Publications by authors named "Ralf Junker"

48 Publications

Analysis of SARS-CoV-2 RT-qPCR Ct values vis-à-vis anti-SARS-CoV-2 antibodies from a high incidence region.

Int J Infect Dis 2021 Jul 14. Epub 2021 Jul 14.

Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany.

Objectives: To examine the relationship between antibody status and Ct values and the prognostic value of the latter for COVID-19 patients, and the inter-assay comparability of SARS-CoV-2 Ct values.

Methods: In 347 COVID-19 inpatients, SARS-CoV-2 Ct values (via RT-qPCR) on admission were compared in between two assays and correlated with the antibody response (in the course of the disease), the clinical course and the time since onset of symptoms.

Results: Ct values for two of three target genes showed significant differences between the two assays used (p=0.012 and p<0.0001). Ct values were significantly higher for antibody positive patients (p<0.0001). Ct values were positively correlated with the amount of time since onset of symptoms (R: 0.332-0.363; p<0.001). Patients with fatal outcomes showed higher viral loads than survivors (p<0.0001).

Conclusions: Ct values depend strongly on the assay used and the target gene examined and should not be used as quantitative values to guide therapeutic or diagnostic decisions. The inverse association between the antibody status and the viral load suggests that antibodies contribute to the elimination of the virus, independent of the outcome, which is influenced by the viral load on admission and might depend more strongly on other parts of the immune response.
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http://dx.doi.org/10.1016/j.ijid.2021.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278831PMC
July 2021

Short-term physical exercise impacts on the human holobiont obtained by a randomised intervention study.

BMC Microbiol 2021 Jun 2;21(1):162. Epub 2021 Jun 2.

Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Rosalind-Franklin-Str. 12, 24105, Kiel, Germany.

Background: Human well-being has been linked to the composition and functional capacity of the intestinal microbiota. As regular exercise is known to improve human health, it is not surprising that exercise was previously described to positively modulate the gut microbiota, too. However, most previous studies mainly focused on either elite athletes or animal models. Thus, we conducted a randomised intervention study that focused on the effects of different types of training (endurance and strength) in previously physically inactive, healthy adults in comparison to controls that did not perform regular exercise. Overall study duration was ten weeks including six weeks of intervention period. In addition to 16S rRNA gene amplicon sequencing of longitudinally sampled faecal material of participants (six time points), detailed body composition measurements and analysis of blood samples (at baseline and after the intervention) were performed to obtain overall physiological changes within the intervention period. Activity tracker devices (wrist-band wearables) provided activity status and sleeping patterns of participants as well as exercise intensity and heart measurements.

Results: Different biometric responses between endurance and strength activities were identified, such as a significant increase of lymphocytes and decrease of mean corpuscular haemoglobin concentration (MCHC) only within the strength intervention group. In the endurance group, we observed a significant reduction in hip circumference and an increase in physical working capacity (PWC). Though a large variation of microbiota changes were observed between individuals of the same group, we did not find specific collective alterations in the endurance nor the strength groups, arguing for microbiome variations specific to individuals, and therefore, were not captured in our analysis.

Conclusions: We could show that different types of exercise have distinct but moderate effects on the overall physiology of humans and very distinct microbial changes in the gut. The observed overall changes during the intervention highlight the importance of physical activity on well-being. Future studies should investigate the effect of exercise on a longer timescale, investigate different training intensities and consider high-resolution shotgun metagenomics technology.

Trial Registration: DRKS, DRKS00015873 . Registered 12 December 2018; Retrospectively registered.
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http://dx.doi.org/10.1186/s12866-021-02214-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170780PMC
June 2021

Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.

Gut 2021 Apr 22. Epub 2021 Apr 22.

Department of Medicine I, Institute of Cancer Research, Medical University Vienna, Vienna, Austria.

Objective: Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date.

Design: We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry.

Results: We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix.

Conclusion: HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
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http://dx.doi.org/10.1136/gutjnl-2020-323868DOI Listing
April 2021

Clinical correlates of anti-SARS-CoV-2 antibody profiles in Spanish COVID-19 patients from a high incidence region.

Sci Rep 2021 02 23;11(1):4363. Epub 2021 Feb 23.

Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany.

Laboratory testing for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consists of two pillars: the detection of viral RNA via rt-PCR as the diagnostic gold standard in acute cases, and the detection of antibodies against SARS-CoV-2. However, concerning the latter, questions remain about their diagnostic and prognostic value and it is not clear whether all patients develop detectable antibodies. We examined sera from 347 Spanish COVID-19 patients, collected during the peak of the epidemic outbreak in Spain, for the presence of IgA and IgG antibodies against SARS-CoV-2 and evaluated possible associations with age, sex and disease severity (as measured by duration of hospitalization, kind of respiratory support, treatment in ICU and death). The presence and to some degree the levels of anti-SARS-CoV-2 antibodies depended mainly on the amount of time between onset of symptoms and the collection of serum. A subgroup of patients did not develop antibodies at the time of sample collection. Compared to the patients that did, no differences were found. The presence and level of antibodies was not associated with age, sex, duration of hospitalization, treatment in the ICU or death. The case-fatality rate increased exponentially with older age. Neither the presence, nor the levels of anti-SARS-CoV-2 antibodies served as prognostic markers in our cohort. This is discussed as a possible consequence of the timing of the sample collection. Age is the most important risk factor for an adverse outcome in our cohort. Some patients appear not to develop antibodies within a reasonable time frame. It is unclear, however, why that is, as these patients differ in no respect examined by us from those who developed antibodies.
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http://dx.doi.org/10.1038/s41598-021-83969-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902674PMC
February 2021

Single- and Multimarker Genome-Wide Scans Evidence Novel Genetic Risk Modifiers for Venous Thromboembolism.

