Publications by authors named "Pall T Onundarson"

29 Publications

  • Page 1 of 1

A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis.

Commun Biol 2021 Feb 3;4(1):156. Epub 2021 Feb 3.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.
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http://dx.doi.org/10.1038/s42003-020-01575-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859200PMC
February 2021

On ignoring instead of chasing after coagulation factor VII during warfarin management; an interrupted time series study.

Blood 2021 Jan 21. Epub 2021 Jan 21.

University of Iceland Faculty of Medicine, Iceland.

During warfarin management, prothrombin time (PT) based PT-INR variability is partly due to clinically inconsequential fluctuations of factor (F) VII. The new Fiix-PT and Fiix-normalized ratio (Fiix-NR), unlike PT-INR, is only affected by reduced FII and FX. Starting July 1st 2016 we replaced PT-INR monitoring of warfarin with Fiix-NR in our patients. Using interrupted time series methods, we retrospectively assessed if this affected thromboembolism (TE) and major bleeding (MB) incidence during 12 months prior to and 18 months after the replacement, months 13-18 being predefined as transitional months. The dynamic cohort comprised all our service´s 2,667 maintenance phase warfarin patients managed at any time during the 30 months. Using two-segmented regression, a breakpoint in total TE monthly incidence became evident six months after laboratory monitoring test replacement, followed by 56% reduction in TE incidence (from 2.82% to 1.23% per patient year, P=0.019 by ANOVA). Three-segmented regression found no significant TE incidence trend (slope +0.03) prior to test replacement but during months 13-18 and 19-30 the TE incidence gradually decreased (slope -0.12; R2=0.20;P=0.007). Based on segmented regressions, MB incidence (2.79% ppy) did not differ pre- or post-intervention. Incidence comparison during the 12 month Fiix- and PT-periods confirmed a statistically significant 55-62% reduction in TE. Fiix-monitoring reduced testing, dose adjustments and normalized ratio variability, and prolonged testing intervals and time in range. We conclude that ignoring FVII during Fiix-NR monitoring in real world practice stabilizes the anticoagulant effect of warfarin and associates with major reduction in thromboembolism without increasing bleeding.
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http://dx.doi.org/10.1182/blood.2020008698DOI Listing
January 2021

A comparison of platelet quality between platelets from healthy donors and hereditary hemochromatosis donors over seven-day storage.

Transfusion 2021 Jan 9;61(1):202-211. Epub 2020 Nov 9.

Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

Background: Therapeutic phlebotomy is the standard treatment of hereditary hemochromatosis (HH), the most common genetic disease in people of Northern European descent. Red cell concentrates from HH donors have been reported safe for transfusion, but little data is available on the storage properties of platelet concentrates from HH donors.

Study Design And Methods: Whole blood was collected from 10 healthy individuals and 10 newly diagnosed HH patients with elevated serum ferritin. Platelet-rich plasma (PRP) was prepared and split into four 20-mL units. Platelet quality tests were performed on days 0, 1, 3, 5, and 7 of storage, including platelet aggregation (ADP, arachidonic acid, collagen, and epinephrine agonists), blood gas analysis, flow cytometry (CD41, CD42b, and CD62P expression), and ELISA (sCD40L and sCD62p in supernatant).

Results: Mean serum ferritin levels were higher in HH patients than in controls (847.5 vs 45.8 ng/mL, P < .001). Overall, no difference in quality test results was observed between the two study groups over 7-day storage (P > .05), including blood gas analysis, platelet aggregation, and expression of surface (CD62p and CD42b) and secreted (sCD62P and sCD40L) activation markers. Expected alterations in metabolic (CO and glucose decrease, O and lactate increase, P < .001) and platelet activation markers (CD42b decrease, CD62P increase, P < .05) over time were observed in both groups.

Conclusion: Although these findings indicate that platelets of individuals with HH are comparable to platelets from healthy donors, more extensive studies are needed before definite conclusions can be drawn.
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http://dx.doi.org/10.1111/trf.16176DOI Listing
January 2021

FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease.

Nature 2020 08 24;584(7822):619-623. Epub 2020 Jun 24.

Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk of autoimmune thyroid disease (odds ratio (OR) = 1.46, P = 2.37 × 10). rs76428106-C is also associated with systemic lupus erythematosus (OR = 1.90, P = 6.46 × 10), rheumatoid factor and/or anti-CCP-positive rheumatoid arthritis (OR = 1.41, P = 4.31 × 10) and coeliac disease (OR = 1.62, P = 1.20 × 10). FLT3 encodes fms-related tyrosine kinase 3, a receptor that regulates haematopoietic progenitor and dendritic cells. RNA sequencing revealed that rs76428106-C generates a cryptic splice site, which introduces a stop codon in 30% of transcripts that are predicted to encode a truncated protein, which lacks its tyrosine kinase domains. Each copy of rs76428106-C doubles the plasma levels of the FTL3 ligand. Activating somatic mutations in FLT3 are associated with acute myeloid leukaemia with a poor prognosis and rs76428106-C also predisposes individuals to acute myeloid leukaemia (OR = 1.90, P = 5.40 × 10). Thus, a predicted loss-of-function germline mutation in FLT3 causes a reduction in full-length FLT3, with a compensatory increase in the levels of its ligand and an increased disease risk, similar to that of a gain-of-function mutation.
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http://dx.doi.org/10.1038/s41586-020-2436-0DOI Listing
August 2020

Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis.

Commun Biol 2020 04 23;3(1):189. Epub 2020 Apr 23.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (Effect = -1.61 SD, CI = [-1.98, -1.35]; Effect = 0.63 SD, CI = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.
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http://dx.doi.org/10.1038/s42003-020-0921-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181819PMC
April 2020

Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis.

Nat Commun 2020 01 20;11(1):393. Epub 2020 Jan 20.

deCODE genetics/Amgen, Inc., Reykjavik, Iceland.

Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3' UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFβR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.
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http://dx.doi.org/10.1038/s41467-019-14144-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971247PMC
January 2020

The need for an adapted initiation nomogram during Fiix prothrombin time monitoring of warfarin.

J Thromb Thrombolysis 2019 Nov;48(4):685-689

Landspitali National University Hospital of Iceland, Reykjavík, Iceland.

The new Fiix prothrombin time (Fiix-PT) and its derived Fiix-normalized ratio (Fiix-NR) is affected only by reductions in coagulation factors (F) II and X, the two factors responsible for the antithrombotic effect of vitamin K antagonists (VKA). Due to insensitivity to reductions in the short half-life FVII, the Fiix-NR rises later than standard PT-INR during warfarin initiation. To describe a warfarin initiation nomogram adapted for monitoring with Fiix-NR, anticoagulation development was assessed during use of standard PT-INR based initiation nomogram and after adapting the initiation nomogram for Fiix-NR monitoring. Normalized ratios were retrospectively assessed in consecutive warfarin naïve patients during their first 60 days of warfarin intake for one year prior to (PT-INR period) and for one year after replacing the PT-INR with the Fiix-NR (Fiix-NR period). The INR target was NR 2.0-3.0. We evaluated 160 patients monitored with PT-INR and dosed with the PT-nomogram, 57 monitored with Fiix-INR but dosed with PT-nomogram, and 163 Fiix-NR monitored patients dosed using a new Fiix nomogram. Mean PT-INR over 2.0 was reached on day 7 during the PT-period and remained around 2.5 thereafter. When the PT-nomogram continued in use during Fiix-monitoring significantly more patients became overanticoagulated during days 11-29. After the nomogram was modified to respond to rising Fiix-NR with larger initial dose reduction, the mean Fiix-NR reached over 2 on day 8-9 and remained around 2.5 thereafter. When warfarin is monitored with Fiix-NR, an adjusted dosing nomogram should be used during initiation to prevent early overanticoagulation.
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http://dx.doi.org/10.1007/s11239-019-01928-4DOI Listing
November 2019

Oral anticoagulant monitoring: Are we on the right track?

Int J Lab Hematol 2019 May;41 Suppl 1:40-48

Landspitali/The National University Hospital of Iceland, Reykjavik, Iceland.

Vitamin K antagonists (VKAs) cannot be administered without regular monitoring in order to assure their efficacy and safety. Indeed, if well managed, the VKAs appear to be no less efficacious or safe than the newer direct oral anticoagulants (DOACs). Although it is claimed that no regular monitoring of the DOACs is needed, their levels are increasingly being measured under a variety of circumstances, for example, prior to surgery, in suspected overdose, to confirm effective reversal, in patients with malabsorption and to assess patient compliance. Although no therapeutic range has been identified for the DOACs, it has been demonstrated for dabigatran and edoxaban that their antithrombotic effect increases gradually with increasing concentrations and that the risk of major bleeding also gradually increases. Furthermore, it has been determined that almost all dabigatran-related thrombotic events occur in patients with the lowest quartile concentration of the drug. This suggests that to assure an ideal effect of DOACs in all patients taking them, some form of regular monitoring and dose tailoring should be performed. For the vitamin K antagonists, the best outcome is obtained using formal algorithms and centralized management. Furthermore, data suggest that replacing the standard prothrombin time as a monitoring test may increase the stability of VKA anticoagulation with consequent reduction in thromboembolism without an increase in bleeding. Thus, it is likely that the outcome of all current oral anticoagulants can be improved in the coming years by improving monitoring and tailoring their effect.
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http://dx.doi.org/10.1111/ijlh.13008DOI Listing
May 2019

A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis.

