Special Issue "The Role of Thrombosis and Haemostasis in Cancer"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: 30 November 2018

Special Issue Editors

Guest Editor
Prof. Dr. Marco Falasca

School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, WA, Australia
Website | E-Mail
Interests: signal transduction, cancer invasion and metastasis in prostate, breast and pancreatic cancers; phosphoinositide signalling; PI3-kinase/PDK1 signalling pathway
Guest Editor
Dr. Pat Metharom

Platelet Research Laboratory, Curtin Health and Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA, Australia
Website | E-Mail
Phone: 0892669271
Interests: platelet biology; signal transduction; cancer-associated thrombosis

Special Issue Information

Dear Colleagues,

Cancer-associated thrombosis is a lethal complication in cancer sufferers. The association between malignancy and thrombosis was first described over a century and half ago, by Jean-Baptiste Bouillard in 1823 and later in 1865 by Armand Trousseau. It is now well accepted that cancer patients are at an estimated four to seven-fold increased risk of developing venous thromboembolism (VTE) compared to non-cancer patients. The mechanisms by which cancer elicit thromboembolic events are not entirely understood. A significant role is attributed to the capability of cancer cells to activate the coagulation system, thus inducing a hypercoagulable or prothrombotic state in cancer patients. Cancer cells can activate the coagulation cascade through the expression of tissue factor, the release of proinflammatory cytokines, and interactions with endothelial and circulating blood cells. Platelets, a key regulator cell population of haemostasis and thrombosis, are known to be an important contributor of VTE, not only to through their involvement in thrombus formation but also in promoting cancer survival and spread. Recently, neutrophils are implicated as an important mediator of cancer-associated thrombosis. Neutrophil extracellular traps (NETs), released from activated neutrophils, have been reported in tumour samples and their presence in vivo is associated with metastasis. 

This Special Issue will cover the current research of thrombosis and haemostasis in cancer development. Both basic mechanisms underlying the processes, clinical observations and therapeutic implications of targeting key regulators of thrombosis and haemostasis will be discussed

Prof. Dr. Marco Falasca
Dr. Pat Metharom
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer biology
  • cancer-associated thrombosis
  • platelets
  • metastasis
  • neutrophils

Published Papers (5 papers)

