Platelets, traditionally regarded as passive mediators of hemostasis, are now recognized as pivotal regulators in the tumor microenvironment, establishing metabolic feedback loops with tumor and immune cells. Tumor-derived signals trigger platelet activation, which induces rapid metabolic reprogramming, particularly glycolysis, to support activation-dependent functions such as granule secretion, morphological changes, and aggregation. Beyond self-regulation, platelets influence the metabolic processes of adjacent cells. Through direct mitochondrial transfer, platelets reprogram tumor and immune cells, promoting oxidative phosphorylation. Additionally, platelet-derived cytokines, granules, and extracellular vesicles drive metabolic alterations in immune cells, fostering suppressive phenotypes that facilitate tumor progression. This review examines three critical aspects: (1) the distinctive metabolic features of platelets, particularly under tumor-induced activation; (2) the metabolic crosstalk between activated platelets and other cellular components; and (3) the therapeutic potential of targeting platelet metabolism to disrupt tumor-promoting networks. By elucidating platelet metabolism, this review highlights its essential role in tumor biology and its therapeutic implications.

Transparent reporting is key to improving the reproducibility of scientific research. In 2023, the International Society for Extracellular Vesicles updated the "Minimal information for studies of extracellular vesicles" (MISEV) reporting guidelines and published new recommendations for blood extracellular vesicle (EV) research entitled "MIBlood-EV: Minimal information to enhance the quality and reproducibility of blood extracellular vesicle research." The MIBlood-EV recommendations are part of MISEV 2023 and promote reporting not only the protocols used for blood collection and handling but also the composition of the prepared samples that are used to measure EVs. Plasma and serum are commonly used starting materials for EV research; reporting their composition can help to improve reproducibility, comparison of measurement results, and support evidence-based guideline development. We conducted an online survey among the International Society on Thrombosis and Haemostasis (ISTH) EV researchers. Of the 20 respondents, 95% were familiar with MISEV, but 35% were unaware of the 2023 update, and only 65% applied these guidelines to their reports. With regard to MIBlood-EV, 40% were unaware of this reporting tool, and 20% did not follow its recommendations. This is surprising because most respondents agree that preanalytical variables of blood EV research are not satisfactorily described (75%), confirm that having a standardized reporting tool is beneficial for blood EV research (90%), and consider MIBlood-EV applicable to other fields of ISTH research (80%). In this Scientific and Standardization Committee communication, we summarize the survey results, as well as the background and goals of MISEV and how MIBlood-EV can be useful to improve the reproducibility of blood research within the ISTH community.

Activation of invasion and metastasis is a central hallmark of cancer, contributing to the primary cause of death for patients with cancer. In the multistep metastatic process, cancer cells must infiltrate the circulation, survive, arrest at capillary beds, extravasate, and form metastatic clones in distant organs. However, only a small proportion of circulating tumor cells (CTC) successfully form metastases, with transit of CTCs in the circulation being the rate-limiting step. The fate of CTCs is influenced by the circulating tumor microenvironment (cTME), which encompasses factors affecting their biological behaviors in the circulation. This liquid and flowing microenvironment differs significantly from the primary TME or the premetastatic niche. This review summarizes the latest advancements in identifying the biophysical cues, key components, and biological roles of the cTME, highlighting the network among biophysical attributes, blood cells, and nonblood factors in cancer metastasis. In addition to the potential of the cTME as a therapeutic target for inhibiting metastasis, the cTME could also represent as a biomarker for predicting patient outcomes and developing strategies for treating cancer.

Colorectal cancer (CRC), the third most prevalent cancer globally, exhibits a notable association with venous thromboembolism (VTE), significantly impacting patient morbidity and mortality. We delve into the complex pathogenesis of cancer-associated thrombosis (CAT) in CRC, highlighting the interplay of clinical risk factors and tumor-specific mechanisms. Our comprehensive review synthesizes the current understanding of CRC's pro-thrombotic tendencies, examining both general clinical factors (e.g., age, gender, obesity, prior VTE history) and tumor-specific aspects (e.g., tumor location, stage, targeted therapies). Key findings illustrate how CRC cells themselves actively contribute to coagulation cascade activation through various procoagulant elements such as tissue factor, cancer procoagulant, and extracellular vesicles. We also explore how CRC influences host cells to adopt a procoagulant phenotype, thereby exacerbating thrombotic risks. This review underscores the role of genetic mutations in CRC (e.g., KRAS, p53) in modulating coagulation-related protein expression and thrombosis risks. An in-depth understanding of the genetic landscape specific to CRC subtypes is essential for developing targeted anticoagulation strategies and could significantly advance thrombosis prevention while improving the overall management of patients with CRC. This highlights the urgent need for precision in addressing CAT within clinical settings.

Cancer-associated thrombosis (CAT) remains a leading cause of morbidity and mortality among oncology patients, with an incidence influenced by tumor type, stage, treatment, and molecular characteristics. This review explores the molecular determinants of venous thromboembolism (VTE) in cancer, emphasizing its pathophysiology and association with specific oncogenic alterations. Certain molecular profiles exhibit heightened VTE risk. In lung cancer, due to hypercoagulability mechanisms linked to tissue factor overexpression, an increased incidence of VTE has been reported in populations with ALK (30-40 %) and ROS1 rearrangements (34.7-46.6 %). In gastrointestinal cancers, while pancreatic adenocarcinoma has the highest VTE rates (up to 22 %), KRAS mutations seem to be implicated but not conclusively validated. Similarly, colorectal cancer mutations (KRAS/BRAFV600E) and antiangiogenic therapies may elevate thrombotic risk, warranting further study. High-grade gliomas, particularly glioblastomas, present VTE rates up to 30 %, driven by podoplanin-induced platelet aggregation. IDH1 mutations inversely correlate with thrombosis, highlighting its protective role. Emerging evidence suggests that agnostic biomarkers such as STK11 mutations influence VTE risk across tumor types, while others like KRAS, MET and BRCA mutations show inconclusive results. Large-scale validation studies are imperative to integrate molecular profiles into clinical practice. Until then, management decisions should be individualized, balancing the thrombotic risks with oncologic considerations.

Tissue factor (TF)-rich cancer microvesicles are correlated with thrombosis risk. Intrinsic coagulation factors are also associated with the risk of thrombosis in cancer patients. This study explored the roles of pancreatic cancer-derived microvesicles and intrinsic factors in thrombogenesis.

