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Article

Thrombosis: Risk Factors Among Pediatric Patients With Cancer

Gina M. Newman
CJON 2020, 24(1), 58-64 DOI: 10.1188/20.CJON.58-64

Background: Thrombosis is the formation of a blood clot, or thrombus, inside of a blood vessel. Pediatric patients with cancer are at a higher risk of developing a thrombus because of their underlying disease, as well as their treatment and supportive care. Thrombosis can lead to significant morbidity, such as pulmonary embolism, in pediatric patients with cancer.

Objectives: The purpose of this study is to identify risk factors for developing a thrombus among pediatric patients with cancer, along with treatment and prevention protocols. This study also examines the clinical nurse’s role in preventing thrombosis and caring for pediatric patients who present with thrombosis.

Methods: The thrombosis literature was reviewed to identify risk factors, treatment regimens, and strategies for prevention.

Findings: Thrombosis in pediatric patients with cancer requires management of potential complications so that cancer treatment may continue.

Clinical care of pediatric patients with cancer is complex because of the potential for serious complications. Thrombosis, which entails the development of a thrombus (blood clot) inside of a blood vessel, is one of the most severe complications. Venous thromboembolism (VTE) can progress into deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Pediatric patients with cancer are at increased risk for thrombosis. Although there has been extensive research on thrombosis in the adult population, a gap in the literature exists regarding prevention and treatment of thrombosis in children, particularly pediatric patients with cancer.

The incidence of symptomatic VTE in pediatric patients with cancer is between 7% and 14%, whereas the incidence of asymptomatic VTE is about 40% (Piovesan, Attard, Monagle, & Ignjatovic, 2014). Cancer registry data indicate that pediatric patients with cancer are more likely to develop thrombosis than the general pediatric population. A Canadian registry of DVT and PE among 15 pediatric hospitals reported that 25% of patients admitted were diagnosed with a malignancy (Monagle et al., 2000). Pediatric patients with cancer diagnosed with thrombosis experience frequent hospitalizations, which, ultimately, increase costs for patients and their families and the medical institution. Compared to children without a cancer diagnosis, pediatric patients with cancer have an increased risk for mortality, thrombus-related morbidity, and recurrence of VTE (Raffini, Huang, Witmer, & Feudtner, 2009). About 25%–30% of symptomatic thrombi in children are related to the presence of a central venous line (CVL) (Athale & Chan, 2003).

With survival rates increasing for pediatric patients with cancer, clinical nursing care can prevent thrombosis or support its early treatment. This article will further explore the risk factors associated with the development of thrombosis among pediatric patients with cancer, as well as preventive measures, treatment modalities, and nursing implications for pediatric hematology-oncology nurses and advanced practice nurses (APNs).

Pathophysiology

The pathophysiology of cancer-associated thrombosis in children is multifaceted and involves interactions among the underlying cancer, prothrombotic factors inherent in patients, and the effects of therapy. Cancer is known to cause a hypercoagulable, prothrombotic state. This is in large part because of tissue factor (TF), a transmembrane protein that is secreted minimally by normal human cells. However, TF is increasingly expressed by malignant cells. TF forms a complex with factor VII to activate factor IX and factor X (both are clotting factors), which, in turn, initiates blood coagulation and the clotting cascade. This results in the generation of thrombin and fibrin (Grover & Mackman, 2018). When TF is expressed by malignant cells, it not only causes thrombosis but also contributes to metastasis, tumor growth, and tumor angiogenesis, which can subsequently affect prognosis. Malignant cells can also release TF microparticles into the systemic circulation, which can trigger a VTE (Grover & Mackman, 2018).

Children with cancer often present in a proinflammatory state and release proinflammatory cytokines, such as tumor necrosis factor and interleukin-1. These inflammatory cytokines enhance the expression of TF, platelet activation, and leukocyte adhesion, which, in turn, contribute to thrombosis (Prodger, Saha, Smith, & Evans, 2017). Under the influence of these inflammatory cytokines, platelets become more reactive, increasing monocyte activation and transforming endothelial cells into cells that are procoagulant.

Chemotherapy agents, surgery, and the presence of a CVL can enhance this prothrombotic state and can contribute to endothelial injury. In addition, tumor cells can compress vasculature and contribute to immobility, leading to vascular stasis and the formation of a thrombus.

