Coagulation and platelet biology at the intersection of health and disease: illustrated capsules of the 11th Symposium on Hemostasis at the University of North Carolina.

The University of North Carolina Symposia on Hemostasis began in 2002, with The First Symposium on Hemostasis with a Special Focus on FVIIa and Tissue Factor. They have occurred biannually since and have maintained the primary goal of establishing a forum for the sharing of outstanding advances made in the basic sciences of hemostasis. The 2024 11th Symposium on Hemostasis will bring together leading scientists from around the globe to present and discuss the latest research related to coagulation factors and platelet biology. In keeping with the tradition of the conference, we expect novel cross-disciplinary collaborations to result from bringing together fundamental scientists and physician-scientists from different backgrounds and perspectives. The aim of these collaborations is to springboard the next generation of important advances in the field. This year's program was designed to discuss Coagulation and Platelet Biology at the Intersection of Health and Disease. The goal is to develop a better understanding of the pathophysiologic mechanisms leading to hemostatic and thrombotic disorders as this understanding is critical for the continued development of safe and efficacious therapeutics. Included in this review article are illustrated capsules provided by our speakers that highlight the main conclusions of the invited talks.

Agreement of aptamer proteomics with standard methods for measuring venous thrombosis biomarkers.

BACKGROUND: Venous thromboembolism (VTE) is a complex disease with an incidence rate of about 1 in 1000 per year. Despite the availability of validated biomarkers for VTE, unprovoked events account for 50% of first events. Therefore, emerging high-throughput proteomics are promising methods for the expansion of VTE biomarkers. One such promising high-throughput platform is SomaScan, which uses a large library of synthetic oligonucleotide ligands known as aptamers to measure thousands of proteins. OBJECTIVE: The aim of this study was to evaluate the viability of the aptamer-based SomaScan platform for VTE studies by examining its agreement with standard laboratory methods. METHODS: We examined the agreement between eight established VTE biomarkers measured by SomaScan and standard laboratory immunoassay and viscosity-based instruments in 54 individuals (27 cases and 27 controls) from the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism study. We performed the agreement analysis by using a regression model and predicting the estimates and the 95% prediction interval (PI) of the laboratory instrument values using SomaScan values. RESULTS: SomaScan measurements exhibited overall poor agreement, particularly for D-dimer (average fit, 492.7 ng/mL; 95% PI, 110.0-1998.2) and fibrinogen (average fit, 3.3 g/L; 95% PI, 2.0-4.7). CONCLUSION: Our results indicate that SomaScan measurement had poor agreement with the standard laboratory measurements. These results may explain why some genome-wide association studies with VTE proteins measured by SomaScan did not confirm previously identified loci. Therefore, SomaScan should be considered with caution in VTE studies.

Venous Thrombosis Risk after Arthroscopy of the Knee: Derivation and Validation of the L-TRiP(ascopy) Score.

Patients at high risk for venous thrombosis (VT) following knee arthroscopy could potentially benefit from thromboprophylaxis. We explored the predictive values of environmental, genetic risk factors and levels of coagulation markers to integrate these into a prediction model. Using a population-based case-control study into the aetiology of VT, we developed a Complete (all variables), Screening (easy to use in clinical practice) and Clinical (only environmental risk factors) model. The Clinical model was transformed into the Leiden-Thrombosis Risk Prediction (arthroscopy) score [L-TRiP(ascopy) score]. Model validation was performed both internally and externally in another case-control study. A total of 4,943 cases and 6,294 controls were maintained in the analyses, 107 cases and 26 controls had undergone knee arthroscopy. Twelve predictor variables (8 environmental, 3 haemorheological and 1 genetic) were selected from 52 candidates and incorporated into the Complete model (area under the curve [AUC] of 0.81, 95% confidence interval [CI], 0.76-0.86). The Screening model (9 predictors: environmental factors plus factor VIII activity) reached an AUC of 0.76 (95% CI, 0.64-0.88) and the Clinical (and corresponding L-TRiP(ascopy)) model an AUC of 0.72 (95% CI, 0.60-0.83). In the internal and external validation, the Complete model reached an AUC of 0.78 (95% CI, 0.52-0.98) and 0.75 (95% CI, 0.42-1.00), respectively, while the other models performed slightly less well.

