http://informahealthcare.com/plt ISSN: 0953-7104 (print), 1369-1635 (electronic) Platelets, 2015; 26(2): 114–118 ! 2015 Informa UK Ltd. DOI: 10.3109/09537104.2014.894969
REVIEW
Hypercoagulation in colorectal cancer: What can platelet indices tell us? Charalampos Seretis, Haney Youssef, & Mark Chapman Department of Colorectal Surgery, Good Hope Hospital, Heart of England NHS Foundation Trust, Birmingham, UK
Abstract
Keywords
Colorectal cancer, as all solid malignancies, is accompanied by changes in the haemostatic mechanism favoring the establishment of a thrombotic potential, with platelets playing a key-role in this framework; they further link colorectal cancer progression and hypercoagulation with the immune-response against the neoplastic spread. Under this rationale, various studies have assessed the use of platelet indices as prognostic markers of the biological behavior of colorectal cancer, demonstrating significant results. We herein attempt to summarize in a narrative and critical approach the relevant available data and the underlying pathophysiology, stressing the necessity of a more thorough understanding and future implementation of platelet indices in all stages of care we deliver to colorectal cancer patients.
Cancer, coagulation, colorectal, metastasis, platelet
Introduction The firm association between cancer progression and haemostatic disorders is well-established, with the initial clinical remarks made by Trousseau in 1865 [1]. The elucidation of the mechanisms regulating the vicious circle between cancer growth and hypercoagulation is considered to be one of the most promising fields of anticancer research, with colorectal cancer not being an exception [2, 3]. It is now undisputed that the local growth of colorectal cancer, as well as its metastatic potential, are associated with the establishment of a hypercoagulative profile, fact which highlights the need for implementing holistic approaches to confront the disease [4]. An explosive number of both clinical and laboratory studies is currently focusing on decoding a framework of complex interactions between cancer cells and the components of the haemostatic mechanisms, even at the early stages of neovascularization, a pre-requisite for local and metastatic cancer growth.
Hypercoagulation and neovascularization: The basis of the vicious circle? The increased metabolic state and the logo-regional expansion of colorectal cancer require the formation of new vessels [5–7]; this process of neovascularization, is characterized by the exhibition of a highly pre-coagulative phenotype of the newly formed vessels, leading to the local formation of micro-emboli which, through local thrombotic events, favor the establishment of a locally hypoxic environment [8, 9]. Sequentially, in a compensatory way, local hypoxia results in the expression of molecules, which favor neovascularization, with the most known being the vascular endothelial growth factor (VEGF) and the hypoxia inducible factors (HIFs) [10]. As mentioned above, the neovasculature is characterized by the possession of pre-coagulant phenotypic characteristics, such as the great extent of exposed Correspondence: Charalampos Seretis, Clinical Research Fellow in General Surgery, Good Hope Hospital, Heart of England NHS Foundation Trust, Rectory Road, Sutton Coldfield, B75 7RR, Birmingham, United Kingdom. E-mail: [email protected]
History Received 3 December 2013 Revised 15 January 2014 Accepted 9 February 2014 Published online 5 September 2014
sub-endothelial matrix due to the loose junctions between the endothelial cells, which is interpreted as endothelial breach, triggering the primary phase of haemostasis, which finally results in the accumulation of platelets and formation thrombi in order to contain the presumed vascular leak [11–13]. These early changes in the fragile balances of the haemostatic mechanism in favor of hypercoagulation, with the establishment of a hypoxic, oxidative potential, appear to represent a hallmark in the course of colorectal cancer, enhancing its local growth and promoting its ability to escape the local immuno-surveillance mechanisms [14, 15].
