Thromboembolism in children with cancer

INTRODUCTION — 

Compared with the general pediatric population, children with cancer are at increased risk for thrombotic complications, including venous thrombosis and thromboembolism (VTE) and arterial thrombosis (eg, stroke). The following discussion will review the incidence, risk factors, evaluation, prevention, and management of thrombosis in children with cancer.

The pathogenesis, clinical manifestations, diagnosis, and treatment of VTE and stroke in the general pediatric population are discussed separately:

●(See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis".)

●(See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome".)

●(See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors".)

●(See "Arterial ischemic stroke in children and adolescents: Clinical presentation and evaluation".)

●(See "Ischemic stroke in children: Management and prognosis".)

EPIDEMIOLOGY — 

In studies of children with cancer, reported rates of symptomatic VTE range from 4 to 8 percent [1,2]. This is considerably higher than in hospitalized children without cancer (which is approximately 20 to 60 per 10,000). (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Incidence'.)

Several studies have shown that the incidence of VTE in pediatric cancer patients has increased since the late 20^th century [3,4]. This may be related to increased detection of VTE due to more sensitive and more frequent testing and/or increased use of prothrombotic interventions (eg, central venous catheters [CVCs]).

The risk of thrombotic complications varies depending on the type of malignancy:

●Acute lymphocytic leukemia (ALL) – Reported rates of VTE in children with ALL ranged from 3 to 15 percent [1,5-8]. Thrombotic events in this population can include CVC-related thrombosis, deep vein thrombosis (DVT), cerebral sinovenous thrombosis, and pulmonary embolism.

Reported risk factors for VTE in children with ALL include [1,5-11]:

•Age (adolescents are at higher risk than young children)

•T cell immunophenotype

•Treatment with asparaginase

•Concomitant use of steroids

•Use of anthracycline

•Presence of a CVC

•Inherited thrombophilia

•Non-O blood group

•Obesity

Asparaginase-related thrombosis in children undergoing treatment for ALL is discussed in detail separately. (See "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Asparaginase'.)

●Acute myeloid leukemia (AML) – Reported rates of VTE in children with AML range from 4 to 6 percent [1,2,4,5,12].

●Lymphoma – Reported rates of VTE in children with lymphoma range from 5 to 12 percent [1,2,4,5,13]. In children with lymphoma, VTE is more likely if there is a mediastinal mass, CVC, and/or peripherally inserted central catheter [14].

●Solid tumors – The overall reported rate of VTE in children with solid tumors ranges from 12 to 19 percent [1,4,15-18]. Proposed risk factors associated with thrombosis in children with solid tumors include:

•Presence of a CVC [1,13,15-22]

•Age >10 years [4,15,17,18,23]

•Type of tumor (eg, Ewing sarcoma is associated with a higher risk of VTE) [1,4,15,17,18]

•Site of cancer either by direct invasion of the vessels (eg, Wilms tumor or hepatoblastoma) or by vessel compression (eg, mediastinal mass in lymphoma) [24]

•Metastatic disease [4,17]

•Inherited thrombophilia [25]

•Obesity [2]

•Type of therapy (surgical intervention, radiation, and chemotherapeutic agents like anthracyclines and platinum were associated with significantly higher risk of VTE) [2]

●Central nervous system (CNS) tumors – VTE is an uncommon event in children with CNS tumors compared with other types of cancer. Reported rates of VTE in pediatric patients with CNS tumors ranged from 0.5 to 3 percent [1,2,5,22,26].

CLINICAL MANIFESTATIONS — 

In children with cancer, clinical manifestations of thrombosis are similar to those seen in children without malignancy and vary depending on both the location and extension of the thrombus, acuity of the event, and age of the patient [27]. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

Central venous catheter (CVC)-related thrombosis is by far the most common scenario, many of which are located in the upper venous system [21]. Non-CVC-related VTE can occur in any venous system but most commonly presents in the lower extremities, especially in the iliac, femoral, and/or popliteal veins. Thrombosis may also develop in the central nervous system (CNS), lung, liver, and kidney. CNS thromboses can include arterial ischemic stroke or cerebral sinovenous thrombosis (CVT). CVT is most commonly seen in patients with acute lymphocytic leukemia. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".).

Asymptomatic and incidental thromboses are sometimes detected when surveillance imaging studies are performed to monitor the malignancy. (See 'Asymptomatic right atrial thrombosis' below.)