Human pancreatic cancer cell lines rich in TF (AsPC-1-TFhigh, MIAPaCa-2-TFhigh) or poor in TF [AsPC-1-TFKO(knockout) and MIAPaCa-2-TFlow] were generated for microvesicle preparation and injected into coagulation-defective mice. Inferior vena cava (IVC) clots and lung thrombosis were evaluated. Immunodeficient hemophilia A (NSG-HA) mice were orthotopically injected with the cells mentioned above, and the tumor and IVC clot weights were analyzed.

With the injection of TFhigh microvesicles, IVC clots were rarely found in hemophilic mice. The TFlow and TFKO microvesicles resulted in few IVC clots in any mouse. Lung thrombosis was substantially reduced in the hemophilic mice infused with any microvesicle type. In orthotopic tumor models, TFhigh cells grew faster than did TFlow cells. TFhigh tumor-bearing NSG-WT mice had the most enormous IVC clots, whereas NSG-HA mice had no IVC clots.

Pancreatic cancer thrombosis induced by TF-expressing microvesicles strongly depended on FVIII and FIX, while VWF played a minor role. Moreover, TF, but not FVIII, was significantly related to tumor growth.

The management and treatment of tumor complications pose continuous challenges due to the inherent complexity. However, the advent of drug delivery systems (DDSs) brings promising opportunities to address the tumor complications using innovative technological approaches. This review focuses on common oncological complications, including cancer thrombosis, malignant serous effusion, tumor-associated infections, cancer pain, and treatment-related complications. Emphasis was placed on the application and potential of DDSs in mitigating and treating these tumor complications, and we delved into the underlying mechanisms of common cancer-associated complications, discussed the limitations of conventional treatments, and outlined the current status and potential development of DDSs for various complications in this review. Moreover, we have discussed the existing challenges in DDSs research, underscoring the need for addressing issues related to biocompatibility and targeting of DDSs, optimizing drug delivery routes, and enhancing delivery efficiency and precision. In conclusion, DDSs offer promising avenues for treating cancer complications, offering the potential for the development of more effective and safer drug delivery strategies, thereby improving the quality of life and survival rates of cancer patients.

Cancer is characterized by chronic inflammation and hypercoagulability, with an excess of venous thromboembolism (VTE). Tissue factor, the initiator of blood coagulation, circulates associated with extracellular vesicles (EV-TF). Studies investigating EV-TF between cancer-associated and non-cancer-associated VTE are lacking. We therefore compared EV-TF in unprovoked VTE (U-VTE), cancer-associated VTE (C-VTE), and cancer without VTE (C-w/o VTE). We also investigated interleukin-6 (IL-6) levels between the same groups. The final population included 68 patients (U-VTE: n = 15; C-VTE: n = 24; C-w/o VTE: n = 29). All patients with VTE were enrolled within 48 h of diagnosis; non-VTE patients were recruited in the oncologic outpatient services. EV were isolated by differential centrifugation from 4 mL of peripheral blood; the final EV pellet (16,000× g for 45 min) was resuspended in 100 μL saline and tested for TF using a one-step clotting assay. There was a statistically significant difference for higher EV-TF in C-VTE and C-w/o VTE compared to U-VTE (p = 0.024; Kruskal-Wallis test). There was no significant difference between C-VTE and C-w/o VTE. Moreover, we did not find any difference in IL-6 levels. These preliminary data suggest that cancer represents, per se, a strong driver of EV-TF generation.

Breast cancer (BC) is a global challenge that affects a large portion of individuals, especially women. It has been suggested that microparticles (MPs) can be used as a diagnostic, prognostic, or therapeutic biomarker in various diseases. Moreover, MPs are known to elevate in cancer cases. Platelet-derived MPs (PMPs) play a crucial role in the metastasis of BC, warranting specific focus. This study aimed to explore the involvement of procoagulant MPs in BC.

This systematic review was carried out using the Preferred Reporting Items for Systematic reviews, and Meta-Analyses (PRISMA). Terms defined as MESH keywords were searched PubMed/MEDLINE, Embase, Web of Science, and Cochrane Library searched in from 2011 to March 2024. Experimental and quasi-experimental studies were assessed by the CONSORT checklist.

Eventually, 15 studies were included. 426 participants were studied in the included articles. The potential clinical relevance of MPs as biomarkers in BC was indicated. Also, the role of MPs in immune modulation and multidrug resistance was approved. PMPs were found to enhance malignant features, including migration and invasion. Moreover, there were lower levels of MPs before neo-adjuvant chemotherapy, suggesting a potential impact of chemotherapy on MPs levels. The study highlights the remarkable capacity of multidrug-resistant BC-derived MPs to alter the phenotype and functionality of immune cells.

The findings underscore the intricate interplay between MPs and cellular signaling pathways, shedding light on their potential as diagnostic biomarkers, and therapeutic targets in cancer. Specifically, the association between MPs levels and disease severity, as evidenced by their correlation with tissue-based biomarkers, tumor grading, and distant metastasis, highlights their clinical relevance in prognostication and risk stratification.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare paraneoplastic syndrome associated with various adenocarcinomas, most commonly gastric adenocarcinoma. This condition can progressively worsen pulmonary arterial hypertension, leading to acute or subacute pulmonary heart failure and respiratory insufficiency. This paper examines the pathogenesis, clinical presentation, diagnosis, treatment, and prognosis of PTTM. Given PTTM's poor prognosis, we emphasize treatment strategies. PTTM in adenocarcinoma patients can mimic other pulmonary diseases, causing diagnostic delays. Current PTTM treatment strategies primarily focus on managing the underlying malignancy and addressing thrombotic complications. Anti-angiogenic therapy with bevacizumab and the platelet-derived growth factor receptor antagonist imatinib have shown promise in multiple cases. Further research is needed to develop more effective and targeted therapies for this challenging condition. The precise mechanisms underlying this association remain to be fully elucidated.

Venous thromboembolism (VTE) is a prevalent and serious complication among cancer patients, necessitating therapeutic anticoagulation for many individuals with brain metastases. Simultaneously, patients with brain metastases, particularly those with high-risk primary tumors, have an increased risk of intracranial hemorrhage (ICH). Managing anticoagulation in these patients presents a dual challenge: preventing thromboembolism while avoiding hemorrhagic events. Here, we present our approach to anticoagulation for acute VTE in patients with brain metastases, based on the available evidence. We review potential risk factors for anticoagulation-associated ICH in this population and discuss strategies for managing acute VTE in patients with and without ICH.

