Search

Background: High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices.Methods: The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.Results: Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education.Conclusions: We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) involves blood clot formation in veins, resulting in serious health issues. Fibrinogen, a crucial clotting protein, consists of three polypeptides encoded by the fibrinogen genes: alpha (FGA), beta (FGB) and gamma (FGG). We genotyped most common missense variants in the fibrinogen genes in relation to VTE, recurrence and family history in Malmö Thrombophilia Study, including 1465 VTE patients followed for ~10 years and 429 healthy donors. FGG (rs6063) was significantly associated with increased odds of primary VTE (odds ratio [OR] = 8.2; 95% confidence interval [CI] = 1.05-63.6) after adjusting for age and sex. For recurrent VTE, Cox-regression analysis indicated a higher risk associated with FGA (rs6050) (hazard ratio [HR] = 1.8; 95% CI = 1.1-2.8), with even greater risk for unprovoked recurrent VTE (HR = 2.3; 95% CI = 1.3-4.2), surpassing the well-known factor V Leiden (FVL) (HR = 1.9; 95% CI = 1.2-3.0). Combining risk alleles from FVL and FGA (rs6050) significantly raised the risk for unprovoked recurrent VTE: ≥3 risk alleles (HR = 4.6; 95% CI = 1.9-11.3), two risk alleles (HR = 2.6; 95% CI = 1.4-4.8) and one risk allele (HR = 1.5; 95% CI = 0.8-2.7) compared to 0 risk allele. Prevalence of FGA (rs6050) risk allele was significantly higher in cases with a family history of VTE. We propose FGA (rs6050) as a novel predictor for unprovoked recurrent VTE and it may contribute to the familial occurrence of VTE., (© 2025 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: In Sweden, surgical treatment of Hirschsprung's disease (HSCR) was centralized from four to two pediatric surgery centers 1st of July 2018. In adults, centralization of surgical care for complex or rare diseases seems to improve quality of care. There is little evidence supporting centralization of pediatric surgical care. The aim of this study was to assess surgical management and postoperative outcome in HSCR patients following centralization of care., Methods: This study retrospectively analyzed data of patients with HSCR that had undergone pull-through at a pediatric surgery center in Sweden from 1st of July 2013 to 30th of June 2023. Patients managed from 1st of July 2013 to 30th of June 2018 (before centralization) were compared with patients managed from 1st of July 2018 to 30th of June 2023 (after centralization) regarding surgical treatment, unplanned procedures under general anesthesia or readmissions up to 90 days after pull-through as well as complications classified according to Clavien-Madadi up to 30 days after pull-through., Results: In the 5-year period prior to centralization, 114 individuals from 4 treating centers were included and compared to 83 patients from 2 treating centers in the second period. There was no difference regarding age at pull-through or proportion of patients with a stoma prior to pull-through. An increase of laparoscopically assisted endorectal pull-through (8.8% to 39.8%) was observed (p < 0.001). No significant differences were seen in postoperative hospital stay, unplanned procedures under general anesthesia, or readmissions up to 90 days after pull-through. There was no difference in severe complications (Clavien-Madadi ≥ 3); however, HAEC treated with antibiotics increased following centralization (10.5-24.1%; p = 0.018)., Conclusion: Centralization of care for HSCR does not seem to delay time to pull-through nor reduce severe complications, unplanned procedures under general anesthesia or readmissions up to 90 days after pull-through. The increased HAEC rate may be due to increased awareness of mild HAEC., Level of Evidence:  Level III., (© 2024. The Author(s).)

Background: Surgical treatment of Hirschsprung's disease (HSCR) in Sweden was centralized to two tertiary pediatric surgery centers 1st of July 2018. Although complex surgical care in adults seems to benefit from centralization there is little evidence to support centralization of pediatric surgical care. The aim of this study was to assess centralization of HSCR in Sweden, with special consideration to preoperative management and outcomes in this group of patients., Methods: This study retrospectively analyzed data of patients with HSCR that had undergone or were planned to undergo pull-through at our center, from 1st of July 2013 to 30th of June 2023. Patients managed from 1st of July 2013 to 30th of June 2018 were compared with patients managed from 1st of July 2018 to 30th of June 2023 regarding diagnostic procedures, preoperative treatment, complications and time to definitive surgery., Results: Thirty-six patients were managed during the first five-year period compared to 57 during the second period. There was an increased number of patients referred from other Swedish regions to our center following the centralization. Time from diagnosis to pull-through increased from 33 to 55 days after centralization. There were no significant differences in pre-operative management or complications, general or related to stoma., Conclusions: Despite increasing patient volumes and longer time from diagnosis to pull through, centralization of care for HSCR does not seem to change the preoperative management and risk of complications. With access to support from the specialist center, transanal irrigations remain a safe mode of at home management until surgery, regardless of distance to index hospital., Level of Evidence: Level III., Competing Interests: Conflicts of interest None to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Mitochondrial dysfunction is a recognized factor in the pathogenesis of deep vein thrombosis (DVT). The role of 7S RNA, a long noncoding RNA that plays an important role in mitochondrial function, in DVT remains unclear. In this study, we aimed to investigate the potential use of 7S RNA as a biomarker in DVT. Plasma samples were obtained from 237 patients (aged 16-95 years) with suspected DVT recruited in a prospective multicenter management study (SCORE) where 53 patients were objectively confirmed with a diagnosis of DVT and the rest were diagnosed as non-DVT. 7S RNA was measured using quantitative real-time polymerase chain reaction in plasma samples. The plasma expression of 7S RNA was significantly lower in DVT compared with non-DVT (0.50 vs. 0.95, p  = 0.043). With the linear regression analysis, we showed that the association between the plasma expression of 7S RNA and DVT (β = -0.72, p  = 0.007) was independent of potential confounders. Receiver-operating characteristic curve analysis showed the area under the curve values of 0.60 for 7S RNA. The findings of the present study showed a notable association between 7S RNA and DVT. However, further investigations are needed to fully elucidate the exact role of 7S RNA in the pathophysiology of DVT and its diagnostic value., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: The development of entrustable professional activities (EPAs) as a framework for work-based training and assessment in undergraduate medical education has become popular. EPAs are defined as units of a professional activity requiring adequate knowledge, skills, and attitudes, with a recognized output of professional labor, independently executable within a time frame, observable and measurable in its process and outcome, and reflecting one or more competencies. Before a new framework is implemented in a specific context, it is valuable to explore social validity, that is, the acceptability by relevant stakeholders., Aim: The aim of our work was to define Core EPAs for undergraduate medical education and further explore the social validity of the constructs., Method and Material: In a nationwide collaboration, EPAs were developed using a modified Delphi procedure and validated according to EQual by a group consisting of teachers nominated from each of the seven Swedish medical schools, two student representatives, and an educational developer (n = 16). In the next step, social validity was explored in a nationwide survey. The survey introduced the suggested EPAs. For each EPA, the importance of the EPA was rated, as was the rater's perception of the present graduates' required level of supervision when performing the activity. Free-text comments were also included and analyzed., Results: Ten Core EPAs were defined and validated. The validation scores for EQual ranged from 4.1 to 4.9. The nationwide survey had 473 responders. All activities were rated as "important" by most responders, ranging from 54 to 96%. When asked how independent current graduates were in performing the ten activities, 6 to 35% reported "independent". The three themes of the free text comments were: 'relevant target areas and content'; 'definition of the activities'; and 'clinical practice and learning'., Conclusion: Ten Core EPAs were defined and assessed as relevant for Swedish undergraduate medical education. There was a consistent gap between the perceived importance and the certainty that the students could perform these professional activities independently at the time of graduation. These results indicate that the ten EPAs may have a role in undergraduate education by creating clarity for all stakeholders., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background Whether sex-specific differences exist for risk factors for pulmonary embolism (PE) and deep venous thrombosis (DVT), with the exception of pregnancy and estrogen therapy, has been sparsely studied. We aimed to study whether sex-specific differences of risk factors exist for noncancer-related DVT and PE in middle-aged and older individuals without cardiovascular history or previous diagnosis in a population-based historical (retrospective) cohort. Methods and Results Potential venous thromboembolism (VTE) risk factors were registered at baseline in 15 807 women and 9996 men aged 44 to 74 years, who participated in the Malmö Diet and Cancer study (1991-1996). We excluded subjects with a previous history of VTE, cancer, a diagnosis of cardiovascular disease, or a diagnosis of cancer-associated VTE during follow-up. Patients were followed up from baseline until the first event of PE or DVT, death, or December 31, 2018. During the follow-up period, 365 (2.3%) women and 168 (1.7%) men were affected by first DVT, and 309 (2.0%) women and 154 (1.5%) men were affected by first PE. In the multivariable Cox regression models, the anthropometric obesity markers of weight, body mass index, waist and hip circumference, fat percentage, and muscle weight were in a dose-dependent way associated with DVT and PE among women but not men. In an analysis that included patients with cardiovascular disease and cancer-related VTE, the results were similar for women. For men, several obesity measures became significantly associated with PE or DVT but were weaker than in women, especially for DVT. Conclusions Anthropometric obesity measures are more important risk factors for both DVT and PE among women than men, especially for individuals without cardiovascular history or previous diagnosis or cancer-related VTE.

