bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recombinant Tumor Necrosis Factor Receptor p75 Fusion Protein (TNFR:Fc) Alters Endotoxin-Induced Activation of the Kinin, Fibrinolytic, and Coagulation Systems in Normal Humans
Authors: Majluf-Cruz Abraham , Stadnicki Antoni , Tropea Margaret , Reda Debra , Agosti Jan , Colman Robert , Suffredini Anthony , DeLa Cadena Raul 
Published: March 2018

SummaryThe effects of inhibition of tumor necrosis factor (TNF) on cell and protease activation were evaluated in 18 normal volunteers given endotoxin (4 ng/kg, iv) after an infusion of low (10 mg/m2 iv, n = 6) or high dose (60 mg/m2 iv, n = 6) recombinant human dimeric TNF receptor protein (TNFR:Fc) or its vehicle (placebo n = 6). Activation of the coagulation system occurred by 2 h in the TNFR:Fc vehicle-placebo group manifested by decreased prekallikrein functional levels and increased levels of prothrombin F1+2 fragments (p <0.0001). High or low dose TNFR:Fc delayed the fall in prekallikrein functional levels by 1 h and 4 h, respectively (p <0.0002), but did not inhibit the increase in circulating levels of prothrombin F1+2 fragments. In contrast, endothelium activation, characterized by increased levels of tissue plasminogen activator, plasminogen activator inhibitor-1, and von Willebrand Factor antigen was blunted by both low and high dose TNFR:Fc (p <0.001). While the endotoxin-associated decrease in platelet number was not altered, platelet-derived β-thromboglobulin peak levels were blunted and delayed by TNFR:Fc (p <0.02). Increased levels of neutrophil elastase were attenuated by low and high dose TNFR:Fc (p <0.001). These results suggest that although TNF is functionally linked to the activation of endothelium, neutrophils, coagulation, and fibrinolysis, alternative pathways are present in vivo that result in activation of the kallikrein-kinin system after endotoxin-induced TNF release. These alternative pathways may limit some of the anti-inflammatory effects of TNFR:Fc.
Turnover of Thrombomodulin at the Cell Surface Occurs at a Similar Rate to Receptors that Are Not Actively Internalized
Authors: Chu Michael , Bird Catherina , Teasdale Melvena , Bird Phillip 
Published: March 2018

SummaryLoss of thrombomodulin (TM) from the endothelial cell surface is thought to contribute to thrombosis encountered in malignant and inflammatory disease. Internalization or endocytosis of TM from the cell surface has been proposed to be one mechanism by which TM levels are reduced. Previous work has led to a view that TM is rapidly internalized using a non-conventional pathway, under the direction of a signal motif in its extracellular domain. This is contrary to the clathrin-dependent route taken by most rapidly internalized receptors that possess signals in their cytoplasmic domains. However the internalization rate of TM has never been directly compared to known internalizing or non-internalizing molecules. Here we show that the rate and amount of uptake of TM (5-10% per hour) is indistinguishable from the non-internalizing influenza virus haemagglutinin (HA), and is considerably less than the actively internalizing low density lipoprotein receptor, which reaches a steady state of approximately 50% internalized in 15 min. The low level rate of TM and HA internalization observed is comparable to the rate of normal plasma membrane turnover. Furthermore, this uptake of TM does not require a signal in its extracellular domain.
Hemostatic Risk Factors and Arterial Thrombotic Disease
Authors: Siscovick David , Rosendaal Frits , Reiner Alexander 
Published: March 2018

