bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Antithrombotic and Antihemostatic Effects of the Direct Factor Xa Inhibitors, Apixaban and Rivaroxaban, and the Direct Thrombin Inhibitors, Dabigatran and Lepirudin, in Rabbit Models of Venous Thrombosis and Bleeding Time
Authors: Wong Pancras C. , Crain Earl , Watson Carol 
Published: April 2020

Abstract
Background: Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development for the prevention and treatment of venous thromboembolism, stroke prevention in patients with atrial fibrillation, and secondary prevention in patients with acute coronary syndrome. The objective of this study was to assess the antithrombotic and antihemostatic effects of apixaban in rabbits, compared to the direct FXa inhibitor, rivaroxaban, and thrombin inhibitors, dabigatran and lepirudin.
Methods: We induced the formation of non-occlusive thrombus in venous thrombosis (VT) models by placing threads in the vena cava, and induced bleeding by the incision of cuticles in anesthetized rabbits. Apixaban, rivaroxaban, dabigatran and lepirudin were given as a bolus injection and supplemented with a constant IV infusion to achieve a stable plasma level.
Results: Control thrombus weight in the prevention VT model ranged from 65±3 to 88±5 mg, and in the VT treatment model ranged from 76±5 to 90±5 mg. Control bleeding time (BT) ranged from 163±5 s to 173±8 s (n=6 per group). In the prevention VT model, apixaban, rivaroxaban, dabigatran and lepirudin (infusion started at 30 min before VT initiation) exhibited dose-related efficacy in preventing VT with ED50s (doses for 50% reduction of control thrombus weight; mg/kg) of 0.17±0.003, 0.15±0.03, 0.37±0.04 and 0.24±0.07 mg/kg, respectively. Apixaban, rivaroxaban and dabigatran, at doses for 80% reduction of control thrombus weight, prolonged BT by 13±2, 91±9*, 343±38* and 505±12%*, respectively (*P&lt;0.05, vs. apixaban, n=6 per group). In the treatment VT model, these inhibitors (infusion started at 30 min after VT initiation) were equally effective in preventing growth of a preformed thrombus. Clot regression was observed following administration of apixaban, rivaroxaban and dabigatran at 2.7 mg/kg, and lepirudin at 3.5 mg/kg. The preformed thrombus decreased from an initial weight of 38±2 mg to 26±4*, 17±2*, 20±3* and 25±1* mg, respectively (*P&lt;0.05, vs. control, n=6 per group).
Conclusion: In summary, apixaban was as efficacious as rivaroxaban, dabigatran and lepirudin in the prevention and treatment VT models in rabbits. At equivalent antithrombotic doses, apixaban preserved hemostasis better than the other three agents in the rabbit cuticle BT model. Clinical studies will be required to assess the therapeutic windows in humans.
Case Fatality Rates of Recurrent Venous Thromboembolism during and Following Anticoagulation Therapy
Authors: Carrier Marc , Le Gal Gregoire , Wells Philip , Rodger Marc 
Published: April 2020

Abstract
Background: The optimal duration of anticoagulation treatment in patients with unprovoked VTE is unknown. In order to counsel VTE patients on the risks and benefits of discontinuing anticoagulants, clinicians need to balance the long-term risk of recurrent VTE with major bleeding on anticoagulants. For all VTE patients on oral anticoagulant, the case-fatality rate of major bleeding was previously reported to be 13.4% (95% confidence intervals (CI): 9.4% to 17.4%). A major knowledge gap exists regarding the case-fatality rate of recurrent pulmonary embolism (PE) during and following anticoagulation therapy for VTE.
Purpose: To summarize the case fatality rate of recurrent VTE during and following anticoagulation therapy.
Data Source: A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Study Outcome: We selected 62 studies that reported the rates of fatal PE in patients with recurrent VTE. Fatal PE was defined as
confirmed autopsy report; death preceding with confirmed deep vein thrombosis (DVT) or non-fatal PE; sudden death not explained by a condition other than PE.
Measurements: Pooled case fatality rates were generated. Ninety-five percent CI were calculated for each case fatality rate using averaged, inverse variance-weighted estimates from each study.
Data Synthesis: 30,885 VTE patients were included (17,650 DVT, 8801 PE and 4434 DVT or PE
Limitations: Unable to determine the case fatality rate by etiology of VTE (i.e. provoked, unprovoked).
