bluuebunny/crossref_metadata_2025_split huggingface dataset:
Out of Hospital Antithrombotic Prophylaxis after Total Hip Replacement: Low-molecular-weight Heparin, Warfarin, Aspirin or Nothing?
Authors: Bounameaux Henri , Sarasin François 
Published: March 2018

SummarySeveral studies have suggested that after hip replacement the risk of deep vein thrombosis and subsequent pulmonary embolism (PE) may persist for some weeks. Antithrombotic prophylaxis, however, is generally stopped at hospital discharge. Using a Markov-based decision analysis, we measured the clinical and economical consequences of extending prophylaxis after hospital discharge up to 4 weeks and 6 weeks, using either low-molecular-weight heparin (LMWH), warfarin, or aspirin. In the reference strategy, antithrombotic prophylaxis was stopped at hospital discharge. Outcome measures included the number of PE prevented, major haemorrhages induced, overall costs in Euro (EUR) and specific costs generated by each PE prevented for all strategies.Extending prophylaxis up to 4 weeks after discharge was safe and cost saving for all prophylactic regimens, although LMWH was the most effective strategy. Our results were most sensitive to the rate of haemorrhages, the efficacy of treatment and its costs. Specifically, the number of PEs prevented exceeded that of haemorrhages induced if the efficacy of antithrombotic prophylaxis was 2:40% (assuming a low rate of haemorrhages of 0.1% per week), and 2:70% (assuming a high rate of haemorrhages of 0.25% per week). LMWH and warfarin remained cost saving unless their costs were more than doubled compared to that of baseline value. Although less effective than LMWH and warfarin, prophylaxis with aspirin was cost saving in all scenarios tested. Extending prophylaxis up to 6 weeks was also effective (the number of PEs prevented overwhelmed that of major haemorrhages induced), but only for the scenario of a low bleeding risk (0.1%/week). In this strategy, aspirin remained cost saving, while the costs for each PE prevented became high (EUR 10,000 to EUR 20,000) if the costs of LMWH and warfarin increased.After hip replacement, extending antithrombotic prophylaxis up to 4 weeks after hospital discharge is effective and cost saving. Although LMWH is the most effective strategy, warfarin, and to a lesser extent aspirin may be alternate options if ressources are a major concern.Extending prophylaxis up to 6 weeks is more risky in patients at high bleeding risk, and generates additional costs.
Alboluxin, a Snake C-type Lectin from Trimeresurus albolabris Venom is a Potent Platelet Agonist acting via GPIb and GPVI
Authors: Du Xiao-Yan , Magnenat Edith , Wells Timothy , Clemetson Kenneth 
Published: March 2018

SummaryAlboluxin, a potent platelet activator, was purified from Trimeresurus albolabris venom with a mass of 120 kDa non-reduced and, after reduction, subunits of 17 and 24 kDa. Alboluxin induced a tyrosine phosphorylation profile in platelets that resembles those produced by collagen and convulxin, involving the time dependent tyrosine phosphorylation of Fc receptor γ chain (Fcγ), phospholipase Cγ2 (PLCγ2), LAT and p72SYK. Antibodies against both GPIb and GPVI inhibited platelet aggregation induced by alboluxin, whereas antibodies against α2β1 had no effect. Inhibition of αIIbβ3 reduced the aggregation response to alboluxin, as well as tyrosine phosphorylation of platelet proteins, showing that activation of αIIbβ3 and binding of fibrinogen are involved in alboluxin-induced platelet aggregation and it is not simply agglutination. N-terminal sequence data from the β-subunit of alboluxin indicates that it belongs to the snake C-type lectin family. The C-type lectin subunits are larger than usual possibly due to post-translational modifications such as glycosylation. Alboluxin is a hexameric (αβ)3 snake C-type lectin which activates platelets via both GPIb and GPVI.
Two Regions of the Human Platelet F11-Receptor (F11R) Are Critical for Platelet Aggregation, Potentiation and Adhesion
Authors: Babinska Anna , Kedees Mamdouh , Athar Humra , Sobocki Tomasz , Sobocka Malgorzata , Ahmed Tahir , Ehrlich Yigal , Hussain M. , Kornecki Elizabeth 
Published: March 2018

