Venous thromboembolism (VTE) is a well known complication of malignant diseases in children either at the time of diagnosis or during treatment .
Children with cancer are at increased risk for VTE while compared with the general pediatric population. The overall reported prevalence ranges from 7 to 10% [2,3]. Walker et al.  performed a population-based cohort study about VTE in children with cancer, and concluded that childhood cancer was associated with a highly increased risk of VTE [adjusted hazard ratio 28.3; 95% confidence interval (CI) 7.0–114.5].
Children with cancer make up one of the largest subsets of patients who experience VTE. The cause of VTE in children with cancer is multifactorial and includes genetic predisposition (thrombophilia), disease-related factors, and treatment-related factors including use of central venous catheter (CVC), surgery, and chemotherapy [5,6].
The following discussion will review the incidence, risk factors, clinical manifestation, evaluation, prevention, and management of VTE in children with cancer.
Venous thromboembolism and childhood malignancy
According to data from Canadian registry, the incidence of VTE in the general pediatric population was estimated to be about 0.0007% compared with the reported incidences ranging from 7 to 10% in children with cancer [2,7].
Other studies reported the incidence of thrombosis in childhood cancer from 2.1 to 16% [8–10], which is much higher than the general population.
The incidence of thrombosis also varies with the type of cancer. It was estimated to be 1–36% in acute lymphoblastic leukemia [11,12] compared with 12–16% in solid tumors [13–15]. Among sarcomas, Ewing sarcoma had higher incidence . On the other hand, children suffering from brain tumor experienced fewer episodes of VTE compared with their adult counterparts and other solid tumors (0.6–2.8%) [2,16,17].
Epidemiological studies have identified cancer as an important VTE risk factor and show that cancer patients are at substantially increased risk of both initial and recurrent VTE events. The risk because of cancer is compounded by the effects of chemotherapy and other treatments [18,19].
Pathophysiology of thromboembolism in pediatric cancer
The pathogenesis of VTE in cancer is complex involving multiple interactions between tumors and components of the hemostasis system. A number of general prothrombotic mechanisms occur related to the host response to cancer including hemodynamic compromise, inflammation, necrosis and para protein production. However, the development of a persistent hypercoagulable state mediated by tumor activity is considered a key feature in VTE pathogenesis [19,20]. The pathogenesis of VTE is often described in terms of a hypothesis known as Virchow's triad, which states that VTE tends to occurs in conditions of venous stasis, vascular damage, and blood hypercoagulability, all of which are features of malignant diseases . Venous stasis may occur in cancer as a result of tumor expansion causing compression of the nearby blood vessels. Moreover, cancer-associated thrombocytosis and immobilization because of surgery, treatment or other complications may contribute to venous stasis. Vascular trauma may occur because of endothelial damage resulting from tumor invasion or chemotherapy/radiotherapy side effects as well as endothelial dysfunction mediated by loss of antithrombotic mechanisms. Finally, a persistent hypercoagulable state occurs because of tumor-mediated mechanisms, which cause a systemic activation of hemostasis [19,21]. Tumor cells activate hemostasis either directly by secreting molecules with procoagulant, fibrinolytic, or proaggregating activities or indirectly by releasing proinflammatory cytokines and through interactions between tumor cells and host vascular cells . The direct procoagulant mechanisms are principally considered responsible for the development of the cancer-associated hypercoagulable state [20,23]. The presence of tissue factor on the surface of tumor cells and of coagulation factors in peritumor environment facilitates activation of the coagulation cascade and following fibrin formation . Although the presence of plasminogen activator receptors on the surface of blasts may be important in the pathogenesis of bleeding tendency in some types of leukemia, defective generation of plasma fibrinolytic activity found in patients with solid tumors may contribute to the development of a prothrombotic state [19,25]. Tumor necrosis factor alpha and IL-1β released by tumor cells act on endothelial cells simultaneously causing them to express tissue factor and to down-regulate expression of the cell surface protein thrombomodulin, a key factor of the protein C anticoagulant pathway. Expression of tissue factor by endothelial cells is also induced by exposure to tumor-derived vascular endothelia growth factor . The ability of tissue factor to influence tumor cell behavior including angiogenesis is related to its participation in intracellular signaling initiated by activation of protease-activated receptors. These are a group of membrane receptor proteins that mediate cell activation via G proteins [26,27].