Risk Factors

Risk factors associated with the development of thrombosis among pediatric patients with cancer can be categorized as patient-related risk factors and therapy-related risk factors. Patient-related risk factors include age, diagnosis and site of cancer, body mass index (BMI), inherited or acquired thrombophilia, and blood type. Therapy-related risk factors include chemotherapeutic agents, radiation, infection, presence of a CVL, and surgery and immobility. These risk factors are listed in Figure 1.

Patient-Related Risk Factors

Age at the time of cancer diagnosis is a risk factor for the development of thrombosis among pediatric patients with cancer. Children aged 2 years or younger are at an increased risk for CVL-associated complications because of their smaller vasculature diameter relative to the diameter of the CVL (Spavor et al., 2016). Thrombosis is also more common in adolescents, particularly in adolescents aged older than 10 years and in members of the adolescent and young adult (AYA) population aged 18–24 years. A study of AYAs by McKillop, Wu, Bruce, and Brandwein (2016) demonstrated the highest VTE incidence, with 94 cases per 10,000 hospital admissions. Similar epidemiologic rates have been reported in the adult literature; about 20% of reported cases of VTE in adults occur among patients with cancer (Ageno, Squizzato, Garcia, & Imberti, 2006).

In terms of diagnosis, children with acute lymphoblastic leukemia (ALL) are those within the pediatric oncology population at highest risk for thrombosis (Athale, 2013). This is mainly because ALL chemotherapies, including asparaginase and corticosteroids, result in a hypercoagulable state. Another malignancy associated with a high risk for thrombosis is acute myeloid leukemia (AML), particularly acute promyelocytic leukemia (APL), because of thrombocytopenia, disseminated intravascular coagulation, and systemic fibrinolysis associated with this subtype of AML (Vignoli, Marchetti, & Falanga, 2018).

The site of cancer is also a risk factor for thrombosis development. Of particular concern is when cancer cells compress major vessels and veins, leading to thrombosis. Patients with lymphoma can develop venous stasis caused by tumor compression or invasion of an affected blood vessel, and those with hepatoblastoma may develop thrombosis at the portal vein, particularly if undergoing surgery on the liver or liver transplantation (Trobaugh-Lotrario, Meyers, Tiao, & Feusner, 2016). In Wilms tumor, thrombosis can occur at the site of the renal vein (Athale, 2013). Individuals with sarcomas, particularly those of the lower limbs, are at an increased risk for thrombosis, most likely because of the presence of deep veins in the lower limbs, triggering a DVT. Neuroblastoma may create a hypercoagulable situation. However, thrombosis among pediatric patients with brain tumors is relatively uncommon when compared to pediatric patients with other malignancies (Forbrigger, Digout, Fernandez, Bernstein, & Kulkarni, 2016).

Obesity is a major risk factor for the development of thrombosis among adult patients with cancer, but little is known regarding obesity as a thrombosis risk factor in pediatric patients with cancer. A retrospective study by Stokes, Breheny, Radulescu, and Radulescu (2014) evaluated the relationship between obesity and VTE in 48 pediatric patients with various health conditions, reporting that higher BMI is associated with a greater risk of developing thrombosis. Another risk factor for thrombosis is inherent or acquired thrombophilia, such as a protein C or S deficiency, antithrombin deficiency, factor V Leiden gene mutation, or elevated lipoprotein. Individuals with these conditions are more likely to develop thrombosis because they may lack the coagulation factors and necessary proteins, such as fibrinogen, required for the clotting cascade (Alqasim, Al-Hadithi, & Al-Khalidi, 2019).

Blood type can be a risk factor for thrombosis in children with leukemia. A retrospective study by Mizrahi, Leclerc, David, Ducruet, and Robitaille (2015) of 523 children with ALL reported that 75% of the patients with VTE also had a non-O blood type (42 of 56 patients). This study was one of the first to confirm a significant association between non-O blood type and thrombosis among pediatric patients with cancer. Although the etiology is unclear, there may be an interaction between von Willebrand factor and blood type based on evidence linking non-O blood type status with elevated von Willebrand factor plasma levels (Mizrahi et al., 2015).