Antiphospholipid antibodies and recurrent thrombosis after a first unprovoked venous thromboembolism.

It is uncertain whether antiphospholipid antibodies (APAs) increase the risk of recurrence after a first unprovoked venous thromboembolism (VTE). We tested for anticardiolipin antibodies, anti-ß2 glycoprotein 1 antibodies, and lupus anticoagulant on 2 occasions ∼6 months apart in 307 patients with a first unprovoked VTE who were part of a prospective cohort study. We then determined if APAs were associated with recurrent thrombosis in the 290 patients who stopped anticoagulant therapy in response to negative D-dimer results. Compared with those without an APA, the hazard ratios for recurrent VTE were 1.8 (95% confidence interval [CI], 0.9-3.7; P = .09) in the 25.9% of patients with an APA on ≥1 occasions, 2.7 (95% CI, 1.1-.7; P = .03) in the 9.0% of patients with the same APA on 2 occasions, and 4.5 (95% CI, 1.5-13.0; P = .006) in the 3.8% of patients with 2 or 3 different APA types on either the same or different occasions. There was no association between having an APA and D-dimer levels. We conclude that having the same type of APA on 2 occasions or having >1 type of APA on the same or different occasions is associated with recurrent thrombosis in patients with a first unprovoked VTE who stop anticoagulant therapy in response to negative D-dimer tests. APA and D-dimer levels seem to be independent predictors of recurrence in patients with an unprovoked VTE. This trial was registered at www.clinicaltrials.gov as #NCT00720915.

Novel targets for anticoagulants lacking bleeding risk.

PURPOSE OF REVIEW: Arterial and venous thromboembolic diseases are associated with significant morbidity and mortality and present a major medical burden. Currently used anticoagulants for the prevention or treatment of thromboembolic events including heparins, vitamin K-antagonists and inhibitors of thrombin or factor Xa target enzymes of the coagulation cascade that are critical for fibrin formation. However, fibrin is also necessary for hemostatic mechanisms to terminate blood loss at injury sites. As a result currently used anticoagulants substantially raise the risk of bleeding and are associated with an increase in potentially life-threatening hemorrhage, partially offsetting the benefits of reduced thrombosis. RECENT FINDINGS: Within the last decade, experimental and preclinical data have revealed the existence of coagulation mechanisms that principally differ in thrombosis and haemostasis. Some coagulation proteins including, XI and XII have a differential role in haemostasis and thrombosis. Targeting these proteins may provide an opportunity to prevent thromboembolic disease without causing bleeding. SUMMARY: This review summarizes recent studies on selective targeting of coagulation proteins that may allow prevention and treatment of thrombosis without causing bleeding. These novel approaches present a possibility for selective interference with fibrin formation in pathologic thrombosis that may lead to a new generation of safe anticoagulant drugs.

Targeting activated protein C to treat hemophilia.

PURPOSE OF REVIEW: Hemophilia is a debilitating disease, marked by frequent, painful bleeding events, joint deterioration and early death. All current treatments consist of i.v. infusions of replacement factor or other procoagulant factors, and are incompletely effective, due in part to the short half-lives of the proteins. An alternative approach is to rebalance hemostasis by inhibiting natural anticoagulant mechanisms. In this article, we explain why activated protein C (APC) is an appropriate and safe target for the treatment of hemophilia. RECENT FINDINGS: A serpin (serine protease inhibitor) was engineered to specifically inhibit APC and was found to rescue hemostasis in a hemophilia mouse model, even after a severe tail clip injury. However, APC is also anti-inflammatory and has cytoprotective activities, raising safety concerns over the use of an APC inhibitor to treat hemophilia. We summarize the molecular basis of the anticoagulant and signaling activities of APC to assess the potential impact of targeting APC. SUMMARY: We conclude that the signaling and anticoagulant functions of APC are in spatially and kinetically distinct compartments, and that it is possible to specifically inhibit the anticoagulant activity of APC. Targeting APC with a serpin is remarkably effective and may be safe for long-term prophylactic use in the treatment of hemophilia.

Design and characterization of an APC-specific serpin for the treatment of hemophilia.