Conclusion: Case fatality rates for recurrent VTE are elevated during and following anticoagulation treatment for VTE but appear lower than the case-fatality rate for major bleeding with oral anticoagulants. This information must be considered by clinicians when counseling patients on whether to continue or discontinue anticoagulant therapy following VTE. Not only must absolute recurrent VTE and major bleeding rates be compared between groups that continue and discontinue anticoagulants but the relative consequences (i.e. case fatality rates) must be also considered with more weight placed on major bleeding episodes.
Initial event During anticoagulation Treatment (%, 95% CI) Following anticoagulation Treatment (%, 95% CI) DVT 10.6 (8.3–13.0) 7.3 (5.0–9.7) PE 12.3 (5.9–18.7) 12.5 (6.4–28.7) Any event 10.2 (7.9–12.5) 9.0 (7.3–10.8)
Validation of Pharmacokinetic {PK} Simulation for Fondaparinux (FPX) Dosing by FPX-Specific Anti-Factor Xa Assay in Elderly Cancer Patients with Severe Renal Dysfunction
Authors: Liu Chin Y , Andersen Judith C. 
Published: April 2020

Abstract
Background: Fondaparinux (FPX) is a synthetic pentasaccharide inhibitor of factor Xa indicated for prophylaxis and treatment of venous thromboembolism (VTE). It has an 18 hr half-life (T 1/2), thus is suitable for once-daily dosing, but is cleared by the kidney and not recommended for patients with SRD (creatinine clearance (CrCl) &lt;30 mL/min) in whom drug accumulation could increase bleeding risk. No published clinical trials have evaluated the use of FPX in this population. However, in a pharmacokinetic simulation, serum FPX concentrations in such patients receiving FPX for VTE prophylaxis every other day were predicted to be similar to those in patients with mild renal impairment on daily dosing. Validation of this dosing regimen with an automated assay that determines anti-factor Xa activity levels using FPX calibrators could make this versatile drug accessible to many hypercoagulable patients with severe renal dysfunction
Methods: A retrospective analysis of institutional pharmacokinetic protocol outcomes was conducted in a small population of elderly cancer patients with chronic or acute-on- chronic SRD (CrCl &lt; 30ml/min for &gt;72 hrs) who received subcutaneous FPX 2.5 mg every 48 hrs for VTE prophylaxis. Peak and trough levels were determined at 3 hours post-dose and 1hr pre-dose respectively, for at least 3 doses. FPX levels were assayed with FPX-specific calibrators.
Descriptive data appear in Table 1.
Pt Age Sex Race D Height (cm) Weight (kg) Creatinine (mg/dL) CrCl (ml/min) Peak (mcg/mL) Trough (mcg/mL) 1 71 F W Bladder CA 167.6 71.9 2.7 18 0.52 0.15 2 86 M B Lung CA 166.4 76.2 1.7 28 0.47 0.14 3 67 M W Giloma 180.3 75.0 3.2 24 0.27 0.12 4 83 M W Bladder CA 175.3 90.0 1.9 29 0.33 0.08 5 75 M W Prostate CA 167 74.5 5.4 11 0.6 0.11 6 62 M W Lymphoma 172 61.5 3.1 22 0.28 0.03 7 59 F B Uterine CA 160 115.0 4.8 10 0.37 0.1 8 53 M B Multiple myeloma 177.8 57.0 6.0 10 0.27 0.2
Results: Eight patients were included in this study with mean age of 69.5 ± 11.5 years and creatinine clearance of 19 ± 7.9 mL/min. The mean peak FPX concentration was 0.39 ± 0.13 mcg/mL, in the lower target range for prophylaxis efficacy (0.39–0.50 mcg/mL) and mean trough concentration, thought to be an indicator of drug accumulation, 0.12 ± 0.05 mcg/mL (target range: 0.14–0.19 mcg/mL). No major bleeding or VTE events were noted during FPX administration.
Conclusion: A pharmacokinetic simulation permitting extrapolation of FPX dosing for VTE prophylaxis in patients with severe renal dysfunction from data in patients with mild dysfunction has been shown to be valid in a small population of sick elderly cancer patients by PK monitoring using a FPX -specific anti-Factor Xa assay, showing no drug accumulation over at least three doses (144 hrs) [cyl1] and the drug clinically safe as dosed.