Nat Genet 2019 02 14;51(2):267-276. Epub 2019 Jan 14.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10, odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.
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http://dx.doi.org/10.1038/s41588-018-0314-6DOI Listing
February 2019

Sequence variants associating with urinary biomarkers.

Hum Mol Genet 2019 04;28(7):1199-1211

Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

Urine dipstick tests are widely used in routine medical care to diagnose kidney and urinary tract and metabolic diseases. Several environmental factors are known to affect the test results, whereas the effects of genetic diversity are largely unknown. We tested 32.5 million sequence variants for association with urinary biomarkers in a set of 150 274 Icelanders with urine dipstick measurements. We detected 20 association signals, of which 14 are novel, associating with at least one of five clinical entities defined by the urine dipstick: glucosuria, ketonuria, proteinuria, hematuria and urine pH. These include three independent glucosuria variants at SLC5A2, the gene encoding the sodium-dependent glucose transporter (SGLT2), a protein targeted pharmacologically to increase urinary glucose excretion in the treatment of diabetes. Two variants associating with proteinuria are in LRP2 and CUBN, encoding the co-transporters megalin and cubilin, respectively, that mediate proximal tubule protein uptake. One of the hematuria-associated variants is a rare, previously unreported 2.5 kb exonic deletion in COL4A3. Of the four signals associated with urine pH, we note that the pH-increasing alleles of two variants (POU2AF1, WDR72) associate significantly with increased risk of kidney stones. Our results reveal that genetic factors affect variability in urinary biomarkers, in both a disease dependent and independent context.
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http://dx.doi.org/10.1093/hmg/ddy409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423415PMC
April 2019

A truncating mutation in EPOR leads to hypo-responsiveness to erythropoietin with normal haemoglobin.

Commun Biol 2018 17;1:49. Epub 2018 May 17.

deCODE genetics/Amgen, Inc, 101, Reykjavik, Iceland.

The cytokine erythropoietin (EPO), signalling through the EPO receptor (EPO-R), is essential for the formation of red blood cells. We performed a genome-wide association study (GWAS) testing 32.5 million sequence variants for association with serum EPO levels in a set of 4187 individuals. We detect an association between a rare and well imputed stop-gained variant rs370865377[A] (p.Gln82Ter) in , carried by 1 in 550 Icelanders, and increased serum EPO levels (MAF = 0.09%, Effect = 1.47 SD,  = 3.3 × 10). We validated these findings by measuring serum EPO levels in 34 additional pairs of carriers and matched controls and found carriers to have 3.23-fold higher EPO levels than controls ( = 1.7 × 10;  = 1.6 × 10). In contrast to previously reported EPOR mutations, p.Gln82Ter does not associate with haemoglobin levels (Effect = -0.045 SD,  = 0.32,  = 273,160), probably due to a compensatory EPO upregulation in response to EPO-R hypo-responsiveness.
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http://dx.doi.org/10.1038/s42003-018-0053-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123817PMC
May 2018

Reduced anticoagulation variability in patients on warfarin monitored with Fiix-prothrombin time associates with reduced thromboembolism: The Fiix-trial.

J Thromb Thrombolysis 2017 May;43(4):550-561

Department of Laboratory Hematology, Landspitali National University Hospital of Iceland, K-building, Hringbraut, 101, Reykjavik, Iceland.

Fiix-prothrombin time (Fiix-PT) differs from traditional PT in being affected by reduced factor (F) II or FX only. In the randomized controlled Fiix-trial, patients on warfarin monitored with Fiix-PT (Fiix-warfarin patients) had fewer thromboembolisms (TE), similar major bleeding (MB) and more stable anticoagulation than patients monitored with PT (PT-warfarin patients). In the current Fiix-trial report we analyzed how reduced anticoagulation variability during Fiix-PT monitoring was reflected in patients with TE or bleeding. Data from 1143 randomized patients was used. We analyzed the groups for anticoagulation intensity (time within target range; TTR), international normalized ratio (INR) variability (variance growth rate B; VGR) and dose adjustment frequency. We assessed how these parameters associated with clinically relevant vascular events (CRVE), ie TE or MB or clinically relevant non-MB. TTR was highest in Fiix-warfarin patients without CRVE (median 82%;IQR 72-91) and lowest in PT-warfarin patients with TE (62%;56-81). VGR was lowest in Fiix-warfarin patients without CRVE (median VGR B 0.17; 95% CI 0.08-0.38) and with TE (0.20;0.07-0.26) and highest in PT-warfarin patients with TE (0.50;0.27-0.90) or MB (0.59;0.07-1.36). The mean annual dose adjustment frequency was lowest in Fiix-warfarin patients with TE (mean 5.4;95% CI 3.9-7.3) and without CRVE (mean 6.0; 5.8-6.2) and highest in PT-warfarin patients with TE (14.2;12.2-16.3). Frequent dose changes predicted MB in both study arms. Compared to patients monitored with PT, high anticoagulation stability in Fiix-warfarin patients coincided with their low TE rate. Those with bleeding had high variability irrespective of monitoring method. Thus, although further improvements are needed to reduce bleeding, stabilization of anticoagulation by Fiix-PT monitoring associates with reduced TE.
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http://dx.doi.org/10.1007/s11239-017-1482-4DOI Listing
May 2017

