bluuebunny/crossref_metadata_2025_split huggingface dataset:
Magnetic resonance direct thrombus imaging: a novel technique for imaging venous thromboemboli
Authors: Hunt Beverley , Moody Alan , Kelly James 
Published: March 2018

SummaryInvasive testing is now seldom required in patients with suspected venous thromboembolism (VTE). However, a corollary of noninvasive imaging is increased complexity as results are often yielded as probabilities rather than definitive answers and additional testing is frequently required following initial imaging. This creates a milieu in which misunderstandings and protocol violations are common, potentially leading to diagnostic errors. A highly accurate noninvasive imaging technique which allows immediate treatment decisions to be made is needed. Magnetic resonance direct thrombus imaging (MRDTI) is a novel technique which detects methaemoglobin in clot, allowing visualisation of thrombus without using intravenous contrast. It has two major advantages over conventional modalities which identify it as having the potential to fill this role. Firstly, direct visualisation of thrombus overcomes many of the pitfalls of conventional techniques, which have either identified thrombus as a filling defect or in terms of surrogates. Secondly, simultaneous imaging of the legs and chest allows a comprehensive assessment of thrombus load, minimising the importance of overlooked subsegmental pulmonary embolism (PE) and potentially facilitating more titrated treatment.Early data suggest MRDTI is highly accurate for the detection of both deep vein thrombosis (DVT) and PE, and ongoing outcome studies are evaluating the safety of withholding treatment in suspected DVT and PE on the basis of negative MRDTI alone. If favorable, a multi-centre outcome study evaluating cost-effectiveness as well as safety would be justified. Subject to further evaluation, this technique has the potential greatly to simplify and standardise the investigation of suspected VTE.
Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement
Authors: Müller Iris , Besta Felicitas , Schulz Christian , Massberg Steffen , Schönig Albert , Gawaz Meinrad 
Published: March 2018

SummaryDual antiplatelet therapy with aspirin and clopidogrel decreases the rate of stent thrombosis in patients undergoing percutaneous coronary intervention (PCI). However, despite intensified antiplatelet treatment, up to 4.7% of the patients undergoing coronary stenting develop thrombotic stent occlusion, suggesting incomplete platelet inhibition due to clopidogrel resistance. We evaluated the percentage of clopidogrel nonresponders among 105 patients with coronary artery disease (CAD) undergoing elective PCI. All patients were treated regularly with aspirin 100 mg/d and received a loading dose of 600 mg clopidogrel followed by a maintenance dose of 75 mg/d before PCI. Clopidogrel non-responders were defined by an inhibition of ADP (5 and 20 μMol/L) induced platelet aggregation that was less than 10% when compared to baseline values 4 h after clopidogrel intake. Semi-responders were identified by an inhibition of 10 to 29%. Patients with an inhibition over 30% were regarded as responders. We found that 5 (ADP 5 μMol/L) to 11% (ADP 20 μMol/L) of the patients were non-responders and 9 to 26% were semi-responders. Among the group of nonresponders there were two incidents of subacute stent thrombosis after PCI. We conclude that a subgroup of patients undergoing PCI does not adequately respond to clopidogrel, which may correspond to the occurrence of thromboischemic complications. Point-of-care testing may help to identify these patients who may then benefit from an alternative antiplatelet therapy.
Anticoagulant serine fibrinogenases from Vipera lebetinavenom: structure-function relationships
Authors: Aaspõllu Anu , Siigur Jüri , Siigur Ene 
Published: March 2018

SummaryAmino acid sequences of two anticoagulant serine fibrinogenases – α- and β-fibrinogenase (VLAF and VLBF) from Vipera lebetina venom have been deduced from the cDNA sequences encoding the enzymes. The mature protein sequences of 234 amino acids (VLAF) and 233 amino acids (VLBF) exhibit significant similarity with other snake venom serine proteinases. Both enzymes contain the catalytic triad His57, Asp102, Ser195, and twelve conserved cysteines forming six disulfide bridges. Unlike typical trypsin-like serine proteinases, they lack the third aspartate, Asp189 which is replaced by Gly189. VLBF is a typical representative of arginine esterases – β-fibrinogenases. α-Fibrinogenase, VLAF, is unique among snake venom serine proteinases with homologous structure. Until now there is no evidence of the anticoagulant serine enzymes degrading fibrinogen α-chain only and lacking esterolytic activity.Parts of this paper were presented at the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.The sequence data of Vipera lebetina mRNA for α- and β-fibrinogenase have been deposited in the GenBank database under accession numbers AF528193 (VLAF) and AF536235 (VLBF).
Clopidogrel and warfarin: absence of interaction in patients receiving long-term anticoagulant therapy for non-valvular atrial fibrillation
Authors: Lidell Christer , Svedberg Lars-Erik , Lindell Peter , Bandh Stellan , Job Bernhard , Wallentin Lars 
Published: March 2018

