Mechanism and management of cancer-associated thrombosis

Mechanism and management of cancer-associated thrombosisReview
Mikio Mukai (MD, PhD)*, Toru Oka (MD, PhD) Osaka Prefectural Hospital Organization, Osaka International Cancer Institute, Department of Medical Check up, Onco-Cardiology Unit, Osaka, Japan
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 CAT and its mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Venous thromboembolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Arterial thromboembolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Future prospective assignment of treatment-related thromboembolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Concluding remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
A R T I C L E I N F O
Article history: Received 23 February 2018 Accepted 27 February 2018 Available online 24 March 2018
Keywords: Cancer Venous thromboembolism Atrial thromboembolism Anti-angiogenic agents Direct oral anticoagulants
A B S T R A C T
Thromboembolism is considered to have a substantial impact on outcomes in patients with cancer. Although progress in cancer therapy and the advent of new anticancer agents such as molecular targeted drugs have improved the outcomes of patients with cancer, the incidence of cancer-therapy-related thromboembolism is increasing, and the management of this adverse reaction has become a major problem. Cancer is intimately related to thrombosis. Thrombus formation results from the complex interaction of various factors, such as tissue factors, coagulation abnormalities, activated platelet activation, activated adhesion activation, and endothelial cell dysfunction. Thrombosis has an impact on cancer proliferation and extension. The condition known as “cancer-related thrombosis” must therefore be managed differently from thrombosis in patients without cancer.
© 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
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Introduction
The history of the relation between cancer and thrombosis dates back to 1823, the year in which Bouilland first reported that cancer is related to thrombosis [1]. In 1865, Trousseau reported a relation between potential cancer and migrating thrombophlebitis [2]. Thromboembolism is the second leading cause of death in patients with cancer who receive chemotherapy on an outpatient
* Corresponding author at: Osaka Prefectural Hospital Organization, Osaka International Cancer Institute, Department of Medical Check up, Onco-Cardiology Unit, 3-1-69 Otemae, Chuo-ku, Osaka 541-8567, Japan.
E-mail address: [email protected] (M. Mukai).
https://doi.org/10.1016/j.jjcc.2018.02.011 0914-5087/© 2018 Japanese College of Cardiology. Published by Elsevier Ltd. All rights
basis. Cancer therapy is therefore considered intimately related to thromboembolism, and thromboembolism is the most important cardiovascular complication in patients who receive cancer treatment [3]. Venous thromboembolism (VTE) is the most common type of thromboembolism occurring in patients during cancer treatment. Recent studies of patients with VTE have reported that the incidence of VTE is increasing year by year in patients with cancer. On the other hand, the advent of new molecular targeted drugs for cancer has led to increased risks of atrial thromboembolism (ATE) as well as VTE. These phenomena have suggested that the mechanisms leading to the development of thromboembolism in patients with cancer are diverse [4,5]. Therefore, thrombosis developing as a complication of
reserved.
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cancer is referred to as “cancer-associated thrombosis (CAT)” (Fig. 1). In this report, we review the characteristics and pathologic features of CAT.
CAT and its mechanism
The mechanisms of thrombosis occurring as a complication of cancer are shown in Fig. 2. Cancer tissue is in a state of coagulopathy, inflammation, and hypoxia, and various substances are produced by the induction of cancer proliferation genes, resulting in the formation of thrombi. The series of reactions involved in thrombus formation are related to the proliferation and metastasis of cancer [6]. Thrombosis in patients with cancer proceeds by a different mechanism from that in patients without cancer. Thrombosis developing in patients with cancer is treated as CAT [7]. Tissue factors (TFs) produced by cancer cells are considered the starting point of coagulation reactions that trigger CAT. TF activates factor VII, and a complex is formed between factor VII and TF. The TF complex promotes the activation of factor X, leading to the formation of factor Xa. On the other hand, some types of cancer cells produce cancer procoagulant (CP) and directly act on factor Xa. Factor Xa activated by these factors produces thrombin and simultaneously stimulates and amplifies the coagulation cascade. The amplified coagulation cascade further
Fig. 2. Multiple mechanisms in cancer-associated thrombosis. There are multiple, overlapping, and interacting mechanisms that can explain the increased incidence of thrombosis in patients with malignancies. In cancer-associated thrombosis, hypercoagulability is probably the result of products arising from the tumor itself. CP, cancer procoagulant; DIC, disseminated intravascular coagulation; NBTE, non- bacterial thrombotic endocarditis; PAI-1, plasminogen activator inhibitor-1.
promotes platelet activation, leading to the formation of many thrombi on the vascular endothelium.
