Continuing Education Activity

Cancer-associated thrombosis is one of the leading causes of morbidity and mortality for cancer patients. It commonly occurs in patients with clinically active malignancy; however, there is a subset of patients where thrombosis can be the first manifestation of their cancer. This article outlines the etiology of this disease as well as describes the evaluation process and management of these patients. It also highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Describes the etiology of cancer-associated thrombosis
• Summarize the diagnostic examination process for cancer-associated thrombosis
• Reviews current guidelines for the treatment of cancer-associated thrombosis
• Outlines the importance of collaboration and communication amongst the interprofessional team to improve outcomes for cancer patients with thromboembolic disease, especially if they are receiving anticoagulation.

Introduction

Patients with malignancy often experience increased risk of thrombosis, both venous and arterial. Clinical venous thromboembolism (VTE) remains one of the most common causes of mortality and morbidity among cancer patients. Pathophysiology of this disease stems from the hypercoagulable state related to the increasing production of substances like tissue factor that has high procoagulant activity. The thromboembolic disease can be the first manifestation of occult malignancy or more commonly occur within six months of a cancer diagnosis. 

Etiology

Multiple factors contribute to the increased risk of arterial and venous thromboembolism in cancer patients:

1. Tumor's tissue and anatomical factors 
2. Patient's comorbidities including obesity and advanced age
3. Surgical and medical oncological treatment 

Epidemiology

The correlation between malignancy and thrombosis has been reported as early as 1823. Multiple published accounts show an increased risk of VTE in patients with malignancy with prevalence as high as 20%. A large case-control study in the Netherlands examined 3220 patients aged 18 to 70; the study found the overall risk of venous thrombosis to be 7-fold higher in patients with malignancy, the highest risk was in the first few months after diagnosis with the highest risk increase seen in patients with hematological malignancies, lung cancer, gastrointestinal cancer, or with distant metastases.[1] In another case-control study in Minnesota, a 4-fold increase risk of VTE was found in patients with cancer, while patients receiving chemotherapy experienced an even higher risk.[2]  

Cancer patients also face an increased risk of arterial thromboembolism. In a large retrospective study with 279,719 pairs of cancer patients and matched controls, the 6-month incidence of myocardial infarction was 2.0% in cancer patients compared to 0.7% in control patients, while for ischemic stroke, the incidence was 3.0% for cancer patients compared to 1.6% for control patients. The study also found that cancer patients experiencing arterial thromboembolism had a poor prognosis, with a 3-fold increased hazard for death.[3]

Pathophysiology

The mechanisms of cancer-associated thrombosis are diverse. Tissue factor produced by malignant cells appears to trigger the coagulation cascade leading to the formation of Factor Xa, while some cancer cells can produce cancer procoagulant that acts directly on Factor Xa. In addition to the potential procoagulant effect of cancer cells, anti-cancer therapy has shown to be an additional cause of cancer-associated thrombosis. Different chemotherapeutic agents, including methotrexate, cyclophosphamide, cisplatin, doxorubicin, 5-fluorouracil, and lenalidomide, have been found to increase the risk of VTE and mortality significantly. Other causes include venous stasis due to compression of blood vessels by tumor or prolonged immobility in critically ill cancer patients.[4][5]

History and Physical

Taking a thorough history and performing a complete physical exam is essential. Thromboembolic events can either occur in patients with a known history of malignancy or can be the first manifestation. Patients can present with venous thromboembolism as deep venous thrombosis or pulmonary embolism and less likely as arterial thromboembolism with ischemic stroke and myocardial infarction.

Evaluation

In patients with unprovoked venous thromboembolism as well as patients with arterial thrombosis without identifiable cardiovascular risk factors should always raise suspicion for occult malignancy. Currently, there is insufficient evidence that extensive testing for occult malignancy in patients with unprovoked thrombotic disease would reduce cancer-related mortality.[6] However, age-appropriate cancer screening is necessary.

Treatment / Management

Given the increased risk of thromboembolism, patients with clinically active malignancy would benefit from thromboprophylaxis. A meta-analysis looking at a total of 33 trials and 11,972 patients provided more evidence that thromboprophylaxis decreased the incidence of VTE in cancer patients who were undergoing chemotherapy or surgery, while no apparent increase in the incidence of significant bleeding.[7]

Current guidelines from the National Comprehensive Cancer Network (NCCN) recommend anticoagulation with unfractionated heparin or low molecular weight heparin in hospitalized cancer patients as thromboprophylaxis. Mechanical prophylaxis should be used instead of anticoagulation therapy in patients experiencing active bleeding, thrombocytopenia (platelet count below 50,000/mcL), evidence of hemorrhagic coagulopathy, or have an indwelling neuraxial catheter. Contraindications to the use of mechanical prophylaxis include acute deep venous thrombosis and severe arterial insufficiency.