Cause, risk assessment, and evaluation
A Canadian multicenter case–control study in survivors of childhood cancer reported that age 2 years or less, blood group (non-O), and use of L-asparaginase are independent risk factors for VTE .
Other reported risk factors of thrombosis in childhood cancer include CVC for chemotherapy and supportive care (the most common risk factor), surgical management of cancer, immobility because of pain, sepsis, and other invasive infections secondary to immunocompromised state, and medications including corticosteroids and L-asparaginase [5,28,29]. The clinical symptoms of thrombosis differ based on the site of thrombosis. Central nervous system thrombosis can cause ischemic stroke, hemorrhage, sinovenous thrombosis, which may manifest as unexplained headaches, vomiting, visual problems, neurologic deficits, seizures, mental status changes including drowsiness, and signs of increased intracranial pressure. Computerized tomography (CT) angiography and magnetic resonance venogram can be used to visualize the venous blood flow in the cerebral venous sinuses. Pulmonary embolism may manifest as respiratory distress (tachypnea, shortness of breath), hypoxia, chest pain, and syncope. Pulmonary embolism in children is best evaluated with CT angiography. Upper and lower extremities deep vein thrombosis (DVT) can manifest as swelling, pain, tenderness, erythema, and dilated vessels. Color flow Doppler ultrasound is the preferred study to detect DVT in the extremities given that it is not invasive, has no radiation, does not require sedation, and offers reliable information regarding the blood flow through the vessels. The Doppler ultrasound may also be used for the evaluation of portal and renal veins, but it is less reliable for evaluation of the inferior vena cava (IVC) and its main tributaries. Cardiac thrombosis is primarily associated with an indwelling CVC, and could manifest as CVC malfunction, arrhythmia, or heart failure. Other causes and findings of cardiac thrombosis include sepsis and heart failure, respectively. Right atrium and the proximal portions of the superior vena cava and IVC can be visualized through echocardiography. CVC-related VTE usually present with CVC malfunction, or swelling, pain, tenderness, and erythema in the thrombosed site. Moreover, it may cause headache as well as swelling and discoloration of the face and neck, a condition that is called superior vena cava (SVC) syndrome. CVC-related VTE can be diagnosed by echocardiography, Doppler ultrasound, or contrast venogram depending on the site of thrombosis [30–33].
There is no need for thrombophilia testing following an episode of thrombosis in children with cancer because a positive result is not a sufficient basis to offer extended anticoagulation following an episode of provoked VTE .
Management and prevention of venous thromboembolism in pediatric cancer
Management of venous thromboembolism in thrombocytopenic children
In children with hematological malignancy, those with solid tumors and bone marrow involvement as well as children undergoing chemotherapy, they may develop thrombocytopenia. The management of thrombosis in this setting is a real challenge as the use of unfractionated heparin (UFH) may lead to exaggerated bleeding because of thrombocytopenia and coagulopathy. In addition, UFH itself may induce immune-mediated thrombocytopenia. On the other hand, osteoporosis is another late complication of UHF, which may be a concern in cancer patients who are prone to osteoporosis because of a variety of reasons [35,36]. Therefore, the preferred anticoagulant agents in cancer patient with thrombocytopenia is low-molecular weight heparin (LMWH) [30,37,38]. Guidelines issued by the Memorial Sloan Kettering Cancer Center (MSKCC) recommended administration of full dose of LMWH in platelet count more than 50 000/μl, half dose for platelet count between 25 000 to 50 000/μl, and temporary discontinuation of LMWH in platelet count less than 25 000/μl. However, the patient should be carefully monitored both clinically and with laboratory tests [37,39].