Hemophilia is a bleeding disorder caused by deficiency in factors VIII or IX, the two components of the intrinsic Xase complex. Treatment with replacement factor can lead to the development of inhibitory antibodies, requiring the use of bypassing agents such as factor VIIa and factor concentrates. An alternative approach to bypass the Xase complex is to inhibit endogenous anticoagulant activities. Activated protein C (APC) breaks down the complex that produces thrombin by proteolytically inactivating factor Va. Defects in this mechanism (eg, factor V Leiden) are associated with thrombosis but result in less severe bleeding when co-inherited with hemophilia. Selective inhibition of APC might therefore be effective for the treatment of hemophilia. The endogenous inhibitors of APC are members of the serpin family: protein C inhibitor (PCI) and α1-antitrypsin (α1AT); however, both exhibit poor reactivity and selectivity for APC. We mutated residues in and around the scissile P1-P1' bond in PCI and α1AT, resulting in serpins with the desired specificity profile. The lead candidate was shown to promote thrombin generation in vitro and to restore fibrin and platelet deposition in an intravital laser injury model in hemophilia B mice. The power of targeting APC was further demonstrated by the complete normalization of bleeding after a severe tail clip injury in these mice. These results demonstrate that the protein C anticoagulant system can be successfully targeted by engineered serpins and that administration of such agents is effective at restoring hemostasis in vivo.

Differences in microbial metabolites in urine headspace of subjects with Immune Thrombocytopenia (ITP) detected by volatile organic compound (VOC) analysis and metabolomics.

ITP is an organ-specific autoimmune disorder characterised by a low platelet count whose cause is uncertain. A possible factor is food intolerance, although much of the information linking this with ITP is anecdotal. The role of food intolerance in ITP was studied by replacing a normal diet with an elemental diet (E028), but this did not increase platelet counts. Clear differences, however, were apparent between the volatile organic compounds (VOCs) in the urine headspace of patients with ITP and those present in healthy volunteers, which leads to speculation that abnormal metabolic activity of the intestinal microbiome may be a factor causing ITP. However, further work is needed to confirm this. There were also differences between the VOCs of patients on a normal diet and those on the elemental diet, and in this case, the VOCs involved are very likely to be of bacterial origin, as their production is affected by dietary manipulation. Many of these VOCs are known to be toxic.

Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines.

The risk of endoscopy in patients on antithrombotics depends on the risks of procedural haemorrhage vs. thrombosis due to discontinuation of therapy. P2Y12 receptor antagonists (clopidogrel, prasugrel, ticagrelor): For low-risk endoscopic procedures we recommend continuing P2Y12 receptor antagonists as single or dual antiplatelet therapy (low quality evidence, strong recommendation);For high-risk endoscopic procedures in patients at low thrombotic risk, we recommend discontinuing P2Y12 receptor antagonists five days before the procedure (moderate quality evidence, strong recommendation). In patients on dual antiplatelet therapy, we suggest continuing aspirin (low quality evidence, weak recommendation).For high-risk endoscopic procedures in patients at high thrombotic risk, we recommend continuing aspirin and liaising with a cardiologist about the risk/benefit of discontinuation of P2Y12 receptor antagonists (high quality evidence, strong recommendation). Warfarin: The advice for warfarin is fundamentally unchanged from BSG 2008 guidance. Direct Oral Anticoagulants (DOAC): For low-risk endoscopic procedures we suggest omitting the morning dose of DOAC on the day of the procedure (very low quality evidence, weak recommendation). For high-risk endoscopic procedures, we recommend that the last dose of DOAC be taken ≥ 48 hours before the procedure (very low quality evidence, strong recommendation). For patients on dabigatran with CrCl (or estimated glomerular filtration rate, eGFR) of 30 - 50 mL/min we recommend that the last dose of DOAC be taken 72 hours before the procedure (very low quality evidence, strong recommendation). In any patient with rapidly deteriorating renal function a haematologist should be consulted (low quality evidence, strong recommendation).

Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines.

