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  • 1.
    Ali Abdi, Abshir
    et al.
    East Africa University, Somalia.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Prevalence of common hereditary risk factors for thrombophilia in Somalia and identification of a novel Gln544Arg mutation in coagulation factor V2017Ingår i: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 44, nr 4, s. 536-543Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Thrombophilia, commonly manifested as venous thromboembolism (VTE), is a worldwide concern but little is known on its genetic epidemiology in many parts of the globe particularly in the developing countries. Here we employed TaqMan genotyping and pyrosequencing to evaluate the prevalence of known common nucleotide polymorphisms associated with thrombophilia in a Somali population in the Puntland region of Somalia. We also employed next generation sequencing (NGS) to investigate other genetic variants in a Somali patient with deep venous thrombosis (DVT). As expected, we found no existence of factor V Leiden (rs6025) and prothrombin G20210A (rs1799963) in the Somali population. The G allele of ABO [261G/delG] polymorphism (rs8176719) was found at a frequency of 29%, similar to that observed in other African populations. We found the lowest so far reported frequency of MTHFR C677T (rs1801133) polymorphism in the Somali population (T allele frequency 1.5%). A novel and deleterious single nucleotide variation in exon 11 of coagulation factor V (c.1631A amp;gt; G) causing Gln544Arg exchange in factor V was identified in a 29 years old Somali female with DVT. The same patient was heterozygous to VKORC1 Asp36Tyr polymorphism (rs61742245) that predisposes to warfarin resistance. In conclusion, this study shows that common hereditary factors for thromboembolism found in Caucasians are either less frequent or absent in the Somali population-similar to the situation in other Africans. NGS is possibly a better choice to detect genetic risk variants for thrombosis in this ethnic group.

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  • 2.
    Ali, Abshir A.
    et al.
    East Africa Univ, Somalia.
    Aalto, Mikko
    Bosaso Gen Hosp, Somalia.
    Jonasson, Jon
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Genome-wide analyses disclose the distinctive HLA architecture and the pharmacogenetic landscape of the Somali population2020Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 10, nr 1, artikel-id 5652Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    African populations are underrepresented in medical genomics studies. For the Somali population, there is virtually no information on genomic markers with significance to precision medicine. Here, we analyzed nearly 900,000 genomic markers in samples collected from 95 unrelated individuals in the North Eastern Somalia. ADMIXTURE program for estimation of individual ancestries revealed a homogenous Somali population. Principal component analysis with PLINK software showed approximately 60% East African and 40% West Eurasian genes in the Somali population, with a close relation to the Cushitic and Semitic speaking Ethiopian populations. We report the unique features of human leukocyte antigens (HLA) in the Somali population, which seem to differentiate from all other neighboring regions compared. Current study identified high prevalence of the diabetes type 1 (T1D) predisposing HLA DR-DQ haplotypes in Somalia. This finding may explain the increased T1D risk observed among Somali children. In addition, ethnic Somalis were found to host the highest frequencies observed thus far for several pharmacogenetic variants, including UGT1A4*2. In conclusion, we report that the Somali population displays genetic traits of significance to health and disease. The Somali dataset is publicly available and will add more information to the few genomic datasets available for African populations.

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  • 3.
    Bastami, Salumeh
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Gupta, A.
    Department of Anesthesia and Intensive Care, Örebro University, Örebro, Sweden.
    Zackrisson, Anna Lena
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden .
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Influence of UGT2B7, OPRM1 and ABCB1 gene polymorphisms on morphine use2014Ingår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, nr 5, s. 423-431Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Therapeutic modulation of pain with morphine and other opioids is associated with significant variation in, both, effects and adverse effects in individual patients. Many factors including gene polymorphisms have been shown to contribute to the interindividual variability in the response to opioids. The aim of this study was to investigate the significance of UGT2B7, OPRM1 and ABCB1 polymorphisms for interindividual variability in morphine induced analgesia in patients undergoing hysterectomy. The frequency of these polymorphisms was also investigated in forensic autopsy cases as morphine is also a very commonly abused drug

    Blood samples were collected from 40 patients following abdominal hysterectomy, 24 hours after initiation of analgesia through a PCA pump. Samples were genotyped and analysed for morphine and its metabolites. We also genotyped approximately 200 autopsy cases found positive for morphine in routine forensic analysis.

    Patients homozygous for UGT2B7 802C needed significantly lower dose of morphine for pain relief. The same trend was observed for patients homozygous for ABCB1 1236T and 3435T, as well as to OPRM1 118A. Dose of morphine in patients included in this study was significantly related to variation in UGT2B7 T802C. Age was significantly related to both dose and concentration of morphine in blood.

    Regression analysis showed that 30% of differences in variation in morphine dose could be explained by SNPs in these genes. The genotype distribution was similar between the forensic cases and the patients. However, the mean concentration of morphine was higher in forensic cases compared to patients.

    We conclude that gene polymorphisms contribute significantly to the variation in morphine levels observed in individual patients.

  • 4.
    Diallo, Idrissa
    et al.
    CHU Quebec, Canada; Univ Laval, Canada.
    Benmoussa, Abderrahim
    CHU Quebec, Canada; Univ Laval, Canada.
    Laugier, Jonathan
    CHU Quebec, Canada; Univ Laval, Canada.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Hitzler, Walter E.
    Johannes Gutenberg Univ Mainz, Germany.
    Provost, Patrick
    CHU Quebec, Canada; Univ Laval, Canada.
    Platelet Pathogen Reduction Technologies Alter the MicroRNA Profile of Platelet-Derived Microparticles2020Ingår i: Frontiers in Cardiovascular Medicine, E-ISSN 2297-055X, Vol. 7, artikel-id 31Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite improvements in donor screening and increasing efforts to avoid contamination and the spread of pathogens in clinical platelet concentrates (PCs), the risks of transfusion-transmitted infections remain important. Relying on an ultraviolet photo activation system, pathogen reduction technologies (PRTs), such as Intercept and Mirasol, utilize amotosalen, and riboflavin (vitamin B2), respectively, to mediate inactivation of pathogen nucleic acids. Although they are expected to increase the safety and prolong the shelf life of clinical PCs, these PRTs might affect the quality and function of platelets, as recently reported. Upon activation, platelets release microparticles (MPs), which are involved in intercellular communications and regulation of gene expression, thereby mediating critical cellular functions. Here, we have used small RNA sequencing (RNA-Seq) to document the effect of PRT treatment on the microRNA profiles of platelets and derived MPs. PRT treatment did not affect the microRNA profile of platelets. However, we observed a specific loading of certain microRNAs into platelet MPs, which was impaired by treatment with Intercept or its Additive solution (SSP+). Whereas, Intercept had an impact on the microRNA profile of platelet-derived MPs, Mirasol did not impact the microRNA profile of platelets and derived MPs, compared to non-treated control. Considering that platelet MPs are able to transfer their microRNA content to recipient cells, and that this content may exert biological activities, those findings suggest that PRT treatment of clinical PCs may modify the bioactivity of the platelets and MPs to be transfused and argue for further investigations into PRT-induced changes in clinical PC content and function.

