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1.
Liver Int ; 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32052552

RESUMO

BACKGROUND AND AIMS: Non-O blood type (BT) is a risk factor for thromboses, which has been attributed to its effects on von Willebrand factor (VWF)/factor VIII (FVIII) levels. Although high VWF/FVIII may be risk factors for portal vein thrombosis (PVT) in patients with advanced chronic liver disease (ACLD), the impact of BT on PVT is unknown. We aimed to assess (I) whether non-O-BT is a risk factor for PVT and (II) whether non-O-BT impacts VWF/factor VIII in patients with ACLD. METHODS: Retrospective analysis comprising two cohorts: (I) "US" including all adult liver transplantations in the US in the MELD era and (II) "Vienna" comprising patients with a hepatic venous pressure gradient (HVPG) ≥6 mmHg. RESULTS: (I) The "US cohort" included 84 947 patients (non-O: 55.43%). The prevalence of PVT at the time of listing (4.37% vs 4.56%; P = .1762) and at liver transplantation (9.56% vs 9.33%; P = .2546) was similar in patients with O- and non-O-BT. (II) 411 patients were included in the "Vienna cohort" (non-O: 64%). Mean HVPG was 18(9) mmHg and 90% had an HVPG ≥10 mmHg. Patients with non-O-BT had slightly increased VWF levels (318(164)% vs 309(176)%; P = .048; increase of 23.8%-23.9% in adjusted analyses), but this difference was driven by patients with less advanced disease. However, non-O-BT explained only 1% of the variation in VWF and had no effect on FVIII. CONCLUSIONS: Although non-O-BT impacts VWF in patients with early stage ACLD, its contribution to VWF variation is considerably smaller than in the general population. Moreover, non-O-BT had no impact on FVIII. These findings may explain the absence of an association between non-O-BT and PVT in patients with advanced cirrhosis.

2.
Transl Res ; 215: 41-56, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525325

RESUMO

A prothrombotic state is frequently observed in patients with cancer and contributes to the risks of venous thromboembolism (VTE), arterial thromboembolism (ATE), tumor progression, and death. Altered ex vivo properties of plasma clot formation and lysis have been observed in patients with cancer. The aim of this prospective study was to comprehensively characterize the relationship between plasma clot properties, inflammation, hypercoagulability, thrombotic complications, and mortality in patients with cancer using a tissue-factor-based turbidimetric assay of clot formation and lysis. Turbidity parameters were determined in 815 patients with newly-diagnosed or recurrent cancer and 97 healthy controls. Patients were followed-up for 2 years and rates of VTE (n = 72 events), ATE (n = 21 events), and death (n = 304 events) were assessed. Compared to controls, cancer patients' turbidity profiles showed an increased clot formation potential and higher resistance toward fibrinolysis. Elevated biomarkers of inflammation and hemostasis, such as C-reactive protein, FVIII, and thrombin generation explained substantial amounts of variation in turbidity parameters. In a prospective analysis, altered parameters of clot formation identified cancer patients at high risk of ATE (Hazard ratio [HR] per doubling of peak absorbance: 4.43, 95% CI: 1.50-13.07, P = 0.007) and death (HR per doubling of peak absorbance: 2.73, 2.00-3.72, P< 0.0001); these findings were independent of other prognostic covariates. Contrarily, turbidity parameters were not associated with risk of VTE (HR per doubling of peak absorbance: 1.15, 0.66-2.01, P = 0.62). We conclude that patients with cancer have altered ex vivo properties of clot formation which predict risks of ATE and mortality but not VTE.

3.
Blood ; 134(26): 2346-2353, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31697819

RESUMO

Genetic predispositions to venous thromboembolism (VTE) are relatively frequent in the general population and comprise a heterogeneous group of disorders. Whereas the most frequent congenital risk factors for thrombosis only moderately increase the risk, a deficiency in antithrombin (AT), one of the most important natural inhibitors of blood coagulation, carries a higher risk. Congenital AT deficiency is an infrequently encountered genetic risk factor for VTE, and different subtypes vary with regard to their thrombotic risk. Patients with congenital AT deficiency, especially those with quantitative deficiency (type 1), may develop thrombosis early in life and often have a conspicuous family history of first- and second-degree relatives with VTE. Women are particularly affected because of the risk potentiation by combined estrogen/progestogen oral contraceptive use or pregnancy. The lack of controlled trials or even observational studies of large cohorts does not allow therapeutic decisions to be based on scientific evidence. In this review, we will discuss cases with thrombotic manifestations and the tailored management of patients with this congenital thrombosis risk factor.