If children with cancer who had a life-threatening thrombosis within the last 3 months and developed thrombocytopenia, it is recommended to continue anticoagulation therapy while maintaining platelet count more than 50 000/μl because of high risk of recurrence. For patients whose life-threatening thrombosis has occurred more than 3 months, we can do according to MSKCC guideline .
Management of venous thromboembolism in children receiving asparaginase and corticosteroid
Asparaginase, a key component of therapy in children with acute lymphocytic leukemia (ALL), is associated with hemorrhagic and thrombotic complications [41,42]. The antileukemia effect of asparaginase is related to depletion of the amino acid ‘asparagine.’ Prolonged asparagine depletion is associated with the development of coagulation defects [43,44]. L-asparaginase seems to diminish the synthesis of both procoagulant and anticoagulant proteins by the liver. Deficiency of the anticoagulant proteins C, S and antithrombin III contributes to an increased risk of thrombosis . In addition, asparaginase enhances endothelial activation by increasing the levels of soluble P-selectin, high-molecular weight von Willebrand factor antigen and plasminogen activator inhibitor-1. The net result of the decline in anticoagulant proteins, platelet activation, and endothelial activation is development of thrombosis . Previous studies in Caucasian ALL patients who were treated with L-asparginase prepared from Escherichia coli revealed that the incidence of VTE ranged from 2.4 to 8% in children. The most common site of thrombosis was upper extremities . The reported risk factors include older age, the asparaginase type (E. coli has been associated with higher incidence of thrombosis than Erwinia-derived asparaginase), genetic predisposition to thrombosis, the presence of CVC, and the concomitant use of steroid (especially prednisolone) . Corticosteroids increase coagulation factors II and VIII and induce a hypofibrinolytic condition with elevation of plasminogen activator inhibitor type 1 and reduction of a2-macroglobulin and tissue-type plasminogen activator. The effect of dexamethasone on the fibrinolytic system is dose-dependent. Use of dexamethasone instead of prednisone is associated with a lower incidence of thromboembolism in children [30,42].
Management of children with thromboembolism following asparaginase therapy includes discontinuation of asparaginase, and starting LMWH and antithrombin replacement therapy (to keep antithrombin activity >60%). Anticoagulation therapy is continued for at least 3 months or until the course of asparaginase is completed, whichever is longer. Interruption of asparaginase has been shown to negatively affect outcome in ALL. Therefore, once the child is stable, hematological parameters normalize, and anti-Factor Xa levels are in a therapeutic range, asparaginase therapy can be safely resumed. The decision to restart asparaginase mainly depends on the site and complications of thrombosis. In case of life-threatening thromboembolism, resuming of asparaginase should be done with caution. Asparaginase can cause depletion of antithrombin and LMWH profoundly depends on antithrombin activity. Thus, in case of thrombosis following asparaginase therapy, it seems logical to start antithrombin replacement by fresh frozen plasma (FFP) or cryoprecipitate and LMWH [30,43,44,47]. If the patient developed recurrent thrombosis upon resumption of asparaginase, the drug should be permanently discontinued and the patient should be evaluated for other risk factors including genetic predisposition .
The existing evidence regarding FFP or antithrombin use for prevention of asparaginase-associated thrombosis is inconclusive. It is not routine to administer FFP and/or antithrombin supplement to prevent thromboembolism in children receiving asparaginase [43,47,48].
Routinely, there is no need for thrombophilia work-up following first episode of thrombosis because of asparaginase therapy [34,49].
Unlike LMWH, novel oral anticoagulants, which are direct inhibitors of thrombin or Xa, are not dependent on antithrombin level for their activity. Hence, we speculate that these agents may be as effective as or even more effective than LMWH and/or antithrombin supplement in the prevention and therapy of asparaginase-related thrombosis .