The risk of endoscopy in patients on antithrombotics depends on the risks of procedural haemorrhage versus thrombosis due to discontinuation of therapy. P2Y12 RECEPTOR ANTAGONISTS CLOPIDOGREL, PRASUGREL, TICAGRELOR: For low-risk endoscopic procedures we recommend continuing P2Y12 receptor antagonists as single or dual antiplatelet therapy (low quality evidence, strong recommendation); For high-risk endoscopic procedures in patients at low thrombotic risk, we recommend discontinuing P2Y12 receptor antagonists five days before the procedure (moderate quality evidence, strong recommendation). In patients on dual antiplatelet therapy, we suggest continuing aspirin (low quality evidence, weak recommendation). For high-risk endoscopic procedures in patients at high thrombotic risk, we recommend continuing aspirin and liaising with a cardiologist about the risk/benefit of discontinuation of P2Y12 receptor antagonists (high quality evidence, strong recommendation). WARFARIN: The advice for warfarin is fundamentally unchanged from British Society of Gastroenterology (BSG) 2008 guidance. DIRECT ORAL ANTICOAGULANTS DOAC: For low-risk endoscopic procedures we suggest omitting the morning dose of DOAC on the day of the procedure (very low quality evidence, weak recommendation); For high-risk endoscopic procedures, we recommend that the last dose of DOAC be taken ≥48 h before the procedure (very low quality evidence, strong recommendation). For patients on dabigatran with CrCl (or estimated glomerular filtration rate, eGFR) of 30-50 mL/min we recommend that the last dose of DOAC be taken 72 h before the procedure (very low quality evidence, strong recommendation). In any patient with rapidly deteriorating renal function a haematologist should be consulted (low quality evidence, strong recommendation).

Prolonged clot lysis time increases the risk of a first but not recurrent venous thrombosis.

The role of the fibrinolytic system in the development of venous thrombosis (VT) is unclear. We studied the risk of first and recurrent VT associated with reduced fibrinolysis, as measured by clot lysis time (CLT). We also studied the relationship between CLT and thrombin generation to determine if any relationship between CLT and VT was affected by thrombin generation. Analyses were performed in the Thrombophilia Hypercoagulability Environmental risk for Venous Thromboembolism Study, a two-centre population-based case-control study, including 579 patients and 338 controls, with patients followed from the event to determine incidence of recurrent VT. Hypofibrinolysis was associated with a 1·8-fold increased risk of a first VT [95% confidence interval (CI) 1·2-2·7]. Adjustment for sex, age, study location and Endogenous Thrombin Potential (ETP) did not change the result. The risk of VT was 2·9-fold increased when the 90th percentiles of prolonged CLT and high ETP were combined, with the highest risk for unprovoked first events (Odds Ratio = 4·2, 95% CI 1·3-13·5). In the follow-up study the Hazard Ratio for a recurrent VT associated with hypofibrinolysis was 1·5 (95% CI 0·9-2·6). A weak dose response effect was observed in relation to prolongation of CLT and recurrent VT. Although hypofibrinolysis constitutes a risk factor for a first VT, an association with recurrence is, at best, weak.

Venous Thrombosis Risk after Cast Immobilization of the Lower Extremity: Derivation and Validation of a Clinical Prediction Score, L-TRiP(cast), in Three Population-Based Case-Control Studies.

