bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autoantibodies Against the Protease Inhibitor Calpastatin: A New Risk Factor for Venous Thrombosis?
Authors: Schlosser Udo , Lackner Karl J , Scheckenhofer Christine , Spannagl Michael , Spengel Florentin A , Hahn Gabriele , Lang Bernhard , Schmitz Gerd 
Published: July 2018

SummaryAutoantibodies reactive against human calpastatin were detected by screening a cDNA expression library with the serum of a 53 year old white female patient with a history of venous thrombosis and suspected antiphospholipid syndrome. When further sera were analyzed it could be shown that >90% of calpastatin autoantibodies, detected by Western blotting against the partial calpastatin clone, react with the C-terminal amino acids of the protein. Therefore, an ELISA based on a synthetic peptide containing the C-terminal 27 amino acids of calpastatin was developed and 205 healthy blood donors and 138 random sera from hospital patients were analyzed. A total of 11 sera (3.2%) were positive with no significant difference between the two groups (7/205 and 4/138). In 80 consecutive patients with a history of venous thrombosis 9 positive sera (11.3%; p < 0.01 vs. blood donors, p<0.02 vs. hospital patients) were detected. Our results indicate that autoantibodies against calpastatin may constitute a so far unknown risk factor for venous thrombosis.
Efficacy and Safety of Low Molecular Weight Heparin (Ardeparin Sodium) Compared to Warfarin for the Prevention of Venous Thromboembolism after Total Knee Replacement Surgery: A Double-blind, Dose-ranging Study
Authors: Heit John A , Berkowitz Scott D , Bona Robert , Cabanas Victor , Corson John D , Elliott C Gregory , Lyons Roger ,   (Ardeparin Arthroplasty Study Group)
Published: July 2018

SummaryWe performed a double-blind, randomized clinical trial to compare the efficacy and safety of three different subcutaneous (SC) low molecular weight heparin doses (ardeparin sodium 25,35, or 50 anti-XaU/kg twice daily [BID]) to adjusted-dose warfarin (international normalized ratio [INR] = 2.0 to 3.0), as venous thromboembolism prophylaxis after total knee replacement surgery. The primary endpoint was total venous thromboembolism prevalence, defined as deep vein thrombosis discovered at postoperative venography of the operated leg, or symptomatic, objectively-documented pulmonary embolism. Of 860 patients randomized, 680 (79%) had an evaluable venogram or pulmonary embolism. The total venous thromboembolism prevalence was significantly greater among patients prophylaxed with warfarin compared to ardeparin 50 BID (38% vs 27%, p = 0.019); the prevalence among ardeparin 25 BID (37%) and 35 BID (28%) patients was similar to warfarin and ardeparin 50 BID patients, respectively. Overt bleeding occurred in 22 (7.9%) ardeparin 50 BID patients compared to 12 (4.4%) warfarin patients (p = 0.08), and in seven ardeparin 25 and 35 BID patients each (5.2% and 5.0%, respectively). Compared to the warfarin group, blood loss was significantly greater in the ardeparin 50 and 25 BID groups, and not different in the ardeparin 35 BID group.
Conclusions: Postoperative, unmonitored, fixed-dose ardeparin 50 anti-Xa U/kg SC BID is significantly more effective than adjusted-dose warfarin for this indication. Although overt bleeding among warfarin and ardeparin 50 BID patients did not differ significantly, ardeparin 50 BID patients had significantly greater blood loss. Ardeparin 35 anti-Xa U/kg SC BID may provide efficacy similar to ardeparin 50 anti-Xa U/kg SC BID but with reduced bleeding.
Family History of Coronary Heart Disease and Hemostatic Variables in Middle-Aged Adults
Authors: Pankow James S , Folsom Aaron R , Province Michael A , Rao D C , Eckfeldt John , Heiss Gerardo , Shahar Eyal , Wu Kenneth K ,   on behalf of the Atherosclerosis Risk in Communities Investigators and Family Heart Study Research Group
Published: July 2018