Platelets: The Foes’ allies A major step towards the success of primary hemostasis in the case of endothelial breach is the activation of platelets; the latter is achieved through their transformation from disk-shaped to round-shaped, with subsequent increase of their volume, fact which is essential for the exposure of their surface receptors that will facilitate the migration and adhesion to the area of the injured endothelium [16]. Following their activation, platelets de-granulate, releasing a variety of molecules, which, apart from their primary role in the regulation of haemostasis, induce the process of neovascularization and regulate the profile of the inflammatory reaction to and from the cancerous cells [17]. More specifically, platelets’ delta-granules mainly release ADP, ATP, serotonin and catecholamines, while the alphagranules release VEGF, fibrinogen, von Willebrand factor, P-selectin, platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), endothelial cell growth factor (ECGF), transforming growth factor (TGF), insulin-like growth factor (IGF) and Matrix Metalloproteinases (MMPs) [18, 19]. The above-mentioned molecules are involved in the process of local migration of the circulating white cell indices and therefore determine to a great extent the peritumoral inflammatory response, contributing to the local desmoplastic reaction through deposition of fibrin, which acts as a scaffold for the local tumor progression [20–23]. It is also important to mention that platelets release molecules that inhibit neovascularization, such as
DOI: 10.3109/09537104.2014.894969
thrombospondin, with the relevant molecular background still remaining in the shades; however, it appears that their effect is overwhelmed by the agents favoring neovascularization [24, 25]. Apart from the participation of activated platelets in the colorectal cancer local growth, they appear to play a crucial role in the development of distant metastases, with the blood-borne ones being currently the most extensively investigated, although it is possible that they are also engaged in various aspects of the lymphatic spread as well [26, 27]. To put in a nutshell, the main of these mechanisms could be summarized as follows [28–35]: Using their surface receptors, activated platelets bind with the circulating tumor cells and form a protective ‘‘cloak’’ around them, reducing the capability of T-lymphocytes and Natural Killer cells (NK cells) to successfully recognize and target them. The activated platelets surrounding the circulating tumor cells degranulate and release numerous adhesion molecules, such as selectines, that facilitate the attachment of the activated platelet-cancer cells complex to the metastatic niches. The release of PDGF kai TGF-b by the activated platelets suppresses directly the cytotoxic properties of NK cells. Platelets are involved in the process of lymphatic spread of the cancer cells, probably by mediating the formation of new lymphatic vessels from the primitive endothelial cells. Therefore, it is more than evident that platelets, and especially the activated platelets, stand as major mediators of colorectal cancer growth and enhance significantly its metastatic potential, exhibiting simultaneously local and systematic immune-regulating actions, which further impair the host’s immuno-reaction against the progression of the malignancy.
Colorectal cancer-induced hypercoagulation: The other side of the coin There is ample evidence that colorectal cancer, as well as the rest of gastrointestinal cancers, is accompanied by a trend to induce thrombocytosis per se, with this hypercoagulative potential reflecting the cancer cells’ biological aggressiveness [36, 37]. In a rough description if the relevant underlying mechanisms, it is believe that thrombocytosis is induced through a paraneoplastictype over-expression of thrombopoietin (TPO) and through the local and systematic release of cytokines, such as IL-1, IL-3, IL-6, IL-11 and other proteins like granulocyte macrophage colonystimulating factor (GM-CSF), FMS-like tyrosine kinase 3 (FLT3) ligand and fibroblast growth factor (FGF), which induce the production of platelets [38–40]. Moreover, the peripheral consumption of platelets during the formation of micro-emboli in the framework of a chronic, compensated subclinical disseminated intravascular coagulation, which accompanies the natural course of colorectal cancer, is a strong stimulus for the production of new platelets in order to maintain the platelet count within the normal range [41, 42]. Nevertheless, a more careful insight to this dynamic balance between platelet consumption and platelet production in the course of colorectal cancer provides a wider understanding of the impact of cancer-induced thrombocytosis regarding the progression of the disease. To be more specific, this reactive thrombocytosis is an qualitative turning point, as it does not only have a quantitative substance (maintenance of the total platelet count within the normal range), since the newly formed, immature platelets are enzymatically more active than the mature ones; the reason is that the immature platelets contain more granules in their cytoplasm and have a rounder shape, fact which facilitates the exposure of their surface receptors [43, 44]. Therefore, even in the absence of an abnormal total platelet count, cancer progression results in the presence of an increasing percentage
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of activated platelets, triggering a vicious circle of hypercoagulation-induced cancer spread and cancer-induced hypercoagulation. The above-mentioned dynamic interactions are diagrammatically presented in Figure 1. Taking all the above into account, it appears that a substantial aspect of the accurate estimation of the biological behavior of colorectal cancer lies on the correct evaluation of these laboratory parameters reflecting the presence of actual thrombocytosis and the trend for thrombocytosis. We believe that a valuable asset in the daily clinical practice is the careful interpretation of the most widely available paraclinical investigation, the routine full blood count. Although the presence of active fibrinolysis, the compensatory action against the impact of hypercoagulation, can be also assessed in the clinical practice, the cost of even the simple d-dimer essay which prohibits its routine use in the absence of suspected major thromboembolic event, restrains and simultaneously challenges us to attempt to obtain the maximum amount of information from the often overlooked routine full blood count. Therefore, we strongly believe that it is high time to critically revise our basic hematology knowledge, aiming in the long-term to develop new prognostic scores and adjust our treatment plans under a tailored approach perspective. In this effort, paying attention to simple details of clinical practice, starting with the routinely available platelet indices as they appear in the full blood count, can be an unexpected ally.
