catheter (maximum 2 mL/lumen)

After a dwell time of one to two hours, aspiration from the catheter should be attempted (the lumen should not be used until the tPA is withdrawn). If the first attempt is unsuccessful, the CVC may be treated with a second course of tPA [1,7]. If the CVC remains blocked after two doses of tPA, other causes of catheter malfunction (eg, kinking or malposition) should be excluded and an imaging study (ultrasound or contrast venography) should be performed to determine if there is a CVC-associated thrombosis. (See "Overview of complications of central venous catheters and their prevention in adults", section on 'Catheter malfunction'.)

Prospective and retrospective studies in children have demonstrated that alteplase is safe and effective in the restoration of function to occluded CVCs in infants and children [8-11].

Pulmonary embolism — Treatment of pulmonary embolism (PE) includes initial treatment with a parenteral anticoagulant (LMWH or UFH) for 5 to 10 days, then ongoing anticoagulation with LMWH, a DOAC, or VKA. As with venous thrombosis, the duration of anticoagulant therapy depends upon the severity of the PE and the nature of underlying risk factors [5,12,13]:

For nonsevere PE associated with a transient risk factor (eg, surgery), anticoagulation therapy is continued for six weeks

For PE that is severe and/or associated with a persistent risk factor (eg, cancer), anticoagulation therapy is continued for a minimum of three months

For unprovoked PE, the duration of treatment is 6 to 12 months

Choice of agent and guidance for transitioning from parenteral to oral therapy are discussed below. (See 'Choice of agent' below and 'Transitioning from parenteral to oral therapy' below.)

The decision to use a thrombolytic agent (eg, tPA or urokinase) should be individualized and considered only in children with extensive and hemodynamically compromising PE [1,2]. Consultation with a pediatric hematologist is recommended. Thrombectomy may also be considered if there is cardiovascular compromise; however, experience in children is extremely limited [2]. (See 'Thrombolytic therapy' below.)

Central nervous system — Treatment of cerebral venous thrombosis is discussed separately. (See "Cerebral venous thrombosis: Treatment and prognosis".)

Major vessel occlusion — For infants and children with major vessel occlusion causing compromise of organs or limbs, systemic or catheter-directed thrombolytic therapy may be warranted, as discussed below. (See 'Thrombolytic therapy' below.)

Inherited thrombophilia — Inherited thrombophilia is a genetic tendency to VTE. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Inherited thrombophilia' and "Thrombophilia testing in children and adolescents".)

Management considerations relevant to specific types of inherited thrombophilia are summarized in the algorithm and are discussed in detail separately (algorithm 2):

Factor V Leiden (see "Factor V Leiden and activated protein C resistance", section on 'Management')

Prothrombin 20210 mutation (see "Prothrombin G20210A", section on 'Management')

Protein S deficiency (see "Protein S deficiency", section on 'Management')

Protein C deficiency (see "Protein C deficiency", section on 'Thromboembolism management')

Antithrombin deficiency (see "Antithrombin deficiency", section on 'Management')

Choice of agent — The choice of anticoagulant agent is influenced by patient comorbidities, drug interactions, clinician preference and experience (eg, familiarity with newer agents), and other considerations specific to each drug (eg, cost, availability, formulation, ease of administration, and need for monitoring). Our general approach is outlined in the following sections. However, decisions should be individualized, weighing the benefits and risks and considering the values and preferences of the individual patient/family.

Initial therapy (first 5 to 10 days) — For the initial acute treatment of newly diagnosed VTE in children, we suggest administering parenteral anticoagulant therapy for at least five days. For most patients, we suggest LMWH rather than UFH. This is because LMWH has a more predictable anticoagulant response, requires less laboratory monitoring and dose adjustment, and can be administered subcutaneously (which is critically important for infants and young children with poor venous access) (table 1) [14].

However, UFH may be preferred for initial therapy in some circumstances, such as in patients with kidney failure or those with considerable bleeding risks who require finely tuned titration and the ability to quickly turn the infusion on or off (eg, patients requiring multiple surgeries or other invasive procedures). (See 'Low molecular weight heparin' below and 'Unfractionated heparin' below.)

The rationale for providing initial parenteral therapy in pediatric patients with VTE is based upon the design of the pediatric DOAC trials, in which all patients received parenteral therapy for at least five days before switching to an oral agent (see 'Efficacy' below). Thus, most regulatory approvals for DOACs in pediatric patients stipulate that their use should be limited to patients who have received initial parenteral therapy. This practice differs somewhat from adult practice, in which some DOACs (eg, rivaroxaban and apixaban) can be used for initial treatment without prior parenteral therapy. Based on the experience in adults, it may be reasonable to use rivaroxaban or apixaban for initial treatment in select older adolescents (ie, ≥15 years) if they are low risk (eg, hemodynamically stable, minimal signs and symptoms attributable to the thrombosis, and tolerating oral diet). This is an off-label use of these agents. (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)", section on 'Direct factor Xa and thrombin inhibitors'.)

Subsequent treatment — For subsequent treatment after the first 5 to 10 days, our suggested approach is as follows:

Adolescent patients (age ≥12 years) – For most adolescent patients, we suggest a DOAC (eg, dabigatran or rivaroxaban) for ongoing therapy after the initial 5 to 10 days. DOACs are preferred because they are orally administered, do not require frequent laboratory monitoring, and appear to have similar efficacy and bleeding risk compared with LMWH or VKA (table 1). The efficacy of DOACs in this age group is supported directly by pediatric clinical trials (most patients in these trials were adolescents) and indirectly by adult clinical trials, which had similar findings. (See 'Direct oral anticoagulants' below and "Venous thromboembolism: Anticoagulation after initial management", section on 'Direct thrombin and factor Xa inhibitors'.)

Children 2 to <12 years old – For children ages 2 to <12 years old, either a DOAC or LMWH is reasonable. The choice is based upon caregiver and clinician preference, comorbidities, and availability and cost of the drug. DOACs are often preferred by patients and families because they do not require injections or laboratory monitoring. However, they are relatively new agents in pediatric practice, there is less experience with them in this age group, and some clinicians may not be sufficiently familiar with them to use them routinely. The advantages of LMWHs are that there is greater experience with their use in children, the response is highly predicable, and their safety is well established. However, the need for subcutaneous injections can be very burdensome to patient and families. (See 'Direct oral anticoagulants' below and 'Low molecular weight heparin' below.)

Infants and children <2 years old – For most infants and young children (<2 years old), we suggest LMWH rather than other agents. LMWH is preferred over DOACs because there is greater experience with LMWHs and their efficacy and safety are well established in this age group. By contrast, the efficacy and safety of DOACs remain uncertain in this population since patients <2 years old were underrepresented in the pediatric DOAC trials. However, cautious use of a DOAC is a reasonable alternative to LMWH in select circumstances (eg, if the child requires long-term anticoagulation). LMWH is generally preferred over a VKA at this age because the response to VKA therapy is unpredictable due to considerable variation in vitamin K intake in young children's diets. Furthermore, warfarin is only available in tablet form, which presents an additional challenge when administering this drug to young children. (See 'Low molecular weight heparin' below and 'Direct oral anticoagulants' below and 'Vitamin K antagonists' below.)

Special circumstances – Special considerations may be needed when selecting an anticoagulant in the following circumstances:

Active cancer – While there are data supporting use of DOACs in adult cancer patients, pediatric evidence in this setting is scant. The clinical trials discussed below included relatively few patients with active cancer (see 'Efficacy' below). Thus, some clinicians prefer LMWH for treatment of VTE in pediatric patients with active cancer. However, a DOAC may be a reasonable option for an older adolescent patient, based upon indirect evidence from the adult trials. This issue is discussed in greater detail separately. (See "Thromboembolism in children with cancer", section on 'Management' and "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Direct oral anticoagulants'.)

Nephrotic syndrome – There are limited data on the use of DOACs in patients with nephrotic syndrome. Some clinicians prefer LMWH or VKA when treating VTE in these patients. This issue is discussed separately. (See "Symptomatic management of nephrotic syndrome in children", section on 'Treatment of venous thromboembolism' and "Hypercoagulability in nephrotic syndrome".)

