scholarly journals Pathogenesis of Trousseau’s syndrome

2015 ◽  
Vol 64 (4) ◽  
pp. 85-94
Author(s):  
Alexander Viktorovich Vorobev ◽  
Alexander Davidovich Makatsaria ◽  
Andrey Mikhailovich Chabrov ◽  
Alexander Anatol’evich Savchenko
Keyword(s):  
Cancer Patients ◽  
Tissue Factor ◽  
Tumor Cells ◽  
Blood Clot ◽  
Coagulation Cascade ◽  
Severe Bleeding ◽  
Trousseau’S Syndrome ◽  
Thrombotic Complications ◽  
Significant Release ◽  
Coagulation Pathway

Malignancies and thrombosis have common pathogenetic features that was shown by A. Trousseau in 1865. There is now no doubt that the cancer patients occur much more frequently thromboembolism, and migratory venous thrombosis is a manifestation of paraneoplastic syndrome in cancer patients. In general, any manifestation of thrombohemorrhagic complications in cancer patients called Trousseau’s syndrome. While thrombotic complications such as venous thromboembolism are most frequent in cancer patients, may also experience severe bleeding symptoms due to systemic coagulopathies, including disseminated intravascular coagulation, haemolytic thrombotic microangiopathy, and hyperfibrinolysis. The basis of the pathophysiology of Trousseau’s syndrome, except the classic triad of Virchow, is overproduction of tissue factor (TF), the main initiator of extrinsic coagulation pathway. Thus a significant release of microparticles from tumor cells bearing tissue factor is critical not only for the formation of a blood clot, but the growth and progression of tumors. Tumor cells activate the coagulation cascade or fibrinolysis system, providing conditions for its further spread, stimulation of angiogenesis, increased vascular permeability, which in turn promotes metastasis.

scholarly journals Should We Replace the Terms Intrinsic and Extrinsic Coagulation Pathways With Tissue Factor Pathway?

2016 ◽  
Vol 23 (8) ◽  
pp. 922-927 ◽  
Author(s):  
Jan F. Vojacek
Keyword(s):  
Tissue Factor ◽  
Coagulation Cascade ◽  
Coagulation System ◽  
Bleeding Complications ◽  
Antithrombotic Agents ◽  
Risk Of Bleeding ◽  
Tissue Factor Pathway ◽  
The Common ◽  
Coagulation Pathway

Present review highlights some new aspects of the role of individual components of blood coagulation process and proposes a modified concept of hemocoagulation cascade. The role of FXII in the initiation of the so-called intrinsic coagulation system is currently questioned. Its role has been recently demonstrated mainly in the thrombus propagation and final stabilization together with factors XI and XIII. The edited concept underlines the common part of the tissue factor (TF) in the initiation of both the intrinsic and extrinsic pathways of the coagulation system and therefore may make it not improperly be called the TF coagulation pathway. The search for new antithrombotic agents shows that the level of the coagulation system blockade depends on which step in the coagulation cascade is targeted and results in different degrees of the antithrombotic efficiency and the risk of bleeding complications.

scholarly journals Activation of factor XI in plasma is dependent on factor XII [see comments]

Blood ◽  
1993 ◽  
Vol 81 (3) ◽  
pp. 580-586 ◽  
Author(s):  
T Brunnee ◽  
C La Porta ◽  
SR Reddigari ◽  
VM Salerno ◽  
AP Kaplan ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Dextran Sulfate ◽  
Coagulation Cascade ◽  
Factor Xii ◽  
Factor Xi ◽  
Extrinsic Pathway ◽  
Physiological Relevance ◽  
Factor Xiia ◽  
Kinetics Of ◽  
Coagulation Pathway