Background: Tissue factor is the main initiator of blood coagulation, and tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the initiation of blood coagulation.The genetic variation of TFPI and the relation to venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, remains to be clarified. This exome sequencing study aimed to determine the molecular epidemiology of the TFPI gene and the relation to VTE in a large population-based cohort of middle-aged and older adults., Methods: The exomes of TFPI were analyzed for variants in 28,794 subjects without previous VTE (born 1923-1950, 60% women), who participated in the Malmö Diet and Cancer Study (1991-1996). Patients were followed until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequency less than 0.1%., Results: No common variant was associated with VTE. Nine rare variants (two loss-of-function and seven nonbenign missense) were classified as qualifying and included in collapsing analysis. Prevalence of qualifying variants was 0.09%. Five individuals with VTE compared to 17 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and ancestry showed a hazard ratio of 2.9 (95% CI, 1.2-7.1) for rare qualifying variants., Conclusion: Rare qualifying TFPI variants were associated with VTE, suggesting that rare variants in TFPI contribute to the development of VTE. The qualifying TFPI gene variants were very rare, suggesting a constrained gene., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

To evaluate the hemostatic system with ROTEM in patients undergoing surgery for acute type aortic dissection (ATAAD) using elective aortic procedures as controls. This was a prospective, controlled, observational study. The study was performed at a tertiary referral center and university hospital. Twenty-three patients with ATAAD were compared to 20 control patients undergoing elective surgery of the ascending aorta or the aortic root. ROTEM (INTEM, EXTEM, HEPTEM and FIBTEM) was tested at 6 points in time before, during and after surgery for ATAAD or elective aortic surgery. The ATAAD group had an activated coagulation coming into the surgical theatre. The two groups showed activation of both major coagulation pathways during surgery, but the ATAAD group consistently had larger deficiencies. Reversal of the coagulopathy was successful, although none of the groups reached elective baseline until postoperative day 1. ROTEM did not detect low levels of clotting factors at heparin reversal nor low levels of platelets. This study demonstrated that ATAAD is associated with a coagulopathic state. Surgery causes additional damage to the hemostatic system in ATAAD patients as well as in patients undergoing elective surgery of the ascending aorta or the aortic root. ROTEM does not adequately catch the full coagulopathy in ATAAD. A transfusion protocol in ATAAD should be specifically created to target this complex coagulopathic state and ROTEM does not negate the need for routine laboratory tests., (© 2022. The Author(s).)