Impaired kidney function – LMWH and DOACs should not be used in patients with severe kidney failure (ie, estimated glomerular filtration rate <30 mL/minute); warfarin is generally the preferred agent for such patients. In patients with mild to moderate kidney impairment, LMWH can be used with dose reduction and/or adjustment based on anti-factor Xa levels (for details, refer to the drug information monograph for enoxaparin and other LMWH agents). There are limited data on use of DOACs in pediatric patients with kidney impairment.

Heavy menstrual bleeding – In postmenarchal females, there is increased risk of heavy menstrual bleeding in patients receiving DOACs compared with VKA; the risk appears to be greatest with rivaroxaban. While this does not preclude using a DOAC in this population, the issue should be discussed up front with the patient as part of shared decision-making. If the patient chooses DOAC therapy and experiences heavy menstrual bleeding while on treatment, it may be necessary to switch to another agent. This issue is discussed in greater detail separately. (See "Abnormal uterine bleeding: Management in premenopausal patients", section on 'Anticoagulant therapy'.)

Pregnancy – LMWH is the preferred agent for treatment of VTE during pregnancy, as discussed in detail separately. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment" and "Use of anticoagulants during pregnancy and postpartum".)

APSWarfarin is generally the preferred agent in patients with APS. An extended duration is often warranted. This is discussed separately. (See "Management of antiphospholipid syndrome".)

Heparin-induced thrombocytopenia (HIT) – HIT is uncommon in pediatric patients. For patients with VTE and a diagnosis of HIT, a non-heparin anticoagulant should be administered. The management of patients with HIT is discussed in detail separately. (See "Management of heparin-induced thrombocytopenia".)

Limited role for other agents — Anticoagulants in the four categories discussed in the sections below (ie, UFH, LMWH, DOACs, and VKAs) are the agents used most commonly in children. Other agents that are used less frequently include argatroban, bivalirudin, and fondaparinux. Data on these agents in pediatric patients are fairly limited [15-23]. Fondaparinux has been used as alternative to LMWH for initial treatment of pediatric VTE, but this is uncommon [23]. Otherwise, use of these agents in children is generally limited to patients with HIT who require cessation of heparin and ongoing anticoagulation with non-heparin agents (argatroban and fondaparinux are the agents most commonly used in this setting) [16,17,19,24]. These agents are discussed in greater detail separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Parenteral direct thrombin inhibitors' and "Fondaparinux: Dosing and adverse effects" and "Management of heparin-induced thrombocytopenia".)

Transitioning from parenteral to oral therapy — The approach to transitioning from parenteral to oral therapy in patients undergoing therapeutic anticoagulation is as follows:

DOACs – After at least five days of initial parenteral therapy, the DOAC can be started at the appropriate dose for age and/or weight, as summarized in the tables (table 4 and table 5). When transitioning from LMWH, the DOAC should be started at the time of or up to two hours prior to the next scheduled LMWH dose. When transitioning from a continuous UFH infusion, the DOAC is started at the time that the UFH infusion is discontinued. (See 'Direct oral anticoagulants' below.)

As previously discussed, the practice of administering initial parenteral therapy in children with VTE differs somewhat from adult practice, in which some DOACs (eg, rivaroxaban and apixaban) can be used for initial treatment without prior parenteral therapy. Based on the experience in adults, it may be reasonable to use rivaroxaban or apixaban for initial treatment in select older adolescents (ie, ≥15 years) if they are low risk (eg, hemodynamically stable, minimal signs and symptoms attributable to the thrombosis, and tolerating oral diet). This is an off-label use of these agents. (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)", section on 'Direct factor Xa and thrombin inhibitors'.)

VKA – If VKA (eg, warfarin) is chosen for subsequent therapy, it can be started after one to two days of parenteral therapy. Treatment should overlap with UFH or LMWH until the international normalized ratio (INR) is in the therapeutic range (ie, 2.0 to 3.0) on two consecutive days. (See 'Vitamin K antagonists' below.)

APPROACH TO VTE PROPHYLAXIS

Primary prophylaxis — Indications for primary prophylaxis in children without a prior episode of VTE are not well established. Pediatric data on VTE prophylaxis are limited. Important considerations include the number and nature of risk factors for VTE (table 2), whether the risk factors are transient or chronic, and the bleeding risk [25].

Hospitalized patients — Our suggested approach to thromboprophylaxis for hospitalized pediatric patients who are acutely ill or recovering from surgery is as follows:

Mechanical prophylaxis – The use of mechanical methods for VTE risk reduction (eg, compression stockings and, size permitting, intermittent pneumatic compression devices) is encouraged if there are risk factors for VTE (eg, immobility and/or critical illness). However, these devices are not available in appropriate sizes for small children and, therefore, this approach may not be feasible for young children. Early mobilization is encouraged whenever possible, and this may be sufficient prophylaxis in patients who are low risk (ie, ≤1 VTE risk factor). Early mobilization and mechanical methods are also the primary means for providing prophylaxis in patients with high bleeding risks since pharmacologic thromboprophylaxis is generally avoided in such patients until bleeding risks lessen [25].

Indications for pharmacologic thromboprophylaxis – There are no established standards of practice regarding when to initiate thromboprophylaxis in hospitalized children; decisions are individualized, based chiefly on the number and nature of underlying risk factors.

Use of prophylactic anticoagulant therapy is limited to children who have multiple risk factors and who are not at high risk of bleeding complications [4,26]. Important risk factors of VTE in this setting include [25,27-32]:

Prior history of VTE or known thrombophilia

Critical illness

Surgery (particularly orthopedic and cardiac surgery)

Trauma

Mechanical ventilation

Presence of a central venous catheter (CVC)

Systemic infection

Anticipated hospital length of stay of ≥3 days

Prolonged immobility

Age (risk is highest among neonates and postpubertal adolescents)

Estrogen-containing contraceptive use

Obesity

Of these, a prior history of VTE and known thrombophilia are particularly strong predictors and either of these risk factors alone may be sufficient reason to administer thromboprophylaxis during an acute hospitalization, provided that there are no contraindications [32,33].

Pediatric VTE risk prediction rules and decision algorithms are available [28,29,31,32,34-37]; however, none has been prospectively validated. Guidelines have been proposed for pediatric trauma patients [38]; however, as the authors of the guideline indicate, their recommendations are based on very low-quality evidence. (See "Venous thromboembolism risk and prevention in the severely injured trauma patient", section on 'Pediatric trauma considerations'.)

Limited clinical trial data and observational studies support the efficacy of pharmacologic thromboprophylaxis in hospitalized children with risk factors for VTE, particularly those with prior VTE [33,39].

Pharmacologic thromboprophylaxis is generally not indicated for the following groups of patients, unless there are additional clinically relevant risk factors (eg, known inherited thrombophilia or history of prior VTE) [1]:

Children with CVCs without other risk factors

Children with cancer and CVCs without additional risk factors (see "Thromboembolism in children with cancer", section on 'Primary prevention')

Anticoagulant therapy is routinely prescribed for VTE prophylaxis in hospitalized adult patients; however, it is not appropriate to apply this practice broadly to the pediatric population, because the risk of VTE is far lower in children compared with adults and, therefore, the risk:benefit ratio is less favorable (see "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Risk of VTE in children versus adults'). Nevertheless, if an adult patient (ie, >18 years old) is cared for in a pediatric setting, clinicians should generally follow adult practice guidelines for VTE prophylaxis. The approach in adult patients is discussed separately. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Select high-risk conditions – Thrombotic risk is particularly high in children hospitalized with the following conditions or circumstances. The role of thromboprophylaxis in these conditions is discussed separately:

Cardiac surgery (eg, repair of congenital heart disease; see individual topics on specific congenital heart disease lesions)

Severe acute heart failure (eg, severe myocarditis or other etiology) (see "Heart failure in children: Management", section on 'Thromboembolism' and "Treatment and prognosis of myocarditis in children", section on 'Anticoagulation')

Kawasaki disease (affected patients are mostly at risk for arterial thrombosis [coronary artery thrombosis] rather than VTE) (see "Cardiovascular sequelae of Kawasaki disease: Management and prognosis", section on 'Antithrombotic therapy')

Acute severe traumatic injury (see "Venous thromboembolism risk and prevention in the severely injured trauma patient", section on 'Pediatric trauma considerations')

Coronavirus disease 2019 (COVID-19)-related multisystem inflammatory syndrome (see "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome", section on 'Antithrombotic therapy')

Asparaginase therapy for acute lymphoblastic leukemia (see "Overview of the treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Thrombosis' and "Antithrombin deficiency", section on 'VTE prophylaxis (asparaginase)')

Acute flare of inflammatory bowel disease (see "Management of severe or refractory ulcerative colitis in children and adolescents", section on 'Venous thromboembolism')

Nephrotic syndrome (see "Symptomatic management of nephrotic syndrome in children", section on 'Hypercoagulability' and "Hypercoagulability in nephrotic syndrome", section on 'Prevention of thromboembolism')

Choice of agent and dosing – When the decision is made to administer pharmacologic thromboprophylaxis in the acute inpatient setting, low molecular weight heparin (LMWH) is generally the preferred agent since there is greater experience with this agent (see 'Choice of agent' above). Prophylactic doses for different LMWH agents in children are presented in the table (table 6). (See 'Low molecular weight heparin' below.)