SummaryThe pathogenesis of arterial thrombotic disease involves multiple genetic and environmental factors related to atherosclerosis and thrombosis. Acute thrombosis at the site of a ruptured, lipid-rich atherosclerotic plaque is the usual precipitating event in the transition from stable or subclinical atherosclerotic disease to acute myocardial infarction (MI), stroke, or peripheral arterial occlusion (1). Pathologic studies of coronary arteries in acute MI suggest that the acute thrombosis likely involves activation of both platelets and the coagulation system.
Fc-receptor Dependent Platelet Aggregation Induced by Monoclonal Antibodies against Platelet Glycoprotein Ib or von Willebrand Factor
Authors: Cauwenberghs Nancy , Schlammadinger Agotha , Vauterin Stephan , Cooper Susan , Descheemaeker Gretel , Tornai Istvan , Deckmyn Hans 
Published: March 2018

SummaryIn this paper we describe two pathways leading to platelet activation by crosslinking glycoprotein (GP) Ib to the platelet Fc-receptor (FcγRII). First the monoclonal antibody (MoAb) 9C8, raised against human platelet GPIbα, dose-dependently induced platelet aggregation of citrate-anticoagulated platelet-rich plasma, an effect that can be inhibited by several activation inhibitors. The FcγRII-inhibitory MoAb IV.3 was able to prevent the aggregatory effects of MoAb 9C8, indicating that crosslinking of the antigen GPIbαto the FcγII-receptor is necessary for the activating effect. Secondly we observed a synergistic activating effect of two anti-von Willebrand factor (vWF) MoAbs 1C1E7 and B724, both known to enhance vWF binding to GPIbαin the presence of shear or ristocetin. When these antibodies are added together to PRP, platelet aggregation is induced without further need for an additional modulator. This effect can be blocked by either MoAb IV.3 or an inhibitory anti-GPIbαMoAb, indicating that again the platelet activation results from signaling through FcγRII crosslinked to vWF bound to GPIbα. In addition, both the anti-GPIbαMoAb 9C8, or the two anti-vWF MoAbs 1C1E7 and B724 induce genuine platelet activation, as evidenced by the secretion of ATP and protein tyrosine phosphorylation. These findings with both anti-GPIbαand anti-vWF MoAbs add further proof to recent reports demonstrating an interaction between the platelet receptors GPIbαand FcγRII, suggesting a role for the FcγII-receptor in GPIb-related signaling.
High Density Lipoproteins Induce Cell Cycle Entry in Vascular Smooth Muscle Cells Via Mitogen Activated Protein Kinase-dependent Pathway
Authors: Junker Ralf , Pulawski Ewa , Fobker Manfred , Levkau Bodo , Eckardstein Arnold von , Seedorf Udo , Assmann Gerd , Walter Michael , Nofer Jerzy-Roch 
Published: March 2018

SummaryIn this study we found that HDL acts as a potent and specific mitogen in vascular smooth muscle cells (VSMC) by stimulating entry into S-phase and DNA synthesis in a time- and concentration-dependent manner, induction of cyclins D1, E, and A, as well as activation of cyclin D-dependent kinases as inferred from phosphorylation of the retinoblastoma protein (pRb). Moreover, HDL induced activation of the mitogen-activated protein kinase pathway including Raf-, MEK-1, and ERK1/2, as well as the expression of proto-oncogen c-fos, which is controlled by ERK1/2. PD98059, an inhibitor of MEK-1 blocked the mitogenic activity of HDL and cyclin D1 expression. HDL-induced VSMC proliferation, cell cycle progression, cyclin D1 expression, and activation of the Raf-1/MEK-1/ERK1/2 cascade were blocked by pre-incubation of cells with pertussis toxin indicating involvement of trimeric G-protein. By contrast, none of these responses was inhibited by the protein kinase C inhibitor, GF109203X. The mitogenic effects of native HDL were not mimicked by apo A-I, reconstituted HDL containing apo A-I, or cholesterol-containing liposomes. In conclusion, HDL possesses an intrinsic property to induce G-protein- and MAP-kinase-dependent proliferation and cell cycle progression in VSMC. The strong and specific mitogenic effect of HDL should be taken into account, when therapeutic strategies to elevate the plasma level of these lipoproteins are developed.
Symptomatic Onset of Severe Hemophilia A in Childhood is Dependent on the Presence of Prothrombotic Risk Factors
Authors: Halimeh S. , Kurnik K. , Schobess R. , Wermes C. , Junker R. , Kreuz W. , Pollmann H. , Nowak-Göttl U. , Escuriola Ettingshausen C. 
Published: March 2018