5.
Ann Hematol ; 98(2): 313-319, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30467688

RESUMO

Lupus anticoagulants (LA) are a heterogeneous group of antiphospholipid antibodies (aPLAs) that promote thrombosis. Tissue factor (TF)-bearing extracellular vesicles (EVs) might contribute to the prothrombotic state of patients with persistent LA and a history of thrombosis. To investigate if EV-associated TF activity is elevated in a well-defined group of LA-positive patients with a history of thrombosis in comparison to that of healthy controls. Adult patients (n = 94, median age 40.1 years, interquartile range (IQR) 29.9-53.4; 87% females) positive for LA and a history of thrombosis (78% venous thrombosis, 17% arterial thrombosis, 5% venous thrombosis and arterial thrombosis) and healthy age- and sex-matched controls (n = 30, median age 42.9 years, IQR 38.6-45.8, 77% females) were included in this study. EV-TF activity was determined with a factor Xa generation assay and anti-ß2-glycoprotein (anti-ß2GPI) and anticardiolipin (aCL) antibodies by enzyme-linked immunoassays. EV-TF activity did not differ between 94 LA-positive patients with a history of thrombosis (median 0.05 pg/mL, IQR 0.00-0.14) and 30 healthy controls (median 0.06, IQR 0.00-0.11, p = 0.7745). No correlation was found between EV-TF activity and lupus-sensitive activated partial thromboplastin time (aPTT-LA) (rho = 0.034), Rosner index (rho = - 0.056), anti-ß2GPI IgG (rho = 0.05), anti-ß2GPI IgM (rho = - 0.08), aCL IgG (rho = 0.12), and aCL IgM (rho = - 0.11) in LA-positive patients. We found low EV-TF activity levels in LA-positive patients and a history of thrombosis and no correlation with analyzed aPLAs. Our data indicate that circulating TF-bearing EVs do not contribute to the prothrombotic state of patients with LA.


Assuntos
Vesículas Extracelulares/metabolismo , Inibidor de Coagulação do Lúpus/sangue , Trombose Venosa/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
Wien Klin Wochenschr ; 130(13-14): 446-455, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29916054

RESUMO

BACKGROUND: Non-malignant portal vein thrombosis (PVT) is common in patients with advanced liver disease. Anticoagulation (AC) increases the chances of recanalization and may improve liver function in patients with cirrhosis. AIM: We retrospectively assessed the course of non-malignant PVT in patients receiving AC. METHODS: Parameters related to hepatic injury (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]), severity of disease (ascites) and synthesis function (albumin) as well as AC, rates of PVT regression/progression and AC-associated complications were documented. RESULTS: Among 122 patients with PVT, 51 patients with non-malignant PVT (27 incomplete, 24 complete) were included, 12 patients (25%) received long-term AC therapy (≥9 months) as compared to 36 patients without long-term AC. We observed a trend towards higher regression rates with long-term AC of 58% (vs. 28% without AC; p = 0.08) and lower progression rates of 25% (vs. 42% without AC; p = 0.15). In the subgroup of patients with decompensation prior to PVT diagnosis (n = 39), long-term AC (n = 10, 25.6%) resulted in a significantly higher rate of PVT regression/resolution (70% vs. 24%, p = 0.031). Interestingly, AST/ALT tended to decrease (-19%/-16%) and the proportion of patients with ascites became lower (-33%) with long-term AC (without AC: ±0%). Furthermore, there was a significant improvement in albumin levels (+9%/+3.6 g/dl) when compared to patients without long-term AC (-2%/-0.8 g/dl; p = 0.04). Additionally, 10 patients were treated with direct oral anticoagulants (DOACs) for splanchnic vein thrombosis. Importantly, there were no AC-associated bleeding events in patients with conventional AC and one bleeding event in patients with DOAC treatment (10%). CONCLUSION: Our findings support anticoagulation in patients with non-malignant PVT, since AC seems safe and associated with superior PVT regression rates and might also decrease hepatic injury and improve liver synthesis.


