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The clinical diagnosis of von Willebrand disease (VWD), particularly type 1, can be complex because several genetic and environmental factors affect von Willebrand factor (VWF) plasma levels. An estimated 60% of the phenotypic variation is attributable to hereditary factors, with the ABO blood group locus being the most influential. However, recent studies provide strong evidence that nonsynonymous single nucleotide variants (SNVs) contribute to VWF and factor VIII phenotypic variability in healthy individuals. This study aims to investigate the role of common VWF SNVs on VWD phenotype by analyzing data from 219 unrelated patients included in the “Molecular and Clinical Profile of von Willebrand Disease in Spain project.” To that end, generalized linear mixed-effects regression models were fitted, and additive and epistatic analyses, and haplotype studies were performed, considering five VWD-related measures (bleeding score, VWF:Ag, VWF:RCo, factor VIII:C, and VWF:CB). According to these analyses, homozygotes: for p.Thr789Ala(C) would be expected to show 39% higher VWF:Ag levels; p.Thr1381Ala(C), 27% lower VWF:Ag levels; and p.Gln852Arg(C), 52% lower VWF:RCo levels. Homozygotes for both p.Thr789Ala(C) and p.Gln852Arg(T) were predicted to show 185% higher VWF:CB activity, and carriers of two copies of the p.Thr1381Ala(T)/p.Gln852Arg(T) haplotype would present a 100% increase in VWF:RCo activity. These results indicate a substantial effect of common VWF variation on VWD phenotype. Although additional studies are needed to determine the true magnitude of the effects of SNVs on VWF, these findings provide new evidence regarding the contribution of common variants to VWD, which should be taken into account to enhance the accuracy of the diagnosis and classification of this condition. ClinicalTrials.gov identifier: NCT02869074.

Aim: In placenta-mediated pregnancy complications, evidence-based guidelines are based on studies with controversial results or expert opinion. In this context, the implementation of those guidelines is quite different among physicians. Our aim was to analyze the management of PMC in a real-world scenario. Methods: From 2010 until 2016, we started the “TEAM Project” as a nested project within a working group of the Spanish Society of Thrombosis and Hemostasis (SETH : Sociedad Espanola de Trombosis y Hemostasia). Results: We included 666 women with PMC, including recurrent pregnancy loss (50%), fetal death (25%), preeclampsia- eclampsia (20%), intrauterine growth restriction (5%) and placental abruption. Although a thrombophilia test was indicated in more than 80% of these patients, antiphospholipid antibodies were tested in less than 70% cases. The presence of PT20210A mutation and positive antiphospholipid antibodies were the most common findings observed. Among the 257 women with previous PMC who were assessed for thrombotic risk, 88.7% received antithrombotic prophylaxis, most frequently (46.8%) low molecular weight heparin (LMWH)+aspirin (AAS) and recurrence was observed in 14% of women. Conclusion: This is the first observational, multicentric and multidisciplinar phase IV study analyzing the real-life clinical management of PMC and other hemostatic/thrombotic events in women from Spain and Uruguay. Our results evidence a lack of homogeneity in the management of these complications as a result of the wide discordance among the existing guidelines, as well as a need for a call to action in fetal-maternal medicine.

In recent years, direct oral anticoagulants (DOACs) have become an alternative to vitamin K antagonists (VKA) for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) as well as for prevention and treatment of deep venous thrombosis. Pivotal trials have demonstrated non-inferiority and potential superiority compared to warfarin, which increases the options of anticoagulant treatment. In our setting, the Anticoagulant Treatment Units (ATUs) and Primary Care Centres (PCCs) play an important role in the education, follow-up, adherence control and management in special situations of anticoagulated patients. These considerations have motivated us to elaborate the present consensus document that aims to establish clear recommendations that incorporate the findings of scientific research into clinical practice to improve the quality of care in the field of anticoagulation.A group of experts from the Catalan Thrombosis Group (TROMBOC@T) reviewed all published literature from 2009 to 2016, in order to provide recommendations based on clinical evidence.As a result of the project, a set of practical recommendations have been established that will facilitate treatment, education, follow-up and management in special situations of anticoagulated patients with ACODs.Progressive increase in the use of DOACs calls for measures to establish and homogenise clinical management guidelines for patients anticoagulated with DOACs in ATUs and PCCs.