Background:  The protein C (PC) anticoagulant system has a key role in maintaining hemostatic balance. One missense (Ser219Gly) variant in the PC receptor ( PROCR ) was associated with venous thromboembolism (VTE) in genome-wide association studies., Objectives:  This study aimed to determine the thrombotic risk of rare and common PROCR variants in a large population-based cohort of middle-aged and older adults., Methods:  The exonic sequence of PROCR was analyzed for the Ser219Gly variant and other qualifying variants in 28,794 subjects (born 1923-1950, 60% women) without previous VTE, who participated in the Malmö Diet and Cancer study (1991-1996). Incidence of VTE was followed up until 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequencies (MAFs) <0.1%., Results:  Re-sequencing identified 36 PROCR variants in the study population (26,210 non-VTE exomes and 2,584 VTE exomes), 11 synonymous, 22 missense, and three loss-of-function variants. Kaplan-Meier analysis of the known Ser219Gly variant (rs867186) showed that homozygosity for this variant increased the risk of disease, whereas heterozygosity showed no effect. Cox multivariate regression analysis revealed an adjusted hazard ratio (HR) of 1.5 (95% confidence interval [CI]: 1.1-2.0). Fifteen rare variants were classified as qualifying and were included in collapsing analysis (burden test and SKAT-O). They did not contribute to risk. However, a Arg113Cys missense variant (rs146420040; MAF = 0.004) showed an increased VTE risk (HR = 1.3; 95% CI: 1.0-1.9)., Conclusion:  Homozygosity for the Ser219Gly variant and a previously identified functional PROCR variant (Arg113Cys) was associated with VTE. Other variants did not contribute to VTE., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Severe alpha-1-antitrypsin deficiency (AATD), phenotype PiZZ, was associated with venous thromboembolism (VTE) in a case-control study., Objectives: This study aimed to determine the genetic variation in the SERPINA1 gene and a possible thrombotic risk of these variants in a population-based cohort study., Patients/methods: The coding sequence of SERPINA1 was analyzed for the Z (rs28929474), S (rs17580), and other qualifying variants in 28,794 subjects without previous VTE (born 1923-1950, 60% women), who participated in the Malmö Diet and Cancer study (1991-1996). Individuals were followed from baseline until the first event of VTE, death, or 2018., Results: Resequencing the coding sequence of SERPINA1 identified 84 variants in the total study population, 21 synonymous, 62 missense, and 1 loss-of-function variant. Kaplan-Meier analysis showed that homozygosity for the Z allele increased the risk of VTE whereas heterozygosity showed no effect. The S (rs17580) variant was not associated with VTE. Thirty-one rare variants were qualifying and included in collapsing analysis using the following selection criteria, loss of function, in frame deletion or non-benign (PolyPhen-2) missense variants with minor allele frequency (MAF) <0.1%. Combining the rare qualifying variants with the Z variant showed that carrying two alleles (ZZ or compound heterozygotes) showed increased risk. Cox regression analysis revealed an adjusted hazard ratio of 4.5 (95% confidence interval 2.0-10.0) for combinations of the Z variant and rare qualifying variants. One other variant (rs141620200; MAF = 0.002) showed an increased risk of VTE., Conclusions: The SERPINA1 ZZ genotype and compound heterozygotes for severe AATD are rare but associated with VTE in a population-based Swedish study., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background: The protein C anticoagulant system plays a key role in maintaining the hemostatic balance. Although several studies have identified thrombomodulin gene (THBD) variants among venous thromboembolism (VTE) patients, the role of THBD in relation to VTE in humans remains to be clarified., Objectives: This study aimed to determine the thrombotic risk of rare and common THBD variants in a large population-based cohort of middle-aged and older adults., Patients/methods: The exome sequence of THBD was analyzed for qualifying variants in 28,794 subjects (born 1923-1950, 60% women), who participated in the Malmö Diet and Cancer study (1991-1996). Patients were followed from baseline until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequency <0.1%., Results: The single common coding variant rs1042579 was not associated with incident VTE. Sixteen rare variants were classified as qualifying and included in collapsing analysis. Seven individuals with VTE compared to 24 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and the top two eigenvectors from a principal components analysis showed a hazard ratio of 3.0 (95% confidence interval 1.4-6.3) for the rare qualifying variants. The distributions of qualifying variants in THBD showed a difference for individuals with and without incident VTE indicating a possible position effect., Conclusions: Rare qualifying THBD variants were associated with VTE, suggesting that rare variants in THBD contribute to development of VTE., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background Five classic thrombophilias have been recognized: factor V Leiden (rs6025), the prothrombin G20210A variant (rs1799963), and protein C, protein S, and antithrombin deficiencies. This study aimed to determine the thrombotic risk of classic thrombophilias in a cohort of middle-aged and older adults. Methods and Results Factor V Leiden, prothrombin G20210A and protein-coding variants in the PROC (protein C), PROS1 (protein S), and SERPINC1 (antithrombin) anticoagulant genes were determined in 29 387 subjects (born 1923-1950, 60% women) who participated in the Malmö Diet and Cancer study (1991-1996). The Human Gene Mutation Database was used to define 68 disease-causing mutations. Patients were followed up from baseline until the first event of venous thromboembolism (VTE), death, or Dec 31, 2018. Carriership (n=908, 3.1%) for disease-causing mutations in the PROC , PROS1 , and SERPINC1 genes was associated with incident VTE: Hazard ratio (HR) was 1.6 (95% CI, 1.3-1.9). Variants not in Human Gene Mutation Database were not linked to VTE (HR, 1.1; 95% CI, 0.8-1.5). Heterozygosity for rs6025 and rs1799963 was associated with incident VTE: HR, 1.8 (95% CI, 1.6-2.0) and HR, 1.6 (95% CI, 1.3-2.0), respectively. The HR for carrying 1 classical thrombophilia variant was 1.7 (95% CI, 1.6-1.9). HR was 3.9 (95% CI, 3.1-5.0) for carriers of ≥2 thrombophilia variants. Conclusions The 5 classic thrombophilias are associated with a dose-graded risk of VTE in middle-aged and older adults. Disease-causing variants in the PROC , PROS1 , and SERPINC1 genes were more common than the rs1799963 variant but the conferred genetic risk was comparable with the rs6025 and rs1799963 variants.

Background This is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance. Methods and Results The Swedish Multi-Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish-born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64-bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE. VTE occurred in 2 or more affected relatives in 61 217 (13.6%) of the pedigrees. Heritability showed age and sex dependence with higher heritability for men and young individuals. In 18 933 pedigrees, VTE occurred only in the first generation and was not inherited. Segregation analysis was performed in the remaining 42 284 pedigrees with inherited VTE and included 939 192 individuals. Prevalence constraints were imposed in the models to allow for the selection of the pedigrees analyzed. The sporadic nongenetic model could be discarded. The major-type-only model, with a correlation structure compatible with some polygenic effects, was the preferred model. Among the Mendelian models, the mixed codominant (plus polygenic) model was preferred. Conclusions This nationwide segregation analysis of VTE supports a genetic cause of the familial aggregation of VTE. Heritability was higher for men and younger individuals, suggesting a Carter effect, in agreement with a multifactorial threshold inheritance.

Alterations in DNA methylation patterns have been associated with many diseases. However, the role of DNA methylation in venous thromboembolism (VTE) is not well established. The aim of this study was to investigate a possible association between global DNA methylation and VTE. The study participants consisted of 168 individuals including 74 patients with primary VTE from the Malmö Thrombophilia Study (MATS) and 94 healthy controls. Among 74 primary VTE patients, 37 suffered VTE recurrence during the follow-up period; 37 nonrecurrent VTE patients were included for comparison. Blood-based global DNA methylation was assessed by an enzyme-linked immunosorbent assay. Global DNA methylation was significantly higher in primary VTE patients compared with the healthy controls (median: 0.17 vs. 0.08%; p  < 0.001). After stratification of data from primary VTE patients according to sex, the association between higher global DNA methylation and shorter recurrence-free survival time was of borderline statistical significance in males ( β = -0.2; p  = 0.052) but not in females ( β  = 0.02; p  = 0.90). Our results show that global DNA methylation is associated with primary VTE and that higher levels of global DNA methylation may be associated with early VTE recurrence in males but not in females. Further investigation on the role of DNA methylation as a diagnostic or preventive biomarker in VTE is warranted., Competing Interests: None declared., (Thieme. All rights reserved.)

Competing Interests: None declared.