There are limited data on the use of direct oral anticoagulants (DOACs) for primary thromboprophylaxis in hospitalized pediatric patients, and they are not approved for this indication. (See 'Direct oral anticoagulants' below.)

Duration – Thromboprophylaxis is continued only so long as important clinically relevant risk factors persist. For example, an adolescent patient with risk factors including bloodstream infection, mechanical ventilation, CVC, and immobility can have prophylaxis discontinued once they are extubated, afebrile, and ambulating regularly (note that the presence of a CVC alone is not a reason for ongoing prophylaxis).

Our suggestions for thromboprophylaxis in hospitalized patients are distinct from the routine use of low-dose heparin flushes or infusions to maintain CVC patency. (See "Overview of central venous access in adults", section on 'Catheter management' and "Neonatal thrombosis: Management and outcome", section on 'Prevention of catheter-associated thrombosis'.)

Patients with long-lasting VTE risk — Long-term prophylactic antithrombotic therapy may be warranted for patients who have considerable long-lasting risk of VTE. Warfarin is the agent that historically has been used for this indication, and, thus, there is greater experience and more data available regarding its use. DOACs are increasingly being used in the modern era, though this is an off-label use and there are few published reports to support their efficacy in this setting. DOACs should not be used in patients with patients with mechanical heart valves.

The following are some examples of clinical settings where long-term anticoagulant therapy may be used for primary prophylaxis, some of which are discussed in greater detail separately [1]:

Children receiving long-term home total parenteral nutrition [40,41]

Children undergoing hemodialysis via an arteriovenous fistula or central venous access device [42]

Selected patients with congenital and infantile nephrotic syndrome (see "Neonatal thrombosis: Management and outcome", section on 'Congenital nephrotic syndrome' and "Congenital and infantile nephrotic syndrome")

Children with certain forms of cardiac disease, including:

Univentricular heart following palliation with cavopulmonary shunt (see "Management of complications in patients with Fontan circulation", section on 'Thrombosis')

Following mechanical valve replacement (warfarin is the preferred agent for this indication) (see "Antithrombotic therapy for mechanical heart valves")

Severe cardiomyopathy (see "Heart failure in children: Management", section on 'Thromboembolism')

Pulmonary hypertension (see "Pulmonary hypertension in children: Management and prognosis", section on 'Conventional medical therapy')

Aspirin may be a reasonable alternative to anticoagulation in some patients with these cardiac conditions, with the exception of mechanical valve replacement.

Secondary prevention — For patients with a prior episode of VTE, we suggest long-term anticoagulant thromboprophylaxis if the patient has either of the following:

Prior history of provoked VTE with ongoing or recurrent VTE risk factor(s) other than CVC; examples include:

One of the chronic conditions requiring long-term primary prophylaxis, as listed above (long-term total parenteral nutrition dependency, hemodialysis dependency, certain forms of heart disease, congenital nephrotic syndrome) (see 'Primary prophylaxis' above)

Inflammatory bowel disease, during disease flares (see "Clinical manifestations and complications of inflammatory bowel disease in children and adolescents", section on 'Venous thromboembolism')

Systemic lupus erythematosus (SLE), during flares and/or if there are persistent antiphospholipid antibodies (aPL) (see "Management of antiphospholipid syndrome", section on 'Secondary thrombosis prevention')

Recurrent unprovoked VTE (see 'Unprovoked VTE' above)

ANTICOAGULANT AGENTS — The anticoagulant agents used most commonly in children include low molecular weight heparin (LMWH), unfractionated heparin (UFH), direct oral anticoagulants (DOACs; eg, dabigatran, rivaroxaban), and vitamin K antagonists (VKA; eg, warfarin). The use of other anticoagulant agents such as fondaparinux, argatroban, and bivalirudin is limited in children.

The following sections provide guidance for using these agents in pediatric patients. The advantages and disadvantages of these agents are summarized in the table (table 1). The approach to selecting an anticoagulant agent for treating VTE in children is discussed above (see 'Choice of agent' above). The pharmacology and general principles of use for these agents are discussed in separate topic reviews. (See "Heparin and LMW heparin: Dosing and adverse effects" and "Biology of warfarin and modulators of INR control" and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Low molecular weight heparin

Dose and monitoring

Dose – Guidance for therapeutic and prophylactic dosing for different LMWH agents (including enoxaparin, dalteparin, nadroparin, reviparin, and tinzaparin) in children is presented in the table (table 6) [43-46].

Dose adjustment and close monitoring of anti-factor Xa levels are necessary in children with renal insufficiency. If renal insufficiency is severe, LMWH should be avoided. The therapeutic dose of LMWH is age dependent, with newborns having increased dose requirements per body weight compared with older children [47-50]. Higher doses may also be necessary in critically ill children [51].

Monitoring – LMWH therapy is monitored using the anti-factor Xa assay. The approach depends on whether the drug is used for treatment or prophylaxis:

Treatment – Because of individual variation in responsiveness, patients receiving treatment doses of LMWH should be monitored periodically by checking anti-factor Xa levels. Samples should be taken four to six hours after the last subcutaneous injection; with this timing, the therapeutic range is between 0.5 and 1 units/mL. A nomogram for dose titration of LMWH according to anti-Xa levels is presented in the table (table 6).

The anti-factor Xa response to LMWH is fairly predictable, though minor dose adjustments are often required. In a systematic review and meta-analysis of 16 studies (1013 patients), 42 percent of patients had therapeutic anti-Xa levels after the initial LMWH dose, an additional 38 percent of patients reached therapeutic levels after one to two dose adjustments, and the remaining 20 percent required ongoing dose titration or did not achieve therapeutic levels during treatment [48].

Prophylaxis – Laboratory monitoring is generally not necessary when LMWH is used at prophylactic dosing. However, monitoring anti-Xa levels may be appropriate in select circumstances (eg, patients with renal insufficiency).

Efficacy — The efficacy of LMWH in pediatric patients is supported by observational data and a few small clinical trials [48,52]. Enoxaparin is the agent that has been studied the most. In a systematic review and meta-analysis of 19 prospective and retrospective studies including 986 pediatric patients treated with LMWH, 97 percent remained free of VTE recurrence during treatment [48]. Of patients who had radiographic follow-up, 64 percent had partial or complete resolution of the thrombus.

A randomized trial in children with VTE comparing treatment with LMWH (reviparin) versus UFH followed by a VKA was closed prematurely due to slow patient accrual [52]. The study, as published, was underpowered to detect any significant differences between these two treatment approaches.

Adverse effects — The risk of clinically significant bleeding in children treated with LMWH is approximately 2 to 3 percent [48,53]. In a systematic review and meta-analysis of 30 prospective and retrospective studies (1329 children), 1.8 percent of patients experienced major bleeding; minor bleeding complications occurred in 16 percent of patients [48].

Patients receiving LMWH who undergo lumbar puncture or neuraxial anesthesia can experience epidural or spinal hematomas, which can result in long-term or permanent paralysis. For children undergoing lumbar puncture, at least two scheduled doses of LMWH should be omitted prior to the procedure.

Other complications, including heparin-induced thrombocytopenia (HIT) and osteoporosis, are relatively rare with LMWH compared with UFH [54,55]. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Drugs that affect bone metabolism", section on 'Anticoagulants'.)

Reversal — If clinically significant bleeding occurs with LMWH therapy, protamine sulfate should be administered intravenously (IV) and will neutralize approximately 75 percent of the anti-factor Xa activity [56].