Hyperhemolysis syndrome (HHS) is characterized by severe intravascular hemolysis with a decrease in the reticulocyte count, which is triggered and aggravated by transfusion and cannot be explained by standard immunohematological studies. A nationwide study was conducted in order to retrospectively identify thalassemia patients with HHS in Spain in order to assess pre-disposing mechanisms for this syndrome. For this, the expression of adhesion (CD49, CD36) and complement-related molecules (C3a, CD59) and the levels of reticulocyte apoptosis and macrophage activation were measured in 4 thalassemia patients with HHS, 14 patients without HHS, and 10 healthy subjects. Five of the six thalassemia patients had δβ-thalassemia. The patients were not alloimmunized prior to the syndrome, which was developed after the first transfusion in all but one case. Patients with δβ-thalassemia did not respond to corticoids or immunoglobulins; only splenectomy was successful. The expression of CD49 (α4β1 integrin) was far higher in patients who had experienced HHS (85.07 ± 18.46 vs. 46.28 ± 24.31; p

Resumen Antecedentes y objetivos En los ultimos anos los anticoagulantes orales directos (ACOD) se han convertido en una alternativa a los antagonistas de la vitamina K (AVK) para la prevencion del ictus y embolia sistemica en pacientes con fibrilacion auricular no valvular (FANV), asi como para la prevencion y tratamiento de la trombosis venosa profunda. Los ensayos clinicos han demostrado la no inferioridad y la potencial superioridad en comparacion con la warfarina, lo cual permite ampliar las opciones de anticoagulacion. En nuestro medio, las Unidades de Tratamiento Anticoagulante (UTA) y los Centros de Atencion Primaria (CAP) son los encargados de la educacion, seguimiento, control de adherencia y del manejo en situaciones especiales de los pacientes anticoagulados. Estas consideraciones han motivado la preparacion del presente documento de consenso, que tiene como objetivo establecer recomendaciones que incorporen los hallazgos de la investigacion cientifica a la practica clinica para mejorar la calidad asistencial en el ambito de la anticoagulacion. Material y metodos Un grupo de expertos del Grupo Catalan de Trombosis (TROMBOC@T) ha revisado la bibliografia publicada entre 2007 y 2016 para poder establecer recomendaciones basadas en la evidencia clinica. Resultados Como resultado del proyecto se han establecido un conjunto de recomendaciones de caracter practico que facilitaran el tratamiento, educacion, seguimiento y manejo en situaciones especiales de los pacientes anticoagulados con ACOD. Conclusiones El aumento progresivo del uso de los ACOD requiere establecer y homogeneizar las directrices de actuacion clinica en el paciente anticoagulado con estos antitromboticos tanto en las UTA como en los CAP.

Summary Objective We performed a systematic review and meta-analysis of studies to evaluate the diagnostic accuracy of expression of CD64 on polymorphonuclear neutrophils (PMN) as a marker for bacterial infection. Methods The analysis included studies of patients from all age groups that prospectively evaluated CD64 expression on PMNs for the diagnosis of bacterial infection. We evaluated the methodological quality of the studies according to the 25-item criteria developed by the Standards for Reporting of Diagnostic Accuracy (STARD) committee. We calculated a summary receiver operating characteristic (SROC) curve across studies included in the meta-analysis. Results The methodological quality score of the 13 included studies ranged from 9 to 16 points (maximum score was 25 points). The pooled sensitivity and specificity for CD64 expression on PMNs were 79% (95% CI: 70–86%) and 91% (95% CI: 85–95%), respectively. The area under curve (AUC) was 0.94. Conclusions On the basis of this meta-analysis, CD64 expression on PMNs could be a useful diagnostic cell-based parameter of bacterial infections. However, published studies about this topic showed a low methodological quality.