Novel Antimicrobial Peptide-Based Blood Safety Strategies for Bacterial Reduction
Authors: Mohan Ketha V. K. , Rao Shilpakala Sainath , Atreya Chintamani D 
Published: April 2020

Abstract
Bacterial contamination of blood and blood components is a major safety concern in transfusion medicine. In order to facilitate safer transfusion products to the end users, there is a critical need for novel proof-of-concept ideas for pathogen reduction, which are different from the current ones that outweigh the associated toxicity and/or contamination risk. Present study involves use of nine novel synthetic antimicrobial peptides (four originated from thrombin-induced human platelet derived antimicrobial proteins named PP1-PP4 and five having 1–5 repeats of arginine and tryptophan residues, named DP1-DP5. These peptides were tested on plasma samples spiked with 10-fold dilutions of 5 different bacteria (Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Bacillus cereus) that are important to the field of transfusion medicine and analyzed whether these spiked plasma samples could be cured of the pathogens. Each spiked sample was incubated with a peptide (PP1-PP4 and DP1-DP5) for 2 hours at 37°C. Following incubation, a fixed volume of the inoculum was plated on nutrient agar plates and incubated overnight at 37°C for colony count. Spiked sample without any peptide was included as control. Results revealed that out of nine peptides tested, while DP3 and DP4 were active against all 5 organisms tested resulting in 50–100 % of inhibition of specific organisms, peptide PP4 was only active against E. coli, P. aeruginosa and Bacillus cereus resulting in a 30–100% reduction in the CFU/ml compared to the controls.
Table 1
Organism Colony count expressed in % Control PP1 PP2 PP3 PP4 DP1 DP2 DP3 DP4 DP5 S. aureus 100 90 100 26 100 100 20 10 56 100 E. coli 100 95 100 100 71 100 93 4 18 85 P. aeruginosa 100 100 100 100 0 100 0 0 13 100 K. pneumoniae 100 100 100 100 100 74 3 0 0 25 B. cereus 100 100 100 100 50 100 100 25 77 100
Based on these results, it appears that peptides used in this study provide a new antibacterial strategy against a range of bacteria and with further studies and refinement, these peptides could prove useful towards bacterial reduction in blood and blood products.
The findings and conclusions in this abstract have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy.
The Addition of Rituximab to First-Line Chemotherapy (R-CHOP) Results in Superior Response Rates, Time to Treatment Failure and Response Duration in Patients with Advanced Stage Mantle Cell Lymphoma: Long Term Results of a Randomized GLSG Trial
Authors: Hoster Eva , Unterhalt Michael , Wörmann Bernhard , Dührsen Ulrich , Metzner Bernd , Eimermacher Hartmut , Neubauer Andreas , Wandt Hannes , Steinhauer Hjalmar , Martin Sonja , Heidemann Else , Aldaoud Ali , Hiddemann Wolfgang , Dreyling Martin 
Published: April 2020

Abstract
Background: The addition of rituximab to chemotherapy (R-CHOP) has been shown to improve response rates in mantle cell lymphoma (MCL), but prolongation of response duration or overall survival was not observed (Lenz et al., JCO 2005). In a similar randomized comparison of 90 patients, again the addition of rituximab to MCP showed a tendency towards higher CR rates, but no improvement of overall response rate, progression free, or overall survival (Herold et al., ICML-10, 2008).
Methods: We present an update of a previously published trial randomly comparing efficacy and safety of R-CHOP to CHOP induction in previously untreated patients with advanced stage MCL.
Results: Of the 123 evaluable patients, 63 patients were randomized to R-CHOP. Median age was 62 years, and risk profiles of the two treatment arms were comparable. Overall response rates were 92% vs. 75% for R-CHOP vs. CHOP (p = 0.0139) and complete remission rates 33% vs. 8% (p = 0.0008). After a median follow-up of 65 months, median time to treatment failure was prolonged from 14 months for CHOP to 28 months for R-CHOP (p = 0.0003). Similarly, median response duration was prolonged from 18 (CHOP) to 29 months (R-CHOP, p = 0.0052). So far, no significant improvement of overall survival has been observed with median not reached vs. 59 months and 5-years OS rates of 59% and 46% (p = 0.27) after R-CHOP and CHOP, respectively. Toxicity was not significantly higher for R-CHOP treated patients.
Conclusions: After longer follow-up, superior remission rates, time to treatment failure, and response duration of combined immuno-chemotherapy were confirmed. However, in contrast to other lymphoma entities, improvement of overall survival has not yet been proven in MCL patients. Therefore new therapeutic options are urgently warranted to further improve the long term outcome in this otherwise dismal disease.