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  • 5. Enström, Camilla
    et al.
    Osman, Abdimajid
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Lindahl, Tomas
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    A genotyping method for VKORC1 1173C>T by Pyrosequencing® technology2008Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 68, nr 5, s. 427-430Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Vitamin K epoxide reductase complex subunit 1 (VKORC1) is the site of inhibition by warfarin and other anti-vitamin K drugs during oral anticoagulant therapy. The SNP rs9934438 in intron 1 of VKORC1 (c.173+1000C>T or 1173C>T) discriminating the VKORC1*2 haplotype is associated with low warfarin dose requirement and unstable prothrombin time - international normalized ratio. To genotype this SNP, we have developed a rapid method using Pyrosequencing® technology. The proposed method takes a post-PCR sample preparation of less than 1 h and a DNA sequencing time of less than 15 min to genotype 96 samples. The current method was compared with a dHPLC method that we reported previously. Genotype frequencies at VKORC1 1173C>T for our Swedish population were 38 % wild-type, 40 % heterozygote and 22 % homozygote. The frequency of the T-allele was 0.42, which exactly matches the frequency previously reported for Germans. The current method can be used to determine whether patients initiating warfarin therapy are carriers of SNP 1173 C>T that is strongly associated with low warfarin dose requirement. © 2008 Informa UK Ltd (Informa Healthcare, Taylor & Francis AS).

  • 6.
    Heenkenda, Menikae K.
    et al.
    Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Frequency of PAR4 Ala120Thr variant associated with platelet reactivity significantly varies across sub-Saharan African populations2018Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132, nr 19, s. 2103-2106Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

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  • 7.
    Heenkenda, Menikae Kanchena
    et al.
    Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Närsjukvården i centrala Östergötland, Närvårdskliniken.
    Lysiak, Malgorzata
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Mudaisi, Munila
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Bratthall, Charlotte
    Dist Hosp, Sweden.
    Milos, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Sinnescentrum, Neurokirurgiska kliniken US.
    Strandeus, Michael
    Ryhov Hosp, Sweden.
    Åkesson, Lisa
    Linköpings universitet, Institutionen för tema. Linköpings universitet, Filosofiska fakulteten.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Uppugunduri, Srinivas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för verksamhetsstöd och utveckling, Regionalt Cancercentrum.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för klinisk kemi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Assessment of genetic and non-genetic risk factors for venous thromboembolism in glioblastoma - The predictive significance of B blood group2019Ingår i: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 183, s. 136-142Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: Venous thromboembolism (VTE) is a common problem among patients with glioblastoma multi-forme (GBM) and with some other cancers. Here, we evaluated genetic and non-genetic potential risk factors for VTE among GBM patients. Materials and methods: A cohort of 139 patients treated with concomitant radiotherapy and temozolomide were included in the study. Next generation sequencing and genotyping approaches were applied to assess genetic risk factors in the haemostatic system. Clinical data including surgery, reoperation as well as blood group and patient information such as age and gender were available from patient records. Logistic regression analysis was performed to asses VTE risk. Results: In the study 47 patients (34%) were diagnosed for VTE during the course of their disease. When genetic and non-genetic potential risk factors were evaluated, only B blood group was found to be significantly associated with VTE incidence (odds ratio [OR] = 6.91; confidence interval [CI] = 2.19-24.14; P = 0.001). In contrast, A and O blood groups did not correlate with VTE risk. Frontal lobe tumor location also seemed to slightly increase VTE risk compared to other brain sites (OR = 3.14; CI = 1.1-10.7) although the significance level was at borderline (P = 0.05). Current study identified B blood group as the component in non-O blood groups that is responsible for increased VTE risk. Conclusion: In conclusion, these results suggest for the first time that B blood group is predictive for VTE incidence among patients with glioblastoma, information that may be potentially valuable when selecting GBM patients who are at risk for VTE for anticoagulant prophylaxis.

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  • 8.
    Kissopoulou, Antheia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Jonasson, Jon
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Molekylär och immunologisk patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Next Generation Sequencing Analysis of Human Platelet PolyA plus mRNAs and rRNA-Depleted Total RNA2013Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 8, nr 12, s. 81809-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Platelets are small anucleate cells circulating in the blood vessels where they play a key role in hemostasis and thrombosis. Here, we compared platelet RNA-Seq results obtained from polyA+ mRNA and rRNA-depleted total RNA. Materials and Methods: We used purified, CD45 depleted, human blood platelets collected by apheresis from three male and one female healthy blood donors. The Illumina HiSeq 2000 platform was employed to sequence cDNA converted either from oligo(dT) isolated polyA+ RNA or from rRNA-depleted total RNA. The reads were aligned to the GRCh37 reference assembly with the TopHat/Cufflinks alignment package using Ensembl annotations. A de novo assembly of the platelet transcriptome using the Trinity software package and RSEM was also performed. The bioinformatic tools HTSeq and DESeq from Bioconductor were employed for further statistical analyses of read counts. Results: Consistent with previous findings our data suggests that mitochondrially expressed genes comprise a substantial fraction of the platelet transcriptome. We also identified high transcript levels for protein coding genes related to the cytoskeleton function, chemokine signaling, cell adhesion, aggregation, as well as receptor interaction between cells. Certain transcripts were particularly abundant in platelets compared with other cell and tissue types represented by RNA-Seq data from the Illumina Human Body Map 2.0 project. Irrespective of the different library preparation and sequencing protocols, there was good agreement between samples from the 4 individuals. Eighteen differentially expressed genes were identified in the two sexes at 10% false discovery rate using DESeq. Conclusion: The present data suggests that platelets may have a unique transcriptome profile characterized by a relative over-expression of mitochondrially encoded genes and also of genomic transcripts related to the cytoskeleton function, chemokine signaling and surface components compared with other cell and tissue types. The in vivo functional significance of the non-mitochondrial transcripts remains to be shown.

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  • 9.
    Nylander, Martina
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Ramström, Sofia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Åklint, Emma
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Larsson, Anders
    Department of Medical Sciences, University Hospital, Uppsala, Sweden.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    The role of thrombin receptors PAR1 and PAR4 for PAI-1 storage, synthesis and secretion by human platelets2012Ingår i: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 129, nr 4, s. E51-E58Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION:

    Arterial thrombi contain more platelets than venous thrombi and are more resistant to fibrinolysis. This resistance could partly be due to plasminogen activator inhibitor 1 (PAI-1) secreted by platelets. The aim of this study was to elucidate differences between thrombin receptors protease-activated receptor (PAR) 1 and 4 and platelet storage, secretion and synthesis of platelet PAI-1, as compared to other platelet α-granule proteins such as VEGF and endostatin.

