bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tirofiban optimizes platelet inhibition for immediate percutaneous coronary intervention in high-risk acute coronary syndromes
Authors: Keck Frieder , Staritz Peter , Lehrke Stephanie , Katus Hugo A. , Giannitsis Evangelos , Ivandic Boris T. , Kurz Kerstin 
Published: September 2008

SummaryIt was the aim of this study to compare the efficacy of early platelet inhibition by 600 mg clopidogrel and acetylsalicylic acid (ASA) to a triple therapy including a glycoprotein IIb-IIIa receptor blocker. Immediate percutaneous coronary intervention (PCI) is recommended for high-risk acute coronary syndromes. In this setting the efficacy of platelet inhibition is unknown. One hundred patients were randomized to receive ASA and 600 mg clopidogrel, or additional open-label tirofiban (bolus of 10 µg/kg body weight followed by continued infusion of 0.15 µg/kg body weight per minute) as soon as non-ST - segment elevation myocardial infarction was diagnosed. The primary endpoint was the reduction of infarct size determined by post-interventional increases of cardiac troponin T (cTnT). Secondary endpoints included platelet function measured by optical and impedance aggregometry using ADP (5 and 20 µM) and collagen (1 µg/ml) as platelet agonists. Tirofiban maximized platelet inhibition (p<0.0001) immediately and was associated with significantly lower post-interventional cTnT concentrations (p=0.0352). In the dual platelet inhibition arm, clopidogrel was not effective in 69% of patients at the time of coronary intervention, and still in 47%, if pre-treatment time was >120 minutes. The frequency of cardiovascular (death, myocardial infarction, revascularization) and bleeding events was comparable. Platelet aggregation is not adequately inhibited in cTnT - positive patients in the setting of immediate PCI with very short pre-treatment times. Only tirofiban provided consistent and effective inhibition of platelet aggregation at the time of immediate or very early invasive therapy.
Comparison of bivalirudin, enoxaparin, and unfractionated heparin in preventing cardiac catheter thrombosis
Authors: Buerke Michael , Schubert Sebastian , Reindl Iris , Michel Thomas , Hauroeder Baerbel , Carter Justin M. , Peetz Dirk , Werdan Karl , Schlitt Axel , Maegdefessel Lars 
Published: September 2008

SummaryBivalirudin, a direct thrombin inhibitor binds specifically and reversibly to both fibrin-bound and unbound thrombin. Bivalirudin is approved for use as an anticoagulant in patients undergoing percutaneous coronary intervention. The OASIS-5 trial presented a significant increase in cardiac catheter thrombosis for the pentasaccharid fondaparinux compared to enoxaparin. Catheter thrombosis has never been reported in any trial using bivalirudin. Our study compared the development of catheter thrombosis for bivalirudin, enoxaparin, and unfractionated heparin in a controlled in-vitro environment. Ten healthy male volunteers were pretreated with aspirin 500 mg 2 hours before venesection of 50 ml of blood. The seven groups of anticoagulant combinations tested were:UFH, UFH + eptifibatide, enoxaparin, enoxaparin + eptifibatide, bivalirudin bolus, bivalirudin + eptifibatide, bivalirudin bolus + continuous infusion. The blood/anticoagulant mix continuously circulated through a cardiac guiding catheter for 60 minutes or until the catheter became blocked with thrombus. Thrombus development was assessed by weighing each catheter before and after the procedure. Electron microscopy was used to quantify the degree of erythrocyte, platelet and fibrin deposition. Following anticoagulation with bolus dose bivalirudin, the catheter was invariably occluded with thrombus after 33 minutes of circulation. However, a continuous infusion of Bivalirudin prevented the development of occlusive catheter thrombosis. In the bolus bivalirudin group the mean thrombus weight was significantly greater than in all other groups (p-value < 0.01 in all analyses). Bivalirudin given as a bolus was not sufficient to prevent cardiac catheter thrombosis in our in-vitro study. However, a continuous infusion of bivalirudin had similar anti-thrombotic efficacy compared to other treatment strategies.
Comparison of the two-year outcomes and costs of prophylaxis in medical patients at risk of venous thromboembolism
Authors: Becker Russ , Lin Jay , Benner Josh , Deitelzweig Steven B. 
Published: September 2008