SummaryIndividuals with a family history of coronary heart disease (CHD) may be predisposed to atherothrombosis. To investigate this hypothesis, a family CHD risk score was computed for approximately 13,000 men and women aged 45 to 64; hemostatic variables (fibrinogen, factor VIIc, factor VIIIc, von Willebrand factor, antithrombin III, protein C) were also measured in plasma. After adjustment for age and ethnicity, there was a statistically significant, positive association between the family risk score and four of the six hemostatic variables (fibrinogen, factor VIIc, factor VIIIc, von Willebrand factor) in women and all six hemostatic variables in men. In general, these associations were weak and substantially attenuated after adjustment for constitutional, lifestyle, and biochemical covariates. These results indicate that mean levels of selected hemostatic variables, like traditional CHD risk factors, are higher in individuals with a family history of heart disease.
Rapid Direct Determination of Low and High Molecular Weight Kininogen in Human Plasma by Particle Concentration Fluorescence Immunoassay (PCFIA)
Authors: Scott Cheryl F , Shull Bruce , Müller-Esterl Werner , Colman Robert W 
Published: July 2018

SummaryIn this study, we employed Particle Concentration Fluorescence Immunoassay (PCFIA), for directly measuring both high and low molecular weight kininogens (HK and LK) in human plasma. In 38 normal donors, the mean values for plasma kininogens were 93 mg/ml +/- 19 SD, 82 mg/ml +/- 12 SD, and 175 mg/ml +/- 29 SD, respectively for LK, HK, and TotK (the sum of LK and HK detected by their common heavy chains). Plasma completely deficient in HK and LK was unreactive (<0.25 mg/ml) in all 3 assays whereas plasma from a patient with Fitzgerald Trait had an HK value of 11 mg/ml, an LK value of 36 mg/ml and a TotK value of 59 mg/ml. The reagents can be prepared in advance and all three kininogen determinations can be performed, using the same diluted sample, on 24 plasma samples, in triplicate, or 40 plasma samples, in duplicate, in less than 1 h. By performing all 3 kininogen determinations, it is possible to differentiate cleaved from intact kininogens. This technique will facilitate the widespread screening of kininogen levels in biological fluids of normal humans as well as of patients with various diseases.
Identification of the NO Synthase isoforms Expressed in Human Neutrophil Granulocytes, Megakaryocytes and Platelets
Authors: Wallerath Thomas , Gath Ingolf , Aulitzky Walter E , Pollock Jennifer S , Kleinert Hartmut , Förstermann Ulrich 
Published: July 2018

SummaryUsing Western blot and fluorescent immunocytochemistry, NOS III (or ecNOS) and NOS II (or iNOS), but no NOS I (or ncNOS), were identified in preparations of human platelets. Reverse-transcription polymerase chain reactions (RT-PCR) demonstrated NOS III mRNA, but no NOS II mRNA (which is short-lived) and no NOS I mRNA in platelets. Immunofluorescent staining of human bone marrow smears showed the presence of NOS III, but not NOS I in megakaryocytes. A subpopulation of megakaryocytes also expressed NOS II. In preparations of human neutrophils, immunocytochemistry demonstrated NOS I in all cells, whereas no NOS III was detected. The few NOS II positive cells were characterized as contaminating eosinophils. Similarly, in RT-PCR, transcripts for NOS I and NOS II, but not for NOS III, were identified. Thus, the constitutive NOS isoform in megakaryocytes and platelets is NOS III, whereas neutrophils express NOS I. Some megakaryocytes and eosinophils also express NOS II.
PEGylation of lnterleukin-6 Effectively Increases Its Thrombopoietic Potency
Authors: Tsutsumi Yasuo E , Tsunoda Shin-ichi S , Kamada Haruhiko , Kihira Tetsunari , Kaneda Yoshihisa , Ohsugi Yoshiyuki , Mayumi Tadanori 
Published: July 2018