Assuntos
Anticoagulantes/uso terapêutico , Cirrose Hepática , Veia Porta , Trombose Venosa/tratamento farmacológico , Varizes Esofágicas e Gástricas , Feminino , Hemorragia Gastrointestinal , Humanos , Rim/efeitos dos fármacos , Rim/fisiologia , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
8.
J Exp Med ; 214(7): 2121-2138, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28566277

RESUMO

Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease.


Assuntos
Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Coagulação Sanguínea , Eosinófilos/metabolismo , Hemostasia , Lipídeos/análise , Trombose/metabolismo , Adulto , Idoso , Animais , Araquidonato 12-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/genética , Aterosclerose/diagnóstico , Aterosclerose/metabolismo , Western Blotting , Células Cultivadas , Proteína Catiônica de Eosinófilo/metabolismo , Humanos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Modelos Logísticos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Oxirredução , Fosfatidiletanolaminas/metabolismo , Estudos Prospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Trombina/metabolismo
9.
Transl Res ; 184: 12-20.e1, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28236427

RESUMO

Embolization of amniotic fluid (AF) into the blood circulation leads to disseminated intravascular coagulation (DIC). Procoagulant phosphatidylserine (PS)- and tissue factor (TF)-exposing extracellular vesicles (EVs) might play an important role in AF embolism-induced DIC. It was the aim of the present study to perform analyses of the procoagulant properties of AF with a panel of functional coagulation assays and flow cytometry. We applied a prothrombinase assay (that quantifies PS exposure on EVs), an EV-associated TF activity assay, a fibrin generation assay, a thrombin generation assay, a whole blood clotting model, and flow cytometry in AF and control plasma. We found that PS exposure on EVs was 21-fold increased in AF compared with plasma. Also, EV-associated TF activity was highly increased in AF compared with plasma. AF-derived EVs activated the blood coagulation cascade via PS and TF in the fibrin and thrombin generation assays. In a whole blood clotting model, AF-derived EVs significantly shortened the clotting time from 734 ± 139 seconds in the presence to 232 ± 139 seconds in the absence of an anti-TF antibody. The contact activation pathway via factor XII (FXII) was not affected. Applying flow cytometry, a subpopulation of PS+ and TF+ EVs was identified in AF but not in control plasma. In conclusion, we investigated the effect of AF on blood coagulation and found that PS+ and TF+ EVs determine their procoagulant potential. Taken together, our data further delineate the pathomechanisms underlying AF-induced coagulopathy.


Assuntos
Líquido Amniótico/citologia , Líquido Amniótico/metabolismo , Coagulação Intravascular Disseminada/sangue , Vesículas Extracelulares , Fosfatidilserinas/metabolismo , Coagulação Intravascular Disseminada/patologia , Embolia Amniótica/patologia , Feminino , Fibrina/metabolismo , Citometria de Fluxo , Humanos , Gravidez , Trombina/metabolismo , Tromboplastina/metabolismo , Trombose
10.
Blood ; 129(13): 1831-1839, 2017 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-28073783

RESUMO

Venous thromboembolism (VTE) is common in patients with brain tumors, and underlying mechanisms are unclear. We hypothesized that podoplanin, a sialomucin-like glycoprotein, increases the risk of VTE in primary brain tumors via its ability to induce platelet aggregation. Immunohistochemical staining against podoplanin and intratumoral platelet aggregates was performed in brain tumor specimens of 213 patients (mostly high-grade gliomas [89%]) included in the Vienna Cancer and Thrombosis Study, a prospective observational cohort study of patients with newly diagnosed cancer or progressive disease aimed at identifying patients at risk of VTE. Platelet aggregation in response to primary human glioblastoma cells was investigated in vitro. During 2-year follow-up, 29 (13.6%) patients developed VTE. One-hundred fifty-one tumor specimens stained positive for podoplanin (33 high expression, 47 medium expression, 71 low expression). Patients with podoplanin-positive tumors had lower peripheral blood platelet counts (P < .001) and higher D-dimer levels (P < .001). Podoplanin staining intensity was associated with increasing levels of intravascular platelet aggregates in tumor specimens (P < .001). High podoplanin expression was associated with an increased risk of VTE (hazard ratio for high vs no podoplanin expression: 5.71; 95% confidence interval, 1.52-21.26; P =010), independent of age, sex, and tumor type. Podoplanin-positive primary glioblastoma cells induced aggregation of human platelets in vitro, which could be abrogated by an antipodoplanin antibody. In conclusion, high podoplanin expression in primary brain tumors induces platelet aggregation, correlates with hypercoagulability, and is associated with increased risk of VTE. Our data indicate novel insights into the pathogenesis of VTE in primary brain tumors.