For reversal of enoxaparin, the dose of protamine sulfate depends upon the dose and time since the dose was administered [57]:

If enoxaparin was given within eight hours, the dose of protamine is 1 mg per 1 mg enoxaparin, given by slow IV push

If >8 hours have passed since the last enoxaparin dose, the dose of protamine is 0.5 mg per 1 mg enoxaparin, given by slow IV push

Additional details regarding heparin reversal are provided separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Reversal'.)

Unfractionated heparin

Dose and monitoring

Dose – For treatment of VTE, UFH is administered as a continuous IV infusion, usually with an initial loading dose:

Loading dose – The initial loading dose is 75 units/kg (based on actual body weight; maximum adult dose 10,000 units) IV over 10 minutes. Boluses should be reduced or withheld for patients with significant bleeding risks (eg, children recovering from a neurosurgical procedure or with other risks for intracranial bleeding).

Maintenance dose – The initial maintenance dose of depends on the age of the patient [1,58-60]:

-Infants – 28 units/kg per hour. The increased requirement for UFH in the young reflects a faster clearance of UFH due to a larger volume of distribution [61,62].

-Children (≥1 year old) and adolescents – 20 units/kg per hour (based on actual body weight; maximum adult dose 2,000 units per hour).

Monitoring – UFH therapy in children is monitored by measuring anti-factor Xa activity; the target range for therapeutic heparinization is 0.35 to 0.7 units/mL [1]. A nomogram for dose titration is provided in the table (table 7). Monitoring activated partial thromboplastin time (aPTT) alone can be used to facilitate dose adjustments only after establishing the aPTT range that corresponds to the target anti-factor Xa activity range in an individual patient.

In infants and children, aPTT monitoring is not a reliable marker for therapeutic UFH levels, because of age-dependent variations in the mechanism of action of UFH [1,59,63-67]. One study of 187 children treated with UFH demonstrated that a considerable number of aPTT results were >180 seconds or unrecordable (>600 seconds) even when the anti-factor Xa levels were in a therapeutic range [59]. These results suggest that using only aPTT test results to titrate UFH dosing in children may result in reducing UFH to subtherapeutic levels. This is in contrast with adults, in whom the correlation is more predictable and aPTT can be used to make dose adjustments. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Laboratory monitoring and dose titration (unfractionated heparin)'.)

In infants and children requiring high doses of UFH and/or with difficulty achieving target anti-factor Xa activity, it may be reasonable to check the patient's antithrombin (AT) level and administer AT concentrate if AT levels are low, although data to support this practice are limited [68]. Infants and young children often exhibit relatively low circulating AT levels secondary to developmental hemostasis, and AT concentrate may facilitate anticoagulation with UFH in these patients. However, AT administration is generally avoided in preterm infants, as discussed separately. (See "Neonatal thrombosis: Management and outcome", section on 'Unfractionated heparin'.)

UFH dosing strategies also should take into account the significance of the clot and potential risk of bleeding in an individual patient [1,65,66].

Adverse effects — Adverse effects may include bleeding, osteoporosis, and HIT:

Bleeding – Reported rates of bleeding associated with UFH in children vary considerably depending on the population studied [65,67,69]. In one study of critically ill children treated with UFH, the reported rate of clinically significant bleeding was 24 percent [69]. In studies of lower-risk children, bleeding occurred in 2 to 10 percent [65,67].

Osteoporosis – There is some evidence that prolonged use of heparin reduces bone density and contributes to osteoporosis. Although there are only a few case reports suggesting this possible association in children, the available information in adults suggests that prolonged use of UFH should be avoided [1]. (See "Drugs that affect bone metabolism", section on 'Heparin'.)

HIT – HIT is caused by heparin-dependent antiplatelet antibodies. In children, HIT seems to be relatively uncommon, but it should be considered in a patient receiving heparin who develops thrombocytopenia without an obvious other cause [70-75]. In retrospective studies, the 4Ts score (calculator 1) appeared to be useful to exclude HIT in children, but prospective data are lacking [76,77]. If HIT is strongly suspected or confirmed, heparin therapy (including both UFH and LMWH) and all other forms of heparin (eg, heparin flushes) should be stopped and another anticoagulant (eg, argatroban, fondaparinux) employed [52,78]. HIT is discussed in great detail separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Management of heparin-induced thrombocytopenia".)

Adverse effects of heparin are discussed in greater detail separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Bleeding' and "Heparin and LMW heparin: Dosing and adverse effects", section on 'Other complications'.)

Reversal — Bleeding complications secondary to UFH can usually be controlled by termination of the infusion. If the bleeding is life-threatening or immediate reversal is required, heparin can be neutralized rapidly by protamine sulfate given by slow IV push. The dose of protamine sulfate is based upon the amount of heparin received in the previous two hours; 1 mg of protamine sulfate inactivates 100 units of UFH [1].

Additional details regarding heparin reversal are provided separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Reversal'.)

Direct oral anticoagulants — DOACs include the direct thrombin inhibitors dabigatran and factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. Dabigatran and rivaroxaban are the agents that are best studied in pediatric patients. Both agents are approved by the US Food and Drug Administration for treatment and secondary prevention of VTE in pediatric patients [79,80]. They are also approved for use in pediatric patients in other parts of the world, including Canada, the United Kingdom, and Europe [81-83].

Compared with VKAs, DOACs have the advantage of having a more predictable dose response and less need for laboratory monitoring. As experience is gained with using DOACs in children and as long-term data become available, they are likely to play an important role in managing and preventing VTE in pediatric patients.

The available clinical trial data on dabigatran and rivaroxaban in pediatric patients suggest that these agents have similar efficacy compared with standard anticoagulants (ie, LMWH and warfarin) without increased bleeding [84-88]. Clinical trials involving other DOAC agents (apixaban and edoxaban) are ongoing [89-91].

General properties of DOACs, including mechanism of action, side effects, and dosing for adult patients, are discussed separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Dosing and administration — Pediatric dosing guidance for dabigatran and rivaroxaban for treatment of VTE is summarized in the tables (table 4 and table 5).

When DOACs are used for treatment of VTE, the patient should receive at least five days of parenteral anticoagulant therapy (typically with LMWH) before transitioning to the DOAC. (See 'Transitioning from parenteral to oral therapy' above.)

When DOACs are used for primary or secondary VTE prevention, a lower dose may be appropriate depending on the agent (for rivaroxaban, we typically use one-half of the treatment dose; for dabigatran, we generally do not use reduced dosing in this setting).

Pretreatment testing and monitoring — Laboratory testing prior to initiating dabigatran or rivaroxaban should include a complete blood count with platelet count, prothrombin time (PT), and aPTT to assess and document coagulation and measurement of serum creatinine, as a baseline. For rivaroxaban, liver function tests should also be obtained as a baseline prior to treatment.

During DOAC treatment, routine monitoring of coagulation studies is not required, because drug levels are relatively predictable for a given dose and there is no established therapeutic range.

Tests that can be performed to determine whether anticoagulant activity is present (eg, for a patient with bleeding or emergency surgery) are discussed in a separate topic review. (See "Clinical use of coagulation tests", section on 'Monitoring direct oral anticoagulants'.)

Efficacy — The efficacy and safety of dabigatran and rivaroxaban in pediatric patients were established in two large multicenter randomized trials [86,87]:

Dabigatran – The DIVERSITY trial was an open-label trial involving 267 children with VTE who were randomly assigned to treatment with dabigatran (after 5 to 20 days of parenteral therapy) or standard anticoagulation (which consisted of VKA in 54 percent, LMWH in 44 percent, and fondaparinux in 1 percent) [87]. After a median treatment duration of 85 days, patients treated with dabigatran had similar rates of complete thrombus resolution compared with patients in the control arm (46 versus 42 percent, respectively; weighted absolute risk difference 4 percent, 90% CI -7 to 14 percent). Partial thrombus resolution was also seen in a similar proportion of patients in both groups (32 versus 28 percent). Rates of VTE recurrence were not statistically different (4 versus 8 percent). Major bleeding events occurred at the same rate in both groups (2 percent). There was only one death during study treatment (in the control arm).

An important limitation of the DIVERSITY trial is that patients assigned to the dabigatran arm had drug levels monitored and the trial protocol allowed for one dose adjustment based upon these levels (if the level remained sub- or supratherapeutic after one dose adjustment, patents were switched to a standard anticoagulant). Overall, 35 percent of patients in the dabigatran arm had their dose adjusted based upon plasma drug concentration (most were up titrations due to subtherapeutic levels). This limits the generalizability of the findings of the DIVERSITY trial since therapeutic drug monitoring for dabigatran is not routinely used in clinical practice.

