| 11. |
- van der Harst, Pim, et al.
(författare)
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Seventy-five genetic loci influencing the human red blood cell
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7429, s. 369-375
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Tidskriftsartikel (refereegranskat)abstract
- Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
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| 12. |
- Hinz, P, et al.
(författare)
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[Thrombosis prophylaxis in trauma surgery units in Germany : a survey].
- 2009
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Ingår i: Der Unfallchirurg. - : Springer Science and Business Media LLC. - 1433-044X .- 0177-5537. ; 112:12, s. 1029-33
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A questionnaire study was conducted to ask trauma surgery centers about thrombosis prophylaxis methods and strategies for the diagnosis and therapy of heparin-induced thrombocytopenia (HIT). METHODS: Questionnaires were sent by post to German hospitals with trauma surgery units inquiring about the use of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH), the duration of medication, and the HIT diagnosis. Questionnaires were evaluated descriptively. RESULTS: 314 of 685 questionnaires sent out were evaluable (46%): half were from general hospitals, 96 (31%) from specialized hospitals, and 53 (17%) from tertiary care hospitals (others: 8). In more than 90%, only LMWH was used. The mean duration of pharmacological thrombosis prophylaxis was 16.6+/-10.4 days (inpatient/outpatient). Only 10% adhered to the recommended platelet count controls every 2 days (days 5-14) for early detection of HIT. CONCLUSIONS: While pharmacological thrombosis prophylaxis following trauma surgery seems to be generally performed according to guidelines, diagnosis and treatment of HIT need to be systematized.
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| 13. |
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| 14. |
- Balduini, Carlo, et al.
(författare)
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The EHA research roadmap : Platelet disorders
- 2021
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Ingår i: HemaSphere. - 2572-9241. ; 5:7
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Forskningsöversikt (refereegranskat)abstract
- In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1 to 2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally a more funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cellbased Immune Therapies; and Gene Therapy.
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| 15. |
- Block, Stephan, 1978, et al.
(författare)
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Characterization of bonds formed between platelet factor 4 and negatively charged drugs using single molecule force spectroscopy
- 2014
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Ingår i: Soft Matter. - : Royal Society of Chemistry (RSC). - 1744-6848 .- 1744-683X. ; 10:16, s. 2775-2784
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Tidskriftsartikel (refereegranskat)abstract
- Immunogenicity (i.e., the ability to initiate immune reactions) is one of the major challenges for the development of new drugs, as it may turn the developed drug therapeutically ineffective or cause severe immune-related effects. Using single molecule force spectroscopy, we study rupture forces between the positively charged, endogenous protein platelet factor 4 (PF4; also known as CXC chemokine ligand 4, CXCL4) and the antithrombotic drug heparin and other negatively charged glycosaminoglycans (GAGs), which are known to form immunogenic PF4/GAG-complexes (e. g., heparin and dextran sulfate) as well as non-immunogenic complexes (e. g., chondroitin sulfate A). Our measurements suggest that the average number of sulfate groups per monosaccharide unit (i.e., the degree of sulfation DS) does not affect the unbinding characteristics of single PF4/GAG-bonds (reaction coordinate x(0) = 2.2 +/- 0.2 angstrom, energy barrier Delta G approximate to -1 k(B)T). However, the average number of GAG bonds formed to a single PF4 molecule increases with increasing DS as indicated by a rising frequency of unbinding events, suggesting a multivalent binding scheme between PF4 and GAGs. Our studies show that at least three GAG bonds have to be formed to each PF4 molecule to induce epitope formation on the PF4/GAG-complex to which PF4/GAG-complex specific antibodies bind. Hence, GAG-based drugs that form less than three bonds per PF4 molecule are unlikely to constitute PF4/drug-complexes that are of immunologic relevance.
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| 16. |
- de Vries, Paul S., et al.
(författare)
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Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5x10(-8) is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5x10(-8)), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.