EVALUATION AND DIAGNOSIS — 

In children with cancer, the presentation of a thrombotic event may be complicated or confused by other cancer-associated problems with similar signs and symptoms. For example, a headache due to cerebral sinovenous thrombosis (CVT) may be attributed to intrathecal chemotherapy. As a result, making the diagnosis may be challenging and/or delayed. Hence, a high index of suspicion is essential for earlier diagnosis of thrombosis in children with cancer.

The diagnostic approach of a thrombosis in the child with cancer is the same as in children without malignancy and is dependent upon the clinical findings and likely site of involvement.

The diagnostic approach for different types of thrombotic complications is reviewed in detail separately:

●Venous thrombosis and thromboembolism (including pulmonary embolism) (see "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Diagnosis')

●CVT (see "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Diagnosis')

●Arterial ischemic stroke (see "Arterial ischemic stroke in children and adolescents: Clinical presentation and evaluation", section on 'Urgent evaluation')

MANAGEMENT — 

Therapeutic anticoagulation in children with cancer is challenging because this population is at risk for both thrombosis and bleeding due to chemotherapy-related thrombocytopenia and coagulopathy. The management of VTE in this setting must balance the risk of thrombosis progression or recurrence with the increased risk of bleeding due to anticoagulation therapy. In addition, children with cancer are more likely to undergo invasive procedures (eg, lumbar puncture, bone marrow aspiration and biopsy, and surgical procedures), which can increase the risk of bleeding.

Evidence-based guidelines for the management of VTE in children with cancer are lacking, and the optimal approach is uncertain [28]. Management decisions are informed by limited data on anticoagulant therapy specifically in the pediatric oncology population [29-32] in combination with indirect data from studies involving children without cancer and adults with cancer [33-43].

There are important limitations of extrapolating from studies involving adult patients or children without malignancy. These include:

●Age-related differences in hemostasis between children and adults (see "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Risk of VTE in children versus adults')

●Differences in the biology of adult and pediatric malignancies, and the difference in anticancer treatments

●Differences in the relative risks of bleeding and thrombosis in children with cancer versus the general pediatric population

Whom to treat — In the absence of an obvious contraindication for anticoagulation therapy (eg, active bleeding), anticoagulation therapy should be started in children with cancer and symptomatic TE.

Choice of agent — Low molecular weight heparin (LMWH) is generally the preferred agent for initial treatment of cancer-associated VTE in children [41]. LMWH has several advantages over unfractionated heparin and warfarin, as outlined in the table (table 1). LMWH is also preferred over direct acting oral anticoagulants (DOACs) for initial treatment because there is greater experience with LMWH in this setting.

For ongoing treatment after the initial 5 to 10 days of parenteral therapy, the decision to continue LMWH or transition to an oral agent (typically a DOAC) is complex and is individualized based upon the child's risk profile, comorbidities, and the preferences of the clinician and parent/caregivers. As experience with DOACs increases, we are using DOACs with greater frequency in appropriately selected patients.

Rivaroxaban and dabigatran are approved for use in children. However, data on the use of these agents in children with cancer are limited. Clinical trials that established the efficacy and safety of DOACs in children (eg, EINSTEIN-Jr for rivaroxaban and DIVERSITY for dabigatran) enrolled few patients with cancer. All patients in these trials we treated initially with parenteral therapy (either LMWH or unfractionated heparin) before transitioning to DOAC therapy. These trials are discussed in detail separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Efficacy'.)

A post-hoc subgroup analysis of EINSTEIN-Jr reported the outcomes of 56 patients with cancer who were enrolled in the trial (40 received rivaroxaban; 16 received standard therapy, largely consisting of LMWH) [30]. No children in either treatment group experienced symptomatic VTE recurrence or major bleeding. Of the 52 children who underwent repeat imaging, most had resolved or improved thrombus regardless of the assigned treatment (87 percent in the rivaroxaban group and 80 percent in the standard therapy group). Treatment interruptions were common, with nearly one-half of patients experiencing at least one interruption, most commonly due to low platelet count.

Additional data on the use of DOACs in children with cancer come from observational studies. In two retrospective studies including a total of 81 pediatric cancer patients with VTE who received DOAC therapy (rivaroxaban in 68 percent, apixaban in 31, and dabigatran in 1 percent), major bleeding occurred in 2.5 percent of patients, and nonmajor clinically relevant bleeding occurred in 10 percent [31,32]. Recurrent thrombosis occurred in 9 patients (11 percent). The higher incidence of bleeding and TE recurrence in these studies as compared with EINSTEIN-Jr may be explained, at least in part, by the longer follow-up duration.

