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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).

Razzaghian H.R.,Uppsala University | Shahi M.H.,Uppsala University | Forsberg L.A.,Uppsala University | De Stahl T.D.,Uppsala University | And 4 more authors.
American Journal of Medical Genetics, Part A | Year: 2010

Somatic genetic variation in health and disease is poorly explored. Monozygotic (MZ) twins are a suitable model for studies of somatic mosaicism since genetic differences in twins derived from the same zygote represent an irrefutable example of somatic variation. We report the analysis of a pair of generally healthy female MZ twins, discordant for somatic mosaicism for aneuploidy of chromosomes X and Y. Both twins are heterozygous carriers of sickle cell disease mutation. Genotyping of blood DNA from both twins using Illumina Human 610 SNP array revealed a copy number imbalance for chromosome X in a proportion of cells in one twin. Fluorescent in situ hybridization (FISH) analysis confirmed monosomy X (45,X) in 7% of proband nucleated blood cells. Unexpectedly, FISH analysis of cells from the other twin revealed 45,X and 46,XY lineages, both present in 1% of cells. The mechanism behind formation of these aneuploidies suggests several aberrant chromosome segregation events in meiosis and mitoses following conception. Our report contributes to the delineation of the frequency of somatic structural genomic variation in normal MZ twins. These results also illustrate the plasticity of the human genome for tolerating large copy number changes in healthy subjects and show the sensitivity of the Illumina platform for detection of aberrations that are present in a minority of the studied cells. © 2010 Wiley-Liss, Inc.

Holm E.,Skane University Hospital | Abshire T.C.,Medical science Institute | Bowen J.,Rho Inc. | Alvarez M.T.,Hospital Universitario La Paz | And 17 more authors.
Blood Coagulation and Fibrinolysis | Year: 2015

Clinically, the leading symptom in von Willebrand disease (VWD) is bleeding, chiefly of mucosal type, for example, epistaxis, gingival, or gastrointestinal bleeding, and menorrhagia. In severe forms of VWD with secondary deficiency of factor VIII, spontaneous joint bleeding, resembling that observed in severe haemophilia A, may also be observed. The bleeding patterns of VWD can affect quality of life, and may be life-threatening. The von Willebrand Disease Prophylaxis Network is an international study group formed with the goal of investigating the role of prophylaxis in clinically severe VWD. The objective of the present study is to investigate the response to prophylaxis focusing primarily on epistaxis, joint bleeding, gastrointestinal bleeding, and heavy bleeding associated with menses. Data from 105 subjects, 10 enrolled in a prospective study and 95 in a retrospective study between 2008 and 2013, were available for analysis. The median annualized rate reductions in bleeding were significant for epistaxis (P<0.0001), gastrointestinal bleeding (P=0.0003), joint bleeding (P<0.0001), and menorrhagia (P=0.008). Doses on a group level were approximately the same prior to and during prophylaxis, but more patients with gastrointestinal bleeding had prophylaxis three or more times per week as well as higher dosages. Our study, which primarily used retrospective data, indicates that prospective studies are needed to better delineate the doses and dose intervals that should be used for prophylactic treatment of VWD. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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.

Razzaghian H.R.,Uppsala University | Forsberg L.A.,Uppsala University | Prakash K.R.,Uppsala University | Przerada S.,Uppsala University | And 13 more authors.
PLoS ONE | Year: 2013

Although historically considered as junk-DNA, tandemly repeated sequence motifs can affect human phenotype. For example, variable number tandem repeats (VNTR) with embedded enhancers have been shown to regulate gene transcription. The post-zygotic variation is the presence of genetically distinct populations of cells in an individual derived from a single zygote, and this is an understudied aspect of genome biology. We report somatically variable VNTR with sequence properties of an enhancer, located upstream of IFNAR1. Initially, SNP genotyping of 63 monozygotic twin pairs and multiple tissues from 21 breast cancer patients suggested a frequent post-zygotic mosaicism. The VNTR displayed a repeated 32 bp core motif in the center of the repeat, which was flanked by similar variable motifs. A total of 14 alleles were characterized based on combinations of segments, which showed post-zygotic and inter-individual variation, with up to 6 alleles in a single subject. Somatic variation occurred in ~24% of cases. In this hypervariable region, we found a clustering of transcription factor binding sites with strongest sequence similarity to mouse Foxg1 transcription factor binding motif. This study describes a VNTR with sequence properties of an enhancer that displays post-zygotic and inter-individual genetic variation. This element is within a locus containing four related cytokine receptors: IFNAR2, IL10Rβ, IFNAR1 and IFNGR2, and we hypothesize that it might function in transcriptional regulation of several genes in this cluster. Our findings add another level of complexity to the variation among VNTR-based enhancers. Further work may unveil the normal function of this VNTR in transcriptional control and its possible involvement in diseases connected with these receptors, such as autoimmune conditions and cancer.

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