The activation of factor XI initiates the intrinsic coagulation pathway. Until recently it was believed that the main activator of factor XI is factor XIIa in conjunction with the cofactor high molecular weight kininogen on a negatively charged surface. Two recent reports have presented evidence that in a purified system factor XI is activatable by thrombin together with the soluble polyanion dextran sulfate. To assess the physiological relevance of these findings we studied the activation of factor XI in normal and factor XII-deficient plasma. We used either kaolin/cephalin or dextran sulfate as a surface for the intrinsic coagulation pathway, tissue factor to generate thrombin via the extrinsic pathway, or the addition of alpha-thrombin directly. 125I-factor XI, added to factor XI-deficient plasma at physiologic concentrations (35 nmol/L), is rapidly cleaved on incubation with kaolin. The kinetics appear to be exponential with half the maximum cleavage at 5 minutes. Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided. Tissue factor (1:500) added to plasma did not induce cleavage of factor XI during a 90-minute incubation, although fibrin formation within 30 seconds indicated that thrombin was generated via the extrinsic pathway. Adding 1 mumol/L alpha-thrombin (equivalent to 50% prothrombin activation) directly to factor XII deficient or normal plasma (with or without kaolin/cephalin/Ca2+ or dextran sulfate) led to instantaneous fibrinogen cleavage, but again no cleavage of factor XI was observable. We conclude that in plasma surroundings factor XI is not activated by thrombin, and that proposals of thrombin initiation of the intrinsic coagulation cascade are not supportable.

The Pleiotropic Effects of Tissue Factor: a Possible Role for Factor VIIa-induced Intracellular Signalling?

2001 ◽  
Vol 86 (12) ◽  
pp. 1353-1359 ◽  
Author(s):  
Maikel Peppelenbosch ◽  
Arnold Spek ◽  
Henri Versteeg
Keyword(s):  
Tissue Factor ◽  
Map Kinases ◽  
Factor Viia ◽  
Blood Clot ◽  
Calcium Signalling ◽  
Small Gtpases ◽  
Pleiotropic Effects ◽  
Intracellular Signalling ◽  
Coagulation Cascade ◽  
Extrinsic Pathway

SummaryTissue factor, a 47 kDa membrane glycoprotein, lies at the basis of the extrinsic pathway of the coagulation cascade. Interaction of TF with factor VIIa results in the formation of fibrin from fibrinogen, thereby inducing the formation of a blood clot. In addition to this well-established role in blood coagulation, TF is associated with various other physiological processes such as sepsis, inflammation, angiogenesis, metastasis and atherosclerosis. The molecular basis of the latter events is slowly emerging. It has become clear that TF-FVIIa interaction elicits a variety of intracellular signalling events that may be implicated in these actions. These events include the sequential activation of Src-like kinases, MAP kinases, small GTPases and calcium signalling. How this progress in the understanding of TF associated signal transduction may generate answers as to the mechanism through which TF exerts it pleiotropic effects will be focus of this review.

scholarly journals Activation of factor XI in plasma is dependent on factor XII [see comments]

Blood ◽  
1993 ◽  
Vol 81 (3) ◽  
pp. 580-586 ◽  
Author(s):  
T Brunnee ◽  
C La Porta ◽  
SR Reddigari ◽  
VM Salerno ◽  
AP Kaplan ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Dextran Sulfate ◽  
Coagulation Cascade ◽  
Factor Xii ◽  
Factor Xi ◽  
Extrinsic Pathway ◽  
Physiological Relevance ◽  
Factor Xiia ◽  
Kinetics Of ◽  
Coagulation Pathway

Abstract The activation of factor XI initiates the intrinsic coagulation pathway. Until recently it was believed that the main activator of factor XI is factor XIIa in conjunction with the cofactor high molecular weight kininogen on a negatively charged surface. Two recent reports have presented evidence that in a purified system factor XI is activatable by thrombin together with the soluble polyanion dextran sulfate. To assess the physiological relevance of these findings we studied the activation of factor XI in normal and factor XII-deficient plasma. We used either kaolin/cephalin or dextran sulfate as a surface for the intrinsic coagulation pathway, tissue factor to generate thrombin via the extrinsic pathway, or the addition of alpha-thrombin directly. 125I-factor XI, added to factor XI-deficient plasma at physiologic concentrations (35 nmol/L), is rapidly cleaved on incubation with kaolin. The kinetics appear to be exponential with half the maximum cleavage at 5 minutes. Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided. Tissue factor (1:500) added to plasma did not induce cleavage of factor XI during a 90-minute incubation, although fibrin formation within 30 seconds indicated that thrombin was generated via the extrinsic pathway. Adding 1 mumol/L alpha-thrombin (equivalent to 50% prothrombin activation) directly to factor XII deficient or normal plasma (with or without kaolin/cephalin/Ca2+ or dextran sulfate) led to instantaneous fibrinogen cleavage, but again no cleavage of factor XI was observable. We conclude that in plasma surroundings factor XI is not activated by thrombin, and that proposals of thrombin initiation of the intrinsic coagulation cascade are not supportable.