A recent meta-analysis addressed the question of the optimum duration of anticoagulation in cancer patients who are hospitalized with acute illnesses. This study looked at trials comparing standard-duration versus extended-duration anticoagulation prophylaxis. The risk of VTE was not significantly lower in the extended-duration prophylaxis group of patients but the risk of bleeding was about two-fold higher.[8] 

Regarding outpatient VTE prophylaxis, surgical pelvic or abdominal oncology patients would benefit from continuing VTE prophylaxis up to four weeks post-operation. The use of aspirin or anticoagulation therapy for patients with multiple myeloma on immunomodulatory medications is recommended based on risk stratification with the IMPEDE VTE score.[9][10] For patients with solid cancers on chemotherapy and high Khorana score, prophylactic anticoagulation with direct oral anticoagulation or low molecular weight heparin showed a decrease in the incidence of pulmonary embolism.[11]

Low molecular weight heparin (LMWH) remains the preferred anticoagulation option for the management of cancer-associated thrombosis.[12] The dosage recommendation for LMWH is 1 mg/kg every 12 hours, and 1 mg/kg once daily for patients with creatinine clearance less than 30 mL/minute. Avoid the use of LMWH in patients on dialysis. Other treatment options include direct oral anticoagulants like apixaban, rivaroxaban, edoxaban, fondaparinux, and warfarin. In the Caravaggio trial, researchers found apixaban to be non-inferior to LMWH in the treatment of cancer-associated VTE without an increased risk of significant bleeding.[13]

Thrombolytic therapy can be used in patients with life or limb-threatening pulmonary embolism or acute deep vein thrombosis with consideration of the contraindications as intracranial tumors or metastasis, active bleeding, and history of intracranial hemorrhage. NCCN recommends a treatment duration minimum of 3 months or for the duration of active malignancy. For patients with non-catheter-related deep venous thrombosis or pulmonary embolism, indefinite anticoagulation is the recommendation.

Continuing to assess for benefit vs. risks as well as monitoring for complications is essential. In patients with DVT located in inferior vena cava, iliac, femoral, and popliteal veins in addition to a contraindication to therapeutic anticoagulation, placement of retrievable vena cava filters can prevent pulmonary embolism. Once placed, it is important to periodically assess patients for resolution of contraindication, removal of the vena cava filters, and switching to therapeutic anticoagulation. For patients with catheter-associated thrombosis, treatment consists of removing the catheter or anticoagulation if the catheter remains.[10] 

In patients with superficial venous thrombosis, if it is related to peripheral catheter, current NCCN guidelines recommend removing the catheter and consider anticoagulation if thrombus progression occurs. In patients with superficial venous thrombosis non-catheter related especially in lower extremities, recommendations are for at least six weeks of anticoagulation.

Differential Diagnosis

Malignancy is a cause of unprovoked thromboembolic disease. In a recently published retrospective study of 245 patients with venous thromboembolism, 4.1% had an occult malignancy.[14] However, during the evaluation of unprovoked thromboembolic disease, workup needs to include ruling out of thrombophilic disorders, nephrotic syndrome, antiphospholipid syndrome, myeloproliferative neoplasms, severe liver disease, and inflammatory bowel disease.

Prognosis

Cancer-associated thrombosis increases mortality in cancer patients. In a review of 8 million Medicare patients admitted for VTE, the probability of death within six months of admission for cancer patients was 94% compared to 29% with non-cancer patients.[15]

The majority of deaths in patients with cancer-associated thrombosis were related to arterial thrombosis (myocardial infarction, ischemic stroke) rather than VTE. In a review of 4466 ambulatory patients, thromboembolic disease accounted for 9.2% of deaths. 5.6% were related to arterial thrombosis.[16]

Complications

In cancer patients, experiencing a thromboembolic event has serious complications, including increased risk of recurrent thrombosis, increased risk of bleeding during anticoagulation therapy, increased hospitalization rates, and increased mortality. 

Deterrence and Patient Education

Patients with active malignancy are at risk of developing venous and arterial thromboembolism. It is important to educate patients on their increased risk of developing cancer-associated thrombosis and possible presenting symptoms, including unilateral leg swelling, palpitations, chest pain, dyspnea, and stroke. 

For non-cancer patients with unprovoked venous thromboembolism, it is crucial to perform age-appropriate cancer screening to evaluate for hidden malignancy. 

Enhancing Healthcare Team Outcomes

Cancer-associated thrombosis adds to the complexity of care for cancer patients. The utilization of multidisciplinary care is essential. Primary care physicians, as well as primary oncologist/hematologist, will initiate evaluation and the discussion with the patient regarding benefits vs. risks of anticoagulation therapy if it is needed. They are also responsible for educating patients about side effects and perform close monitoring for risks of bleeding. Pharmacists are necessary to ensure correct dose adjustments—nursing staff, whether inpatient or ambulatory, play a significant role in education and medication administration.