Cancer-associated thrombosis

doi:10.1016/j.critrevonc.2007.01.001

Critical Reviews in Oncology/Hematology

Volume 62, Issue 2, May 2007, Pages 126-136

https://doi.org/10.1016/j.critrevonc.2007.01.001 Get rights and content

Abstract

There is strong evidence linking venous thromboembolic events and malignancy. Laboratory markers of coagulation activation such as thrombin–antithrombin complex or prothrombin fragments 1 + 2 support the premise that malignancy is a hypercoagulable state. Inflammatory cytokines (e.g. tumor necrosis factor and interferon-γ), coagulation proteins (e.g. tissue factor and factor VIII), and procoagulant microparticles may be elevated in patients with malignancy. However, the molecular basis for cancer associated thrombosis remains unknown and the relative contribution of chemotherapeutics, tumor cells, endothelium, and circulating procoagulants in promoting thrombus formation continues to be investigated.

Introduction

The association between malignancy and thrombosis dates back to the mid 1800's when Armand Trousseau first observed the thrombotic predilection of patients suffering from cancer. He astutely commented that “I have long been struck with the frequency with which cancer patients are affected with painful edema in the superior or inferior extremities, whether one or the other was the seat of cancer” [1]. This link between cancer and thrombosis has since been validated both in studies demonstrating a high rate of venous thromboembolic events in patients suffering from cancer and in the 3–25% of individuals who present with an unprovoked thrombotic event and are later diagnosed with cancer within two years [2], [3], [4], [5].

Almost one in five cases of all symptomatic deep venous thrombosis are thought to be cancer-related [6]. There is limited prospective data assessing the incidence of venous thromboembolic events in cancer patients through systematic screening and thus most estimates regarding the frequency of events are derived from autopsy series, epidemiologic surveys, and prospective chemotherapeutic trials. The prevalence of thrombosis in autopsy series ranges from 10 to 20% [7], [8], [9]. Among residents of Olmsted County, individuals diagnosed with cancer experienced a 4.1-fold increased risk of venous thromboembolic events compared to the general population—a risk that increased an additional 2-fold following the administration of chemotherapy [10]. Thrombosis is a well-recognized complication of specific chemotherapeutics such as anti-estrogens [11], [12], [13], [14] and several anti-angiogenic agents [15], [16]. For instance, approximately 25% of patients with myeloma treated with thalidomide in combination with either dexamethasone or chemotherapy suffer a venous thromboembolic event [17], [18], [19]. Thrombosis also commonly complicates surgery whereby nearly one-quarter of individuals who undergo surgery for cancer demonstrate venographic evidence of deep vein thrombosis postoperatively [20], [21].

The risk of thrombosis attributed to the malignant state also is not uniform across all forms of cancer. In a large autopsy series of 6197 cancer patients, pulmonary embolism was apparent in 34.5% of 55 patients with ovarian cancer but none of the 38 patients with head or neck cancer [7]. Levitan et al. analyzed the discharge diagnosis for 1,211,944 Medicare patients diagnosed with cancer and hospitalized between 1988 and 1990. Similar to the autopsy findings, they noted almost a 10-fold greater rate of venous thromboembolic events among patients suffering from ovarian, brain, and pancreatic cancers compared to those with head or neck cancer [22]. In a recent record linkage study that compared data from a cancer registry in the Netherlands with a clinical anticoagulation database, the cumulative incidence of venous thromboembolic events was highest for pancreatic, brain, ovarian, and bone malignancies [23]. The preliminary results of two prospective trials investigating the efficacy of prophylactic anticoagulation in breast and lung cancer patients were recently reported [24]. Deep vein thrombosis was diagnosed by screening duplex ultrasonography in 4% of patients. With strong evidence linking deep vein thrombosis and malignancy there has been considerable interest in understanding the molecular basis for thrombosis in cancer patients and identifying hemostatic markers most predictive of thrombosis.

Section snippets

Hemostatic markers

A number of studies published have detailed the laboratory abnormalities apparent in patients with malignancy. These include the shortening of the activated partial thromboplastin time, elevated levels of coagulation proteins (fibrinogen, factors V, VIII, IX, and XI), thrombocytosis, elevated fibrin/fibrinogen degradation products, and an accelerated rate of fibrinogen turnover [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. However, these laboratory measurements have not proven

Molecular basis for thrombosis

Several substances elaborated by malignant cells have been identified that can activate the blood coagulation cascade. These include cytokines, a cysteine protease, tissue factor, and microparticles bearing tissue factor.

Catheter-related thrombosis

Central venous access catheters are commonly utilized in cancer patients for the delivery of blood products and chemotherapy. In prospective studies, the incidence of thrombosis as detected by venography is between 32 and 66% [130], [131]. Direct endothelial irritation is thought to play a major role in catheter thrombosis although catheter-specific risk factors have also been identified, including insertion site, technique, and material. A prospective study which enrolled 85 children with

Chemotherapy-induced thrombosis

Chemotherapy has been implicated in contributing to the hypercoagulability of malignancy. The overall annual incidence of deep venous thrombosis in patients treated with chemotherapy is about 11% [137]. Different regimens and classes of chemotherapeutics carry different thrombotic risks, a problem that has become particularly apparent with the advent of several anti-angiogenic agents. The mechanisms underlying the hypercoagulability are not understood.