scholarly journals Biologically Active Tissue Factor-Bearing Larger Ectosome-Like Extracellular Vesicles in Malignant Effusions from Ovarian Cancer Patients: Correlation with Incidence of Thrombosis

2021 ◽  
Vol 22 (2) ◽  
pp. 790
Author(s):  
Corinna Steidel ◽  
Fanny Ender ◽  
Achim Rody ◽  
Nikolas von Bubnoff ◽  
Frank Gieseler
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Cancer Patients ◽  
Tissue Factor ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Thromboembolic Events ◽  
Advanced Ovarian Carcinoma ◽  
Venous Thromboembolic Events ◽  
Malignant Effusions

The development of malignant effusions such as ascites reflects a massive progression of a malignant disease. In patients with ovarian carcinoma, a high amount of ascites (>500 mL) is an independent negative prognostic marker. The composition and constituents of ascites reflect the inflammatory environment of the underlying tumor. Increased cellular resistance of ascites-derived tumor cells and the development of venous thromboembolic events (VTE) are major risks for these patients, especially in patients with advanced ovarian carcinoma. In this study, we discuss the release of tissue factor-bearing extracellular vesicles (TF+ EVs) from tumor cells into the environment (ascites fluid) and their systemic spreading as a possible causal explanation of the pathologic coagulation status in these patients. We obtained ascites from patients with advanced ovarian carcinoma, collected during surgery or therapeutic paracentesis (n = 20). Larger ectosome-like EVs were isolated using sequential centrifugation, quantified by high-resolution flow cytometry and analyzed using nanoparticle tracking analysis. Furthermore, the pro-coagulant properties (TF activity) of EVs were determined. Compared to published TF activities of EVs from healthy persons, TF activities of EVs derived from ascites of patients with ovarian cancer were very high, with a median of 80 pg/mL. The rate of VTE, as reported in the patient files, was high as well (35%, 7 out of 20). Furthermore, all but one patient with VTE had EV concentrations above the median within their ascetic fluid (p < 0.02). Since VTE continues to be a frequent cause of death in cancer patients, prophylactic antithrombotic treatment might be worth considering in these patients. However, given the risk of bleeding, more clinical data are warranted. Although the study is too small to enable reaching a conclusion on direct clinical implementation, it can well serve as a proof of principle and a rationale to initiate a prospective clinical study with different patient subgroups. We also show ex vivo that these larger ectosome-like EVs induce intracellular ERK phosphorylation and tumor cell migration, which is not directly related to their pro-coagulative potency, but might help to understand why cancer patients with thromboembolic events have a poorer prognosis.

scholarly journals Extracellular Vesicle-Associated Tissue Factor Activity in Prostate Cancer Patients with Disseminated Intravascular Coagulation

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1487
Author(s):  
Lena Hell ◽  
Thomas Däullary ◽  
Vanessa Burghart ◽  
Lisa-Marie Mauracher ◽  
Ella Grilz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Tissue Factor ◽  
Disseminated Intravascular Coagulation ◽  
Mononuclear Cells ◽  
Coagulation Cascade ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Intravascular Coagulation