SummaryThe effect of concomitantly administered clopidogrel on anticoagulation status was investigated in patients receiving long-term warfarin therapy. Forty-three patients with non-valvular atrial fibrillation who were receiving long-term warfarin and had a stable international normalized ratio (INR) between 2 and 3 were randomly assigned to clopidogrel 75 mg daily or placebo for 8 days (Days 1–8). INR (primary endpoint) and plasma levels of warfarin enantiomers (secondary endpoint) were evaluated at Days 3, 6, 9, 13 and 22. Mean INR remained extremely stable in the clopidogrel group, the maximum percentage change from baseline being 0.6% at Day 6. Plasma levels of R- and S-warfarin also remained very stable in those receiving clopidogrel. No serious adverse events, premature discontinuations of study drug or bleeding occurred with clopidogrel. In conclusion, the stable anticoagulation status of patients receiving long-term warfarin therapy is unaffected by concomitant administration of clopidogrel 75 mg daily.
Preoperative plasma fibrinogen levels predict mortality after coronary artery bypass grafting
Authors: Robinson Daniel , Kleine Volker , Hertwig Sabine , Schwahn Christian , Grimm Rita , Eckel Lothar , Rettig Rainer , Völzke Henry 
Published: March 2018

SummaryThis study was designed to investigate whether plasma fibrinogen levels as well as the β-fibrinogen –455 G/A genotype are associated with outcome after coronary artery bypass graft (CABG) operation.We enrolled 249 consecutive CAD patients one day before they underwent a CABG operation. Data from 220 patients with available plasma fibrinogen levels were analyzed. The primary end-point was total mortality, the secondary end-point mortality from cardiac causes or the need for myocardial revascularization. The 2-year total mortality was 9.1% in the entire cohort. Multivariable analysis revealed an independent relationship between the primary end-point and preoperative plasma fibrinogen levels but not the β-fibrinogen –455 G/A geno-type. Neither preoperative plasma fibrinogen levels nor the β-fibrinogen –455 G/A genotype could predict the secondary end-point.We conclude, that elevated preoperative plasma fibrinogen levels, but not the β-fibrinogen -455 G/A genotype predict the total mortality after CABG operation.
Tissue kallikreins: new players in normal and abnormal cell growth?
Authors: Yousef George , Diamandis Eleftherios 
Published: March 2018

SummarySerine proteases are proteolytic enzymes with an active serine residue in their catalytic site. Kallikreins are a subgroup of the serine protease family and are known to have diverse physiological functions. The human tissue kallikrein gene family has now been fully characterized and includes 15 members, clustered in a 300 kb region on chromosome 19q13.4. In this review, we discuss the common structural features of kallik-reins at the DNA, mRNA and protein levels. Kallikreins are secreted as inactive zymogens and are activated by cleavage of an N-terminal peptide. Some kallikreins can undergo autoactivation while others may be activated by other kallikreins or other proteases. Most kallikreins are predicted to have trypsin-like enzymatic activity except for three members which may have chymotrypsin-like activity. Circumstantial evidence suggests that at least some kallikreins may be part of an enzymatic cascade pathway which is activated in aggressive forms of ovarian and probably other cancers. Accumulating evidence suggests potential diagnostic and/or prognostic roles of kallikreins in diverse malignancies. In addition to PSA, many other kallik-reins show differential expression in malignancy. For example, hK6, 10 and 11 are promising serological markers for ovarian cancer diagnosis. KLK10 may act as a tumor suppressor. In addition to their diagnostic and prognostic values, kallikreins may also be good therapeutic targets.Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.
Risk of venous thromboembolism in relatives of symptomatic probands with thrombophilia: a systematic review
Authors: Langlois Nicole , Wells Philip 
Published: March 2018