BACKGROUND: Guidelines and clinical practice vary considerably with respect to thrombosis prophylaxis during plaster cast immobilization of the lower extremity. Identifying patients at high risk for the development of venous thromboembolism (VTE) would provide a basis for considering individual thromboprophylaxis use and planning treatment studies. The aims of this study were (1) to investigate the predictive value of genetic and environmental risk factors, levels of coagulation factors, and other biomarkers for the occurrence of VTE after cast immobilization of the lower extremity and (2) to develop a clinical prediction tool for the prediction of VTE in plaster cast patients. METHODS AND FINDINGS: We used data from a large population-based case-control study (MEGA study, 4,446 cases with VTE, 6,118 controls without) designed to identify risk factors for a first VTE. Cases were recruited from six anticoagulation clinics in the Netherlands between 1999 and 2004; controls were their partners or individuals identified via random digit dialing. Identification of predictor variables to be included in the model was based on reported associations in the literature or on a relative risk (odds ratio) > 1.2 and p ≤ 0.25 in the univariate analysis of all participants. Using multivariate logistic regression, a full prediction model was created. In addition to the full model (all variables), a restricted model (minimum number of predictors with a maximum predictive value) and a clinical model (environmental risk factors only, no blood draw or assays required) were created. To determine the discriminatory power in patients with cast immobilization (n = 230), the area under the curve (AUC) was calculated by means of a receiver operating characteristic. Validation was performed in two other case-control studies of the etiology of VTE: (1) the THE-VTE study, a two-center, population-based case-control study (conducted in Leiden, the Netherlands, and Cambridge, United Kingdom) with 784 cases and 523 controls included between March 2003 and December 2008 and (2) the Milan study, a population-based case-control study with 2,117 cases and 2,088 controls selected between December 1993 and December 2010 at the Thrombosis Center, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy. The full model consisted of 32 predictors, including three genetic factors and six biomarkers. For this model, an AUC of 0.85 (95% CI 0.77-0.92) was found in individuals with plaster cast immobilization of the lower extremity. The AUC for the restricted model (containing 11 predictors, including two genetic factors and one biomarker) was 0.84 (95% CI 0.77-0.92). The clinical model (consisting of 14 environmental predictors) resulted in an AUC of 0.77 (95% CI 0.66-0.87). The clinical model was converted into a risk score, the L-TRiP(cast) score (Leiden-Thrombosis Risk Prediction for patients with cast immobilization score), which showed an AUC of 0.76 (95% CI 0.66-0.86). Validation in the THE-VTE study data resulted in an AUC of 0.77 (95% CI 0.58-0.96) for the L-TRiP(cast) score. Validation in the Milan study resulted in an AUC of 0.93 (95% CI 0.86-1.00) for the full model, an AUC of 0.92 (95% CI 0.76-0.87) for the restricted model, and an AUC of 0.96 (95% CI 0.92-0.99) for the clinical model. The L-TRiP(cast) score resulted in an AUC of 0.95 (95% CI 0.91-0.99). Major limitations of this study were that information on thromboprophylaxis was not available for patients who had plaster cast immobilization of the lower extremity and that blood was drawn 3 mo after the thrombotic event. CONCLUSIONS: These results show that information on environmental risk factors, coagulation factors, and genetic determinants in patients with plaster casts leads to high accuracy in the prediction of VTE risk. In daily practice, the clinical model may be the preferred model as its factors are most easy to determine, while the model still has good predictive performance. These results may provide guidance for thromboprophylaxis and form the basis for a management study.

The British Society for Haematology: 'What have the Romans ever done for us?'.

'….Alright, but apart from the sanitation, medicine, education, wine, public order, irrigation, the roads, fresh water and public health………………what have the Romans ever done for us?' From Monty Python's Life of Brian An organizational review of the British Society for Haematology (BSH) was started in November 2013 and completed in June 2014. Many members of the Society participated in the surveys and have given their views, including those on the Shape of Training Greenaway report. Members' views were incorporated in the review and these have informed the eight strategic aims agreed at the Board meeting on 10 June 2014. The BSH will aim to realise these strategic aims over the next three to five years.

D-dimer testing to select patients with a first unprovoked venous thromboembolism who can stop anticoagulant therapy: a cohort study.

BACKGROUND: Normal D-dimer levels after withdrawal of anticoagulant therapy are associated with a reduced risk for recurrence in patients with unprovoked venous thromboembolism (VTE) and may justify stopping treatment. OBJECTIVE: To determine whether patients with a first unprovoked VTE and negative D-dimer test result who stop anticoagulant therapy have a low risk for recurrence. DESIGN: Prospective management study with blinded outcome assessment. (ClinicalTrials.gov: NCT00720915). SETTING: 13 university-affiliated clinical centers. PATIENTS: 410 adults aged 75 years or younger with a first unprovoked proximal deep venous thrombosis or pulmonary embolism who had completed 3 to 7 months of anticoagulant therapy. INTERVENTION: Anticoagulant therapy was stopped if D-dimer test results were negative and was not restarted if results were still negative after 1 month. MEASUREMENTS: Recurrent VTE during an average follow-up of 2.2 years. RESULTS: In 319 patients (78%) who had 2 negative D-dimer results and did not restart anticoagulant therapy, rates of recurrent VTE were 6.7% (95% CI, 4.8% to 9.0%) per patient-year overall (42 of 319), 9.7% (CI, 6.7% to 13.7%) per patient-year in men (33 of 180), 5.4% (CI, 2.5% to 10.2%) per patient-year in women with VTE not associated with estrogen therapy (9 of 81), and 0.0% (CI, 0.0% to 3.0%) per patient-year in women with VTE associated with estrogen therapy (0 of 58) (P = 0.001 for the 3-group comparison). LIMITATIONS: Imprecision in female subgroups. Results may not be generalizable to different D-dimer assays from the one used in the study. CONCLUSION: The risk for recurrence in patients with a first unprovoked VTE who have negative D-dimer results is not low enough to justify stopping anticoagulant therapy in men but may be low enough to justify stopping therapy in women. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research.