Fiix-prothrombin time versus standard prothrombin time for monitoring of warfarin anticoagulation: a single centre, double-blind, randomised, non-inferiority trial.

Lancet Haematol 2015 Jun 25;2(6):e231-40. Epub 2015 May 25.

The National University Hospital of Iceland, Reykjavik, Iceland.

Background: Rapid fluctuations in factor VII during warfarin anticoagulation change the international normalised ratio (INR) but contribute little to the antithrombotic effect. We aimed to assess non-inferiority of anticoagulation stabilisation with a warfarin monitoring method affected only by factors II and X (Fiix-prothrombin time [Fiix-PT]) compared with standard PT-INR monitoring that includes factor VII measurement as well.

Methods: The Fiix trial was a single centre, double-blind, prospective, non-inferiority, randomised controlled clinical trial. Ambulatory adults on warfarin with an INR target of 2-3 managed by an anticoagulation dosing service using software-assisted dosing at the National University Hospital of Iceland, Reykjavik, Iceland, were eligible for inclusion in this study. We excluded patients undergoing electroconversion and nursing home residents. Patients were randomly assigned (1:1) to either the Fiix-PT monitoring group or the PT monitoring group by block randomisation. A blinded research INR (R-INR) based on results of the respective test was reported to the dosing staff. Participants were contacted by a study nurse at 4-week intervals to elicit information about thromboembolism or bleeding otherwise unknown to the anticoagulation management centre. The primary efficacy outcome was a composite of objectively diagnosed non-fatal and fatal arterial or venous thromboembolism, including myocardial infarction and transient ischaemic attacks, assessed in all eligible patients who were randomised (intention-to-monitor population). The safety endpoint was major bleeding or other clinically relevant bleeding, assessed in the per-protocol population. We assumed a 3% annual thromboembolism incidence and a non-inferiority margin of 2·5%. This trial is registered with ClinicalTrials.gov, number NCT01565239.

Findings: Between March 1, 2012, and Feb 28, 2014, we enrolled 1156 patients. 573 patients were assigned to Fiix-PT and 575 to PT-INR monitoring after exclusion of four patients from each group for various reasons. Median follow-up was 1·7 years (IQR 1·1-1·9). During days 1-720, ten (1·2% per patient year) thromboembolic events occurred in the Fiix-PT group versus 19 (2·3% per patient year) in the PT group (relative risk [RR] 0·52, 95% CI 0·25-1·13; pnon-inferiority<0·0001). Major bleeding occurred in 17 of 571 patients in the Fiix group (2·2% per patient year) versus 20 of 573 patients in the PT group (2·5% per patient year; RR 0·85, 0·45-1·61; pnon-inferiority=0·0034). Anticoagulation stability was improved with Fiix-PT monitoring as manifested by fewer tests, fewer dose adjustments, increased time in range and less INR variability than reported with standard PT monitoring.

Interpretation: Monitoring of warfarin with Fiix-PT improved anticoagulation and dosing stability and was clinically non-inferior to PT monitoring. Results from this trial suggest that during vitamin K antagonist treatment INR monitoring could be replaced by Fiix-PT and that this would lead to at least a non-inferior clinical outcome compared with monitoring with PT-INR.

Funding: Innovation Center Iceland, University of Iceland Science Fund, Landspitali Science Fund and Actavis.
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http://dx.doi.org/10.1016/S2352-3026(15)00073-3DOI Listing
June 2015

Clinical phenotype in heterozygote and biallelic Bernard-Soulier syndrome--a case control study.

Am J Hematol 2015 Feb 24;90(2):149-55. Epub 2014 Nov 24.

Laboratory Hematology and Coagulation Disorder Unit, Central Laboratory, Landspitali University Hospital, Reykjavik, Iceland.

