Cancer-Associated Thrombosis: A Two-Way Street

2019 ◽  
Vol 45 (06) ◽  
pp. 559-568 ◽  
Author(s):  
Bal Krishan Sharma ◽  
Matthew J. Flick ◽  
Joseph S. Palumbo
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Coagulation System ◽  
Cancer Pathogenesis ◽  
Bidirectional Relationship ◽  
Clotting Cascade ◽  
Tumor Growth And Metastasis ◽  
Cancer Associated Thrombosis

AbstractPathological activation of the coagulation system occurs with virtually all forms of cancer, particularly epithelial malignancies. Accordingly, thrombosis is one of the most common comorbidities associated with cancer. Indeed, cancer-associated thromboembolism is the second leading cause of death for cancer patients, second only to the cancer itself. The identification of specific molecular mechanisms whereby tumor cells activate the coagulation system and drive thrombosis has been an active area of investigation for several decades. Studies in animal models and human trials have revealed that there is a bidirectional relationship between coagulation factor activity and cancer, whereby the pathological hemostatic system activation associated with cancer not only promotes thromboembolism but also drives progression of the malignancy. Numerous studies indicate that factors up and down the clotting cascade can contribute to various stages of cancer, including tumorigenesis, primary tumor growth, and metastasis. Although there are some mechanistic points of commonality, there are also clearly context-dependent contributions of coagulation components to cancer progression dependent on the type of cancer and stage of disease. It is also notable that in some instances, coagulation factors appear to contribute to cancer progression independently of their traditional roles in hemostasis and thrombosis. Here, the authors review the current state of the field with regard to hemostatic factor-driven cancer pathogenesis.

scholarly journals Progress in research on the role of fibrinogen in lung cancer

2020 ◽  
Vol 15 (1) ◽  
pp. 326-330
Author(s):  
Xing Liu ◽  
Bin Shi
Keyword(s):  
Lung Cancer ◽  
Coagulation Factor ◽  
Coagulation System ◽  
Plasma Coagulation ◽  
Hepatic Cells ◽  
Tumor Growth And Metastasis ◽  
Cancer Côlon ◽  
The Relationship ◽  
Multiple Interactions

AbstractLung cancer is one of the most prevalent malignancies worldwide. Local recurrence and distant metastasis remain the major causes of treatment failure. It has been recognized that the process of tumor growth and metastasis involves multiple interactions between tumor and host. Various biomarkers have been used for predicting tumor recurrence, metastasis, and prognosis in patients with lung cancer. However, these biomarkers are still controversial and require further validation. The relationship between malignancy and coagulation system disorders has been explored for more than a century. Fibrinogen is the most abundant plasma coagulation factor synthesized mainly by hepatic cells. Increased plasma fibrinogen levels were observed in various carcinomas such as gastric cancer, colon cancer, and pancreatic cancer. Recent studies have also investigated the role of fibrinogen in patients with lung cancer. This review aimed to address the role of fibrinogen in lung cancer.

scholarly journals Molecular Mechanisms and Determinants of Innovative Correction Approaches in Coagulation Factor Deficiencies

2019 ◽  
Vol 20 (12) ◽  
pp. 3036 ◽  
Author(s):  
Dario Balestra ◽  
Alessio Branchini
Keyword(s):  
Gene Editing ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Therapeutic Approaches ◽  
Protein Levels ◽  
Functional Factors ◽  
New Strategies ◽  
I Gene

Molecular strategies tailored to promote/correct the expression and/or processing of defective coagulation factors would represent innovative therapeutic approaches beyond standard substitutive therapy. Here, we focus on the molecular mechanisms and determinants underlying innovative approaches acting at DNA, mRNA and protein levels in inherited coagulation factor deficiencies, and in particular on: (i) gene editing approaches, which have permitted intervention at the DNA level through the specific recognition, cleavage, repair/correction or activation of target sequences, even in mutated gene contexts; (ii) the rescue of altered pre-mRNA processing through the engineering of key spliceosome components able to promote correct exon recognition and, in turn, the synthesis and secretion of functional factors, as well as the effects on the splicing of missense changes affecting exonic splicing elements; this section includes antisense oligonucleotide- or siRNA-mediated approaches to down-regulate target genes; (iii) the rescue of protein synthesis/function through the induction of ribosome readthrough targeting nonsense variants or the correction of folding defects caused by amino acid substitutions. Overall, these approaches have shown the ability to rescue the expression and/or function of potentially therapeutic levels of coagulation factors in different disease models, thus supporting further studies in the future aimed at evaluating the clinical translatability of these new strategies.