SummaryA decision-analytic model incorporating a Markov process to assess the incremental cost and effectiveness of venous throm-boembolism (VTE) prevention strategies was used. Modeling was carried out using a hypothetical cohort of medical patients at risk of VTE.The model compared clinical effectiveness (primary and recurrent VTE, death), safety (adverse events), and direct medical costs between patients receiving enoxaparin prophylaxis, unfractionated heparin (UFH) prophylaxis, and no prophylaxis (n=10,000 for each arm). Monte Carlo simulation was performed to identify changes in inputs that would affect the results.The estimated incidence of VTE at two years (including recurrentVTE) was 6.8% with enoxaparin prophylaxis, 7.9% with UFH prophylaxis,and 17.9% with no prophylaxis.Two-year mortality occurred in 15.7% of enoxaparin patients and 16.0% of UFH patients, with the incidences of major bleeding in these groups being 0.7% and 1.2%, respectively. However, both enoxaparin and UFH prophylaxis were associated with higher rates of major bleeds than no prophylaxis (0.6%).Total average costs per patient were (US dollars) $1,264 (for enoxaparin prophylaxis, $1,585 for UFH prophylaxis,and $2,245 for no prophylaxis).No realistic parameter changes resulted in enoxaparin prophylaxis being more costly than UFH prophylaxis. For the healthcare payer, considering all direct medical costs associated with VTE up to two years after an admission for acute illness, prophylaxis with enoxaparin was more effective and less costly than UFH. This identifies enoxaparin as a potentially favorable VTE prophylaxis regimen compared with UFH and no prophylaxis in at-risk medical patients
Growth arrest-specific gene 6 (GAS6)
Authors: Fernández-Fernández Laura , Bellido-Martín Lola , García de Frutos Pablo 
Published: September 2008

SummaryGAS6 (growth arrest-specific 6) belongs structurally to the family of plasma vitamin K-dependent proteins. GAS6 has a high structural homology with the natural anticoagulant protein S, sharing the same modular composition and having 40% sequence identity. Despite this, the low concentration of GAS6 in plasma and the pattern of tissue expression of GAS6 suggest a distinct function among vitamin-K dependent proteins. Indeed, GAS6 has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family; Tyro3, Axl and MerTK. GAS6 employs a unique mechanism of action, interacting through its vitamin K-dependent GLA (γ-carboxyglutamic acid) module with phosphatidylserine-containing membranes and through its carboxy-terminal LamG domains with the TAM membrane receptors. During the last years there has been a considerable expansion of our knowledge of the biology of TAM receptors that has lead to a clear picture of their importance in inflammation, haemostasis and cancer, making this system an interesting target in biomedicine. The innate immune response and the coagulation cascade have been shown to be interconnected. Mediators of inflammation are essential in the initiation and propagation of the coagulation cascade, while natural anticoagulants have important anti-inflammatory functions. GAS6 represents a new player in this context, while protein S seems to have new functions beyond its anticoagulant role through its interaction with TAM receptors.
Factor IX: Insights from knock-out and genetically engineered mice
Authors: Monahan Paul E. 
Published: September 2008

SummaryThe study of coagulation factors has been rapidly advanced by studies performed in genetically engineered mouse strains. Investigation of factor IX (FIX) has benefited from excellent genedeleted mouse models that recapitulate many of the features of human haemophilia B. Moreover, advanced positional cloning techniques and availability of technology to allow not only knock-out mice, but also knock-in and knock-down mice, provide new opportunities to observe genotype-phenotype and structure-function correlations regarding FIX, as well as the interaction of FIX with inflammatory, immune, and tissue repair systems. In this paper, available FIX knock-out mice and additional haemophilia B mouse models are reviewed specifically in regards to observations these models have facilitated concerning: factor IX gene expression and factor IX protein pharmacokinetics; the role of FIX in haemostasis, thrombosis and wound healing; insights into coagulation FIX arising out of gene therapy applications in haemophilia mouse models; immunology of tolerance or loss of tolerance of FIX and inhibitor antibody formation.
Risk factors of vitamin K antagonist overcoagulation
Authors: Cadiou Gwenaëlle , Varin Rémi , Levesque Hervé , Grassi Vanessa , Benichou Jacques , Tiret Isabelle , Dieu Bernard , Lecam-Duchez Véronique , Borg Jeanne-Yvonne , Muller Jean-Michel , Benhamou Ygal , Marie Isabelle 
Published: September 2008