Management of central venous catheter-related thrombosis in childhood cancer
The use of CVC significantly increases the risk of thrombosis in children with cancer, though sometimes it is mandatory to insert a CVC to administer chemotherapy agents or blood products, and even for repeated blood sampling . Thrombosis happens less commonly in CVCs with internal lines (Port-A-Cath) than external tunneled lines .
The British Society for Hematology (BSH) guideline recommends that an internal device (Port-A-Cath) is preferable to an external tunneled device for childhood cancer needing a CVC (Grade 2B) . International guidelines recommend that symptomatic CVC-related VTE in children should be treated with 3 months of anticoagulation preferably LMWH . However, some experts recommend that in uncomplicated CVC-related thrombosis that the CVC has been removed, an anticoagulant period of 6 weeks is sufficient [51,52].
There is insufficient evidence in cancer patients to recommend thrombolytic therapy to restore catheter patency unless the benefits of rapid clot resolution in specific circumstances with life, limb, or organ-threatening thrombosis outweighs the risk of major bleeding . Given that most cancer patients during intensive chemotherapy courses suffer from bleeding tendency because of thrombocytopenia, the risk–benefit ratio of this therapy should be assessed on an individual basis. The choice of thrombolytic agent in this setting is also a matter of debate, though some small single-center studies have tried recombinant tissue plasminogen activators such as alteplase and reteplase in occluded CVC in children with cancer with good efficacy and safety profile .
The American College of Chest Physicians (ACCP) recommends prophylactic anticoagulation for more than 3 months whereas our plan is to maintain functional CVC with thrombosis .
Removal of the CVC is not necessary if it is still required for venous access, is in a good position and functions well (Grade 2C) . If our plan is to remove the catheter with thrombosis, it is recommended to use 2–5 days of therapeutic anticoagulation with LMWH before removing the catheter (Grade 2C) . There is insufficient evidence to recommend primary thromboprophylaxis in patients who have an indwelling CVC without thrombosis (Grade 2B) . ACCP recommend using UFH at a dose of 0.5 units/kg/h for patency of CVC (Grade 1A) .
Childhood cancer and genetic predisposition
An Italian study of 48 children demonstrated a numerically higher prevalence of factor V Leiden and prothrombin mutation in ALL patients with VTE, as compared with the general population .
Thrombophilia tests do not help with clinical decision-making in cases with provoked VTE and should not be implemented . Therefore, in pediatric cancer patients with first episode of VTE, there is no need for thrombophilia tests because a positive thrombophilia evaluation is not a sufficient basis to offer extended anticoagulation following an episode of provoked VTE . There is inconsistent evidence to prove the role of hereditary thrombophilia as a risk factor in the development of VTE in children with cancer [30,50]. The thrombophilia tests may be helpful in pediatric cancer patients with recurrent thrombosis in order to extend anticoagulation therapy, though this theory need confirmation by large population-based studies. Thrombophilia testing should not be done at the time of diagnosis of VTE or during the first 3 months of anticoagulation therapy. In addition, the tests should be requested in a step-wise fashion, and the anticoagulants should be withheld for at least 2–4 weeks .
Incidental right atrial thrombosis in childhood cancer
CVCs may provoke right atrial thrombosis if the tip of catheter is mistakenly inserted in the right atrium . For low-risk patients with a clot less than 2 cm in size, which is nonmobile, attached to atrial wall, and not pedunculated or snake shape, removing CVC with or without anticoagulation seems an appropriate strategy. For children with a large (more than 2 cm), mobile, pedunculated or snake shape clot in right atrium, the ACCP suggest anticoagulation, with appropriately scheduled CVC removal, and consideration of surgical intervention or thrombolysis based on individualized risk–benefit assessment (Grade 2C) [57,58].