Another prospective single-arm study conducted by the same investigators describes the experience using dabigatran for secondary prevention of VTE [88]. In this study, 203 children with VTE who had completed three months of anticoagulant therapy (either with a standard anticoagulant or with dabigatran), and with a persistent risk factor requiring ongoing anticoagulation, received dabigatran for up to 12 months (with a shorter duration if the risk factor resolved). Over a median treatment duration of 36 weeks, two patients (1 percent) experienced VTE recurrence, two patients (1 percent) developed post-thrombotic syndrome (PTS), and three patients (1.5 percent) experienced major bleeding events.

Rivaroxaban – The EINSTEIN-Jr trial was an open-label trial involving 500 children with VTE who were randomly assigned to treatment with rivaroxaban (after five to nine days of parenteral therapy) or standard anticoagulation (continued LMWH or switched to VKA) [86]. Most patients in the trial were treated for three months, except for infants and children <2 years old with catheter-associated venous thrombosis, who were treated for only one month. At the end of treatment, more children in the rivaroxaban treatment group had complete resolution of the thrombus on follow-up imaging compared with patients in the control group (38 versus 26 percent, respectively; adjusted odds ratio 1.70, 95% CI 1.11-2.58). Symptomatic recurrent VTE occurred in 1 percent of patients receiving rivaroxaban compared with 3 percent of those receiving standard anticoagulants (hazard ratio 0.40, 95% CI 0.11-1.41). Major or clinically relevant nonmajor bleeding occurred in 3 percent of patients receiving rivaroxaban compared with 2 percent of patients receiving standard anticoagulants (hazard ratio 1.58, 95% CI 0.51-6.27). There was one death that was unrelated to anticoagulant therapy (a rivaroxaban-treated child who died of cancer progression).

The findings in these trials are similar to the findings in trials that established the efficacy and safety of DOACs in adult patients, which are discussed separately. (See "Venous thromboembolism: Anticoagulation after initial management", section on 'Direct thrombin and factor Xa inhibitors'.)

Overall, the DIVERSITY and EINSTEIN-Jr trials provide moderate-certainty evidence supporting the efficacy and safety of DOACs in adolescent patients (particularly when viewed together with the similar findings in adult trials). However, the efficacy and safety of DOACs in infants and young children are less certain since they were underrepresented in the DIVERSITY and EINSTEIN-Jr trials (of the 767 patients in the two trials combined, 58 percent were adolescents, 30 percent were age >2 to 11 years, and only 12 percent were ≤2 years old). In addition. there are important differences in the coagulation system and risks of VTE and bleeding in young children and infants compared with adolescents and adults, as discussed separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Risk of VTE in children versus adults'.)

As use of DOACs in pediatric patients rises, more will be learned about how these agents perform outside of the clinical trial setting. We encourage clinicians to engage with the International Pediatric Thrombosis Network to collect real-world data regarding the use of DOACs in children.

Adverse effects — In the clinical trials described above, bleeding events occurred at similar rates in patients treated with DOACs as in patients treated with other anticoagulants. Major or clinically relevant nonmajor bleeding events occurred in 2 to 3 percent of patients, and minor bleeding episodes occurred in approximately 20 percent of patients [86-88].

Other adverse events reported in the trials included headaches and gastrointestinal upset; however, these occurred at similar rates in DOAC-treated patients and the control group.

Adverse effects of DOACs are discussed in greater detail separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Management of bleeding — The approach to managing patients who experience excessive bleeding while on DOAC therapy depends upon the severity:

For minor bleeding, we hold the DOAC and any other anticoagulant or antiplatelet agents until bleeding has resolved.

For moderate bleeding, we stop the DOAC and any other anticoagulant or antiplatelet agents and administer desmopressin (DDAVP).

For severe or life-threatening bleeding, we stop the DOAC and any other anticoagulant or antiplatelet agents, administer DDAVP, and give prothrombin complex concentrate (PCC).

Other strategies for reversing the anticoagulant effect of DOAC agents are summarized in the table (table 8). In adults, specific reversal agents (idarucizumab for dabigatran, andexanet alfa for direct factor Xa inhibitors [eg, rivaroxaban]) are available for use in emergency situations. However, the efficacy and safety of these agents have not been established in pediatric patients. Furthermore, they are not available in all settings.

Management of bleeding in patients receiving DOACs is discussed in greater detail separately. (See "Management of bleeding in patients receiving direct oral anticoagulants".)

Vitamin K antagonists

Dose, monitoring, and adverse effects

Initial dose – The initial dose of warfarin is 0.2 mg/kg orally (maximum 5 mg) [1]. In patients with mild liver dysfunction and/or elevated baseline PT, a lower initial dose should be used (eg, 0.1 mg/kg). Warfarin should be avoided in patients with severe liver failure. A lower initial dose (0.1 mg/kg) is also appropriate when warfarin is used for VTE prophylaxis (eg, after the Fontan procedure) [92]. (See "Management of complications in patients with Fontan circulation", section on 'Thrombosis'.)

Monitoring – VKA therapy is monitored with the PT, which is reported as an international normalized ratio (INR) in order to assure comparability among the various laboratories [93]. (See "Clinical use of coagulation tests", section on 'Prothrombin time (PT) and INR'.)

The therapeutic range for VKA therapy for treatment of VTE in children is typically an INR of 2 to 3; this range is largely based on recommendations for adults. Patients with mechanical heart valves should be treated according to adult recommendations, in which the target INR varies depending on the valve position and type. (See "Antithrombotic therapy for mechanical heart valves".)

The INR should be checked daily until levels are in the target range for two or more consecutive days (table 9). The interval between testing can be gradually increased if the INR remains stable. In the maintenance phase, the INR is typically checked every one to two weeks, depending on the child's clinical stability and age (more frequent testing may be necessary in young children).

Monitoring VKA therapy in children requires more frequent INR measurements and dose adjustments than in adult patients because children's diets have a wide range of vitamin K intake. Patients receiving VKA therapy should receive dietary counseling on maintaining a diet with a relatively constant vitamin K intake; however, this can be challenging in young children. Diets with poor sources of vitamin K, such as breast milk, induce sensitivity to VKA. Diets supplemented with vitamin K, such as total parenteral nutrition or nutrient formula, induce resistance to VKA [40,92]. In addition, many children who are treated with VKA are taking other medications that can reduce absorption from the intestine or alter the metabolic clearance of VKA [1,92].

Adverse effects – The major side effect of VKA is bleeding. The risk of major bleeding in children treated with VKAs appears to be low (ie, <2 percent) [40,42,94]. Other side effects of VKAs, such as tracheal calcification or hair loss, are rarely seen in children [95]. Teratogenic effects are a potential concern in adolescent females should pregnancy occur. This is discussed separately. (See "Warfarin and other VKAs: Dosing and adverse effects" and "Use of anticoagulants during pregnancy and postpartum".)

Reversal — When reversal of VKA anticoagulation therapy is required, management consists of vitamin K administration with or without transfusion of PCC or fresh frozen plasma (FFP). (See "Management of warfarin-associated bleeding or supratherapeutic INR".)

The approach depends upon the clinical situation:

Patients with active bleeding – In patients with life-threatening bleeding (eg, intracranial hemorrhage), IV vitamin K can be administered at a dose of 5 to 10 mg by slow infusion over 10 to 20 minutes, in combination with infusion of PCC (50 units/kg). If PCC is not available, FFP (20 mL/kg) can be used. IV administration of recombinant factor VIIa also may be considered.

In patients with clinically significant but not life-threatening bleeding, IV vitamin K can be administered at a dose of 0.5 to 2 mg, in combination with transfusion of either PCC or FFP.

Supratherapeutic INR without active bleeding – For patients with an excessively elevated INR (eg >8) who lack active bleeding, we typically administer small doses of vitamin K (0.5 to 1 mg orally). The aim is to modestly improve the INR without fully reversing the effect. If the response is not adequate, larger doses (2 to 5 mg orally) can be given. Lower doses of vitamin K are preferred in patients who will require ongoing VKA therapy since larger doses can make the patient temporarily resistant to the further action of VKA. Alternatively, based on limited data, a single IV dose of vitamin K (30 micrograms/kg) can be used to lower the INR [96]. In addition to administering vitamin K, subsequent doses of VKA should be held until the INR falls into the therapeutic range. For patients with supratherapeutic INR in a range that is not excessively elevated (eg, 3.5 to 8) who lack active bleeding, reversal is generally not necessary and management consists of holding VKA until the INR is in the therapeutic range and then restarting at a lower dose (table 9).