SummaryThe in vivo thrombopoietic activity of polyethylene glycol-modified interleukin-6 (MPEG-IL-6), in which 54% of the 14 lysine amino groups of IL-6 were coupled with PEG, was compared to that of native IL-6. Native IL-6 and MPEG-IL-6, which showed about 51% of the specific bioactivity of native IL-6, were administered subcutaneously to mice every 2 days for 7 days. Native IL-6 increased not only the peripheral platelet count, but also the plasma-IgGl level in a dose-dependent manner. MPEG-IL-6 showed about 500 times higher thrombopoietic potency than native IL-6. Further, in comparison to native IL-6, MPEG-IL-6 did not enhance IgGl production as much as it enhanced platelet production. MPEG-IL-6 significantly stimulated platelet recovery in mice treated with 5-fluorouracil, whereas the administration of native IL-6 had a negligible effect. The plasma halflife of MPEG-IL-6 was about 100-fold longer than that of native IL-6. The decrease in the plasma clearance of MPEG-IL-6 was thought to be due, in part, to the shielding of the proteolytic sites in the IL-6 molecule by the PEG chain. The uptake of IL-6 by the reticuloendothelial system, such as the liver and spleen, was markedly limited by PEGylation. The PEGylation of IL-6 markedly enhanced the blood-residency of IL-6, resulting in effective augmentation of its thrombopoietic activity and a marked decrease in its side-effects. These findings suggest that MPEG-IL-6 may be a potential candidate for thrombopoietic agent.
Low Prevalence of Factor V:Q506 in 41 Patients with Isolated Pulmonary Embolism
Authors: Martinelli Ida , Cattaneo Marco , Panzeri Daniela , Mannucci Pier Mannuccio 
Published: July 2018

SummaryIn 70-80% of cases, pulmonary embolism is the consequence of lower extremity deep vein thrombosis. It has been demonstrated that the most common coagulation defect predisposing to venous thrombosis, resistance to activated protein C (APC), is not associated with an increased risk for pulmonary embolism, but the evidence was based on a functional assay to diagnose APC resistance and no information about concomitant deep vein thrombosis was provided. The aim of our study was to evaluate the prevalence of factor V:Q506, the gene mutation responsible for APC resistance, in patients with symptomatic non-fatal pulmonary embolism, whether or not associated with deep vein thrombosis. Patients with uncomplicated deep vein thrombosis and healthy controls were investigated as comparison groups. The overall prevalence of factor V:Q506 in 106 patients with pulmonary embolism was 12.3%, lower than that found in 106 patients with deep vein thrombosis (22.6%, OR 0.5, 95% Cl 0.2-1.0) but significantly higher than that found in 212 healthy subjects taken as controls (2.8%, OR 4.8,95% Cl 1.8-13.0). In the 41 patients with isolated pulmonary embolism, i.e., without the presence of deep vein thrombosis, the prevalence was 4.9%, similar to that in controls (OR 1.8,95% Cl 0.3-9.6), while in the remaining 65 patients with pulmonary embolism associated with deep vein thrombosis the prevalence was significantly higher (16.9%, OR 5.5, 95% Cl 2.0-15.8). In conclusion, the prevalence of factor V:Q506 is high in patients with pulmonary embolism associated with deep vein thrombosis, whereas in patients with isolated pulmonary embolism it is similar to that found in control subjects. This intriguing finding is of difficult interpretation and needs confirmation by further studies.
Blood Coagulation and Thrombosis in Patients with Ovarian Malignancy
Authors: von Tempelhoff Georg-Friedrich , Dietrich Michael , Niemann Frank , Schneider Dirk , Hommel Gerhard , Heilmann Lothar 
Published: July 2018

