Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite the development of highly effective treatment strategies for acute promyelocytic leukaemia around 10% of patients die in the presentation period as a consequence of the associated bleeding diathesis. The cause of the coagulopathy is complex resulting from a combination of tissue factor (TF) and cancer procoagulant (CP) induced disseminated intravascular coagulation, exaggerated fibrinolysis due predominantly to enhanced expression of annexin II on APL blast cell membranes and blast cell production of cytokines. All-trans retinoic acid (ATRA) has revolutionised the treatment of APL. When combined with chemotherapy long term survival rates of up to 80% can be achieved. Commencement of ATRA induces APL blast cell differentiation and is associated with a rapid resolution of the bleeding tendency through a combination of effects which include up regulation of thrombomodulin and down regulation of TF and CP production and cell surface expression of annexin II.
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PMID:Haemostatic problems in acute promyelocytic leukaemia. 1675 74

An essential coagulation factor, tissue factor (TF), is rapidly expressed by human monocytes when exposed to a variety of agonists, such as lipopolysaccharide or tumor necrosis factor (TNF). We previously found that 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and its potent synthetic analogs downregulate TF and upregulate thrombomodulin expression on monocytic cells, counteracting the effects of TNF at the level of transcription. The human TF gene has characteristic binding sequences for activator protein-1 (AP-1) (c-Jun/c-Fos), nuclear factor-kappaB (NF-kappaB), Sp-1, and early growth response factor-1 (Egr-1). In this study, we investigated the regulatory mechanisms by which 1,25(OH)(2)D(3) inhibits TNF-induced TF expression in human monocytic cells. 1,25(OH)(2)D(3) reduced basal and TNF-induced TF activities. Gel-shift assay and luciferase assay with the respective reporter vectors showed that 1,25(OH)(2)D(3) reduced basal and TNF-induced activities of the nuclear proteins AP-1 and NF-kappaB, but not Egr-1. 1,25(OH)(2)D(3) inhibited TNF-induced phosphorylation of c-Jun without affecting phosphorylation of the other pathways. On the other hand, 1,25(OH)(2)D(3) directly inhibited nuclear binding and activities of NF-kappaB in the nucleus without affecting phosphorylation of the NF-kappaB activation pathway. These results indicate that 1,25(OH)(2)D(3) suppresses basal and TNF-induced TF expression in monocytic cells by inhibition of AP-1 and NF-kappaB activation pathways, but not of Egr-1. Our results may help to elucidate the regulatory mechanisms of 1,25(OH)(2)D(3) in TF induction, and may have physiological significance in the clinical challenge to use potential 1,25(OH)(2)D(3) analogs in antithrombotic therapy as well as immunomodulation and antineoplastic therapy of leukemia.
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PMID:1,25(OH)(2)D(3) blocks TNF-induced monocytic tissue factor expression by inhibition of transcription factors AP-1 and NF-kappaB. 1740 35

Different signaling routes seem to be simultaneously triggered in leukemia, with distinct and overlapping activities. To analyze if altered signals are coordinated and to evaluate their effect on this disease, we have investigated in acute myeloid leukemia samples (AML) the expression and activation status of procoagulant/proangiogenic tissue factor receptor (TF), angiogenic protein VEGF, its cell surface receptor, KDR, and two intracellular proteins involved in their regulation: extracellular regulated kinase (ERK1/2) and nuclear factor kappa-B (NFkappaB). Significantly higher mRNA and protein levels of VEGF, KDR, and TF were found in the AML samples versus controls. Enhanced ERK phosphorylation and NFkappaB activation in most AML samples were also found. In vitro MEK/ERK and NFkappaB-binding activity blockade suppressed the constitutive expression of TF, VEGF, and KDR. Anti-TF antibody treatment significantly suppressed VEGF and KDR expression as well as ERK activation, suggesting that TF expressed by AML cells may be both a regulatory target and a mediator of tumor-associated angiogenesis. Patients showing parallel activation of the studied proteins trended to exhibit higher incidence of fatal outcome. Our results show a coordinated deregulation of cellular receptors, proangiogenic factors, and intracellular pathways in leukemia cells, which may help to design mechanism-based combinations of single transduction-related therapies.
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PMID:Coordinated deregulation of cellular receptors, proangiogenic factors and intracellular pathways in acute myeloid leukaemia. 1757 83

Malignant effusions are a frequent problem for cancer patients. Due to the high resistance of tumor cells within these effusions, no effective treatment has been defined yet. Most patients exhibit additional phenomena related to hyper-coagulability such as elevated levels for d-dimers and prothrombin fragments f1.2; half of them suffer from manifest thrombosis or complications. We followed the hypothesis that the activated coagulation system contributes to the resistance of tumor cells and analyzed the effusions from cancer patients. The majority of isolated tumor cells aberrantly expressed PAR-1 thrombin receptors. In vitro pre-incubation of PAR-1 expressing human leukemia cells with thrombin resulted in a dose-dependent resistance to idarubicin. Within the effusions, we did not only find high concentrations of VEGF and tissue factor, but also all coagulation factors of the tissue factor pathway. Very high levels of prothrombin fragments f1.2 indicate constant thrombin generation. Upon the basis of these findings, we developed a multistep model elucidating the pathophysiological generation of malignant effusions, which might serve as a basis for further examinations.
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PMID:[Coagulation and formation of malignant effusions]. 1793 66