Coagulation Factors Are Activators Of Human Plasma “Prorenin”

1981 ◽  
Author(s):  
D H Osmond ◽  
S R Tatemichi ◽  
E A Wilczynski ◽  
A D Purdon
Keyword(s):  
Human Plasma ◽  
Coagulation Factor ◽  
Plasma Renin ◽  
Coagulation Factors ◽  
Coagulation System ◽  
Activation Process ◽  
Special Importance ◽  
Factor Xii ◽  
Renin Content

We have demonstrated that human plasma “prorenin”, an inactive precursor of the blood pressure regulating enzyme renin, can be activated by cold, e.g. -4 to +4°C for 1-30 days (Can. J. Physiol. Pharmacol. 51:705, 1973). Several workers have reported cold activation of the coagulation system. Suspecting a link between these two cold- activated enzyme systems, we established that in factor XII deficient plasma, the rate of cold activation of prorenin is halved (Lancet i, 1313, 1978). Trypsinization of plasma can mimic within 1 minute the effect of prolonged cold (Circ. Res. Suppl . 1, 41:171, 1977), and can overcome specific coagulation factor deficiencies in varying degrees. FXII, VII, V, and especially FX deficient plasmas, all have subnormal basal active renin levels, implying an impaired state of prorenin conversion in vivo. FXII deficientplasma activates least by cold, suggesting special importance of FXII for operation of cold activation. All the plasmas activate better with 0.5 mg trypsin/ml plasma than with cold, except FX, suggesting that it especially mediates tryptic activation. Increasing the trypsin concentration corrects for factor deficiencies in varying degrees, implying some non-specificity and interchangeability of factor requirements for prorenin activation. Our data point to a hierarchy of factor importance, and to a “cascade7#x201D; of prorenin activation, by which plasma renin content can be rapidly increased. Thus, plasma renin activity is a function of renal release of renin, plus renin formation from renal (and possibly extrarenal) prorenin by an activation process involving the coagulation system.

scholarly journals Biological Functions of Gasdermins in Cancer: From Molecular Mechanisms to Therapeutic Potential

2021 ◽  
Vol 9 ◽  
Author(s):  
Man Wang ◽  
Xinzhe Chen ◽  
Yuan Zhang
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Effector Proteins ◽  
Biological Functions ◽  
Cancer Cell Growth ◽  
Cancer Pathogenesis

Pyroptosis is a type of lytic programmed cell death triggered by various inflammasomes that sense danger signals. Pyroptosis has recently attracted great attention owing to its contributory role in cancer. Pyroptosis plays an important role in cancer progression by inducing cancer cell death or eliciting anticancer immunity. The participation of gasdermins (GSDMs) in pyroptosis is a noteworthy recent discovery. GSDMs have emerged as a group of pore-forming proteins that serve important roles in innate immunity and are composed of GSDMA-E and Pejvakin (PJVK) in human. The N-terminal domains of GSDMs, expect PJVK, can form pores on the cell membrane and function as effector proteins of pyroptosis. Remarkably, it has been found that GSDMs are abnormally expressed in several forms of cancers. Moreover, GSDMs are involved in cancer cell growth, invasion, metastasis and chemoresistance. Additionally, increasing evidence has indicated an association between GSDMs and clinicopathological features in cancer patients. These findings suggest the feasibility of using GSDMs as prospective biomarkers for cancer diagnosis, therapeutic intervention and prognosis. Here, we review the progress in unveiling the characteristics and biological functions of GSDMs. We also focus on the implication and molecular mechanisms of GSDMs in cancer pathogenesis. Investigating the relationship between GSDMs and cancer biology could assist us to explore new therapeutic avenues for cancer prevention and treatment.

scholarly journals The consistent use of recombinant and plasma coagulation factors in the intensive care of massive obstetric hemorrhage

2020 ◽  
Vol 17 (3) ◽  
pp. 101-108
Author(s):  
A. V. Kuligin ◽  
A. V. Lushnikov ◽  
E. E. Zeulina
Keyword(s):  
Intensive Care ◽  
Blood Coagulation ◽  
Clinical Manifestations ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Coagulation System ◽  
Obstetric Hemorrhage ◽  
Blood Coagulation System ◽  
Coagulation Factor Vii