Objectives: Estimating blood loss is an important factor in several surgical procedures. The accuracy of blood loss measurements in situations where blood is mixed with saliva and saline is however uncertain. The purpose of this laboratory study was to ascertain if blood loss measurements in mixtures of blood, saline, and saliva are reliable and could be applicable in a clinical setting., Material and Methods: Venous blood and resting saliva were collected from six volunteers. Saliva, saline, and combinations thereof were mixed with blood to obtain different concentrations. A portable spectrophotometer was first used to measure the haemoglobin concentration in undiluted venous blood followed by measurements of the haemoglobin concentration after each dilution. To examine the strength of linear relationships, linear regression and Pearson correlations were used., Results: The measurements of haemoglobin concentrations in mixtures of blood, saline, and saliva were proven to be accurate for haemoglobin measurements > 0.3 g/dl (correlation = 0.986 to 1). For haemoglobin measurements < 0.3 g/dl, a small increase in haemoglobin values were reported, which was directly associated to the saliva concentration in the solution (correlation = 0.983 to 1). This interference of saliva was significantly eliminated by diluting the samples with saline, mimicking the clinical situation., Conclusions: The results suggest that a portable spectrophotometer can be used clinically to preoperatively measure the haemoglobin value of a venous blood sample and postoperatively measure the haemoglobin value of the collected liquids, including shed blood, thereby achieving a highly accurate method of measuring blood loss during oral and maxillofacial surgery., (Copyright © Johansson K, Lindström M, Alhabshi M, Ahmad M, Svensson PJ, Becktor JP. Published in the JOURNAL OF ORAL & MAXILLOFACIAL RESEARCH (http://www.ejomr.org), 30 June 2021.)

Excessive bleeding is a serious complication associated with impaired survival after surgery for acute type A aortic dissection (ATAAD). Different ABO blood groups are associated with variable levels of circulating von Willebrand factor and therefore potentially altered risks of surgical haemorrhage. The current study aimed to assess the impact of blood group on bleeding complications after ATAAD surgery. This was a retrospective cohort study including 336 patients surgically treated for ATAAD between January 2004 and January 2019. Patients with blood group O were compared with non-O patients. In total, 152 blood group O patients were compared with 184 non-O patients. There were no differences in rates of massive bleeding (27.0 vs. 25.5%, P = 0.767) or re-exploration for bleeding (16.4 vs. 13.0%, P = 0.379) in blood group O and non-O patients, respectively. Median chest tube output 12 h after surgery was 520 ml (350-815 ml) in blood group O and 490 ml (278-703 ml) in non-O patients (P = 0.229). Blood group O patients received more fibrinogen concentrate (6.1 ± 4.0 vs. 4.9 ± 3.3 g, P = 0.023) but administered units of packed red blood cells [5 (2-8) vs. 4 (2-9) U, P = 0.736], platelets [4 (2-4) vs. 3 (2-5) U, P = 0.521] or plasma [4 (1-7) vs. 4 (0-7) U, P = 0.562] were similar. This study could not demonstrate any association between blood group and bleeding after surgery for ATAAD. It cannot be ruled out that potential differences were levelled out by blood group O patients receiving significantly more fibrinogen concentrate., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Venous thromboembolism (VTE) is a complex disease that aggregates in families. Both acquired and genetic risk factors are important. Proper recognition and management of high-risk individuals are important., Areas Covered: The genetic risk factors for VTE, the clinical consequences, and future perspectives are summarized. Classical thrombophilia i.e., factor V Leiden (rs6025), the prothrombin G20210A mutation (rs1799963), deficiencies of antithrombin, protein C, and protein S and the recent findings from genome wide association studies (GWAS), transcriptome-wide association studies (TWAS), genetic risk score (GRS), VTE candidate genes, expression studies, animal studies, studies using next generation sequencing, pathway analysis, and clinical implications are discussed., Expert Opinion: Screening of inherited thrombophilia should be performed in special cases. Identification of strong risk variants might affect the management. The increasing number of genetic risk variants is likely to change management of VTE.

Objective: To evaluate the hemostatic system in patients undergoing surgery for acute type A aortic dissection (ATAAD) compared with those undergoing elective aortic procedures., Design: This was a prospective, observational study., Setting: The study was performed at a single university hospital., Participants: Twenty-five patients with ATAAD were compared with 20 control patients undergoing elective surgery of the ascending aorta or the aortic root., Interventions: No interventions were performed., Measurements and Main Results: Platelet count and levels of fibrinogen, D-dimer, prothrombin time/international normalized ratio, activated partial thromboplastin time, and antithrombin were analyzed perioperatively and compared between the 2 groups. Patients with ATAAD had lower preoperative levels of platelets (188 [156-217] × 10 9 /L v 221 [196-240] × 10 9 /L; p = 0.018), fibrinogen (1.9 [1.6-2.4] g/L v 2.8 [2.2-3.0] g/L; p = 0.003), and antithrombin (0.81 [0.73-0.94] kIU/L v 0.96 [0.92-1.00] kIU/L; p = 0.003) and significantly higher levels of D-dimer (2.9 [1.7-9.7] mg/L v 0.1 [0.1-0.2] mg/L; p < 0.001) and prothrombin time/international normalized ratio (1.15 [1.1-1.2] v 1.0 [0.93-1.0]; p = 0.001). Surgery caused significant changes of the coagulation system in both groups. Intraoperative bleeding volumes were larger in the ATAAD group (2,407 [1,804-3,209] mL v 1,212 [917-1,920] mL; p < 0.001), and patients undergoing ATAAD surgery received significantly more transfusions of red blood cells (2.5 [0.25-4.75] U v 0 [0-2.75] U; p = 0.022), platelets (4 [3.25-6] U v 2 [2-4] U; p = 0.002), and plasma (2 [0-4] U v 0 [0-0] U; p = 0.004) compared with the elective group., Conclusions: This study demonstrates that ATAAD is associated with a coagulopathic state. Surgery causes additional damage to the hemostatic system in ATAAD patients, but also in patients undergoing elective surgery of the ascending aorta or the aortic root., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background/purpose: The aims of this study were to evaluate bowel and urinary tract function, to identify predictors for dysfunctional outcome and to evaluate health-related quality-of life (QoL) in patients treated for sacrococcygeal teratomas (SCT)., Methods: Medical records of patients with SCT born between 1985 and 2015 treated at three Swedish pediatric surgical centers were reviewed. Questionnaires regarding urinary tract function, bowel function and QoL were sent to patients and parents. Different QoL instruments were used for the different age groups., Results: Totally 85 patients were identified. Four patients died in the neonatal period. Forty-nine patients answered the questionnaires (60%). Median age at follow-up was 8.9 years (range 3.6-28.8). Bowel dysfunction was reported by 36% and urinary tract dysfunction by 46% of the patients. Univariate analysis revealed that urinary tract dysfunction correlated with gestational age (p = 0.018) and immature histology (p = 0.008), and bowel dysfunction correlated with gestational age (p = 0.016) and tumor size (p = 0.042). Low gestational age was an independent predictor for both urinary tract and bowel dysfunction. Good or very good QoL was reported by 56% of children aged 4-7 years, 90% of children aged 8-17 years and 67% of the adults., Conclusion: Although a considerable proportion of bowel and urinary tract dysfunction was found, the reported QoL was good in a majority of the patients with SCT. Low gestational age was found to be a predictor for bowel- and urinary tract dysfunction., Level of Evidence: Level III., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Massive bleeding is a serious complication associated with impaired survival after surgery for acute type A aortic dissection (ATAAD). There are no previous reports evaluating the effect of ATAAD and associated surgery on von Willebrand factor (VWF). The aim of the present study was to analyze VWF activity (VWF:GPIbM) and thus the potential of Factor (F) VIII/VWF concentrate as a treatment for refractory bleeding in surgery for acute type A aortic dissection., Material and Methods: We prospectively compared serial measurements of VWF:GPIbM in 25 patients with ATAAD to 20 control patients undergoing elective surgery of the ascending aorta or the aortic root. In 10 of the ATAAD patients, high molecular weight multimer distribution was measured., Results: Preoperatively, ATAAD patients demonstrated significantly higher VWF:GPIbM (1.58 (1.40-2.05) kIU/L vs 1.25 (1.02-1.42) kIU/L, p = 0.003). In the ATAAD group, VWF:GPIbM significantly decreased to 1.24 (0.98-1.44) kIU/L at lowest core temperature (T0 vs T1 p < 0.001), but remained unchanged in the elective group (1.25 (1.04-1.43) kIU/L, T0 vs T1 p < 0.625). Neither aortic dissection nor hypothermia caused any changes to the proportion of high molecular weight multimers when compared to control patients. Both groups demonstrated supernormal VWF:GPIbM on the first and fifth day after surgery., Conclusions: This report showed that patients with acute aortic dissection had increased levels of VWF:GPIbM before surgery that decreased slightly during surgery. Our study could not provide evidence that would encourage administration of FVIII/VWF concentrate for major bleeding in patients undergoing surgery for ATAAD as well as elective aortic procedures., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Patients with unprovoked first venous thromboembolism (VTE) are at a high risk of recurrence. Although circulating microRNAs (miRNAs) have been found to be associated with VTE and are markers of hypercoagulability, this study is the first to examine whether circulating miRNAs are associated with the risk of VTE recurrence., Results: A nested case-control study design was used where plasma samples were obtained from 78 patients with unprovoked VTE from the Malmö Thrombophilia Study (MATS). A total of 39 VTE patients with recurrent VTE (cases) were matched with 39 VTE patients without recurrent VTE (controls) defined by age and sex (MATS population). Plasma levels of 179 different miRNAs were evaluated in the 78 samples (after anticoagulant treatment was stopped) using qPCR. A total of 110 miRNAs were detected in all samples. Among those, 12 miRNAs (miR-15b-5p, miR-106a-5p, miR-197-3p, miR-652-3p, miR-361-5p, miR-222-3p, miR-26b-5p, miR-532-5p, miR-27b-3p, miR-21-5p, miR-103a-3p, and miR-30c-5p) were found to be associated with recurrent VTE after multiple correction test and conditional logistic regression analysis. A further analysis showed that miR-15b-5p, miR-197-3p, miR-27b-3p, and miR-30c-5p exhibited a trend over time, with a larger difference in miRNA levels between cases and controls for earlier recurrence. Of these 12 miRNAs, 8 miRNAs significantly correlated with circulating transforming growth factor β1/2 (TGFβ1/2). Three of them correlated with platelet count., Conclusion: We have identified 12 plasma miRNAs that may have the potential to serve as novel, non-invasive predictive biomarkers for VTE recurrence.