Monitoring of anticoagulation parameters before invasive procedures in children with cancer
A child with cancer may need an invasive procedure (lumbar puncture with or without chemotherapy, bone marrow aspiration and biopsy, second look surgery, tissue biopsy, or neurosurgery) as part of his/her cancer treatment. This can be a challenge when the patient is on anticoagulant therapy for VTE. Given the risk of hemorrhage and spinal cord hematoma, it is recommended that at least two doses of LMWH be discontinued before lumbar or epidural puncture and anti-Xa level should be measured before the procedure. For higher risk patients with life-threatening thrombosis, it is highly advised to keep the patient anticoagulated with UFH till 4 h before the procedure . LMWH should be started again 12 h after the surgery, although in neurosurgical procedures, it is preferable to restart LMWH at least 24 h postsurgery .
Children and neonates receiving single or twice-daily doses of subcutaneous LMWH, the drug should be monitored by anti-Xa activity. The target level should range from 0.5 to 1.0 U/ml in a blood sample taken 4–6 h after subcutaneous injection or 0.5–0.8 U/ml when the sample was taken 2–6 h after the last subcutaneous injection .
The preferable target level of anti-Xa activity before invasive procedures is 0.3 and 0.1 U/ml for neurosurgical procedures .
Tumor thrombosis is more commonly observed in children suffering from Wilms tumor, hepatoblastoma, and neuroblastoma. The common sites of tumor thrombus include portal vein, IVC, right atrium, and renal veins. Treatment needs a multidisciplinary approach with collaboration of pediatric surgeon, pediatric oncologist, cardiac surgeon, and radiotherapist. It is very important to distinguish tumor thrombosis from thrombosis because of hypercoagulability condition in cancer as tumor thrombus may progress in spite of anticoagulant therapy [59–61].
Although preoperative chemotherapy for tumor thrombus extending above the hepatic vein is a commonly accepted treatment, there has not been much research on the choice and duration of anticoagulant therapy in these cases [60,62].
In the setting of tumor thrombus, especially, those involving IVC, the benefit of anticoagulation is not exactly known. The anticoagulant of choice is usually LMWH. The decision to how long continued anticoagulation is a matter of debate. Although no randomized trials have demonstrated a clear benefit to routine anticoagulation, some authors recommend LMWH until 24 h before surgery. Postoperatively, the decision to continue anticoagulation depends in part on how successful the surgeon was in complete tumor resection .
Prophylaxis and prevention
Anticoagulation therapy in children with cancer is a challenging issue as these children are at risk for both VTE and bleeding tendency as a result of chemotherapy-related thrombocytopenia and coagulopathy. Currently, there is insufficient data to support that anticoagulation in children with cancer will prevent all VTE events [4,5,64].
Children with cancer who do not have obvious contraindication for anticoagulation therapy (e.g. active bleeding) should be treated in case of symptomatic VTE. In these patients, LMWH is the preferred anticoagulation agent compared with either UFH or warfarin . LMWH is an easier option to handle as its dosing is not affected by diet and is less affected by age compared with warfarin. In addition, LMWH has fewer drug interactions, especially with chemotherapeutic agents [55,65,66].
The studies on VTE prophylaxis in children with cancer are limited. It is hardly advised to give prophylactic anticoagulation to prevent thromboembolism [64,67]. The Italian Association of Pediatric Hematology and Oncology made recommendations regarding prolonged use of CVC in children with cancer and blood disorders. They recommend insertion of CVC on the right side of the upper venous system and to leave the tip of catheter at the right atrial–superior vena cava junction. These recommendations are based on studies showing higher rates of thrombosis when CVCs were placed on the left side and the tip of catheter passing the mentioned junction .
In conclusion, children with cancer have increased risk of thrombosis compared with healthy children. The most common risk factor of thrombosis in childhood cancer is CVC. Treatment with LMWH for at least 3 months is the preferred anticoagulation therapy in pediatric cancer with thrombosis. The primary prophylactic anticoagulation to prevent thromboembolism in pediatric cancer is not recommended. Conditions such as thrombocytopenia, chemotherapy with asparaginase, catheter-related thrombosis, right atrial thrombosis, and tumor thrombus need special attention and should be treated more cautiously.
Conflicts of interest
There are no conflicts of interest.
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