Platelet indices and colorectal cancer prognosis: Do we know enough? In the daily clinical setting, the most commonly available platelet indices are the total platelet count (TPC), the mean platelet volume (MPV), the platelet distribution width (PDW), which measures the morphological heterogeneity of platelets, and the platelet-large cell ratio (L-PCR), which corresponds to the percentage of large platelets in the total platelet count. Total platelet count and colorectal cancer prognosis The value of total platelet count is determined by the balance between the rate of production and the rate of consumption of platelets. As already analyzed, in the case of colorectal cancer – and cancer in general– there is a clear trend of both overproduction and over-consumption of platelets. Therefore, both thrombocytosis and thrombopenia would be indicative of a biologically aggressive cancer; however, even a normal platelet count could be present in cases of adequate compensation, when these two opposing forces are equal. Consequently, a normal platelet count could conceal the presence of highly hypercoagulative and pro-inflammatory cancer phenotypes in the presence of efficient compensatory mechanisms. As a result, the presence of actual thrombocytosis might be associated with a stage were the disease has already overwhelmed the patients compensatory reservoirs, implicating the existence of greater dissemination. Various clinical studies in colorectal cancer patients have demonstrated a prognostic significance of elevated total platelet counts. Specifically, Cravioto-Villanueva et al. [45] reported that a pre-operative platelet count higher than 350 000/ml was associated with 3- and 5-year survival of 30 and 0% respectively, compared to 86 and 81% of 3- and 5-year survival in a cohort of 163 patients with rectal cancer. Similarly, Ishizuka et al. [46] stratified a total of 453 colorectal cancer patients with operable colorectal cancer using as a total platelet count of 300 000/ml as a cut-off value, with the study results revealing the overall survival was associated with the pre-operative platelet count (odds ratio, 1.642; 95% CI, 1.025–2.629; p ¼ 0.039). Moreover, pre-operative
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Platelets, 2015; 26(2): 114–118
Dynamic balance between platelet production and consumption in colorectal cancer Platelet activation at sites of neovascularization
Increase of platelet volume
Peripheral consumption of platelets at sites of neovascularization and/or due to formation of cancer emboli Paraneoplastic-type thrombocytosis
“THROMBOCYTOPENIA” FORCE ? total platelet count
Increased platelet production de novo and as compensatory mechanism
“THROMBOCYTOSIS” FORCE
Increasing numbers of immature, enzymatically more active platelets released
Establishment of hypercoagulative status – (micro)thrombotic events multiplied with increased rate of platelet consumption
Figure 1. Simplified diagram of the dynamic balance between platelet production and consumption in the natural course of colorectal cancer, demonstrating that the presence of these two opposite forces affecting the total platelet count. It is evident that the presence of a normal platelet count can be a result of equal tends of thrombocytosis and thrombocytopenia, not reflecting a possible biological aggressive type of underlying malignancy, when adequate compensation is maintained. However, it should be noticed that there is a qualitative shift of platelets activity in the course of the disease, as the consumed platelets are replaced by immature platelets only, which are enzymatically more active. Therefore, there is a gradual dominance of the large platelet count, which comprises both of the immature platelets and the activated (regardless their morphological maturity) platelets, fact which contributes to the enhancement of hypercoagulation along with the progression of cancer, irrespectively from the total platelet count.