THROMBOLYTIC THERAPY — Use of systemic or catheter-directed thrombolytic therapy in infants and children is limited to cases wherein major vessel occlusion is causing compromise of organs or limbs [1]. Recombinant tissue plasminogen activator (tPA; alteplase) is the thrombolytic agent used most commonly in children; urokinase (not available in the United States) is used infrequently.

Data on the efficacy, dose, and safety of thrombolytic agents in this setting are limited, and indications for thrombolytic therapy remain highly individualized [1,97-101]. Consultation with a vascular specialist and/or pediatric hematologist is advised. The use of thrombolytic agents in neonates is discussed separately. (See "Neonatal thrombosis: Management and outcome", section on 'Thrombolytic therapy'.)

Thrombolytic therapy should not be used in patients with right-to-left cardiac shunts, because of the risk of arterial emboli to the central nervous system.

Systemic thrombolysis – The optimal dose of recombinant tPA for systemic thrombolysis in children is not established. The available evidence is limited to case reports and single-institution case series. The doses used in these reports ranged from 0.1 to 0.6 mg/kg per hour for a duration of six hours [1]. Some patients may require a longer or shorter duration of therapy. An alternative dosing regimen consisting of low-dose infusion (0.01 to 0.06 mg/kg per hour) for up to 96 hours may have a decreased incidence of major bleeding [99,101]. Unfractionated heparin (UFH) therapy is typically discontinued or provided at a low dose (eg, 10 units/kg per hour) during thrombolytic infusion.

Catheter-directed thrombolysis – Catheter-directed thrombolysis refers to a low-dose infusion of recombinant tPA through a catheter with the tip situated within the thrombus. This approach may offer several advantages over systemic thrombolysis, including higher response rate and decreased rate of major bleeding complications [97]. The recommended dose for catheter-directed thrombolysis with recombinant tPA is 0.01 mg/kg per hour for 24 hours. UFH therapy is typically provided at a low dose (eg, 10 units/kg per hour) during thrombolytic infusion.

Monitoring – Pretreatment testing prior to starting thrombolytic therapy includes a complete blood count, fibrinogen level, and coagulation studies (ie, prothrombin time [PT], international normalized ratio [INR], and activated partial thromboplastin time [aPTT]). Fresh frozen plasma (FFP) should be administered if the fibrinogen level is<100 mg/dL. Fibrinogen and hemoglobin levels are then monitored every six hours during the infusion; FFP should be provided for fibrinogen levels <100 mg/dL.

Prevention and management of bleeding – The major complication of thrombolytic therapy is bleeding. Before thrombolytic therapy is initiated, any derangements that may increase the risk of bleeding (eg, thrombocytopenia, vitamin K deficiency) should be corrected. In patients who are at high risk for bleeding, thrombolytic therapy should be avoided [98].

Mild hemorrhagic complications of thrombolytic therapy can be treated with local pressure and topical thrombin preparations. Major bleeding from a local site is managed by stopping thrombolytic therapy and administration of FFP or cryoprecipitate along with other blood products if necessary. If bleeding is life-threatening, addition of an antifibrinolytic agent (eg, aminocaproic acid) may help restore hemostasis.

OUTCOME

Recurrence — Recurrence risk depends on whether the thrombosis was provoked or unprovoked and the nature of underlying VTE risk factors. In pediatric studies, reported VTE recurrence rates ranges from 1 to 20 percent, depending on the population studied and whether the study defined recurrence (eg, symptomatic versus asymptomatic) [5,102-106].

In children with provoked VTE (eg, central venous catheter [CVC]-associated or due to an underlying medical condition), recurrence is uncommon if the underlying cause is removed or resolved [5,102]. In a clinical trial that involved 417 children with provoked VTE attributable to a transient risk factor (CVC, surgery, trauma, infection) that resolved by the end of treatment, 2 percent experienced symptomatic VTE recurrence within one year after treatment.

By contrast, the risk of recurrence is considerably higher for children with unprovoked VTE, particularly among those who are found to have an acquired or inherited thrombophilia (IT). In a study of 301 children with a first episode of unprovoked VTE who were followed for a median of seven years following withdrawal of anticoagulation, recurrent VTE occurred in 21 percent at a median time of 3.5 years after cessation of anticoagulants [103]. In this study, the risk of VTE recurrence was nearly fivefold higher among children with IT compared with children without IT. However, the risk of VTE recurrence among infants and young children (<2 years old) with IT is uncertain.

Post-thrombotic syndrome — The PTS is a chronic complication of VTE. It is characterized by chronic venous insufficiency, with symptoms varying from mild edema to chronic pain and ulceration of the affected limb [107]. PTS occurs secondary to a combination of pathophysiologic mechanisms, including an initial inflammatory process within the involved vein, venous outflow obstruction, destruction of venous valves, and venous reflux [108,109]. (See "Pathophysiology of chronic venous disease" and "Post-thrombotic (postphlebitic) syndrome".)

Diagnosis of PTS is primarily based upon clinical symptoms including localized edema; pain; alterations in skin temperature; differences in limb circumference; and presence of varicose veins, trophic skin changes (stasis dermatitis), and skin ulceration [110,111]. (See "Clinical manifestations of lower extremity chronic venous disease".)

In a 2010 systematic review that included 19 studies with nearly 1000 pediatric patients, the overall rate of PTS was 26 percent [112]. A subsequent clinical trial reported a similar rate of PTS (25 percent) at one-year follow-up among 316 children with extremity deep vein thrombosis [5]. However, in other studies, reports rates of PTS after pediatric VTE vary considerably (ranging from 10 to 70 percent) due to differences in the populations studied and the definition of PTS [112-118]. The frequency of PTS is lower among children with catheter-associated VTE compared with non-catheter-associated VTE and in neonates compared with older children [118,119]. Patients with occlusive venous thrombosis also appear to be at greater risk of developing PTS [115].

Pediatric PTS scales for both the upper and lower venous systems have been developed [120-122]. However, all scales have limitations and further efforts to standardize the diagnosis of PTS in children are needed [110,111].

For children with nonextremity VTE (eg, renal or portal vein thrombosis), the risk of long-term complications is not well established. Patients should generally be followed every 6 to 12 months with organ-specific assessments [123]. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Other venous thrombosis'.)

Mortality — The overall risk of mortality among pediatric patients with any type of VTE ranges from 8 to 17 percent [104,105,124,125]; the risk for patients with pulmonary embolism (PE) is approximately 10 to 20 percent [126,127]. However, these estimates are difficult to interpret since most patients in these studies had associated chronic conditions (eg, cancer, cardiac disease). In registry studies wherein the cause of death was ascertained, mortality as a direct result of thrombotic complications occurred in 2 to 4 percent of patients. Most VTE-related deaths in these studies were due to PE.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thrombotic diseases in infants and children".)

SUMMARY AND RECOMMENDATIONS

Goals of treatment – The goals of treating venous thromboembolism (VTE; which includes venous thrombosis and/or pulmonary embolism [PE]) are to prevent local extension and embolization of the thrombus, aid in resolving the existing thrombus, prevent recurrence of VTE, and minimize long-term complications such as the post-thrombotic syndrome (PTS). (See 'Overview' above.)

Indications for and duration of anticoagulant therapy – The treatment of VTE in children depends on upon the severity of the thrombosis and whether it was provoked (ie, due to identified underlying reversible risk factors) or unprovoked (see 'Approach to VTE treatment' above):

Low-risk provoked VTE – Low-risk patients are those who meet all the following criteria (see 'Provoked VTE' above):

-No prior history of VTE

-VTE is not severe or life threatening

-Provoking risk factor is transient (central venous catheter [CVC], recent surgery, trauma) and has resolved within six weeks

-Thrombus has resolved or is nonocclusive within six weeks

For these patients, we suggest anticoagulation for six weeks rather than observation or shorter or longer courses of treatment (Grade 2C).