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| 17. |
- Greinacher, A, et al.
(författare)
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Heparin-induced thrombocytopenia : a prospective study on the incidence, platelet-activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes.
- 2007
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 5:8, s. 1666-73
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Platelet-activating antiplatelet factor 4/heparin (anti-PF4/heparin) antibodies are the major cause of heparin-induced thrombocytopenia (HIT). However, the relative utility of functional (platelet activation) vs. antigen [enzyme-immunoassay (EIA)] assays, and the significance of assay discrepancies remain unresolved. METHODS: Consecutive patient sera (n = 1650) referred for diagnostic HIT testing were screened prospectively by both the heparin-induced platelet activation (HIPA) test and anti-PF4/heparin EIA - including individual classes (IgG, IgA, IgM) - with clinical correlations studied. Platelet microparticle and annexin-V-binding properties of the sera were also investigated. RESULTS: Only 205 (12.4%) sera tested positive in either the HIPA and/or EIA: 95 (46.3%) were positive in both, 109 (53.1%) were only EIA-positive, and, notably, only one serum was HIPA-positive/EIA-negative. Of 185 EIA-positive sera, only 17.6% had detectable IgM and/or IgA without detectable IgG. Among sera positive for EIA IgG, optical density values were higher when the sera were HIPA-positive (1.117 vs. 0.768; P < 0.0001), with widely overlapping values. Two HIPA-positive but EIA-IgG-negative sera became HIPA-negative following IgG depletion, suggesting platelet-activating antibodies against non-PF4-dependent antigens. Clinical correlations showed that HIPA-negative/EIA-positive patients did not develop thrombosis and had reasons other than HIT to explain thrombocytopenia. IgM/A antibodies did not increase microparticle penetration, but increased annexin-V binding. CONCLUSIONS: The anti-PF4/heparin EIA has high ( approximately 99%) sensitivity for HIT. However, only about half of EIA-positive patients are likely to have HIT. Anti-PF4/heparin antibodies of IgM/A class and non-PF4-dependent antigens have only a minor role in HIT.
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| 18. |
- Hinz, P, et al.
(författare)
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[Informed consent on heparin-induced thrombocytopenia during thrombosis prophylaxis. A pilot study including 460 patients].
- 2003
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Ingår i: Deutsche Medizinische Wochenschrift. - : Georg Thieme Verlag KG. - 0012-0472 .- 1439-4413. ; 128:42, s. 2184-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The practicability and acceptance of written information about heparin thrombosis prophylaxis and the associated risk of heparin-induced thrombocytopenia (HIT) was evaluated in a pilot study. PATIENTS AND METHODS: All patients consecutively admitted to the department of trauma- and reconstructive surgery at the Ernst-Moritz-Arndt-University, Greifswald, Germany, with an indication for heparin thrombosis prophylaxis were give written information about thrombosis prophylaxis and the undesired drug effect HIT. After this, acceptance was evaluated using a standardized questionnaire. Primary endpoint was refusal of heparin for thrombosis prophylaxis, secondary endpoint acceptance and comprehensibility of the information. RESULTS: None of the 460 patients included in the study subsequently refused thrombosis prophylaxis with heparin. The majority welcomed the information and thought it should be given to all patients that are about to be treated with heparin. Only 0.9 % of patients judged comprehensibility of the information to be insufficient. Anticipation of imminent heparin therapy (good/very good in 90 %) and appreciation of the quality of care was not judged to be unacceptable by any patient. CONCLUSIONS: The present study demonstrates that giving information about heparin-induced thrombocytopenia during explanation of the risks and benefits of heparin thrombosis prophylaxis is feasible. This information--given in writing in our pilot study--was judged by patients to be comprehensible and necessary and did not lead to refusal of treatment. Lower incidence of HIT with use of low molecular weight heparins should be considered in the choice of drug for thrombosis prophylaxis.
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| 19. |
- Schenk, S, et al.