A single genetic biomarker is unable to accurately predict the risk for venous thromboembolism (VTE) recurrence. We aimed to: (a) develop a multiple single nucleotide polymorphisms (SNPs) model to predict the risk of VTE recurrence and (b) validate a previously described genetic risk score (GRS) and compare its performance with the model developed in this study. Twenty-two SNPs, including established and putative SNPs associated with VTE risk, were genotyped in the Malmö thrombophilia study cohort (MATS; n = 1465, follow-up ~ 10 years) by using TaqMan PCR. Out of 22-SNPs, 12 had an association with the risk of VTE recurrence and were included for calculating GRSs. The risk of VTE recurrence was calculated by stratifying patients according to number of risk alleles. In 12-SNP GRS, patients with ≥ 7 risk alleles were associated with higher risk of VTE recurrence compared to patients having ≤ 6 risk alleles. In a simplified model (8-SNP GRS), the discriminative power of 8-SNP GRS was similar to that of 12-SNP GRS based on post-test probabilities (PP). Furthermore, 8-SNP GRS further improved the risk prediction of VTE recurrence in unprovoked VTE and male patients (PP% = 15.4 vs 8.3, 17.1 vs 7.2 and 19.0 vs 7.1 for high risk groups vs low risk groups in whole population, males and unprovoked VTE patients respectively). In addition, we also validated previously described 5-SNP GRS in our cohort and found that the 8-SNP GRS performed better than the 5-SNP GRS in terms of higher PP. Our results show that a multiple SNP GRS consisting of 8-SNPs may be an effective model for prediction of VTE recurrence, particularly in unprovoked VTE and male patients.

Importance: It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE)., Objective: To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism., Design, Setting, and Participants: This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018., Exposures: A panel of several established cardiovascular risk factors., Main Outcomes and Measures: Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI)., Results: Of the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers., Conclusions and Relevance: Older age, smoking, and adiposity were consistently associated with higher VTE risk.

Importance: The associations of a family history of venous thromboembolism (FH-VTE) with postoperative venous thromboembolism (VTE) and major bleeding after joint replacement surgical procedures are unknown., Objective: To determine the risk of VTE and major bleeding in patients after primary hip or knee replacement surgical procedures., Design, Setting, and Participants: Cohort study using nationwide population-based databases of Swedish patients without a history of VTE who underwent joint replacement surgical procedures. Patients who had primary hip or knee replacement surgical procedures between July 1, 2005, and August 31, 2012, were identified. Patients born after 1931 without previous VTE were identified in the Swedish Multi-Generation Register. Only individuals with at least 1 parent and 1 full sibling alive between 1964 and the date for the surgical procedure were included. The data analysis was performed from September 1, 2017, to June 15, 2018., Exposures: Family history of VTE in a parent and/or a full sibling before the date of the surgical procedure., Main Outcomes and Measures: Venous thromboembolism and major bleeding within 90 days of the surgical procedure., Results: Of 69 505 study participants, 37 989 (54.7%) were women, and the median (interquartile range) age at the date of discharge was 65 (59-70) years. A total of 803 of 69 505 (1.2%) patients experienced postoperative VTE and 1285 (1.8%) experienced major bleeding. The cumulative VTE risk for those with FH-VTE was 231 of 15 858 (1.5%) and for those without an FH-VTE was 572 of 53 647 (1.1%) (P < .001). The cumulative bleeding risk for those with FH-VTE was 261 of 15 858 (1.6%) and for those without an FH-VTE was 1024 of 53 647 (1.9%) (P = .03). There was an association of patients with an FH-VTE who had increased VTE risk (adjusted hazard ratio [HR], 1.36; 95% CI, 1.17-1.59) and reduced bleeding risk (adjusted HR, 0.84; 95% CI, 0.74-0.97). There was an interaction between time after discharge and FH-VTE regarding VTE and major bleeding. An FH-VTE was not associated with VTE after discharge during the first week (HR, 1.13; 95% CI, 0.86-1.49). After 7 days from discharge, FH-VTE was associated with VTE (HR, 1.49; 95% CI, 1.24-1.79). An FH-VTE reduced major bleeding risk during the first 7 days after discharge (HR, 0.78; 95% CI, 0.66-0.91) but not thereafter (HR, 1.10; 95% CI, 0.84-1.44). Postoperative VTE heritability (SE) was 20% (6%)., Conclusions and Relevance: Familial and most likely genetic factors appear to affect VTE and major bleeding risk following hip and knee replacement surgical procedures. Prolonged VTE prophylaxis might be beneficial in predisposed individuals. There may be a possible evolutionary advantage of prothrombotic genes protecting against traumatic bleeding.

