Hematology Research

Rochester, MN, United States

Hematology Research

Rochester, MN, United States
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Park M.S.,Mayo Medical School | Xue A.,Mayo Medical School | Spears G.M.,Mayo Medical School | Halling T.M.,Mayo Medical School | And 6 more authors.
Journal of Trauma and Acute Care Surgery | Year: 2015

OBJECTIVE The two sides of trauma-induced coagulopathy, the hypocoagulable and the hypercoagulable states, are poorly understood. To identify potential mechanisms for venous thromboembolism and bleeding after acute trauma, we estimated changes in circulating procoagulant microparticles (MPs) and thrombin activity during hospitalization for trauma. METHODS Whole blood was collected by venipuncture into 3.2% trisodium citrate at 0, 6, 12, 24, and 72 hours after injury and discharge. Platelet-poor plasma was harvested and stored at -80°C until analysis. Thrombin generation was determined using the calibrated automated thrombogram (CAT), reported as lag time (minutes), peak height (nM thrombin), and time to reach peak height (ttPeak, minutes). The concentration of total procoagulant MPs (number/μL) was measured by flow cytometry. Data are presented as median (interquartile range [IQR]). RESULTS Among 443 trauma patients (1,734 samples; Injury Severity Score [ISS], 13.0 [IQR, 6.0-22.0]; hospital length of stay, 4.0 days [IQR, 2.0-10.0]; age, 48 years [IQR, 28-65]; 70.7% male; 95% with blunt mechanism; mortality, 3.2%), no discernable patterns in thrombin generation or MP concentration were observed over time. The peak height and MPs were significantly different from healthy volunteers and were 337 nM (IQR, 285-395) and 400/μL plasma (IQR, 211-772), respectively. Extreme (defined as highest or lowest 5%) values reflecting a possible "hypercoagulable state" (lag time ≤ 1.98, peak height ≥ 486.2, ttPeak ≤ 3.61, and total procoagulant MP ≥ 2,278) were reached within 12 hours after acute trauma, while extreme values representing a possible "hypocoagulable state" (lag time ≥ 18.6, peak height ≤ 17.8, and ttPeak ≥ 29.45) were not reached until 1 day to 3 days. CONCLUSION Although there was no predictable pattern of coagulopathy observed in each patient after trauma, those who reached extreme values did so relatively early after injury. These findings should be taken into account when designing risk model tools involving coagulation laboratory parameters. LEVEL OF EVIDENCE Epidemiologic study, level III. © 2015 Wolters Kluwer Health, Inc. All rights reserved.


PubMed | U.S. Food and Drug Administration, Hematology Research, Cleveland State University and University of North Carolina at Chapel Hill
Type: | Journal: Journal of medical genetics | Year: 2016

Haemophilia B is caused by genetic aberrations in the F9 gene. The majority of these are non-synonymous mutations that alter the primary structure of blood coagulation factor IX (FIX). However, a synonymous mutation c.459G>A (Val107Val) was clinically reported to result in mild haemophilia B (FIX coagulant activity 15%-20% of normal). The F9 mRNA of these patients showed no skipping or retention of introns and/or change in mRNA levels, suggesting that mRNA integrity does not contribute to the origin of the disease in affected individuals. The aim of this study is to elucidate the molecular mechanisms that can explain disease manifestations in patients with this synonymous mutation.We analyse the molecular mechanisms underlying the FIX deficiency through in silico analysis and reproducing the c.459G>A (Val107Val) mutation in stable cell lines. Conformation and non-conformation sensitive antibodies, limited trypsin digestion, activity assays for FIX, interaction with other proteins and post-translation modifications were used to evaluate the biophysical and biochemical consequences of the synonymous mutation.The Val107Val synonymous mutation in F9 was found to significantly diminish FIX expression. Our results suggest that this mutation slows FIX translation and affects its conformation resulting in decreased extracellular protein level. The altered conformation did not change the specific activity of the mutated protein.The pathogenic basis for one synonymous mutation (Val107Val) in the F9 gene associated with haemophilia B was determined. A mechanistic understanding of this synonymous variant yields potential for guiding and developing future therapeutic treatments.