thrombocytosis was found to be an independent prognostic factor of cancer specific survival (hazard ratio ¼ 2.96, 95% CI ¼ 1.72– 5.00) in another retrospective study which included a total of 636 patients with operable colorectal cancer, defining as thrombocytosis a total platelet count greater than 370 000/ml [47]. Furthermore, Wan et al. [48] reported that colorectal patients with pre-operative platelet count above 400 000/ml had a significantly unfavorable survival (HR ¼ 1.66, 95% CI 1.34–2.05, plog-rank ¼ 1.1 1011) and recurrence p ¼ 2.6 106, (HR ¼ 1.90, 1.24–2.93, p ¼ 0.003, plog-rank ¼ 0.003). In accordance with the previously mentioned studies, Kandir et al. [49] demonstrated a significant difference in overall survival (OS),comparing again colorectal cancer patients with or without pre-operative thrombocytosis (p ¼ 0.00001, log-rank test). Specifically, in patients with thrombocytosis, defined as platelet count greater than 400 000/ml, the median OS was 50 months (95% CI 37–63 months), whereas patients without thrombocytosis had a longer OS (cumulative survival 70.7%). However, in contrast, Nyasavajjala et al. [50] concluded that there was no statistically significant difference in mean survival (p ¼ 0.067) observed in colorectal cancer patients with platelet count higher than 450 000/ml (n ¼ 576; 95% CI: 1550.5–1405.4, SE 37.0) vs. 450 000 (n ¼ 51, CI: 1261.6–955.0, SE 78.2), failing to detect as well a correlation between Dukes stage and thrombocytosis. Mean platelet volume, platelet distribution width platelet-large cell ratio and colorectal cancer prognosis These three laboratory parameters are widely available by the majority of the modern automated analysts and are included in the
routine full blood count. The common characteristic of these markers is that their elevation is indicative of greater platelet activity [51], which, as mentioned above, is of paramount importance in all aspects of colorectal cancer progression, from local growth to the development of distant metastases [52]. In contrast to the existence of clinical studies assessing the prognostic significance of total platelet count in colorectal cancer, there are no published data investigating any similar potential role for any of these three parameters. The only relevant study reported that in a group of 74 colorectal cancer patients with metastatic disease, treatment with the anti-VEGF antibody Bevacizumab resulted in a decrease of the mean platelet volume and platelet distribution width, in the 3-month follow-up framework, indicating a possible benefit regarding the cancer-related thrombotic incidents [53].
Discussion Considering the available data, it appears that pre-operative elevated platelet counts can be suggestive of a worse prognosis in colorectal cancer. Undoubtedly, the different cut-off values used to define thrombocytosis in the published studies certain pose certain limitations. However, they provide an important insight to the possible significance of co-evaluating the platelet count as a variable that could be incorporated in the current riskstratification and staging tools. Unfortunately, except from the prognostic role of thrombocytosis, there is virtually complete lack of published studies evaluating a potential prognostic role of the other routinely available platelet indices, which can be indicative of platelet activity and therefore reflect in a qualitative way the
DOI: 10.3109/09537104.2014.894969
platelet-mediated growth and metastatic spread potential of colorectal cancer. So far, the prognostic scores used in colorectal cancer are based only on the tumor’s characteristics, failing to take into account the distinct impact a ‘‘same’’ tumor can have on different patients, largely depending on the immune’s system capability to withstand and overcome the disease. Platelet-mediated colorectal cancer growth and subsequent metastasis is well-established concept in modern oncology, which is proven by the increased thromboembolic risk of these patients. Without the need to implement in the daily practice expensive laboratory investigations, the routine full blood count could provide a gross estimation of the relevant dynamic balances, which are firmly associated with the existence of aggressive biological features of colorectal cancer. The latter could be of significant importance in various aspects of the treatment of colorectal cancer patients, enabling for instance the development of chemoprevention protocols for cancer recurrence with anti-platelet medications. Moreover, patients with hyper-coagulative cancer could possibly benefit from the intensification of the post-operative thromboprophylactic protocols. Finally, the development of new prognostic scores that will classify and stage colorectal cancer according to not only the tumor characteristics, but also the systematic impact of the disease, will be an important step towards moving our practice standards to higher level, where personalized treatment will be more feasible and safe for (colorectal) cancer patients. Therefore, it might be high time to revise our basic hematology knowledge, in order to be able to take full advantage of the information we can obtain even from the ‘‘humble’’ full blood count test and set the foundations for improving the standards of care in colorectal cancer.