    MATERIALS AND METHODS:

    Human isolated platelets were incubated with thrombin (0.5U/ml), PAR1-activating peptide (AP) (0.4-30μM) or PAR4-AP (1.5-300μM) for up to 24hours. ELISA, western blot and fluorescence microscopy were used to measure secretion, contents and localization of PAI-1, VEGF and endostatin.

    RESULTS:

    Our results show that PAI-1 and VEGF might be co-localized and that endostatin does not co-localize with either PAI-1 or VEGF. PAI-1 and VEGF show a similar secretion pattern, being more sensitive to low grade PAR1 activation, but secretion was also observed with higher concentrations of PAR4-APs. PAI-1 is secreted in an active form. PAI-1 mRNA was found in platelets, and elevated levels of PAI-1 were detected after 24hours incubation of platelets.

    CONCLUSIONS:

    PAI-1 and VEGF, but not endostatin, might be stored in the same α-granule in human platelets. PAI-1 and VEGF also show a similar secretion pattern, being more sensitive to PAR1 than to PAR4 activation, but the secretion is not exclusively selective. Our results also show that platelet PAI-1 is increased if incubated for 24hours, both with addition of PAR1-activating peptide and without activation, which could indicate de novo synthesis.

  • 10.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    MicroRNAs in Health and Disease - Basic Science and Clinical Applications2012Ingår i: CLINICAL LABORATORY, ISSN 1433-6510, Vol. 58, nr 5-6, s. 393-402Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    MicroRNAs (miRs) are small RNAs that fine-tune gene expression at posttranscriptional level. They are involved in virtually all physiological processes, such as development and differentiation, heart function, metabolism, haemostasis, and apoptosis. Anucleated human platelets were revealed to contain comparatively many different miR species relative to nucleated cells, suggesting a functional impact of miRs on these small cells. In recent years, numerous studies have established the significance of miRs in different physiological states. Sufficient evidence exists to suggest that miRs are involved in a range of diseases, including cancer and cardiovascular disorders. Aberrant expression levels of miRs are found in tissues and in sera from patients with different forms of malignant tumours. Utilising these miRs as biomarkers for disease is a valuable diagnostic strategy. In addition, a novel class of synthetic oligonucleotides, called antagomirs, has recently been introduced as efficient silencers of overexpressed miRs in cancer. Overall, miRs represent an important class of small RNAs with a huge impact on health and disease. Future studies will further illuminate the potential value of miRs in diagnostics and therapeutics.

  • 11. Beställ onlineKöp publikationen >>
    Osman, Abdimajid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Studies on warfarin treatment with emphasis on inter-individual variations and drug monitoring2007Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [sv]

    Waran används sedan 60 år som blodförtunnande läkemedel för att förebygga eller förhindra progress av blodproppssjukdom. I Sverige behandlas årligen cirka 1 % av befolkningen med waran. I Östergötland uppskattas antal waranpatienter till cirka 3000. Waran hämmar enzymet VKORC1 som ansvarar för vitamin K omsättningen i kroppen. Vitamin K behövs som kofaktor för flera koagulationsfaktorer.

    Behandling med waran är förenad med en svår balansgång och kräver en noggrann dosering. Stora skillnader i dosbehov mellan olika individer, beroende på ärftliga och miljöfaktorer, gör waran till ett svårhanterligt läkemedel. För låg dos medför otillräcklig effekt och därmed risk för minskat skydd mot blodproppssjukdom. För hög dos leder till allvarliga blödningskomplikationer. Uppskattningsvis 1 – 3 % livshotande blödningsfall registreras årligen efter waranbehandling. Därför måste behandlingen kontrolleras noga med analys av protrombinkomplex (PK) och dosjusteringar göras med ledning av resultaten. Två olika metoder finns att använda för mätning av PK. I Norden och i Japan används Owrens metod (utvecklat i Norge under 40- och 50-talet av Paul Owren). I de flesta andra länder används Quickmetoden (utvecklat i USA under 30-talet av Armand Quick). Den senare metoden är förenad med stora variationer mellan olika analyslaboratorier. I Norden, däremot, där Owrens metod används finns det ofta bra överensstämmelse mellan olika laboratorier i PK-resultat. Beroende på vilken PK-metod som används, kan samma patient få olika warandoser vilket ökar risker för under- eller överbehandling.

    Vi har i samarbete med flera sjukhus och antikoagulationsmottagningar (AK-mottagningar) i sydöstra Sverige studerat dels mekanismerna bakom skillnader i warandos mellan olika patienter, och dels tittat varför de olika PK-metoder skiljer sig så mycket som de gör.

    I studien har vi identifierat genetiska varianter av enzymet VKORC1. Av de undersökta patienter som gick på waran under längre tid, har vi identifierat en grupp som markant skiljde sig från de övriga. Denna grupp hade warandoser som var betydligt lägre än de övriga. När vi kartlade deras arvsmassa, fann vi att lågdospatienterna hade genvarianten VKORC1*2. Dessutom hade patienter med denna variant svårigheter att få stabila PK-värden. De gjorde också fler besök på AK-mottagningar än andra patienter. Vi har därför konstaterat att en del av de problem som är förenade med waranbehnadlingen kan förklaras av VKORC1*2 varianten. Vetskap om denna variant skulle troligen underlätta behandlingen framför allt under inledningsfasen då patienter med VKORC1*2 riskerar blödningar på grund av överdosering.

    Vi har identifierat att provförspädning enligt Owrens metod är nödvändig för harmonisering av PK-resultatet mellan olika länder. Quickmetoden använder inte förspädning av patientprov till skillnad från Owrens metod. När vi modifierade en Quickmetod genom att förspäda prover enligt Owrens metod noterade vi en bra överensstämmelse mellan de två olika metoderna. Däremot var resultatet sämre utan provförspädning. Vi anser att Quickmetoder kan uppnå lika bra resultat som Owrens metod om prover förspäds som i Owrens metod. Det skulle gynna patienter som reser mellan olika regioner eller länder och leda till en bättre övervakning av waranbehandling internationellt.

    I studien har dessutom en metod för mätning av waran i blodet utvecklats. Metoden som är den enda i sitt slag i Norden ger möjlighet att studera hur läkemedlet beter sig i kroppen. Vi har med denna metod kunnat upptäcka patienter som har onormala nedbrytningar av waran.