SummaryOvarian cancer cells appear to be capable of both thrombin formation and induction of fibrin degradation which may be essential prerequisites for the development of deep vein thrombosis (DVT) as well as the spread of malignancy. To study further this coagulation – cancer interaction in 60 patients with untreated ovarian cancer of FIGO stage I-IV the incidence of DVT was recorded pre-operatively, postoperatively on day 1, 3, 5, 7, 10, before each of six cycles of Cisplati- num/Epirubicin/Cyclophosphamide chemotherapy, during follow-up and in the post-operative period of second look surgery. In addition, blood coagulation tests results were determined prospectively. Two patients were excluded from these calculations due to previous DVT 5 to 6 weeks before the diagnosis of ovarian cancer but all patients were eligible for surgery and randomized to receive either daily low molecular weight heparin (LMWH) (n = 28) or unfractionated heparin (UFH) (n = 32) for perioperative thrombosis prophylaxis until the 7th postoperative day. According to the FIGO stage, patients were equally distributed in the 2 heparin treatment groups. The predictive value of pre-operative coagulation test results, clinical parameters, and type of heparin used were tested in univariate and multivariate analysis for development of post-operative DVT and overall patients survival. Impedance plethysmography for DVT screening was used. The presence of DVT was then confirmed by phlebography. Only D-dimer and fibrinogen levels were correlated significantly with the FIGO stage while antithrombin, protein C, and plasminogen activator inhibitor activity were not. The incidence of DVT was 6.7% (4/60) up to the 7th and 8.3% (5/60) between the 8th and 29th post-operative day. DVT occurred in 10.6 % (5/47) during chemotherapy. Pre-operative coagulation test results, the type of heparin used, and clinical parameters were not significant risk factors for post-operative DVT development in univariate analysis. The D-dimer and fibrinogen levels were significant risk factors for reduced overall survival in univariate analysis but only the FIGO stage was an independent predictor (in multivariate analysis). After a median follow up of 26.5 months (min. 8 months, max. 41 months), 21.4% of LMWH treated and 37.5% of UFH-treated patients died of cancer (p = 0.26). Pre-operative test results were neither predictive for DVT nor the outcome of cancer but patients showed an improved though not statistically significant overall survival after LMWH treatment.
Degree of Polymer Organization Decreases the Binding of a Monoclonal Antibody Raised against the β-Chain Amino Terminus of Fibrin
Authors: Morris Timothy A , Marsh James J , Fagnani Roberto , Hagan Michael , Moser Kenneth M 
Published: July 2018

SummaryAccurate non-invasive diagnosis of deep venous thrombosis and pulmonary embolism remains an elusive goal. Radiolabeled antibodies specific for the epitope exposed on the β-chain of fibrin after fibrino- peptide B release (anti-β) enabled in situ imaging of thrombi in experimental subjects with nuclear medicine techniques. When used in patients anticoagulated for thrombo-embolic disease, however, the antibody was unable to reliably image the thrombi. We postulated that the neoepitope on the β-chain of fibrin is covered up as fibrin organizes into a polymer network and is therefore exposed to the antibody only during active incorporation of fibrin subunits. We determined the equilibrium binding kinetics of an anti-β monoclonal antibody to fibrin in various stages of organization. The concentration of exposed epitopes on immobilized fibrin monomers was equal to the molar concentration of fibrin β-chains. The percentage of β-chains exposed to the antibodies markedly decreased as the fibrin network was allowed to organize, a process catalyzed by calcium. Conclusions: The β-chain amino terminus of fibrin is exposed transiently as subunits are added to the enlarging fibrin network. Anti-β antibodies bind preferentially to actively enlarging fibrin polymers.
Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G Promoter Polymorphism and Levels in Subjects with Cerebrovascular Disease
Authors: Catto Andrew J , Carter Angela M , Stickland Max , Bamford John M , Davies J Andrew , Grant Peter J 
Published: July 2018