(författare)
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IgG classification of anti-PF4/heparin antibodies to identify patients with heparin-induced thrombocytopenia during mechanical circulatory support.
- 2007
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Ingår i: Journal of Thrombosis and Haemostasis. - : Elsevier BV. - 1538-7933 .- 1538-7836. ; 5:2, s. 235-41
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Tidskriftsartikel (refereegranskat)abstract
- Commercial immunoassays frequently detect anti-PF4/heparin antibodies during mechanical circulatory support (MCS), but only a small minority of patients develops heparin-induced thrombocytopenia (HIT). Whereas platelet functional tests can distinguish between platelet-activating and non-platelet-activating antibodies, commercial PF4-dependent immunoassays do not. Between 2003 and 2004, 113 patients were placed on MCS. Blood samples were obtained on postimplant day 5-7 for analyses by antibody assays and the functional heparin-induced platelet activation (HIPA) assay. Three distinct groups of patient sera were identified: platelet-activating anti-PF4/heparin antibodies (n = 10), non-platelet-activating anti-PF4/heparin antibodies (n = 53), and anti-PF4/heparin antibody negative (n = 50). Patients with platelet-activating antibodies had the highest risk for thromboembolic events (P < 0.005), whereas those with non-platelet-activating antibodies did not differ from antibody negative patients (P = 0.369). The enzyme-immunoassay and column agglutination assays, which cover all immunoglobulin classes, demonstrated adequate sensitivity and negative predictive value; yet, both lacked specificity with respect to the platelet-activating antibodies. If all antibody positive patients were further classified by an IgG-specific anti-PF4/heparin enzyme-immuno assay, specificity for platelet-activating antibodies increased. Whereas IgG-specific optical density (OD) values below 1.0 were likely for non-platelet-activating anti-PF4/heparin antibodies, higher values were progressively predictive for pathogenic platelet activation. The probability of the development of clinical HIT also increased steeply. In conclusion, platelet-activating anti-PF4/heparin antibodies are relatively common (about 9%) in patients on MCS and are associated with significantly higher thrombotic event rates. Low IgG-specific OD values (< 1.0) in the enzyme-immunoassay indicate low likelihood for the presence of platelet-activating antibodies. These results justify further validation so that anticoagulation during MCS becomes safer and adequate.
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| 20. |
- Suemnig, A., et al.
(författare)
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Motivational factors for blood donation in first-time donors and repeat donors : a cross-sectional study in West Pomerania
- 2017
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Ingår i: Transfusion Medicine. - : Wiley. - 0958-7578 .- 1365-3148. ; 27:6, s. 413-420
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: This study aimed to analyse motivational factors for blood donation in different donor groups.BACKGROUND: As the demographic change will result in a decrease of the population in age groups of blood donors, the risk of blood product shortage increases.METHODS: During a 12-month period, every sixth blood donor presenting at the blood donation centre of the University Hospital was asked to complete a self-administered questionnaire assessing motivational factors for blood donation. Despite the formalised enrolment protocol, frequent donors were over-represented in the study cohort, which was adjusted by weighting donors with different numbers of donations per year in such a way that the distribution of numbers of donations per year was the same in the sample as in the donor population.RESULTS: Of 2443 participants, 14·3% were first-time and 85·3% repeat donors. To "help other people" (>90%) and receiving "medical assessment of my blood values" (63-69%) were the strongest motivational factors in all donor groups. Receiving remuneration (49·2% vs 38·1%) was more important for repeat donors than for first-time donors, whereas it was the opposite for "being taken by a friend to the donor clinic" (47·0% vs 15·5%). A potentially important observation is that 33·9% of frequent donors reported feeling physically better after blood donation compared to infrequent donors (29·5%).CONCLUSION: Identification of motivational factors can lead to the design of targeted motivation campaigns for blood donation. The underlying cause of the perceived well-being after blood donation requires further studies.
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