Tumors with anaplastic lymphoma kinase (ALK) fusion rearrangements, including non-small-cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. Although mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, because of lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germline FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Monotherapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 mo treatment, the residual primary tumor shrunk, was surgically removed, and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 mo treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma., (© 2018 Guan et al.; Published by Cold Spring Harbor Laboratory Press.)

Recent studies indicate that mitochondrial DNA (mtDNA) dysfunction is a biomarker of oxidative stress and can predict the risk of cardiovascular diseases (CVDs). Genetic variants in PARK2 (rs4708928) and MRPL37 (rs10888838) genes have been shown to be associated with altered levels of mtDNA in a sex-specific manner. However, the role of these genetic variants in risk assessment of recurrent venous thromboembolism (VTE) is unknown. We investigated the role of these polymorphisms in VTE recurrence in patients from the Malmö thrombophilia study (MATS, n = 1465), followed for ~ 10 years. Genotyping was performed by TaqMan polymerase chain reaction. Female patients with PARK2 polymorphism had significantly higher risk of VTE recurrence (Hazard ratio [HR] = 2.39, 95% confidence interval [CI] 1.09-5.24) and male patients with MRPL37 polymorphism had a significantly higher risk of VTE recurrence (HR = 1.79, 95% CI 1.01-3.17) on multivariate Cox regression analysis. Combined analysis of these polymorphism with factor V Leiden (FVL) showed that female patients with both, FVL and PARK2 polymorphism had even higher risk of VTE recurrence (HR = 4.49, 95% CI 1.58-12.75) compared to FVL or PARK2 polymorphism alone or both wild-type (reference). Similarly, male patients with both FVL and MRPL37 polymorphism had significantly higher risk of VTE recurrence (HR = 2.97, 95% CI 1.45-6.08) compared to those with FVL or MRPL37 polymorphisms alone or the reference group. Polymorphisms in nuclear genome regulating mtDNA together with FVL may be promising biomarkers for predicting VTE recurrence in a sex specific manner. The abstract should be followed by 3-4 bullet points that highlight the major findings. The final bullet point should address future research.

The combination of a negative D-dimer and a Wells score can rule out, but not confirm, a diagnosis of deep venous thrombosis (DVT). We aimed to identify new diagnostic biomarkers for DVT and to investigate their relationship with hypercoagulability markers [D-dimer and activated protein C-protein C inhibitor (APC-PCI) complex]. We screened 92 cardiovascular-specific proteins in plasma samples from 45 confirmed DVT patients and 45 age- and sex-matched non-DVT patients selected from a prospective multicentre diagnostic management study (SCORE) by Proseek Multiplex CVDIII 96×96 . Plasma levels of 30 proteins were significantly different between DVT and non-DVT patients. After Bonferroni correction, plasma levels of seven proteins: P-selectin, transferrin receptor protein 1, von Willebrand factor, tissue factor pathway inhibitor, osteopontin (OPN), bleomycin hydrolase and ST2 protein remained significantly different. The area under curve (AUC) for these proteins ranged from 0·70 to 0·84. Furthermore, all seven identified proteins were significantly associated with markers of hypercoagulability. A combination of OPN and APC-PCI had the best ability to discriminate DVT from non-DVT patients (AUC = 0·94; sensitivity = 89% and specificity = s84%). In conclusion, we identified multiple proteins associated with markers of hypercoagulability and with a potential to become novel diagnostic biomarkers for DVT., (© 2018 John Wiley & Sons Ltd.)

Recently, decreased levels of apolipoprotein M (ApoM) were shown to be associated with higher risk of recurrent venous thromboembolism (VTE) in male patients. However, the role of ApoM in primary VTE is unknown. We aimed in our study to analyze the plasma levels of ApoM in patients with VTE in order to evaluate the diagnostic importance of ApoM in primary VTE. A total of 357 patients with suspected first episode of VTE were recruited prospectively in the SCORE study. Plasma samples from 307 patients were available for quantifying the plasma levels of ApoM in patients with VTE using sandwich enzyme-linked immunosorbent assay method. Among the whole population, plasma levels (mean [standard deviation]) of ApoM were not significantly different between patients with VTE (0.72 [0.20]) and non-VTE patients (0.72 [0.16]), P = .99. Similarly, in regression analyses, no significant association of ApoM plasma levels with the risk of VTE was found on univariate (odds ratio [OR] =1.0, 95% confidence interval [CI] 0.21-4.84, P = .99) and multivariate analysis (OR = 1.25, 95% CI = 0.19-8.34, P = .819) after adjusting for age, body mass index, and smoking. Moreover, results did not differ significantly after stratification of data according to sex ( P > .05). In this study, our results do not suggest a diagnostic role for ApoM plasma levels in patients with primary VTE. Moreover, the current study suggests that role of ApoM as a risk factor may differ for primary VTE and recurrent VTE in male patients.