    Delarbeten
    1. A new high-performance liquid chromatographic method for determination of warfarin enantiomers.
    Öppna denna publikation i ny flik eller fönster >>A new high-performance liquid chromatographic method for determination of warfarin enantiomers.
    2005 (Engelska)Ingår i: Journal of Chromatography B, ISSN 1570-0232, Vol. 826, nr 1-2, s. 75-80Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Warfarin is the most common agent used for control and prevention of venous as well as arterial thromboembolism. Although warfarin is administered as a racemic mixture of two stereoisomers (S and R), the S-form is mainly responsible for the anticoagulant effect. The anticoagulant effect of the drug is monitored by analysis of prothrombin complex (International Normalised Ratio,INR). In some cases, however, the measurements of plasma warfarin concentration are needed. Here, we present a new, rapid, sensitive and cost-effective HPLC-method for the determination of warfarin enantiomers in plasma. The chromatographic system consisted of Waters 616 gradient pump, Waters 996 photo diode array detector, Gilson 230 autoinjector and Pirkle (R,R) Whelk-O1 column (25 cm × 4.6 mm I.D., 5 μm). An isocratic mobile phase of methanol/acetonitrile/water (50/10/40, v/v) with 0.1% glacial acetic acid was used. The follow rate was 1 mL/min. Data analysis was carried out with Waters Millennium32. The absorbance at 305 nm was measured with a total run-time of 15 min. Method linearity was studied by establishing regression data containing eight points over the range 0.08–10 μg/mL. In this range, warfarin showed to be linear (r2 = 0.9997 for S-warfarin and r2 = 0.9998 for R-warfarin). The limit of detection in plasma was 16 ng/mL for S-warfarin and 18 ng/mL for R-warfarin. Limit of quatitation was defined as 10 × LOD. The extraction recovery was approximately 80%. Also the relation between INR and warfarin concentration was investigated. As expected, there was a low correlation between these two variables (r = 0.23, y = 0.3044x + 0.9712). This method offers a rapid and cost-effective determination of warfarin enantiomers in human plasma.

    Nyckelord
    S- and R-warfarin; Oxybenzone; INR
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14487 (URN)10.1016/j.jchromb.2005.08.011 (DOI)
    Tillgänglig från: 2007-05-21 Skapad: 2007-05-21 Senast uppdaterad: 2022-04-19
    2. Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: A retrospective analysis of case records
    Öppna denna publikation i ny flik eller fönster >>Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: A retrospective analysis of case records
    Visa övriga...
    2006 (Engelska)Ingår i: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, Vol. 4, nr 8, s. 1723-1729Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background: Vitamin K epoxide reductase (VKORC1) is the site of inhibition by coumarins. Several reports have shown that mutations in the gene encoding VKORC1 affect the sensitivity of the enzyme for warfarin. Recently, three main haplotypes of VKORC1; *2, *3 and *4 have been observed, that explain most of the genetic variability in warfarin dose among Caucasians.

    Objectives: We have investigated the main haplotypes of the VKORC1 gene in a Swedish population. Additional objective was to screen the studied population for mutations in the coding region of VKORC1 gene.

    Patients/methods: Warfarin doses and plasma S- and R-warfarin of 98 patients [with a target International Normalized Ratio (INR) of 2.0–3.0] have been correlated to VKORC1 haplotypes. Controls of 180 healthy individuals have also been haplotyped. Furthermore, a retrospective analysis of case records was performed to find any evidence indicating influence of VKORC1 haplotypes on warfarin response in the first 4 weeks (initiation phase) and the latest 12 months of warfarin treatment.

    Results and conclusions: Our result shows that VKORC1*2 is the most important haplotype for warfarin dosage. Patients with VKORC1*2 haplotype had more frequent visits than patients with VKORC1*3 or *4 haplotypes, higher coefficient of variation (CV) of prothrombin time-INR and higher percentage of INR values outside the therapeutic interval (i.e. 2.0–3.0) than patients with VKORC1*3 or *4 haplotypes. Also, there was a statistically significant difference in warfarin dose (P < 0.001) and R-warfarin plasma levels (P < 0.01) between VKORC1*2 and VKORC1*3 or 4 haplotypes. Patients with VKORC1*2 haplotype seem to require much lower warfarin doses than other patients.

    Nyckelord
    INR, VKORC1, warfarin
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14488 (URN)10.1111/j.1538-7836.2006.02039.x (DOI)
    Tillgänglig från: 2007-05-21 Skapad: 2007-05-21 Senast uppdaterad: 2023-10-31
    3. Plasma S/R ratio of warfarin co-varies with VKORC1 haplotype
    Öppna denna publikation i ny flik eller fönster >>Plasma S/R ratio of warfarin co-varies with VKORC1 haplotype
    2007 (Engelska)Ingår i: Blood Coagulation and Fibrinolysis, ISSN 0957-5235, E-ISSN 1473-5733, Vol. 18, nr 3, s. 293-296Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We recently reported that the low-dose VKORC1*2 haplotype is an important genetic determinant for warfarin dose requirement and is associated with difficulties to attain stable therapeutic prothrombin time-International Normalized Ratio in patients undergoing anticoagulation therapy. The aim of this study was to investigate whether patients with VKORC1*2 compared with patients carrying high-dose haplotypes VKORC1*3 or VKORC1*4 had different warfarin S/R ratios in their plasma, and whether that was related to CYP2C9 variants CYP2C9*2 and CYP2C9*3 or other factors. Samples from patients previously haplotyped for VKORC1 and measured for plasma warfarin concentration were genotyped for the CYP2C9 variants CYP2C9*2 and CYP2C9*3. Nonparametric statistical analysis was performed to elucidate whether there was any significant difference in the warfarin S/R ratio between the two patient groups. Our result shows that there is a significant difference (P < 0.01) in warfarin S/R ratios between VKORC1*2 and VKORC1*3 or VKORC1*4 patients. This difference did not originate from CYP2C9 variants CYP2C9*2 and CYP2C9*3. We speculate that VKORC1 haplotypes possibly are linked to some unidentified factors involved in the metabolic clearance of warfarin enantiomers. Dose-dependent variations in (S)-warfarin and (R)-warfarin clearance in these patients can also be a probable explanation for the difference in warfarin S/R ratios.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14489 (URN)10.1097/MBC.0b013e3280444bfd (DOI)
    Tillgänglig från: 2007-05-21 Skapad: 2007-05-21 Senast uppdaterad: 2022-04-19Bibliografiskt granskad
    4. Plasma sample dilution improves the correlation: between reagents for PT methods
    Öppna denna publikation i ny flik eller fönster >>Plasma sample dilution improves the correlation: between reagents for PT methods
    2007 (Engelska)Ingår i: XXIst ISTH Congress, 2007Konferensbidrag, Publicerat paper (Refereegranskat)
    Abstract [en]

    Introduction: The Quick (plain thromboplastins) and Owren (combined thromboplastins) PT methods are used worldwide for the monitoring of anticoagulation therapy with vitamin K antagonists. Although both methods measure the activity of vitamin K dependent coagulation factors, the Quick PT-result in addition is dependent on the activity of factor V and of fibrinogen. The Quick PT-methods are also associated with larger inter-laboratory variations than Owren PT-methods. We have investigated whether the dilution of the sample, the source of depleted plasma or the source of thromboplastin have an impact on the correlation between the different PT-reagents.

