bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Point Mutation in Glycoprotein IX Coding Sequence (Cys73(TGT) to Tyr(TAT)) Causes Impaired Surface Expression of GPIb/IX/V Complex in Two Families with Bernard-Souiier Syndrome
Authors: Noda Masaaki , Fujimura Kingo , Takafuta Toshiro , Shimomura Takeshi , Fujii Teruhisa , Katsutani Shinya , Fujimoto Tetsuro , Kuramoto Atsushi , Yamazaki Tomio , Mochizuki Toshihiro , Matsuzaki Miwako , Sano Masayuki 
Published: July 2018

SummaryBernard-Soulier syndrome (BSS) is a rare inherited bleeding disorder which is caused by abnormal expression or function of the glycoprotein (GP) Ib/IX/V complex, a platelet major receptor for von Wille-brand factor. We studied four BSS patients in two unrelated families in which the same and novel mutation was found. Flow cytometric analysis showed that GPIX was completely absent but residual amounts of GPIbα and GPV were detectable in these patients. We analyzed all coding regions of GPIbα, GPIbβ, GPV and GPIX which were amplified from the patients’ genomic DNA by the polymerase chain reaction (PCR). In all four cases, we identified a point mutation in the GPIX coding region that changes the codon for cysteine 73 (TGT) to a codon for tyrosine (TAT). Furthermore, we confirmed by a transient expression study that the mutation caused the loss of adequate surface expression of GPIX. Since cysteine might be important for the secondary structure, this mutation of GPIX gene would lead to a dramatic conformational change of GPIX protein, resulting in the reduced surface expression. We concluded that this novel point mutation of the GPIX gene was responsible for BSS in these families
Activation of Coagulation and Fibrinolysis in Heatstroke
Authors: Bouchama Abderrezak , Bridey Françoise , Hammami Muhammad M , Lacombe Catherine , Al-Shail Essam , Al-Ohali Yazid , Combe Frédéric , Al-Sedairy Sultan , Prost Dominique de 
Published: July 2018

SummaryHemorrhagic diathesis and widespread microthrombosis are common in heatstroke. To assess the early stages of coagulopathy in heatstroke, thrombin-antithrombin III (TAT), fibrin monomers, plasmin-a2-antiplasmin (PAP), plasminogen and D-Dimer were measured in 16 heatstroke patients (means ± SE rectal temperature 42.3 ± 0.2° C) pre- and postcooling and compared with 8 heatstressed and 23 normal controls.Comparing heatstroke patients with normal controls, TAT, fibrin monomers, PAP and D-Dimer were elevated to (median (range)) 16.5 (4-1000) versus 3.5 (2-7.2) Μg/l p<0.001,16 (4-113) versus 2 (2-9) nM p<0.001; 3300 (1000-36500) versus 255 (136-462) Μg/l p<0.001 and 0.72 (0.22-64.8) versus 0.15 (0.05-0.25) Μg/ml p<0.01 respectively. Plasminogen decreased to 81% (34-106); PAP, TAT and D-Dimer correlated significantly with hyperthermia (r = 0.577, p = 0.02; r = 0.635, p = 0.01; r = 0.76, p = 0.003). Postcooling PAP decreased to 545 (260-850) Μg/1 p<0.005, TAT 10 (6-70) |ig/l, and fibrin monomers 22 (18-86) nM remained unchanged. Heatstressed controls showed mild but significant increase in all markers.Activation of coagulation and fibrinolysis occurs early and is profound and sustained in heatstroke. Cooling seems to attenuate the activation of fibrinolysis only, however, this requires confirmation in a larger study population.
Age-related Differences in Outcome and Severity of DIC in Children with Septic Shock and Purpura
Authors: Hazelzet Jan A , Risseeuw-Appe Inge M , Kornelisse René F , Hop Wim C J , Dekker Ina , Joosten Koen F M , Groot Ronald de , Erik Hack C 
Published: July 2018