Standard-risk provoked VTE – For children with provoked VTE who do not meet low-risk criteria, we suggest three months of anticoagulant therapy rather than observation or shorter courses of treatment (Grade 2C). (See 'Provoked VTE' above.)

Unprovoked VTE – For children with unprovoked VTE, we suggest anticoagulation for 6 to 12 months rather than a shorter course of treatment (Grade 2C). Children with recurrent unprovoked VTE are treated indefinitely. (See 'Unprovoked VTE' above.)

Choice of agent – Our general approach to selecting an anticoagulant is as follows (see 'Choice of agent' above):

For initial treatment of VTE, we suggest parenteral therapy for at least five days (Grade 2C). For most patients, we suggest low molecular weight heparin (LMWH) rather than unfractionated heparin (UFH) for the initial parenteral agent (Grade 2C) for the reasons outlined in the table (table 1). However, UFH may be preferred for initial therapy in some circumstances (eg, patients with kidney failure and those who require finely tuned titration). (See 'Initial therapy (first 5 to 10 days)' above and 'Low molecular weight heparin' above and 'Unfractionated heparin' above.)

For subsequent anticoagulation after the first 5 to 10 days, we suggest the following (see 'Subsequent treatment' above):

-Adolescent patients (age ≥12 years) – For most adolescent patients, we suggest a direct oral anticoagulant (DOAC; eg, dabigatran or rivaroxaban) rather than other agents (Grade 2B). DOACs are preferred because they are orally administered, do not require frequent laboratory monitoring, and appear to have similar efficacy and bleeding risk compared with LMWH or vitamin K antagonist (VKA) (table 1). (See 'Direct oral anticoagulants' above.)

-Children ages 2 to <12 years – For children ages 2 to <12 years old, either a DOAC or LMWH is reasonable. The choice is based upon caregiver and clinician preference, comorbidities, and availability and cost of the drug. (See 'Direct oral anticoagulants' above and 'Low molecular weight heparin' above.)

-Infants and children <2 years old – For most infants and young children (<2 years old), we suggest LMWH rather than other agents (Grade 2C). LMWH is preferred over DOACs because there is greater experience with LMWHs and their efficacy and safety are well established in this age group. However, cautious use of a DOAC is a reasonable alternative to LMWH in select circumstances (eg, if the child requires long-term anticoagulation). VKA therapy is challenging in this age group because the response is unpredictable due to considerable variation in vitamin K intake in young children's diets. (See 'Low molecular weight heparin' above.)

-Special circumstances – Special considerations may be needed when selecting an anticoagulant in patients with active cancer, nephrotic syndrome, impaired kidney function, heavy menstrual bleeding, pregnancy, antiphospholipid syndrome (APS), and heparin-induced thrombocytopenia (HIT). (See 'Choice of agent' above.)

Pediatric dosing guidance for different anticoagulants is provided in the tables (see 'Anticoagulant agents' above):

-LMWH (table 6)

-UFH (table 7)

-DOACs (dabigatran (table 4), rivaroxaban (table 5))

-Warfarin (table 9)

Blocked CVC – When a CVC is blocked but no definite thrombus is identified, recombinant tPA (alteplase) may be used to lyse intraluminal thrombus and restore catheter patency as follows (see 'Blocked central venous catheter' above):

Instill a volume equal to the internal volume of the catheter lumen (for patients ≤10 kg, the maximum is 1 mL of a 0.5 mg/mL solution; for patients >10 kg, the maximum is 2 mL of a of 1 mg/mL solution)

After a dwell time of one to two hours, attempt to draw back from the catheter; the lumen should not be used until the tPA is withdrawn

If the first attempt is unsuccessful, the CVC may be treated with a second course of tPA

Major vessel occlusion – For children with major vessel occlusion causing compromise of organs or limbs, systemic or catheter-directed thrombolytic therapy may be warranted. Data on the efficacy, dose, and safety of thrombolytic agents in pediatric patients are limited, and indications for thrombolytic therapy are highly individualized. (See 'Thrombolytic therapy' above.)

VTE prophylaxis – Indications for VTE prophylaxis in children without a prior episode of VTE are not well established. Important considerations include the number and nature of risk factors for VTE and whether the risk factors are transient or persistent. (See 'Primary prophylaxis' above.)

Hospitalized patients – For hospitalized patients who are acutely ill or recovering from surgery, mechanical methods for VTE prevention (eg, compression stockings, intermittent pneumatic compression devices) are encouraged, if appropriate-sized devices are available. Pharmacologic thromboprophylaxis is limited to children who have multiple risk factors for VTE. When the decision is made to administer thromboprophylaxis, we suggest LMWH rather than other agents (Grade 2C). (See 'Hospitalized patients' above.)

Patients with long-lasting VTE risk – For patients requiring long-term prophylaxis due to risk of recurrent VTE from underlying medical conditions (eg, certain cardiac conditions, chronic hemodialysis, long-term parenteral nutrition, inherited thrombophilia, nephrotic syndrome, APS), oral agents are preferred as a general principle. Either warfarin or a DOAC is acceptable in most cases (with the exception of patients with mechanical heart valves and those with APS, for whom warfarin is the preferred agent). (See 'Patients with long-lasting VTE risk' above.)

Outcome – Long-term complications of VTE in children include recurrent VTE and PTS. PTS is characterized by chronic venous insufficiency, with symptoms varying from mild edema to chronic pain and ulceration of the affected limb. The risk of mortality as a direct result of thrombotic complications is approximately 2 to 4 percent. Most VTE-related deaths are due to PE. (See 'Outcome' above.)

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Topic 5916 Version 39.0

References

1 : Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

2 : American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism.

3 : Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study.

4 : Guideline on the investigation, management and prevention of venous thrombosis in children.

5 : Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial.

6 : Effect of Anticoagulant Therapy for 6 Weeks vs 3 Months on Recurrence and Bleeding Events in Patients Younger Than 21 Years of Age With Provoked Venous Thromboembolism: The Kids-DOTT Randomized Clinical Trial.

7 : The use of alteplase to restore patency of central venous lines in pediatric patients: a cohort study.

8 : Alteplase for the treatment of central venous catheter occlusion in children: results of a prospective, open-label, single-arm study (The Cathflo Activase Pediatric Study).

9 : Recombinant tissue plasminogen activator (alteplase) for restoration of function to occluded central venous catheters in pediatric patients.

10 : Use of tissue plasminogen activator (rt-PA) in young children with cancer and dysfunctional central venous catheters.

11 : Safety, dose, and timing of reteplase in treating occluded central venous catheters in children with cancer.

12 : Clinical features and outcome of pulmonary embolism in children.

13 : Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

14 : Ex-vivo and in-vitro evidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin.

15 : Pilot dose-finding and safety study of bivalirudin in infants<6 months of age with thrombosis.

16 : Argatroban therapy in pediatric patients requiring nonheparin anticoagulation: an open-label, safety, efficacy, and pharmacokinetic study.

17 : Diagnosis and treatment of heparin-induced thrombocytopenia in neonates and children.

18 : Pediatric catheterization laboratory anticoagulation with bivalirudin.

19 : FondaKIDS: a prospective pharmacokinetic and safety study of fondaparinux in children between 1 and 18 years of age.

20 : Argatroban anticoagulation in pediatric patients: a literature analysis.

21 : UNBLOCK: an open-label, dose-finding, pharmacokinetic and safety study of bivalirudin in children with deep vein thrombosis.

22 : FondaKIDS II: long-term follow-up data of children receiving fondaparinux for treatment of venous thromboembolic events.

23 : FondaKIDS III: A long-term retrospective cohort study of fondaparinux for treatment of venous thromboembolism in children.

24 : Novel paediatric anticoagulants: a review of the current literature.

25 : Pediatric issues in thrombosis and hemostasis: The how and why of venous thromboembolism risk stratification in hospitalized children.

26 : Use of low molecular weight heparin for thromboprophylaxis in a pediatric inpatient population: reasons for use and incidence of bleeding complications.

27 : Risk factors for in-hospital venous thromboembolism in children: a case-control study employing diagnostic validation.

28 : Risk-prediction tool for identifying hospitalized children with a predisposition for development of venous thromboembolism: Peds-Clot clinical Decision Rule.

29 : Venous thromboembolism in hospitalized adolescents: an approach to risk assessment and prophylaxis.

30 : Hospital-associated venous thromboembolism in pediatrics: a systematic review and meta-analysis of risk factors and risk-assessment models.