The clinical utility of Multiplate analyser measurement in platelet function testing following stroke and transient ischaemic attack.

BACKGROUND: Platelet responsiveness to aspirin in people with cerebrovascular disease is poorly understood. OBJECTIVES: To determine: (i) normal reference range, imprecision and reproducibility of the Multiplate instrument in healthy volunteers naive to aspirin; (ii) imprecision and reproducibility of the Multiplate instrument in acute stroke and transient ischaemic attack (TIA); (iii) the relationship between aspirin responsiveness and clinical outcome. MATERIALS AND METHODS: We evaluated platelet function response to three agonists [Adenosine Diphosphate (ADP), Arachidonic Acid (AA), Collagen (Col)] using the Mulitplate platelet function analyser in a two-phase pilot study. In phase 1, we recruited healthy volunteers to determine the normal reference range and imprecision of the Multiplate instrument. In phase 2, we assessed platelet function in acute stroke or TIA patients presenting to hospital. These patients were bled within 24 h of presentation and between 12 and 24 h after ≥75 mg dose of Aspirin. Patients were followed up to 1 yr to assess mortality and recurrent cardiovascular event. RESULTS: Overall, 29 healthy volunteers and 81 stroke/TIA patients were recruited. On assessing components of variance, Multiplate testing is reproducible and precise in volunteers and stroke/TIA patients. In stroke patients receiving aspirin, Bland-Altman plots show initial day 1 measurement provided a reliable measure of continuing response to aspirin at day 3. We defined one-third of patients as aspirin resistant [31.8% (95% CI: 22.1%-42.8%)] using cut off mean aggregation of ≥23.08% for AA and mean aggregation of ≥80.76% for ADP. CONCLUSION: The Multiplate device gives reproducible, precise results in volunteers and stroke/TIA patients.

Venous thrombosis.

Venous thromboembolism (VTE) encompasses deep-vein thrombosis (DVT) and pulmonary embolism. VTE is the leading cause of lost disability-adjusted life years and the third leading cause of cardiovascular death in the world. DVT leads to post-thrombotic syndrome, whereas pulmonary embolism can cause chronic pulmonary hypertension, both of which reduce quality of life. Genetic and acquired risk factors for thrombosis include non-O blood groups, factor V Leiden mutation, oral contraceptive use, hormone replacement therapy, advanced age, surgery, hospitalization and long-haul travel. A combination of blood stasis, plasma hypercoagulability and endothelial dysfunction is thought to trigger thrombosis, which starts most often in the valve pockets of large veins. Animal studies have revealed pathogenic roles for leukocytes, platelets, tissue factor-positive microvesicles, neutrophil extracellular traps and factors XI and XII. Diagnosis of VTE requires testing and exclusion of other pathologies, and typically involves laboratory measures (such as D-dimer) and diagnostic imaging. VTE is treated with anticoagulants and occasionally with thrombolytics to prevent thrombus extension and to reduce thrombus size. Anticoagulants are also used to reduce recurrence. New therapies with improved safety profiles are needed to prevent and treat venous thrombosis. For an illustrated summary of this Primer, visit: http://go.nature.com/8ZyCuY.

Clinical decision rules and D-Dimer in venous thromboembolism: current controversies and future research priorities.

Venous thromboembolism (VTE) is a potentially lethal clinical condition that is suspected in patients with common clinical complaints, in many and varied, clinical care settings. Once VTE is diagnosed, optimal therapeutic management (thrombolysis, IVC filters, type and duration of anticoagulants) and ideal therapeutic management settings (outpatient, critical care) are also controversial. Clinical prediction tools, including clinical decision rules and D-Dimer, have been developed, and some validated, to assist clinical decision making along the diagnostic and therapeutic management paths for VTE. Despite these developments, practice variation is high and there remain many controversies in the use of the clinical prediction tools. In this narrative review, we highlight challenges and controversies in VTE diagnostic and therapeutic management with a focus on clinical decision rules and D-Dimer.