Tisotumab vedotin (TV) holds promise for treating recurrence or metastatic cervical cancer (r/mCC), with recent FDA approval for second-line use in recurrent or metastatic cases. Our research aims to evaluate TV's efficacy and safety in these patients, focusing on overall survival (OS) and progression-free survival (PFS) outcomes.

We searched five electronic databases in February 2024, retrieved articles, screened them based on inclusion and exclusion criteria, and assessed their quality. A meta-analysis of the extracted data was performed and applied a random-effects model for our analysis.

The search identified 86 articles, with six meeting the inclusion criteria. Meta-analysis revealed 80.8% and 48.0% OS at 6 and 12 months, and a 29.9% PFS at 6 months. Combined treatment with carboplatin or pembrolizumab showed 33.0% PFS at 1 year and 15.1% at 2 years. The objective response rate (ORR) was 21.0%, reaching 43.3% with combined treatment. Confirmed disease control rate (CDCR) was 70.0% overall and in combination. The median duration of response (DOR) was 6.1 months, increasing to 9.5 months in combined treatment, with a consistent time to response (TTR) of 1.4 months. Adverse events included ocular issues (conjunctivitis 30.3%, dry eye 18.7%) and common side effects (nausea 38.4%, epistaxis 35.7%).

This systematic review and meta-analysis highlights the potential of TV as a treatment option for r/mCC patients. However, healthcare providers must communicate safety profiles and recommend prophylactic measures for optimal patient outcomes. Further studies, particularly assessing combination treatments, are needed to clarify TV's role in treatment algorithms and improve clinical outcomes.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have obvious advantages over MSC therapy. But the strong procoagulant properties of MSC-EVs pose a potential risk of thromboembolism, an issue that remains insufficiently explored. In this study, we systematically investigated the procoagulant activity of large EVs derived from human umbilical cord MSCs (UC-EVs) both in vitro and in vivo. UC-EVs were isolated from cell culture supernatants. Mice were injected with UC-EVs (0.125, 0.25, 0.5, 1, 2, 4 μg/g body weight) in 100 μL PBS via the tail vein. Behavior and mortality were monitored for 30 min after injection. We showed that these UC-EVs activated coagulation in a dose- and tissue factor-dependent manner. UC-EVs-induced coagulation in vitro could be inhibited by addition of tissue factor pathway inhibitor. Notably, intravenous administration of high doses of the UC-EVs (1 μg/g body weight or higher) led to rapid mortality due to multiple thrombus formations in lung tissue, platelets, and fibrinogen depletion, and prolonged prothrombin and activated partial thromboplastin times. Importantly, we demonstrated that pulmonary thromboembolism induced by the UC-EVs could be prevented by either reducing the infusion rate or by pre-injection of heparin, a known anticoagulant. In conclusion, this study elucidates the procoagulant characteristics and mechanisms of large UC-EVs, details the associated coagulation risk during intravenous delivery, sets a safe upper limit for intravenous dose, and offers effective strategies to prevent such mortal risks when high doses of large UC-EVs are needed for optimal therapeutic effects, with implications for the development and application of large UC-EV-based as well as other MSC-EV-based therapies.

Venous thromboembolism (VTE) is a common complication in patients with brain tumors. The management of acute VTE is particularly challenging due to an elevated risk of intracranial hemorrhage (ICH). Risk of developing ICH on anticoagulation is influenced by a number of factors including tumor type, recent surgery, concomitant medications, platelet counts, and radiographic features. In patients with a heightened risk for ICH, the benefits of anticoagulation need to be balanced against a likelihood of developing major hemorrhagic complications. Management decisions include whether to administer anticoagulation, at what dose, placement of an inferior vena cava filter, monitoring for development of hemorrhage or progressive thrombus, and escalation of anticoagulant dose. This article discusses the complexities of treating acute VTE in patients with brain tumors and outlines treatment algorithms based on the presence or absence of ICH at the time of VTE diagnosis. Through case-based scenarios, we illustrate our approach to anticoagulation, emphasizing individualized risk assessments and evidence-based practices to optimize treatment outcomes while minimizing the risks of hemorrhagic events in patients with brain tumors.

Venous thromboembolism, which is common in cancer patients and accompanies or even precedes malignant tumors, is known as cancer-related thrombosis and is an important cause of cancer- associated death. At present, the exact etiology of the elevated incidence of venous thrombosis in cancer patients remains elusive. Platelets play a crucial role in blood coagulation, which is intimately linked to the development of arterial thrombosis. Additionally, platelets contribute to tumor progression and facilitate immune evasion by tumors. Tumor cells can interact with the coagulation system through various mechanisms, such as producing hemostatic proteins, activating platelets, and directly adhering to normal cells. The relationship between platelets and malignant tumors is also significant. In this review article, we will explore these connections.

Coagulopathy and associated bleeding and deep vein thrombosis (DVT) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated.

To evaluate the associations between biomarker levels and bleeding and DVT in acute leukemia patients.

We examined plasma levels of activators, inhibitors, and biomarkers of the coagulation and fibrinolytic pathways in patients aged ≥18 years with newly diagnosed acute leukemia compared with those of normal controls. Multivariable regression models were used to examine the association of biomarkers with bleeding and DVT in acute leukemia patients. The study included 358 patients with acute leukemia (29 with acute promyelocytic leukemia [APL], 253 with non-APL acute myeloid leukemia, and 76 with acute lymphoblastic leukemia) and 30 normal controls.

Patients with acute leukemia had higher levels of extracellular vesicle tissue factor (EVTF) activity, phosphatidylserine-positive extracellular vesicles, plasminogen activator inhibitor-1, plasmin-antiplasmin complexes, and cell-free DNA and lower levels of citrullinated histone H3-DNA complexes compared with normal controls. APL patients had the highest levels of EVTF activity and the lowest levels of tissue plasminogen activator among acute leukemia patients. There were 41 bleeding and 23 DVT events in acute leukemia patients. High EVTF activity was associated with increased risk of bleeding (subdistribution hazard ratio, 2.30; 95% CI, 0.99-5.31), whereas high levels of plasminogen activator inhibitor-1 were associated with increased risk of DVT (subdistribution hazard ratio, 3.00; 95% CI, 0.95-9.47) in these patients.

Our study shows alterations in several biomarkers in acute leukemia and identifies biomarkers associated with risk of bleeding and DVT.