SummaryIt has been recently suggested that the clinical phenotype of severe hemophilia A (HA) is influenced by co-inheritance with the factor V G1691A mutation. We therefore investigated 124 pediatric PUP patients with hemophilia (A: n = 111) consecutively admitted to German pediatric hemophilia treatment centers. In addition to factor VIII activity, the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, antithrombin, protein C, protein S and anti-thrombin were investigated. 92 out of 111 HA patients (F VIII activity < 1%) were suffering from severe HA. The prevalence of prothrombotic risk factors in children with severe HA was no different from previously reported data: FV G1691A 6.5%, PT G20201A 3.2%, and protein C type I deficiency 1.1%. No deficiency states of antithrombin or protein S were found in this cohort of hemophilic patients. The first symptomatic bleeding leading to diagnosis of severe hemophilia (< 1%) occurred with a median (range) age of 1.6 years (0.5-7.1) in children carrying defects within the protein C pathway or the PT gene mutation compared with non-carriers of prothrombotic risk factors (0.9 years (0.1-4.0; p = 0.01). The cumulative event-free bleeding survival was significantly prolonged in children carrying additionally prothrombotic defects (log-rank/Mantel-Cox: p = 0.0098). In conclusion, data of this multicenter cohort study clearly demonstrate that the first symptomatic bleeding onset in children with severe HA carrying prothrombotic risk factors is significantly later in life than in non-carriers.
Beneficial Effect of the Active Form of Vitamin D3 against LPS-induced DIC but not against Tissue-factor-induced DIC in Rat Models
Authors: Aoshima Keiji , Suga Yukio , Yamazaki Masahide , Morishita Eriko , Saito Masanori , Miyamoto Ken-ichi , Nakao Shinji , Asakura Hidesaku 
Published: March 2018

Summary1 α,25-dihydroxyvitamin D3 (active form of vitamin D3; vitamin D3) has been reported to induce the upregulation of thrombomodulin and downregulation of tissue factor (TF) on monocytes. The possibility exists that vitamin D3 prevents the development of disseminated intravascular coagulation (DIC). In particular, monocyte TF production plays an important role in the pathophysiology of DIC in septic patients. We have attempted to determine whether vitamin D3 is effective against DIC in a rat model induced by lipopolysaccharides (LPS) (30 mg/kg, 4 h) or TF (3.75 U/kg, 4 h) using selective hemostatic parameters, markers of organ dysfunction and pathological findings (assessment of glomelular fibrin deposition). Vitamin D3 was administered orally each day at a dose of 2.0 mg/kg/day for 3 days, or low molecular weight heparin (LMWH 200 u/kg; I. V.) was given 10 min before the injection of TF or LPS in each treatment group. Vitamin D3 was effective against DIC in the rat model induced by LPS only, whereas LMWH was effective against DIC in both rat models induced by either TF or LPS. The anti-DIC effect of vitamin D3 was equal to (or more potent than) that of LMWH. The results suggested that vitamin D3 was useful for the treatment of LPS-induced DIC, and that the assessment of a drug’s efficacy should be done carefully given the markedly different results obtained according to the agents used to induce DIC.
Tissue Factor Pathway Inhibitor (TFPI) Levels in the Plasma and Urine of Children with Meningococcal Disease
Authors: Eling M. , Stephens A. C. , Oragui E. E. , Rivers R. P. A. , Levin M. 
Published: March 2018