Therapy-Related Risk Factors

For pediatric patients with cancer, a significant therapy-related risk factor for thrombus development is the presence of a CVL or asparaginase therapy (Merlen et al., 2015). The underlying mechanism of asparaginase as treatment is that it depletes the asparagine pool in the body. Less asparagine leads to reduced protein synthesis and cell proliferation, which has a cytotoxic effect on lymphoblasts. Asparaginase also lowers the levels and changes the ratios of coagulation factors and anticoagulant proteins, particularly antithrombin (Merlen et al., 2015). In addition, asparaginase promotes TF through activation of white cells and endothelium, resulting in thrombin initiation. Of note, Erwinia asparaginase has less toxicity and risk for thrombosis than Escherichia coli (E. coli) asparaginase, but E. coli asparaginase is more effective at killing leukemia cells (Merlen et al., 2015).

Another therapy-related risk factor for thrombosis is the use of corticosteroids. Corticosteroids increase factors II and VIII, which causes a hypercoagulable state by increasing plasminogen activator inhibitor, reducing overall tissue plasminogen activator (Athale, 2013). Athale (2013) studied the risk factors for thrombosis in children with ALL protocols between 1995 and 2003, reporting that prednisone is associated with TF more than dexamethasone and that the higher the dose of steroids, the greater the risk for thrombosis. Anthracyclines, another class of chemotherapy agents used in pediatric oncology treatment, may increase TF activity and enhance thrombogenesis (Mitrovic et al., 2015). Cisplatin-based chemotherapy can increase the risk f0r thrombosis. A retrospective study by Zahir, Shaikh, Shabbir-Moosajee, and Jabbar (2017) examined 200 patients who had received cisplatin-based chemotherapy and compared them to 200 patients who had received non-cisplatin–based chemotherapy. Both groups were evaluated for VTE development during treatment and one month after therapy ended. Results indicated that in the cisplatin group, crude relative incidence of VTE was 2.8 times more than in the non-cisplatin group. The mechanism is likely because of increased TF activity, endothelial damage, and platelet activation (Zahir et al., 2017). All-trans retinoic acid, another chemotherapeutic agent, reduces the coagulopathy associated with APL, ultimately causing an overall imbalance of pro-coagulant and fibrinolytic forces, which results in a prothrombotic state (Choudhry & DeLoughery, 2012). This is most likely because of an upregulation of production of cytokines and adhesion molecules. Granulocyte–colony-stimulating factor may also increase thrombin activation, heightening the risk for thrombosis (Spiel et al., 2011).

Radiation causes direct vascular damage near the site of radiation, resulting in an increased risk for thrombosis at that site, which may persist after treatment. This is most often because of decreased blood flow to the affected vessels, which may cause vascular disease over time (Schaue et al., 2015).

Surgery increases the risk for thrombosis because of immobilization. A retrospective study by Lipay, Zmitrovich, and Aleinikova (2011) reported that immobilization for more than three weeks is a leading cause of thrombosis in children with cancer. Pediatric patients with cancer are particularly prone to immobility because of pain, surgery, and deconditioning.

Most pediatric patients with cancer experience an infection at some point during treatment because of a compromised immune system, resulting in neutropenia and myelosuppression. Infection triggers a proinflammatory state in the body and activates the coagulation pathway, increasing the risk for thrombosis.

The presence of a CVL represents a major risk factor for the development of thrombosis. All pediatric patients with cancer using a CVL are at risk for catheter-related thrombosis (van Ommen & Chan, 2014). CVLs, regardless of type, cause vascular injury during insertion into large vessels, which enhances the risk of developing a thrombus. While the catheter remains in the lumen of the blood vessel, it causes turbulent blood flow. An even higher risk for thrombosis exists if the catheter is placed in the femoral or jugular vein; the subclavian vein is preferred (Parienti et al., 2015). Although a thrombus is more likely to develop in the vessel in which the catheter is placed, patients can still develop thrombosis at sites distant from the catheter (Parienti et al., 2015).

Discussion

Prevention

Evidence-based guidelines have not been established for the prevention of thrombosis in pediatric patients with cancer; most protocols dictate care only for adult patients (Schoot, Kremer, van de Wetering, & van Ommen, 2013). Although studies report benefits of prophylactic anticoagulant therapy for pediatric patients with cancer, this type of therapy has not been associated with reduction of CVL-related thrombosis (Ko & Thornburg, 2017). Providers are cautioned to prescribe anticoagulant therapy because patients are already at risk for bleeding and can be thrombocytopenic.