Patients with cancer are at an increased risk of developing a hypercoagulative phenotype and venous thromboembolism. However, no clinical trial has yet confirmed that anticoagulant therapy improves cancer prognosis, and the mechanism underlying hypercoagulation in patients with bladder cancer is not well understood.

We hypothesized that the prognostic genes affect tumor progression via tumor-mediated coagulation.

We detected the most significant prognostic genes of bladder cancer with The Cancer Genome Atlas dataset and validated them in 2 Gene Expression Omnibus datasets and 1 ArrayExpress dataset. Immunohistochemical tests were performed on a cohort of 80 individuals to further examine the prognostic genes. For the most reliable prognostic gene, its influence on coagulation was evaluated with gene knockdown followed by next-generation sequencing and cellular and animal experiments.

Depletion of microtubule interacting and trafficking domain containing 1 (MITD1), a major prognostic gene of bladder cancer, significantly increased the tissue factor (TF) expression. MITD1 deficiency led to cytokinesis arrest, which, in turn, promoted the TF expression via unfolded protein response and c-Jun. The knockdown of IRE1, an essential kinase of unfolded protein response or the inactivation of c-Jun using c-Jun N-terminal kinase inhibitors weakened MITD1 deficiency- or dithiothreitol-induced TF upregulation. Cells lacking MITD1 promoted coagulation and metastasis in the experimental metastasis assay.

Our findings suggest the novel role of tumor prognostic genes upon the development of hypercoagulative phenotype and venous thromboembolism, thereby underlining the importance of anticoagulant therapy and shedding light on the therapeutic value of targeting MITD1 in bladder cancer.

Patients with cancer have a higher risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), compared to the general population. Cancer-associated thrombosis (CAT) is a thrombotic event that occurs as a complication of cancer or cancer therapy. Major factors determining VTE risk in cancer patients include not only treatment history and patient characteristics, but also cancer type and site. Cancer types can be broadly divided into three groups based on VTE risk: high risk (pancreatic, ovarian, brain, stomach, gynecologic, and hematologic), intermediate risk (colon and lung), and low risk (breast and prostate). This implies that the mechanism of VTE differs between cancer types and that specific VTE pathways may exist for different cancer types. This review summarizes the specific pathways that contribute to VTE in cancer patients, with a particular focus on leukocytosis, neutrophil extracellular traps (NETs), tissue factor (TF), thrombocytosis, podoplanin (PDPN), plasminogen activator inhibitor-1 (PAI-1), the intrinsic coagulation pathway, and von Willebrand factor (VWF).

Neutrophil extracellular traps (NETs) are extracellular fibers composed of deoxyribonucleic acid (DNA) and decorated proteins produced by neutrophils. Recently, NETs have been associated with the development of many diseases, including tumors. Herein, we reviewed the correlation between NETs and tumors. In addition, we detailed active compounds from traditional herbal medicine formulations that inhibit NETs, related nanodrug delivery systems, and antibodies that serve as "guiding moieties" to ensure targeted delivery to NETs. Furthermore, we discussed the strategies used by pathogenic microorganisms to evade NETs.

Low-grade inflammation is believed to be a risk factor for chronic diseases and is nutritionally responsive. Cottonseed oil (CSO), which is rich in n-6 polyunsaturated fats, has been shown to lower cholesterol and other chronic disease risk factors. The purpose of this secondary analysis was to determine the comparative responses of markers of inflammation and coagulation potential of healthy adult males consuming diets rich in CSO vs. olive oil (OO).

Fifteen normal-weight males, ages 21.7 ± 2.58y, completed a randomized crossover trial. Each intervention consisted of a 3-day lead-in diet and a 5-day outpatient, controlled feeding intervention (CSO or OO). There was a 2 to 4-week washout period between interventions. The 5-day intervention diets were 35 % carbohydrate, 15 % protein, and 50 % fat, enriched with either CSO or OO (44 % of total energy from oil). At pre- and post- diet intervention visits, a fasting blood draw was collected for analysis of markers of inflammation (Tumor Necrosis Factor Alpha (TNF-α), Interleukin-6 (IL-6), C-Reactive Protein (CRP)) and coagulation potential (Tissue Factor (TF), Plasminogen Activator Inhibitor-1 (PAI-1)).

The CSO-enriched diets reduced TNF-α (CSO: -0.12 ± 0.02 pg/ml, OO: -0.01 ± 0.05 pg/ml; p < 0.01) and TF (CSO: -0.59 ± 0.68 pg/ml, OO: 1.13 ± 0.83 pg/ml; p = 0.02) compared to OO diets. There were no differences in IL-6, CRP, or PAI-1 between diets.

A 5-day, CSO-enriched diet may be sufficient to reduce inflammation and coagulation potential compared to OO-enriched diets in a healthy male population which could have implications in chronic disease prevention.

Extracellular vesicles (EVs) are a class of substances that feature vesicle-like structures. Initially deemed to be "biological waste", recent studies have highlighted the crucial role of EVs in mediating information communication between cells by transporting bioactive components. Specifically, tumor cell-derived extracellular vesicles (TEVs) contain components that can be utilized for disease diagnosis and as vaccines to activate the immune system. Moreover, since TEVs have a phospholipid bilayer shell and can transport exogenous substances, they are being increasingly explored as drug delivery vehicles in anti-tumor therapy. TEVs have proven highly compatible with their corresponding tumor cells, allowing for efficient drug delivery and exerting killing effects on tumor cells through various mechanisms such as domino effects, lysosomal pathways, and inhibition of drug efflux from tumor tissues. Despite these promising developments, challenges remain in the clinical applications of EVs derived from tumor cells. This paper outlines the current advances and limitations in this field, highlighting the potential of TEVs as a powerful tool for combating cancer.