NEW YORK, Dec. 16, 2016 (GLOBE NEWSWIRE) -- TG Therapeutics, Inc. (NASDAQ:TGTX) announced the publication of clinical data from a Phase 2 study of TG-1101 (ublituximab), the Company's novel glycoengineered anti-CD20 monoclonal antibody, in combination with ibrutinib, the oral BTK inhibitor, in patients with Chronic Lymphocytic Leukemia (CLL). The data, which was presented at the 2015 International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, demonstrates the combination to be well tolerated with limited grade 3/4 adverse events observed. An 88% overall response rate (ORR) was reported at month 6 for all patients treated, with a 95% ORR observed in patients with high risk CLL (presence of a 17p or 11q deletion or a TP53 mutation).  These data are described further in the manuscript titled, “Ublituximab (TG-1101), a novel, glycoengineered anti-CD20 antibody, in combination with ibrutinib is safe and highly active in patients with relapsed and/or refractory chronic lymphocytic leukemia: results of a phase 2 trial,” which was published online today in the British Journal of Haematology. The online version of the article can be accessed at http://onlinelibrary.wiley.com/.  “We want to thank Dr. Jeff Sharman and the team at the US Oncology Network for their work on this important Phase 2 study and congratulate them on this peer-reviewed publication.  We believe the chemo-free combination of TG-1101 and ibrutinib is an effective and much needed treatment option for patients with high-risk CLL who continue to exhibit a poor prognosis, and the data in this publication underscores our belief.  The results from this study support the GENUINE Phase 3 study, and given the dramatic and rapid responses seen in this Phase 2, we are confident in the success of GENUINE.  We recently announced the completion of enrollment in the revised GENUINE trial and look forward to announcing top line data in the first half of 2017,” stated Michael S. Weiss, the Company's Executive Chairman and Interim Chief Executive Officer. “While ibrutinib is effective in patients with CLL, it is not the only answer. In this study, the addition of ublituximab to ibrutinib not only produced high response rates, but also allowed patients to achieve deeper responses with complete responses and minimal residual disease (MRD) negativity seen, which is rare with ibrutinib alone.  We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients,” stated Dr. Jeff Sharman, Medical Director of Hematology Research for the US Oncology Network. TG Therapeutics is a biopharmaceutical company focused on the acquisition, development and commercialization of novel treatments for B-cell malignancies and autoimmune diseases. Currently, the company is developing two therapies targeting hematological malignancies and autoimmune diseases. TG-1101 (ublituximab) is a novel, glycoengineered monoclonal antibody that targets a specific and unique epitope on the CD20 antigen found on mature B-lymphocytes. TG Therapeutics is also developing TGR-1202, an orally available PI3K delta inhibitor. The delta isoform of PI3K is strongly expressed in cells of hematopoietic origin and is believed to be important in the proliferation and survival of B‐lymphocytes. Both TG-1101 and TGR-1202 are in clinical development for patients with hematologic malignancies, with TG-1101 recently entering clinical development for autoimmune disorders. The Company also has preclinical programs to develop IRAK4 inhibitors, BET inhibitors, and anti-PD-L1 and anti-GITR antibodies. TG Therapeutics is headquartered in New York City. Some of the statements included in this press release, particularly those with respect to anticipating the timing of the completion of the GENUINE study, timing of topline data for the GENUINE study, the usability of the results from GENUINE for accelerated approval, timing of initial data from the UNITY-DLBCL study, timing of the release of data and commencement of our MS pivotal program may be forward-looking statements that involve a number of risks and uncertainties.  For those statements, we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995.  Among the factors that could cause our actual results to differ materially are the following: our ability to successfully and cost-effectively complete the GENUINE, the UNITY-CLL or the UNITY-DLBCL trials; the risk that the clinical results from the GENUINE, UNITY-CLL and/or UNITY-DLBCL studies will be not positive and/or will not support regulatory approval of TG-1101 or TGR-1202; the risk that the FDA will not grant us a pre-BLA meeting to discuss the results of the GENUINE study; the risk that we will not file a BLA for TG-1101 or an NDA for TGR-1202 based on either the GENUINE or the UNITY-CLL; the risk that despite early positive trends in enrollment in the UNITY-CLL study that enrollment will be delayed beyond our projections; the risk that the planned interim analysis will not allow early closure of the single agent arms in the UNITY-CLL study, necessitating enrollment beyond the projected 450 patients, which would extend enrollment beyond our projections; the risk that safety issues or trends will be observed in the GENUINE study, the UNITY-CLL and/or the UNITY-DLBCL study that prevent approval of either TG-1101 and/or TGR-1202 or require us to terminate either the GENUINE study or the UNITY-CLL or the UNITY-DLBCL study prior to completion; the risk that the data (both safety and efficacy) from future clinical trials will not coincide with the data produced from prior pre-clinical and clinical trials; the risk that the GENUINE study, as amended or the UNITY-CLL or the UNITY-DLBCL studies, or any of our other registration-directed clinical trials as designed or amended may not be sufficient or acceptable to support regulatory approval; the risk that trials will take longer to enroll than expected; the risk that the projected cost savings to be realized by amending the GENUINE trial will not be realized; our ability to achieve the milestones we project over the next year; our ability to manage our cash in line with our projections, and other risk factors identified from time to time in our reports filed with the Securities and Exchange Commission. Any forward-looking statements set forth in this press release speak only as of the date of this press release. We do not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. This press release and prior releases are available at www.tgtherapeutics.com. The information found on our website is not incorporated by reference into this press release and is included for reference purposes only.  TGTX - G


