Improving the diagnostic strategy of pulmonary embolism

Pulmonary embolism is a common clinical disorder that is associated with high morbidity and mortality if untreated. In the only randomized study comparing anticoagulant therapy with no treatment in patients with pulmonary embolism, 26% of untreated patients had a fatal embolic event and another 26% developed nonfatal recurrent emboli1. With a course of anticoagulant treatment, the recurrence rate of thromboembolic events decreases to approximately 2% to 9% over 3 to 6 months2, 3. However, anticoagulation always carries a risk for bleeding (annual rate of major bleeding, 7%)4, 5. To avoid unnecessary anticoagulant therapy, it is therefore important to rapidly confirm or exclude pulmonary embolism in patients who present with suspicion of the disorder. Diagnosing or excluding pulmonary embolism on the basis of clinical manifestations alone is difficult because such manifestations are nonspecific6. Approximately 25% of patients with suspected pulmonary embolism have the disease confirmed by objective testing7-9. The goal of the first diagnostic strategies introduced was to confirm rather than exclude the presence of pulmonary emboli. The more recently evaluated diagnostic approaches have focused on identifying patients who probably do not have pulmonary embolism and therefore do not require anticoagulant therapy. Various invasive and noninvasive diagnostic methods have been advocated for excluding the disease. We performed a systematic review of the literature to evaluate diagnostic strategies designed to exclude pulmonary embolism. Our objective was to investigate whether clinical outcome evaluation properly documented the safety of withholding anticoagulant treatment in patients in whom pulmonary embolism was excluded according to a given diagnostic strategy. We assessed the accuracy of the various diagnostic strategies by examining the number of symptomatic thromboembolic events (deep venous thrombosis or pulmonary embolism) that occurred without anticoagulant treatment during a follow-up period of at least 3 months. Studies were grouped according to the number of rounds of diagnostic testing performed before pulmonary embolism was ruled out

Statin use decreases coagulation in users of vitamin K antagonists

Purpose: The purpose of the study is to determine the immediate and long-term effect of statins on coagulation in patients treated with vitamin K antagonists (VKAs). Methods: We selected patients on VKAs of two Dutch anticoagulation clinics who initiated treatment with a statin between 2009 and 2013. Patients who initiated or stopped concomitant drugs that interact with VKAs or were hospitalised during follow-up were excluded. The VKA dosage (mg/day) after statin initiation was compared with the last VKA dosage before the statin was started. Immediate and long-term differences in VKA dosage (at 6 and 12 weeks) were calculated with a paired student t test. Results: Four hund

Effect of genetic variation in STXBP5 and STX2 on von willebrand factor and bleeding phenotype in type 1 von willebrand disease patients

Background: In type 1 von Willebrand Disease (VWD) patients, von Willebrand Factor (VWF) levels and bleeding symptoms are highly variable. Recently, the association between genetic variations in STXBP5 and STX2 with VWF levels has been discovered in the general population. We assessed the relationship between genetic variations in STXBP5 and STX2, VWF levels, and bleeding phenotype in type 1 VWD patients. Methods: In 158 patients diagnosed with type 1 VWD according to the current ISTH guidelines, we genotyped three tagging-SNPs in STXBP5 and STX2 and analyzed their relationship with VWF:Ag levels and the severity of the bleeding phenotype, as assessed by the Tosetto bleeding score. Results: In STX2, rs7978987 was significantly associated with VWF:Ag levels (bèta-coefficient (β) = -0.04 IU/mL per allele, [95%CI -0.07;-0.001], p = 0.04) and VWF:CB activity (β = -0.12 IU/mL per allele, [95%CI -0.17;-0.06], p<0.0001). For rs1039084 in STXBP5 a similar trend with VWF:Ag levels was observed: (β = -0.03 IU/mL per allele [95% CI -0.06;0.003], p = 0.07). In women, homozygous carriers of the minor alleles of both SNPs in STXBP5 had a significantly higher bleeding score than homozygous carriers of the major alleles. (Rs1039084 p = 0.01 and rs9399599 p = 0.02). Conclusions: Genetic variation in STX2 is associated with VWF:Ag levels in patients diagnosed with type 1 VWD. In addition, genetic variation in STXBP5 is associated with bleeding phenotype in female VWD patients. Our findings may partly explain the variable VWF levels and bleeding phenotype in type 1 VWD patients

FIBTEM clot firmness parameters correlate well with the fibrinogen concentration measured by the Clauss assay in patients and healthy subjects