In general, humoral factors released from the placenta influence pregnancy progression, but the involvement of the canine placenta is often unidentified. We investigated specific genes in canine placentas and analyzed the blood dynamics of the translated proteins. Furthermore, RNAs are known to be released from placentas embedding in exosomes, a type of extracellular vesicles. Here, the presence of cell-free RNAs in pregnant serums was also confirmed. RNA specimens were purified from the normal healthy dog placentas and applied to RNA-Seq analysis. Expressions of frequent genes were confirmed by RT-PCR using placentas from other individuals and breeds. Relaxin (RLN) 2, lipocalin (LCN) 2, and tissue factor pathway inhibitor (TFPI) 2 were selected as high-expressed and placenta-specific genes. By western blot, the three factors were clearly detected in the pregnant serums. Quantitative analysis revealed that the amount of RLN2 increased significantly from non-pregnancy to day 41 of pregnancy. Regarding LCN2 and TFPI2, the protein serum levels elevated during pregnancy, but the statistical differences were not detected. Exosomes were found in all pregnant serums; however, the percentage was less than 6% in total extracellular vesicles. The cell-free RNA related to RLN2 was detected, but no elevation was confirmed during pregnancy. We found specific genes in the canine placenta and the transition of their translated protein into the blood. These factors may become useful tools for research on canine pregnancy and monitoring of reproductive management. Exosomes and cell-free RNA could not be found to be valid in canine reproduction.

Among multiple pathways of intercellular communication operative in multicellular organisms, the trafficking of extracellular vesicles (EVs) and particles (EP) represents a unique mode of cellular information exchange with emerging roles in health and disease, including cancer. A distinctive feature of EV/EP-mediated cell-cell communication is that it involves simultaneous short- or long-range transfer of numerous molecular constituents (cargo) from donor to recipient cells. EV/EP uptake by donor cells elicits signalling or metabolic responses, or else leads to EV-re-emission or degradation. EVs are heterogeneous membranous structures released from cells via increasingly defined mechanisms involving either formation of multivesicular endosomes (exosomes) or budding from the plasma membrane (ectosomes). EPs (exomeres, supermeres) are membraneless complex particles, smaller than EVs and of less defined biogenesis and function. EVs/EPs carry complex assemblies of proteins, lipids and nucleic acids (RNA, DNA), which they shuttle into intercellular milieu, body fluids and recipient cells, via surface contact, fusion and different forms of internalization (endocytosis, micropinocytosis). While the physiological functions of EVs/EPs communication pathways continue to be investigated, their roles in cancer are increasingly well-defined. For example, EVs are involved in the transmission of cancer-specific molecular cargo, including mutant, oncogenic, transforming, or regulatory macromolecules to indolent, or normal cells, sometimes triggering their quasi-transformation-like states, or phenotypic alterations. Conversely, a reciprocal and avid uptake of stromal EVs by cancer cells may be responsible for modulating their oncogenic repertoire, as exemplified by the angiocrine effects of endothelial EVs influencing cancer cell stemness. EV exchanges during cancer progression have also been implicated in the formation of tumour stroma, angiogenesis and non-angiogenic neovascularization processes, immunosuppression, colonization of metastatic organ sites (premetastatic niche), paraneoplastic and systemic pathologies (thrombosis, diabetes, hepatotoxicity). Thus, an EV/EP-mediated horizontal transfer of cellular content emerges as a new dimension in cancer pathogenesis with functional, diagnostic, and therapeutic implications.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal metastatic disease associated with robust activation of the coagulation and fibrinolytic systems. However, the potential contribution of the primary fibrinolytic protease plasminogen to PDAC disease progression has remained largely undefined. Mice bearing C57Bl/6-derived KPC (KRasG12D , TRP53R172H ) tumors displayed evidence of plasmin activity in the form of high plasmin-antiplasmin complexes and high plasmin generation potential relative to mice without tumors. Notably, plasminogen-deficient mice (Plg- ) had significantly diminished KPC tumor growth in subcutaneous and orthotopic implantation models. Moreover, the metastatic potential of KPC cells was significantly diminished in Plg- mice, which was linked to reduced early adhesion and/or survival of KPC tumor cells. The reduction in primary orthotopic KPC tumor growth in Plg- mice was associated with increased apoptosis, reduced accumulation of pro-tumor immune cells, and increased local proinflammatory cytokine production. Elimination of fibrin(ogen), the primary proteolytic target of plasmin, did not alter KPC primary tumor growth and resulted in only a modest reduction in metastatic potential. In contrast, deficiencies in the plasminogen receptors Plg-RKT or S100A10 in tumor cells significantly reduced tumor growth. Plg-RKT reduction in tumor cells, but not reduced S100A10, suppressed metastatic potential in a manner that mimicked plasminogen deficiency. Finally, tumor growth was also reduced in NSG mice subcutaneously or orthotopically implanted with patient-derived PDAC tumor cells in which circulating plasminogen was pharmacologically reduced. Collectively, these studies suggest that plasminogen promotes PDAC tumor growth and metastatic potential, in part through engaging plasminogen receptors on tumor cells.

Accumulating evidence links the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement to venous thromboembolism (VTE) in non-small cell lung cancer (NSCLC) patients. However, the corresponding mechanisms remain unclear.

High-throughput sequencing analysis of H3122 human ALK-positive NSCLC cells treated with ALK inhibitor/ dimethyl sulfoxide (DMSO) was performed to identify coagulation-associated differential genes between EML4-ALK fusion protein inhibited cells and control cells. Sequentially, we confirmed its expression in NSCLC patients' tissues and in the plasma of a subcutaneous xenograft mouse model. An inferior vena cava (IVC) ligation model was used to assess clot formation potential. Additionally, pathways involved in tissue factor (TF) regulation were explored in ALK-positive cell lines H3122 and H2228. Statistical significance was determined by Student t-test and one-way ANOVA using SPSS.

Sequencing analysis identified a significant downregulation of TF after inhibiting EML4-ALK fusion protein activity in H3122 cells. In clinical NSCLC cases, TF expression was increased especially in ALK-positive NSCLC tissues. Meanwhile, H3122 and H2228 with high TF expression exhibited shorter plasma clotting time and higher TF activity versus ALK-negative H1299 and A549 in cell culture supernatant. Mice bearing H2228 tumor showed a higher concentration of tumor-derived TF and TF activity in plasma and the highest adjusted IVC clot weights. Limiting EML4-ALK protein phosphorylation downregulated extracellular regulated protein kinases 1/2 (ERK1/2)-activating the protein-1(AP-1) signaling pathway and thus attenuated TF expression.

EML4-ALK fusion protein may enhance venous thrombogenicity by regulating coagulation factor TF expression. There was potential involvement of the pERK1/2-AP-1 pathway in this process.