Inhibition of Pulmonary Coagulopathy by Nebulized Natural Anticoagulants during Streptococcus Pneumoniae Pneumonia in Rats
Authors: Hofstra J. J. , van den Boogaard F. E. , Cornet A. D. , Vlaar A. P.J. , van der Poll T. , Levi M. , Schultz M. J. 
Published: April 2020

Abstract
RATIONALE: Alveolar fibrin deposition is intrinsic to pneumonia and acute lung injury. Activation of coagulation during pulmonary inflammation is primarily mediated by the tissue factor–factor VIIa pathway. Tissue factor levels in the lungs increase during pulmonary inflammation due to disruption of endothelial–epithelial barrier and expression of tissue factor on alveolar macrophages. Intravenous infusion of the natural anticoagulants activated protein C (APC) or antithrombin (AT) has been shown to have lung–protective effects in critically ill patients, but increases the risk of severe bleeding. Local administration may allow for higher treatment dosages and increased local efficacy while at the same time reducing the risk of bleeding. We evaluated the effect of nebulized tissue factor pathway inhibitor (TFPI), APC or AT on pulmonary coagulopathy and inflammation in a rat model of Streptococcus pneumoniae pneumonia.
DESIGN: Randomized controlled in vivo study in a rat model of S. pneumoniae pneumonia. Twenty–eight male Sprague–Dawley rats were challenged intratracheally with S. pneumoniae (serotype 3, 106 colony forming units), inducing pneumonia. Rats were randomized to nebulization with TFPI, APC, AT or normal saline.
RESULTS: Rats infected with S. pneumoniae had increased pulmonary and systemic levels of thrombin–antithrombin complexes (TATc) and fibrin degradation products (FDP), indicating increased coagulation. Simultaneously, pulmonary plasminogen activator inhibitor 1 (PAI–1) activity was increased and plasminogen activator activity (PAA) was reduced, indicating inhibition of endogenous fibrinolysis. Treatment with any nebulized natural anticoagulant significantly attenuated the rise in bronchoalveolar TATc (3.5 ± 0.9 ng/mL (TFPI), 3.6 ± 0.6 ng/mL (APC) and 4.6 ± 0.6 ng/mL (AT) versus 9.1 ± 0.75 ng/mL in saline treated rats, P&lt;.01) and FDP (290 ± 92 ng/mL (TFPI), 310 ± 90 ng/mL (APC) and 158 ± 44 ng/mL (AT) versus 559 ± 116 ng/mL in saline treated rats, P&lt;.01). TFPI and APC also significantly reduced systemic TATc levels while AT did not have any effect on systemic coagulopathy (17 ng/mL ± 3.4 (TFPI) and 13.8 ± 2.3 ng/mL (APC) versus 19.7 ± 1.6 ng/mL in saline treated rats, P&lt;.05 and P&lt;.01 respectively). While TFPI and APC did not affect host defense to S. pneumoniae, treatment with AT resulted in a reduction of bacterial outgrowth from the lungs, a reduction of neutrophil influx into the pulmonary compartment and less histopathologic lung injury.
CONCLUSIONS: Nebulization of natural anticoagulants attenuates pulmonary coagulopathy during S. pneumoniae pneumonia. While APC and TFPI leaves local inflammation and host defense unaltered, AT exerts significant lung–protective effects in pneumococcal pneumonia in rats.
Inhibition of γ′ Fibrinogen Production in Liver Cells by D-Dimers
Authors: Rein Chantelle M , Chu May-Lynn , Farrell David H. 