Multiple genetic variations have been identified in FTO (fat mass and obesity-associated) gene. Among them, FTO rs9939609 polymorphism is shown to be associated with the risk of primary venous thromboembolism (VTE). However, its role in recurrent VTE is not known. The aim of our study was to investigate the association between FTO rs9939609 polymorphism and the risk of VTE recurrence in a prospective follow-up study in both male and female patients. FTO rs9939609 polymorphism (T/A) was analyzed in the Malmö thrombophilia study (MATS, followed for ~10 years) by using TaqMan PCR. MATS patients (n = 1050) were followed from the discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of follow-up. A total of 126 patients (12%) had VTE recurrence during follow-up. Cox regression analyses showed that sex modified the potential effect of FTO rs9939609 polymorphism on VTE recurrence. Male patients with the AA genotype for the FTO rs9939609 polymorphism had significantly higher risk of VTE recurrence as compared to the TT or AT genotypes (univariate hazard ratio [HR] = 2.05, 95% confidence interval [CI] = 1.2-3.5, P = 0.009 and adjusted HR = 2.03, 95% CI 1.2-3.6, P = 0.013). There was no association between FTO rs9939609 polymorphism and VTE recurrence in female patients. In conclusion, our results show that FTO rs9939609 polymorphism in recurrent VTE may differ according to gender and FTO polymorphism may predict VTE recurrence in male patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: There are very few data in the current literature regarding the short- and long-term outcome of surgery for pediatric pancreatic tumors (PPT). No data are available on the impact of pancreatic surgery on the children's growth., Methods: This is a retrospective cohort study on a consecutive series of pediatric/adolescent patients who underwent pediatric surgery at Karolinska University Hospital from January 2005 to July 2017., Results: Overall 14 pancreatic operations were performed in 13 patients. The median age was 11.4 years (range 3-15). Six pancreaticoduodenectomies (42.8%), 5 distal pancreatectomies (35.7%), and 3 enucleations (21.5%) were performed. The final histology revealed a solid pseudopapillary tumor in 9 cases (69.2%), neuroblastoma in 1 (7.7%), ganglioneuroma in 1 (7.7%), pancreatoblastoma in 1 (7.7%), and insulinoma in 1 (7.7%). Overall, 3 patients developed post-operative complications (23%). There was no peri-operative mortality. All patients are alive after a median follow-up time of 80 months. Exocrine insufficiency was detected post-operatively in 4 patients (30.7%) Endocrine insufficiency requiring insulin treatment developed in one patient (7.7%). No significant impact on growth was detected in any of the patients after pancreatic resection., Conclusions: In our series, surgery performed for PPTs seems to be safe and effective. The effect of pancreatic surgery on children's growth does not seem to be significant., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Few prospective studies have examined the factor V paradox: factor V Leiden (FVL) is a stronger risk factor for deep venous thrombosis (DVT) than for pulmonary embolism (PE). The present study, to the best of our knowledge, is the first population-based study aimed to examine the relationship between FVL and incidence of venous thromboembolism (VTE), DVT and PE in a prospective cohort study of middle-aged Swedish individuals. FVL was determined in 4890 subjects (aged 46-68 years, 57% women) from the general population without previous VTE or cancer, who participated in the Malmö Diet and Cancer study between 1991 and 1994. Incident cases of VTE were identified from the Swedish patient register during a mean follow-up of 15.6 years. Of 4890 subjects with determination of FVL (10.2% carriers), 220 had VTE during follow-up (113 DVT, 78 PE, 29 both). Incidence of VTE was significantly higher in subjects with heterozygous and homozygous FVL: adjusted hazard ratios (HR) were 1.8 (95% CI 1.3-2.6, p=0.001) and 6.5 (2.1-21, p=0.001), respectively. The population attributable fraction was 8.7% for FVL. Adjusted HRs for DVT were 2.2 (1.4-3.3, p<0.001) for heterozygotes and 3.3 (0.5-24, p=0.233) for homozygotes. Adjusted HRs for PE were 1.2 (0.65-2.2, p=0.582) for heterozygotes and 8.7 (2.1-36, p=0.003) for homozygotes. The FVL paradox was confirmed for heterozygotes for FVL. However, homozygotes for FVL had a high risk for PE, suggesting that the FVL paradox is related to the carriership of one wild type and one mutated factor V allele.

Background: Genome-wide association studies are useful for discovering genotype-phenotype associations but are limited because they require large cohorts to identify a signal, which can be population-specific. Mapping genetic variation to genes improves power and allows the effects of both protein-coding variation as well as variation in expression to be combined into "gene level" effects., Methods: Previous work has shown that warfarin dose can be predicted using information from genetic variation that affects protein-coding regions. Here, we introduce a method that improves dose prediction by integrating tissue-specific gene expression. In particular, we use drug pathways and expression quantitative trait loci knowledge to impute gene expression-on the assumption that differential expression of key pathway genes may impact dose requirement. We focus on 116 genes from the pharmacokinetic and pharmacodynamic pathways of warfarin within training and validation sets comprising both European and African-descent individuals., Results: We build gene-tissue signatures associated with warfarin dose in a cohort-specific manner and identify a signature of 11 gene-tissue pairs that significantly augments the International Warfarin Pharmacogenetics Consortium dosage-prediction algorithm in both populations., Conclusions: Our results demonstrate that imputed expression can improve dose prediction and bridge population-specific compositions. MATLAB code is available at https://github.com/assafgo/warfarin-cohort.

Low-molecular-weight heparin (LMWH) is often recommended as a bridging therapy during temporary interruptions in warfarin treatment, despite lack of evidence. The aim of this study was to see whether we could find benefit from LMWH bridging. We studied all planned interruptions of warfarin within the Swedish anticoagulation register Auricula during 2006 to 2011. Low-molecular-weight heparin bridging was compared to nonbridging (control) after propensity score matching. Complications were identified in national clinical registers for 30 days following warfarin cessation, and defined as all-cause mortality, bleeding (intracranial, gastrointestinal, or other), or thrombosis (ischemic stroke or systemic embolism, venous thromboembolism, or myocardial infarction) that was fatal or required hospital care. Of the 14 556 identified warfarin interruptions, 12 659 with a known medical background had a mean age of 69 years, 61% were males, mean CHADS 2 (1 point for each of congestive heart failure, hypertension, age ≥75 years, diabetes, and 2 points for stroke or transient ischemic attack) score was 1.7, and CHA 2 DS 2 -VASc score was 3.4. The total number of LMWH bridgings was 7021. Major indications for anticoagulation were mechanical heart valve prostheses 4331, atrial fibrillation 1097, and venous thromboembolism 1331. Bridging patients had a higher rate of thrombotic events overall. Total risk of any complication did not differ significantly between bridging (1.5%) and nonbridging (1.2%). Regardless of indication for warfarin treatment, we found no benefit from bridging. The type of procedure prompting bridging was not known, and the likely reason for the observed higher risk of thrombosis with LMWH bridging is that low-risk procedures more often meant no bridging. Results from randomized trials are needed, especially for patients with mechanical heart valves.