Cancer patients represent a growing population with drastically difficult care and a lowered quality of life, especially due to the heightened risk of vast complications. Thus, it is well established so far that one of the most prominent complications in individuals with cancer is venous thromboembolism. Since there are various improved methods for screening and diagnosing cancer and its complications, the incidence of cancer-associated thrombosis has been on the rise in recent years. Therefore, the high mortality and morbidity rates among these patients are not a surprise. Consequently, there is an excruciating need for understanding the mechanisms behind this complex process, as well as the imperative for adequate analysis and application of the most suitable steps for cancer-associated thrombosis prevention. There are various and numerous mechanisms offering potential answers to cancer-associated thrombosis, some of which have already been elucidated in various preclinical and clinical scenarios, yet further and more elaborate studies are crucial to understanding and preventing this complex and harsh clinical entity. This article elaborates on the growing incidence, mortality, morbidity, and risk factors of cancer-associated thrombosis while emphasizing the pathophysiological mechanisms in the light of various types of cancer in patients and summarizes the most novel therapy and prevention guidelines recommendations.

Single cell analysis of cancer cell transcriptome may shed a completely new light on cancer-associated thrombosis (CAT). CAT causes morbid, and sometimes lethal complications in certain human cancers known to be associated with high risk of venous thromboembolism (VTE), pulmonary embolism (PE) or arterial thromboembolism (ATE), all of which worsen patients' prognosis. How active cancers drive these processes has long evaded scrutiny. While "unspecific" microenvironmental effects and consequences of patient care (e.g., chemotherapy) have been implicated in pathogenesis of CAT, it has also been suggested that oncogenic pathways driven by either genetic (mutations), or epigenetic (methylation) events may influence the coagulant phenotype of cancer cells and stroma, and thereby modulate the VTE/PE risk. Consequently, the spectrum of driver events and their downstream effector mechanisms may, to some extent, explain the heterogeneity of CAT manifestations between cancer types, molecular subtypes, and individual cases, with thrombosis-promoting, or -protective mutations. Understanding this molecular causation is important if rationally designed countermeasures were to be deployed to mitigate the clinical impact of CAT in individual cancer patients. In this regard, multi-omic analysis of human cancers, especially at a single cell level, has brought a new meaning to concepts of cellular heterogeneity, plasticity, and multicellular complexity of the tumour microenvironment, with profound and still relatively unexplored implications for the pathogenesis of CAT. Indeed, cancers may contain molecularly distinct cellular subpopulations, or dynamic epigenetic states associated with different profiles of coagulant activity. In this article we discuss some of the relevant lessons from the single cell "omics" and how they could unlock new potential mechanisms through which cancer driving oncogenic lesions may modulate CAT, with possible consequences for patient stratification, care, and outcomes.

Neuroendocrine neoplasms (NENs) differ from other malignancies in their ability to produce hormones and biogenic amines, as well as offer a better prognosis in well-differentiated tumors. There are no definite data on the occurrence of thromboembolic events in NENs and no recommendations regarding the use of antithrombotic prophylaxis in this group. Accurate assessment of the thromboembolic risk in NENs represents an important issue, in order to reduce morbidity and mortality due to complications of VTE. The aim of this work was to review the occurrence of thromboembolic events in NENs and the use of antithrombotic prophylaxis in this group. A total of 28 studies identified on PubMed were analyzed. NENs, especially of pancreatic primary, exhibit an increased thrombotic risk. Atypical VTE locations are quite common in NENs. Hormonally active NENs are associated with a significantly increased thromboembolic risk. Further studies in NENs are needed to evaluate the parameters of coagulation and fibrinolysis as predictive biomarkers for VTE complications.

Coagulopathy and associated bleeding and venous thromboembolism (VTE) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated.

To evaluate the associations between biomarker levels and bleeding and VTE in acute leukemia patients.

We examined plasma levels of activators, inhibitors and biomarkers of the coagulation and fibrinolytic pathways in patients ≥18 years with newly diagnosed acute leukemia compared to healthy controls. Multivariable regression models were used to examine the association of biomarkers with bleeding and VTE in acute leukemia patients. The study included 358 patients with acute leukemia (29 acute promyelocytic leukemia [APL], 253 non-APL acute myeloid leukemia [AML] and 76 acute lymphoblastic leukemia [ALL]), and 30 healthy controls.

Patients with acute leukemia had higher levels of extracellular vesicle (EV) tissue factor (TF) activity, phosphatidylserine-positive EVs, plasminogen activator inhibitor-1 (PAI-1), plasmin-antiplasmin complexes, cell-free DNA and lower levels of citrullinated histone H3-DNA complexes compared to healthy controls. APL patients had the highest levels of EVTF activity and the lowest levels of tissue plasminogen activator among the acute leukemia patients. There were 41 bleeding and 37 VTE events in acute leukemia patients. High EVTF activity was associated with increased risk of bleeding (sHR 2.30, 95%CI 0.99-5.31) whereas high PAI-1 was associated with increased risk of VTE (sHR 3.79, 95%CI 1.40-10.28) in these patients.

Our study shows alterations in several biomarkers in acute leukemia and identifies biomarkers associated with risk of bleeding and VTE.

Cancer is a well-known risk factor for venous thromboembolism (VTE). A combined strategy of D-dimer testing and clinical pre-test probability is usually used to exclude VTE. However, its effectiveness is diminished in cancer patients due to reduced specificity, ultimately leading to a decreased clinical utility. This review article seeks to provide a comprehensive summary of how to interpret D-dimer testing in cancer patients.

In accordance with PRISMA standards, literature pertaining to the diagnostic and prognostic significance of D-dimer testing in cancer patients was carefully chosen from reputable sources such as PubMed and the Cochrane databases.

D-dimers have not only a diagnostic value in ruling out VTE but can also serve as an aid for rule-in if their values exceed 10-times the upper limit of normal. This threshold allows a diagnosis of VTE in cancer patients with a positive predictive value of more than 80%. Moreover, elevated D-dimers carry important prognostic information and are associated with VTE reoccurrence. A gradual increase in risk for all-cause death suggests that VTE is also an indicator of biologically more aggressive cancer types and advanced cancer stages. Considering the lack of standardization for D-dimer assays, it is essential for clinicians to carefully consider the variations in assay performance and the specific test characteristics of their institution.

Standardizing D-dimer assays and developing modified pretest probability models specifically for cancer patients, along with adjusted cut-off values for D-dimer testing, could significantly enhance the accuracy and effectiveness of VTE diagnosis in this population.