SummaryWe studied the influence of age on mortality and severity of clotting abnormalities in 79 children (median age: 3.1 years) with meningococcal sepsis. Parameters of coagulation and fibrinolysis and plasma levels of cytokines were prospectively measured on admission. The mortality rate was 27%. The age of survivors was significantly different from that of non-survivors (p = 0.013). With the exception of FVII, vWF and t-PA, parameters of coagulation and fibrinolysis, as well as plasma cytokine levels were related to outcome. Patients were divided in two groups: younger and older than median age. The mortality in children ≤3.1 years was 40% versus 13% in children >3.1 years (p = 0.006). In contrast to cytokine levels, which were not different between the two age groups, fibrinogen, prothrombin, factors V, VII, VIII, vWF, protein C, antithrombin, FDP, and the ratio PAI-l/t-PA were related to age, indicating a more severe coagulopathy in children ≤ 3.1 years despite a similar degree of inflammatory response. A relative deficiency of coagulation factors due to an immature state of the clotting system, as well as an inadequate fibrinolytic response, both related to age may have caused this more severe coagulative response in younger children, and may have contributed to the higher mortality rate.
Influence of Sialic Acid on Erythrocyte Aggregation in Hypercholesterolemi
Authors: Hadengue A , Razavian S M , Del-Pino M , Simon A , Levenson J 
Published: July 2018

SummaryThe respective role of adhesive forces induced by fibrinogen and repulsive forces induced by erythrocyte sialic acid content on erythrocyte aggregation, was investigated in hypercholesterolemic and control subjects. Aggregation index (AI) and disaggregation shear rate threshold (³t) were determined in the presence of either autologous plasma or dextran. Compared with controls, fibrinogen (p <0.001) and aggregation parameters (AI p <0.01; ³t p <0.01) were higher in hypercholester-olemics while erythrocyte sialic acid content (p <0.001) was lower; in addition total serum sialic acid was increased (p <0.01). The aggregation properties of erythrocytes, independent of plasma environment using dextran as a bridging macromolecule, showed an enhanced disaggregation shear rate threshold and an inverse relationship with erythrocyte sialic acid content. We conclude that decreased erythrocyte sialic acid content may intensify the effect of fibrinogen on aggregation and disaggregation of erythrocytes and participate in the development of atherothrombotic complications.
Purification and Characterization of Lupus Anticoagulant Like Protein from Agkistrodon Halys Brevicaudus Venom
Authors: Li Zhao-Yan , Wu Xiao-Wei , Yu Tie-Fu , Lian Eric C-Y 
Published: July 2018

SummaryBy means of CM-Sephadex C-25, DEAE-Sephadex A-50, Sephadex G-200, and Sephadex G-75 chromatographies, a lupus anticoagulant like protein (LALP) from Agkistrodon halys brevicaudus was purified. On SDS-PAGE, the purified LALP had a molecular weight of 25,500 daltons under non-reducing condition and 15,000 daltons under reducing condition. The isoelectric point was pH 5.6. Its N terminal amino acid sequencing revealed a mixture of 2 sequences: DCP(P/S)(D/G)WSSYEGH(C/R)Q(Q/K). It was devoid of phospho-lipaseA, fibrino(geno)lytic, 5′-nucleotidase, L-amino acid oxidase, phosphomonoesterase, phosphodiesterase and thrombin-like activities, which were found in crude venom. In the presence of LALP, PT, aPTT, and dRVVT of human plasma were markedly prolonged and its effects were concentration-dependent but time-independent. The inhibitory effect of LALP on the plasma clotting time was enhanced by decreasing phospholipid concentration in TTI test. The individual clotting factor activity was not affected by LALP when higher dilutions of LALP-plasma mixture were used for assay. Russell’s viper venom time was shortened when high phospholipid confirmatory reagent was used. Therefore, the protein has lupus anticoagulant property.
Systemic Thrombin Generation and Activity Resistant to Low Molecular Weight Heparin Administered Prior to Streptokinase in Patients with Acute Myocardial Infarction
Authors: Nilsen Dennis W T , Gøransson Lasse , Larsen Alf-Inge , Hetland Øyvind , Kierulf Peter 
Published: July 2018