Introduction: The impact of the increased anticoagulants uptake on incidence rate of ischemic stroke is largely unknown. We assessed time trends in rates of ischemic stroke in patients with incident atrial fibrillation (AF) diagnosed between 2011 and 2013., Materials and Methods: Population-based retrospective registry study of all 11,500 adults diagnosed with incident non-valvular atrial fibrillation in 2011-2013 in primary and secondary care and receiving oral anticoagulants (n=4847), aspirin (n=2850) or no treatment (n=3766) in Skåne County, Sweden. The primary outcome was the rate of ischemic stroke within 365days after AF diagnosis., Results and Conclusion: Cumulative incidence of ischemic stroke decreased from 2.87% (95% confidence interval (CI) 2.37-3.45%) to 1.93% (95% CI 1.54-2.41%) while the uptake of oral anticoagulants increased from 36.6% to 48.4% between 2011 and 2013 (regression coefficient -0.08; 95% CI, -0.09 to -0.07, p<0.001). The increased uptake of oral anticoagulants in the community is associated with decreased incidence of ischemic stroke in AF patients., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: For patients with atrial fibrillation, non-vitamin K oral anticoagulants, or NOACs (dabigatran, rivaroxaban, edoxaban, and apixaban) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, and in risk of haemorrhage. In the pivotal NOAC studies, quality of warfarin treatment was poor with mean time in therapeutic range (TTR) 55-65%, compared with ≥70% in Swedish clinical practice., Methods: We compared NOACs (as a group) to warfarin in non-valvular atrial fibrillation, studying all 12,694 patients starting NOAC treatment within the Swedish clinical register and dosing system Auricula, from July 1, 2011 to December 31, 2014, and matching them to 36,317 patients starting warfarin using propensity scoring. Endpoints were thromboembolic events and major bleedings that were fatal or required hospital care. Outcome data were collected from validated Swedish hospital administrative and clinical registers., Results: Mean age was 72.2 vs 72.3 years, proportion of males 58.2% vs 57.0%, and mean follow-up time 299 vs 283 days for NOACs and warfarin. Distribution of NOACs was: dabigatran 40.3%, rivaroxaban 31.2%, and apixaban 28.5%. Mean TTR was 70%. There were no significant differences in rates of thromboembolic/thrombotic events or gastrointestinal bleeding. NOAC treated patients had lower rates of major bleeding overall, hazard ratio 0.78 (95% confidence interval 0.67-0.92), intracranial bleeding 0.59 (0.40-0.87), haemorrhagic stroke 0.49 (0.28-0.86), and other major bleeding 0.71 (0.57-0.89)., Conclusion: For patients with atrial fibrillation, NOACs are as effective for stroke prevention as well-managed warfarin but cause fewer major bleedings.

Recent gene knockout studies on mice have shown the role of toll-like receptor 9 (TLR9) in resolution of venous thromboembolism (VTE) through sterile inflammation. However, the role of a putative functional TLR9 polymorphism (rs5743836) in risk assessment of VTE recurrence remains unknown. The aim of our study was to investigate the TLR9 rs5743836 polymorphism in VTE patients and its association with the risk of VTE recurrence. We analyzed TLR9 rs5743836 polymorphism in Malmö thrombophilia study patients; a prospective follow-up study of 1465 VTE patients by Taqman PCR. From a total of 1465 VTE patients, those who had VTE before inclusion and those who died or had VTE recurrence during anticoagulant treatment were excluded (n = 415). Cox regression analyses were performed on the remaining 1050 VTE patients, including 126 (12.5%) patients that had recurrent VTE during follow-up period. TLR9 polymorphism was significantly associated with higher risk of VTE recurrence in female patients (HR 3.46, 95% CI 1.06-11.33) independent of acquired risk factors for VTE, family history, risk of thrombophilia and deep vein thrombosis (DVT) location. Similarly, in unprovoked VTE patients, TLR9 polymorphism was significantly associated with higher risk of VTE recurrence in female patients (HR 5.94, 95% CI 1.25-28.13) after adjusting for family history, risk of thrombophilia and DVT location. No association between TLR9 polymorphism and risk of VTE recurrence was found in male patients. Our results suggest that TLR9 rs5743836 polymorphism is an independent risk factor for VTE recurrence in female patients but not in males.

Thrombomodulin (THBD) serves as a cofactor for thrombin-mediated activation of anticoagulant protein C pathway. Genetic aberrations in THBD have been studied in arterial and venous thrombosis. However, genetic changes in THBD and their role in the risk assessment of recurrent venous thromboembolism (VTE) are not well understood. The aim of the present study was to identify the genetic aberrations in THBD and their association with the risk of VTE recurrence in a prospective population-based study. We sequenced the entire THBD gene, first in selected patients with VTE (n = 95) by Sanger sequencing and later validated those polymorphisms with minor allele frequency (MAF) ≥5% in the whole study population (n = 1465 with the follow-up period of 1998-2008) by Taqman polymerase chain reaction. In total, we identified 8 polymorphisms in THBD, and 3 polymorphisms with MAF ≥5% were further validated. No significant association between THBD polymorphisms and risk of VTE recurrence on univariate or multivariate Cox regression analysis was found (hazard ratio [HR] = 0.89, 95% confidence interval [CI] = 0.62-1.28, HR = 1.27, 95% CI = 0.88-1.85, and HR = 1.15, 95% CI = 0.80-1.66 for THBD rs1962, rs1042580, and rs3176123 polymorphisms, respectively), adjusted for family history, acquired risk factors for VTE, location of deep vein thrombosis, and risk of thrombophilia. Subanalysis of patients with unprovoked first VTE also showed no significant association of identified THBD polymorphisms with the risk of VTE recurrence. Our results show that aberrations in the THBD gene may not be useful for the assessment of VTE recurrence; however, further studies with large sample size are needed to confirm these findings.

Objectives: To study the impact of time in therapeutic range (TTR) and international normalised ratio (INR) variability on the risk of thromboembolic events, major bleeding complications and death after mechanical heart valve (MHV) implantation. Additionally, the importance of different target INR levels was elucidated., Methods: A retrospective, non-randomised multicentre cohort study including all patients with mechanical heart valve (MVH) prosthesis registered in the Swedish National Quality Registry Auricula from 2006 to 2011. Data were merged with the Swedish National Patient Registry, SWEDEHEART and Cause of Death Registry., Results: In total 4687 ordination periods, corresponding to 18 022 patient-years on warfarin, were included. High INR variability (above mean ≥0.40) or lower TTR (≤70%) was associated with a higher risk of bleeding (rate per 100 years 4.33 (95% CI 3.87 to 4.82) vs 2.08 (1.78 to 2.41); HR 2.15 (1.75 to 2.61) and 5.13 (4.51 to 5.82) vs 2.30 (2.03 to 2.60); HR 2.43 (2.02 to 2.89)), respectively. High variability and low TTR combined was associated with an even higher risk of bleedings (rate per 100 years 4.12 (95% CI 3.68 to 4.51) vs 2.02 (1.71 to 2.30); HR 2.16 (1.71 to 2.58) and 4.99 (4.38 to 5.52) vs 2.36 (2.06 to 2.60); HR 2.38 (2.05 to 2.85)) compared with the best group.Higher treatment intensity (mean INR 2.8-3.2 vs 2.2-2.7) was associated with higher rate of bleedings (2.92 (2.39 to 3.47) vs 2.48 (2.21 to 2.77); HR 1.29 (1.06 to 1.58)), death (3.36 (2.79 to 4.02) vs 1.89 (1.64 to 2.17), HR 1.65 (1.31 to 2.06)) and complications in total (6.61 (5.74 to 7.46) vs 5.65 (5.20 to 6.06); HR 1.24 (1.06 to 1.41)) after adjustment for MHV position, age and comorbidity., Conclusions: A high warfarin treatment quality improves outcome after MHV implantation, both measured with TTR and INR variability. No benefit was found with higher treatment intensity (mean INR 2.8-3.2 vs 2.2-2.7)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)