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Thromboembolism in children with cancer

Thromboembolism in children with cancer
Authors:
Uma H Athale, MD, MSc
Janet YK Yang, MBBS, MRCPCH
Anthony KC Chan, MBBS, FRCPC, FRCPath
Section Editors:
Alberto S Pappo, MD
Sarah O'Brien, MD, MSc
Deputy Editor:
Carrie Armsby, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: May 17, 2021.

INTRODUCTION — Children with cancer are at increased risk for thrombosis and thromboembolism (TE) compared with the general pediatric population. The following discussion will review the incidence, risk factors, evaluation, prevention, and management of TE in children with cancer.

The pathogenesis, clinical manifestations, diagnosis, and treatment of TE in the general pediatric population and newborns 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 "Neonatal thrombosis: Clinical features and diagnosis".)

(See "Neonatal thrombosis: Management and outcome".)

EPIDEMIOLOGY — Although there are few prospective studies that directly compare the incidence of TE in children with cancer with the general pediatric population, evidence from registries clearly demonstrates that children with cancer are more likely to develop TE than those without cancer. In studies of children with cancer, reported rates of TE 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 TE in pediatric cancer patients has increased since the late 20th century [3,4]. This may be related to increased detection of TE due to more sensitive and more frequent testing and/or increased use of prothrombotic interventions (eg, central venous catheters [CVCs]).

The rates of TE vary for specific malignancies. In one retrospective study of 726 children with cancer, the risk of TE was highest in patients with acute lymphocytic leukemia (ALL), followed by sarcoma and lymphoma, and the lowest risk was seen in children with brain tumors [1].

ALL – Thrombotic events, including deep vein thrombosis, cerebral sinovenous thrombosis, and pulmonary embolism are not uncommon in children with ALL. Major risk factors for TE in this population include age (adolescents are at higher risk than young children), treatment with asparaginase, concomitant use of steroids, use of anthracycline, thrombophilic genetic abnormalities, and presence of a CVC. In addition, non-O blood group has been identified as an independent risk factor for thrombotic events in prospective and retrospective studies [5-7]. In one study, obese children had a threefold increased risk of symptomatic TE [8].

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 'Remission induction'.)

Acute myeloid leukemia and lymphoma – Limited data based on small studies estimate that the prevalence of TE is 11 percent in children with acute myeloid leukemia and lymphoma [9] and 12 percent in those with lymphoma [10]. In children with lymphoma, TE is more likely if there is a mediastinal mass, CVC, and/or peripherally inserted central catheter [11].

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

Presence of a CVC [1,10,12-19]

Age >10 years [4,12,14,15,20]

Type of tumor (eg, children with Ewing sarcoma are reported to have a greater chance of a TE) [1,4,12,14,15]

Site of cancer either by direct invasion of the vessels (eg, Wilms tumor or hepatoblastoma) or by vessel compression (eg, mediastinal mass in lymphoma) [21]

Metastatic disease [4,14]

Prothrombotic defects [18,20,22]

Obesity [2]

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

Brain tumors – TE is an uncommon event in children with brain tumors compared with children with other malignancies and adults with brain tumors. In three retrospective studies of children with brain tumors, the reported rate of symptomatic thrombosis ranged from 0.6 to 2.8 percent [1,19,23].

CLINICAL MANIFESTATIONS — In children with cancer, clinical manifestations of TE are similar to those seen in children without malignancy and vary depending on both the location and extension of the thrombus, acuteness of the event, and age of the patient [9]. Central venous catheter (CVC)-related TE is by far the most common scenario, many of which are located in the upper venous system [18]. Non-CVC-related TE 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. The CNS thromboses include arterial ischemic stroke or hemorrhage as well as cerebral sinovenous thrombosis. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

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 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. Diagnosis of venous thrombosis, thromboembolism, cerebral sinovenous thrombosis, and stroke are discussed in separate topic reviews. (See "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Diagnosis' and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Diagnosis' and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis", section on 'Urgent evaluation'.)

MANAGEMENT — Anticoagulation therapy in children with cancer is challenging because these children are at risk for both thrombosis and bleeding due to chemotherapy-related thrombocytopenia and coagulopathy. The management of TE 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 may result in bleeding or clinically significant bleeding.