Assuntos
Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/metabolismo , Glicoproteínas de Membrana/biossíntese , Agregação Plaquetária , Tromboembolia Venosa/etiologia , Neoplasias Encefálicas/sangue , Estudos de Coortes , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Estudos Prospectivos , Trombofilia/etiologia
11.
Cytometry A ; 89(7): 663-72, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27442840

RESUMO

Microvesicles (MVs) are small membrane bound vesicles released from various cell types after activation or apoptosis. In the last decades, MVs received an increased interest as biomarkers in inflammation, coagulation and cancer. However, standardized pre-analytical steps are crucial for the minimization of artifacts in the MV analysis. Thus, this study evaluated the MV release in whole blood samples under the influence of different anticoagulants, storage time and various temperature conditions. Samples were collected from healthy probands and processed immediately, after 4, 8, 24 and 48 hours at room temperature (RT) or 4°C. To identify MV subpopulations, platelet free plasma (PFP) was stained with Annexin V, calcein AM, CD15, CD41 and CD235a. Analysis was performend on a CytoFLEX flow cytometer. Procoagulatory function of MVs was measured using a phospholipid dependent activity and a tissue factor MVactivity assay. Without prior storage, sodium citrate showed the lowest MV count compared to heparin and EDTA. Interestingly, EDTA showed a significant release of myeloid-derived MVs (MMVs) compared to sodium citrate. Sodium citrate showed a stable MV count at RT in the first 8 hours after blood collection. Total MV counts increased after 24 hours in sodium citrated or heparinzed blood which was related to all subpopulations. Interestingly, EDTA showed stable platelet-derived MV (PMV) and erythrocyte-derived MV (EryMV) count at RT over a 48 h period. In addition, the procoagulatory potential increased significantly after 8-hour storage. Based on both, this work and literature data, the used anticoagulant, storage time and storage temperature differently influence the analysis of MVs within 8 hours. To date, sodium citrated tubes are recommended for MV enumeration and functional analysis. EDTA tubes might be an option for the clinical routine due to stable PMV and EryMV counts. These new approaches need to be validated in a clinical laboratory setting before being applied to patient studies. © 2016 International Society for Advancement of Cytometry.


Assuntos
Preservação de Sangue/métodos , Preservação de Sangue/normas , Micropartículas Derivadas de Células , Humanos
12.
Clin Cancer Res ; 22(1): 200-6, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26302981

RESUMO

PURPOSE: Cancer patients are at an increased risk of venous thromboembolism (VTE). VEGF promotes the growth of highly thrombogenic tumor vessels. Here, we explored the utility of soluble plasma VEGF-A (sVEGF) as a biomarker for the prediction of VTE in patients with cancer. EXPERIMENTAL DESIGN: Eight hundred four patients with newly diagnosed cancer or progression after remission were prospectively followed for 2 years until the occurrence of VTE or death [tumor sites: brain (n = 87), breast (n = 137), lung (n = 120), gastrointestinal (n = 143), pancreas (n = 53), prostate (n = 95), kidney (n = 22), myeloma and lymphoma (n = 99), and others (n = 48)]. Primary endpoint was symptomatic or fatal VTE. sVEGF was measured by immunoassay in baseline plasma. RESULTS: Fifty-five patients developed VTE (6.8%) and 364 patients (45.3%) died. Five-hundred and forty-two (68.3%) participants had sVEGF levels above the detection limit of 0.5 pg/mL. The median sVEGF level (25th-75th percentile) was 8.1 pg/mL (0-17.7). The cumulative 2-year incidence of VTE was 10.2% [95% confidence interval (CI), 6.4-14.9] in patients with sVEGF greater than the 75th percentile of the sVEGF distribution (Q3, cutoff: 17.7 pg/mL), and 5.9% (95% CI, 4.2-7.9) in patients with lower levels (P = 0.03). The corresponding 2-year risk of death was 52.8% (95% CI, 46.0-60.0) and 43.9% (95% CI, 40.0-48.0), respectively (P = 0.02). In univariable time-to-VTE regression, elevated sVEGF was associated with VTE [subhazard ratio (SHR) per 10 pg/mL increase, 1.04; 95% CI,1.00-1.09; P = 0.04)]. The association between sVEGF and risk of VTE prevailed after multivariable adjustment for high-risk tumor sites, age, gender, factor VIII, thrombin generation potential, and soluble P-Selectin (adjusted SHR, 1.04; 95% CI, 1.00-1.09, P = 0.05). CONCLUSIONS: Elevated sVEGF is associated with an increased risk of VTE in patients with cancer.