SummaryOne hundred patients were included in a randomized open trial to assess the systemic factor Xa (FXa) and thrombin inhibitory effect as well as the safety profile of low molecular weight heparin (LMWH) given subcutaneously in conjunction with streptokinase (SK) in patients with acute myocardial infarction (MI). The treatment was initiated prior to SK, followed by repeated injections every 12 h for 7 days, using a dose of 150 anti-Xa units per kg body weight. The control group received unfractionated heparin (UFH) 12,500 IU subcutaneously every 12 h for 7 days, initiated 4 h after start of SK infusion. All patients received acetylsalicylic acid (ASA) initiated prior to SK.Serial blood samples were collected prior to and during the first 24 h after initiation of SK infusion for determination of prothrombin fragment 1+2 (Fl+2), thrombin-antithrombin III (TAT) complexes, fibrinopeptide A (FPA) and cardiac enzymes. Bleeding complications and adverse events were carefully accounted for.Infarct characteristics, as judged by creatine kinase MB isoenzyme (CK-MB) and cardiac troponin T (cTnT), were similar in both groups of patients.A comparable transient increase in Fl+2, TAT and FPA was noted irrespective of heparin regimen. Increased anti-Xa activity in patients given LMWH prior to thrombolytic treatment had no impact on indices of systemic thrombin activation.The incidence of major bleedings was significantly higher in patients receiving LMWH as compared to patients receiving UFH. However, the occurrence of bleedings was modified after reduction of the initial LMWH dose to 100 anti-Xa units per kg body weight.In conclusion, systemic FXa- and thrombin activity following SK-infusion in patients with acute MI was uninfluenced by conjunctive LMWH treatment.
Modulation of Plasma Fibrinogen Levels by Ciprofibrate and Gemfibrozil in Primary Hyperlipidaemia
Authors: de Maat M P M , Knipscheer H C , Kastelein J J P , Kluft C 
Published: July 2018

SummaryAn elevated plasma fibrinogen level is increasingly accepted as an independent risk indicator of cardiovascular disease. This has enhanced the interest in identifying agents that can normalize elevated plasma fibrinogen levels. One group of agents with this capacity are the fibric acid derivatives, e.g. ciprofibrate and gemfibrozil.We studied fibrinogen levels after 12 weeks of treatment with ciprofibrate (n = 48) and gemfibrozil (n = 51) in hypercholesterolemic patients. The correlation of the decrease in fibrinogen with lipid lowering and the contribution of the acute phase and genetic polymorphisms to this decrease were also evaluated.After 12 weeks of treatment, the fibrinogen levels were significantly decreased (p<0.0005) with both drugs, although the decrease in the ciprofibrate group (mean 3.4 g/1 pre-treatment to 2.4 g/1 after 12 weeks) was larger than in the gemfibrozil group (mean 3.4 g/1 to 3.0 g/1.). The lipid lowering effect was comparable for the two drugs but there was no correlation for either ciprofibrate or gemfibrozil between the lipid lowering and the magnitude or the velocity of the fibrinogen lowering effect. An attenuation of the major regulatory mechanism of plasma fibrinogen levels, the acute phase reaction, was invoked as the underlying mechanism. However, pre-treatment C-reactive protein levels were not increased and did not change after treatment. Moreover, no effects of the polymorphisms of the fibrinogen β-gene on the decrease of the plasma fibrinogen levels were observed. This suggests that a new, as yet unknown, mechanism is involved in fibrinogen lowering by fibrates.
Factor VIII Inhibitors in Previously Treated Haemophilia A Patients with a Double Virus-inactivated Plasma Derived Factor VIII Concentrate
Authors: Peerlinck K , Arnout J , Di Giambattista M , Gilles J G , Laub R , Jacquemin M , Saint-Remy J M R , Vermylen J 
Published: July 2018