The Clauss assay is the assay most often used for measuring plasma fibrinogen levels. However, the FIBTEM-assay, determined using thromboelastometry (ROTEM) can also be used to estimate fibrinogen levels. A major advantage of the FIBTEM is that it can provide information about fibrinogen levels within minutes, while the Clauss assay needs 30–60 min before the result is available. The aim of this study was to investigate the correlation between fibrinogen levels measured by the Clauss assay and results from the FIBTEM-assay. We included 111 patients 18 years for whom both ROTEM analyses and a fibrinogen measurement using the Clauss assay were available. In addition, ROTEM and Clauss measurements from 75 healthy subjects were included. Spearman correlation was used to determine the association between the results of both assays. The patients included were mostly patients with major trauma or undergoing large surgery (e.g. cardiac surgery or liver transplantation). Strong correlations were found between FIBTEM clot firmness parameters and fibrinogen levels measured by the Clauss assay in patients (Spearman’s correlation coefficients (rs) above 0.80 (p < .001) for all subgroups) and healthy subjects (rs ¼ 0.66, p < .001). The correlation between early FIBTEM parameters (clot firmness at 5 or 10 min) and the maximum clot firmness was almost perfect (rs above 0.96). Also, the correlation between the a-angle a

Development of a clinical prediction model for an international normalised ratio ≥ 4·5 in hospitalised patients using vitamin K antagonists

Vitamin K antagonists (VKAs) used for the prevention and treatment of thromboembolic disease, increase the risk of bleeding complications. We developed and validated a model to predict the risk of an international normalised ratio (INR) ≥ 4·5 during a hospital stay. Adult patients admitted to a tertiary hospital and treated with VKAs between 2006 and 2010 were analysed. Bleeding risk was operationalised as an INR value ≥4·5. Multivariable logistic regression analysis was used to assess the association between potential predictors and an INR ≥ 4·5 and validated in an independent cohort of patients from the same hospital between 2011 and 2014. We identified 8996 admissions of patients treated with VKAs, of which 1507 (17%) involved an INR ≥ 4·5. The final model included the following predictors: gender, age, concomitant medication and several biochemical parameters. Temporal validation showed a c statistic of 0·71. We developed and validated a clinical prediction model for an INR ≥ 4·5 in VKA-treated patients admitted to our hospital. The model includes factors that are collected during routine care and are extractable from electronic patient records, enabling easy use of this model to predict an increased bleeding risk in clinical practice

Pharmacokinetic Modelling to Predict FVIII:C Response to Desmopressin and Its Reproducibility in Nonsevere Haemophilia A Patients

Background Nonsevere haemophilia A (HA) patients can be treated with desmopressin. Response of factor VIII activity (FVIII:C) differs between patients and is difficult to predict. Objectives Our aims were to describe FVIII:C response after desmopressin and its reproducibility by population pharmacokinetic (PK) modelling. Patients and Methods Retrospective data of 128 nonsevere HA patients (age 7–75 years) receiving an intravenous or intranasal dose of desmopressin were used. PK modelling of FVIII:C was performed by nonlinear mixed effect modelling. Reprodu

Antithrombotic stewardship: A multidisciplinary team approach towards improving antithrombotic therapy outcomes during and after hospitalisation

_Introduction:_ Antithrombotic therapy carries high risks for patient safety. Antithrombotics belong to the top 5 medications involved in potentially preventable hospital admissions related to medication. To provide a standard for antithrombotic therapy and stress the importance of providing optimal care to patients on antithrombotic therapy, the Landelijke Standaard Ketenzorg Antistolling (LSKA; Dutch guideline on integrated antithrombotic care) was drafted. However, the mere publication of this guideline does not guarantee its implementation. This may require a multidisciplinary team effort. Therefore, we designed a study aiming to determine the influence of hospital-based antithrombotic stewardship on the effect and safety of antithrombotic therapy outcomes during and after hospitalisation. _Methods and analysis:_ In this study, the effect of the implementation of a multidisciplinary antithrombotic team is compared with usual care using a pre-post study design. The study is performed at the Erasmus University Medical Center Rotterdam and the Reinier de Graaf Hospital Delft. Patients who are or will be treated with antithrombotics are included in the study. We aim to include 1900 patients, 950 in each hospital. Primary outcome is the proportion of patients with a composite end point consisting of ≥1 bleeding or ≥1 thrombotic event from the beginning of antithrombotic therapy (or hospitalisation) until 3 months after hospitalisation. Bleeding is defined according to the International Society of Thrombosis and Haemostasis (ISTH) classification. A thrombotic event is defined as any objectively confirmed arterial or venous thrombosis, including acute myocardial infarction or stroke for arterial thrombosis and deep venous thrombosis or pulmonary embolism or venous thrombosis. An economic evaluation is performed to determine whether the implementation of the multidisciplinary antithrombotic team will be cost-effective. _Ethics and dissemination:_ This protocol was approved by the Medical Ethical Committee of the Erasmus University Medical Center. The findings of the study will be disseminated through peer-reviewed journals and presented at relevant conferences