SummaryThe F11 receptor (F11R) was first identified on the surface of human platelets as a target for a stimulatory monoclonal antibody (M.Ab.F11) that induces secretion, followed by exposure of fibrinogen receptors and aggregation. Cloning of the gene of F11R has revealed that this protein is a cell adhesion molecule (CAM), a member of the Ig superfamily and an ortholog of the murine protein called junctional adhesion molecule (JAM). The present study has identified two domains through which M.Ab.F11 triggers a platelet response culminating with aggregation. M.Ab.F11-mediated platelet adhesion, and the potentiation of collagen and ADP-induced platelet aggregation by M.Ab.F11, were found to involve the same two domains. A F11R recombinant protein (sF11R) completely inhibited platelet aggregation, adhesion and potentiation induced by M.Ab.F11, indicative that the active conformation of the external domain of F11R is present in the soluble, secreted recombinant protein. Furthermore, a specific peptide containing the sequence of the N-terminal amino acids S-1 to C-23 of F11R, and a peptide with the sequence of K-70 to C-82 in the 1st immunoglobulin-like (Ig) fold of F11R, both inhibited M.Ab.F11-induced aggregation, adhesion and potentiation of the aggregation of human platelets. Modeling of the 3D structure of the extracellular domain of the human platelet F11R suggests that these two regions form an active site within the conformation of this CAM. The sequence of these functional domains of F11R (in the N-terminus and 1st Ig-fold) provide the basis for new drug development in the treatment of certain types of thrombocytopenia and inflammatory thrombosis.
Role of the PAR4 Thrombin Receptor in Stabilizing Platelet-platelet Aggregates as Revealed by a Patient with Hermansky-Pudlak Syndrome
Authors: Covic Lidija , Singh Christopher , Smith Hedy , Kuliopulos Athan 
Published: March 2018

SummaryIndividuals with Hermansky-Pudlak Syndrome (HPS) lack platelet dense granules and have no ADP-autocrine response. Despite these platelet deficiencies, HPS patients exhibit a surprisingly mild bleeding phenotype. We hypothesize that activation of the PAR4 thrombin receptor compensates for the lack of an ADP-autocrine response by the P2Y12 ADP receptor in individuals with HPS. Here, we determine that PAR4 activation by thrombin occurs well after ADP release from dense granules in normal individuals. However, the signal from PAR4 stabilizes platelet-platelet aggregate formation in the absence of P2Y12 activation by ADP. Thus, the strong signal emanating from PAR4 during platelet aggregation would provide an explanation for the mild bleeding diathesis of HPS.
Brain-derived Neurotrophic Factor Is Stored in Human Platelets and Released by Agonist Stimulation
Authors: Fujimura Hironobu , Chen Ruoyan , Nakamura Takashi , Nakahashi Takeshi , Kambayashi Jun-ichi , Sun Bing , Altar C. , Tandon Narendra 
Published: March 2018

SummaryBrain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays critical roles in the survival, growth, and maintenance of brain and peripheral neurons. We report the presence of BDNF protein in human platelets and its release upon agonist stimulation. The BDNF content of washed platelets varied widely, from 3.5 to 67 ng/ 4 X 108 platelets, averaging 25.2 ± 21.2 ng/4 X 108 platelets (mean ± SD). The BDNF concentration in platelet-poor plasma was low (1.7 ± 1.7 ng/ml, n = 11). Thrombin, collagen, the Ca++ ionophore A23187, and shear stress each induced a rapid release of BDNF from platelets. Up to only half of platelet BDNF was secreted upon agonist stimulation, suggesting that platelets may have a non-releasable pool of BDNF, or that the released BDNF binds to a recognition site on the platelet surface and is internalized, as occurs with serotonin. However, the cognate BDNF receptor, TrkB, was not detected in platelets. Nevertheless, the ability of BDNF to bind washed platelets was shown by FACS analysis confocal microscopy and by the binding and apparent internalization of [125I]-BDNF by platelets. A very high affinity site (Kd = 130 X 10−15 M, ∼80 sites/platelet) and a moderately high affinity site (Kd = 20 nM, ∼3750 sites/platelet) were identified. The BDNF content in two mega-karyocytic cell lines, DAMI and Meg-01, was only 0.1% of the content measured in platelets. No BDNF mRNA was detected by Northern blotting in these cell lines or in platelets. The pituitary gland was also ruled out as a source for platelet BDNF, since the BDNF content of rat platelets did not decrease 2 weeks after hypophysectomy. Thus, platelet BDNF is not acquired from the megakaryocyte or pituitary gland, but is probably acquired from other sources via the blood circulation. Platelets appear to bind, store and release BDNF upon activation at the site of traumatic injury to facilitate the repair of peripheral nerves or other tissues that contain TrkB.
Patients with Essential Thrombocythaemia have an Increased Prevalence of Antiphospholipid Antibodies which may be associated with Thrombosis
Authors: Donohoe S. , Carr P. , Dave M. , Mackie I. , Machin S.J. , Harrison C.N. 
Published: March 2018