After microparticles including TF and adhesion factors are carried in the bloodstream, pathologic thrombi are formed on vascular endothelial cells that were damaged by cytokines produced by cancer cells. Plasminogen activator inhibitor (PAI)-1 secreted by cancer cells inhibits the fibrinolytic system, promoting the deposition of fibrin and leading to the formation of fibrin thrombi. Formed thrombin, activated platelets, fibrin, and abnor- malities of coagulation and fibrinolysis can lead to the develop- ment of disseminated intravascular coagulation (DIC). In patients with cancer, pathologic thrombi are formed by complex coagula- tion mechanisms involving platelets and leukocytes (mainly monocytes) induced by the action of coagulation cascades and the activation of vascular endothelial cells. The mechanisms of these coagulation abnormalities and thrombosis may play impor- tant roles in the metastasis and proliferation of cancer cells as well as the presence of thromboembolism [8].
Venous thromboembolism
The common type of thromboembolism associated with the diagnosis and treatment of cancer is VTE. VTE is found in 10–20% of patients with cancer. The incidence of VTE in patients with cancer is estimated to be 4–7 times higher than that in patients without cancer [9,10] and has been increasing year by year. One of the reasons for this increase is that progress in lower extremity venous ultrasonography and contrast-enhanced computed tomography (CT) has enhanced the diagnosis of thromboembolism. Second, improved outcomes in patients with cancer have prolonged the duration of cancer therapy. Third, the development and increased use of new anticancer treatments, particularly molecular targeted drugs, have led to an increase in the incidence of treatment-related thromboembolism in patients with cancer [11]. The characteristics contributing to the pathogenesis of VTE in patients with cancer are shown according to Virchow's triad in Table 1. Venous stasis can be caused by factors such as prolonged bed rest (such as after surgery) and compression of blood vessels by tumors or ascites (particular- ly, in the pelvic cavity). Hypercoagulability can be caused by dehydration, malnutrition, transfusions, postoperative conditions, coagulation-promoting factors secreted by tumor cells, platelet activation, and chemotherapy. Vascular endothelial injury is likely to be caused by direct tumor invasion, the placement of venous catheters, injury by substances produced by tumors, chemothera- py, and radiotherapy [12].
Clinical signs and symptoms such as chest symptoms and leg edema have an important role in the diagnosis of VTE and are assessed according to the Wells score. Diagnostic imaging studies
Table 1 Virchow's triad in patients with cancer.
1. Venous stasis Prolonged bed rest/immobility (after surgery) Compression of blood vessels by tumor
2. Hypercoagulability Procoagulant effects Tumor cytokines Recent major surgery Active chemotherapy, hormonal therapy Current erythropoiesis-stimulating agents Current or recent antiangiogenic therapy
3. Endothelial injury Direct invasion by tumor Damaged or dysfunctional endothelium Tumor cytokine Presence of central venous catheters Chemotherapy drugs Radiation therapy (late phase complication)
Table 2 Clinical factors associated with increased risk of cancer-associated venous thromboembolism.
1. Cancer-related factors Primary site of cancer (mostly pancreas, brain, stomach, kidney, lung,
lymphoma, myeloma) History (especially adenocarcinoma) Advanced stage (metastatic) Initial period after cancer diagnosis
2. Patient-related factors Demographics: older age, female sex, African ethnicity Comorbidities (infection, chronic kidney disease, pulmonary disease,
atherothrombotic disease, obesity) History of venous thromboembolism, inherited thrombophilia Low performance status
3. Treatment-related factors Major surgery Hospitalization Chemotherapy and anti-angiogenic agents Hormonal therapy Transfusion, central venous catheters
Modified from Khrona AA et al. J Clin Oncol 2009;27:4839–47. Zamorano JL, et al. Eur Heart J 2016;37:2768–801.
M. Mukai, T. Oka / Journal of Cardiology 72 (2018) 89–93 91
such as lower-limb venous ultrasonography and contrast-en- hanced CT, and hemostatic activity testing based on D-dimer levels are also performed [13]. VTE is often accidentally diagnosed on contrast-enhanced CT performed to evaluate cancer. However, symptoms of VTE are often difficult to distinguish from those of cancer in patients who are receiving anticancer treatment, and a considerable number of patients are asymptomatic. Therefore, the diagnosis is made by stratifying the risk of thrombosis. As shown in Table 2, diseases associated with a high risk of VTE include pancreatic cancer, brain tumors, gastric cancer, renal cancer, lung cancer, and ovarian cancer. Histologically, adenocarcinoma carries a high risk of VTE. In addition, elderly patients, women, and patients with complications involving the heart, lungs, or kidneys are at high risk for VTE [14,15].
Guidelines for the treatment of VTE associated with cancer have yet to be established. Treatment is thus performed according to guidelines for the treatment of acute pulmonary thromboembo- lism (JCS 2009) [13]. Acute pulmonary thromboembolism is a disease requiring urgent management. Massive emboli can cause cardiac arrest or circulatory collapse, associated with high mortality rates. However, patients who receive adequate therapy
Fig. 3. Clinical course and effectiveness of anticoagulant therapy for VTE in patients wit Cardiovascular Diseases between August 2011 and July 2014 (Mukai M et al. unpublish UFH, unfractionated heparin; VTE, venous thromboembolism.
in an early phase are likely to survive. The use of percutaneous cardiopulmonary support, thrombolytic therapy, and surgery should be considered in individual patients. In a Swedish study of 23,796 subjects with cancer who underwent autopsy (patho- logical anatomy) from 1970 through 1982, pulmonary embolism (PE) was found in 23% of the patients, and 10% of the patients had fatal PE. In a study of patients with lung cancer, PE was found in 42% of the patients. Histologically, the incidence of PE was 1.65 times higher in patients with pulmonary adenocarcinoma than in those with squamous-cell carcinoma. Adenocarcinoma and carcinoma with metastasis were significant independent risk factors for the development of PE [16].