Dhillon S.K.,Mayo Medical School | Houck M.L.,Mayo Medical School | Jenkins D.H.,Mayo Medical School | Rosedahl J.K.,Health science Research | And 3 more authors.
Journal of Trauma and Acute Care Surgery | Year: 2013

Background: We set out to determine the effects of transfusing stored red blood cells (RBCs) on the levels of procoagulant microparticles (MPs) in the blood of trauma patients. Methods: Blood was drawn and processed to platelet poor plasma for MP analysis for 409 injured patients seen in the trauma bay from February 2011 to January 2013. Blood from 27 noninjured volunteers was also analyzed. Quantification of total procoagulant MP (per microliter plasma) using a direct plasma analysis via flow cytometry was performed. Demographic data, Injury Severity Score (ISS), overall mortality, and units of transfused packed RBCs were collected. Data are presented as median (interquartile range [IQR]). Transfusion groupswere assessed using t test orWilcoxon rank-sum test as appropriate. The > level was set as 0.05 for statistical significance. RESULTS: Median ISS was 12 (IQR, 5-19), 12% were transfused, median age was 48 years (IQR, 29-62 years), 68% were male, and overall mortality was 3%. Median units transfused were 3 (IQR, 2-5). The median number of all procoagulant MP was greater in trauma patients (median 758; IQR, 405-1,627) when compared with our control subjects (median, 232; IQR, 125-372; p G 0.0001). This difference remained significant after adjusting for age and sex (p G 0.0001). In 39 patients who had MP levels measured before transfusionwithRBC, the procoagulantMP levels did not change after transfusion (p = 0.07). Patients transfused withRBCs thatwere 14 days or older did not have increased procoagulantMP levelswhen comparedwith those that receivedRBCs thatwere younger than 14 days (p = 0.5).Thiswas also true for thosewho receivedRBCs thatwere 28 days or olderwhen compared with those that received RBCs that were younger than 28 days (p = 0.84). Conclusion: Procoagulant MP is significantly greater in trauma patients as compared with volunteers, even after adjusting for age and sex. We did not observe any change in the levels of procoagulant MPs after transfusion of stored RBCs. Level of Evidence: Epidemiologic/prognostic study, level III. Copyright © 2014 by Lippincott Williams & Wilkins).