SummaryA significant proportion of patients with Essential Thrombocythaemia (ET) have thrombotic complications which have an important impact upon the quality, and duration of their life. We performed a retrospective cross sectional study of the prevalence of antiphospholipid antibodies (APA) in 68 ET patients. Compared to 200 “elderly” controls (> 50 years) there was a significant increase in anticardiolipin IgM (p < 0.0001) and anti β2 glycoprotein I (anti-β2GPI) IgM (p < 0.0001) antibodies in ET. Thrombosis occurred in 10/20 with APA and 12/48 without, p = 0.04, relative risk 2.0 (95% confidence intervals 1.03–3.86); these patients did not differ in terms of other clinical features. The prevalence of thrombosis in patients with dual APA (6/7) was significant when compared to those with single APA (p = 0.02) and the remaining patients (p < 0.0002). Also anti-β2GP1 IgM antibodies either alone, or in combination with another APA, were associated with thrombosis (p = 0.02). These results suggest that the prevalence of APA in ET and their influence upon thrombotic risk merit investigation in a larger study.
Molecular mechanisms of initiation of fibrinolysis by fibrin
Authors: Nieuwenhuizen Willem , Medved Leonid 
Published: March 2018

SummaryFibrinogen is rather inert in the circulation, however, after conversion into fibrin it participates in various physiological processes including fibrinolysis. Initiation of fibrinolysis occurs through a number of orchestrated interactions between fibrin, plasminogen and its activator tPA which result in generation of plasmin. Numerous studies localized a set of specific low affinity tPA- and plasminogen-binding sites in each D region of fibrin(ogen). The tPA-binding site includes residues γ312-324 and the plasminogen-binding site includes residues Aα148-160; they bind tPA and plasminogen with a Kd of about 1 μM. Another set of high affinity tPA- and plasminogen-binding sites (Kds = 16-33 nM) was identified in the compact portion of each fibrin(ogen) αC-domain within residues Aα392-610. All these sites are cryptic in fibrinogen and become exposed in fibrin. Recent studies with recombinant and proteolytic fibrin(ogen) fragments clarified the molecular mechanisms by which these sites become exposed. Namely, upon fibrin assembly, the interaction between the D and E regions causes conformational changes in the former that expose the low affinity binding sites. The exposure of the high affinity binding sites in the αC-domains is connected most probably with their switch from an intramolecular interaction in fibrinogen to an intermolecular one in fibrin. These mechanisms serve to minimize degradation of circulating fibrinogen and confine fibrinolysis to places of fibrin deposition.
Vascular thrombogenicity induced by progressive LDL oxidation: protection by antioxidants
Authors: Banfi Cristina , Camera Marina , Giandomenico Giovanna , Toschi Vincenzo , Arpaia Magda , Mussoni Luciana , Tremoli Elena , Colli Susanna 
Published: March 2018

SummaryOxidative modification of LDL, which dysregulates the homeostasis between blood and vascular cells, and alterations of endothelial function are considered among the early events in the pathogenesis of atherosclerosis. This study was designed to evaluate the impact of progressive LDL oxidation on the thrombotic response both in vitro and in vivo, and to address the potential effect of antioxidants. Tissue factor was induced by progressive LDL oxidation in HUVEC, and this event was in parallel to the appearance of the apoptotic phenotype. Both these phenomena were mediated by ERK1/2 activation and were prevented by LDL pre-enrichment with antioxidants. In contrast, antioxidants failed to affect tPA and PAI-1 secretion, which was increased by LDL, either native or oxidized. Tissue factor-pathway inhibitor was also increased upon HUVEC exposure to progressively oxidized LDL. LDL, in the presence of an oxidative agent, trigger a thrombogenic response in vivo, mostly TF-dependent, in an in situ model of platelet deposition. This effect was markedly attenuated when LDL were enriched with antioxidants. It can be concluded that vascular thrombogenicity is induced by progressive LDL oxidation and that alterations of the antioxidant/oxidant balance of the LDL particle in favor of the antioxidant tone are protective against the thrombotic response triggered by oxidative stress. The extrapolation of these data in a clinical setting, even if not easy, offers potential insights for the use of antioxidants in the prevention of thrombotic complications associated with atherothrombosis.
Enoxaparin monotherapy without oral anticoagulation to treat acute symptomatic pulmonary embolism
Authors: Beckman Joshua , Dunn Kelly , Sasahara Arthur , Goldhaber Samuel 
Published: March 2018