Patients with advanced prostate cancer may develop fulminant disseminated intravascular coagulation (DIC). Circulating extracellular vesicles (EVs)-exposing tissue factor (TF), the initiator of the coagulation cascade, may play an important role. We included 7 prostate cancer patients with DIC, 10 age- and stage-matched cancer controls without DIC, and 10 age-matched healthy male individuals. EV-TF activity was highly elevated in prostate cancer patients with DIC (11.40 pg/mL; range: 4.34–27.06) compared with prostate cancer patients without DIC (0.09 pg/mL; range: 0.00–0.30, p = 0.001) and healthy controls (0.18 pg/mL; range: 0.09–0.54; p = 0.001). Only EVs from patients with DIC showed reduced fibrin clot formation time of pooled plasma in a TF-dependent manner. Next, we performed in vitro co-culture experiments including EVs derived from a prostate cancer cell line with high (DU145) and low (LNCaP) TF expression, peripheral blood mononuclear cells (PBMCs), and platelets. Co-incubation of DU145 EVs with PBMCs and platelets significantly increased EV-TF activity in conditioned medium and induced TF activity on monocytes. No such effects were seen in co-culture experiments with LNCaP EVs. In conclusion, the findings indicate that elevated EV-TF activity plays a role in the development of prostate-cancer-related DIC and may result from interactions between tumor-derived EVs, monocytes, and platelets.

scholarly journals Cancer-Associated Thrombosis: An Overview of Mechanisms, Risk Factors, and Treatment

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 380 ◽  
Author(s):  
Norbaini Abdol Razak ◽  
Gabrielle Jones ◽  
Mayank Bhandari ◽  
Michael Berndt ◽  
Pat Metharom
Keyword(s):  
Risk Factors ◽  
Cancer Patients ◽  
Current Treatment ◽  
Host Cells ◽  
Coagulation Cascade ◽  
Common Complication ◽  
Increased Risk ◽  
Thrombotic Complications ◽  
Cancer Associated Thrombosis

Cancer-associated thrombosis is a major cause of mortality in cancer patients, the most common type being venous thromboembolism (VTE). Several risk factors for developing VTE also coexist with cancer patients, such as chemotherapy and immobilisation, contributing to the increased risk cancer patients have of developing VTE compared with non-cancer patients. Cancer cells are capable of activating the coagulation cascade and other prothrombotic properties of host cells, and many anticancer treatments themselves are being described as additional mechanisms for promoting VTE. This review will give an overview of the main thrombotic complications in cancer patients and outline the risk factors for cancer patients developing cancer-associated thrombosis, focusing on VTE as it is the most common complication observed in cancer patients. The multiple mechanisms involved in cancer-associated thrombosis, including the role of anticancer drugs, and a brief outline of the current treatment for cancer-associated thrombosis will also be discussed.

TFPI (Tissue Factor Pathway Inhibitor) Is Present in Breast Cancer Tumor Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4035-4035
Author(s):  
Ewa Sierko ◽  
Zbigniew Sawicki ◽  
Adrianna Butkiewicz ◽  
Lech Zimnoch ◽  
Walter Kisiel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Tumor Cells ◽  
Tissue Factor Pathway Inhibitor ◽  
Tissue Factor Pathway ◽  
Immunohistochemical Studies ◽  
Cancer Tissues

Abstract Abnormalities in hemostatic system are common in breast cancer patients. The principal initiator of blood coagulation activation in cancer patients is tissue factor (TF). Tissue factor plays an important role in the processes of angiogenesis, invasion and metastatic dissemination. Tissue factor pathway inhibitor (TFPI) is the main inhibitor of TF-dependent pathway of blood coagulation. The catalytic activity of the TF/VIIa complex triggers activation of factor X, consequently thrombin generation and finally fibrin formation. Thrombin and fibrin facilitate cancer progression. Previous immunohistochemical studies revealed no expression of TFPI in cancer cells of different malignant tumor types (Werling et al, Thromb Haemost1993; 69: 366–369) The aim of the study was to evaluate the expression of TFPI protein and mRNA in tumor cells of breast cancer. Breast cancer tissues were obtained during surgical treatment of 35 women. The patients undergoing surgery had not received any previous anticancer therapy. Tumor fragments were preserved in 4% paraformaldehyde/phosphate buffered saline and than embedded in paraffin. Immunohistochemical studies (avidin-biotin complex-ABC - technique) were performed using polyclonal antibodies against TFPI. In situ hybridization method employed single-stranded DNA oligonucleotide (probe sequence: 5′Biotin-CATCGCCCAGTGCAGCCTCCGTCAG-Biotin3′) directed against locus NM 006287 of TFPI mRNA. Strong expression of TFPI protein was observed in cancer cell bodies in examined specimens. Weak expression of the above protein was observed in tumor infiltrating macrophages. Normal cells revealed much weaker staining for TFPI than cancer cells. Similarly, mRNA for TFPI was observed in cancer cells of all breast cancer tissues. The above data indicate that TFPI is present in neoplastic cells of breast cancer and may play a role in neutralizing TF procoagulant and signaling functions.