    Methods: Patient and quality control samples were analysed undiluted and prediluted 2x, 7x, 10x, and 12x in Owren's buffer. One part of sample was then mixed with two parts of reagent and calcium. Bovine vs. human depleted plasmas and rabbit brain vs. human placenta thromboplastins were compared in combinations. The assays were run on an ACL Top from Instrumentation Laboratory (Italy).

    Results: Our results show that the dilution of the sample is important for the correlation between different PT-reagents. We found the best correlation (r = 0.95) when the sample was 7-fold prediluted (1 part + 6 parts). The lowest correlation was found when the sample was undiluted (r = 0.67). The source of thromboplastin had a small, if any, impact on the PT-results provided the sample was prediluted.The source of depleted plasma had no significance for the relationship between the PT-reagents. The depleted plasma is necessary to in order enable clotting of prediluted plasma.

    Conclusions: We conclude that the Owren style sample dilution is to prefer for the harmonization of PT-results and to overcome the large inter-laboratory variations that are associated with Quick PT-methods.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-14490 (URN)
    Anmärkning
    This paper is published in volume 5, supplement 1 of Journal of Thrombosis and Haemostasis (2007).Tillgänglig från: 2007-05-21 Skapad: 2007-05-21 Senast uppdaterad: 2022-04-19
    Ladda ner fulltext (pdf)
    FULLTEXT01
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    COVER01
  • 12.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Arbring, Kerstin
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    A new high-performance liquid chromatographic method for determination of warfarin enantiomers.2005Ingår i: Journal of Chromatography B, ISSN 1570-0232, Vol. 826, nr 1-2, s. 75-80Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Warfarin is the most common agent used for control and prevention of venous as well as arterial thromboembolism. Although warfarin is administered as a racemic mixture of two stereoisomers (S and R), the S-form is mainly responsible for the anticoagulant effect. The anticoagulant effect of the drug is monitored by analysis of prothrombin complex (International Normalised Ratio,INR). In some cases, however, the measurements of plasma warfarin concentration are needed. Here, we present a new, rapid, sensitive and cost-effective HPLC-method for the determination of warfarin enantiomers in plasma. The chromatographic system consisted of Waters 616 gradient pump, Waters 996 photo diode array detector, Gilson 230 autoinjector and Pirkle (R,R) Whelk-O1 column (25 cm × 4.6 mm I.D., 5 μm). An isocratic mobile phase of methanol/acetonitrile/water (50/10/40, v/v) with 0.1% glacial acetic acid was used. The follow rate was 1 mL/min. Data analysis was carried out with Waters Millennium32. The absorbance at 305 nm was measured with a total run-time of 15 min. Method linearity was studied by establishing regression data containing eight points over the range 0.08–10 μg/mL. In this range, warfarin showed to be linear (r2 = 0.9997 for S-warfarin and r2 = 0.9998 for R-warfarin). The limit of detection in plasma was 16 ng/mL for S-warfarin and 18 ng/mL for R-warfarin. Limit of quatitation was defined as 10 × LOD. The extraction recovery was approximately 80%. Also the relation between INR and warfarin concentration was investigated. As expected, there was a low correlation between these two variables (r = 0.23, y = 0.3044x + 0.9712). This method offers a rapid and cost-effective determination of warfarin enantiomers in human plasma.

  • 13.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Enström, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Arbring, Kerstin
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: A retrospective analysis of case records2006Ingår i: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, Vol. 4, nr 8, s. 1723-1729Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Vitamin K epoxide reductase (VKORC1) is the site of inhibition by coumarins. Several reports have shown that mutations in the gene encoding VKORC1 affect the sensitivity of the enzyme for warfarin. Recently, three main haplotypes of VKORC1; *2, *3 and *4 have been observed, that explain most of the genetic variability in warfarin dose among Caucasians.

    Objectives: We have investigated the main haplotypes of the VKORC1 gene in a Swedish population. Additional objective was to screen the studied population for mutations in the coding region of VKORC1 gene.

    Patients/methods: Warfarin doses and plasma S- and R-warfarin of 98 patients [with a target International Normalized Ratio (INR) of 2.0–3.0] have been correlated to VKORC1 haplotypes. Controls of 180 healthy individuals have also been haplotyped. Furthermore, a retrospective analysis of case records was performed to find any evidence indicating influence of VKORC1 haplotypes on warfarin response in the first 4 weeks (initiation phase) and the latest 12 months of warfarin treatment.

    Results and conclusions: Our result shows that VKORC1*2 is the most important haplotype for warfarin dosage. Patients with VKORC1*2 haplotype had more frequent visits than patients with VKORC1*3 or *4 haplotypes, higher coefficient of variation (CV) of prothrombin time-INR and higher percentage of INR values outside the therapeutic interval (i.e. 2.0–3.0) than patients with VKORC1*3 or *4 haplotypes. Also, there was a statistically significant difference in warfarin dose (P < 0.001) and R-warfarin plasma levels (P < 0.01) between VKORC1*2 and VKORC1*3 or 4 haplotypes. Patients with VKORC1*2 haplotype seem to require much lower warfarin doses than other patients.

  • 14.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Enström, Camilla
    Linköpings universitet, Institutionen för biomedicin och kirurgi. Linköpings universitet, Hälsouniversitetet.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Plasma S/R ratio of warfarin co-varies with VKORC1 haplotype2007Ingår i: Blood Coagulation and Fibrinolysis, ISSN 0957-5235, E-ISSN 1473-5733, Vol. 18, nr 3, s. 293-296Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We recently reported that the low-dose VKORC1*2 haplotype is an important genetic determinant for warfarin dose requirement and is associated with difficulties to attain stable therapeutic prothrombin time-International Normalized Ratio in patients undergoing anticoagulation therapy. The aim of this study was to investigate whether patients with VKORC1*2 compared with patients carrying high-dose haplotypes VKORC1*3 or VKORC1*4 had different warfarin S/R ratios in their plasma, and whether that was related to CYP2C9 variants CYP2C9*2 and CYP2C9*3 or other factors. Samples from patients previously haplotyped for VKORC1 and measured for plasma warfarin concentration were genotyped for the CYP2C9 variants CYP2C9*2 and CYP2C9*3. Nonparametric statistical analysis was performed to elucidate whether there was any significant difference in the warfarin S/R ratio between the two patient groups. Our result shows that there is a significant difference (P < 0.01) in warfarin S/R ratios between VKORC1*2 and VKORC1*3 or VKORC1*4 patients. This difference did not originate from CYP2C9 variants CYP2C9*2 and CYP2C9*3. We speculate that VKORC1 haplotypes possibly are linked to some unidentified factors involved in the metabolic clearance of warfarin enantiomers. Dose-dependent variations in (S)-warfarin and (R)-warfarin clearance in these patients can also be a probable explanation for the difference in warfarin S/R ratios.