Van Der Flier A.,Hematology Research | Liu Z.,Hematology Research | Tan S.,Hematology Research | Chen K.,Hematology Research | And 5 more authors.
PLoS ONE | Year: 2015

We recently developed a longer lasting recombinant factor VIII-Fc fusion protein, rFVIIIFc, to extend the half-life of replacement FVIII for the treatment of people with hemophilia A. In order to elucidate the biological mechanism for the elongated half-life of rFVIIIFc at a cellular level we delineated the roles of VWF and the tissue-specific expression of the neonatal Fc receptor (FcRn) in the biodistribution, clearance and cycling of rFVIIIFc. We find the tissue biodistribution is similar for rFVIIIFc and rFVIII and that liver is the major clearance organ for both molecules. VWF reduces the clearance and the initial liver uptake of rFVIIIFc. Pharmacokinetic studies in FcRn chimeric mice show that FcRn expressed in somatic cells (hepatocytes or liver sinusoidal endothelial cells) mediates the decreased clearance of rFVIIIFc, but FcRn in hematopoietic cells (Kupffer cells) does not affect clearance. Immunohistochemical studies show that when rFVIII or rFVIIIFc is in dynamic equilibrium binding with VWF, they mostly co localize with VWF in Kupffer cells and macrophages, confirming a major role for liver macrophages in the internalization and clearance of the VWF-FVIII complex. In the absence of VWF a clear difference in cellular localization of VWF-free rFVIII and rFVIIIFc is observed and neither molecule is detected in Kupffer cells. Instead, rFVIII is observed in hepatocytes, indicating that free rFVIII is cleared by hepatocytes, while rFVIIIFc is observed as a diffuse liver sinusoidal staining, suggesting recycling of free-rFVIIIFc out of hepatocytes. These studies reveal two parallel linked clearance pathways, with a dominant pathway in which both rFVIIIFc and rFVIII complexed with VWF are cleared mainly by Kupffer cells without FcRn cycling. In contrast, the free fraction of rFVIII or rFVIIIFc unbound by VWF enters hepatocytes, where FcRn reduces the degradation and clearance of rFVIIIFc relative to rFVIII by cycling rFVIIIFc back to the liver sinusoid and into circulation, enabling the elongated half-life of rFVIIIFc. © 2015 van der Flier et al.


PubMed | Hematology Research
Type: Journal Article | Journal: PloS one | Year: 2015

We recently developed a longer lasting recombinant factor VIII-Fc fusion protein, rFVIIIFc, to extend the half-life of replacement FVIII for the treatment of people with hemophilia A. In order to elucidate the biological mechanism for the elongated half-life of rFVIIIFc at a cellular level we delineated the roles of VWF and the tissue-specific expression of the neonatal Fc receptor (FcRn) in the biodistribution, clearance and cycling of rFVIIIFc. We find the tissue biodistribution is similar for rFVIIIFc and rFVIII and that liver is the major clearance organ for both molecules. VWF reduces the clearance and the initial liver uptake of rFVIIIFc. Pharmacokinetic studies in FcRn chimeric mice show that FcRn expressed in somatic cells (hepatocytes or liver sinusoidal endothelial cells) mediates the decreased clearance of rFVIIIFc, but FcRn in hematopoietic cells (Kupffer cells) does not affect clearance. Immunohistochemical studies show that when rFVIII or rFVIIIFc is in dynamic equilibrium binding with VWF, they mostly co localize with VWF in Kupffer cells and macrophages, confirming a major role for liver macrophages in the internalization and clearance of the VWF-FVIII complex. In the absence of VWF a clear difference in cellular localization of VWF-free rFVIII and rFVIIIFc is observed and neither molecule is detected in Kupffer cells. Instead, rFVIII is observed in hepatocytes, indicating that free rFVIII is cleared by hepatocytes, while rFVIIIFc is observed as a diffuse liver sinusoidal staining, suggesting recycling of free-rFVIIIFc out of hepatocytes. These studies reveal two parallel linked clearance pathways, with a dominant pathway in which both rFVIIIFc and rFVIII complexed with VWF are cleared mainly by Kupffer cells without FcRn cycling. In contrast, the free fraction of rFVIII or rFVIIIFc unbound by VWF enters hepatocytes, where FcRn reduces the degradation and clearance of rFVIIIFc relative to rFVIII by cycling rFVIIIFc back to the liver sinusoid and into circulation, enabling the elongated half-life of rFVIIIFc.

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