Thromb Haemost 2021 Feb 16. Epub 2021 Feb 16.

Institute for Clinical Chemistry and Coagulation Center, University Hospital Schleswig Holstein, Kiel/Lübeck, Germany.

Previous genome-wide association studies (GWASs) have established several susceptibility genes for venous thromboembolism (VTE) and suggested many others. However, a large proportion of the genetic variance in VTE remains unexplained. Here, we report genome-wide single- and multimarker as well as gene-level associations with VTE in 964 cases and 899 healthy controls of European ancestry. We report 19 loci at the genome-wide level of association ( ≤ 5 × 10). Our results add to the strong support for the association of genetic variants in , , and with VTE, and identify several loci that have not been previously associated with VTE. Altogether, our novel findings suggest that 20 susceptibility genes for VTE were newly discovered by our study. These genes may impact the production and prothrombotic functions of platelets, endothelial cells, and white and red blood cells. Moreover, the majority of these genes have been previously associated with cardiovascular diseases and/or risk factors for VTE. Future studies are warranted to validate our findings and to investigate the shared genetic architecture with susceptibility factors for other cardiovascular diseases impacting VTE risk.
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http://dx.doi.org/10.1055/s-0041-1723988DOI Listing
February 2021

Saliva for Detection of SARS-CoV-2.

N Engl J Med 2021 03 3;384(9):e31. Epub 2021 Feb 3.

University Hospital Schleswig-Holstein, Kiel, Germany

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http://dx.doi.org/10.1056/NEJMc2032165DOI Listing
March 2021

Acquired von Willebrand syndrome in ECMO patients: A 3-year cohort study.

Blood Cells Mol Dis 2021 03 10;87:102526. Epub 2020 Dec 10.

Institute of Clinical Chemistry, Univ.-Hospital Schleswig-Holstein, Kiel & Lübeck, Germany. Electronic address:

Background: Bleeding is a common but possibly underreported side effect of Extracorporeal Membrane Oxygenation (ECMO). Impairment of primary hemostasis by acquired von Willebrand syndrome (aVWS) and platelet dysfunction as well as activation and consumption of plasmatic coagulation factors contribute to hemorrhage. The aim of the present cohort study of consecutively enrolled patients admitted to our ECMO center was to collect demographic, medical and laboratory data possibly associated with i) development of clinically relevant bleeding and/or ii) death during a 12-months follow-up.

Results: Within a 3-year period 338 white patients aged 18-89 years (median: 60; male 64.5%) were enrolled. 78 of 338 patients (23%) presented with clinical relevant bleeding symptoms. The overall death rate was 74.6% within a median time of 9 days (1-229) post intervention. Logistic-regression analysis adjusted for age and gender revealed that i) the presence of blood group O versus non-O (Odds ratio (OR)/95%CI: 1.9/1.007-3.41), ECMO duration per day (1.1/1.06-1.14), veno-venous versus veno-arterial ECMO cannulation (2.33/1.2-4.5) and the overall need for blood product administered per unit (1.02/1.016-1.028) was independenly associated with bleeding in patients suffering from aVWS. ii) Older age (increase per year) at ECMO start (1.015/1.012-1.029) and an increasing amount of blood product units were significantly related with death (1.007/1.001-1.013). Patients with veno-venous versus veno-arterial cannulation survived longer (0.48/0.24-0.94).

Conclusion: In the present cohort study we found a clinical relevant bleeding rate of 23% in subjects with aVWS associated with blood group O, a longer ECMO duration and veno-venous cannulation.
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http://dx.doi.org/10.1016/j.bcmd.2020.102526DOI Listing
March 2021

Antibody-related movement disorders - a comprehensive review of phenotype-autoantibody correlations and a guide to testing.

Neurol Res Pract 2020 20;2. Epub 2020 Feb 20.

Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.

Background: Over the past decade increasing scientific progress in the field of autoantibody-mediated neurological diseases was achieved. Movement disorders are a frequent and often prominent feature in such diseases which are potentially treatable.

Main Body: Antibody-mediated movement disorders encompass a large clinical spectrum of diverse neurologic disorders occurring either in isolation or accompanying more complex autoimmune encephalopathic diseases. Since autoimmune movement disorders can easily be misdiagnosed as neurodegenerative or metabolic conditions, appropriate immunotherapy can be delayed or even missed. Recognition of typical clinical patterns is important to reach the correct diagnosis.

Conclusion: There is a growing number of newly discovered antibodies which can cause movement disorders. Several antibodies can cause distinctive phenotypes of movement disorders which are important to be aware of. Early diagnosis is important because immunotherapy can result in major improvement.In this review article we summarize the current knowledge of autoimmune movement disorders from a point of view focused on clinical syndromes. We discuss associated clinical phenomenology and antineuronal antibodies together with alternative etiologies with the aim of providing a diagnostic framework for clinicians considering underlying autoimmunity in patients with movement disorders.
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http://dx.doi.org/10.1186/s42466-020-0053-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650144PMC
February 2020

Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19.

Immunity 2020 12 26;53(6):1296-1314.e9. Epub 2020 Nov 26.

Institute of Clinical Molecular Biology, Kiel University and University Medical Center Schleswig-Holstein, 24105 Kiel, Germany.

Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is needed for understanding skewed immune responses and defining predictors of outcome. Here, we performed a longitudinal multi-omics study using a two-center cohort of 14 patients. We analyzed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of interferon-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signaling. Megakaryocyte- and erythroid-cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond adaptive immune cells and provides an entry point toward developing biomarkers and targeted treatments of patients with COVID-19.
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http://dx.doi.org/10.1016/j.immuni.2020.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689306PMC
December 2020

Gender issues of antibody-mediated diseases in neurology: (NMOSD/autoimmune encephalitis/MG).

Ther Adv Neurol Disord 2020 25;13:1756286420949808. Epub 2020 Aug 25.

Department of Neurology, St. Josef Hospital Bochum, Ruhr University of Bochum, Gudrunstrasse 56, Bochum, 44791, Germany.

Neuromyelitis optica spectrum disorder (NMOSD), autoimmune encephalitis (AE), myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are antibody-mediated neurological diseases. They have mostly female predominance, affecting many women during childbearing age. Interactions between the underlying disease (or necessary treatment) and pregnancy can occur in every of these illnesses. Herein, we present the characteristics of NMOSD, AE, MG and LEMS in general, and review published data regarding the influence of the different diseases on fertility, pregnancy, puerperium, treatment strategy during pregnancy and post-partum period, and menopause but also male factors. We summarise key elements that should be borne in mind when confronted with such cases.
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http://dx.doi.org/10.1177/1756286420949808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450460PMC
August 2020

ADAMTS12, a new candidate gene for pediatric stroke.

PLoS One 2020 20;15(8):e0237928. Epub 2020 Aug 20.

Institute of Human Genetics, Genetic Epidemiology, University of Münster, Münster, Germany.

We recently reported a family-based genome wide association study (GWAS) for pediatric stroke pointing our attention to two significantly associated genes of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family ADAMTS2 (rs469568, p = 8x10-6) and ADAMTS12 (rs1364044, p = 2.9x10-6). To further investigate these candidate genes, we applied a targeted resequencing approach on 48 discordant sib-pairs for pediatric stroke followed by genotyping of the detected non-synonymous variants in the full cohort of 270 offspring trios and subsequent fine mapping analysis. We identified eight non-synonymous SNPs in ADAMTS2 and six in ADAMTS12 potentially influencing the respective protein function. These variants were genotyped within a cohort of 270 affected offspring trios, association analysis revealed the ADAMTS12 variant rs77581578 to be significantly under-transmitted (p = 6.26x10-3) to pediatric stroke patients. The finding was validated in a pediatric venous thromboembolism (VTE) cohort of 189 affected trios. Subsequent haplotype analysis of ADAMTS12 detected a significantly associated haplotype comprising the originally identified GWAS variant. Several ADAMTS genes such as ADAMTS13 are involved in thromboembolic disease process. Here, we provide further evidence for ADAMTS12 to likely play a role in pediatric stroke. Further functional studies are warranted to assess the functional role of ADAMTS12 in the pathogenesis of stroke.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237928PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446847PMC
October 2020

Antiparanodal antibodies and IgG subclasses in acute autoimmune neuropathy.

Neurol Neuroimmunol Neuroinflamm 2020 09 24;7(5). Epub 2020 Jul 24.

From the Department of Neurology (L.A., A.-M.B., C.S., K.D.), University Hospital of Würzburg; Neuroimmunology Section (A.H., K.-P.W., R.J., F.L.), Institute of Clinical Chemistry, University Hospital of Schleswig-Holstein Campus Kiel; Department of Neurology (P.K.), University Hospital of Magdeburg; and Institute for Clinical Neurobiology (C.V.), University Hospital of Würzburg, Germany.

Objective: To determine whether IgG subclasses of antiparanodal autoantibodies are related to disease course and treatment response in acute- to subacute-onset neuropathies, we retrospectively screened 161 baseline serum/CSF samples and 66 follow-up serum/CSF samples.

Methods: We used ELISA and immunofluorescence assays to detect antiparanodal IgG and their subclasses and titers in serum/CSF of patients with Guillain-Barré syndrome (GBS), recurrent GBS (R-GBS), Miller-Fisher syndrome, and acute- to subacute-onset chronic inflammatory demyelinating polyradiculoneuropathy (A-CIDP). We evaluated clinical data retrospectively.

Results: We detected antiparanodal autoantibodies with a prevalence of 4.3% (7/161), more often in A-CIDP (4/23, 17.4%) compared with GBS (3/114, 2.6%). Longitudinal subclass analysis in the patients with GBS revealed IgG2/3 autoantibodies against Caspr-1 and against anti-contactin-1/Caspr-1, which disappeared at remission. At disease onset, patients with A-CIDP had IgG2/3 anti-Caspr-1 and anti-contactin-1/Caspr-1 or IgG4 anti-contactin-1 antibodies, IgG3 being associated with good response to IV immunoglobulins (IVIg). In the chronic phase of disease, IgG subclass of one patient with A-CIDP switched from IgG3 to IgG4.

Conclusion: Our data (1) confirm and extend previous observations that antiparanodal IgG2/3 but not IgG4 antibodies can occur in acute-onset neuropathies manifesting as monophasic GBS, (2) suggest association of IgG3 to a favorable response to IVIg, and (3) lend support to the hypothesis that in some patients, an IgG subclass switch from IgG3 to IgG4 may be the correlate of a secondary progressive or relapsing course following a GBS-like onset.
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http://dx.doi.org/10.1212/NXI.0000000000000817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413710PMC
September 2020

Role of prothrombin 19911 A>G polymorphism, blood group and male gender in patients with venous thromboembolism: Results of a German cohort study.

J Thromb Thrombolysis 2021 Feb;51(2):494-501

UKSH, Institute of Clinical Chemistry, Hemostasis Unit, Arnold-Heller-Str. 3 Building 17, Kiel, 24105, Germany.