Khorana et al. recently reported the

Hereditary thrombophilia

Hereditary risk factors are associated with VTE. These include Factor V Leiden and prothrombin G20210A gene mutation which carry a 3- to 8-fold increased risk of thrombosis in outpatients who present with an idiopathic VTE. While malignancy alone is clearly a risk factor for thrombosis, the additional influence of such hereditary thrombophilic risk factors has been difficult to distinguish. In a large case-control study, carriers of Factor V Leiden with malignancy were 12 times more likely to

Conclusion

Although progress has been made in developing anticoagulant strategies for the management of thromboembolic disease in cancer patients, VTE remains a leading cause of death in cancer patients. With the advent of several anti-angiogenic agents clearly associated with thrombotic complications, there is now a renewed sense of urgency in the field. The interplay of chemotherapeutics, tumor cells, endothelium, and circulating procoagulants in promoting thrombus formation is under investigation, but

Reviewers

Dr. Kenneth A. Bauer, Director Thrombosis Clinical Research, Beth Israel Deaconess Medical Center, Department of Medicine - Hematology, Oncology, 330 Brookline Avenue, Boston, MA 02215, United States

Dr. Frederiek van Doormaal, Academic Medical Center, Vascular Medicine, Meibergdreef 9, Amsterdam 1105 AZ, Netherlands

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Citation Excerpt :
Although this system is usually in a quiescent state, it is rapidly activated upon vascular injury and leads to the generation of a thrombus [1]. Since thrombotic events can be fatal (secondary to myocardial infarction, stroke) [2,3], a better understanding of the cellular and molecular events governing this process is crucial for the development of novel therapeutic approaches. In 1856, Virchow first enumerated the three predisposing factors contributing to thrombosis: blood hypercoagulability, stasis and vessel wall abnormalities (Virchow's triad; Fig. 1).
Despite significant evidence implicating an important role for neutrophils in thrombosis, their impact on the thrombotic process has remained a matter of controversy. Until 2010, platelets, coagulation factors, fibrinogen and monocytes were implicated in the thrombotic process. Several studies conducted over the last decade now support the growing notion that neutrophils indeed do contribute significantly to this process. Neutrophils can contribute to pathologic venous and arterial thrombosis or ‘immunothrombosis’ by the release of neutrophil extracellular traps (NETs) and NET release is emerging as a major contributor to thrombogenesis in pathologic situations such as sepsis and malignancy. Further, blood-cell derived microparticles, including those from neutrophils, have been implicated in thrombus formation. Finally, inflammasome activation in the neutrophil identifies another important mechanism that may be operative in neutrophil-driven risk for thrombosis. The knowledge of these roles of neutrophils in thrombosis may pave the road for novel anti-thrombotic agents in the future that do not affect hemostasis.

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Dr. Bruce Furie (Professor): Dr. Furie's research interests focus within the area of hemostasis and thrombosis. Major activities in the laboratory involve the study of the structure-function relationships of the blood coagulation proteins, with special attention directed toward the vitamin K-dependent proteins, and the assembly of Factor IX and Factor VIII on membrane surfaces. In addition, his laboratory discovered P-selectin, and the study of vascular cell adhesion molecules has been a central theme of the laboratory. This group has developed novel instrumentation for real time in vivo confocal and widefield imaging of thrombus formation in the microcirculation of a living mouse. This work has attracted considerable attention because of the opportunity that it affords to study a complex physiologic system – blood coagulation and thrombosis – in a living animal. Dr. Bruce Furie was the recipient of the William Dameshek Prize of the American Society of Hematology in 1984. He was the recipient of a MERIT Award from the NIH and an honorary degree from Lund University in 2003. Dr. Furie is a co-editor of the hematology textbook, Hematology: Basic Principles and Practice and lead editor of Clinical Hematology–Oncology: Presentations, Diagnosis and Treatment. He serves as the President of the 2009 Congress of the International Society for Thrombosis and Haemostasis.

Dr. Barbara C. Furie (Professor): Interested in the posttranslational processing of blood clotting proteins, she has made major contributions to our knowledge of the molecular basis of γ-carboxylation and of the role of γ-carboxyglutamic acid in the calcium binding properties of the vitamin K-dependent blood clotting proteins. Her current work includes the study of the mechanism of action of the vitamin K-dependent carboxylase and its interaction with vitamin K. She has completed the structure of prothrombin bound to phosphatidylserine, thus contributing to our understanding of the assembly of blood coagulation complexes on membrane surfaces. The laboratory has used both NMR spectroscopy and X-ray crystallographic techniques. Dr. Furie has served on the Hematology Study Section of the NIH for which she was Chairperson. Dr. Furie was the recipient of the William Dameshek Prize of the American Society of Hematology in 1984 and an Outstanding Investigator Award from the International Society of Thrombosis and Hemostasis. She was a recipient of a MERIT Award from the NIH, an honorary degree from Lund University in 2003, and served on the Editorial Board of Blood. She has been a critical female role model for woman postdoctoral fellows. She also serves as the President of the 2009 ISTH Congress.

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