Overall haemostatic potential assay for prediction of outcomes in venous and arterial thrombosis and thrombo-inflammatory diseases.

Thromboembolic diseases including arterial and venous thrombosis are common causes of morbidity and mortality globally. Thrombosis frequently recurs and can also complicate many inflammatory conditions through the process of 'thrombo-inflammation,' as evidenced during the COVID-19 pandemic. Current candidate biomarkers for thrombosis prediction, such as D-dimer, have poor predictive efficacy. This limits our capacity to tailor anticoagulation duration individually and may expose lower risk individuals to undue bleeding risk. Global coagulation assays, such as the Overall Haemostatic Potential (OHP) assay, that investigate fibrin generation and fibrinolysis, may provide a more accurate and functional assessment of hypercoagulability. We present a review of fibrin's critical role as a central modulator of thrombotic risk. The results of our studies demonstrating the OHP assay as a predictive biomarker in venous thromboembolism, chronic renal disease, diabetes mellitus, post-thrombotic syndrome, and COVID-19 are discussed. As a comprehensive and global measurement of fibrin generation and fibrinolytic capacity, the OHP assay may be a valuable addition to future multi-modal predictive tools in thrombosis.

A ten-year comparison of treatment and outcomes of cancer-associated thrombosis to non-cancer venous thromboembolism: from traditional anticoagulants to direct oral anticoagulants.

DOACs have emerged as first-line treatment in most cancer-associated thrombosis (CAT), representing a paradigm shift in its management. However, CAT management remains challenging and requires careful risk-benefit considerations. A retrospective analysis of CAT presentations to a tertiary referral centre from January 2011 to December 2020. Outcomes in CAT patients were compared to VTE patients without malignancy. Subgroup analysis was also conducted for CAT according to anticoagulation type. 514 CAT cases from 491 patients were identified from 3230 total VTE cases. CAT patients had higher rates of major VTE (PE and/or proximal DVT) compared to patients without malignancy (78.4% vs. 66.8%, p < 0.001). CAT patients also had higher rates of VTE recurrence (HR 1.66, 95%CI 1.23-2.26), major bleeding (HR 3.41, 95%CI 2.36-4.93), VTE-related mortality (HR 2.59, 95%CI 1.46-4.62) and bleeding-related mortality (HR 2.66, 95%CI 1.05-6.73). There were no significant differences in rates of VTE recurrence, major bleeding, VTE-related mortality or fatal bleeding between CAT patients treated with DOACs, enoxaparin or warfarin. In the subgroup of CAT treated with DOACs, there was no significant difference in rates of GI bleeding compared to the enoxaparin subgroup (HR 0.17, 95%CI 0.02-1.26). CAT was associated with a larger clot burden and higher rates of VTE recurrence, major bleeding and mortality compared to VTE patients without malignancy in this large real-world study. This study demonstrated no significant differences in complication rates for CAT patients treated with DOACs over enoxaparin, suggesting that DOACs can be safely used in most cases of CAT.

A systematic review of venous thromboembolism mechanical prophylaxis devices during surgery.

PURPOSE: Hospitalisation and surgery are major risk factors for venous thromboembolism (VTE). Intermittent pneumatic compression (IPC) and graduated compression stockings (GCS) are common mechanical prophylaxis devices used to prevent VTE. This review compares the safety and efficacy of IPC and GCS used singularly and in combination for surgical patients. METHODS: Ovid Medline and Pubmed were searched in a systematic review of the literature, and relevant articles were assessed against eligibility criteria for inclusion along PRISMA guidelines. RESULTS: This review is a narrative description and critical analysis of available evidence. Fourteen articles were included in this review after meeting the criteria. Results of seven studies comparing the efficacy of IPC versus GCS had high heterogeneity but overall suggested IPC was superior to GCS. A further seven studies compared the combination of IPC and GCS versus GCS alone, the results of which suggest that combination mechanical prophylaxis may be superior to GCS alone in high-risk patients. No studies compared combination therapy to IPC alone. IPC appeared to have a superior safety profile, although it had a worse compliance rate and the quality of evidence was poor. The addition of pharmacological prophylaxis may make mechanical prophylaxis superfluous in the post-operative setting. CONCLUSION: IPC may be superior to GCS when used as a single prophylactic device. A combination of IPC and GCS may be more efficacious than GCS alone for high-risk patients. Further high-quality research is needed focusing on clinical relevance, safety and comparing combination mechanical prophylaxis to IPC alone, particularly in high-risk surgical settings when pharmacological prophylaxis is contraindicated.