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Review

Open AccessReview Impacts of Cancer on Platelet Production, Activation and Education and Mechanisms of Cancer-Associated Thrombosis
Cancers 2018, 10(11), 441; https://doi.org/10.3390/cancers10110441
Received: 30 September 2018 / Revised: 31 October 2018 / Accepted: 10 November 2018 / Published: 14 November 2018
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Abstract
Platelets are small anucleate cells that are traditionally described as the major effectors of hemostasis and thrombosis. However, increasing evidence indicates that platelets play several roles in the progression of malignancies and in cancer-associated thrombosis. A notable cross-communication exists between platelets and cancer
[...] Read more.
Platelets are small anucleate cells that are traditionally described as the major effectors of hemostasis and thrombosis. However, increasing evidence indicates that platelets play several roles in the progression of malignancies and in cancer-associated thrombosis. A notable cross-communication exists between platelets and cancer cells. On one hand, cancer can “educate” platelets, influencing their RNA profiles, the numbers of circulating platelets and their activation states. On the other hand, tumor-educated platelets contain a plethora of active biomolecules, including platelet-specific and circulating ingested biomolecules, that are released upon platelet activation and participate in the progression of malignancy. The numerous mechanisms by which the primary tumor induces the production, activation and aggregation of platelets (also known as tumor cell induced platelet aggregation, or TCIPA) are directly related to the pro-thrombotic state of cancer patients. Moreover, the activation of platelets is critical for tumor growth and successful metastatic outbreak. The development or use of existing drugs targeting the activation of platelets, adhesive proteins responsible for cancer cell-platelet interactions and platelet agonists should be used to reduce cancer-associated thrombosis and tumor progression. Full article
(This article belongs to the Special Issue The Role of Thrombosis and Haemostasis in Cancer)
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Open AccessReview Cancer-Associated Thrombosis: An Overview of Mechanisms, Risk Factors, and Treatment
Cancers 2018, 10(10), 380; https://doi.org/10.3390/cancers10100380
Received: 11 September 2018 / Revised: 4 October 2018 / Accepted: 7 October 2018 / Published: 11 October 2018
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Abstract
Cancer-associated thrombosis is a major cause of mortality in cancer patients, the most common type being venous thromboembolism (VTE). Several risk factors for developing VTE also coexist with cancer patients, such as chemotherapy and immobilisation, contributing to the increased risk cancer patients have
[...] Read more.
Cancer-associated thrombosis is a major cause of mortality in cancer patients, the most common type being venous thromboembolism (VTE). Several risk factors for developing VTE also coexist with cancer patients, such as chemotherapy and immobilisation, contributing to the increased risk cancer patients have of developing VTE compared with non-cancer patients. Cancer cells are capable of activating the coagulation cascade and other prothrombotic properties of host cells, and many anticancer treatments themselves are being described as additional mechanisms for promoting VTE. This review will give an overview of the main thrombotic complications in cancer patients and outline the risk factors for cancer patients developing cancer-associated thrombosis, focusing on VTE as it is the most common complication observed in cancer patients. The multiple mechanisms involved in cancer-associated thrombosis, including the role of anticancer drugs, and a brief outline of the current treatment for cancer-associated thrombosis will also be discussed. Full article
(This article belongs to the Special Issue The Role of Thrombosis and Haemostasis in Cancer)
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Open AccessReview The Role of Direct Oral Anticoagulants in Treatment of Cancer-Associated Thrombosis
Cancers 2018, 10(8), 271; https://doi.org/10.3390/cancers10080271
Received: 3 July 2018 / Revised: 7 August 2018 / Accepted: 13 August 2018 / Published: 15 August 2018
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Abstract
Venous thromboembolism (VTE) complicates the clinical course of approximately 5–10% of all cancer patients. Anticoagulation of the cancer patient often presents unique challenges as these patients have both a higher risk of recurrent VTE and a higher risk of bleeding than patients without
[...] Read more.
Venous thromboembolism (VTE) complicates the clinical course of approximately 5–10% of all cancer patients. Anticoagulation of the cancer patient often presents unique challenges as these patients have both a higher risk of recurrent VTE and a higher risk of bleeding than patients without cancer. Although low molecular weight heparins (LMWH) are the standard of care for the management of cancer-associated VTE, their use requires once or twice daily subcutaneous injections, which can be a significant burden for many cancer patients who often require a long duration of anticoagulation. The direct oral anticoagulants (DOACs) are attractive options for patients with malignancy. DOACs offer immediate onset of action and short half-lives, properties similar to LMWH, but the oral route of administration is a significant advantage. Given the higher risks of recurrent VTE and bleeding, there has been concern about the efficacy and safety of DOACs in this patient population. Data are now emerging for the use of DOACs in the cancer patient population from dedicated clinical trials. While recently published data suggest that DOACs hold promise for the treatment of cancer associated VTE, additional studies are needed to establish DOACs as the standard-of-care treatment. Many such studies are currently underway. The available data for the use of DOACs in the treatment of cancer-associated VTE will be reviewed, focusing on efficacy, safety, and other considerations relevant to the cancer patient. Full article
(This article belongs to the Special Issue The Role of Thrombosis and Haemostasis in Cancer)
Open AccessFeature PaperReview Antithrombotic Agents and Cancer
Cancers 2018, 10(8), 253; https://doi.org/10.3390/cancers10080253
Received: 2 July 2018 / Revised: 27 July 2018 / Accepted: 28 July 2018 / Published: 31 July 2018
Cited by 1 | PDF Full-text (906 KB) | HTML Full-text | XML Full-text
Abstract
Platelet activation is the first response to tissue damage and, if unrestrained, may promote chronic inflammation-related cancer, mainly through the release of soluble factors and vesicles that are rich in genetic materials and proteins. Platelets also sustain cancer cell invasion and metastasis formation
[...] Read more.
Platelet activation is the first response to tissue damage and, if unrestrained, may promote chronic inflammation-related cancer, mainly through the release of soluble factors and vesicles that are rich in genetic materials and proteins. Platelets also sustain cancer cell invasion and metastasis formation by fostering the development of the epithelial-mesenchymal transition phenotype, cancer cell survival in the bloodstream and arrest/extravasation at the endothelium. Furthermore, platelets contribute to tumor escape from immune elimination. These findings provide the rationale for the use of antithrombotic agents in the prevention of cancer development and the reduction of metastatic spread and mortality. Among them, low-dose aspirin has been extensively evaluated in both preclinical and clinical studies. The lines of evidence have been considered appropriate to recommend the use of low-dose aspirin for primary prevention of cardiovascular disease and colorectal cancer by the USA. Preventive Services Task Force. However, two questions are still open: (i) the efficacy of aspirin as an anticancer agent shared by other antiplatelet agents, such as clopidogrel; (ii) the beneficial effect of aspirin improved at higher doses or by the co-administration of clopidogrel. This review discusses the latest updates regarding the mechanisms by which platelets promote cancer and the efficacy of antiplatelet agents. Full article
(This article belongs to the Special Issue The Role of Thrombosis and Haemostasis in Cancer)
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Open AccessReview Bone Marrow Defects and Platelet Function: A Focus on MDS and CLL
Cancers 2018, 10(5), 147; https://doi.org/10.3390/cancers10050147
Received: 20 April 2018 / Revised: 11 May 2018 / Accepted: 16 May 2018 / Published: 18 May 2018
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Abstract
The bloodstream typically contains >500 billion anucleate circulating platelets, derived from megakaryocytes in the bone marrow. This review will focus on two interesting aspects of bone marrow dysfunction and how this impacts on the quality of circulating platelets. In this regard, although megakaryocytes
[...] Read more.
The bloodstream typically contains >500 billion anucleate circulating platelets, derived from megakaryocytes in the bone marrow. This review will focus on two interesting aspects of bone marrow dysfunction and how this impacts on the quality of circulating platelets. In this regard, although megakaryocytes are from the myeloid lineage leading to granulocytes (including neutrophils), erythrocytes, and megakaryocytes/platelets, recent evidence has shown that defects in the lymphoid lineage leading to B cells, T cells, and natural killer (NK) cells also result in abnormal circulating platelets. Current evidence is limited regarding whether this latter phenomenon might potentially arise from (a) some form of as-yet-undetected defect common to both lineages; (b) adverse interactions occurring between cells of different lineages within the bone marrow environment; and/or (c) unknown disease-related factor(s) affecting circulating platelet receptor expression/function after their release from megakaryocytes. Understanding the mechanisms underlying how both myeloid and lymphoid lineage bone marrow defects lead to dysfunction of circulating platelets is significant because of the potential diagnostic and predictive value of peripheral platelet analysis for bone marrow disease progression, the additional potential effects of new anti-cancer drugs on platelet function, and the critical role platelets play in regulation of bleeding risk, inflammation, and innate immunity. Full article
(This article belongs to the Special Issue The Role of Thrombosis and Haemostasis in Cancer)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Use of DOACs in Cancer-Related Venous Thromboembolism