SummaryThe exact role of the fibrinolytic system in the pathogenesis of stroke remains to be established. Elevated circulating levels of plasminogen activator inhibitor-1, the principle inactivator of the fibrinolytic system, have been related to the development of myocardial infarction. There is evidence that a polymorphism in the promoter region of the PAI-1 gene is associated with circulating PAI-1 levels.We studied a common single nucleotide insertion/deletion (4G/5G) polymorphism by PCR in 558 patients with stroke, the pathological type of which was established by cranial computed tomography, and in 172 controls. 4G/5G genotype and PAI-1 activity were investigated in relation to 1) stroke type and 2) mortality occurring within four weeks, three months and six months of the stroke.No difference in genotype frequency was observed when all cases of stroke were compared with controls nor between the clinically determined subtypes of cerebral infarction. PAI-1 activity was significantly higher in patients with stroke (n = 245) both at presentation (11.6 U/ml) and after three months (11.8 U/ml), in paired samples, than in control subjects (8.8 U/ml, p <0.0001). Thirty-seven (6.2%), 86 (14.5%) and 122 (20.5%) patients had died within one, three and six months of admission, respectively. PAI-1 activity was independently associated with all-cause mortality at one and three months after stroke (p = 0.02 and p = 0.03 respectively), but not after six months.In this population the 4G/5G promoter polymorphism is not associated with an increased risk of stroke. PAI-1 levels were elevated at the time of acute stroke which persisted after three months. PAI-1 level but not genotype was associated with early mortality following stroke.
Inhibition of Leucocyte and Platelet Adhesion Reduces Neointimal Hyperplasia after Arterial Injury
Authors: Golino Paolo , Ambrosio Giuseppe , Ragni Massimo , Cirillo Plinio , Esposito Nicolino , Willerson James T , Rothlein Robert , Petrucci Luisa , Condorelli Mario , Chiariello Massimo , Buja Maximilian L 
Published: July 2018

SummaryRestenosis following coronary angioplasty is thought to result from migration and proliferation of medial smooth muscle cells. However, the factors that initiate this proliferation are still unknown. In a rabbit model of carotid artery injury, we tested the hypothesis that activated platelets and leucocytes might contribute to the development of neointimal hyperplasia. Following arterial injury, rabbits received either no treatment, R15.7, a monoclonal antibody against the leucocyte CD ll/CD 18 adhesion complex, aurintricarboxylic acid (ATA), a sub stance that inhibits platelet glycoprotein Ib-von Willebrand factor interaction, or the combination of R15.7 and ATA. After 21 days, the extent of neointimal hyperplasia was evaluated by planimetry on histological arterial sections. The area of neointima averaged 0.51 ±0.07 mm2 in control animals and it was significantly reduced by administrationof either R15.7 or ATA alone to 0.12 ± 0.05 and 0.20 ±0.01 mm2, respectively (p <0.05 vs controls for both groups). The animals that received the combination of R15.7 and ATA showed a further reduction in neointimal hyperplasia, as compared to animals that received ATA alone (p <0.05 vs ATA alone). These data indicate that platelets and leucocytes play animportant role in the pathophysi ology of neointimal hyperplasia in this experimental model. Interven tions that reduce platelet and leucocyte adhesion to vessel wall might have beneficial effects in reducing restenosis following coronary angioplasty.
Human Urinary Soluble Thrombomodulin (MR-33) Improves Disseminated Intravascular Coagulation without Affecting Bleeding Time in Rats: Comparison with Low Molecular Weight Heparin
Authors: Takahashi Yasuo , Hosaka Yoshitaka , Imada Kazunori , Adachi Takehiro , Niina Hiromi , Watanabe Mitsutoshi , Mochizuki Hidenori 
Published: July 2018