Evidence-based guidelines for the management of TE in children with cancer are lacking [24]. Data are available from studies in the general pediatric population and in adults with cancer [25-35]; however, neither provide the information for optimal management for children with cancer. This is, in part, due to the following differences among the three groups:

Age-related hemostasis between children and adults

Biology of adult and pediatric malignancies, and the difference in anticancer treatment

Risks of bleeding and thrombosis in children with cancer and the general pediatric population

As a result, management for TE in children with cancer is primarily based upon the expert interpretation of the available data in general pediatrics and adult cancer patients as well as clinical experience.

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.

Preferred agent (low molecular weight heparin) — Low molecular weight heparin (LMWH) is the preferred anticoagulation agent in children with cancer, as it is in children without cancer [33]. LMWH has several advantages over unfractionated heparin and warfarin, as 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'.)

The dose of LMWH used to treat TE in children with cancer is similar to that used in the general pediatric population (table 2) [30]. A nomogram has been developed for dose titration of LMWH in children. (See "Enoxaparin (including biosimilars available in Canada): Pediatric drug information".)

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 could be restarted 12 to 24 hours after the invasive procedures.

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'.)

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 LMWH treatment, 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, we administer a platelet transfusion to patients with platelet counts <30,000/microL to permit treatment with the full therapeutic dose of LMWH. In patients with stabilized or resolving TE, we adjust anticoagulation dosing as follows:

Platelet counts >30,000/microL – Full dose of LMWH

Platelet counts 20,000 to 30,000/microL – One-half of the dose of LMWH

Platelet counts <20,000/microL – LMWH is held

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 acute lymphocytic leukemia (ALL), is associated with hemorrhagic and thrombotic complications (eg, cerebral sinovenous thrombosis) [36]. In the event of development of TE 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 [37,38]. The concern with this approach is that interruption of asparaginase may negatively impact the likelihood of ALL cure [39]. An alternative approach is to use anticoagulation, 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 'Remission induction'.)

Asymptomatic right atrial thrombosis — The management approach for children with asymptomatic or incidental TE is as yet unclear. 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] and not pedunculated, mobile, or snake-shaped) can be treated conservatively [40]. However, it should be noted that the critical clot size depends on the age of the child [41]. In infants and young children, smaller thrombi may be considered high risk.

In patients with right atrial thrombi 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, mobile, or snake-shaped), anticoagulation therapy may be warranted.

IMPACT OF THROMBOEMBOLISM ON OUTCOME — Children with cancer and TE have increased risk of mortality compared with children with cancer who do not experience TE [3,42-44]. In addition, children with cancer and TE have higher rates of TE recurrence and TE-related morbidity compared with children without cancer [3]. In a study of >2000 children with acute lymphocytic leukemia (ALL), TE occurred in 5.6 percent and was independently associated with worse five-year overall survival (80.2 versus 93.7 percent; adjusted hazard ratio for death 2.61, 95% CI 1.62-4.22) [44].

Most thrombotic events in children with cancer are not acutely life-threatening. In a study of 283 pediatric cancer patients with TE, 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 TE, such as risk of bleeding from anticoagulation therapy and interruption of cancer treatment (asparaginase), as discussed above. (See 'Asparaginase management' above.)

PREVENTION

Primary prevention — 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 is warranted in children with cancer only if there are additional clinically important risk factors such as prior history of thrombosis, known inherited thrombophilia, or multiple combined risk factors (eg, CVC, asparaginase therapy, obesity, adolescence, hormonal contraceptives, or hospitalization for surgery) [45]. Our approach is consistent with the recommendations of the International Society on Thrombosis and Haemostasis [45]. (See 'Society guideline links' below.)

Practice regarding CVC placement in pediatric cancer patients may play a role in preventing TE. TE occurs less commonly in CVCs with internal lines than external tunneled lines [46]. 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 [47]. 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 TE when CVCs were placed on the left side and with the tip further into the right atrium [48].

Pediatric venous TE risk prediction models have been developed for children with acute lymphoblastic leukemia (ALL) [49,50]; however, they have not been prospectively validated. Prophylaxis in patients receiving asparaginase is discussed separately. (See "Antithrombin deficiency", section on 'VTE prophylaxis (asparaginase)'.)