SummaryAntibodies to factor VIII (inhibitors) are usually produced at the beginning of treatment with factor VIII and are rare in multitransfused patients. Such antibodies are deemed to be patient-related, as supported by the description of a number of associated risk factors. However, a second category of inhibitors has recently been identified, namely antibodies occurring in multitransfused patients as a result of exposure to a particular factor VIII concentrate. A first outbreak of product-related inhibitors was recently described. The present paper describes the second well-documented occurrence of such inhibitors.Eight out of 140 multitransfused patients with severe haemophilia A developed an inhibitor to factor VIII shortly after changing treatment to a double-virus inactivated plasma-derived factor VIII concentrate. In addition to solvent-detergent treatment, this concentrate was pasteurised at 63° C for 10 hours. Exposure to the pasteurised product before inhibitor detection ranged from 9 to 45 days. Inhibitor titers varied between 2.2 and 60 Bethesda Units and recovery of transfused factor VIII ranged from 0.21 to 0.68 (expressed as IU/dl factor VIII rise per IU/kg administered). In contrast to usual inhibitors in haemophilia A patients, these product-related inhibitors showed complex inhibition kinetics. They were found specific for the factor VIII light chain. The inhibitors gradually declined when exposure to the pasteurised product was stopped, despite further treatment with other factor VIII concentrates. The present data stress the importance of carefully monitored clinical studies, both in previously treated and previously untreated patients, before introduction of a new or modified clotting factor concentrate.
Detection of Polymorphisms in the Human Urokinase-type Plasminogen Activator Gene
Authors: Conne B , Berczy M , Belin D 
Published: July 2018

SummaryExpressed polymorphisms in the genes encoding components of the fibrinolytic cascade could have implications for the predisposition to thrombolytic disorders and/or for tumor metastasis. The occurrence of published two amino acid sequences at position 194 of the human urokinase-type plasminogen activator prompted us to search by SSCP for frequent polymorphisms in several exons of the gene. Surprisingly, only one sequence was detected in codon 194 (>200 alleles). Two polymorphisms were observed in this study: the most frequent one, a C to T change near the beginning of exon 8, is probably silent; a less frequent polymorphism results in the replacement of a Leu residue by a Pro, in the kringle domain.
Emergency Oral Anticoagulant Reversal: The Relative Efficacy of Infusions of Fresh Frozen Plasma and Clotting Factor Concentrate on Correction of the Coagulopathy
Authors: Makris Mike , Greaves Mike , Phillips Wendy S , Kitchen Steve , Rosendaal Frits R , Preston F Eric 
Published: July 2018

SummaryHaemorrhage, including intracranial bleeding, is a common, potentially lethal complication of warfarin therapy and rapid and complete reversal of anticoagulation may be life-saving. Fresh frozen plasma (FFP) and vitamin K are most frequently administered. Because of the variable content of vitamin K-dependent clotting factors in FFP, and the effects of dilution, the efficacy of this approach is open to doubt. We have therefore compared the effects of FFP and clotting factor concentrates on the INRs and clotting factor levels of orally anticoagulated subjects requiring rapid correction of their haemostatic defect. In many, the pre-treatment INR was considered to be dangerously above the target therapeutic range. In the 12 patients given FFP, the INR did not completely correct (range 1.6-3.8, mean 2.3) indicating an ongoing anticoagulated state in all. In contrast, the INR in 29 subjects given clotting factor concentrates was completely corrected in 28 (range 0.9-3.8, mean 1.3). Following treatment, marked differences were observed in clotting factor IX levels between the two groups. The median factor IX level was 19 u/dl (range 10-63) following FFP infusion and 68.5 u/dl (range 31-111) following concentrate. In FFP treated patients, poorer responses were also observed for each of the other vitamin K-depen- dent clotting factors but these were less marked than for factor IX, which was present in low concentrations in some batches of FFP. Thus, haemostatically effective levels of factor IX cannot be achieved, in most instances, by the conventional use of FFP in patients requiring reversal of their anticoagulant therapy. Clotting factor concentrates are the only effective option where complete and immediate correction of the coagulation defect is indicated in orally anticoagulated patients with life or limb-threatening haemorrhage.
Reliability of a Modified Tissue Factor-Dependent Factor V Assay for Activated Protein C Resistant Factor Va Using a Calcium-Containing Thromboplastin
Authors: The Le Dzung , Donnelly Kathleen J , Wu Ning , Sevilla Barbara K , Rapaport Samuel I 
Published: July 2018