Assuntos
Neoplasias/sangue , Neoplasias/complicações , Fator A de Crescimento do Endotélio Vascular/sangue , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Idoso , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Prognóstico , Risco , Tromboembolia Venosa/diagnóstico
13.
Front Cardiovasc Med ; 2: 30, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26664901

RESUMO

Venous thromboembolism (VTE), a disease entity comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a frequent and potentially life-threatening event. To date different agents are available for the effective treatment of acute VTE and the prevention of recurrence. For several years, the standard of care was the subcutaneous application of a low molecular weight heparin (LMWH) or fondaparinux, followed by a vitamin K antagonist (VKA). The so-called direct oral anticoagulants (DOAC) were introduced rather recently in clinical practice for the treatment of VTE. DOAC seem to have a favorable risk-benefit profile compared to VKA. Moreover, DOAC significantly simplify VTE treatment because they are administered in fixed doses and no routine monitoring is needed. Patients with objectively diagnosed DVT or PE should receive therapeutic anticoagulation for a minimum of 3 months. Whether a patient ought to receive extended treatment needs to be evaluated on an individual basis, depending mainly on risk factors determined by characteristics of the thrombotic event and patient-related factors. In specific patient groups (e.g., pregnant women, cancer patients, and elderly patients), treatment of VTE is more challenging than that in the general population and additional issues need to be considered in those patients. The aim of this review is to give an overview of the currently available treatment modalities of acute VTE and secondary prophylaxis. In particular, specific aspects regarding the initiation of VTE treatment, duration of anticoagulation, and specific patient groups will be discussed.

14.
J Extracell Vesicles ; 4: 26901, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25773446

RESUMO

Although the association between cancer and venous thromboembolism (VTE) has long been known, the mechanisms are poorly understood. Circulating tissue factor-bearing extracellular vesicles have been proposed as a possible explanation for the increased risk of VTE observed in some types of cancer. The International Society for Extracellular Vesicles (ISEV) and International Society on Thrombosis and Haemostasis (ISTH) held a joint Educational Day in April 2014 to discuss the latest developments in this field. This review discusses the themes of that event and the ISEV 2014 meeting that followed.

15.
Thromb Haemost ; 112(5): 1071-5, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25183383

Assuntos
Antifibrinolíticos/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Intravascular Disseminada/tratamento farmacológico , Fibrinogênio/uso terapêutico , Hemorragia/tratamento farmacológico , Ácido Tranexâmico/uso terapêutico , Adenocarcinoma/sangue , Adenocarcinoma/complicações , Adenocarcinoma/diagnóstico , Adenocarcinoma/secundário , Idoso , Anemia/tratamento farmacológico , Anemia/etiologia , Anemia/terapia , Antifibrinolíticos/efeitos adversos , Antifibrinolíticos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/complicações , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/cirurgia , Neoplasias do Ceco/sangue , Neoplasias do Ceco/complicações , Neoplasias do Ceco/diagnóstico , Coagulação Intravascular Disseminada/etiologia , Evolução Fatal , Feminino , Fibrinogênio/farmacologia , Fibrinólise , Fluoruracila/administração & dosagem , Cardiopatias , Hemorragia/etiologia , Humanos , Leucovorina/administração & dosagem , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/secundário , Metástase Linfática/diagnóstico , Insuficiência de Múltiplos Órgãos/etiologia , Neoplasias Primárias Múltiplas/sangue , Neoplasias Primárias Múltiplas/complicações , Neoplasias Primárias Múltiplas/diagnóstico , Compostos Organoplatínicos/administração & dosagem , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Trombose , Ácido Tranexâmico/efeitos adversos , Ácido Tranexâmico/farmacologia , Neoplasias Vulvares/sangue , Neoplasias Vulvares/complicações , Neoplasias Vulvares/cirurgia
16.
Thromb Res ; 134(5): 1093-6, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25262106