SummaryClinical equipoise exists regarding whether relatives of individuals with venous thromboembolism (VTE) and thrombophilia should be screened for thrombophilia. There have been no systematic attempts to summarize studies that have assessed the incidence of VTE in relatives. The purpose of this review was to systematically identify and review observational studies with thrombophilic relatives and to summarize their findings with respect to their risk of VTE.We conducted a systematic literature review and included nine observational studies meeting a priori inclusion criteria. Potentially eligible studies evaluated VTE incidence in relatives of index patients (probands) with symptomatic thrombophilia. In the four prospective studies, the incidence of VTE for asymptomatic family members with factor V Leiden ranged from 0.58-0.67% per year, 1.0-2.5% for protein C deficiency, 0.7-2.2% for protein S deficiency, and 4% for antithrombin deficiency. About half of all VTEs occurred during well-known risk periods but incidence rates were decreased by use of prophylaxis. No deaths from pulmonary embolism or fatal hemorrhages from anticoagulants were reported. The incidence of VTE was generally lower in the retrospective studies. The pooled relative risk from four retrospective studies for factor V Leiden carriers was 3.69 (CI 2.27, 6.00) and from two studies the pooled relative risk for deficiencies of protein C, protein S, and antithrombin was 10.58 (CI 5.38, 20.81).In conclusion, the risk of VTE events in asymptomatic relatives is low, but this may be an underestimate. Anticoagulant prophylaxis during risk periods appears to be of benefit but further research in this area is required.
Immunohistochemical localization of tissue factor pathway inhibitor-2 in human tumor tissue
Authors: Sierko Ewa , Zimnoch Lech , Kozlowski Leszek , Kisiel Walter , Wojtukiewicz Marek 
Published: March 2018

SummaryThe progression of neoplasms is frequently associated with thromboembolic complications. Coagulation proteins, particularly tissue factor (TF), have been shown to play a role in tumor growth and metastatic dissemination. TFPI is the principal inhibitor of TF-dependent pathway of blood coagulation, but previous studies failed to detect antigenic TFPI in cancer tissue. Recently, a second inhibitor of tissue factor dependent pathway, TFPI-2 (also known as placental protein 5 [PP5] or matrix-associated serine protease inhibitor [MSPI]), has been described. Information on the presence of TFPI-2 within the malignant tumor tissue still remains obscure, and thus the aim of this study was to evaluate the expression of TFPI-2 in loco in several different neoplasms. TFPI-2 expression was demonstrated by immu-nohistochemical procedures in neoplastic cells of laryngeal, breast, gastric, colon, pancreatic, renal and endometrial cancer, as well as glial neoplasms. The intensity of staining was not uniform, with higher intensity in more differentiated tumors. G3 breast, gastric, endometrial and colon cancer cells revealed populations of cells that were either TFPI-2 positive or negative. Gastric and renal cancer tissue exhibited the presence of TFPI-2 in tumor infiltrating macrophages. TFPI-2 was also observed in normal tissue of the breast, stomach, colon and pancreas. These data demonstrate that the expression of TFPI-2 diminishes with an increasing degree of malignancy, which may suggest a role for TFPI-2 in the maintenance of tumor stability and inhibition of the growth of neoplasms.
Mutations in the R2 FV Gene Affect the Ratio between the Two FV Isoforms in Plasma
Authors: Castoldi Elisabetta , Rosing Jan , Girelli Domenico , Hoekema Lico , Lunghi Barbara , Mingozzi Federico , Ferraresi Paolo , Friso Simonetta , Corrocher Roberto , Tans Guido , Bernardi Francesco 
Published: March 2018

SummaryMolecular genetics and biochemical studies were performed in homozygotes for the R2 allele (4070G) in the factor V gene, most of them affected by coronary artery disease. Novel polymorphisms (G642T, 156Ser; T1328C, 385Met/Thr), among which a functional candidate (A6755G, 2194Asp/Gly) located in the C2 domain of FV, were identified in the R2 gene. In chromatographic studies R2 FV appeared qualitatively identical to normal FV. However, a relative increase of the more thrombogenic and more glycosylated FV isoform (FV1) was observed in plasma of 2194Gly homozygotes (mean FV1/FV2 ratio 0.71, 95% CI 0.66-0.77) as compared to R2-free controls (0.37, 95% CI 0.34-0.40). We conclude that carriership of the R2 FV gene is associated with an imbalance between the two functionally different FV isoforms, and propose that genetically determined differential glycosylation of FV could represent a novel mechanism of thrombotic disease.
Value of Chest X-ray Combined with Perfusion Scan versus Ventilation/Perfusion Scan in Acute Pulmonary Embolism
Authors: Turkstra Franktien , van Marwijk Kooy Marinus , Oostdijk Ad H. , van Beek Edwin J. , Büller Harry , de Groot Marco 
Published: March 2018