SummaryWe compared the antithrombotic and hemorrhagic effects of naturally existing human urinary soluble thrombomodulin (MR-33) with those of low molecular weight heparin (LMW-heparin) in rats. In in vitro experiments, MR-33 prolonged APTT in a dose-dependent fashion; its effect in this respect was as potent as that of LMW-heparin, but it was less potent than unfractionated heparin (UF-heparin). MR-33 was effective on endotoxin- or thromboplastin-induced disseminated intravascular coagulation (DIC) in rats. In both DIC models, infusion of MR-33 improved hematological abnormalities compatible with DIC in a dose-dependent fashion without excessive prolongation effect on APTT. Although LMW-heparin and UF-heparin also improved both DIC models, excessive prolongation of APTT was observed at high doses. It is well-known that the excessive prolongation of APTT with antithrombotic drugs like heparins is an index for hemorrhage, which is a major side effect in the treatment of DIC. We therefore further compared the antithrombotic (Benefit: dose required for 50% inhibition of fibrinogen decrease: ED50) and hemorrhagic (Risk: minimum dose required for significant prolongation of bleeding time) effects of MR-33 and LMW-heparin in the thromboplastin-induced DIC model. As a result, Benefit-Risk ratio was 1:27 for MR-33 and 1:3 for LMW heparin. These results indicate that MR-33 may be a clinically useful antithrombotic agent with reduced risk for hemorrhage compared with LMW-heparin.
The Mutation Ala677→Val in the Methylene Tetrahydrofolate Reductase Gene: A Risk Factor for Arterial Disease and Venous Thrombosis
Authors: Arruda Valder R , von Zuben Paula M , Chiaparini Luiz C , Annichino-Bizzacchi Joyce M , Costa Fernando F 
Published: July 2018

SummaryMild hyperhomocysteinemia has been identified as a risk factor for arterial disease and for venous thrombosis. Individuals homozygous for the thermolabile variant of the methylene tetrahydrofolate reductase gene (MTHFR) which results from a common mutation Ala677→Val and is found in 5-15% of the general population, have significantly elevated plasma homocysteine levels and may account for one of the genetic risk factors in vascular disease. We have analyzed the prevalence of MTHFR-T homozygotes in patients with arterial disease or venous thrombosis. We studied 191 patients with arterial disease and 127 individuals with venous thrombosis and compared with 296 unmatched controls. The results showed that there was a high prevalence of homozygotes for the mutated MTHFR-T allele among a group of patients with arterial disease (19%) in the absence of hyperlipoproteinemia, hypertension, and diabetes mellitus when compared to controls (4%), odds ratio of 5.52 (95% C.I., 2.27 to 13.51). The prevalence of homozygotes among patients with venous thrombosis was 11%, odds ratio of 2.93 (95% C.I., 1.23 to 7.01). The risk of venous thrombosis remained high, odds ratio of 2.63, even after we excluded 27 patients with hereditary thrombophilia (e.g. factor V Leiden, dysfibrinogene- mia, deficiency of protein C, protein S, antithrombin III, or factor XII) from the 127 overall cases with venous thrombosis. These data support the hypothesis that being a homozygote for the MTHFR-T is a risk factor for the development of arterial diasease and also for venous thrombosis.
Defective Interaction between von Willebrand Factor and Platelet Glycoprotein I b – A Familial Study of Peripheral Arterial Occlusive Disease
Authors: Kauhanen Petteri , Beer Jürg H , Lassila Riitta 
Published: July 2018

SummaryHemostatic variables and platelet function were assessed as a part of a genetic study in 15 patients with symptomatic peripheral arterial occlusive disease (PAOD) and 15 healthy siblings from ten families. D-dimer, a degradation product of cross-linked fibrin, was increased in the PAOD group (mean ± SD) (448 ± 177 vs. 333 ± 121 ng/ml, p <0.05). Ristocetin-induced maximal platelet aggregation (RIPA) was reduced in the PAOD group in response to both a higher (0.75 mg/ml) (67 ± 28 vs. 87 ± 14%, p = 0.02) and a lower (0.55 or 0.60 mg/ml) (33 ± 21 vs. 59 ± 32%, p = 0.02) concentration of ristocetin. Accordingly, the rate of primary aggregation was smaller, and a larger threshold concentration of ristocetin was needed to cause aggregation. However, ristocetin cofactor activity, von Willebrand factor (vWF) antigen and its multimer distribution, plasma glycocalicin, platelet glycoprotein lb content and the binding of vWF to frozen and thawed washed platelets were equal in both groups. Thus, the observed reduced RIPA in patients with PAOD is likely to reflect a down-regulation or blunted binding affinity in the platelet surface glycoprotein Ib.