The role of the A>G polymorphism at position 19911 in the prothrombin gene (factor [F] 2 at rs3136516) as a risk factor for venous thromboembolism [VTE] is still unclear. To evaluate the presence of the F2 polymorphism in VTE patients compared to healthy blood donors and to adjust the results for common inherited thrombophilias [IT], age at onset and blood group [BG], and to calculate the risk of VTE recurrence. We investigated 1012 Caucasian patients with a diagnosis of VTE for the presence of the F2 rs3136516 polymorphism and compared these with 902 healthy blood donors. Odds ratios [OR] together with their 95% confidence intervals were calculated adjusted for F5 at rs6025, F2 at rs1799963, blood group, age and gender. In addition, we evaluated the risk of recurrent VTE during patient follow-up calculating hazard ratios [HR] together with their 95% CI. Compared with the AA wildtype, the F2 GG and AG genotypes (rs3136516) were associated with VTE (OR 1.48 and 1.45). The OR in F5 carriers compared to controls was 5.68 and 2.38 in patients with F2 (rs1799963). BG "non-O" was significantly more often diagnosed in patients compared to BG "O" (OR 2.74). VTE recurrence more often occurred in males (HR 2.3) and in carriers with combined thrombophilia (HR 2.11). Noteworthy, the rs3136516 polymorphism alone was not associated significantly with recurrence. In Caucasian patients with VTE the F2 GG/GA genotypes (rs3136516) were moderate risk factors for VTE. Recurrence was associated with male gender and combined thrombophilia.
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http://dx.doi.org/10.1007/s11239-020-02169-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886710PMC
February 2021

Cross-Sectional and Longitudinal Construct Validity of the Generic KINDL-A(dult)B(rief) Questionnaire in Adults with Thrombophilia or with Hereditary and Acquired Bleeding Disorders.

Acta Haematol 2021 5;144(2):166-175. Epub 2020 Jun 5.

Institute for Clinical Chemistry and Coagulation Center, University Hospital Schleswig Holstein, Lübeck/Kiel, Germany,

Background/aims: The newly adapted generic KINDL-A(dult)B(rief) questionnaire showed satisfactory cross-sectional psychometric properties in adults with bleeding disorders or thrombophilia. This investigation aimed to evaluate its cross-sectional and longitudinal construct validity.

Methods: After ethical committee approval and written informed consent, 335 patients (mean age 51.8 ± 16.6 years, 60% women) with either predominant thrombophilia (n = 260) or predominant bleeding disorders (n = 75) participated. At baseline, patients answered the KINDL-AB, the MOS 36-item Short-Form Health Survey (SF-36), and the EQ-5D-3L. A subgroup of 117 patients repeated the questionnaire after a median follow-up of 2.6 years (range: 0.4-3.5). A priori hypotheses were evaluated regarding convergent correlations between KINDL-AB overall well-being and specific subscales, EQ-5D-3L index values (EQ-IV), EQ-5D visual analog scale (EQ-VAS), and SF-36 subscales.

Results: Contrary to hypothesis, baseline correlations between the KINDL-AB and EQ-IV/EQ-VAS were all moderate while, as hypothesized, several KINDL-AB subscales and SF-36 subscales correlated strongly. At follow-up, no significant changes in all three instruments occurred. Correlations between instruments over the follow-up were mostly moderate and partially strong. Contrary to hypothesis but consistent with no significant changes in health-related quality of life, convergent correlations between changes in KINDL-AB overall well-being, physical and psychological well-being, and EQ-IV/EQ-VAS were all weak.

Conclusions: While repeated measures of KINDL-AB showed moderate to strong correlations, changes in KINDL-AB overall well-being and subscales correlated more weakly than expected with changes involving two established instruments of generic health status.
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http://dx.doi.org/10.1159/000507602DOI Listing
April 2021

Antibodies to nodal/paranodal proteins in paediatric immune-mediated neuropathy.

Neurol Neuroimmunol Neuroinflamm 2020 07 2;7(4). Epub 2020 Jun 2.

From the Division of Neuropathology and Neurochemistry (D.D.S., G.R., M.W., I.K., R.H.), Department of Neurology, Medical University of Vienna, Austria; Department of Neurology (D.D.S.), University Hospital St. Poelten, Austria; Department of General Pediatrics, Neonatology and Pediatric Cardiology (M.K.), University Children's Hospital, Heinrich Heine University Duesseldorf, Germany; Department of Neuropediatric Rehabilitation (U.H.), Vamed Clinic Hattingen, Germany; Department of Neuropediatrics (U.S.), Charité University, Berlin, Germany; Paediatric Neurology (O.A.-M.), Great Ormond Street Hospital for Children, London, United Kingdom; Dubowitz Neuromuscular Centre (P.M.), Great Ormond Street Hospital for Children, London, United Kingdom; Nuffield Department of Clinical Neurosciences (S.R.), University of Oxford and Oxford University Hospitals NHS Foundation Trust; Department of Paediatric and Adolescent Medicine (C.S.), St Joseph Hospital, Berlin, Germany; Department of Pediatrics and Adolescent Medicine (M.F., M.B., R.S.), Medical University of Vienna, Austria; Department of Neurology (M.R., J.W.), Medical University of Innsbruck, Austria; Neuromuscular Diseases Unit (C.L., L.Q.), Hospital de la Santa Creu i Sant Pau, Universitat Autónoma de Barcelona, Spain; SMZ Süd (G.B.), Kaiser-Franz Josef Hospital with Gottfried von Preyer Children Hospital, Vienna, Austria; Institute of Clinical Chemistry (K.-P.W., R.J., F.L.), University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany; Department of Neurology (F.L.), University Hospital Schleswig-Holstein, Kiel, Germany; and Department of Pediatric Neurology (K.R.), Witten/Herdecke University, Children's Hospital Datteln, Germany.