Massive obstetric hemorrhage is one of the most threatening complications of pregnancy, delivery and early postpartum period, which are part of the triad of leading causes of maternal mortality both in the world and in the Russian Federation. In recent years, to stop coagulopathy, which is one of the clinical manifestations of massive obstetric hemorrhage, recombinant and plasma factors of the blood coagulation system are successfully used, which include a concentrate of prothrombin complex and activated coagulation factor VII (eptacog alfa activated). The authors present results of successful consistent use of the blood coagulation system factors within comprehensive intensive care of coagulopathy in a patient with massive obstetric hemorrhage.

scholarly journals Intracellular maturation of the γ-carboxyglutamic acid (Gla) region in prothrombin coincides with release of the propeptide

1993 ◽  
Vol 291 (3) ◽  
pp. 723-727 ◽  
Author(s):  
R Wallin ◽  
C Stanton ◽  
S M Hutson
Keyword(s):  
Conformational Change ◽  
Vitamin K ◽  
Secretory Pathway ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Coagulation System ◽  
Clotting Factor ◽  
Clotting Factors ◽  
Post Translational Modifications ◽  
Carboxyglutamic Acid

Vitamin K-dependent coagulation factors undergo several post-translational modifications before the proteins are secreted into the blood as functional zymogens of the coagulation system. The modifications include Asn-linked glycosylation, Asn/Asp hydroxylation, removal of a signal peptide for translocation of the polypeptide into the endoplasmic reticulum and removal of a propeptide which, when attached to the intracellular coagulation factor precursor, directs the protein for vitamin K-dependent gamma-carboxylation. gamma-Carboxylation of targeted Glu residues results in formation of Ca(2+)-binding gamma-carboxyglutamic acid (Gla) residues. Ca2+ binding by these residues induces a conformational change in the protein which is a necessary event for optimal activation or activity of the clotting factor in blood. In the present study we have monitored the intracellular prothrombin precursor in the secretory pathway of liver cells to determine the effect that the propeptide has on Ca(2+)-dependent folding of the protein. The data provide evidence that the Ca(2+)-induced conformational change required for activation of prothrombin coincides with release of the propeptide in the trans-Golgi apparatus of the liver cell and elucidates an important function for the endoproteinase furin in biosynthesis of vitamin K-dependent clotting factors.

scholarly journals MicroRNA-520a discourages lung cancer pathogenesis and progression involving the downregulation of RRM2 and Wnt signaling deficits

2020 ◽  
Author(s):  
Yi Xie ◽  
Congyu Xue ◽  
Shuai Guo ◽  
Lei Yang
Keyword(s):  
Lung Cancer ◽  
Survival Rate ◽  
Wnt Signaling ◽  
Cell Lines ◽  
Cancer Progression ◽  
Altered Expression ◽  
Cancer Pathogenesis ◽  
Tumor Growth And Metastasis

Abstract Background Increasingly evidence has noted the critical functions of microRNAs (miRNAs) in disease control including cancer progression. This paper aimed to explore the functions of miR-520a in lung cancer (LC) and the downstream molecules implicated. Methods Aberrantly expressed miRNAs in LC tissues were screened out by miRNA microarrays. miR-520a expression in LC tissues and cell lines was determined, and the correlation between miR-520a level and survival rate of patients was analyzed. Altered expression of miR-520a was introduced to evaluate its function in LC cell malignant behaviors. The target mRNA and the potential signaling pathway mediated by miR-520a were figured out. Xenograft tumors were induced in mice to test the role of miR-520a in tumorigenesis in vivo. Results Poor expression of miR-520a was found in LC tissues and cell lines. A higher miR-520a level indicated a better survival rate in LC patients. Overexpression of miR-520a led to declines in cell viability, proliferation, migration, invasion and resistance to apoptosis. The target mRNAs of miR-520a were enriched on the Wnt signaling. miR-520a inactivated the Wnt pathway. miR-520a could bind to RRM2 and downregulate RRM2 expression in LC cells. Overexpression of RRM2 promoted the malignant behaviors of cancer cells, but this promotion was inhibited by miR-520a. Overexpression of miR-520a also inhibited the tumor growth and metastasis in nude mice. Conclusion The present study provided evidence that miR-520a could inhibit LC progression through RRM2 down-regulation and Wnt signaling deficit. This paper may offer novel ideas concerning LC treatment.