Summary
BackgroundThe main purpose of ventilation scanning, as adjunct to perfusion lung scintigraphy, in acute pulmonary embolism is to allow for the classification of segmental perfusion defects as mismatched, which is generally accepted as proof for the presence of pulmonary embolism. We examined whether this function of the ventilation scan could be replaced by the chest X-ray.MethodsIn 389 consecutive patients with suspected pulmonary embolism and at least one segmental perfusion defect we classified the ventilation/perfusion (V/Q) scan and chest X-ray/perfusion (X/Q) scan as either mismatched or matched. Furthermore we analyzed whether this comparison was different in subgroups of patients with concomitant congestive heart failure or chronic obstructive pulmonary disease.Results Overall agreement between the X/Q and V/Q scan diagnostic category was found in 341 of 389 patients (88%; 95% CI 84-92%). The positive predictive value for obtaining a mismatched V/Q scan result in case of a mismatched X/Q scan result was 86% (95% CI 81-90%). If the X/Q scan yielded only matched defects the V/Q scan resulted in the same classification in 90% (95% CI 85-95%). Analysis of the small subgroup of patients with chronic obstructive pulmonary disease showed that a mismatched X/Q scan was confirmed by V/Q scanning in 21 of 34 cases (62%; 95% CI 45-78%).ConclusionThis study shows that in the great majority of patients with clinically suspected acute pulmonary embolism combination of chest X-ray with perfusion scintigraphy reliably replaced ventilation/perfusion scintigraphy in defining (mis)-matching of segmental perfusion defects. These results need confirmation before the chest X-ray can fully obviate the use of ventilation scintigraphy.
Haemostatic Factors in Human Peripheral Afferent Lymph
Authors: Howarth David , Attfield Janet , Cooke C. , Nanjee M. , Olszewski Waldemar , Morrissey James , Miller Norman , Miller George 
Published: March 2018

SummaryPeripheral afferent lymph was obtained by cannulation of a collecting vessel in 17 healthy men (mean age 26 years). Lymph/plasma ratios of all vitamin K-dependent factors were lower than expected from molecular weight. Factor VII, factor IX and tissue factor pathway inhibitor (TFPI) lymph/plasma activity ratios were higher than antigen ratios. Activated factor VII (FVIIa) and TFPI-Xa complex concentrations were higher in lymph than plasma, and the raised FVIIa did not appear to be due to cannulation. The fibrinogen lymph/plasma activity (Clauss) ratio averaged about 20% of the antigen ratio. The result of an ELISA for D-dimer was higher in lymph than plasma, often more than five-fold. This high level in lymph was not explored but may indicate proteolysis of fibrinogen and fibrin with release of D-like and D-dimerlike fragments in interstitial fluid.
Cloning of Guinea Pig Tissue Factor cDNA: Comparison of Primary Structure among Six Mammalian Species
Authors: Shi Rui-Jin , Li Wen-Zhou , Marder Victor , Sporn Lee 
Published: March 2018

SummaryTissue factor (TF) is a transmembrane glycoprotein that serves as an essential cofactor for plasma coagulation factor VII. TF procoagulant activity exhibits varying species specificity. In particular, guinea pig (GP) TF is unable to activate clotting in heterologous plasma systems, but the molecular basis for this phenomenon is not yet understood. The full-length GP TF cDNA was cloned and sequenced. The open reading frame encoded a predicted precursor protein of 289 amino acids (aa) which was expressed in a reticulocyte lysate system as a protein of apparent molecular weight of 34 kD. The identity of the predicted aa sequence of mature GP TF with rabbit, human, bovine, rat and mouse TF was 66.4, 64.4, 60.6, 53.2 and 52.2%, respectively. With a focus on sites of potential functional significance, we compared sequences within the known binding regions. The eleven residues at the interface region between the TF1 and TF2 modules, which bind to the EGF domain of VIIa, were perfectly conserved among the six species, with the exception of an isoleucine replacing a lysine in the guinea pig sequence. However, only four of the eleven binding residues in the TF1 module, known to interact with the catalytic domain of factor VII, and three of the five residues in the TF2 module, involved in binding the factor VII Gla domain, were conserved among species. We hypothesize that divergence at these regions contributes to the specificity and non-reciprocity of TF procoagulant activity between species.
Use of Recombinant Factor VIIa in 3 Patients with Inherited Type I Glanzmann’s Thrombasthenia Undergoing Invasive Procedures
Authors: Ménart C. , Trzeciak M. C. , Nurden P. , Fressinaud E. , Dreyfus M. , Laurian Y. , Négrier C. , d’Oiron R. 
Published: March 2018