  • 15.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Fälker, Knut
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    Characterization of human platelet microRNA by quantitative PCR coupled with an annotation network for predicted target genes2011Ingår i: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 22, nr 6, s. 433-441Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    latelets are anucleate blood cells that play a crucial role in thrombosis and hemostasis. Despite their lack of nuclear DNA, platelets contain significant amounts of microRNA (miRNA) that may have vital functions in post-transcriptional gene regulation. Here, we combined comprehensive miRNA expression profiling by quantitative PCR with target prediction analysis for the most abundant miRNAs in human platelets. A network composed of predicted platelet miRNA target genes was then constructed, using annotations available in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. In addition, we evaluated possible differences in miRNA levels between resting and thrombin-stimulated platelets. We identified 281 transcripts, including 228 mature miRNAs and 53 minor miRNAs (or miR(star)), of which six miRNAs (miR-15 a, miR-339-3 p, miR-365, miR-495, miR-98, and miR-361-3 p) were up-or down-regulated in activated human platelets (P andlt;= 0.001). A redundancy-reduced network was established that encompassed 246 genes in five statistically significant functional clusters representing platelet miRNA regulating pathways. Comparison of the 246 network genes with the platelet mRNA expression data available at ArrayExpress database confirmed that most of these genes (89%) are expressed in human platelets. In conclusion, this work affirms a recent microarray study reporting a wide-spread existence of miRNAs in human platelets. Further, we observed that thrombin stimulation was associated with altered levels of some miRNAs in platelets. The proposed functional network, combining computational prediction analysis with annotations from experimental observations, may in addition provide some information about probable miRNA target pathways in human platelets.

  • 16.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Hannestad, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi.
    A possible ethanol-catalyzed rearrangement of vitamin K-1 detected by gas chromatography/mass spectrometry2008Ingår i: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 22, nr 23, s. 3861-3866Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We studied vitamin K-1(20), vitamin K-1(25), and vitamin K, epoxide in n-hexane and ethanol solutions by gas chromatography/mass spectrometry (GC/MS) utilizing a DB-5 MS fused-silica capillary column. In ethanol solutions of K-1, we observed an extra peak eluting from the GC column with somewhat longer retention time than K-1(20). A similar peak following K-1(25) was also found. These peaks were not found in n-hexane solutions of K-1. A close examination of the mass spectra of these peaks indicated that they were vitamin K-1 variants containing a base peak at m/z 225 characteristic of the methylnaphthoquinone ring with a four-carbon side chain. In addition, they contained the molecular ions of K-1(20) and K-1(25), respectively. We conclude that K-1(20) and K-1(25), but not K-1 epoxide, might undergo rearrangements in ethanol involving an intramolecular proton transfer and a shift of the beta,gamma-double bond on the phytyl side chain toward the ring. The conjugation of the phytyl double bond with the quinone ring is probably the driving force of the rearrangement. We emphasize, however, that our conclusion is based only on mass spectral analysis and would require further investigation by other spectroscopic methods.

  • 17.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Region Östergötland, Diagnostikcentrum, Klinisk kemi. Linköpings universitet, Medicinska fakulteten.
    Hitzler, Walter E.
    Johannes Gutenberg University of Mainz, Germany.
    Ameur, Adam
    Uppsala University, Sweden.
    Provost, Patrick
    University of Laval, Canada.
    Differential Expression Analysis by RNA-Seq Reveals Perturbations in the Platelet mRNA Transcriptome Triggered by Pathogen Reduction Systems2015Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 10, nr 7, s. e0133070-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Platelet concentrates (PCs) are prepared at blood banks for transfusion to patients in certain clinical conditions associated with a low platelet count. To prevent transfusion-transmitted infections via PCs, different pathogen reduction (PR) systems have been developed that inactivate the nucleic acids of contaminating pathogens by chemical cross-linking, a mechanism that may also affect platelets nucleic acids. We previously reported that treatment of stored platelets with the PR system Intercept significantly reduced the level of half of the microRNAs that were monitored, induced platelet activation and compromised the platelet response to physiological agonists. Using genome-wide differential expression (DE) RNA sequencing (RNA-Seq), we now report that Intercept markedly perturbs the mRNA transcriptome of human platelets and alters the expression level of greater than800 mRNAs (Pless than0.05) compared to other PR systems and control platelets. Of these, 400 genes were deregulated with DE corresponding to fold changes (FC) greater than= 2. At the p-value less than 0.001, as many as 147 genes were deregulated by greater than= 2-fold in Intercept-treated platelets, compared to none in the other groups. Finally, integrated analysis combining expression data for microRNA (miRNA) and mRNA, and involving prediction of miRNA-mRNA interactions, disclosed several positive and inverse correlations between miRNAs and mRNAs in stored platelets. In conclusion, this study demonstrates that Intercept markedly deregulates the platelet mRNA transcriptome, concomitant with reduced levels of mRNA-regulatory miRNAs. These findings should enlighten authorities worldwide when considering the implementation of PR systems, that target nucleic acids and are not specific to pathogens, for the management of blood products.