SummaryThe diagnosis of von Willebrand disease (VWD) remains difficult in a significant proportion of patients. A Spanish multicentre study investigated a cohort of 556 patients from 330 families who were analysed centrally. VWD was confirmed in 480. Next generation sequencing (NGS) of the whole coding VWF was carried out in all recruited patients, compared with the phenotype, and a final diagnosis established. A total of 238 different VWF mutations were found, 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 463 were found to have VWF mutation/s. A good phenotypic/ genotypic association was estimated in 96.5 % of the patients. One hundred seventy-four patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred sixteen patients presented with mutations that had previously been associated with increased von Willebrand factor (VWF) clearance. RIPA unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 70 patients. The NGS study facilitated an appropriate classification in 63 of them. The remaining seven patients presented with a VWF novel mutation pending further investigation. In five patients with a type 3 and two with a type 2A or 2B phenotype with no mutation, an acquired von Willebrand syndrome (AVWS) was suspected/confirmed. These data seem to support NGS as a first line efficient and faster paradigm in VWD diagnosis.Supplementary Material to this article is available online at www.thrombosis-online.com.

The correct diagnosis and classification of von Willebrand disease (VWD) is difficult because of the variability of its clinical expression and limitations of laboratory methods. However, correctly diagnosing VWD is important for therapy and genetic counselling. A survey related to the referred VWD patients in Spain revealed local diagnostic problems in at least one third of the cases of VWD. Consequently, a Spanish multicenter study was carried out in which a cohort of 556 patients from 330 families was analyzed centrally. VWD was confirmed in 480 patients. Next generation sequencing (NGS) of the whole coding von Willebrand factor gene ( VWF ) was carried out in all recruited patients, compared with the phenotype, and a final diagnosis was established. A total of 238 different VWF mutations were found: 154 were not included in the Leiden Open Variation Database (LOVD). Of the patients, 467 were found to have a VWF mutation/s. A good phenotype/genotype association was estimated in 94.6% of the cases. One hundred and eighty patients had two or more mutations. Occasionally a predominant phenotype masked the presence of a second abnormality. One hundred and sixteen patients presented with mutations that had previously been associated with an increased VWF clearance. Ristocetin induced platelet agglutination (RIPA) unavailability, central phenotypic results disagreement and difficult distinction between severe type 1 and type 3 VWD prevented a clear diagnosis in 74 patients. A local/central disagreement over diagnosis occurred in 42.3% of the whole cohort. The NGS study facilitated an appropriate classification in 60 of them. Based on these results, a proposal for a change in the VWD diagnostic paradigm, suggesting the inclusion of the analysis of VWF at the initial diagnostic process, has been made. An extension of this project to include 400 new VWD patients has begun. A diagnostic strategy has been developed, and a Spanish consensus guideline for optimal treatment of VWD was developed in Spain. Desmopressin (DDAVP) is the treatment of choice in responsive VWD patients. VWF concentrates (VWF/FVIII) are used in individuals unresponsive to DDAVP, when DDAVP is contraindicated, or in VWD types 2B and 3, and for long term management needs (e.g., post major surgery).

The purpose of this study was to evaluate the diagnostic accuracy and prognostic value of neutrophil CD64 expression for bacterial infection in febrile adult patients presenting to our hospital emergency department. We prospectively included 132 patients with fever ≥ 38oC (≥ 100.4oF) during the last 24 hours and we measured CD64 expression on neutrophils the day after admission at the emergency department. We followed the patients until full recovery or death. There were 115 (87%) patients with bacterial infection and 108 (94%) of them survived. There were 17 (13%) patients without bacterial infection and 12 (71%) of them survived. Patients with bacterial infection and patients who survived showed a CD64 index higher when compared with patients without bacterial infection and patients who died, respectively (3.7 ± 3.2 vs. 2.5 ± 2.3; p = 0.03; and 3.7 ± 3.1 vs. 1.7 ± 0.6; p = 0.002; Mann-Whitney U test). The receiver operating characteristic (ROC) curve analysis for detecting bacterial infection and predicting survival with the CD64 index showed an area under curve (AUC) of 0.66 (95% CI, 0.52-0.8; p = 0.03) and 0.71 (95% CI, 0.57-0.85; p = 0.01), respectively. Diagnostic accuracy and prognostic value of CD64 expression was good in adult patients with fever.