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http://dx.doi.org/10.1212/NXI.0000000000000763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286658PMC
July 2020

Recent advances in immunodiagnostics based on biosensor technologies-from central laboratory to the point of care.

Anal Bioanal Chem 2019 Nov 31;411(29):7607-7621. Epub 2019 May 31.

Klinikum rechts der Isar der TU München, Institut für Klinische Chemie und Pathobiochemie, Ismaninger Str. 22, 81675, Munich, Germany.

Immunological methods are widely applied in medical diagnostics for the detection and quantification of a plethora of analytes. Associated analytical challenges usually require these assays to be performed in a central laboratory. During the last several years, however, the clinical demand for rapid immunodiagnostics to be performed in the immediate proximity of the patient has been constantly increasing. Biosensors constitute one of the key technologies enabling the necessary, yet challenging transition of immunodiagnostic tests from the central laboratory to the point of care. This review is intended to provide insights into the current state of this transition process with a focus on the role of biosensor-based systems. To begin with, an overview on standard immunodiagnostic tests presently employed in the central laboratory and at the point of care is given. The review then moves on to demonstrate how biosensor technologies are reshaping this landscape. Single analyte as well as multiplexed immunosensors applicable to point of care scenarios are presented. A section on the areas of clinical application then creates the bridge to day-to-day diagnostic practice. Finally, the depicted developments are critically weighed and future perspectives discussed in order to give the reader a firm idea on the forthcoming trends to be expected in this diagnostic field.
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http://dx.doi.org/10.1007/s00216-019-01915-xDOI Listing
November 2019

Linking pre-existing biorepositories for medical research: the PopGen 2.0 Network.

J Community Genet 2019 Oct 29;10(4):523-530. Epub 2019 Mar 29.

Department of Pneumology, Leibniz Lung Center for Medicine and Biosciences, Borstel, Germany.

The significance of human biorepositories for modern medical research, particularly for comprehensive population-based genetic analyses, is constantly growing. While large and centralized institutions are usually considered best suited to meet the increasing demand for high-quality "biobanks," most medical research institutions still host rather heterogeneous and fragmented biobanking activities, undertaken by clinical departments with oftentimes rather different scientific scope. Undoubtedly, most clinicians and medical researchers would appreciate infrastructural support in terms of the storage and handling of their biosamples, but they are also likely to expect access to their samples avoiding extensive formal requirements. We report on the establishment of the PopGen 2.0 Network (P2N), an overarching alliance of initially seven biobanks from Northern Germany which adopted a joint but lean governance structure and use-and-access policy for their samples and data. In addition, the members of P2N have pursued an intense collaboration on ethical, legal and social issues and maintain a common IT infrastructure. The implementation of P2N has substantially improved the prospects of biobank-based research at the participating institutions. The network may thus serve as a role model for similar initiatives geared at linking pre-existing biorepositories for the benefit of research quality, efficiency, and transparency.
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http://dx.doi.org/10.1007/s12687-019-00417-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754520PMC
October 2019

Autoantibody-Mediated Encephalitis.

Dtsch Arztebl Int 2018 11;115(40):666-673

Institute of Clinical Chemistry, University Hospital Schleswig-Holstein.

Background: Acute and subacute disturbances of wakefulness and cognitive function are common neurological manifestations in the hospital and in outpatient care. An important element of the differential diagnosis was described only a few years ago: autoimmune encephalitis, a condition whose diagnosis and treatment pose an interdisciplinary challenge.

Methods: This review is based on pertinent publications from the years 2005-2017 that were retrieved by a selective search in PubMed, and on the authors' personal experience and case reports.

Results: The incidence of autoimmune encephalitis in Germany is estimated at 8-15 cases per million persons per year. In some patients with psychotic manifestations or impaired consciousness of acute or subacute onset, an autoimmune patho - genesis can be demonstrated by the laboratory detection of autoantibodies against neuronal target antigens (e.g., glutamate receptors). Testing of this type should be performed in patients with inflammatory changes in the cerebrospinal fluid or on magnetic resonance imaging (MRI), or those who have had an otherwise unexplained first epileptic seizure or status epilepticus. The cumulative sensitivity of testing for all potentially causative antineuronal antibodies in patients with clinically defined autoimmune encephalitis is estimated at 60-80 %. Figures on cumulative specificity are currently unavailable.

Conclusion: The detection of antineuronal antibodies in patients with the corresponding appropriate symptoms implies the diagnosis of autoimmune encephalitis. Observational studies have shown that rapidly initiated immunosuppressive treatment improves these patients' outcomes. Further studies are needed to determine the positive predictive value of antineuronal antibody detection and to develop further treatment options under randomized and controlled conditions.
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http://dx.doi.org/10.3238/arztebl.2018.0666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234470PMC
November 2018

Critical Deviations of Ionized Calcium Measurements When Using Blood Gas Analyzers to Monitor Citrate Dialysis.

Clin Lab 2016 Oct;62(10):2025-2031

Background: During the course of acute kidney injury (AKI) patients may require renal replacement therapy (RRT). The preferred therapeutic measure for such patients is continuous RRT (CRRT). Anticoagulation is required to prevent clotting of the extracorporeal circuit. The actual KDIGO guidelines recommend citrate as the first line anticoagulant.