    Ladda ner fulltext (pdf)
    fulltext
  • 18.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Hitzler, Walter E
    Transfusion Center, University Medical Center of the Johannes Gutenberg University, Mainz , Germany.
    Meyer, Claudius U
    Division of Pediatric Immunology, Department of Pediatrics, University Medical Center of the Johannes Gutenberg University, Mainz , Germany.
    Landry, Patricia
    CHUQ Research Center/CHUL, Quebec, QC , Canada / Faculty of Medicine, Université Laval, Quebec, QC , Canada.
    Corduan, Aurélie
    CHUQ Research Center/CHUL, Quebec, QC , Canada / Faculty of Medicine, Université Laval, Quebec, QC , Canada.
    Laffont, Benoit
    CHUQ Research Center/CHUL, Quebec, QC , Canada / Faculty of Medicine, Université Laval, Quebec, QC , Canada.
    Boilard, Eric
    CHUQ Research Center/CHUL, Quebec, QC , Canada / Faculty of Medicine, Université Laval, Quebec, QC , Canada.
    Hellstern, Peter
    Institute of Hemostaseology and Transfusion Medicine, Academic City Hospital Ludwigshafen, Ludwigshafen , Germany.
    Vamvakas, Eleftherios C
    Los Angeles, CA , USA.
    Provost, Patrick
    CHUQ Research Center/CHUL, Quebec, QC , Canada / Faculty of Medicine, Université Laval, Quebec, QC , Canada.
    Effects of pathogen reduction systems on platelet microRNAs, mRNAs, activation, and function.2015Ingår i: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 26, nr 2, s. 154-163Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pathogen reduction (PR) systems for platelets, based on chemically induced cross-linking and inactivation of nucleic acids, potentially prevent transfusion transmission of infectious agents, but can increase clinically significant bleeding in some clinical studies. Here, we documented the effects of PR systems on microRNA and mRNA levels of platelets stored in the blood bank, and assessed their impact on platelet activation and function. Unlike platelets subjected to gamma irradiation or stored in additive solution, platelets treated with Intercept (amotosalen + ultraviolet-A [UVA] light) exhibited significantly reduced levels of 6 of the 11 microRNAs, and 2 of the 3 anti-apoptotic mRNAs (Bcl-xl and Clusterin) that we monitored, compared with platelets stored in plasma. Mirasol (riboflavin + UVB light) treatment of platelets did not produce these effects. PR neither affected platelet microRNA synthesis or function nor induced cross-linking of microRNA-sized endogenous platelet RNA species. However, the reduction in the platelet microRNA levels induced by Intercept correlated with the platelet activation (p < 0.05) and an impaired platelet aggregation response to ADP (p < 0.05). These results suggest that Intercept treatment may induce platelet activation, resulting in the release of microRNAs and mRNAs from platelets. The clinical implications of this reduction in platelet nucleic acids secondary to Intercept remain to be established.

  • 19.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Hitzler, Walter E.
    Johannes Gutenberg University of Mainz, Germany.
    Provost, Patrick
    CHUL, Canada; University of Laval, Canada.
    Peculiarities of studying the effects of pathogen reduction technologies on platelets2016Ingår i: PROTEOMICS - Clinical Applications, ISSN 1862-8346, E-ISSN 1862-8354, Vol. 10, nr 8, s. 805-815Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The transfusion of platelet concentrates (PCs) is mainly used for treatment of thrombocytopenic, trauma or surgery patients. The integrity and safety of these platelet preparations, however, is compromised by the presence of pathogens, such as viruses, bacteria and parasites. The transfer of allogeneic donor leukocytes contaminating PCs can also potentially cause adverse reactions in recipients. These considerations prompted the development and implementation of pathogen reduction technologies (PRT), which are based on chemically induced cross-linking and inactivation of nucleic acids. While the incumbent PRT may provide some protection against transfusion-transmitted infections, they are ineffective against infectious prions and may not inactivate other emerging pathogens. In addition, the safety of PRT concerning platelet viability and function has been questioned in several reports. Recent studies suggest that PRT, such as Intercept, may adversely affect the messenger RNA (mRNA) and microRNA content of platelets, as well as their functional integrity, which may compromise the clinical benefits of PRT. Here, we will discuss about the peculiarities of studying the effects of PRT on platelets, which will need to be taken into account in future studies aimed to characterize further, and polish, the rugged side of this otherwise useful and potentially important approach in transfusion medicine.

  • 20.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Hitzler, Walter E.
    Johannes Gutenberg Univ Mainz, Germany.
    Provost, Patrick
    CHUL, Canada; Univ Laval, Canada.
    The platelets perspective to pathogen reduction technologies2018Ingår i: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 29, nr 2, s. 140-147Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    A wide variety of clinical conditions, associated with low circulating platelet counts, require platelet transfusion in order to normalize hemostatic function. Although single-donor apheresis platelets bear the lowest risk of transfusion-transmitted infections, pathogen reduction technologies (PRT) are being implemented worldwide to reduce this risk further through inactivation of known, emergent and as yet to be discovered nucleic acid-based pathogens. Human blood platelets are now known to harbor a diverse transcriptome, important to their function and comprised of amp;gt;5000 protein-coding messenger RNAs and different classes of non-coding RNAs, including microRNAs. Our appreciation of the nucleic acid-dependent functions of platelets is likely to increase. On the other hand, the side effects of PRT on platelet function are underappreciated. Recent evidences suggest that PRT may compromise platelets responsiveness to agonists, and induce platelet activation. For instance, platelets have the propensity to release proinflammatory microparticles (MPs) upon activation, and the possibility that PRT may enhance the production of platelet MPs in platelet concentrates (PCs) appears likely. With this in mind, it would be timely and appropriate to investigate other means to inactivate pathogens more specifically, or to modify the currently available PRT so to better preserve the platelet function and improve the safety of PCs; platelets perspective to PRT deserves to be considered.

  • 21.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk kemi.
    Jonasson, Jon
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk genetik.
    Cross-ethnic analysis of common gene variants in hemostasis show lopsided representation of global populations in genetic databases2022Ingår i: BMC Medical Genomics, E-ISSN 1755-8794, Vol. 15, nr 1, artikel-id 69Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A majority of studies reporting human genetic variants were performed in populations of European ancestry whereas other global populations, and particularly many ethnolinguistic groups in other continents, are heavily underrepresented in these studies. To investigate the extent of this disproportionate representation of global populations concerning variants of significance to thrombosis and hemostasis, 845 single nucleotide polymorphisms (SNPs) in and around 34 genes associated with thrombosis and hemostasis and included in the commercial Axiom Precision Medicine Research Array (PMRA) were evaluated, using gene frequencies in 3 African (Somali and Luhya in East Africa, and Yoruba in West Africa) and 14 non-African (admixed American, East Asian, European, South Asian, and sub-groups) populations. Among the populations studied, Europeans were observed to be the best represented population by the hemostatic SNPs included in the PMRA. The European population also presented the largest number of common pharmacogenetic and pathogenic hemostatic variants reported in the ClinVar database. The number of such variants decreased the farther the genetic distance a population was from Europeans, with Yoruba and East Asians presenting the least number of clinically significant hemostatic SNPs in ClinVar while also being the two genetically most distinct populations from Europeans among the populations compared. Current study shows the lopsided representation of global populations as regards to hemostatic genetic variants listed in different commercial SNP arrays, such as the PMRA, and reported in genetic databases while also underlining the importance of inclusion of non-European ethnolinguistic populations in genomics studies designed to discover variants of significance to bleeding and thrombotic disorders.