Addressing the Issue of the Pathogenesis of Deep Vein Thrombosis In Cancer

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4220-4220
Author(s):  
Grace M Thomas ◽  
Alexander Brill ◽  
Daphne Schatzberg ◽  
Denisa D. Wagner
Keyword(s):  
Deep Vein Thrombosis ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Conflicts Of Interest ◽  
Mesenteric Arteries ◽  
Vein Thrombosis ◽  
Tumor Bearing ◽  
Thrombotic Complications ◽  
Deep Vein

Abstract Abstract 4220 The risk of thrombotic complications during tumor development has been the focus of several clinical studies over the past decades. Thrombotic disease is a common cause of death in cancer patients and almost one in five of all symptomatic cases of Deep Vein Thrombosis (DVT) are thought to be cancer related. Tumor cells generate and profit from a local and systemic hypercoagulable state, which promotes tumor growth, angiogenesis, and metastasis. The resulting procoagulant state is responsible for the heightened risk for thrombotic complications and the etiology of the resulting DVT event. However, despite the fact that some molecules, such as tissue factor, have recently been described as potential modulators of clot formation in DVT, the true trigger of DVT in cancer patients remains unknown. To determine whether the presence of cancer cells can trigger formation of a thrombus in a deep vein in vivo, we combined a murine model of Trousseau's Syndrome with a model of DVT. First, we induced the development of a tumor by subcutaneous injection of syngeneic pancreatic tumor cells in C57BL/6 mice. It was previously demonstrated that these mice have significantly reduced tail bleeding time and time to occlusion in injured mesenteric arteries and veins compared to control vessels. After 3 hours of partial flow restriction of the inferior vena cava, we observed that all tumor-bearing mice developed an occlusive thrombus (n=8) while only 29% of the control mice (n=7) formed occlusive thrombi. Interestingly, perfusion of cancer-derived microparticles in mice also induced thrombus formation in this DVT model, reproducing the tumor-bearing mice phenotype. This new approach showed that microparticles shed by cancer cells have a key role in the pathogenesis of cancer-associated DVT, and they may become a reasonable pharmaceutical target to prevent thrombosis associated with cancer development. Disclosures: No relevant conflicts of interest to declare.

Pathophysiology of Trousseau’s syndrome

2015 ◽  
Vol 35 (01) ◽  
pp. 52-59 ◽  
Author(s):  
C. Dicke ◽  
F. Langer
Keyword(s):  
Cancer Patients ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Thrombus Formation ◽  
Primary Tumour ◽  
Basic Research ◽  
Severe Bleeding ◽  
Contact Activation ◽  
Trousseau’S Syndrome

SummaryClinically relevant clotting abnormalities in cancer patients are referred to as Trousseau’s syndrome. While thrombotic complications such as venous thromboembolism are most frequent in every day’s practice, cancer patients may also experience severe bleeding symptoms due to complex systemic coagulopathies, including disseminated intravascular coagulation, haemolytic thrombotic microangiopathy, and hyperfibrinolysis. The pathophysiology of Trousseau’s syndrome involves all aspects of Virchow’s triad, but previous basic research has mainly focused on the cellular and molecular mechanisms underlying blood hypercoagulability in solid cancers and haematological malignancies. In this regard, over-expression of tissue factor (TF), the principal initiator of the extrinsic coagulation pathway, by primary tumour cells and increased shedding of TF-bearing plasma microparticles are critical to both thrombus formation and cancer progression. However, novel findings on intrinsic contact activation in vivo, such as the release of polyphosphates or DNA by activated platelets and neutrophils, respectively, have pointed to additional pathways in the complex pathophysiology of Trousseau’s syndrome.

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