Authors: Francesco Grandoni and Lorenzo Alberio
Abstract: Cancer patients develop a hypercoagulable state with a four- to seven-fold higher thromboembolic risk compared to non-cancer patients. Thromboembolic events can precede the diagnosis of cancer but they more often occur at diagnosis or during treatment. After malignancy itself, they represents the second cause of deaths. Low molecular weight heparins are the backbone of the treatment of cancer-associated thromboembolism. This treatment paradigm is possibly changing, as direct oral anticoagulants (DOACs) may prove to be an alternative therapeutic option. The currently available DOACs were approved during the first and second decades of the 21st century for various clinical indications. Three molecules (apixaban, edoxaban, rivaroxaban) are targeting the activated factor X and one (dabigatran) is directed against the activated factor II. The major trials analyzed the effect of these agents in the general population, with only a small portion of cancer patients. One published and several ongoing studies are specifically investigating the use of DOACs in cancer-associated thromboembolism. This article will review the current available literature on the use of DOACs in cancer patients. Moreover, we will discuss published data suggesting potential anti-cancer actions exerted by non-anticoagulant effects of DOAC. As soon as more prospective data will be available, DOACs are likely to be considered as a potential new therapeutic possibility in the armamentarium for the cancer-associated thromboembolism.

Title: Thrombin Generation and Cancer: Contributors and Consequences
Authors: Caroline Reddel, Chuen Wen Tan and Vivien Chen
Abstract: The high occurrence of cancer-associated thrombosis is associated with elevated thrombin generation. Tumour cells increase the potential for thrombin generation both directly, through the release of procoagulant factors, and indirectly, through the release of signals that activate other cell types (including platelets, leukocytes and erythrocytes) to promote thrombin generation, or direct action on those cells. Further, cancer treatments can worsen these effects. Coagulation factors, including tissue factor, and inhibitors of coagulation are altered and extracellular vesicles, which can promote and support thrombin generation, are released by tumour and other cells. Some phosphatidylserine expressing platelet subsets and platelet-derived EVs provide the surface for the assembly of coagulation factors essential for thrombin generation in-vivo. This review will explore the causes of increased thrombin production in cancer, and the availability and utility of tests and biomarkers. Increased thrombin production not only increases blood coagulation, but also promotes tumour growth and metastasis and as a consequence, thrombin and its contributors present opportunities for treatment of cancer-associated thrombosis and cancer itself.

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