SummaryThe original tissue factor-dependent factor V assay for activated protein C resistant factor Va (Blood 1995; 85: 1704-1711) has been modified to use a calcium containing thromboplastin and to express results as an observed to expected ratio (Obs./Exp.). The latter permits establishing a normal range independent of variations due to differences in reagents. Comparing Obs/Exp ratios with DNA analysis in 72 persons revealed that an Obs/Exp ratio of 0.6 distinguished without overlap normals from heterozygotes for FV R506Q. Three homozygotes had a ratio of <0.1. Application of this Obs/Exp cut-off ratio of 0.6 to a total of 226 plasma samples tested to date discriminated without overlap between normals and heterozygotes. We conclude that this assay – readily adaptable to any dedicated coagulation laboratory and capable of yielding reliable results in all clinical circumstances in which testing is indicated – can distinguish between normals and heterozygotes for the FV R506Q mutation without the need for confirmatory DNA analysis.
The Importance of the Binding of Factor Xa to Phospholipids in the Inhibitory Mechanism of Tissue Factor Pathway Inhibitor: The Transmembrane and Cytoplasmic Domains of Tissue Factor Are not Essential for the Inhibitory Action of Tissue Factor Pathway Inhibitor
Authors: Kazama Yoshiaki 
Published: July 2018

SummaryTo investigate the inhibitory mechanism of tissue factor pathway inhibitor (TFPI), an attempt was made to examine the inhibitory activity of TFPI toward the factor Vila-truncated tissue factor (TF1-219) complex, which lacks its transmembrane and cytoplasmic domains. Factor VIIa-TF1-219 activity was significantly inhibited by TFPI-factor Xa complex in the presence of phospholipids, but was not in the absence of phospholipids. In addition, TFPI did not inhibit factor VIIa-TF1-219activity in the presence of γ-carboxyglutamic acid-domainless factor Xa. The ability of TFPI-factor Xa complex to inhibit factor VIIa-TF1-219 activity was totally dependent on the presence of phospholipids and was neutralized by prothrombin fragment 1 in a dose-dependent manner. These results indicate that the transmembrane and cytoplasmic domains of tissue factor are not essential for the inhibitory mechanism of TFPI and confirm that the binding of factor Xa to phospholipids through its γ-carboxyglutamic acid domain is essential for this reaction.
The Composition of Complexes between Plasminogen Activator Inhibitor 1, Vitronectin and either Thrombin or Tissue-type Plasminogen Activator
Authors: van Meijer Marja , Stoop Allart , Smilde Annelies , Preissner Klaus T , van Zonneveld Anton-Jan , Pannekoek Hans 
Published: July 2018

SummaryVitronectin (VN) is an obligatory cofactor for the inhibition of thrombin by plasminogen activator inhibitor 1 (PAI-1). It accelerates the rate of association between thrombin and PAI-1 more than two orders of magnitude. In contrast, VN does not accelerate the association between tissue-type plasminogen activator (t-PA) and PAI-1. Previously, we reported that the anti-PAI-1 monoclonal antibody (MoAb) CLB-2C8 binds to a short stretch of amino acids of PAI-1, located between residues 128 and 145, and prevents PAI-1 binding to VN. Furthermore, MoAb CLB-2C8 fully blocks the inhibitory activity of PAI-1 towards t-PA, emphasizing the importance of this area for the interaction with t-PA. Here, we show that this area is also required for the interaction between thrombin and PAI-1, since MoAb CLB-2C8 fully prevents inhibition of thrombin by PAI-1. In spite of similar structural requirements for the interaction between t-PA, PAI-1 and VN and between thrombin, PAI-1 and VN, the intermediate reaction products are clearly distinct. By employing surface plasmon resonance (SPR), using the BIAcore equipment, and by immunoprecipitation we demonstrate that, in the presence of VN, t-PA and PAI-1 form exclusively equimolar binary t-PA/PAI-1 complexes. Thrombin, PAI-1 and VN generate equimolar, binary thrombin/PAI-1 complexes and in addition equimolar, ternary complexes and multimers.
Antiplatelet Effect of FK633, a Platelet Glycoprotein Ilb/IIIa Antagonist, on Thrombus Formation and Vascular Patency after Thrombolysis in the Injured Hamster Carotid Artery
Authors: Kaida Takehiro , Matsuno Hiroyuki , Niwa Masayuki , Kozawa Osamu , Miyata Hideo , Uematsu Toshihiko 
Published: July 2018