Cancer-associated thrombosis (CAT), such as venous thromboembolism (VTE), is a frequent complication in cancer patients, resulting in poor prognosis. Breast cancer is not highly thrombogenic but is highly prevalent, resulting in increased VTE cases. Many cancers express tissue factor (TF), a glycoprotein that triggers coagulation. The cancer cells were shown to express and release substantial amounts of TF-positive microparticles (MPTF), associated with a prothrombotic state. This narrative review evaluated the current use of the procoagulant MPTF as a biomarker for thrombosis risk in breast cancer.

Tumors of epithelial origin with elevated TF expression have been associated with increased VTE incidence. Thus, studies have affirmed the use of MPTF biomarkers for VTE risk in many cancers. Patients with metastatic breast cancer and CAT were found to exhibit elevated procoagulant microparticles in vitro, due to TF expression. The silencing of TF was associated with decreased microparticle release in breast carcinoma cell lines, associated with decreased coagulation.

CAT is a multifactorial condition, with several various underlying diseases. It is proposed that MPTF may be an effective biomarker for thrombosis risk in breast cancer patients but requires a more systemic evaluation utilizing standardized quantification methods.

Venous thromboembolism (VTE) remains a major health burden despite anticoagulation advances, suggesting incomplete management of pathogenic mechanisms. The NLRP3 (NACHT-, LRR- and pyrin domain-containing protein 3) inflammasome, interleukin (IL)-1, and pyroptosis are emerging contributors to the inflammatory pathogenesis of VTE. Inflammasome pathway activation occurs in patients with VTE. In preclinical models, inflammasome signaling blockade reduces venous thrombogenesis and vascular injury, suggesting that this therapeutic approach may potentially maximize anticoagulation benefits, protecting from VTE occurrence, recurrence, and ensuing post-thrombotic syndrome. The nonselective NLRP3 inhibitor colchicine and the anti-IL-1β agent canakinumab reduce atherothrombosis without increasing bleeding. Rosuvastatin reduces primary venous thrombotic events at least in part through lipid-lowering independent mechanisms, paving the way to targeted anti-inflammatory strategies in VTE. This review outlines recent preclinical and clinical evidence supporting a role for inflammasome pathway activation in venous thrombosis, and discusses the, yet unexplored, therapeutic potential of modulating inflammasome signaling to prevent and manage VTE.

Over the past decade, extracellular vesicles and particles (EVPs) have emerged as critical mediators of intercellular communication, participating in numerous physiological and pathological processes. In the context of cancer, EVPs exert local effects, such as increased invasiveness, motility, and reprogramming of tumor stroma, as well as systemic effects, including pre-metastatic niche formation, determining organotropism, promoting metastasis and altering the homeostasis of various organs and systems, such as the liver, muscle, and circulatory system. This review provides an overview of the critical advances in EVP research during the past decade, highlighting the heterogeneity of EVPs, their roles in intercellular communication, cancer progression, and metastasis. Moreover, the clinical potential of systemic EVPs as useful cancer biomarkers and therapeutic agents is explored. Last but not least, the progress in EVP analysis technologies that have facilitated these discoveries is discussed, which may further propel EVP research in the future.

Thrombosis is a common complication of advanced cancer, yet the cellular mechanisms linking malignancy to thrombosis are poorly understood. The unfolded protein response (UPR) is an ER stress response associated with advanced cancers. A proteomic evaluation of plasma from patients with gastric and non-small cell lung cancer who were monitored prospectively for venous thromboembolism demonstrated increased levels of UPR-related markers in plasma of patients who developed clots compared with those who did not. Release of procoagulant activity into supernatants of gastric, lung, and pancreatic cancer cells was enhanced by UPR induction and blocked by antagonists of the UPR receptors inositol-requiring enzyme 1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK). Release of extracellular vesicles bearing tissue factor (EVTFs) from pancreatic cancer cells was inhibited by siRNA-mediated knockdown of IRE1α/XBP1 or PERK pathways. Induction of UPR did not increase tissue factor (TF) synthesis, but rather stimulated localization of TF to the cell surface. UPR-induced TF delivery to EVTFs was inhibited by ADP-ribosylation factor 1 knockdown or GBF1 antagonism, verifying the role of vesicular trafficking. Our findings show that UPR activation resulted in increased vesicular trafficking leading to release of prothrombotic EVTFs, thus providing a mechanistic link between ER stress and cancer-associated thrombosis.

Thrombosis is one of the main complications in cancer patients often leading to mortality. However, the mechanisms underlying platelet hyperactivation are poorly understood.

Murine and human platelets were isolated and treated with small extracellular vesicles (sEVs) from various cancer cell lines. The effects of these cancer-sEVs on platelets were evaluated both in vitro and in vivo using various approaches, including the detection of cancer-sEV-specific markers in murine platelets and patient samples, measurement of platelet activation and thrombosis assays. Signaling events induced by cancer-sEVs and leading to platelet activation were identified, and the use of blocking antibodies to prevent thrombosis was demonstrated.

We demonstrate that platelets very effectively take up sEVs from aggressive cancer cells. The process of uptake is fast, proceeds effectively in circulation in mice, and is mediated by the abundant sEV membrane protein-CD63. The uptake of cancer-sEVs leads to the accumulation of cancer cell-specific RNA in platelets in vitro and in vivo. The human prostate cancer-sEV-specific RNA marker PCA3 is detected in platelets of ~70% of prostate cancer patients. This was markedly reduced after prostatectomy. In vitro studies showed that platelet uptake of cancer-sEVs induces strong platelet activation in a CD63-RPTPα (receptor-like protein tyrosine phosphatase alpha)-dependent manner. In contrast to physiological agonists ADP and thrombin, cancer-sEVs activate platelets via a noncanonical mechanism. Intravital studies demonstrated accelerated thrombosis both in murine tumor models and in mice that received intravenous injections of cancer-sEVs. The prothrombotic effects of cancer-sEVs were rescued by blocking CD63.

Tumors communicate with platelets by means of sEVs, which deliver cancer markers and activate platelets in a CD63-dependent manner leading to thrombosis. This emphasizes the diagnostic and prognostic value of platelet-associated cancer markers and identifies new pathways for intervention.