SummaryConventional anticoagulation for symptomatic pulmonary embolism consists of continuous intravenous unfractionated heparin as a “bridge” to oral anticoagulation. This strategy requires 5 days or more of intravenous heparin while oral vitamin K antagonists gradually achieve a therapeutic effect. Oral vitamin K antagonists require frequent blood testing to optimize dosing, and their interactions with other medications and foods make regulation difficult. Therefore we tested a different approach to therapy: long-term enoxaparin monotherapy.We randomized 60 symptomatic pulmonary embolism patients in a 2:1 ratio to 90 days of enoxaparin as monotherapy without warfarin (N=40) or to intravenous unfractionated heparin as a “bridge” to warfarin, target INR 2.0-3.0 (N=20). Enoxaparin patients received 1 mg/kg twice daily for 14 days during the acute phase followed by randomized assignment during the chronic phase to 1.0 mg/kg vs. 1.5 mg/kg once daily.In an intention-to-treat analysis, 3 of the 40 enoxaparin patients developed recurrent venous thromboembolism compared with 0 of 20 standard therapy patients (p = 0.54). One of the 40 enoxaparin patients had a major hemorrhagic complication compared with 2 of the 20 standard therapy patients (p = 0.26). Median hospital length of stay was shorter with enoxaparin compared to standard therapy (4 vs. 6 days) (p = 0.001). Following our study we can conclude that extended 3-month treatment with enoxaparin as monotherapy for symptomatic, acute pulmonary embolism is feasible and warrants further study in a large clinical trial.
Genetic mapping and characterization of the bleeding disorder in the fawn-hooded hypertensive rat
Authors: C.Wu Francisca , Dumas Pierre , Rangel-Filho Artur , Datta Milton , Ning Gang , Cooley Brian , Majewski Rebecca , Provoost Abraham , Jacob Howard , Datta Yvonne 
Published: March 2018

SummaryRelease of platelet dense granule contents occurs in response to vascular injury, playing an important role in platelet aggregation and primary hemostasis. Abnormalities of the platelet dense granules results in a bleeding disorder of variable severity termed “storage pool defect” (SPD). We have examined the fawn-hooded hypertensive (FHH) rat as a model of SPD in order to genetically map the locus (Bd) responsible for prolonged bleeding. Platelet function assays of the FHH rat confirmed the presence of a platelet dense granule SPD. However electron microscopy and lysosomal enzyme assays indicated differences between the FHH rat and other rodent models of SPD. Genetic mapping through the use of congenic FHH rats localized the Bd locus to an approximately 1 cM region on rat chromosome 1. Through the use of comparative mapping between species and analysis of the initial draft of the rat genome assembly, six known and thirty-four putative genes were identified in the Bd locus. None of these genes have been previously implicated in platelet function. Therefore positional cloning of the gene responsible for the bleeding disorder in the FHH rat will lead to new insights in platelet physiology, with implications for diagnosis and management of hemostatic and thrombotic disorders.
Do oxidized fatty acids activate coagulation factor VII during post-prandial lipemia in women?
Authors: Wilson Robert , Lyall Karin , Millar Margaret , Smyth Louise , Pearson Claire , Riemersma Rudolph 
Published: March 2018