31 : Development of a new risk score for hospital-associated venous thromboembolism in critically-ill children not undergoing cardiothoracic surgery.

32 : A Real-time Risk-Prediction Model for Pediatric Venous Thromboembolic Events.

33 : Prevention of recurrent thrombotic events in children with central venous catheter-associated venous thrombosis.

34 : Perioperative thromboprophylaxis in children: development of a guideline for management.

35 : Perioperative thromboprophylaxis in children: development of a guideline for management.

36 : Development of a Risk Model for Pediatric Hospital-Acquired Thrombosis: A Report from the Children's Hospital-Acquired Thrombosis Consortium.

37 : A New Risk Assessment Model for Hospital-Acquired Venous Thromboembolism in Critically Ill Children: A Report From the Children's Hospital-Acquired Thrombosis Consortium.

38 : Prophylaxis against venous thromboembolism in pediatric trauma: A practice management guideline from the Eastern Association for the Surgery of Trauma and the Pediatric Trauma Society.

39 : Efficacy of Early Prophylaxis Against Catheter-Associated Thrombosis in Critically Ill Children: A Bayesian Phase 2b Randomized Clinical Trial.

40 : Warfarin therapy in children who require long-term total parenteral nutrition.

41 : Prophylactic anticoagulation decreases catheter-related thrombosis and occlusion in children with home parenteral nutrition.

42 : Vitamin K antagonists in children with central venous catheter on chronic haemodialysis: a pilot study.

43 : Low-molecular-weight heparin in pediatric patients with thrombotic disease: a dose finding study.

44 : Dose-finding and pharmacokinetic profiles of prophylactic doses of a low molecular weight heparin (reviparin-sodium) in pediatric patients.

45 : The low molecular weight heparin dalteparin for prophylaxis and therapy of thrombosis in childhood: a report on 48 cases.

46 : Anticoagulation therapy in children.

47 : Dose-finding and pharmacokinetics of therapeutic doses of tinzaparin in pediatric patients with thromboembolic events.

48 : Are low-molecular-weight heparins safe and effective in children? A systematic review.

49 : Enoxaparin for neonatal thrombosis: a call for a higher dose for neonates.

50 : Use of low molecular mass heparin (enoxaparin) in newborn infants: a prospective cohort study of 62 patients.

51 : Higher doses of low-molecular-weight heparin (enoxaparin) are needed to achieve target anti-Xa concentrations in critically ill children*.

52 : An open-label randomized controlled trial of low molecular weight heparin compared to heparin and coumadin for the treatment of venous thromboembolic events in children: the REVIVE trial.

53 : Safety and efficacy of low molecular weight heparins in children: a systematic review of the literature and meta-analysis of single-arm studies.

54 : Use of low molecular weight heparin in pregnancy.

55 : Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.

56 : Neutralization of enoxaparine-induced bleeding by protamine sulfate.

57 : Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

58 : Evaluation of weight-based dosing of unfractionated heparin in obese children.

59 : Therapeutic range for unfractionated heparin therapy: age-related differences in response in children.

60 : Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

61 : Heparin clearance and ex vivo recovery in newborn piglets and adult pigs.

62 : Heparin clearance in the newborn.

63 : Unfractionated heparin dosing in young infants: clinical outcomes in a cohort monitored with anti-factor Xa levels.

64 : Monitoring unfractionated heparin in children: a parallel-cohort randomized controlled trial comparing 2 dose protocols.

65 : Heparin therapy in pediatric patients: a prospective cohort study.

66 : Unfractionated heparin therapy in infants and children.

67 : Retrospective cohort study comparing activated partial thromboplastin time versus anti-factor Xa activity nomograms for therapeutic unfractionated heparin monitoring in pediatrics.

68 : Antithrombin Concentrate Use in Children Receiving Unfractionated Heparin for Acute Thrombosis.

69 : A clinically significant incidence of bleeding in critically ill children receiving therapeutic doses of unfractionated heparin: a prospective cohort study.

70 : Heparin-induced thrombocytopenia in children.

71 : Heparin-induced thrombocytopenia-associated thrombosis in pediatric intensive care patients.

72 : Heparin-induced thrombocytopenia in pediatrics.

73 : Heparin-induced thrombocytopenia in children: 12 new cases and review of the literature.

74 : Heparin-induced thrombocytopenia. Pathogenesis, frequency, avoidance and management.

75 : Heparin-induced thrombocytopenia: towards consensus.

76 : Pediatric heparin-induced thrombocytopenia: prevalence, thrombotic risk, and application of the 4Ts scoring system.

77 : Heparin-Induced Thrombocytopenia in a Pediatric Population: Implications for Clinical Probability Scores and Testing.

78 : Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172.

79 : Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172.

80 : Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172.

81 : Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172.

82 : Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172.

83 : Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172.

84 : Rivaroxaban for treatment of pediatric venous thromboembolism. An Einstein-Jr phase 3 dose-exposure-response evaluation.

85 : Safety and efficacy of rivaroxaban in pediatric cerebral venous thrombosis (EINSTEIN-Jr CVT).

86 : Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.

87 : Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial.

88 : Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children.

89 : Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children.

90 : Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children.

91 : Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children.

92 : Analysis of warfarin therapy in pediatric patients: A prospective cohort study of 319 patients.

93 : Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

94 : Readmissions for warfarin-related bleeding in pediatric patients after hospital discharge.

95 : Tracheobronchial calcification: an observation in three children after mitral valve replacement and warfarin sodium therapy.

96 : The use of vitamin K for reversal of over-warfarinization in children.

97 : Thrombolytic therapy in children.

98 : Recommendations for tPA thrombolysis in children. On behalf of the Scientific Subcommittee on Perinatal and Pediatric Thrombosis of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis.

99 : Low-dose tissue plasminogen activator thrombolysis in children.

100 : Safety and outcomes of thrombolysis with tissue plasminogen activator for treatment of intravascular thrombosis in children.

101 : A thrombolytic regimen for high-risk deep venous thrombosis may substantially reduce the risk of postthrombotic syndrome in children.

102 : Prothrombotic conditions in an unselected cohort of children with venous thromboembolic disease.

103 : Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors.

104 : Venous thromboembolic complications (VTE) in children: first analyses of the Canadian Registry of VTE.

105 : Venous thromboembolism in childhood: a prospective two-year registry in The Netherlands.

106 : Elevated plasma factor VIII and D-dimer levels as predictors of poor outcomes of thrombosis in children.

107 : The natural history of deep-vein thrombosis.

108 : [The pathophysiology of post-thrombotic syndrome].

109 : The postphlebitic syndrome. Pathophysiology, prevention and management.

110 : Definition of post-thrombotic syndrome following lower extremity deep venous thrombosis and standardization of outcome measurement in pediatric clinical investigations.

111 : Standardization of post-thrombotic syndrome definition and outcome assessment following upper venous system thrombosis in pediatric practice.

112 : Post-thrombotic syndrome in children: a systematic review of frequency of occurrence, validity of outcome measures, and prognostic factors.

113 : Pediatric venous thromboembolic disease in one single center: congenital prothrombotic disorders and the clinical outcome.

114 : Outcome of pediatric thromboembolic disease: a report from the Canadian Childhood Thrombophilia Registry.

115 : A cross-sectional study evaluating post-thrombotic syndrome in children.

116 : The risk of postthrombotic syndrome in children with congenital heart disease.

117 : Natural history of deep vein thrombosis in children.

118 : Post-thrombotic syndrome and other outcomes of lower extremity deep vein thrombosis in children.

119 : Postthrombotic syndrome following upper extremity deep vein thrombosis in children.

120 : Post-thrombotic syndrome in children: Measurement properties of CAPTSure, a new diagnostic tool.

121 : Post-thrombotic syndrome (PTS) in children: Validation of a new pediatric outcome instrument and results in a comprehensive cohort of children with extremity deep vein thrombosis (DVT)

122 : Validation of upper extremity post-thrombotic syndrome outcome measurement in children.

123 : Recommendations for the assessment of non-extremity venous thromboembolism outcomes: communication from the SSC of the ISTH.

124 : Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007.

125 : Pediatric venous thromboembolism in the United States: a tertiary care complication of chronic diseases.

126 : Clinical probability score and D-dimer estimation lack utility in the diagnosis of childhood pulmonary embolism.

127 : Pulmonary embolism in children.