SummaryThe aims of this case-control study were to identify in vitamin K antagonist (VKA)-treated unselected patients, factors associated with international normalised ratio (INR) values: (i) greater than 6.0.;and (ii) ranging from 4.0 to 6.0 complicated with bleeding. We also assessed VKA-related morbidity in these patients. During a two-month period, 4,188 consecutive and unselected patients were referred to our Emergency Department. At admission, the medical records of each patient and two age- and sex-matched controls were reviewed for: both duration and indication of VKA therapy, previous medical history of VKA-related haemorrhage, underlying co-morbidities, concomitant medications other than VKA, duration of hospitalization and deaths’ causes. Of these 4,188 subjects,50 case-patients (1.19%) were identified; both case-patients and controls did not differ as regards indications and patterns of VKA therapy. Interestingly, two-thirds of case-patients were women, suggesting that female gender may be a risk factor of VKA over-coagulation onset. We identified the following risk factors of VKA over-coagulation: previous medical history of INR levels over therapeutic range, therapy with antibiotics, amiodarone and proton pump inhibitors, as well as fever. A total of 88% of case-patients were hospitalized; mean duration of patients’ hospitalization was seven days [range:1–56 days];no patient died from major bleeding. Our study underscores that it is of utmost importance to consider the strength of indication before starting VKA therapy, as this therapy has been responsible for as high as 1.19% of admissions in unselected subjects referred to an Emergency Department. Our data therefore suggest that internists should be aware of VKA-related high morbidity, particularly in situations at risk of VKA over-coagulation.
Greater reduction of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease
Authors: arenhorst Christoph , James Stefan , Brandt John T. , Jakubowski Joseph A. , Winters Kenneth J. , Wallentin Lars , Erlinge David , Braun Oscar Ö. , Johnell Matilda , Siegbahn Agneta 
Published: September 2008

SummaryPrasugrel, a novel P2Y12 ADP-receptor antagonist, has been reported to achieve greater inhibition of platelet aggregation compared to clopidogrel as assessed by light transmission aggregometry. It was the objective of this study to investigate the effect of prasugrel on alternative markers of platelet activation in comparison to a high loading dose and the approved maintenance dose of clopidogrel. One hundred ten aspirintreated patients with stable coronary artery disease were randomized to a loading dose (LD, day 1)/ maintenance dose (MD, days 2–29) of prasugrel 60 mg/10 mg or clopidogrel 600 mg/75 mg. Platelet activation markers were analyzed by whole blood flow cytometry pre-dose and at 2 and 24 hours after LD and pre-dose at 14 and 29 days. After stimulation with 20 µM ADP, 2 hours after LD, significantly lower expression of activated GPIIb/IIIa (4.3 vs. 21.8 [mean fluorescent intensity (MFI)], p < 0.001) and P-selectin (2.0 vs. 11.7 MFI, p < 0.001) along with decreased formation of platelet-monocyte aggregates (16.4% vs.29.6% positive cells, p < 0.001) was observed with prasugrel versus clopidogrel. All these effects were maintained through 24 hours and during the MD period. In conclusion, prasugrel 60 mg LD and 10 mg MD inhibit several markers of platelet activation and the formation of platelet-monocyte aggregates more effectively than a 600 mg LD and 75 mg MD of clopidogrel. Attenuated platelet aggregation and reduced expression of platelet procoagulant and pro-inflammatory markers with prasugrel suggest the potential to reduce cardiovascular events both in the acute setting and in longterm treatment.
Maintained effectiveness of an electronic alert system to prevent venous thromboembolism among hospitalized patients
Authors: Lecumberri Ramón , Marqués Margarita , Díaz-Navarlaz María , Panizo Elena , Toledo Jon , García-Mouriz Alberto , Páramo José A. 
Published: September 2008

