Development and implementation of common data elements for venous thromboembolism research: on behalf of SSC Subcommittee on official Communication from the SSC of the ISTH.

Clinical research in venous thromboembolism (VTE) is hindered by variability in the collection and reporting of data and outcomes. A consistent data language facilitates efficiencies, leads to higher quality data, and permits between-study comparisons and evidence synthesis. The International Society on Thrombosis and Haemostasis (ISTH) launched an international task force of more than 50 researchers to develop common data elements for clinical research in venous thromboembolism. The project was organized in seven working groups, each focusing on a topic area: General Core Data Elements; Anticoagulation and Other Therapies; Chronic VTE and Functional Outcomes; Diagnosis of VTE; Malignancy; Perioperative; and Predictors of VTE. The groups met via teleconference to collaboratively identify key data elements and develop definitions and data standards that were structured in a project-specific taxonomy. A Steering Committee met by teleconference and in-person to determine the overall scope of the project and resolve questions arising from the working groups. ISTH held an open public comment period to enable broader stakeholder involvement and feedback. The common data elements were then refined by the working groups to create a set of 512 unique data elements that are publicly available at http://isth.breakthrough.healthcare. The ISTH VTE Common Data Elements are intended to be a living project with ongoing curation, future expansion, and adaptation to meet the needs of the thrombosis and hemostasis research community.

A toolkit for the collection of thrombosis-related data elements in COVID-19 clinical studies.

Thrombosis has emerged as an important complication of coronavirus disease 2019 (COVID-19), particularly among individuals with severe illness. However, the precise incidence of thrombotic events remains uncertain due to differences in study design, patient populations, outcome ascertainment, event definitions, and reporting. In an effort to overcome some of these challenges and promote standardized data collection and reporting in clinical studies, the American Society of Hematology Research Collaborative COVID-19 Non-Malignant Hematology Task Force, in collaboration with the International Society on Thrombosis and Haemostasis COVID-19 Task Force, developed sets of data elements in the following domains: venous thromboembolism, myocardial infarction, stroke/transient ischemic attack, peripheral arterial thrombosis, bleeding, laboratory investigations, and antithrombotic therapy. Data elements in each of these domains were developed with 3 levels of detail to facilitate their incorporation into studies evaluating a range of interventions and outcomes. Previously published data elements were included where possible. The use of standardized variables in a range of clinical studies can enhance the quality of data collection, create efficiency, enhance comparison of results across studies, and facilitate future pooling of data sets.

"HERDOO2" clinical decision rule to guide duration of anticoagulation in women with unprovoked venous thromboembolism. Can I use any d-Dimer?

BACKGROUND: The "HERDOO2 rule" is a prospectively validated clinical decision rule used to identify low-risk women who can safely discontinue anticoagulants after completing 5-12 months of anticoagulant treatment for unprovoked venous thromboembolism. The VIDAS®d-Dimer (DD) assay, a component of the rule, was used in the derivation and validation of the rule at half the usual diagnostic cut-point for exclusion of venous thrombosis. It is unknown if other commercial DD assays used at a corresponding cut-point will categorize patients at high concordance with the VIDAS® DD. OBJECTIVE: To determine if other available automated quantitative DD assays have high enough concordance with the VIDAS® DD assay to allow their use within the "HERDOO2" clinical decision rule. METHODS: Frozen plasma samples from a sub-set (n = 248) of female participants in the "HERDOO2" validation study were tested using five DD assays: VIDAS®, Innovance®, HemosIL®, Tina-quant® and Liatest®, with duplicate testing for 50 samples. First, using the mean DD for 50 samples with duplicate results, we determined the optimal cut-point values for each test that corresponded with a VIDAS® DD result of 250 µg/L using linear regression analysis. Next, kappa analysis was conducted on the DD results of the remaining 198 samples to determine concordance between each tested DD at the respective optimal cut-point and the VIDAS® DD at 250 µg/L. In a separate analysis we determined the concordance at half the usual venous thrombosis exclusion cut-point. RESULTS: Regression analysis of the DD results in 50 samples identified the optimal cut-point for each DD assay to match a VIDAS® DD cut-point of 250 µg/L: Innovance® 177 µg/L, Liatest® 233 µg/L, Tina-quant® 48 µg/L and HemosIL® 56 µg/L. Next, in 198 different samples, the concordance of VIDAS® DD (≥250 µg/L or <250 µg/L) was explored at the optimal cut-point of the other DD assays. The concordance was poor for all DD assays: Innovance® (kappa 0.38 (95% CI, 0.26-0.51)), Liatest® (kappa 0.38 (95% CI, 0.25-0.50)), HemosIL® (kappa 0.36 (95% CI, 0.23-0.49)) and Tina-quant® (kappa 0.30 (95% CI, 0.16-0.43)). Similar poor concordance was identified using half of the diagnostic DD cut-point for each tested assay: Innovance® (kappa 0.44 (95% CI, 0.32-0.56)), Liatest® (kappa 0.38 (95% CI, 0.25-0.51)), HemosIL® (kappa 0.04 (95% CI, -0.01-0.08)) and Tina-quant® (kappa 0.04 (95% CI, -0.004-0.07)). CONCLUSION: The "HERDOO2 rule" is the only prospectively validated clinical decision rule that can be used to identify low-risk women with unprovoked venous thrombosis who can safely discontinue anticoagulants. An important implementation issue is whether any commercial DD assay can be used in the HERDOO2 rule, and at what cut-point. Our analysis shows that the HemosIL®, Innovance®, Liatest® and Tina-quant® DD assays should not be used in the "HERDOO2" rule due to poor concordance with the VIDAS® DD assay and unacceptable misclassification of women at high and low risk of recurrent venous thrombosis.

Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials.

BACKGROUND: Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal, fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-molecular-weight heparin, we did an individual patient data meta-analysis. METHODS: We did a systematic review in May, 2013, which identified eight eligible randomised trials done between 2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of participants, intervention stopped too early, and no response from the principal investigator. We requested individual patient data from the study authors for eligible women (women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks' gestation, or two losses after 12 weeks' gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss (≥20 weeks' gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249. FINDINGS: We analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference -8%, 95% CI -17·3 to 1·4, p=0·09; relative risk 0·64, 95% CI 0·36-1·11, p=0·11). We noted significant heterogeneity between single-centre and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary outcome in women with previous abruption (p=0·006) but not in any of the other subgroups of previous complications. INTERPRETATION: Low-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the power of our study to explore. FUNDING: Canadian Institutes of Health Research.

Low-molecular-weight heparin for prevention of placenta-mediated pregnancy complications: protocol for a systematic review and individual patient data meta-analysis (AFFIRM).

BACKGROUND: Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and the small-for-gestational age newborn. They are leading causes of maternal, fetal, and neonatal morbidity and mortality in developed nations. Women who have experienced these complications are at an elevated risk of recurrence in subsequent pregnancies. However, despite decades of research no effective strategies to prevent recurrence have been identified, until recently. We completed a pooled summary-based meta-analysis that strongly suggests that low-molecular-weight heparin reduces the risk of recurrent placenta-mediated complications. The proposed individual patient data meta-analysis builds on this successful collaboration. The project is called AFFIRM, An individual patient data meta-analysis oF low-molecular-weight heparin For prevention of placenta-medIated pRegnancy coMplications. METHODS/DESIGN: We conducted a systematic review to identify randomized controlled trials with a low-molecular-weight heparin intervention for the prevention of recurrent placenta-mediated pregnancy complications. Investigators and statisticians representing eight trials met to discuss the outcomes and analysis plan for an individual patient data meta-analysis. An additional trial has since been added for a total of nine eligible trials. The primary analyses from the original trials will be replicated for quality assurance prior to recoding the data from each trial and combining it into a common dataset for analysis. Using the anonymized combined data we will conduct logistic regression and subgroup analyses aimed at identifying which women with previous pregnancy complications benefit most from treatment with low-molecular-weight heparin during pregnancy. DISCUSSION: The goal of the proposed individual patient data meta-analysis is a thorough estimation of treatment effects in patients with prior individual placenta-mediated pregnancy complications and exploration of which complications are specifically prevented by low-molecular-weight heparin. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (International Prospective Registry of Systematic Reviews) 23 December 2013, CRD42013006249.

Psychological impact of thrombophilia testing in asymptomatic family members.

INTRODUCTION: Psychological distress and worry are commonly described as potential consequences of genetic screening for various disorders. Thrombophilia testing may be offered to asymptomatic persons with a family history of venous thrombosis and thrombophilia. Our objectives were to measure the psychological impacts of thrombophilia testing in first degree relatives and to determine if our intervention, a more intensive care strategy to heighten awareness of both risk and symptoms of thrombosis, caused psychological distress. MATERIALS & METHODS: First degree relatives of patients with a known thrombophilia and history of venous thrombosis were tested for thrombophilia. The Perceived Risk Questionnaire and validated psychological instruments (POMS-SF; SCL-90-R Somatization subscale) were administered before testing, one week after receiving results and a year later. Thrombophilia carriers were randomized in family clusters to receive Standard Care or the Intensive Care intervention. RESULTS: There were 100 carriers who were randomized to Standard (n=48) or Intensive Care (n=52) and 103 non-carriers. One week after receiving results, we did not observe any difference in psychological distress between carriers and non-carriers, with low levels overall. At 1 year, psychological distress scores were similar between the Standard and Intensive Care arms and did not differ from baseline. CONCLUSIONS: The results of this pilot study do not support the concern that thrombophilia screening in asymptomatic relatives triggers psychological distress and worry. Furthermore, our intensive educational approach did not appear to induce undue distress. While the positive benefits of thrombophilia screening remain unproven, clinicians should not be deterred from offering screening by the fear of causing psychological harm.

A pilot study to assess the feasibility of a multicenter cluster randomized trial for the management of asymptomatic persons with a thrombophilia.