RESUMO

BACKGROUND: Tissue factor (TF) is the main in-vivo initiator of blood coagulation. Microparticles (MPs) are small procoagulant membrane vesicles. Elevated TF-bearing MPs have been found in different prothrombotic conditions and MP-associated TF activity may contribute to the pathogenesis of unprovoked deep vein thrombosis (DVT). OBJECTIVE: To determine MP-TF activity levels at diagnosis of DVT and at four additional time points during the course of one year in a well-defined group of patients with unprovoked DVT of the lower limb. PATIENTS/METHODS: In this study, 41 patients with acute unilateral symptomatic and unprovoked DVT of the lower limb were included and followed for 1 year. Venous blood samples for determination of MP-TF activity were drawn at diagnosis of acute DVT, and 1-, 3-, 6-, and 12 months later. In addition, 10 young and healthy control subjects were included. RESULTS: The median MP-TF activity was 0.06 pg/mL (25th-75th percentile: 0.0-0.53) in patients with acute DVT and 0.18 pg/mL (0.07-0.33) in healthy controls, and did not differ significantly (p=0.35). No significant changes in MP-TF activity were found in the follow-up measurements. MP-TF activity did also not differ significantly between patients with proximal- or distal DVT and between those with- or without residual DVT after 6 months. CONCLUSIONS: MP-TF activity is low at the acute event in patients with unprovoked DVT of the lower limb and remains unchanged during the course of the disease. Our data do not support the hypothesis that TF-bearing MPs play a determining role in the pathogenesis of unprovoked DVT.


Assuntos
Micropartículas Derivadas de Células/patologia , Tromboplastina/metabolismo , Trombose Venosa/sangue , Trombose Venosa/metabolismo , Doença Aguda , Adulto , Coagulação Sanguínea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Trombose Venosa/patologia
17.
Neuro Oncol ; 16(12): 1645-51, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24987133

RESUMO

BACKGROUND: High-grade gliomas (HGGs) are among the most prothrombotic of malignancies. METHODS: We performed a prospective study to investigate 11 potential biomarkers for prediction of venous thromboembolism (VTE) in newly diagnosed HGG patients who had undergone a neurosurgical intervention. In addition, we tested 2 VTE risk assessment models (RAMs). The strongest predictors of VTE, which were identified by statistical forward selection, were used for the first RAM. The parameters used for the second RAM were both predictive of VTE and available in routine clinical practice. RESULTS: One hundred forty-one HGG patients were included in this study, and 24 (17%) of them developed VTE during follow-up. An association with the risk of future VTE was found for the following parameters: leukocyte count, platelet count, sP-selectin, prothrombin-fragment 1 + 2, FVIII activity, and D-dimer. The first RAM included low platelet count (<25th percentile of the study population) and elevated sP-selectin (≥75th percentile). The cumulative VTE probability after 12 months was 9.7% for score 0 (n = 76), 18.9% for score 1 (n = 59), and 83.3% for score 2 (n = 6). The second RAM included low platelet count (<25th percentile), elevated leukocyte count, and elevated D-dimer (≥75th percentile). The probability of VTE was 3.3% for score 0 (n = 63), 23.0% for score 1 (n = 53), and 37.7% for score 2 (n = 22) or score 3 (n = 3). CONCLUSIONS: We identified biomarkers suitable for assessing the VTE risk in newly diagnosed HGG patients. The application of 2 RAMs allowed identification of patients at high risk of developing VTE. We could also define patients at low risk of VTE, who would most probably not benefit from extended primary thromboprophylaxis.