Mild to moderate cases of VTE are treated by anticoagulation therapy with heparins (unfractionated heparin or fondaparinux) during the acute phase. In Western countries, the first-line drug for VTE associated with cancer is low-molecular-weight heparin [17]. In Japan, instead of low-molecular-weight heparin, heparins are used as initial treatment, and warfarin is given in a maintenance period.
The treatment outcomes in patients with cancer and VTE in our center are shown in Fig. 3. In accordance with the guidelines for the treatment of VTE (JCS 2009), heparins (unfractionated heparin or fondaparinux) were given as initial treatment, followed by warfarin. The study group comprised 54 patients who were referred to the Department of Cardiology for in-depth examination and treatment. The age at the onset of VTE was 64.7 12.2 years. There were 22 men and 32 women. As for cancer therapy, 68.5% of the patients had surgery-related events and 50.0% had chemo- therapy-related events. The mean treatment period was 34.0 23.7 days. The mean D-dimer concentration was 14.5 13.7 mg/mL before treatment and improved to 1.5 1.4 mg/mL during treatment. There were no serious compli- cations such as bleeding during treatment. However, cancer therapy was difficult to continue in 6 of the 54 patients despite anticoagulation therapy. One patient (a 19-year-old man with colorectal cancer) did not respond to treatment at all, and the D- dimer concentration increased. Three patients (5.6%) had recur- rence of VTE during follow-up. As for outcomes, 29.6% of the patients died during 6 months. Anticoagulation therapy carries a high risk of bleeding and recurrence in patients with cancer and therefore is often difficult to perform in a considerable number of patients. However, careful and effective implement of antic- oagulation therapy has allowed anticancer treatment to be
h cancer. Cancer patients with VTE, treated in Osaka Medical Center for Cancer and ed data).
M. Mukai, T. Oka / Journal of Cardiology 72 (2018) 89–9392
continued or resumed in many patients with cancer (Mukai M, et al. unpublished data).
Patients with cancer have a high rate of recurrence of VTE after the withdrawal of anticoagulant therapy. Treatment guidelines in Western countries recommend that anticoagulation therapy should be given for 3 months or 6 months or longer. Long-term anticoagulation therapy is associated with a 6-fold higher risk of bleeding in patients with cancer than in patients without cancer. Therefore, treatment should be selected on an individual patient basis, taking into account the disease status and prognosis [15,17]. On the other hand, because warfarin can interact with food and cytochrome P450 2C9 during the chronic phase and can have effects on the anticoagulant system, increasing the risk of DIC and bleeding, long-term treatment with warfarin is difficult to perform in an appreciable number of patients. Attention has therefore focused on recently developed direct oral anticoagulants (DOACs) that inhibit factor X. At present, DOACs are expected to be effective because they have a different mechanism of action, although adequate evidence in patients with cancer is currently unavailable. A study of edoxaban for the treatment of VTE in patients with cancer reported that edoxaban was non-inferior to low-molecular-weight heparin in terms of preventing the recur- rence of VTE and bleeding [18]. The long-term use of DOACs has already been studied, and DOACs are expected to be therapeuti- cally useful [19].
Arterial thromboembolism
The incidence of ATE in patients with cancer has been reported to be 1.0–4.7% in clinical practice, which is not that high [15,20]. However, the course of ATE is acute and fulminant, and the incidence of treatment-associated ATE is increasing owing to the development of angiogenesis inhibitors and other molecular target drugs. Adequate caution is thus required. Representative conditions associated with cerebral infarction in patients with cancer are shown in Table 3. Non-bacterial thrombotic endocarditis (NBTE) is most commonly encountered in clinical practice. Cytokines secreted by cancer cells in conjunction with coagulation abnormalities associated with cancer promote hypercoagulability and cause endothelial dysfunction. Consequently, warty nodules develop on the aortic valve and mitral valve, leading to multiple episodes of ATE. ATE is a condition accompanied by cancer-derived coagulopathy and inflammation. It is known that more than half of patients already have metastasis at the onset of ATE [21–23]. The next frequently occurring condition is DIC-related peripheral microcirculatory thromboembolism. ATE has recently tended to increase in patients with cancer. In particular, the number of
Table 3 Arterial thromboembolism in cancer patients with cerebral infarction.
1. Cardiogenic embolism by NBTE 2. Microthrombus/embolization by DIC Due to brain tissue rich in thromboplastin
3. Paradoxical cerebral embolism Due to DVT through the foramen ovale
4. Low perfusion condition Due to dehydration/hyperviscosity…