SummaryFactor VII is activated to VIIa within hours after dietary fat, irrespective of its fatty acid composition. Edible oils contain oxidized material (hydroxy fatty acids, HOFA). Twenty-five fasting women, aged 38 (10) years, consumed 30 g walnut oil containing 26 (6) mg HOFA. Blood was collected 2-hourly to measure plasma triglycerides and plasma lipid HOFA by gas chromatography/mass spectrometry. VII and sTF-dependent VIIa were quantified at 0, 6 and 24 h. Increased plasma triglycerides and HOFA (areas under the-curve 0-8 h, AUC) were related r = 0.83, p <0.001. VIIa increased from 2.6 (1.4) to 4.2 (1.9) ng/mL at 6 h (p <0.001). Plasma VII remained constant. VIIa (6 h) was related to plasma triglycerides- and HOFA-AUC: r = 0.38 and 0.53, respectively (both p <0.05). Plasma VIIa was also related to body weight, fasting triglycerides, HOFA and VII. Only HOFA-AUC and body weight related to VIIa (6 h) in stepwise regression analysis (p = 0.007 and 0.038, respectively). Oxidized, not normal, fat activates VII and could increase coronary risk in humans.
Severe Factor VII Deficiency Caused by a Novel Mutation His348 to Gln in the Catalytic Domain
Authors: Matsushita Tadashi , Yamazaki Tomio , Sugiura Isamu , Kojima Tetsuhito , Saito Hidehiko , Katsumi Akira 
Published: March 2018

SummaryFactor VII is a vitamin K-dependent zymogen that plays a key role in the initiation of the extrinsic pathway. A severe factor VII
deficiency was identified in a 45-year old male whose plasma factor VII antigen was less than 60 ng/ml and expressed 5.2% of normal factor VII activity. DNA sequence analysis of the patient’s factor VII gene showed a thymidine to guanine transversion at nucleotide 10968 in exon VIII that results in a novel amino acid substitution of His348 to Gln. The patient was homozygous for this mutation, whereas some of his family members were heterozygous. Both wild type and mutant factor VII were transiently expressed in COS-1 cells. The level of secreted mutant factor VII antigen was only 11.0% of the level of wild type factor VII. In CHO cells stably transfected with the mutant factor VII, only 37.3% of the total labeled FVII was secreted into the conditioned media and the remainder was retained inside the cells. These data suggest this mutation leads to factor VII deficiency due to the impaired secretion of the molecule.
Mapping and Functional Studies of Two Alloantibodies Developed in Patients with Type 3 von Willebrand Disease
Authors: Tout Hélène , Obert Bernadette , Houllier Anne , Fressinaud Edith , Rothschild Chantal , Meyer Dominique , Girma Jean-Pierre 
Published: March 2018

SummaryInhibitors against von Willebrand factor (vWF) developed in two unrelated multitransfused patients (patients 1 and 2) with severe (type 3) von Willebrand disease (vWD) were analyzed. Both inhibitors were identified as antibodies of the IgG class by ELISA using immobilized purified vWF and either serum or purified Ig from the patients. Typing, mapping and functional studies of both antibodies revealed significantly distinct properties. Patient 1 antibody contained all subclasses of IgG (1, 2, 3 and 4) whereas antibody from patient 2 was a mixture of only IgG1 and 4. By ELISA using a series of immobilized purified proteolytic fragments of vWF, patient 1 antibody mainly bound to fragment SpIII and, to a lower extent, to fragments SpII and SpI; it poorly bound to P34 and the 39/34 kDa fragment. In contrast, patient 2 antibody only bound to fragments corresponding to the N-terminal portion of vWF but failed to bind to SpII. Functional studies were performed by testing the capacity of each antibody to inhibit vWF binding to its various ligands. Both antibodies blocked vWF binding to Factor VIII (FVIII), fibrillar type III collagen, bitiscetin and the subsequent induced binding to GPIb. Patient 1 antibody also blocked vWF binding to platelet GPIb when induced by ristocetin. However it failed to block vWF binding to GPIb when induced by botrocetin as well as the binding of botrocetin itself to vWF. Our data thus suggest that this inhibitor does not recognize the GPIb-binding site on vWF but the sites of vWF involved in its interaction with ristocetin. In contrast, we observed that patient 2 antibody blocked vWF binding to platelet GPIb induced by either agonist as well as vWF binding to botrocetin. Finally, the effect of the antibodies was tested on vWF binding to GPIIb/IIIa. As expected from the mapping experiments, only IgG from patient 1 blocked the interaction while IgG from patient 2 had no effect. In conclusion, we have shown that two multitransfused patients with type 3 vWD have developed alloantibodies with similar properties to those of polyclonal antibodies but with distinct effects on the functions of vWF.