Published: April 2020

Abstract
γ′ fibrinogen contains a variant γ chain that arises from an alternative splicing event within the γ gene mRNA. While the more abundant γA chain contains the platelet-binding AGDV sequence at its carboxyl terminus, the γ′ chain carboxyl terminus has an extended VRPEHPAETEYDSLYPEDDL amino acid sequence that is highly negatively charged and contains two sulfated tyrosine residues. The γ′ chain contains binding sites for factor XIII zymogen and thrombin. This extended γ chain variant confers several unique properties on clots formed with γ′ fibrinogen, including resistance to fibrinolysis. γ′ fibrinogen is also a newly-emerging cardiovascular disease biomarker that shows an inverse association with deep venous thrombosis and thrombotic microangiopathy, and a significant positive association with coronary artery disease, myocardial infarction, and stroke. However, the underlying factors that regulate its production remain unknown. A recent study investigating the role of γ′ fibrinogen in stroke showed that the ratio of γ′ fibrinogen to total fibrinogen was higher in patients during the acute phase of a stroke and lower in the convalescent phase following a stroke. We therefore hypothesized that the end products of fibrinolysis may feed back to regulate γ′ fibrinogen expression. Fibrin(ogen) degradation products, including fibrinopeptides A and B, E-domains, and D-dimers, were therefore assayed for their effects on the production of γ′ fibrinogen in HepG2 human liver cells. The results showed that fibrinopeptide A, fibrinopeptide B, and E-domains had no effect on γ′ fibrinogen production by HepG2 cells, as measured by ELISA. However, the production of γ′ fibrinogen decreased in a dose-dependent manner when incubated with purified cross-linked D-dimers. RT-PCR demonstrated an 85.1 ± 4.6% inhibition in γ′ mRNA levels by 31 nM D-dimers after 24 hours of exposure. For comparison, the lower limit of the pathophysiologic cutoff of D-dimer concentration in disseminated intravascular coagulation is in the range of 41 nM. To further investigate the interactions of the D-dimers with the cells, D-dimers were labeled with fluorescein, incubated with HepG2 cells, and examined by fluorescence microscopy. Fluorescein-labeled D-dimers entered the cells within 20 minutes of incubation and displayed a diffuse cytoplasmic distribution. The D-dimers showed an increasing peri-nuclear localization with increasing time. By 60 minutes, the D-dimers had largely been cleared from within the cells. D-dimer uptake displayed a very different staining pattern than the non-receptor-mediated uptake of fluorescein-labeled albumin, which showed only a weak, diffuse cytoplasmic staining. These results suggest that D-dimers regulate γ′ fibrinogen production in liver cells in a process that involves binding to a cell-surface receptor, internalization, and degradation.
Exploiting ER Stress to Eliminate Inhibitor Antibodies in Hemophilia
Authors: Callaghan Michael U , Kaufman Randal J 
Published: April 2020

Abstract
Hemophilia is the most common severe bleeding disorder, affecting up to 1 in 5,000 males. The most feared complication for patients with hemophilia A is the development of inhibitor antibodies to infused FVIII, occurring in 30% of patients with hemophilia A. Inhibitor antibodies are produced in large numbers by the professional secretory cells of the immune system, the plasma cells, in response to exposures to FVIII. The development of these professional secretory cells has been shown to cause stress in the endoplasmic reticulum (ER) and mechanisms of the unfolded protein response (UPR) are integral to the adaptation of these cells. Proteasome inhibitors, such as bortezomib (Velcade), have been shown to increase ER stress and kill plasma cells by inhibiting the destruction of misfolded proteins and inducing proteotoxicity. Current therapeutic strategies for hemophilia patients with inhibitors revolve around inducing tolerance to FVIII by treating patients with large doses of FVIII daily. We believe this therapy induces antibody production, stressing the plasma cells that manufacture the inhibitor antibodies.
We have tested the hypothesis that the one-two punch of ER stress directed at the anti-FVIII plasma cells and proteasome inhibiting or CHOP inducing agents will induce apoptosis. To this end we have tested bortezomib in vitro and determined that it does potently induce ER stress and the UPR. Further, we have shown that this induces apoptosis and cell death and that cells lacking ATF6α, an upstream mediator of the UPR, are more sensitive to bortezomib while those lacking CHOP, a pro-apoptotic downstream mediator of UPR, are slightly less sensitive. Additionally we have found that the super-oxide scavenger, tiron, protects cells from bortezomib, suggesting a role for reactive oxygen species upstream of UPR activation by bortezomib. We have studied bortezomib in a mouse model of hemophilia A inhibitors and have found that it can effectively eradicate inhibitor antibody producing cells in this model. In contrast when bortezomib was injected into CHOP knock-out inhibitor mice the inhibitor antibodies were not eradicated, in contrast to the wild type controls in which the inhibitor antibodies were eliminated. This is strong evidence in support of CHOP as a primary mediator of plasma cell death induced by bortezomib and suggests that other CHOP inducing agents may also be promising therapeutics for hemophilia inhibitors. To that end we are investigating agents identified through a cell based, luciferase reporter, high throughput screen of 300,000 compounds for CHOP inhibitors. We hope that this work will identify agents that can be used to eradicate inhibitor antibodies in patients with Hemophilia.