SummaryDespite current guidelines, venous thromboembolism (VTE) prophylaxis is underused. Computerized programs to encourage physicians to apply thromboprophylaxis have been shown to be effective in selected populations. Our aim was to analyze the impact of the implementation of a computer- alert system for VTE risk in all hospitalized patients of a teaching hospital. A computer program linked to the clinical record database was developed to assess all hospitalized patients’VTE risk daily. The physician responsible for patients at high risk was alerted, but remained free to order or withhold prophylaxis. Over 19,000 hospitalized, medical and surgical, adult patients between January to June 2005 (pre-intervention phase), January to June 2006 and January to June 2007 (postintervention phase), were included. During the first semesters of 2006 and 2007, an electronic alert was sent to 32.8% and 32.2% of all hospitalized patients, respectively. Appropriate prophylaxis among alerted patients was ordered in 89.7% (2006) and 88.5% (2007) of surgical patients, and in 49.2% (2006) and 64.4% (2007) of medical patients. A sustained reduction of VTE during hospitalization was achieved, Odds ratio (OR): 0.53, 95% confidence interval (CI) (0.25–1.10) and OR: 0.51, 95%CI (0.24–1.05) during the first semesters of 2006 and 2007 respectively, the impact being significant (p<0.05) among medical patients in 2007, OR: 0.36, 95%CI (0.12–0.98). The implementation of a computer- alert program helps physicians to assess each patient’s thrombotic risk, leading to a better use of thromboprophylaxis, and a reduction in the incidence of VTE among hospitalized patients. For the first time, an intervention aimed to improveVTE prophylaxis shows maintained effectiveness over time.
Analysis of the venous thromboembolic risk associated with severe postpartum haemorrhage in the NOHA First cohort
Authors: Chauleur Céline , Cochery-Nouvellon Eva , Mercier Eric , Aya Guy , Marès Pierre , Mismetti Patrick , Lissalde-Lavigne Géraldine , Gris Jean-Christophe 
Published: September 2008

SummarySevere postpartum haemorrhages (PPH) are responsible for maternal morbidity/mortality. Their complex management sometimes requires haemostatic supplementation, and therapeutic trials on fibrinogen or activated factor VII, which may add to the thrombotic risk, are currently being considered. Furthermore, there is a risk of venous thromboembolism (VTE) during the postpartum period, hence we studied the relationship between severe PPH and VTE in women during their first pregnancy. Among the 32,463 women enrolled between January 1, 1999 and February 1, 2004 in the NOHA First cohort, 317 developed severe PPH, 11 postpartum VTE and 60 had postpartum superficial vein thrombosis (SVT). In the women with severe PPH, whilst there were no episodes of VTE, there were three episodes of SVT, which occurred 6 weeks postpartum. All of the women with severe PPH received packed red blood cell (RBC) units, 29 (9.1%) platelets units, 51 (16.1%) fresh frozen plasma and 29 (9.1%) fibrinogen concentrates. Three patients with both severe PPH and SVT received only packed RBC. Severe PPH or packed RBC unit transfusion were associated with postpartum SVT (adjusted relative risk: 5.3 (1.6–17) and 4.7 (1.5–15) respectively), independent of caesarean section delivery and low-molecular- weight heparin (LMWH) use in the postpartum, but were not independent indicators of one another. This the VTE and SVT risks associated with severe PPH are low (<1% and <2%, respectively).Severe PPH increases the risk of postpartum SVT, but transfusion with platelet units and plasma supplementation using fresh frozen plasma or fibrinogen concentrates do not markedly modulate the risk of venous thrombosis.
Factor VIIa and its potential therapeutic use in bleeding-associated pathologies
Authors: Hedner Ulla 
Published: September 2008