SummaryTissue factor pathway inhibitor (TFPI) is a potent inhibitor of the TF-dependent coagulation system. In meningococcal disease, up-regulation of tissue factor expression on blood monocytes and possibly on endothelial cells has the potential to trigger the activation of the TF-dependent pathway of coagulation. Intravascular coagulation is considered to be a major pathogenic factor in meningococcal disease. We postulated that imbalance between TF expression and TFPI concentration might lead to uncontrolled coagulation in meningococcal disease. The aim of this study was to assess the levels of total TFPI in the plasma of patients with meningococcal disease and assess whether increased leaking of the TFPI was occurring. TFPI antigen levels and activity were measured in the plasma of 54 patients with meningococcal disease, and 13 healthy control children. TFPI antigen level were also determined in the urines of 14 of the 54 and 9 healthy control children. Plasma TFPI activity was reduced in the meningococcal diseased patients (mean of 0.503 ± 0.341 U/ml; control, 1.010 ± 0.199 U/ml; p <0.0001), as was the TFPI antigen levels (mean of 54.85 ± 35.05 ng/ ml; Control, 94.51 ± 11.44 ng/ml; p <0.0001). In contrast, TFPI antigen levels were increased in the urine of these patients when compared to the levels found in the urine of the healthy control children (mean of 12.96 ± 5.392 ng/mmol creatinine; Control, 0.239 ± 0.191 ng/mmol creatinine; p <0.035). A lack of correlation between TFPI-activity and TFPI-antigen plasma levels was observed (r = 0.002, p = 0.85). This data is consistent with the hypothesis that in meningococcal disease there is increased inactivation of plasma TFPI by the up regulation of tissue factor expression but in addition increased clearance of TFPI in urine is occurring.
Genetic Variation of the Extra-large Stimulatory G Protein α-Subunit Leads to Gs Hyperfunction in Platelets and Is a Risk Factor for Bleeding
Authors: Freson Kathleen , Hoylaerts Marc , Jaeken Jaak , Eyssen Marijke , Arnout Jozef , Vermylen Jos , Geet Chris Van 
Published: March 2018

SummaryAlternatively spliced GNAS1 and XL-GNAS1, encoding respectively the stimulatory G-protein α-subunit (Gsα) and the extra-large stimulatory G-protein α-subunit (XLsα), are located on the imprinted chromosomal region 20q13.12-13. We presently report a functional polymorphism in the imprinted XL-GNAS1 gene. In three patients, a 36 bp insertion and two basepair substitutions flanking this insertion were found in the paternally inherited XL-GNAS1 exon 1. They clinically manifest an enhanced trauma-related bleeding tendency and a variable degree of mental retardation. A platelet aggregation inhibition test to evaluate Gs function was developed. Their platelets display Gs hyperfunction and an enhanced cAMP generation upon stimulation of Gs-coupled receptors. The prevalence of the XLsα insertion in a normal control group was 2.2%. Normal controls, inheriting the insertion maternally, had a normal platelet Gs activity, whereas controls inheriting the insertion paternally had increased inducible platelet Gs activity, defining the insertion as a functional polymorphism. This paternally inherited XLsα insertion represents a new genetic cause of an inherited bleeding tendency, although to a variable degree.
Plasmin Induces Local Thrombolysis without Causing Hemorrhage: A Comparison with Tissue Plasminogen Activator in the Rabbit
Authors: Landskroner Kyle , Novokhatny Valery , Zimmerman Thomas , Kong Mansze , Kanouse Joel , Jesmok Gary , Marder Victor 
Published: March 2018