Several small studies have evaluated primary thromboprophylaxis in children with cancer [51-54]. Taken together, the data suggest that for the general pediatric oncology population, anticoagulant therapy for primary prevention of TE is unlikely to have meaningful benefit. However, there may be a role for primary prophylaxis in select populations (eg, children with ALL who are receiving asparaginase). Clinical trials evaluating this issue in children with ALL are ongoing [55,56]. (See "Antithrombin deficiency", section on 'VTE prophylaxis (asparaginase)'.)

In a randomized trial of 73 children with cancer and CVCs, the rate of development of CVC-associated thrombosis was similar in patients treated with low-dose warfarin compared with controls (20 and 24 percent, respectively) [51].

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:

We suggest anticoagulation prophylaxis in patients previously treated for TE with ongoing thrombotic risk factors, such as the use of asparaginase

We offer prophylaxis in patients with relapsed cancer who have been diagnosed with TE in association with primary cancer therapy and those who will receive active cancer therapy

We may elect to discontinue anticoagulation, even in the presence of an indwelling CVC, if the line remains for a prolonged period of time (eg, two years or greater), provided other significant risk factors (eg, asparaginase) have been removed.

This is based on the observation that the recurrence rate of TE 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

Children with cancer are at increased risk for thrombosis and thromboembolism (TE) compared with the general pediatric population. The overall reported prevalence ranges from 4 to 8 percent. The rates of TE vary for specific malignancies, with the highest risk of TE in children with acute lymphocytic leukemia (ALL), followed by sarcoma and lymphoma, and the lowest risk in those with brain tumors. (See 'Epidemiology' above.)

The clinical manifestations of TE 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, acuteness of the event, and age of the patient. (See 'Clinical manifestations' above.)

In children with cancer, the presentation of a thromboembolic event may be complicated or be confused by other cancer-associated problems with similar clinical features. Hence, a high index of suspicion is essential. The diagnosis of TE is confirmed by imaging studies. The preferred imaging study varies depending upon the location and extent of the thrombus. (See 'Evaluation and diagnosis' above and "Venous thrombosis and thromboembolism (VTE) in children: Risk factors, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

In children with cancer, the management of TE 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. Management of thrombosis in children with cancer is based on limited evidence and attempts to balance benefits, burdens, and potential risks. Our approach is as follows (See 'Management' above.):

The choice of agent is generally the same as in children without cancer who have TE. Low molecular weight heparin (LMWH) is preferred over unfractionated heparin and warfarin for the reasons outlined in the table and discussed in greater detail separately (table 1). 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). (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Low molecular weight heparin'.)

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 acute management of TE, we suggest platelet transfusion to maintain platelet count ≥30,000/microL rather than holding or reducing the dose of LMWH (Grade 2C). This permits treatment with the full therapeutic dose of LMWH, which is important during the acute phase of management. By contrast, for patients who have thrombocytopenia while on LMWH after the acute phase (ie, once the TE is stabilized or resolving), we suggest adjusting the LMWH dose rather than giving platelet transfusions (Grade 2C). We adjust the LMWH dose as follows (see 'Thrombocytopenia' above):

-Platelet counts >30,000/microL – Full dose of LMWH

-Platelet counts 20,000 to 30,000/microL – One-half the dose of LMWH

-Platelet counts <20,000/microL – LMWH is held

The approach to managing TE 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 'Remission induction'.)

In patients with asymptomatic right atrial thrombus with low-risk features (ie, small size <2 cm and neither mobile nor snake-shaped), we suggest conservative management rather than anticoagulation (Grade 2C). Conservative management consists of removal of the central venous catheter (CVC), if present, and monitoring. Treatment with anticoagulation therapy is reasonable for patients in whom the CVC cannot be removed and those with high-risk features (ie, >2 cm, pedunculated, mobile, or snake-shaped). (See 'Asymptomatic right atrial thrombosis' above.)

We suggest not routinely using anticoagulation for primary prevention of TE in pediatric cancer patients if there are no other risk factors that would place them at high risk for TE (Grade 2C). (See 'Primary prevention' above.)

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