Bernard-Soulier syndrome (BSS) is a rare severe autosomal recessive bleeding disorder. To date heterozygous carriers of BSS mutations have not been shown to have bleeding symptoms. We assessed bleeding using a semi-quantitative questionnaire, platelet parameters, PFA-100 closure times, ristocetin response, GP Ib/IX expression and VWF antigen in 14 BSS patients, 30 heterozygote carriers for related mutations and 29 controls. Eight mutations in GP1BA, GP1BB or GP9 were identified including four previously unknown pathogenic mutations. Subjects with BSS reported markedly more mucocutaneous bleeding than controls. Increased bleeding was also observed in heterozygotes. Compared to controls, patients with BSS had lower optical platelet counts (P < 0.001), CD61-platelet counts (P < 0.001) and higher mean platelet volume (17.7 vs. 7.8 fL, P < 0.001) and ristocetin response and closure times were unmeasurable. Heterozygotes had higher MPV (9.7 fL, P < 0.001) and lower platelet counts (P < 0.001) than controls but response to ristocetin and closure times were normal. The VWF was elevated in both BSS and in heterozygotes (P = 0.005). We conclude that heterozygotes for BSS mutations have lower platelet counts than controls and show a bleeding phenotype albeit much milder than in BSS. Both patients with BSS and heterozygote carriers of pathogenic mutations have raised VWF.
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http://dx.doi.org/10.1002/ajh.23891DOI Listing
February 2015

Complementary effect of fibrinogen and rFVIIa on clotting ex vivo in Bernard-Soulier syndrome and combined use during three deliveries.

Platelets 2014 2;25(5):357-62. Epub 2013 Aug 2.

Department of Medicine, Duke University Medical Center , Durham, North Carolina , USA .

Women with Bernard-Soulier syndrome (BSS) are considered to be at high risk of serious bleeding during childbirth. Due to the frequently occurring platelet transfusion refractoriness, alternative prophylactic therapy is required. Using rotational thromboelastometry, we evaluated the whole blood coagulation profile of a pregnant woman with BSS before and after spiking ex vivo with different concentrations of recombinant activated factor VII (rFVIIa) and fibrinogen. As experiments suggested improved clotting with clinically applicable concentrations of both agents in a complementary manner, the findings were confirmed on blood from a non-pregnant woman and three men suffering from BSS. During delivery, bleeding refractory to platelets occurred and immediately following delivery she received both rFVIIa and fibrinogen intravenously. Immediate cessation of bleeding occurred, and no postpartum hemorrhage was seen. Another woman with BSS later also received the same rFVIIa and fibrinogen treatment prophylactically after delivery without any postpartum bleeding. Eventually, the first woman during her second delivery received the same treatment again prophylactically without any bleeding. No side effects were observed during these three deliveries. Our observations suggest that rFVIIa combined with fibrinogen may provide a beneficial clinical hemostatic effect partly by separate but complementary mechanisms.
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http://dx.doi.org/10.3109/09537104.2013.819971DOI Listing
March 2015

Seventy-five genetic loci influencing the human red blood cell.

Nature 2012 Dec 5;492(7429):369-75. Epub 2012 Dec 5.

Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

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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http://dx.doi.org/10.1038/nature11677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623669PMC
December 2012

Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism.

J Am Coll Cardiol 2012 Aug;60(8):722-9

Population Genomics, deCODE Genetics, Reykjavik, Iceland.

Objectives: The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components.

Background: It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis.

Methods: The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (n(e) = 4,572); venous thromboembolism (n(e) = 4,607); intracranial aneurysm (n(e) = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588).

Results: LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 × 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 × 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 × 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15).

Conclusions: LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.
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http://dx.doi.org/10.1016/j.jacc.2012.01.078DOI Listing
August 2012

Screening for anemia in patients on warfarin facilitates diagnosis of gastrointestinal malignancies and pre-malignant lesions.

Thromb Res 2012 Sep 26;130(3):e20-5. Epub 2012 May 26.

Department of Internal Medicine, University of Iceland School of Health Sciences, Reykjavik Iceland.

Introduction: The prevalence and etiology of occult bleeding among patients on warfarin who are screened systematically for new anemia is largely unknown. We aimed to estimate the usefulness of following hemoglobin and mean red cell volume (MCV) with INR in order to screen for developing anemia as an indicator of occult bleeding.

Material And Methods: All patients on warfarin controlled at our institution had measurements of complete blood count (CBC) with INR during 18 months. Patients who fell>25 g/L and/or decrease of MCV over 5 fL or MCV<80 fL were contacted with instructions to undergo evaluation of anemia.