If a child develops thrombosis after receiving asparaginase, one management option is to withhold the next dose of asparaginase. Asparaginase can also be removed from a treatment protocol entirely, although this has been reported to negatively affect outcomes in pediatric patients with ALL (Silverman et al., 2001).

A prospective patient safety study of hospitalized children aged 14 years or older suggests that patient ambulation can prevent thrombosis (Raffini, Trimarchi, Beliveau, & Davis, 2011). Raffini et al. (2011) emphasized that to ensure safety, clinicians should assess the patient’s mobility status before encouraging patient ambulation. Sequential compression devices are recommended for all children aged 14 years or older undergoing surgical procedures longer than 45 minutes (Raffini et al., 2011).

Treatment Approaches

When treating thrombosis in pediatric patients with cancer, providers should take into consideration underlying thrombocytopenia associated with the disease, its treatment, and thrombotic risk. Because there are no standard guidelines to treat thrombosis in children, thrombosis management is extrapolated from adult treatment guidelines, as well as from the provider’s clinical experience and his or her interpretation of adult guidelines (Schoot et al., 2013). The most common treatment for thrombosis diagnosed in pediatric patients with cancer is low molecular weight heparin (LMWH), known by the brand name Lovenox®. Other anticoagulant treatments for thrombosis include unfractionated heparin (UFH) and warfarin (under the brand name Coumadin®). The mechanism of action for LMWH and UFH is to inhibit factor XI and thrombin.

LMWH stabilizes the clot, preventing fragmentation that could cause embolization, such as a PE. LMWH also works by activating antithrombin. The American College of Chest Physicians recommends that children who have had a VTE and have at least one thrombosis risk factor should be treated with LMWH for three months (Law & Raffini, 2015). LMWH has a greater anticoagulation effect because it has a longer half-life than UFH as a result of decreased binding to plasma proteins, endothelial cells, and macrophages. This longer anticoagulant effect allows for daily or twice-daily dosing. Dosing of LMWH to treat thrombosis in pediatric patients with cancer is the same as that used in the general pediatric population: 1.5 mg/kg every 12 hours for patients aged younger than two months and 1 mg/kg every 12 hours for patients aged two months or older. Fondaparinux is another type of LMWH and is unique in that it is administered only once daily; the typical dose is 0.1 mg/kg for patients weighing less than 50 kg and 7.5 mg for patients weighing 50 kg or greater (Prandoni, 2017).

LMWH should not be administered to pediatric patients with cancer when they are scheduled for procedures and surgery (two doses should be held prior to procedures and surgery) and when platelets are between 10,000 and 20,000 ml (Prandoni, 2017). Monitoring LMWH levels via patient blood draws is easier than monitoring UFH or warfarin levels (Prandoni, 2017). LMWH has well-known pharmacokinetics and few drug–drug interactions, particularly with pediatric oncology chemotherapeutic agents (Prandoni, 2017).

Like LMWH, UFH activates antithrombin. Because UFH is less predictable, it requires more frequent blood draws and dose adjustments compared to LMWH. This may increase the risk for central line–associated bloodstream infection because UFH binds more than LMWH to endogenous plasma proteins, macrophages, and endothelial cells, resulting in decreased anticoagulation (Leentjens, Peters, Esselink, Smulders, & Kramers, 2017). UFH has a shorter half-life, and less time is required for renal elimination; therefore, UFH is recommended for patients who require emergent procedures or for those with significant renal insufficiency (Law & Raffini, 2015).

Warfarin is not commonly used in pediatric patients because no liquid preparation of warfarin exists. Warfarin’s effectiveness is limited to a very narrow therapeutic index. It interacts with multiple drugs and is affected by variations in a patient’s diet. Therefore, warfarin is difficult to manage as a treatment for children (Tousovska, Zapletal, Skotakova, Bukac, & Sterba, 2009).

Another treatment strategy is antithrombin replacement therapy with concomitant administration of asparaginase. Because asparaginase decreases antithrombin, antithrombin concentrate or fresh frozen plasma (FFP) can be administered. However, because minimal clinical evidence supports this treatment strategy, antithrombin replacement therapy is not routinely administered prior to asparaginase. Like all transfusions, FFP has its own set of risks, including hypersensitivity reaction and volume overload.