Methods: Citrate dose infused into the extracorporeal circuit should achieve an extracorporeal calcium concentration of 0.2 - 0.3 mmol/L. Here, we evaluated two blood gas analysers for their ability of covering the calcium concentration range needed for CRRT (Radiometer ABL 835; Instrumentation Laboratory GEM 4000). Measurements of iCa from 0.2 to 3.0 mmol/L were performed in aqueous 0.9% NaCl solutions with and without human serum albumin (HAS) and also in patient samples.

Results: Using the GEM analyser, differences of measured results to target values were low throughout the whole concentration range. Using the ABL system, the difference increased with lower target values and exceeded up to 60% at 0.2 mmol/L. The results were reproduced in patient samples.

Conclusions: Measuring Ca2+ concentrations could result in an overdosing or underdosing of citrate when using an analytical method which is different to the instrument used initially to achieve the recommended concentrations. If measurement of the new method results in lower Ca2+ concentration and, therefore, reduced anticoagulation by citrate infusion this could lead to more clotting events. Overestimation of the calcium concentration by the new method in the extracorporeal circuit would result in an increased citrate dose delivered to the patient, leading to in vivo hypocalcemia and a pronouncement of citrate induced acid base derangements. Therefore, to monitor Ca2+ concentrations in CRRT during citrate anticoagulation, specific target values for each individual instrument must be established.
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http://dx.doi.org/10.7754/Clin.Lab.2016.160331DOI Listing
October 2016

Developmental hemostasis: A lifespan from neonates and pregnancy to the young and elderly adult in a European white population.

Blood Cells Mol Dis 2017 09 5;67:2-13. Epub 2016 Dec 5.

Center of Blood Transfusion, University Hospital Schleswig Holstein, Kiel & Lübeck, Germany.

Absolute values of reference ranges for coagulation assays in humans vary within the entire lifespan and confirm the concept of developmental hemostasis. It is known that physiologic concentrations of coagulation factors (F) gradually increase over age: they are lower in premature infants as compared to full-term babies, healthy children or adults. Here we demonstrate in a cohort of 1011 blood donors and in a group of 193 healthy pregnant women, that the process of developmental hemostasis proceeds in adults. During the course of pregnancy F and activation markers steadily increase until delivery with a parallel decrease noticed for protein S. From adolescents, young adults to the elderly there is a further increase of F, reaching significance starting between 35 and 50years of age compared to younger subjects. Covering the entire lifespan FVIII and von-Willebrand-factor showed the lowest values in carriers of blood group "O". Apart from pregnancy differences related to gender, pill users, smoking habits or the presence of thrombophilic variants were reported. Laboratory test results should be compared to age-related reference intervals when hemostatic defects are suspected to avoid misclassifications as being "healthy", prone to "bleeding" or vice versa to "thrombosis".
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http://dx.doi.org/10.1016/j.bcmd.2016.11.012DOI Listing
September 2017

Impact of high risk thrombophilia status on recurrence among children and adults with VTE: An observational multicenter cohort study.

Blood Cells Mol Dis 2016 11 5;62:24-31. Epub 2016 Nov 5.

Institute of Clinical Chemistry, Univ. Hospital Kiel, Germany; Institute of Clinical Chemistry, Univ. Hospital Lübeck, Germany; Department of Pediatric Hematology/Oncology, Univ. Children Hospital Münster, Germany. Electronic address:

Background: Antithrombin [AT]-, protein C [PC]- or protein S [PS]-deficiency [D] constitutes a major risk factor for venous thromboembolism [VTE]. Primary study objective was to evaluate if the clinical presentation at first VTE onset differs between children and adults and to compare the individual recurrence risk among patients with respect to age at onset and their thrombophilia status ATD, PCD or PSD.

Methods/patients/results: In 137 of 688 consecutively enrolled pediatric and adult VTE patients we calculated the absolute risk of VTE recurrence and event-free-survival adjusted for thrombophilia and positive family VTE history. At first VTE children manifested i) with a lower rate of pulmonary embolism, ii) a higher rate of cerebral vascular events or multiple VTEs, and iii) showed a higher proportion of unprovoked VTE compared to adolescents and adults. Adult patients reported more often a positive VTE history compared to younger study participants. The adjusted odds of recurrence in adults was 2.05 compared to children.

Conclusion: At disease manifestation children and adults differ with respect to i) thrombotic locations, ii) percentage of unprovoked versus provoked VTE, and iii) different rates of positive VTE family histories. Furthermore, adults showed a two-fold increase risk of VTE recurrence compared to children.
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http://dx.doi.org/10.1016/j.bcmd.2016.10.024DOI Listing
November 2016

Impact of gender on safety and efficacy of Rivaroxaban in adolescents & young adults with venous thromboembolism.

Thromb Res 2016 Dec 13;148:145-151. Epub 2016 Sep 13.

Institute of Clinical Chemistry, Univ. Hospital Schleswig-Holstein, Campus Kiel, Germany; Institute of Clinical Chemistry, Univ. Hospital Schleswig-Holstein, Campus Lübeck, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2016.09.007DOI Listing
December 2016

Impact of high-risk thrombophilia status on recurrence among children with a first non-central-venous-catheter-associated VTE: an observational multicentre cohort study.

Br J Haematol 2016 Oct 22;175(1):133-40. Epub 2016 Jun 22.

Institute of Clinical Chemistry, University Hospital Kiel, Kiel, Germany.