Results: Overall 3218 patients on warfarin were monitored at our institution and 442 (13.7%) had anemia and 235 (7.3%) had unexplained anemia. A total of 163/235 (69%) who were notified contacted their doctors and 82/163 (50%) were referred for investigation with upper and/or lower endoscopies. Gastrointestinal malignancies were found in 11 patients (10 colorectal cancers, 1 esophageal) and pre-cancerous lesions among 14 other patients. Additional 25/82 patients (30%) had upper and/or lower bleeding lesions such as ulcers and angiodysplasia. Based on 3669 years of observation, 73 patients needed to be screened for one year in order to identify one gastrointestinal lesion causing occult bleeding.

Conclusions: Thirty percent of those endoscoped had malignant or pre-malignant diseases. Regular measurement of CBC concomitantly with INR in patients on warfarin therapy led to detection of otherwise asymptomatic diseases in a significant proportion of patients and might lead to earlier diagnosis of malignant and premalignant disease.
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http://dx.doi.org/10.1016/j.thromres.2012.05.005DOI Listing
September 2012

Critical role of factors II and X during coumarin anticoagulation and their combined measurement with a new Fiix-prothrombin time.

Thromb Res 2012 Oct 4;130(4):674-81. Epub 2012 Jan 4.

Department of Laboratory Hematology and Hemostasis Center, Landspitali University Hospital and University of Iceland School of Medicine 101 Reykjavik, Iceland.

Vitamin K antagonists (VKA) are monitored with prothrombin time (PT) based assays that are equally sensitive to reductions in factors II, VII or X. We compared the effect of vitamin K dependent (VKD) coagulation factors on PT and also on rotational thromboelastometric (ROTEM) parameters. The PT was equally sensitive to reductions in factors II, VII or X but ROTEM parameters correlated poorly with the PT in anticoagulated patients´ plasmas. ROTEM parameters were more affected by mild and moderate reductions in FII or FX than by FVII or FIX which had little influence except at very low coagulant activity. We developed a modified PT that was sensitive only to reductions in factors II and X. The Fiix-PT (Fiix-INR) correlated well with PT (INR) but the Fiix-INR fluctuated less than the INR in an anticoagulated patient reflecting its insensitivity to FVII. The ROTEM results suggest that mild to moderate reductions in factors II or X are more important during clot formation than factors VII or IX. Reductions in FII and X may better reflect anticoagulation with VKA than FVII or IX. The new Fiix-PT may more accurately reflect the degree of therapeutic anticoagulation in patients treated with VKA than the current PT which is subject to a confounding variation caused by FVII.
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http://dx.doi.org/10.1016/j.thromres.2011.12.013DOI Listing
October 2012

Nordic Haemophilia Council's practical guidelines on diagnosis and management of von Willebrand disease.

Semin Thromb Hemost 2011 Jul 18;37(5):495-502. Epub 2011 Nov 18.

Unit of Coagulation Disorders, Department of Hematology and Clinical Chemistry Laboratory Services, Helsinki University Central Hospital, Helsinki, Finland.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder characterized by spontaneous or tissue injury-related, mostly mucocutaneous, bleeding events. VWD affects both males and females and is caused by quantitative or qualitative deficiency of Von Willebrand factor. The diagnostic procedure is complicated because VWD is highly heterogeneous, and differential diagnosis from platelet disorders may be challenging. Moreover, these defects may even coexist, impacting the bleeding phenotype. Mild and moderate VWD can be difficult to distinguish from the normal population, and VWD subtyping may also be problematic. This article summarizes the guidelines of the Nordic Haemophilia Council (NHC), which are intended to serve as a practical tool and provide the standards for diagnosing and treating VWD patients. The complete Nordic Guidelines on VWD are available at the NHC Web site (http://nordhemophilia.org).
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http://dx.doi.org/10.1055/s-0031-1281034DOI Listing
July 2011

Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm.

Nat Genet 2010 Aug 11;42(8):692-7. Epub 2010 Jul 11.

Population Genomics, deCODE Genetics, Reykjavik, Iceland.

We performed a genome-wide association study on 1,292 individuals with abdominal aortic aneurysms (AAAs) and 30,503 controls from Iceland and The Netherlands, with a follow-up of top markers in up to 3,267 individuals with AAAs and 7,451 controls. The A allele of rs7025486 on 9q33 was found to associate with AAA, with an odds ratio (OR) of 1.21 and P = 4.6 x 10(-10). In tests for association with other vascular diseases, we found that rs7025486[A] is associated with early onset myocardial infarction (OR = 1.18, P = 3.1 x 10(-5)), peripheral arterial disease (OR = 1.14, P = 3.9 x 10(-5)) and pulmonary embolism (OR = 1.20, P = 0.00030), but not with intracranial aneurysm or ischemic stroke. No association was observed between rs7025486[A] and common risk factors for arterial and venous diseases-that is, smoking, lipid levels, obesity, type 2 diabetes and hypertension. Rs7025486 is located within DAB2IP, which encodes an inhibitor of cell growth and survival.
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http://dx.doi.org/10.1038/ng.622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157066PMC
August 2010

The combination of recombinant factor VIIa and fibrinogen correct clotting ex vivo in patient samples obtained following cardiopulmonary bypass surgery.