SummaryRecombinant FVIIa (rFVIIa) was developed for treatment of haemophilia patients with inhibitors against FVIII/FIX. The haemostatic efficacy rate of 80–90% including major orthopaedic surgery (dosing of 90–120 µg/kg every other hour [h] for at least the first 24 h) was achieved in these patients. In a home-treatment setting the efficacy rate of haemostasis in mild-moderate bleedings was 92% (average number of 90 µg/kg doses was 2.2). A wide individual variation regarding recovery of rFVIIa (46 ± 12%; median 43%) as well as of clearance rate (36 ± 8 ml/kg/h; median 32 ml/kg/h in adults;children 2–3 times higher) has been observed. Thus children may require higher doses than adults. Accordingly the use of a dose of 270 µg/kg in one single injection was approved in the EU. Recent experience indicates that repeated doses of rFVIIa may decrease the number of bleeds in “target joints”, and thus may be useful as prophylaxis in severe hemophilia with inhibitors. Pharmacological concentrations of rFVIIa have been shown to enhance the thrombin generation on thrombin activated platelets in a cell-based model. By doing so a tight structured fibrin haemostatic plug resistant against premature lysis is formed. rFVIIa has been shown to induce haemostasis not only in haemophilia but also in other situations characterized by an impaired thrombin generation such as platelet defects, dilution coagulopathy developed as a result of trauma and extensive surgery. A special form of profuse bleeding, that may cause extensive problems is postpartum haemorrhage.
Phorbol 12-myristate 13-acetate (PMA) responsive sequence in Gαq promoter during megakaryocytic differentiation
Authors: Jalagadugula Gauthami , Dhanasekaran Danny N. , Rao A. Koneti 
Published: September 2008

SummaryGαq plays a major role in platelet signal transduction, but little is known regarding its transcriptional regulation. We have reported that Gαq is upregulated during phorbol 12-myristate 13-acetate (PMA)-induced megakaryocytic transformation of human erythroleukemia (HEL) cells and regulated by EGR-1, an early growth transcription factor. These studies focused on the initial 238 bp of the 5’ upstream region of the Gαq gene. In the present studies we characterize a minimal region -1042/-1037 bp from ATG in the 5’ upstream of the Gαq promoter that is associated with PMA responsiveness. In luciferase reporter gene studies in HEL cells, Gαq 5’ upstream promoter sequence -1042/-1 showed an about four-fold increased activity in PMA-treated compared to untreated cells. Deletion of 6-nt-1042/-1037 eliminated the difference. Gel-shift studies on Gαq probe (-1042/-1012 bp) revealed binding of EGR-1 with PMA-treated but not untreated nuclear extracts, and this was dependent on the sequence –1042/-1037.Silencing of endogenous EGR-1 inhibited Gαq induction by PMA. MEK/ERK inhibitor U0126 blocked PMA effect on promoter activity of the -1042/-1 construct. In conclusion, EGR-1 binding to sequence –1042/-1037 bp in Gαq promoter mediates the induction of Gαq gene by PMA via the MEK/ERK signaling pathway. These studies provide the first evidence of a PMA-responsive element in Gαq promoter, and new insights into regulation of Gαq gene by EGR-1.
Spontaneous Abortion in a Danish Population-Based Cohort of Childhood Cancer Survivors
Authors: Winther Jeanette F. , Boice John D. , Svendsen Anne Louise , Frederiksen Kirsten , Stovall Marilyn , Olsen Jørgen H. 
Published: September 2008

Purpose Radiation induces germ-cell mutations in experimental animals that result in adverse pregnancy outcomes, as does uterine damage caused by high-dose radiotherapy. We assessed the risks for spontaneous abortion and stillbirths among cancer survivors who received radiotherapy and subsequently became pregnant. Patients and Methods We identified 1,688 female survivors of childhood cancer in the Danish Cancer Registry. Radiation doses to the ovary and uterus were characterized as high to low. The pregnancy outcomes of survivors, 2,737 sisters, and 16,700 comparison women in the population were identified from nationwide registries. The proportions of pregnancies among survivors that resulted in a livebirth, stillbirth, or abortion were compared with the equivalent proportions among the two comparison groups, and proportion ratios (PRs) were computed with sisters as referent. Results More than 34,000 pregnancies were evaluated, 1,479 of which were among cancer survivors. No significant differences were seen between survivors and comparison women in the proportions of livebirths, stillbirths, or all types of abortions combined. Survivors, however, had a 23% excess risk for spontaneous abortion (PR, 1.23; 95% CI, 1.0 to 1.5), related primarily to prior radiation treatments (PR, 1.58; 95% CI, 1.2 to 2.2) and especially high-dose radiotherapy to the ovaries and uterus (PR, 2.8; 95% CI, 1.7 to 4.7). Conclusion The pregnancy outcomes of survivors were similar to those of comparison women. A slight excess risk for spontaneous abortion may have resulted from uterine damage after high-dose pelvic radiotherapy, consistent with previous studies, although radiation-induced germinal mutations or decreased hypothalamic-pituitary-ovarian function could not be ruled out.