Additional details regarding the advantages and disadvantages of different anticoagulant agents in children are provided separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Anticoagulant agents'.)

Studies supporting the use of DOACs in adult cancer patients are described separately. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy", section on 'Direct oral anticoagulant mono- or dual therapy'.)

Dosing — The dose of LMWH used to treat VTE in children with cancer is similar to that used in the general pediatric population (table 2) [38].  

Dose adjustment and other precautions are necessary in children with severe thrombocytopenia, as discussed below. (See 'Management of anticoagulation in patients with thrombocytopenia' below.)

Due to the risk of bleeding, LMWH therapy should be withheld prior to invasive procedures (eg, lumbar puncture, epidural procedure, or surgery). In our practice, the last dose of LMWH is usually given 24 hours before a procedure. We do not routinely measure anti-Xa before procedures. To be cautious, one may do a trough anti-Xa level at the first time LMWH is being held for invasive procedures. LMWH can be restarted 12 to 24 hours after most minor invasive procedures. Decisions regarding restarting LMWH after major surgery should be made in consultation with the surgical team.

Additional details regarding the use of LMWH in children are provided separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Low molecular weight heparin'.)

For children who are transitioned to a DOAC after initial treatment with LMWH, the dosing is the same as is used in the general pediatric population. Dosing guidance is provided in the tables (for dabigatran (table 3) and rivaroxaban (table 4)). Additional details are provided separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Direct oral anticoagulants'.)

Duration of therapy — The usual duration of anticoagulation for treatment of VTE in pediatric patients with cancer is at least three months. Extended anticoagulation may be warranted if there are ongoing clinically important thrombotic risk factors (eg, use of asparaginase), as discussed below. (See 'Prevention of recurrent thrombosis' below.)

Management of anticoagulation in patients with thrombocytopenia — Thrombocytopenia is common in children undergoing treatment for cancer. Children with platelet counts <30,000/microL are at increased risk of bleeding complications with systemic anticoagulation, particularly when full treatment doses are used.

Evidence is lacking on how to best manage anticoagulation therapy in this setting. In our practice, during the initial acute management (ie, first two to four weeks of therapy), we administer a platelet transfusion to the patient if the platelet count is <30,000/microL to permit treatment with the full therapeutic dose of anticoagulant.

If thrombocytopenia occurs beyond the first two to four weeks of therapy (ie, once the thrombosis is stabilized or resolving), we adjust anticoagulation dosing as follows:

●Platelet counts >30,000/microL – Give full dose of anticoagulant

●Platelet counts 20,000 to 30,000/microL – Give one-half of the dose of anticoagulant

●Platelet counts <20,000/microL – Hold the anticoagulant

Patients should be closely monitored on an ongoing basis for any sign of bleeding (as is the case in all patients receiving anticoagulation therapy), and the platelet count should be measured on a periodic basis. The frequency of platelet count determination is dependent upon the anticipated changes in platelet count, based on the chemotherapeutic regimen. In some cases, platelet counts may need to be measured daily, and, in others, two to three times per week is sufficient.

Asparaginase management — Asparaginase, a key component of therapy in children with ALL, is associated with hemorrhagic and thrombotic complications (eg, cerebral sinovenous thrombosis) [44]. In the event of development of a thrombotic complication while receiving asparaginase, one management option is to withhold asparaginase, treat with an anticoagulant, and resume asparaginase once the child is stable and hematologic parameters normalize [45,46]. The concern with this approach is that interruption of asparaginase may negatively impact the likelihood of ALL cure [47]. An alternative approach is to use anticoagulation at either therapeutic or prophylactic doses, with or without coadministration of antithrombin, to facilitate completion of potentially curative chemotherapy. This issue is discussed separately. (See "Antithrombin deficiency", section on 'Patients receiving asparaginase' and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Asparaginase'.)

Asymptomatic right atrial thrombosis — Right atrial thrombosis is increasingly detected by routine regular echocardiography monitoring in oncology patients, especially for patients at risk of anthracycline-induced cardiomyopathy. A systematic review suggested asymptomatic right atrial thrombosis with low-risk features (ie, small size [<2 cm], nonpedunculated, and nonmobile) can be treated conservatively [48]. However, it should be noted that the critical clot size depends on the age of the child [49]. In infants and young children, smaller thrombi may be considered high risk [48].