Thromb Res 2009 Dec 4;124(6):695-700. Epub 2009 Sep 4.

Center for Haemophilia and Thrombosis, Aarhus University Hospital, Skejby, Denmark.

Cardiac surgery involving cardio pulmonary bypass (CPB) may be associated with development of a coagulopathy that increases risk of bleeding. In the present ex vivo study we investigated the influence of fibrinogen and rFVIIa, alone or in combination, on whole blood coagulation thromboelastometry using pre- and postoperative blood samples from 18 consecutive adult patients undergoing CPB surgery. Dynamic thromboelastometric clotting profiles were recorded using citrated whole blood activated with trace amounts of tissue factor (Innovin, final dilution 1:17000). Blood samples were collected before surgery (control) and postoperative samples were obtained following in vivo neutralization of heparin with protamine sulphate. All blood samples were treated with heparinase to ensure neutralization of possible residual heparin effect. The post-operative blood samples were spiked with buffer, rFVIIa (2 microg/mL), fibrinogen (1 mg/mL), or the combination of rFVIIa and fibrinogen. Despite neutralization of heparin, CPB surgery left a measurable coagulopathy that was thromboelastometrically characterized by prolonged onset of clotting, reduced maximum velocity of clot formation (MaxVel), and decreased maximum clot firmness (MCF). Ex vivo spiking of the postoperative samples with rFVIIa shortened the clotting time. Fibrinogen also shortened the clotting time and, in addition, improved the MaxVel, and MCF. Finally, adding the combination of rFVIIa and fibrinogen to the postoperative samples corrected all thromboelastometric parameters to the preoperative range. In conclusion, the correction of whole blood clotting abnormalities that occurs with rFVIIa and/or fibrinogen suggests that future clinical trials on treatment of bleeding during CPB surgery should study the haemostatic effect of fibrinogen or possibly the combination of rFVIIa and fibrinogen.
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http://dx.doi.org/10.1016/j.thromres.2009.08.008DOI Listing
December 2009

Quantification of menstrual flow by weighing protective pads in women with normal, decreased or increased menstruation.

Acta Obstet Gynecol Scand 2009 ;88(3):275-9

Department of Laboratory Hematology and Hemostasis Center, Landspitali University Hospital, Hringbraut, Reykjavik 101, Iceland.

Objective: To investigate the association between menstrual flow weight measured from modern sanitary pads (converting liquid to non-evaporating gel) and clinically assessed normal, increased or decreased menstrual flow.

Design: Objective method development study.

Setting: Outpatient clinic, University Hospital, Reykjavik.

Population: One hundred and thirteen volunteers included 26 normally menstruating adult women and 52 normally menstruating teenagers not using oral or intrauterine contraception, seven normally menstruating women using oral contraception, 17 women with clinically diagnosed menorrhagia, five women using oral contraception for clinical menorrhagia, and six teenage girls claiming heavy menstrual flow.

Methods: Menstruation length, menstrual flow weight and history of iron deficiency were assessed. During the menstruation following recruitment, all women collected their used protective pads in a hygienic manner and returned them to the laboratory for accurate weighing.

Main Outcome Measures: Menstrual flow total weight measured in grams.

Results: Mean menstrual flow total weight in the 78 asymptomatic women was 51 g (median 44, range 5-144). The mean flow in 17 women clinically diagnosed with menorrhagia was 217 g (median 207, range 63-402) (p<0.0001 compared to healthy women). The seven healthy women using oral contraceptives discharged 13 g (13-19) (p=0.0004 compared with normals). Menstruation lasted < eight days in 77/78 healthy women and in 12 of 17 clinically diagnosed menorrhagic women.

Conclusions: Measurement of menstrual flow total weight accurately reflects clinically assessed normal, increased and decreased flow. The method is an easy and accurate way of objectively estimating menstrual flow.
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http://dx.doi.org/10.1080/00016340802673162DOI Listing
March 2009

[The use of recombinant activated factor VIIa for major bleedings in open heart surgery].

Laeknabladid 2008 Sep;94(9):607-12

Introduction: We evaluated the efficacy of activated recombinant factor VIIa (rFVIIa) administration for critical bleeding during cardiothoracic surgery in Iceland.