SummaryThe direct fibrinolytic enzyme, plasmin, was compared with tissue plasminogen activator (TPA) in rabbit models of local thrombolysis and fibrinolytic hemorrhage. Plasmin was produced by solid-phase urokinase activation of plasminogen and purified on benzamidine Sepharose. Applied as an intra-arterial infusion into the thrombosed abdominal aorta under conditions of unimpeded blood flow, plasmin (4 mg/kg) and TPA (2 mg/kg) achieved equivalent clot dissolution and flow restoration. Using the model of restricted blood flow into the thrombosed aorta, which limits local plasminogen supply, plasmin was superior to TPA in clot lysis and vascular reperfusion. Using similar dosages of plasmin (2 or 4 mg/kg) and TPA (1 or 2 mg/kg) in the earpuncture rebleed model. TPA induced rebleeding in a dose-dependent manner from prior puncture sites in 9 of 10 animals, while none of the 10 animals exposed to plasmin rebled from these sites.These results suggest that plasmin is an effective, unique thrombolytic agent, distinguished from the plasminogen activators in current usage by its striking safety profile.
Thrombophilic Risk Factors in Patients with Central Retinal Vein Occlusion
Authors: Marcucci Rossella , Bertini Laura , Giusti Betti , Brunelli Tamara , Fedi Sandra , Cellai Anna Paola , Poli Daniela , Pepe Guglielmina , Abbate Rosanna , Prisco Domenico 
Published: March 2018

SummaryFew and contrasting data are available on the prevalence of hemostatic risk factors in patients with central retinal vein occlusion (CRVO). Aim of this study was to investigate the metabolic and inherited risk factors for venous thrombosis in 100 CRVO patients (age: 59 yrs; range 18-77) and in 100 controls (age: 56 yrs; range 18-84). In patients homocysteine (Hcy) levels were significantly higher than in controls and were affected by the C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism (p <0.001). The prevalences of activated protein C resistance (APCR), factor V Leiden positivity, elevated PAI-1 and Lp(a) levels were significantly higher in patients with respect to controls. At multivariate analysis, only hyperhomocysteinemia (OR 11, 95% CI 3.6-36.2; p <0.0001) and elevated PAI-1 levels (OR 8.9, 95% CI 3.5-41.3; p <0.01), in addition to hypertension (OR 40.5, 95% CI 8.6-188.8; p <0.00001) and hypercholesterolemia (OR 3.1, 95% CI 1.6-20.5; p <0.05), were independent risk factors for CRVO. These data demonstrate a potential role of hemostatic risk factors in the pathophysiology of CRVO.
Phenotypic APC Resistance in Carriers of the A20210 Prothrombin Mutation Is Associated with an Increased Risk of Venous Thrombosis
Authors: Tosetto Alberto , Simioni Monica , Ruggeri Marco , Madeo Domenico , Rodeghiero Francesco , Castaman Giancarlo 
Published: March 2018

SummaryWe hypothesized that increased prothrombin levels associated with G20210A prothrombin gene mutation could affect the results of activated protein C (APC) resistance phenotype and increase the risk of venous thrombosis (VT). The increasing addition of purified prothrombin in plasma of 90 normal subjects resulted in a parallel significant increase of APC resistance. Significantly different mean n-APC-SR in 879 GG20210 subjects compared to 27 heterozygous carriers of isolated G20210A mutation was observed (1.0 ± 0.12 vs. 0.95 ± 0.11; P = 0.02) in a random sample of 906 normal population subjects. Twenty-seven families with VT and isolated G20210A mutation consecutively diagnosed during 1998-1999 were evaluated. Mean n-APC-SR was significantly lower in the 80 G20210A carriers compared to 58 GG 20210 relatives investigated, even after sex and age adjustment (0.92 ± 0.08 vs. 1.05 ± 0.13; P < 0.0001). A strong relationship between plasma prothrombin level and n-APC-SR was observed in the families. When n-APC-SR values were grouped in tertiles, the odds ratio for VTE, after exclusion of the index cases and adjustment for 20210 status, for subjects in the lowest tertile (n-APC-SR 0.73-0.90) was 4.58 (95% CI 0.78-26.88) compared to upper tertile (n-APC-SR 1.01-1.30). In conclusion, in subjects with G20210A mutation APC resistance is significantly increased, correlates with plasma prothrombin level and the carriers with the lowest APC resistance values have an increased risk of VTE.
Incidence, Natural History and Risk Factors of Deep Vein Thrombosis in Elective Knee Arthroscopy
Authors: Hunt N. , Strachan R. K. , Nicolaides A. N. , Delis K. T. 
Published: March 2018