Deficiency of antithrombin (AT), protein C (PC) or protein S (PS) constitutes a major risk factor for venous thromboembolism (VTE). Individuals at high risk for recurrence who benefit from screening need to be identified. The primary study objective was to determine the individual recurrence risk among children with a first non-central-venous-catheter-associated VTE with respect to their thrombophilia status and to evaluate if the clinical presentation at first VTE onset differs between children with AT, PC or PS deficiency versus no thrombophilia. We calculated the absolute risk of VTE recurrence and event-free-survival adjusted for thrombophilia, age, sex and positive family VTE history in 161 consecutively enrolled paediatric VTE patients. The presence of a deficiency relative to no thrombophilia was evaluated as a potential predictor of recurrence. Predictors for recurrence were AT deficiency (hazard ratio/95% CI: 6·5/2·46-17·2) and female gender (2·6/1·1-6·35). The annual recurrence rates (95% CIs) were 5·4% (2·6-10) in AT-deficient children, 1·3% (0·3-3·8) in patients with PC deficiency, 0·7% (0·08-2·4) in the PS-deficient cohort and 0·9% (0·4-1·8) in patients with no thrombophilia. Positive family VTE history or combined thrombophilias did not predict recurrence. Given the overall annual incidence rate of recurrence of 1·5% we suggest screening for AT deficiency in children with VTE.
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http://dx.doi.org/10.1111/bjh.14192DOI Listing
October 2016

Role of protein S deficiency in children with venous thromboembolism. An observational international cohort study.

Thromb Haemost 2015 Feb 2;113(2):426-33. Epub 2014 Oct 2.

Ulrike Nowak-Göttl, Center of Thrombosis & Hemostasis, Institute of Clinical Chemistry, Univ.Hospital Kiel, Arnold-Heller-Str. 3, building 17, 24105 Kiel, Germany, E-mail:

Venous thromboembolism [TE] is a multifactorial disease, and protein S deficiency [PSD] constitutes a major risk factor. In the present study the prevalence of PSD and the clinical presentation at TE onset in a cohort of children is reported. In 367 unselected paediatric patients with TE (age 0.1-18 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Thirty of 367 paediatric patients (8.2 %) derived from 27 families had PSD. Mean age at first TE onset was 14.5 years (range 0.1 to 18). Thrombotic locations were cerebral veins (n=8), calf vein TE (n=3) deep veins (DVT) of the leg (n=12), DVT & pulmonary embolism (n=5) and intra-cardiac veins (n=1) or purpura fulminans (n=1). PSD co-occurred with the factor 5 mutation at rs6025 or the homozygous factor 2 susceptibility variant at rs1799963 in one case each. The Heerlen polymorphism detected in five children presented with milder PSD. In 18 patients (60 %) a concomitant risk factor for TE was identified. A second TE event within primarily healthy siblings occurred in three of 27 PSD families (11.0 %). In this cohort of children with symptomatic TE, the prevalence of PSD adjusted for family status was 7.4 %. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high-risk population.
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http://dx.doi.org/10.1160/TH14-06-0533DOI Listing
February 2015

Clinical and laboratory characteristics of children with venous thromboembolism and protein C-deficiency: an observational Israeli-German cohort study.

Br J Haematol 2014 Nov 18;167(3):385-93. Epub 2014 Jul 18.

Institute of Clinical Chemistry, University Hospital of Kiel & Lübeck, Lübeck, Germany.

Venous thromboembolism [TE] is a multifactorial disease and protein C deficiency [PCD] constitutes a major risk factor. In the present study the prevalence of PCD and the clinical presentation at TE onset, including neonatal purpura fulminans, in a cohort of children are reported. In 367 unselected children (0·1-19 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Twenty-five of 338 children (7·4%) had PCD. Mean age at first TE onset was 10 years (range 0·1-18). Leading thromboembolic manifestations were neonatal purpura fulminans (n = 5), TE of cerebral veins (n = 3), stroke (n = 2) deep veinthrombosis (DVT) of the leg (n = 10), DVT & pulmonary embolism (n = 2) and DVT & pelvic veins (n = 3). Concomitant risk factors for TE were identified in 12 patients, whereas 13 children spontaneously developed TE. A positive family history of DVT was found in 10 children. In this unselected cohort of paediatric patients with symptomatic TE the overall prevalence of PCD was 7·4%; 1·5% presented with neonatal purpura fulminans. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high-risk population.
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http://dx.doi.org/10.1111/bjh.13039DOI Listing
November 2014

Influence of factor 5 rs6025 and factor 2 rs1799963 mutation on inhibitor development in patients with hemophilia A--an Israeli-German multicenter database study.

Thromb Res 2014 Apr 17;133(4):544-9. Epub 2014 Jan 17.

Thrombosis & Hemophilia Treatment Center, Institute of Clinical Chemistry, Univ. Hospital Schleswig-Holstein, Kiel, Germany. Electronic address:

Objective: The present cohort study was performed to investigate the impact of the factor 5 rs6025 [F5] and the factor 2 rs1799963 [F2] mutations on high-titer inhibitor development [HRI] in patients with severe/moderate-severe hemophilia A [HA].

Patients And Methods: 216 patients with F8<2% born between 1980 and 2011 were followed after initial HA diagnosis over the first 200 exposure days. The first HA patient per family who presented for diagnosis was included in the present study.

Results: 32 of 216 children [14.8%] tested for F5/F2 carried either the F5 or the F2 variant. HRI occurred in 14 out of 32F5/F2-carriers compared with 40 of 184 without F5/F2. Multivariate analysis adjusted for F8 genotype, treatment intensity, first-line use of plasma derived FVIII versus recombinant FVIII concentrates revealed that the presence of F5/F2 independently increases the risk of HRI development to odds [OR] of 3.4. Large deletions in the F8 gene [OR: 5.10], patients from Israel [OR: 4.0], the increase of FVIII per one IU/kgbw [OR: 1.05] and birth year [OR: 1.12] were significantly associated with the risk to develop HRI.