Declaration of interest The authors have no competing interests to declare.
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REVIEW
Hypercoagulation in colorectal cancer: What can platelet indices tell us? Charalampos Seretis, Haney Youssef, & Mark Chapman Department of Colorectal Surgery, Good Hope Hospital, Heart of England NHS Foundation Trust, Birmingham, UK
Abstract
Keywords
Colorectal cancer, as all solid malignancies, is accompanied by changes in the haemostatic mechanism favoring the establishment of a thrombotic potential, with platelets playing a key-role in this framework; they further link colorectal cancer progression and hypercoagulation with the immune-response against the neoplastic spread. Under this rationale, various studies have assessed the use of platelet indices as prognostic markers of the biological behavior of colorectal cancer, demonstrating significant results. We herein attempt to summarize in a narrative and critical approach the relevant available data and the underlying pathophysiology, stressing the necessity of a more thorough understanding and future implementation of platelet indices in all stages of care we deliver to colorectal cancer patients.
Cancer, coagulation, colorectal, metastasis, platelet
Introduction The firm association between cancer progression and haemostatic disorders is well-established, with the initial clinical remarks made by Trousseau in 1865 [1]. The elucidation of the mechanisms regulating the vicious circle between cancer growth and hypercoagulation is considered to be one of the most promising fields of anticancer research, with colorectal cancer not being an exception [2, 3]. It is now undisputed that the local growth of colorectal cancer, as well as its metastatic potential, are associated with the establishment of a hypercoagulative profile, fact which highlights the need for implementing holistic approaches to confront the disease [4]. An explosive number of both clinical and laboratory studies is currently focusing on decoding a framework of complex interactions between cancer cells and the components of the haemostatic mechanisms, even at the early stages of neovascularization, a pre-requisite for local and metastatic cancer growth.
Hypercoagulation and neovascularization: The basis of the vicious circle? The increased metabolic state and the logo-regional expansion of colorectal cancer require the formation of new vessels [5–7]; this process of neovascularization, is characterized by the exhibition of a highly pre-coagulative phenotype of the newly formed vessels, leading to the local formation of micro-emboli which, through local thrombotic events, favor the establishment of a locally hypoxic environment [8, 9]. Sequentially, in a compensatory way, local hypoxia results in the expression of molecules, which favor neovascularization, with the most known being the vascular endothelial growth factor (VEGF) and the hypoxia inducible factors (HIFs) [10]. As mentioned above, the neovasculature is characterized by the possession of pre-coagulant phenotypic characteristics, such as the great extent of exposed Correspondence: Charalampos Seretis, Clinical Research Fellow in General Surgery, Good Hope Hospital, Heart of England NHS Foundation Trust, Rectory Road, Sutton Coldfield, B75 7RR, Birmingham, United Kingdom. E-mail: [email protected]
History Received 3 December 2013 Revised 15 January 2014 Accepted 9 February 2014 Published online 5 September 2014
sub-endothelial matrix due to the loose junctions between the endothelial cells, which is interpreted as endothelial breach, triggering the primary phase of haemostasis, which finally results in the accumulation of platelets and formation thrombi in order to contain the presumed vascular leak [11–13]. These early changes in the fragile balances of the haemostatic mechanism in favor of hypercoagulation, with the establishment of a hypoxic, oxidative potential, appear to represent a hallmark in the course of colorectal cancer, enhancing its local growth and promoting its ability to escape the local immuno-surveillance mechanisms [14, 15].