Activation of protease-activated receptors by gingipains fromPorphyromonas gingivalis leads to platelet aggregation: a new trait in microbial pathogenicity

Blood ◽  
2001 ◽  
Vol 97 (12) ◽  
pp. 3790-3797 ◽  
Author(s):  
Afrodite Lourbakos ◽  
YuPing Yuan ◽  
Alison L. Jenkins ◽  
James Travis ◽  
Patricia Andrade-Gordon ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Cell Activation ◽  
Coagulation Factors ◽  
Human Platelets ◽  
Etiologic Agent ◽  
Coagulation System ◽  
Protease Activated Receptors ◽  
Bacterial Pathogenicity ◽  
Clotting Cascade ◽  
Cellular Components

The bacterium Porphyromonas gingivalis is a major etiologic agent in the pathogenesis of adult periodontitis in humans. Cysteine proteinases produced by this pathogen, termed gingipains, are considered to be important virulence factors. Among many other potentially deleterious activities, arginine-specific gingipains-R (RgpB and HRgpA) efficiently activate coagulation factors. To further expand knowledge of the interaction between gingipains and the clotting cascade, this study examined their effects on cellular components of the coagulation system. The enzymes induced an increase in intracellular calcium in human platelets at nanomolar concentrations and caused platelet aggregation with efficiency comparable to thrombin. Both effects were dependent on the proteolytic activity of the enzymes. Based on desensitization studies carried out with thrombin and peptide receptor agonists, and immunoinhibition experiments, gingipains-R appeared to be activating the protease-activated receptors, (PAR)-1 and -4, expressed on the surface of platelets. This was confirmed by the finding that HRgpA and RgpB potently activated PAR-1 and PAR-4 in transfected cells stably expressing these receptors. Cumulatively, the results indicate the existence of a novel pathway of host cell activation by bacterial proteinases through PAR cleavage. This mechanism not only represents a new trait in bacterial pathogenicity, but may also explain an emerging link between periodontitis and cardiovascular disease.

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

2020 ◽  
Vol 26 ◽  
pp. 107602962095428
Author(s):  
Marwa S. Hamza ◽  
Shaker A. Mousa
Keyword(s):  
Risk Factors ◽  
Thyroid Hormone ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Thyroid Hormone Receptor ◽  
Integrin Αvβ3 ◽  
Cancer Type ◽  
Major Health Problem ◽  
Patients With Cancer ◽  
Cancer Associated Thrombosis

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

scholarly journals Deciphering the Role of the Coagulation Cascade and Autophagy in Cancer-Related Thrombosis and Metastasis

2020 ◽  
Vol 10 ◽  
Author(s):  
Charlotte Nicole Hill ◽  
Maria Paz Hernández-Cáceres ◽  
Catalina Asencio ◽  
Begoña Torres ◽  
Benjamin Solis ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cell Activation ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Coagulation Cascade ◽  
Endothelial Cell Activation ◽  
Hematopoietic Stem

Thrombotic complications are the second leading cause of death among oncology patients worldwide. Enhanced thrombogenesis has multiple origins and may result from a deregulation of megakaryocyte platelet production in the bone marrow, the synthesis of coagulation factors in the liver, and coagulation factor signaling upon cancer and the tumor microenvironment (TME). While a hypercoagulable state has been attributed to factors such as thrombocytosis, enhanced platelet aggregation and Tissue Factor (TF) expression on cancer cells, further reports have suggested that coagulation factors can enhance metastasis through increased endothelial-cancer cell adhesion and enhanced endothelial cell activation. Autophagy is highly associated with cancer survival as a double-edged sword, as can both inhibit and promote cancer progression. In this review, we shall dissect the crosstalk between the coagulation cascade and autophagic pathway and its possible role in metastasis and cancer-associated thrombosis formation. The signaling of the coagulation cascade through the autophagic pathway within the hematopoietic stem cells, the endothelial cell and the cancer cell are discussed. Relevant to the coagulation cascade, we also examine the role of autophagy-related pathways in cancer treatment. In this review, we aim to bring to light possible new areas of cancer investigation and elucidate strategies for future therapeutic intervention.

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