Heparanase is an endoglycosidase which cleaves heparan sulfate (HS) and hence participates in degradation and remodeling of the extracellular matrix (ECM). The enzyme also releases angiogenic factors from the ECM and thereby induces an angiogenic response in vivo. Heparanase is preferentially expressed in human tumors and its over-expression in tumor cells confers an accelerated growth and invasive phenotype in experimental animals. In contrast, heparanase gene silencing is associated with a marked inhibition of tumor progression. Heparanase upregulation correlates with increased tumor vascularity and poor postoperative survival of cancer patients. Studies on relationships between structure and the heparanase-inhibiting activity of nonanticogulant heparins systematically differing in their O-sulfation patterns, degrees of N-acetylation, and glycol-splitting of nonsulfated uronic acid residues, have permitted to select effective inhibitors of the enzymatic activity of heparanase. N-acetylated, glycol-split heparins emerged as highly effective and specific inhibitors of heparanase and tumor growth and metastasis. Several observations support the involvement of heparanase in haemostasis. A marked induction of tissue factor (TF) was noted in response to heparanase over-expression in tumor-derived cell lines and heparanase over-expressing transgenic mice. A direct correlation was also found between heparanase and TF expression levels in leukemia patients. TF induction was even more pronounced upon exogenous addition of heparanase to primary endothelial cells that do not normally express TF, and this induction was associated with enhanced coagulation. These and other results indicate that pro-heparanase is rapidly tethered on cell surfaces, partially depending on cell surface heparan sulfate, generating a local procoagulant effect. In addition, pro-heparanase can reverse the anti-coagulant effect of unfractionated heparin and the Factor Xa inhibitory activity of low molecular weight heparin (LMWH). These effects were also demonstrated in plasma derived from patients treated with LMWH. The pro-coagulant effects of pro-heparanase were also exerted by a peptide corresponding to its major functional heparin-binding domain. Heparanase pro-coagulant activities suggest its possible role as a natural regulator of heparinoid anti-coagulant activities, and point to a possible use of this molecule or its heparin binding domain as antidote for heparinoid therapies.
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PMID:Heparanase, heparin and the coagulation system in cancer progression. 1802 4

The association between thrombosis and cancer has been extensively studied since first pointed out by Trousseau in 1895. It is, however, not commonly appreciated that the incidence of thrombosis in malignant hematologic disorders is as high or even higher than in solid tumors. Thrombotic complications in acute leukemia are often overlooked because bleeding complications generally dominate the clinical picture. Yet, the patient is at risk for both. While there are many thrombogenic factors shared by both solid tumors and leukemia, many additional prothrombotic features are present in leukemia. The prothrombotic factors include hyperleukocytosis, increased expression of tissue factor and its activation in leukemic cells, and the prothrombotic adverse effects of therapeutic agents and vascular access catheters. In addition, comorbid conditions including hereditary thrombophilia, infection, endothelial cell activation by cytokines, antiphospholipid syndrome and acquired activated protein C resistance are major contributory factors. Factors that increase the bleeding risk include thrombocytopenia, disseminated intravascular coagulation, and excessive fibrinolysis, which is enhanced by increased expression of Annexin II by leukemic cells. Therapeutic approaches to both bleeding and thrombotic conditions require special considerations of these factors.
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PMID:Double hazard of thrombophilia and bleeding in leukemia. 1802 23

Patients with haematological malignancies carry increased risk of venous thrombosis (VT). However, the mechanisms that link these malignancies to activated coagulation have not been fully identified. Since anti-haemostatic agents are studied in clinical trials for their potential to prolong survival in cancer patients, a detailed characterisation of haemostatic markers in cancer subtypes is needed. Hence, in this study, we measured the plasma concentrations and mRNA expression in blood mononuclear cells of haemostatic parameters in 93 patients with haematological neoplasias (acute myeloid leukaemia, chronic lymphatic leukaemia, multiple myeloma, and non-Hodgkin's lymphoma) before start and after completion of cancer therapy. At diagnosis we found activation of coagulation and fibrinolysis, especially in patients with acute myeloid leukaemia. This hypercoagulation was not associated with increased levels of tissue factor (TF) or factor VII (fVII) antigen or mRNA, or levels of activated fVII. In conclusion we found a hypercoagulable state in patients with haematological malignancy that did not seem to be initiated by TF.
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PMID:Hypercoagulability in patients with haematological neoplasia: no apparent initiation by tissue factor. 1852 6