Platelets: The Foes’ allies A major step towards the success of primary hemostasis in the case of endothelial breach is the activation of platelets; the latter is achieved through their transformation from disk-shaped to round-shaped, with subsequent increase of their volume, fact which is essential for the exposure of their surface receptors that will facilitate the migration and adhesion to the area of the injured endothelium [16]. Following their activation, platelets de-granulate, releasing a variety of molecules, which, apart from their primary role in the regulation of haemostasis, induce the process of neovascularization and regulate the profile of the inflammatory reaction to and from the cancerous cells [17]. More specifically, platelets’ delta-granules mainly release ADP, ATP, serotonin and catecholamines, while the alphagranules release VEGF, fibrinogen, von Willebrand factor, P-selectin, platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), endothelial cell growth factor (ECGF), transforming growth factor (TGF), insulin-like growth factor (IGF) and Matrix Metalloproteinases (MMPs) [18, 19]. The above-mentioned molecules are involved in the process of local migration of the circulating white cell indices and therefore determine to a great extent the peritumoral inflammatory response, contributing to the local desmoplastic reaction through deposition of fibrin, which acts as a scaffold for the local tumor progression [20–23]. It is also important to mention that platelets release molecules that inhibit neovascularization, such as
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thrombospondin, with the relevant molecular background still remaining in the shades; however, it appears that their effect is overwhelmed by the agents favoring neovascularization [24, 25]. Apart from the participation of activated platelets in the colorectal cancer local growth, they appear to play a crucial role in the development of distant metastases, with the blood-borne ones being currently the most extensively investigated, although it is possible that they are also engaged in various aspects of the lymphatic spread as well [26, 27]. To put in a nutshell, the main of these mechanisms could be summarized as follows [28–35]: Using their surface receptors, activated platelets bind with the circulating tumor cells and form a protective ‘‘cloak’’ around them, reducing the capability of T-lymphocytes and Natural Killer cells (NK cells) to successfully recognize and target them. The activated platelets surrounding the circulating tumor cells degranulate and release numerous adhesion molecules, such as selectines, that facilitate the attachment of the activated platelet-cancer cells complex to the metastatic niches. The release of PDGF kai TGF-b by the activated platelets suppresses directly the cytotoxic properties of NK cells. Platelets are involved in the process of lymphatic spread of the cancer cells, probably by mediating the formation of new lymphatic vessels from the primitive endothelial cells. Therefore, it is more than evident that platelets, and especially the activated platelets, stand as major mediators of colorectal cancer growth and enhance significantly its metastatic potential, exhibiting simultaneously local and systematic immune-regulating actions, which further impair the host’s immuno-reaction against the progression of the malignancy.
Colorectal cancer-induced hypercoagulation: The other side of the coin There is ample evidence that colorectal cancer, as well as the rest of gastrointestinal cancers, is accompanied by a trend to induce thrombocytosis per se, with this hypercoagulative potential reflecting the cancer cells’ biological aggressiveness [36, 37]. In a rough description if the relevant underlying mechanisms, it is believe that thrombocytosis is induced through a paraneoplastictype over-expression of thrombopoietin (TPO) and through the local and systematic release of cytokines, such as IL-1, IL-3, IL-6, IL-11 and other proteins like granulocyte macrophage colonystimulating factor (GM-CSF), FMS-like tyrosine kinase 3 (FLT3) ligand and fibroblast growth factor (FGF), which induce the production of platelets [38–40]. Moreover, the peripheral consumption of platelets during the formation of micro-emboli in the framework of a chronic, compensated subclinical disseminated intravascular coagulation, which accompanies the natural course of colorectal cancer, is a strong stimulus for the production of new platelets in order to maintain the platelet count within the normal range [41, 42]. Nevertheless, a more careful insight to this dynamic balance between platelet consumption and platelet production in the course of colorectal cancer provides a wider understanding of the impact of cancer-induced thrombocytosis regarding the progression of the disease. To be more specific, this reactive thrombocytosis is an qualitative turning point, as it does not only have a quantitative substance (maintenance of the total platelet count within the normal range), since the newly formed, immature platelets are enzymatically more active than the mature ones; the reason is that the immature platelets contain more granules in their cytoplasm and have a rounder shape, fact which facilitates the exposure of their surface receptors [43, 44]. Therefore, even in the absence of an abnormal total platelet count, cancer progression results in the presence of an increasing percentage
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of activated platelets, triggering a vicious circle of hypercoagulation-induced cancer spread and cancer-induced hypercoagulation. The above-mentioned dynamic interactions are diagrammatically presented in Figure 1. Taking all the above into account, it appears that a substantial aspect of the accurate estimation of the biological behavior of colorectal cancer lies on the correct evaluation of these laboratory parameters reflecting the presence of actual thrombocytosis and the trend for thrombocytosis. We believe that a valuable asset in the daily clinical practice is the careful interpretation of the most widely available paraclinical investigation, the routine full blood count. Although the presence of active fibrinolysis, the compensatory action against the impact of hypercoagulation, can be also assessed in the clinical practice, the cost of even the simple d-dimer essay which prohibits its routine use in the absence of suspected major thromboembolic event, restrains and simultaneously challenges us to attempt to obtain the maximum amount of information from the often overlooked routine full blood count. Therefore, we strongly believe that it is high time to critically revise our basic hematology knowledge, aiming in the long-term to develop new prognostic scores and adjust our treatment plans under a tailored approach perspective. In this effort, paying attention to simple details of clinical practice, starting with the routinely available platelet indices as they appear in the full blood count, can be an unexpected ally.