SummaryThe treatment of bleeds in Glanzmann’s thrombasthenia is a challenging issue, especially when repeated platelet transfusions have induced anti-glycoprotein (GP) IIb-IIIa or anti-HLA allo-immunisation. In an attempt to find an alternative treatment regimen, we used recombinant factor VIIa (rFVIIa, NovoSeven®, Novo Nordisk, Denmark) as first-line therapy in 3 patients with Glanzmann’s thrombasthenia and anti-GPIIb-IIIa iso-antibodies who were scheduled for invasive procedures. The administration of an initial bolus dose of rFVIIa (70–110 µg/kg) was immediately followed by continuous infusion at the rate of 9-30 µg/kg/h for 3–15 days. The treatment resulted in an excellent clinical efficacy and tolerance in 2 cases. In the third patient, whereas efficacy was excellent at the surgical site, pharyngonasal bleeds of traumatic origin persisted for 10 days, and a severe thromboembolic complication occurred 5 days after discontinuation of rFVIIa. Complementary studies are needed for patients with congenital platelet disorders in order to evaluate the safety and the potential therapeutic place of rFVIIa treatment.
Hemostatic Changes following the Modified Fontan Operation (Total Cavopulmonary Connection)
Authors: Ries Martin , Hofbeck Michael , Buheitel Gernot , Singer Helmut , Klinge Jens , Rauch Ralf 
Published: March 2018

SummaryThromboembolism is a serious complication after Fontan operation, which may be caused by alterations of the coagulation system. We therefore investigated pro- and anticoagulant factors in 20 patients aged 4 to 21 years, 4 to 63 months following total cavopulmonary connection. Furthermore we compared markers of thrombin activation and fibrinolysis and in vitro clotting and clot-lysis to age-matched healthy subjects.Compared to results of age-matched controls, the Fontan operated individuals had significant decreases in levels of protein C (0.88 U/ml in controls, 0.67 U/ml in patients; p <0.001) and protein S (1.05 in controls, 0.93 U/ml in patients; p <0.05). Moreover, half of the patients had high values of FVIII (>1.5 IU/ml), which are associated with an increased thrombotic risk. These changes may result in enhanced generation of thrombin and plasmin, indicated by our finding of increased thrombin-antithrombin III (TAT) and plasmin-antiplasmin (PAP) levels and a similar trend in prothrombin fragments F1+2. Clot lysis tests, global coagulation tests, red blood cell count, liver enzymes AST, ALT, but not GGT, were generally within the normal ranges.
Involvement of Activated Integrin α2β1 in the Firm Adhesion of Platelets onto a Surface of Immobilized Collagen under Flow Conditions
Authors: Onitsuka Ichiro , Imaizumi Tsutomu , Jung Stephanie , Moroi Masaaki 
Published: March 2018

SummaryRecently, we demonstrated that agonist-induced activation of the platelet surface collagen-receptor integrin α1 β2 converts it to an active form that can bind soluble collagen with high affinity (Jung, SM, Moroi, M: J Biol Chem 1998; 273: 14827-37). Here, the involvement of α2 β1 activation and the high affinity binding property of activated α2β1 in platelet adhesion to a collagen surface under flow conditions were analyzed. Platelet adhesion to immobilized collagen was measured in the presence of TS2/16, an activating anti-integrin α2β1 antibody, and inhibiting antibodies, Gi9 and 6F1. TS2/16 decreased the moving velocity of platelets on the collagen surface, but Gi9 and 6F1 increased it, indicating that α2β1 activation induces the tight binding of platelets to immobilized collagen under flow. Platelet adhesion, expressed as the surface area occupied by adhered platelets, in the presence of TS2/16 was similar to that in its absence. In contrast, adding Gi9 or 6F1 caused biphasic adhesion composed of a first phase, a lag phase whose length differed in each experiment, and a second phase adhesion with a rate similar to that of the control. This biphasic adhesion indicates that α2β1 activity is inhibited and also suggests that some other factor(s) may contribute to the adhesion under flow. At concentrations where neither 6F1 nor Gi9 affected collagen-induced aggregation, these antibodies inhibited soluble collagen binding to thrombin-activated platelets. Only at much higher concentration did 6F1 inhibit collagen-induced aggregation. TS2/16 had no effect on the aggregation. The present results are evidence against the major involvement of integrin α2β1 in platelet aggregation; instead, they indicate that integrin α2β1 would be mainly associated with the tight binding of platelets to collagen.