In patients with right atrial thrombi with low-risk features, we suggest removal of the central venous catheter (CVC), if possible, and ongoing monitoring. In patients in whom the CVC cannot be removed and in those with high-risk features (ie, >2 cm, pedunculated, or mobile), anticoagulation therapy may be warranted.

IMPACT OF THROMBOEMBOLISM ON OUTCOME — 

Children with cancer-related thrombosis have increased risk of mortality compared with children with cancer who do not experience thrombotic complication [3,10,50-53]. In addition, children with cancer-related thrombosis are more likely to experience subsequent thrombotic events and/or thrombosis-related morbidity (eg, post-thrombotic syndrome) [3].

In a study of >2000 children with acute lymphocytic leukemia (ALL), thromboembolism occurred in 6 percent and was independently associated with worse five-year overall survival (80 versus 94 percent; adjusted hazard ratio for death 2.61, 95% CI 1.62-4.22) [52]. In another study of 150 pediatric patients with cancer-related thrombosis, the estimated thrombosis-related mortality rate was 4.7 percent [5].

Most thrombotic events in children with cancer are not acutely life-threatening. In a study of 283 pediatric cancer patients with thromboembolic events, 92 percent of events were non-life-threatening, 6 percent were life-threatening, and 2 percent were fatal [2].

However, there may be indirect adverse consequences associated with thrombosis, such as risk of bleeding from anticoagulation therapy and interruption or cessation of cancer treatment (asparaginase), as discussed above. (See 'Asparaginase management' above.)

PREVENTION

Primary prevention — The best strategies for prevention of thrombotic complications in children with cancer are to use nonpharmacologic measures (eg, encourage mobility/ambulation), clinically monitor for signs and symptoms of thrombosis, and ensure timely diagnosis and treatment when thrombosis occurs. Routine use of thromboprophylaxis does not appear to have a meaningful benefit and it exposes the child to unnecessary bleeding risk.

●No role for routine thromboprophylaxis – We do not consider malignancy itself (with or without the presence of a central venous catheter [CVC]) to be an indication for prophylactic anticoagulation.

Prophylactic anticoagulation may be warranted in select pediatric patients with cancer only if there are additional clinically important risk factors such as [54]:

•Prior history of thrombosis

•Known inherited thrombophilia

•Multiple combined risk factors (eg, CVC plus asparaginase therapy plus obesity, hormonal contraceptives, or hospitalization for surgery)

Risk prediction models have been developed for children with acute lymphoblastic leukemia (ALL) [55,56]; however, they have not been prospectively validated.

The approach outlined here is consistent with the recommendations of the International Society on Thrombosis and Haemostasis [54]. (See 'Society guideline links' below.)

Our suggestion against routine thromboprophylaxis for most pediatric patients with cancer is distinct from the routine use of low-dose unfractionated heparin (UFH) flushes or infusions to maintain CVC patency, which is discussed separately. (See "Routine care and maintenance of intravenous devices", section on 'Flushing and locking' and "Neonatal thrombosis: Management and outcome", section on 'Prevention of catheter-associated thrombosis'.)

●Impact of CVC placement – Practice regarding CVC placement in pediatric cancer patients may play a role in preventing VTE. VTE occurs less commonly in CVCs with internal lines than external tunneled lines [57]. According to guidelines from the British Society for Haematology, an internal device (eg, Port-A-Cath) is preferable to an external tunneled device (eg, Hickmann catheter) for use in pediatric cancer patients [58]. Guidelines from the Italian Association of Pediatric Hematology and Oncology advise placing CVCs on the right side of the upper venous system, leaving the tip of the catheter at the right atrial-superior vena cava junction. This is based on studies showing higher risk of VTE when CVCs were placed on the left side and with the tip further into the right atrium [59]. Peripherally inserted central catheters (PICC) may be associated with higher risk for CVC-related TE compared with other CVCs. (See "Peripherally inserted central catheter (PICC)-related venous thrombosis in adults", section on 'Incidence and risk factors'.)

●Role of antithrombin replacement (in patients receiving asparaginase) – Practices differ among experts regarding monitoring of antithrombin (AT) levels and prophylactic AT administration in patients receiving asparaginase. This issue is discussed separately. (See "Antithrombin deficiency", section on 'VTE prophylaxis (asparaginase)'.)

●Evidence regarding primary thromboprophylaxis in pediatric patients with cancer – Taken together, the available clinical trial and observational data suggest that for the general pediatric oncology population, anticoagulant therapy for primary prevention of VTE is unlikely to have meaningful benefit [60-65].