Platelet indices and colorectal cancer prognosis: Do we know enough? In the daily clinical setting, the most commonly available platelet indices are the total platelet count (TPC), the mean platelet volume (MPV), the platelet distribution width (PDW), which measures the morphological heterogeneity of platelets, and the platelet-large cell ratio (L-PCR), which corresponds to the percentage of large platelets in the total platelet count. Total platelet count and colorectal cancer prognosis The value of total platelet count is determined by the balance between the rate of production and the rate of consumption of platelets. As already analyzed, in the case of colorectal cancer – and cancer in general– there is a clear trend of both overproduction and over-consumption of platelets. Therefore, both thrombocytosis and thrombopenia would be indicative of a biologically aggressive cancer; however, even a normal platelet count could be present in cases of adequate compensation, when these two opposing forces are equal. Consequently, a normal platelet count could conceal the presence of highly hypercoagulative and pro-inflammatory cancer phenotypes in the presence of efficient compensatory mechanisms. As a result, the presence of actual thrombocytosis might be associated with a stage were the disease has already overwhelmed the patients compensatory reservoirs, implicating the existence of greater dissemination. Various clinical studies in colorectal cancer patients have demonstrated a prognostic significance of elevated total platelet counts. Specifically, Cravioto-Villanueva et al. [45] reported that a pre-operative platelet count higher than 350 000/ml was associated with 3- and 5-year survival of 30 and 0% respectively, compared to 86 and 81% of 3- and 5-year survival in a cohort of 163 patients with rectal cancer. Similarly, Ishizuka et al. [46] stratified a total of 453 colorectal cancer patients with operable colorectal cancer using as a total platelet count of 300 000/ml as a cut-off value, with the study results revealing the overall survival was associated with the pre-operative platelet count (odds ratio, 1.642; 95% CI, 1.025–2.629; p ¼ 0.039). Moreover, pre-operative
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Dynamic balance between platelet production and consumption in colorectal cancer Platelet activation at sites of neovascularization
Increase of platelet volume
Peripheral consumption of platelets at sites of neovascularization and/or due to formation of cancer emboli Paraneoplastic-type thrombocytosis
“THROMBOCYTOPENIA” FORCE ? total platelet count
Increased platelet production de novo and as compensatory mechanism
“THROMBOCYTOSIS” FORCE
Increasing numbers of immature, enzymatically more active platelets released
Establishment of hypercoagulative status – (micro)thrombotic events multiplied with increased rate of platelet consumption
Figure 1. Simplified diagram of the dynamic balance between platelet production and consumption in the natural course of colorectal cancer, demonstrating that the presence of these two opposite forces affecting the total platelet count. It is evident that the presence of a normal platelet count can be a result of equal tends of thrombocytosis and thrombocytopenia, not reflecting a possible biological aggressive type of underlying malignancy, when adequate compensation is maintained. However, it should be noticed that there is a qualitative shift of platelets activity in the course of the disease, as the consumed platelets are replaced by immature platelets only, which are enzymatically more active. Therefore, there is a gradual dominance of the large platelet count, which comprises both of the immature platelets and the activated (regardless their morphological maturity) platelets, fact which contributes to the enhancement of hypercoagulation along with the progression of cancer, irrespectively from the total platelet count.