Cancer patients have increased thrombosis and bleeding compared with the general population. Cancer is associated with activation of both platelets and coagulation. Mouse models have been used to study the dysregulation of platelets and coagulation in cancer. We established a mouse model of pancreatic cancer in which tissue factor-expressing human pancreatic tumors (BxPC-3) are grown in nude mice. Tumor-bearing mice have an activated coagulation system and increased venous thrombosis compared to control mice. We also showed that tumor-derived, tissue factor-positive extracellular vesicles activated platelets ex vivo and in vivo. In this study, we determined the effect of tumors on a platelet-dependent arterial thrombosis model. Unexpectedly, we observed significantly reduced carotid artery thrombosis in tumor-bearing mice compared to controls. In addition, we observed significantly increased tail bleeding in tumor-bearing mice compared to controls. These results suggested that the presence of the tumor affected platelets. Indeed, tumor-bearing mice exhibited a significant decrease in platelet count and an increase in mean platelet volume and percentage of reticulated platelets, findings that are consistent with increased platelet turnover. Levels of the platelet activation marker platelet factor 4 were also increased in tumor-bearing mice. We also observed decreased platelet receptor expression in tumor-bearing mice and reduced levels of active αIIb/β3 integrin in response to PAR4 agonist peptide and convulxin in platelets from tumor-bearing mice compared with platelets from control mice. In summary, our study suggests that in tumor-bearing mice there is chronic platelet activation, leading to thrombocytopenia, decreased receptor expression, and impaired platelet adhesive function.

Venous thromboembolism (VTE) is a life-threating condition that is common in patients with adult-type diffuse gliomas, yet thromboprophylaxis is controversial because of possible intracerebral hemorrhage. Effective VTE prediction models exist for other cancers, but not glioma. Our objective was to develop a VTE prediction tool to improve glioma patient care, incorporating clinical, blood-based, histologic, and molecular markers. We analyzed preoperative arterial blood, tumor tissue, and clinical-pathologic data (including next-generation sequencing data) from 258 patients with newly diagnosed World Health Organization (WHO) grade 2 to 4 adult-type diffuse gliomas. Forty-six (17.8%) experienced VTE. Tumor expression of tissue factor (TF) and podoplanin (PDPN) each positively correlated with VTE, although only circulating TF and D-dimers, not circulating PDPN, correlated with VTE risk. Gliomas with mutations in isocitrate dehydrogenase 1 (IDH1) or IDH2 (IDHmut) caused fewer VTEs; multivariable analysis suggested that this is due to IDHmut suppression of TF, not PDPN. In a predictive time-to-event model, the following predicted increased VTE risk in newly diagnosed patients with glioma: (1) history of VTE; (2) hypertension; (3) asthma; (4) white blood cell count; (5) WHO tumor grade; (6) patient age; and (7) body mass index. Conversely, IDHmut, hypothyroidism, and MGMT promoter methylation predicted reduced VTE risk. These 10 variables were used to create a web-based VTE prediction tool that was validated in 2 separate cohorts of patients with adult-type diffuse glioma from other institutions. This study extends our understanding of the VTE landscape in these tumors and provides evidence-based guidance for clinicians to mitigate VTE risk in patients with glioma.

Extracellular vesicles (EVs) and particles (EPs) serve as unique carriers of complex molecular information with increasingly recognized roles in health and disease. Individual EVs/EPs collectively contribute to the molecular fingerprint of their producing cell, reflecting its identity, state, function and phenotype. This property is of particular interest in cancer where enormous heterogeneity of cancer cells is compounded by the presence of altered stromal, vascular and immune cell populations, which is further complicated by systemic responses elicited by the disease in individual patients. These diverse and interacting cellular compartments are dynamically represented by myriads of EVs/EPs released into the circulating biofluids (blood) during cancer progression and treatment. Current approaches of liquid biopsy seek to follow specific elements of the EV/EP cargo that may have diagnostic utility (as biomarkers), such as cancer cell-derived mutant oncoproteins or nucleic acids. However, with emerging technologies enabling high-throughput EV/EP analysis at a single particle level, a more holistic approach may be on the horizon. Indeed, each EV/EP carries multidimensional information (molecular "voxel") that could be integrated across thousands of particles into a larger and unbiased landscape (EV/EP "hologram") reflecting the true cellular complexity of the disease, along with cellular interactions, systemic responses and effects of treatment. Thus, the longitudinal molecular mapping of EV/EP populations may add a new dimension to crucial aspects of cancer biology, personalized diagnostics, and therapy.

Cancer-associated thrombosis (CAT) is a leading cause of mortality in cancer patients and its incidence varies in different parts of the world. Venous thromboembolism (VTE) is a prominent manifestation of CAT, and significantly impacts morbidity and survival compared to arterial thrombosis in cancer patients. Several risk factors for developing VTE such as chemotherapy and immobilization have also been found co-existing with cancer patients and contributing to the increased risk of VTE in cancer patients than in non-cancer patients. This review highlights recent mechanisms in the pathogenesis of hypercoagulable syndromes associated with cancer, multiple mechanisms implicated in promoting cancer-associated thrombosis and their diagnostic approaches. Cancer cells interact with every part of the hemostatic system; generating their own procoagulant factors, through stimulation of the prothrombotic properties of other blood cell components or the initiation of clotting by cancer therapies which can all directly activate the coagulation cascade and contribute to the VTE experienced in CAT. It is our hope that the multiple interconnections between the hemostatic system and cancer biology and the improved biomarkers reported in this study can be relevant in establishing a predictive model for VTE, optimize early detection of asymptomatic microthrombosis for more personalized prophylactic strategies and incorporate effective therapeutic options and patient management to reduce mortality and morbidity, and improve the quality of life of affected cancer patients.

In addition to their pivotal roles in coagulation and thrombosis, platelets are crucial in tumor progression, with plenty of clinical and experimental data demonstrating that the interplay of platelets and tumor cells is essential for hematogenous tumor metastasis. After detach from primary sites, tumor cells intravasate into the blood circulation becoming circulating tumor cells and induce platelet activation, aggregation and encasement around tumor cells to form micro tumor thrombi, which create a permissive tumor microenvironment for metastasis. Platelets in micro tumor thrombi protect tumor cells from immune surveillance and anoikis (detachment-triggered apoptosis) through various pathways, which are significant for tumor cell survival in the bloodstream. Moreover, platelets can facilitate tumor metastasis by expediting epithelial-mesenchymal transition (EMT), adhesion to the endothelium, angiogenesis, tumor proliferation processes and platelet-derived microvesicle (PMV) formation.

Here, we provide a synopsis of the current understanding of the formation of micro tumor thrombi and the role of micro tumor thrombi in tumor hematogenous metastasis based on the tumor-platelet interplay. We also highlight potential therapeutic strategies targeting platelets for tumor treatment, including cancer-associated platelet-targeted nanomedicines.