This question was addressed in a multicenter clinical trial involving 512 children and adolescents with newly diagnosed pre-B or T cell ALL who were randomly assigned to prophylactic anticoagulation (with the direct oral anticoagulant apixaban) or standard care without anticoagulation [64]. All trial participants had a newly inserted CVC in place, and all were receiving planned induction chemotherapy with a glucocorticoid, vincristine, and single or multiple doses of asparaginase, with or without an anthracycline. At one-month follow-up, symptomatic venous thrombosis occurred at similar rates in both groups (1.6 versus 2.3 percent, respectively; relative risk [RR] 0.67, 95% CI 0.19-2.23). Rates of asymptomatic venous thrombosis were also similar in both groups (11 versus 15 percent; RR 0.71, 95% CI 0.45-1.13). There were no episodes of pulmonary embolism or thrombosis-related death in either group. Episodes of nonmajor bleeding (mostly epistaxis) occurred more frequently in the apixaban group (4 versus 1 percent; RR 3.67, 95% CI 1.04-13). Episodes of major bleeding were uncommon in both groups (<1 percent in each).

An earlier quasi-randomized trial evaluated the efficacy of low molecular weight heparin (LMWH) for primary thromboprophylaxis in patients with newly diagnosed ALL [65]. In this trial, 949 children and adolescents with ALL were randomly assigned to thromboprophylaxis with LMWH, prophylactic AT, or standard care (consisting of low-dose UFH flushes to maintain CVC patency), starting on day 8 and ending on day 33 of induction chemotherapy. However, after randomization, patients were permitted to opt out of the assigned treatment or to select a different treatment option. Of the 317 patients assigned to LMWH, one-third declined the assigned treatment and instead opted for no medication, standard care (ie, UFH flushes only), or prophylactic AT therapy. Ultimately, only 216 patients received LMWH, 341 received prophylactic AT, and 372 received standard care alone. In the as-treated analysis, rates of symptomatic VTE at six months were lower in patients receiving LMWH or AT compared with standard care (3.2 and 2.6 versus 6.7 percent, respectively), but the difference was not statistically significant (odds ratio 0.47, 95% CI 0.20-1.09). Major bleeding events were rare in all three groups (1 event in the LMWH group, 3 events in the AT group, and 4 events in the standard care group). Estimated five-year event-free survival was similar in all three groups (85 percent in the LMWH group, 83 percent in the AT group, and 86 percent in the standard care group). Important limitations of this trial include lack of blinding and the high rate of crossover from the LMWH arm to other treatment arms, resulting in loss of randomization. The high refusal rate illustrates the poor acceptability of daily LMWH injections as a routine part of care for patients with newly diagnosed ALL. This is also illustrated by the trial's relatively low enrollment (ie, of 1526 patients who were eligible for the trial, 577 [38 percent] declined because they did not want to receive daily subcutaneous injections).

Prevention of recurrent thrombosis — Based upon studies in pediatric cancer patients and indirect data from adult cancer patients, our approach to secondary prophylaxis is as follows:

●For patients who have been diagnosed with VTE and are receiving therapeutic anticoagulation, we suggest extending anticoagulation if there are ongoing clinically important thrombotic risk factors, such as the use of asparaginase. The exception is the presence of an indwelling CVC. We generally discontinue anticoagulation even if the CVC remains in place for a prolonged period of time (eg, two years or greater), provided other significant risk factors (eg, asparaginase) are resolved.

●We offer prophylactic anticoagulation to patients with relapsed cancer who were previously diagnosed with thrombosis in association with their primary cancer therapy if they will be receiving subsequent cancer therapy with similar thrombotic risk

Use of prophylactic anticoagulation in these circumstances is based on the observation that the recurrence rate of thrombosis is twofold greater in children with cancer compared with those without cancer [3].

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

●Epidemiology – Compared with the general pediatric population, children with cancer are at increased risk for thrombotic complications, including venous thrombosis and thromboembolism (VTE) and arterial thrombosis (eg, stroke). The overall reported prevalence ranges from 4 to 8 percent. The risk of thrombotic complications varies depending on the type of malignancy, with the highest risk in children with acute lymphocytic leukemia (ALL), followed by sarcoma and lymphoma, and the lowest risk in those with brain tumors. (See 'Epidemiology' above.)

●Clinical manifestations – The clinical manifestations of VTE and arterial thrombosis in children with cancer are similar to those seen in children without cancer. Clinical manifestations vary depending upon the location and extent of the thrombus, acuity of the event, and age of the patient. (See 'Clinical manifestations' above.)