thrombocytosis was found to be an independent prognostic factor of cancer specific survival (hazard ratio ¼ 2.96, 95% CI ¼ 1.72– 5.00) in another retrospective study which included a total of 636 patients with operable colorectal cancer, defining as thrombocytosis a total platelet count greater than 370 000/ml [47]. Furthermore, Wan et al. [48] reported that colorectal patients with pre-operative platelet count above 400 000/ml had a significantly unfavorable survival (HR ¼ 1.66, 95% CI 1.34–2.05, plog-rank ¼ 1.1 1011) and recurrence p ¼ 2.6 106, (HR ¼ 1.90, 1.24–2.93, p ¼ 0.003, plog-rank ¼ 0.003). In accordance with the previously mentioned studies, Kandir et al. [49] demonstrated a significant difference in overall survival (OS),comparing again colorectal cancer patients with or without pre-operative thrombocytosis (p ¼ 0.00001, log-rank test). Specifically, in patients with thrombocytosis, defined as platelet count greater than 400 000/ml, the median OS was 50 months (95% CI 37–63 months), whereas patients without thrombocytosis had a longer OS (cumulative survival 70.7%). However, in contrast, Nyasavajjala et al. [50] concluded that there was no statistically significant difference in mean survival (p ¼ 0.067) observed in colorectal cancer patients with platelet count higher than 450 000/ml (n ¼ 576; 95% CI: 1550.5–1405.4, SE 37.0) vs. 450 000 (n ¼ 51, CI: 1261.6–955.0, SE 78.2), failing to detect as well a correlation between Dukes stage and thrombocytosis. Mean platelet volume, platelet distribution width platelet-large cell ratio and colorectal cancer prognosis These three laboratory parameters are widely available by the majority of the modern automated analysts and are included in the
routine full blood count. The common characteristic of these markers is that their elevation is indicative of greater platelet activity [51], which, as mentioned above, is of paramount importance in all aspects of colorectal cancer progression, from local growth to the development of distant metastases [52]. In contrast to the existence of clinical studies assessing the prognostic significance of total platelet count in colorectal cancer, there are no published data investigating any similar potential role for any of these three parameters. The only relevant study reported that in a group of 74 colorectal cancer patients with metastatic disease, treatment with the anti-VEGF antibody Bevacizumab resulted in a decrease of the mean platelet volume and platelet distribution width, in the 3-month follow-up framework, indicating a possible benefit regarding the cancer-related thrombotic incidents [53].
Discussion Considering the available data, it appears that pre-operative elevated platelet counts can be suggestive of a worse prognosis in colorectal cancer. Undoubtedly, the different cut-off values used to define thrombocytosis in the published studies certain pose certain limitations. However, they provide an important insight to the possible significance of co-evaluating the platelet count as a variable that could be incorporated in the current riskstratification and staging tools. Unfortunately, except from the prognostic role of thrombocytosis, there is virtually complete lack of published studies evaluating a potential prognostic role of the other routinely available platelet indices, which can be indicative of platelet activity and therefore reflect in a qualitative way the
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platelet-mediated growth and metastatic spread potential of colorectal cancer. So far, the prognostic scores used in colorectal cancer are based only on the tumor’s characteristics, failing to take into account the distinct impact a ‘‘same’’ tumor can have on different patients, largely depending on the immune’s system capability to withstand and overcome the disease. Platelet-mediated colorectal cancer growth and subsequent metastasis is well-established concept in modern oncology, which is proven by the increased thromboembolic risk of these patients. Without the need to implement in the daily practice expensive laboratory investigations, the routine full blood count could provide a gross estimation of the relevant dynamic balances, which are firmly associated with the existence of aggressive biological features of colorectal cancer. The latter could be of significant importance in various aspects of the treatment of colorectal cancer patients, enabling for instance the development of chemoprevention protocols for cancer recurrence with anti-platelet medications. Moreover, patients with hyper-coagulative cancer could possibly benefit from the intensification of the post-operative thromboprophylactic protocols. Finally, the development of new prognostic scores that will classify and stage colorectal cancer according to not only the tumor characteristics, but also the systematic impact of the disease, will be an important step towards moving our practice standards to higher level, where personalized treatment will be more feasible and safe for (colorectal) cancer patients. Therefore, it might be high time to revise our basic hematology knowledge, in order to be able to take full advantage of the information we can obtain even from the ‘‘humble’’ full blood count test and set the foundations for improving the standards of care in colorectal cancer.
Declaration of interest The authors have no competing interests to declare.
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