Another option for the treatment of thrombosis is to simply withhold the next dose of asparaginase (Silverman et al., 2001). If a child develops thrombosis, asparaginase can be removed from the chemotherapy treatment regimen entirely. However, this decision can affect the patient’s treatment plan.

Implications for Nursing

Nurses play a crucial role in caring for pediatric patients with cancer with thrombosis. They are involved in teaching about thrombosis, its treatment and side effects of medications, risk for excessive bleeding, and administration of LMWH subcutaneous injections to children who have developed thrombosis. Patients who develop thrombosis often receive LMWH injections for multiple months, whether inpatient or outpatient, and nurses typically teach patients and families to administer injections independently (Chen, 2017). Because the injections can be particularly painful for patients and can create bruises, nurses can alleviate or lessen that pain by providing care that addresses soft tissue management. Nurses may wish to offer patients topical lidocaine prior to LMWH injection and rotate the site with each injection to prevent atrophy.

To ensure accurate LMWH dosing and patient safety, nurses monitor laboratory values, including a complete blood count, prothrombin time, partial prothrombin time, and anti-Xa levels. When administering asparaginase, nurses must recognize potential signs of thrombosis in relation to timing of asparaginase, including PE (tachypnea, shortness of breath, chest pain), DVT (erythema, swelling, or pain), and CVL thrombosis (superior vena cava syndrome, tenderness, CVL dysfunction). Patient and family education about thrombosis includes a review of these symptoms so providers can be alerted promptly about potential TF.

Based on nursing assessment of the patient’s risk factors for thrombosis, nurses may encourage patients to ambulate as much as possible. Patients who are immobile require careful attention, with repositioning at least every two hours. If an extremity is affected, it should be elevated.

APNs and other clinicians may familiarize themselves with various anticoagulant therapies to ensure adequate dosing, ordering, and monitoring. APNs play a significant role in assessing children at risk for thrombosis and managing their care. When managing anticoagulation therapy, APNs are aware of the length of therapy so they can advocate for therapy to end when no longer needed.

Related to thrombosis and thrombosis risk, APN and nurse assessment continues when patients have become survivors. For example, patients who received radiation therapy may experience vascular changes that may make them more prone to developing thrombosis, particularly those who received radiation therapy targeted to the heart or chest. Nursing care also includes championing healthy weight behaviors in pediatric cancer survivors because obesity increases thrombosis risk.

Conclusion

Thrombosis is a serious complication in pediatric patients with cancer. In this patient population, the major thrombosis risk factor is presence of a CVL; CVLs are universally placed in pediatric patients with cancer (St. Jude Children’s Research Hospital, 2018). Therapy with asparaginase poses the greatest risk of developing thrombosis; asparaginase protocols require careful assessment of thrombosis signs and patient symptoms, as well as monitoring of coagulation factors. The evidence-based recommended treatment of thrombosis is LMWH.

A lack of evidence exists concerning the use of prophylaxis anticoagulant therapy in children. Thromboprophylaxis is a strategy that may be considered in the pediatric population with standard anticoagulant therapy. Several oral agents also exist, but these are not yet approved by the U.S. Food and Drug Administration (FDA); before they are approved by the FDA, they require additional investigation to determine their safety and efficacy within the pediatric population. Several national clinical trials investigating the use of oral anticoagulants among pediatric patients with cancer are ongoing. For pediatric patients with cancer, an evidence-based foundation for practice is lacking concerning thrombosis risks, prevention, and treatment.

About the Author(s)

Gina M. Newman, MSN, CPNP-AC, CPHON®, is a pediatric nurse practitioner at Children’s Hospital Los Angeles in California. The author takes full responsibility for this content and did not receive honoraria or disclose any relevant financial relationships. The article has been reviewed by independent peer reviewers to ensure that it is objective and free from bias. Mention of specific products and opinions related to those products do not indicate or imply endorsement by the Oncology Nursing Society. Newman can be reached at gnewman425@gmail.com, with copy to CJONEditor@ons.org. (Submitted June 2019. Accepted September 2, 2019.)

 

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