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  • 22.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Plasma predilution with addition of depleted plasma in a prothrombin time reagent improves the agreement between different prothrombin time methods2009Ingår i: SCANDINAVIAN JOURNAL OF CLINICAL and LABORATORY INVESTIGATION, ISSN 0036-5513, Vol. 69, nr 3, s. 395-400Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background . The Quick (plain thromboplastins) and Owren (combined thromboplastins, with the addition of bovine plasma with vitamin K-dependent factors depleted) prothrombin time (PT) methods are used for measuring prothrombin time; for instance, in monitoring anticoagulation therapy with vitamin K antagonists. In most Quick PT methods, the final plasma dilution is 1/3 compared to Owren methods, which have a final dilution of 1/21. The Quick PT methods are associated with larger inter-laboratory variations than the Owren PT methods. Objectives . We investigated whether dilution of the sample or thromboplastin has any impact on the correlation between the different PT methods. Material and methods . Plasma samples were analysed undiluted and prediluted in buffer, with adsorbed bovine plasma added, and by using rabbit brain or human placenta thromboplastins. Bootstrapping (re-sampling) was utilized to estimate the difference in correlations between PT of different reagents at different dilutions of plasma. Results and conclusions . We found the best correlations for combined reagents when the sample was prediluted 7-fold (r=0.95) or more, and lowest when the sample was undiluted (r=0.67). The source of thromboplastin had only a minor impact, if any, on the PT results. It was impossible to test whether predilution of plasma samples improved the correlation between Quick PT methods due to absence of clotting in many samples. We suggest that the Owren-style sample predilution is preferable for the harmonization of PT results and to overcome the large inter-laboratory variations that are associated with Quick PT methods to the benefit of patients on oral anticoagulation.

  • 23.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Lindahl, Tomas
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Plasma sample dilution improves the correlation: between reagents for PT methods2007Ingår i: XXIst ISTH Congress, 2007Konferensbidrag (Refereegranskat)
    Abstract [en]

    Introduction: The Quick (plain thromboplastins) and Owren (combined thromboplastins) PT methods are used worldwide for the monitoring of anticoagulation therapy with vitamin K antagonists. Although both methods measure the activity of vitamin K dependent coagulation factors, the Quick PT-result in addition is dependent on the activity of factor V and of fibrinogen. The Quick PT-methods are also associated with larger inter-laboratory variations than Owren PT-methods. We have investigated whether the dilution of the sample, the source of depleted plasma or the source of thromboplastin have an impact on the correlation between the different PT-reagents.

    Methods: Patient and quality control samples were analysed undiluted and prediluted 2x, 7x, 10x, and 12x in Owren's buffer. One part of sample was then mixed with two parts of reagent and calcium. Bovine vs. human depleted plasmas and rabbit brain vs. human placenta thromboplastins were compared in combinations. The assays were run on an ACL Top from Instrumentation Laboratory (Italy).

    Results: Our results show that the dilution of the sample is important for the correlation between different PT-reagents. We found the best correlation (r = 0.95) when the sample was 7-fold prediluted (1 part + 6 parts). The lowest correlation was found when the sample was undiluted (r = 0.67). The source of thromboplastin had a small, if any, impact on the PT-results provided the sample was prediluted.The source of depleted plasma had no significance for the relationship between the PT-reagents. The depleted plasma is necessary to in order enable clotting of prediluted plasma.

    Conclusions: We conclude that the Owren style sample dilution is to prefer for the harmonization of PT-results and to overcome the large inter-laboratory variations that are associated with Quick PT-methods.

  • 24.
    Osman, Abdimajid
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Uhlin, Fredrik
    Linköpings universitet, Institutionen för medicin och hälsa, Internmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US.
    Frånlund, Ebba
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Fernström, Anders
    Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Njurmedicinska kliniken US. Linköpings universitet, Institutionen för medicin och hälsa, Njurmedicin. Linköpings universitet, Hälsouniversitetet.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Exon resequencing of the gene encoding UCMA/GRP reveals a common carboxy-terminal 138Thr > Ser Polymorphism2013Ingår i: Clinical Laboratory, ISSN 1433-6510, Vol. 59, nr 11-12, s. 1397-1401Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The upper zone of growth plate and cartilage matrix-associated protein (UCMA), also called Gla-rich protein (GRP), is a novel protein found at sites af-fected by pathological calcifications.Methods: We performed a full exon resequencing on DNA samples from 17 chronic kid-ney disease (CKD) patients (stage 5) and compared the results with 121 healthy con-trols in a Swedish population.Results: A novel non-synonymous single nucleotide polymorphism (SNP) causing a car-boxy-terminal amino acid exchange was found. This SNP involves an alteration of the last ACC codon for threonine in exon 5 (adjacent to the stop codon) to an AGC ser-ine codon (138Thr > Ser). Six controls and two CKD patients were heterozygous for the 138Thr > Ser polymorphism. Both patients had histories of vascular calcifica-tion; however, it is uncertain whether this SNP has any significance for the func-tional domains of the UCMA protein. In addition, a heterozygous transversion muta-tion was found in a patient at SNP rs4750328 (A/G) in intron 2, involving an ex-change of the ancestral A allele to a T base.Conclusions: The 138Thr > Ser polymorphism seems to be the only non-synonymous SNP found in the UCMA gene in a Swedish population.

  • 25.
    Pfister, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk kemi.
    Letter: The VKORC1 promoter is occupied by c-Myc transcription factor in HepG2 cells2010Ingår i: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 126, nr 2, s. E150-E151Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 26.
    Saleiban, Amina
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Faxälv, Lars
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Claesson, Kjersti
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Osman, Abdimajid
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    miR-20b regulates expression of proteinase-activated receptor-1 (PAR-1) thrombin receptor in melanoma cells2014Ingår i: Pigment Cell & Melanoma Research, ISSN 1755-1471, E-ISSN 1755-148X, Vol. 27, nr 3, s. 431-441Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The proteinase-activated receptor 1 (PAR-1) plays a central role in melanoma progression and its expression level is believed to correlate with the degree of cancer invasiveness. Here, we show that PAR-1 is post-transcriptionally regulated by miR-20b microRNA in human melanoma cells. PAR-1 was found to be expressed in metastatic melanoma cells but was barely detectable in primary melanoma. By transducing primary melanoma cells with a lentivirus containing a 3-UTR construct of PAR-1 mRNA, we could show that endogenous melanoma microRNAs interacted with PAR-1 3-UTR and silenced a fused luciferase reporter. Transfection of an inhibitor against miR-20b into primary melanoma cells reversed this process. Finally, transfection of miR-20b mimic into metastatic melanoma cells caused downregulation of the luciferase reporter. We conclude that miR-20b regulates expression of melanoma PAR-1 receptor, which may explain the differential expression of PAR-1 observed in human melanoma.

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