Heparanase is an endo-beta- D-glucuronidase that is capable of cleaving heparan sulfate side chains of heparan sulfate proteoglycans on cell surfaces and the extracellular matrix, activity that is strongly implicated in tumor metastasis and angiogenesis. Evidence was provided that heparanase overexpression in human leukemia, glioma, and breast carcinoma cells results in a marked increase in tissue factor (TF) levels. Likewise, TF was induced by exogenous addition of recombinant heparanase to tumor cells and primary endothelial cells, induction that was mediated by p38 phosphorylation and correlated with enhanced procoagulant activity. TF induction was further confirmed in heparanase-overexpressing transgenic mice and correlated with heparanase expression levels in leukemia patients. Heparanase was also found to be involved in the regulation of tissue factor pathway inhibitor (TFPI). It was shown that heparanase overexpression or exogenous addition induces two- to threefold increase of TFPI expression. Similarly, heparanase stimulated accumulation of TFPI in the cell culture medium. Extracellular accumulation exceeded, however, the observed increase in TFPI at the protein level and appeared to be independent of heparan sulfate and heparanase enzymatic activity. Instead, a physical interaction between heparanase and TFPI was demonstrated, suggesting a mechanism by which secreted heparanase interacts with TFPI on the cell surface, leading to dissociation of TFPI from the cell membrane and increased coagulation activity, thus further supporting the local prothrombotic function of heparanase. As heparins are strong inhibitors of heparanase, in view of the effect of heparanase on TF/TFPI pathway, the role of heparins' anticoagulant activity may potentially be expanded.
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PMID:Heparanase, tissue factor, and cancer. 1864 24

Heparanase is an endo-beta-D-glucuronidase capable of cleaving heparan sulphate (HS) side chains of heparan sulphate proteoglycans on cell surfaces and the extracellular matrix; activity that is strongly implicated in tumour metastasis and angiogenesis. It has been shown that heparanase overexpression in human leukaemia, glioma and breast carcinoma cells results in a marked increase in tissue factor (TF) levels. In addition, TF was induced by exogenous addition of recombinant heparanase to tumour cells and primary endothelial cells; induction that was mediated by p38 phosphorylation and correlated with enhanced procoagulant activity. TF induction was further confirmed in transgenic mice overexpressing heparanase, and correlated with heparanase expression levels in leukaemia patients. Heparanase was also found to be involved in the regulation of tissue factor pathway inhibitor (TFPI). It has been shown that heparanase overexpression or exogenous addition induces a two- to three-fold increase in TFPI expression. Similarly, heparanase stimulated accumulation of TFPI in the cell culture medium. However, extracellular accumulation exceeded the observed increase in TFPI at the protein level, and appeared to be independent of HS and heparanase enzymatic activity. Instead, a physical interaction between heparanase and TFPI was demonstrated, suggesting a mechanism by which secreted heparanase interacts with TFPI on the cell surface, leading to dissociation of TFPI from the cell membrane and increased coagulation activity, thus further supporting the local prothrombotic function of heparanase. As heparins are strong inhibitors of heparanase, in view of the effect of heparanase on the TF/TFPI pathway, the role of anticoagulant activity of heparin may potentially be expanded. Taking into account the prometastatic and pro-angiogenic functions of heparanase, its overexpression in human malignancies and abundance in platelets, its involvement in the coagulation machinery is an intriguing novel arena for further research.
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PMID:Heparanase coagulation and cancer progression. 1928 75

Since the initial description of the disease, the life-threatening coagulopathy associated with acute promyelocytic leukaemia (APL) has been the defining clinical characteristic. Historically, this uncommon subtype of acute myeloid leukaemia has been associated with a high mortality rate during induction therapy, most frequently attributable to haemorrhage. Since the introduction of all-trans retinoic acid (ATRA) into the therapy of all patients with APL, disease-free survival and overall survival have improved dramatically, such that the disease is now highly curable. However, induction mortality remains a major problem and haemorrhage still accounts for the majority of such early deaths. Pathogenesis of the coagulopathy is complex and includes disseminated intravascular coagulation (DIC), fibrinolysis and proteolysis. As a result, while the predominant clinical manifestation of the coagulopathy is haemorrhage, thromboembolic events may occur both at presentation and during therapy. A major recent finding is the high expression of annexin II in the leukaemic cells from patients with APL. Annexin II is a protein with high affinity for plasminogen and tissue-type plasminogen activator (tPA), and also acts as a cofactor for plasminogen activation by tPA. As a result, both plasminogen and tPA are increased on the cell surface of the leukaemic cell, increasing plasmin activity. Annexin II is expressed in high amounts in cerebral microvascular endothelial cells, perhaps accounting for the relatively high incidence of intracranial haemorrhage in APL compared with other sites. Microparticles are cell-derived membrane fragments originating from normal cells or released from malignant cells involved in activating coagulation. Recent studies have found that microparticles containing tissue factor, tPA, plasminogen activator inhibitor-1 and annexin II have been found in the plasma of APL patients, suggesting a role in pathogenesis of the coagulopathy. Treatment of the coagulopathy remains primarily supportive. Aggressive transfusions of platelets and cryoprecipitate appear to be important. There is no clear role for the routine use of heparin or antifibrinolytic therapy. The most important factor may be the early introduction of ATRA at the first suspicion of a diagnosis of APL, before it is confirmed genetically.
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PMID:The coagulopathy of acute promyelocytic leukaemia revisited. 1928 82


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