Cancer-Associated Thrombosis: Risk Factors, Molecular Mechanisms, Future Management

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Abstract

Venous thromboembolism (VTE) is a major health problem in patients with cancer. Cancer augments thrombosis and causes cancer-associated thrombosis (CAT) and vice versa thrombosis amplifies cancer progression, termed thrombosis-associated cancer (TAC). Risk factors that lead to CAT and TAC include cancer type, chemotherapy, radiotherapy, hormonal therapy, anti-angiogenesis therapy, surgery, or supportive therapy with hematopoietic growth factors. There are some other factors that have an effect on CAT and TAC such as tissue factor, neutrophil extracellular traps (NETs) released in response to cancer, cancer procoagulant, and cytokines. Oncogenes, estrogen hormone, and thyroid hormone with its integrin αvβ3 receptor promote angiogenesis. Lastly, patient-related factors can play a role in development of thrombosis in cancer. Low-molecular-weight heparin and direct oral anticoagulants (DOACs) are used in VTE prophylaxis and treatment rather than vitamin K antagonist. Now, there are new directions for potential management of VTE in patients with cancer such as euthyroid, blockade of thyroid hormone receptor on integrin αvβ3, sulfated non-anticoagulant heparin, inhibition of NETs and stratifying low and high-risk patients with significant bleeding problems with DOACs.

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Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.

Agnes Lee, Mark N Levine, Ross Baker … (2003)

Patients with cancer have a substantial risk of recurrent thrombosis despite the use of oral anticoagulant therapy. We compared the efficacy of a low-molecular-weight heparin with that of an oral anticoagulant agent in preventing recurrent thrombosis in patients with cancer. Patients with cancer who had acute, symptomatic proximal deep-vein thrombosis, pulmonary embolism, or both were randomly assigned to receive low-molecular-weight heparin (dalteparin) at a dose of 200 IU per kilogram of body weight subcutaneously once daily for five to seven days and a coumarin derivative for six months (target international normalized ratio, 2.5) or dalteparin alone for six months (200 IU per kilogram once daily for one month, followed by a daily dose of approximately 150 IU per kilogram for five months). During the six-month study period, 27 of 336 patients in the dalteparin group had recurrent venous thromboembolism, as compared with 53 of 336 patients in the oral-anticoagulant group (hazard ratio, 0.48; P=0.002). The probability of recurrent thromboembolism at six months was 17 percent in the oral-anticoagulant group and 9 percent in the dalteparin group. No significant difference between the dalteparin group and the oral-anticoagulant group was detected in the rate of major bleeding (6 percent and 4 percent, respectively) or any bleeding (14 percent and 19 percent, respectively). The mortality rate at six months was 39 percent in the dalteparin group and 41 percent in the oral-anticoagulant group. In patients with cancer and acute venous thromboembolism, dalteparin was more effective than an oral anticoagulant in reducing the risk of recurrent thromboembolism without increasing the risk of bleeding. Copyright 2003 Massachusetts Medical Society

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Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.

Steffen Massberg, Lenka Grahl, Marie-Luise von Bruehl … (2010)

Blood neutrophils provide the first line of defense against pathogens but have also been implicated in thrombotic processes. This dual function of neutrophils could reflect an evolutionarily conserved association between blood coagulation and antimicrobial defense, although the molecular determinants and in vivo significance of this association remain unclear. Here we show that major microbicidal effectors of neutrophils, the serine proteases neutrophil elastase and cathepsin G, together with externalized nucleosomes, promote coagulation and intravascular thrombus growth in vivo. The serine proteases and extracellular nucleosomes enhance tissue factor- and factor XII-dependent coagulation in a process involving local proteolysis of the coagulation suppressor tissue factor pathway inhibitor. During systemic infection, activation of coagulation fosters compartmentalization of bacteria in liver microvessels and reduces bacterial invasion into tissue. In the absence of a pathogen challenge, neutrophil-derived serine proteases and nucleosomes can contribute to large-vessel thrombosis, the main trigger of myocardial infarction and stroke. The ability of coagulation to suppress pathogen dissemination indicates that microvessel thrombosis represents a physiological tool of host defense.

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Epidemiology of cancer-associated venous thrombosis.

Jasmijn F. Timp, Sigrid K Braekkan, Henri Versteeg … (2013)

Cancer-associated venous thrombosis is a common condition, although the reported incidence varies widely between studies depending on patient population, start and duration of follow-up, and the method of detecting and reporting thrombotic events. Furthermore, as cancer is a heterogeneous disease, the risk of venous thrombosis depends on cancer types and stages, treatment measures, and patient-related factors. In general, cancer patients with venous thrombosis do not fare well and have an increased mortality compared with cancer patients without. This may be explained by the more aggressive type of malignancies associated with this condition. It is hypothesized that thromboprophylaxis in cancer patients might improve prognosis and quality of life by preventing thrombotic events. However, anticoagulant treatment leads to increased bleeding, particularly in this patient group, so in case of proven benefit of thromboprophylaxis, only patients with a high risk of venous thrombosis should be considered. This review describes the literature on incidence of and risk factors for cancer-associated venous thrombosis, with the aim to provide a basis for identification of high-risk patients and for further development and refinement of prediction models. Furthermore, knowledge on risk factors for cancer-related venous thrombosis may enhance the understanding of the pathophysiology of thrombosis in these patients.

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Journal

Journal ID (nlm-ta): Clin Appl Thromb Hemost

Journal ID (iso-abbrev): Clin. Appl. Thromb. Hemost

Journal ID (publisher-id): CAT

Journal ID (hwp): spcat

Title: Clinical and Applied Thrombosis/Hemostasis

Publisher: SAGE Publications (Sage CA: Los Angeles, CA )

ISSN (Print): 1076-0296

ISSN (Electronic): 1938-2723

Publication date (Electronic): 2 September 2020

Publication date Collection: Jan-Dec 2020

Volume: 26

Electronic Location Identifier: 1076029620954282

Affiliations

[1 ]Clinical Pharmacy Practice Department, Faculty of Pharmacy, Ringgold 120633, universityThe British University in Egypt; , Cairo, Egypt

[2 ]The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, Ringgold 120633, universityThe British University in Egypt; , Cairo, Egypt

[3 ]The Pharmaceutical Research Institute, Ringgold 1091, Albany College of Pharmacy and Health Sciences; , Rensselaer, NY, USA

Author notes

[*]Shaker A. Mousa, PhD, The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY 12144, USA. Email: shaker.mousa@ 123456acphs.edu

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Shaker A. Mousa https://orcid.org/0000-0002-9294-015X

Article

Publisher ID: 10.1177_1076029620954282

DOI: 10.1177/1076029620954282

PMC ID: 7476343

PubMed ID: 32877229

SO-VID: e13851e5-b428-451d-9bc1-7c1789fac55c

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This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Date received : 21 April 2020

Date revision received : 10 July 2020

Date accepted : 10 August 2020

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cover-date January-December 2020

typesetter ts3

Keywords: angiogenesis,anticoagulants,cancer,coagulation,heparins,inflammation,integrin αvβ3,non-anticoagulant heparin,oral anticoagulant,thrombosis,thyroid hormone

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Keywords: angiogenesis, anticoagulants, cancer, coagulation, heparins, inflammation, integrin αvβ3, non-anticoagulant heparin, oral anticoagulant, thrombosis, thyroid hormone

Cancer-Associated Thrombosis: Risk Factors, Molecular Mechanisms, Future Management

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Cancer Metabolism

Most cited references 123

Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.

Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.

Epidemiology of cancer-associated venous thrombosis.

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