Conclusion: Data presented here suggest that HRI development is of multifactorial origin and that F5 and F2 mutations may contribute to this risk.
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http://dx.doi.org/10.1016/j.thromres.2014.01.005DOI Listing
April 2014

Role of reduced ADAMTS13 in arterial ischemic stroke: a pediatric cohort study.

Ann Neurol 2013 Jan 7;73(1):58-64. Epub 2012 Dec 7.

Faculty of Medicine, University of Münster, Germany.

Objective: Previous studies in adults and mice have implicated ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), also known as von Willebrand factor (VWF)-cleaving protease, as a protective factor for stroke. Here we investigated ADAMTS13 in 208 pediatric patients with arterial ischemic stroke (AIS) and 125 population-based control children in a frequency-matched case-control study.

Methods: The proportion of patients/controls with ADAMTS13 activity levels below and above the 10th percentile was compared. Additionally, in a quintile comparison, the proportion of patients versus controls in the lowest ADAMTS13 quintile was compared to those in the 2nd to 5th quintiles. Adjustment was performed for VWF antigen (VWF:Ag), factor VIII activity (FVIII:C), blood group, and age.

Results: Forty-six of 208 patients (22%) showed ADAMTS13 levels below the 10th percentile, compared with 5 of 125 controls (4%; p < 0.001). Odds ratios/95% confidence intervals were 7.30/2.73-19.50 for the lowest percentile and 2.44/1.15-5.16 in the quintile comparison after adjustment for VWF:Ag, FVIII:C, blood group, and age. Comparing the proportion of patients with ADAMTS13 activity below the 10th percentile within the different stroke subtypes (undetermined, cardioembolic, steno-occlusive arteriopathies), no statistically significant differences were found (undetermined, 16 of 89; cardioembolic, 6 of 40; steno-occlusive arteriopathies, 24 of 79; p = 0.08). ADAMTS13 levels did not significantly differ among stroke subtypes (p = 0.29).

Interpretation: Our findings implicate reduced ADAMTS13 activity as a risk factor for pediatric AIS, and support the concept that ADAMTS13 has a role in the pathogenesis of pediatric AIS.
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http://dx.doi.org/10.1002/ana.23735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703929PMC
January 2013

Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study.

Blood 2012 Aug 11;120(7):1510-5. Epub 2012 May 11.

Department of Pediatric Hematology/Oncology, Charité, Augustenburger Platz 1, Berlin, Germany.

Screening for inherited thrombophilia (IT) is controversial; persons at high risk for venous thromboembolism (VTE) who benefit from screening need to be identified. We tested 533 first- and second-degree relatives of 206 pediatric VTE patients for IT (antithrombin, protein C, protein S, factor V G1691A, factor II G20210A) and determined the incidence of symptomatic VTE relative to their IT status. The risk for VTE was significantly increased among family members with, versus without, IT (hazard ratio = 7.6; 95% confidence interval [CI], 4.0-14.5; P < .001) and highest among carriers of antithrombin, protein C, or protein S deficiency (hazard ratio = 25.7; 95% CI, 12.2-54.2; P < .001). Annual incidences of VTE were 2.82% (95% CI, 1.63%-4.80%) among family members found to be carriers of antithrombin, protein C, or protein S deficiency, 0.42% (0.12%-0.53%) for factor II G202010A, 0.25% (0.12%-0.53%) for factor V G1691A, and 0.10% (0.06%-0.17%) in relatives with no IT. Given the high absolute risk of VTE in relatives with protein C, protein S, and antithrombin deficiency, we suggest screening for these forms of hereditary thrombophilia in children with VTE and their relatives. Interventional studies are required to assess whether thromboembolism can be prevented in this high-risk population.
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http://dx.doi.org/10.1182/blood-2012-01-405514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423787PMC
August 2012

Impact of persistent antiphospholipid antibodies on risk of incident symptomatic thromboembolism in children: a systematic review and meta-analysis.

Semin Thromb Hemost 2011 Oct 20;37(7):802-9. Epub 2011 Dec 20.

The Israel National Haemophilia Centre, Sheba Medical Centre, Tel-Hashomer, Israel.

The aim of this study was to estimate the impact of antiphospholipid (aPL) antibodies on the risk of incident thromboembolism (TE; arterial and venous) in children via meta-analysis of published observational studies. A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1966 to 2010 was conducted using keywords in combination both as MeSH terms and text words. Two authors independently screened citations and those meeting the a priori defined inclusion criteria were retained. Data on year of publication, study design, country of origin, number of patients/controls, ethnicity, TE type, and frequency of recurrence were abstracted. Heterogeneity across studies was evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using either fixed-effects or random-effects models. Of 504, 16 pediatric studies met the inclusion criteria. In total 1403 patients and 1667 population-based controls ≤18 years were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. Thus, data from arterial and venous TE were analyzed together. In addition, meta-regression analysis did not reveal statistically significant differences between site of TE, age at first TE, country, or publication year. A statistically significant association with a first TE was demonstrated for persistent aPL antibodies, with an overall summary ORs/CI of 5.9/3.6-9.7 (arterial 6.6/3.5-12.4; deep vein thrombosis 4.9/2.2-10.9). The present meta-analysis indicates that detection of persistent aPL is clinically meaningful in children with, or at risk for, TE and underscores the importance of pediatric thrombophilia screening programs.
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http://dx.doi.org/10.1055/s-0031-1297171DOI Listing
October 2011
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