Materials And Methods: Over a 33 month period, 10 consecutive patients with major life-threatening bleeding during or right after open cardiac surgery that received rFVIIa in 11 operations. Clinical information was retrospectively collected from hospital charts.

Results: The 10 patients were on average 66 year old, ranging 36-82 yrs. All patients were NYHA-class III or IV, there of three underwent emergency surgery. Complicated AVR+/-CABG was the most common type of operation (n=5), with average operation time 673 min. (range 475-932) and perfusion time 287 min. (range 198-615). After the administration of rFVIIa, haemostasis was acquired in 8 of 11 operations, with a significant improvement in coagulation parameters. Three patiens needed reoperation for bleeding. Transfusion of packed red cell (p=0.002) and plasma (p<0.02) decreased significantly after administration of rFVIIa and prothrombin time was shortened (p<0.004). Five patients succumbed, one of them with a cerebral infarction and pulmonary embolus, the latter confirmed at autopsy. Other causes of death were intractable bleeding, myocardial infarction, multiorgan failure and disseminated intravascular coagulopathy.

Conclusions: rFVIIa can be used effectively to stop intractable bleedings in open heart surgery, with 8 out of 11 patients in this small series achieving hemostasis after its administration. Mortality in this group of patients was high (50%), however, in all cases rFVIIa was used as an end-of-the-line treatment where other therapy had failed. One patient died from pulmonary embolism and cerebral infarct, raising the question of hypercoagulation. Further studies on the side effects and indications of rFVIIa treatment are necessary.
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September 2008

Epidemiology of hairy cell leukemia in Iceland.

Hematol J 2002 ;3(3):145-7

Department of Hematology, Landspitali University Hospital, Reykjavik, Iceland.

Introduction: Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder. Previous epidemiological studies have mainly focused on cases derived from single institutions or from localized cancer registries. This is the first study in which all cases diagnosed nationwide over a long period of time in a well defined population are analysed. We report the epidemiology of all HCL patients in Iceland, their clinical characteristics, treatment and follow-up.

Patients And Methods: : All patients diagnosed with HCL in Iceland over a 20 year period, were included in this study. Data was collected retrospectively.

Results: Sixteen patients, 13 males and three females were diagnosed with HCL in Iceland from 1981-2000, giving a mean incidence of 4.7/million/year (95% CI: 2.7-7.6) in the population 20 years and older. Eleven patients were treated with a purine analogue, 10 of whom achieved CR. One other patient obtained CR following splenectomy and IFN, giving a total CR rate of 69%. Three other patients (19%) obtained PR, giving a total response rate of 88%. One patient had a variant of HCL and did not respond to any therapy and one patient died of sepsis before any chemotherapy could be given. Six patients with HCL have died, one from complications of HCL. Three patients developed a second malignancy (19%).

Conclusions: The mean incidence of HCL in Iceland is 4.7/million/year. This is slighty higher than the reported incidence in England and Wales, although not significantly higher. The incidence is based on a nationwide information from a well defined stable and racially homogenous island population. Other results are in accordance with previously published studies.
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http://dx.doi.org/10.1038/sj.thj.6200167DOI Listing
July 2003

Progressive multifocal leukoencephalopathy after fludarabine therapy for low-grade lymphoproliferative disease.

Am J Hematol 2002 May;70(1):51-4

Department of Hematology and Pathology, Landspitali University Hospital, Hringbraut, 101 Reykjavik, Iceland.

Fludarabine is becoming the initial therapy for low-grade lymphoproliferative malignancies, such as CLL and follicular lymphoma. Fludarabine is highly immunosuppressive in addition to being myelosuppressive and has been associated with neurotoxicity. Progressive multifocal leukoencephalopathy (PML) is an infection with JC virus of the white matter of the central nervous system seen mostly in immunosuppressed patients. We describe two patients treated with fludarabine who developed PML. Immunolabeling was positive for JCV in both patients, but PCR was repeatedly negative in one of them. We suggest that fludarabine may increase the risk of PML in patients with lymphoproliferative diseases.
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http://dx.doi.org/10.1002/ajh.10085DOI Listing
May 2002

Mesenteric panniculitis presenting with autoimmune haemolytic anaemia.

Acta Haematol 2002 ;107(1):35-7

Department of Haematology, Landspítali University Hospital, Hringbraut, IS-101 Reykjavik, Iceland.

Mesenteric panniculitis is a rare idiopathic inflammatory disorder that can lead to sclerosis. We describe a patient with mesenteric panniculitis presenting with abdominal symptoms and autoimmune haemolytic anaemia. The symptoms remitted after splenectomy and gradual steroid taper. This may suggest an autoimmune component in the aetiology of mesenteric panniculitis.
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http://dx.doi.org/10.1159/000046627DOI Listing
April 2002