Assuntos
Neoplasias do Sistema Nervoso Central/complicações , Glioma/complicações , Selectina-P/análise , Contagem de Plaquetas , Tromboembolia Venosa/diagnóstico , Adulto , Idoso , Biomarcadores , Neoplasias do Sistema Nervoso Central/sangue , Feminino , Seguimentos , Glioma/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Tromboembolia Venosa/complicações
19.
Transl Res ; 163(2): 145-50, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23973167

RESUMO

Highly elevated microparticle (MP)-associated tissue factor (TF) activity was found in patients with pancreatic cancer, one of the most prothrombotic malignancies. It remains to be elucidated whether MP-TF activity reflects the prothrombotic state in these patients. MP-TF activity levels and the TF-dependent and -independent effect of MPs on fibrin clot formation were determined in patients with metastatic pancreatic cancer (n = 27), in healthy individuals (n = 10) and in plasma samples from lipopolysaccharide (LPS)-stimulated blood (LPS-plasma), which is rich in monocyte-derived TF-bearing MPs. The median MP-TF activity was 1.06 pg/mL (range, from 0.19 to 10.34 pg/mL) in patients with pancreatic cancer, 0.61 pg/mL (range, from 0.36 to 0.79 pg/mL) in LPS-plasma, and 0.18 pg/mL (range, from 0.04 to 0.39 pg/mL) in healthy individuals. MPs derived from LPS-plasma had the strongest impact on fibrin clot formation time (median, 157.6 seconds; range, from 149.5 to 170.4 seconds). Fibrin clot formation occurred significantly later in MPs derived from patients with pancreatic cancer (median, 273.4 seconds; range, from 146.6 to 354.4 seconds; P < 0.001) and in healthy individuals (median, 299.0 seconds; range, from 261.1 to 417.9 seconds; P < 0.001). Only in MPs derived from LPS-plasma the fibrin clot formation time dependent strongly on TF (median prolongation after TF blockade: 68% in LPS-plasma, 10% in patients with pancreatic cancer, and 4% in healthy individuals). In conclusion, highly elevated MP-TF activity was found in patients with metastatic pancreatic cancer, but TF-bearing MPs had a small effect on fibrin clot formation. TF-bearing MPs might not be the main mediators of the prothrombotic state associated with pancreatic cancer. However, the small but significant increase in coagulation potential by TF-bearing MPs might contribute to the multifactorial pathogenesis of venous thromboembolism in pancreatic cancer.


Assuntos
Adenocarcinoma/sangue , Fibrina/metabolismo , Metástase Neoplásica , Neoplasias Pancreáticas/sangue , Tromboplastina/metabolismo , Trombose/etiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Trombose/metabolismo
20.
Blood ; 122(12): 2011-8, 2013 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-23908470

RESUMO

Cancer patients are at increased risk of deep vein thrombosis and pulmonary embolism. The incidence among different groups of cancer patients varies considerably depending on clinical factors, the most important being tumor entity and stage. Biomarkers have been specifically investigated for their capacity of predicting venous thromboembolism (VTE) during the course of disease. Parameters of blood count analysis (elevated leukocyte and platelet count and decreased hemoglobin) have turned out to be useful in risk prediction. Associations between elevated levels and future VTE have been found for d-dimer, prothrombin fragment 1+2, and soluble P-selectin and also for clotting factor VIII and the thrombin generation potential. The results for tissue factor-bearing microparticles are heterogeneous: an association with occurrence of VTE in pancreatic cancer might be present, whereas in other cancer entities, such as glioblastoma, colorectal, or gastric carcinoma, this could not be confirmed. Risk assessment models were developed that include clinical and laboratory markers. In the high-risk categories, patient groups with up to a >20% VTE rate within 6 months can be identified. A further improvement in risk stratification would allow better identification of patients for primary VTE prevention using indirect or novel direct anticoagulants.


Assuntos
Neoplasias/sangue , Neoplasias/complicações , Tromboembolia Venosa/etiologia , Biomarcadores/sangue , Coagulação Sanguínea , Humanos , Prognóstico , Tromboembolia Venosa/diagnóstico
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