There is controversy whether asymptomatic first-degree relatives (FDRs) of patients with venous thromboembolism (VTE) and thrombophilia should be screened, followed, and prescribed prophylaxis during risk periods. We recruited consecutive probands with idiopathic VTE and thrombophilia from our thrombosis clinics. Those FDRs with thrombophilia were randomized in family clusters to receive one-time verbal counseling and no organized follow-up or counseling, educational material, reminder aids and follow-up. Only 203 of 1,129 FDRs were eligible and consented. Dropouts were common; 1 FDR (1.7%) developed VTE. VTE risk, ability to treat and prevent were underestimated by the participants. Patients with VTE and thrombophilia and their FDRs are often not interested in thrombophilia testing. Despite education to inform their knowledge, interest and follow-up were less than ideal. The question of the best educational approach in these patients remains unanswered. The value of testing and following asymptomatic carriers of probands with VTE and thrombophilia remains unknown.

Elevated factor VIII is a risk factor for idiopathic venous thromboembolism in Canada - is it necessary to define a new upper reference range for factor VIII?

Previous studies suggest elevated factor VIII is a common, independent risk factor for venous thromboembolism (VTE); however, these studies included secondary and idiopathic VTE. We sought to explore the association between elevated factor VIII and VTE in Canadian patients with idiopathic thrombosis, and confirm the current upper factor VIII reference range was appropriate. We enrolled 300 consecutive patients with idiopathic VTE who were matched to friend controls by age, sex and ethnicity. Factor VIII levels were measured and compared between cases and controls. The optimal cut-off value to designate factor VIII levels as elevated was determined using a variety of methods. The optimal upper cut-off value for factor VIII levels was 270 IU/dl. In the logistic regression analysis, cases were more likely to have elevated factor VIII levels (OR:8.76), as were females (OR:1.93) and older subjects (OR: 1.05). Factor VIII cutoffs for a 95% specificity by age were 238 IU/dl for subjects <40 years, 248 IU/dl age 40-55 years, 261 IU/dl age 56-70 years, and 313 IU/dl age >70. Our findings confirm that elevated factor VIII is associated with an increased risk of idiopathic VTE. In our patients and matched controls, the current upper limit of normal (150 IU/dl) for factor VIII is not of clinical use. We propose that the upper limit be increased to 270 IU/dl or individual labs should establish their upper limit if they wish their assays to be discriminatory in patients with VTE. Age specific cut-offs may be clinically relevant.

The ACE D/D genotype is protective against the development of idiopathic deep vein thrombosis and pulmonary embolism.

The deletion/deletion (D/D) genotype of the angiotensin converting enzyme (ACE) has been purported to be a risk for post-operative thrombosis.This D/D genotype has not been evaluated as a risk factor for idiopathic venous thromboembolism (VTE). The primary objective of the present study was to determine whether the D/D genotype of ACE is independently associated with the occurrence of idiopathic venous thromboembolic disease. We prospectively enrolled consecutive patients with at least one objectively confirmed idiopathic VTE. Friends of cases were recruited as controls and matched to cases by sex, ethnicity, and age. Patients were tested for the ACE I/D polymorphism in addition to factor V Leiden, prothrombin G20210A, and factor VIII levels. Three hundred cases and 300 controls were enrolled; 97% were Caucasian. There were 148 females and 152 males in each group with a mean age of 56.21 years (SD = 15.33). The ACE D/D genotype was present in 25.3% of cases and 32.4% of controls for an adjusted odds ratio of 0.66 (95% CI = 0.433 to 0.997). We can conclude that the ACE D/D genotype is protective against idiopathic venous thromboembolism.

Risk of venous thromboembolism in relatives of symptomatic probands with thrombophilia: a systematic review.

Clinical equipoise exists regarding whether relatives of individuals with venous thromboembolism (VTE) and thrombophilia should be screened for thrombophilia. There have been no systematic attempts to summarize studies that have assessed the incidence of VTE in relatives. The purpose of this review was to systematically identify and review observational studies with thrombophilic relatives and to summarize their findings with respect to their risk of VTE. We conducted a systematic literature review and included nine observational studies meeting a priori inclusion criteria. Potentially eligible studies evaluated VTE incidence in relatives of index patients (probands) with symptomatic thrombophilia. In the four prospective studies, the incidence of VTE for asymptomatic family members with factor V Leiden ranged from 0.58-0.67% per year, 1.0-2.5% for protein C deficiency, 0.7-2.2% for protein S deficiency, and 4% for antithrombin deficiency. About half of all VTEs occurred during well-known risk periods but incidence rates were decreased by use of prophylaxis. No deaths from pulmonary embolism or fatal hemorrhages from anticoagulants were reported. The incidence of VTE was generally lower in the retrospective studies. The pooled relative risk from four retrospective studies for factor V Leiden carriers was 3.69 (CI 2.27, 6.00) and from two studies the pooled relative risk for deficiencies of protein C, protein S, and antithrombin was 10.58 (CI 5.38, 20.81). In conclusion, the risk of VTE events in asymptomatic relatives is low, but this may be an underestimate. Anticoagulant prophylaxis during risk periods appears to be of benefit but further research in this area is required.