SummaryThe antithrombotic and restenosis-preventing effects of FK633, an inhibitor of platelet aggregation via binding to the glycoprotein (GP) Ilb/IIIa receptor, were studied. IC50 value of FK633 against platelet aggregation ex vivo induced by 2.5 |iM adenosine diphosphate (ADP) was 5.4 X 10"7 M as determined using hamster platelet rich plasma. The inhibitory effect was also investigated in vivo on thrombus formation at the carotid arterial wall injured by a modified catheter. As a control, the left carotid artery was injured and the time required to develop a thrombotic occlusion (3.9 ±1.1 min, mean ± S.E.M., n = 18) was determined. Then, the right carotid artery of the same animal was injured while a continuous intravenous (i.v.) infusion of FK633 was administered at doses of 0 (saline), 0.1,0.3 or 1.0 mg/kg/h. The time to occlusion was dose-dependently prolonged. In a separate experiment, 10% of the total tPA dose (0.52 mg/kg) was injected into the injured artery as a bolus and the remaining was infused i.v. at a constant rate for 30 min. When FK633 (0.3 or 1.0 mg/kg/h) was infused together with tPA, late patency of the reperfused artery was much improved as compared with that of treatment with tPA alone. Bleeding time, measured at the end of the tPA infusion, was markedly prolonged when the higher dose of FK633 (1.0 mg/kg/h) was coadministered, however coadministration of the lower dose of FK633 (0.3 mg/kg/h) was almost without prolongation on the bleeding time, despite a significant effect on the vascular patency after thrombolysis. Next, neointima formation was evaluated 2 weeks after the vascular injury. When FK633 (0.3 mg/kg/h) was continuously infused i. v. by an implanted osmotic pump for 3,7 or 14 days after the vascular injury, the neointimal area formation was significantly suppressed in the treatment groups for 7 or 14 days. These findings suggest that FK633 inhibits platelet activation in the injured artery and improves vascular patency after thrombolysis with tPA with a concomitant suppression of neointima formation.
Genetic Analysis in Japanese Kindreds of Congenital Type I Antithrombin Deficiency Causing Thrombosis
Authors: Nakahara Yoshifumi , Tsuji Hajime , Nakagawa Katsumi , Masuda Haruchika , Kitamura Hidetsugu , Nishimura Hiromi , Kasahara Teruhisa , Sugano Tatsuya , Sawada Shohei , Nakagawa Masao 
Published: July 2018

SummaryWe have identified two novel minor deletions (case 1; -TA or -AT at nucleotide 9831-3 in exon 5 and case 2; -A at nucleotide 7640-1 in exon 4), one novel nonsense mutation (case 3; TAT to TAA at nucleotide 7491 in exon 4), and one recurrent nonsense mutation (case 4; CGA to TGA at nucleotide 5381 in exon 3A) in Japanease kindreds with congenital type I antithrombin deficiency. The deletion detected in case 1 represented a symmetric element (CTCTGTCTC) and possessed a direct repeat (CTCTATGTCTC). The deletion in case 2 was recognized in a consensus sequence (TGAAT) and possessed a direct repeat (GATGAA). The nonsense mutation in case 3 formed a palindrome (CCGTTAACGG) and that in case 4 was caused hy a CpG dinucleotide mutation. These results confirm that the mutations of congenital type I antithrombin deficiency are not random events but are influenced strongly by DNA sequences.