Summary
Aims: to determine the incidence, anatomical distribution and extent of deep vein thrombosis (DVT) in limbs undergoing elective unilateral knee arthroscopy without active prophylaxis, to evaluate its effect on venous function following early diagnosis, and to quantify the impact of risk factors on its incidence. Methods: 102 consecutive patients undergoing unilateral knee arthroscopy without prophylaxis were studied. A history was obtained with emphasis on the risk factors for thromboembolism, and physical examination and colour duplex were performed prior to and within a week after surgery. Patients who developed calf DVT were given aspirin (150 mg) and compression stockings; those with proximal DVT were admitted for anticoagulation (heparin followed by warfarin). Follow-up (mean 118 [range 84-168] days) entailed weekly physical and duplex examinations during the first month and monthly thereafter. Results: 8 patients developed calf DVT in the operated leg (incidence 7.84% [95% Cl: 2.7%-13.2%]); thrombosis was asymptomatic in 4 of those (50%), caused calf tenderness in 4 (50%) and a positive Homan’s sign in one (12.5%). DVT occurred in the following veins: peroneal 4 subjects (50%), soleal 4 (50%), gastrocnemial 2 (25%) and tibial 2 (25%). Propagation of a calf DVT to the popliteal vein was identified in 1 patient (12.5%). After a median period of 118 days, total clot lysis was found in 50% of DVTs, with partial thrombus resorption in the rest; reflux in the thrombosed veins was present in 75% of limbs with DVT. 43% of patients had 1 risk factor for DVT and 20% had ≥2. The incidence of DVT was higher amongst those with two or more risk factors for thromboembolism (p <.05) or those with previous thrombosis alone (p <.005). Symptoms or signs of pulmonary embolism were not documented. Conclusions: Elective unilateral knee arthroscopy performed without prophylaxis is complicated by ipsilateral calf DVT in 7.8% (95% CI: 2.7%-13.2%) of cases. The risk is higher in the presence of previous thrombosis (relative risk: 8.2) and two or more risk factors for DVT (relative risk: 2.94). Thrombosis may propagate to the proximal veins, despite early diagnosis. 50% of calf clots totally lyse in 4 months, yet reflux develops in at least 75% of limbs with DVT. Further studies to determine optimal prophylaxis are warranted.
Fibrin D-dimer, Markers of Coagulation Activation and the Risk of Major Ischaemic Heart Disease in the Caerphilly Study
Authors: Rumley Ann , Sweetnam Peter , Yarnell John , Rumley Joseph , Lowe Gordon 
Published: March 2018

SummaryWe have previously reported that plasma fibrin D-dimer (a marker of turnover of cross-linked fibrin) showed a strong and independent association with incident ischaemic heart disease (IHD) in the Caerphilly Study cohort of 1,998 men aged 49-65. To establish the specificity of this finding, we assayed plasma samples from this cohort with a more specific assay for fibrin D-dimer: this showed an association with incident IHD which was at least as strong and independent as that for the original assay (odds ratio, OR for top fifth compared to bottom fifth 3.79; 95% CI 1.77-8.10; p < 0.0001). To establish potential causes of the increased fibrin turnover, we also assayed several potential markers of coagulation activation or thrombotic tendency (prothrombin fragment F1+2, thrombin-antithrombin complexes, factor VIIc, activated partial thromboplastin time [APTT] and activated protein C resistance): none of these variables were associated with incident IHD in this cohort. We suggest that further studies are required to establish the causes of increased cross-linked fibrin turnover, which is associated with incident IHD in the general population when measured by a specific assay.