●Clinical suspicion and diagnosis – In children with cancer, the presentation of thrombotic events can overlap with that of other cancer-associated problems. Clinicians who treat cancer patients should maintain a high index of suspicion for thrombosis. The diagnosis is confirmed by imaging studies (eg, duplex ultrasound for suspected venous thrombosis, computed tomography pulmonary angiography for suspected pulmonary embolism, contrast-enhanced magnetic resonance imaging for suspected cerebral venous thrombosis or arterial stroke). The diagnostic approach is the same as for children without cancer, as discussed separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

●Management – Management of cancer-related thrombosis is challenging because children with cancer are at risk for both thrombus progression and recurrence, as well as bleeding due to chemotherapy-related thrombocytopenia and coagulopathy. Our approach is as follows (see 'Management' above):

•Choice of agent – For most children with cancer-related VTE, we suggest initial therapy with low molecular weight heparin (LMWH) for at least 5 to 10 days, followed by either LMWH or a direct oral anticoagulant (DOAC; eg rivaroxaban, dabigatran) rather than other agents (Grade 2C). The advantages and disadvantages of LMWH, DOACs, and other agents are outlined in the table and discussed in greater detail separately (table 1). (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Anticoagulant agents'.)

•Dosing – The initial dosing of LMWH and further dose adjustment based on anti-Xa levels are the same as those used in the general pediatric population (table 2). The tables provide dosing guidance for dabigatran (table 3) and rivaroxaban (table 4). Additional details are provided separately. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Anticoagulant agents'.)

•Duration – The usual duration of anticoagulation is at least three months. Extended anticoagulation may be warranted if there are ongoing clinically important thrombotic risk factors (eg, use of asparaginase). (See 'Prevention of recurrent thrombosis' above.)

•Management of anticoagulation in patients with thrombocytopenia – Patients receiving anticoagulation therapy should have platelet counts monitored regularly (ie, daily to twice a week, depending on the chemotherapeutic regimen). For patients with thrombocytopenia during the initial two to four weeks of therapy, we suggest platelet transfusion to maintain platelet count ≥30,000/microL rather than holding or reducing the dose of the anticoagulant (Grade 2C). This permits treatment with the full therapeutic dose of anticoagulant, which is important during the acute phase of management.

By contrast, for patients who have thrombocytopenia beyond the first two to four weeks of therapy (ie, once the thrombosis is stabilized or resolving), we suggest adjusting the dose of anticoagulant rather than giving platelet transfusions (Grade 2C). We adjust the LMWH or DOAC dose as follows (see 'Management of anticoagulation in patients with thrombocytopenia' above):

-Platelet counts >30,000/microL – full dose

-Platelet counts 20,000 to 30,000/microL – Give one-half the dose

-Platelet counts <20,000/microL – Hold the anticoagulant

•Asparaginase management – The approach to managing thrombotic complications in patients receiving asparaginase therapy is discussed separately. (See "Antithrombin deficiency", section on 'Patients receiving asparaginase' and "Treatment of acute lymphoblastic leukemia/lymphoma in children and adolescents", section on 'Emergencies/complications'.)

•Management of asymptomatic right atrial thrombus – In patients with asymptomatic right atrial thrombus with low-risk features (ie, <2 cm, nonpedunculated, and nonmobile), we suggest conservative management rather than anticoagulation (Grade 2C). Conservative management consists of removal of the central venous catheter (CVC), if present, and monitoring. Therapeutic anticoagulation is reasonable for patients in whom the CVC cannot be removed and those with high-risk features (ie, >2 cm, pedunculated, or mobile). (See 'Asymptomatic right atrial thrombosis' above.)

●Prevention – The best strategies for prevention of thrombotic complications in children with cancer are to use nonpharmacologic measures (eg, encourage mobility/ambulation), clinically monitor for signs and symptoms of thrombosis, and ensure timely diagnosis and treatment when thrombosis occurs. Routine use of thromboprophylaxis does not appear to have a meaningful benefit and it exposes the child to unnecessary risk. Prophylactic anticoagulation may be warranted in select children with cancer only if there are additional clinically important risk factors such as a history of recurrent thrombosis, known inherited thrombophilia, or multiple combined risk factors (eg, CVC plus asparaginase therapy plus obesity, hormonal contraceptives, and/or hospitalization for surgery). (See 'Prevention' above and "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Approach to VTE prophylaxis'.)