Current challenges in the prevention and management of post-thrombotic syndrome-towards improved prevention.

Post-thrombotic syndrome (PTS) is a common and potentially debilitating complication of deep vein thrombosis (DVT), affecting up to 50% of DVT patients. The consequence of this chronic condition includes reduced quality of life, increased use of the healthcare system and decreased productivity. The societal impact of this condition is projected to increase, given our ageing population and increased burden of thrombotic diseases. Despite significant recent advances in our understanding of PTS, many unanswered questions remain. Currently, there are few effective and proven options for established PTS; hence, the emphasis should be on instituting effective prevention to reduce the progression to PTS. Effective anticoagulation lowers the risk of PTS, with direct oral anticoagulants appearing to outperform vitamin-K antagonists. However, the evidence for elastic compression stockings and endovascular thrombolysis or thrombectomy techniques remains unclear. Accurate identification of individuals at high risk of developing PTS may also improve the targeting of preventative interventions. This review will examine the current body of evidence regarding PTS, with a focus on preventative strategies as well as novel biomarkers.

Global coagulation assays in patients with chronic kidney disease and their role in predicting thrombotic risk.

BACKGROUND: Despite cardiovascular diseases and thrombosis being major causes of death in patients with chronic kidney disease (CKD), there remains no effective biomarker to predict thrombotic risk in this population. OBJECTIVE: To evaluate global coagulation assays in patients with CKD and correlate the biomarkers to clinical outcomes. MATERIAL AND METHODS: Patients with eGFR<30 mL/min/1.73m2 were recruited (n = 90) in this prospective observational study. Blood samples were collected for global coagulation assays, including thromboelastography, calibrated automated thrombogram (CAT), overall hemostatic potential (OHP) and tissue factor pathway inhibitor (TFPI). RESULTS: Following adjustment for age and gender, CKD subjects (mean age 66 years, 36 % female) had increased maximum amplitude on thromboelastography (70.1 vs 60.2 mm, p < 0.001), higher peak thrombin (233.2 vs 219.7 mm, p = 0.030) and increased OHP (16.1 vs 6.4 units, p < 0.001) compared to healthy controls (n = 153). TFPI was also increased in CKD patients (36.4 vs 14.5 ng/mL, p < 0.001). Compared to hemodialysis patients (n = 43), peritoneal-dialysis patients (n = 25) had more hypercoagulable parameters. Thirty-five CKD patients reported thrombotic complications - key predictors included dialysis, higher fibrinogen, reduced endogenous thrombin potential, elevated D-dimer and increased TFPI. Using the dialysis cohort, the predictive risk model based on the key predictors performed better than Framingham heart score and number of cardiovascular risk factors (Harrell's C-stat 0.862 vs 0.585 vs 0.565). CONCLUSION: CKD appears to confer a hypercoagulable state compared to healthy controls. Interestingly, reduced thrombin generation and raised TFPI was paradoxically associated with increased thrombotic risks, highlighting possible complex compensatory mechanisms within the coagulation system, which may be important in predicting clinical outcomes.

A 10-year Australian experience of rare intraabdominal venous thrombosis with comparison to deep vein thrombosis and pulmonary embolism.

OBJECTIVE: Intra-abdominal venous thromboembolism is rare with heterogeneous management. We aim to evaluate these thrombosis and compare them to deep vein thrombosis and/or pulmonary embolism. METHOD: A 10-year retrospective evaluation of consecutive venous thromboembolism presentations (January 2011-December 2020) at Northern Health, Australia, was conducted. A subanalysis of intraabdominal venous thrombosis involving splanchnic, renal and ovarian veins was performed. RESULTS: There were 3343 episodes including 113 cases of intraabdominal venous thrombosis (3.4%) - 99 splanchnic vein thrombosis, 10 renal vein thrombosis and 4 ovarian vein thrombosis. Of the splanchnic vein thrombosis presentations, 34 patients (35 cases) had known cirrhosis. Patients with cirrhosis were numerically less likely to be anticoagulated compared to noncirrhotic patients (21/35 vs. 47/64, P  = 0.17). Noncirrhotic patients ( n  = 64) were more likely to have malignancy compared to those with deep vein thrombosis and/or pulmonary embolism (24/64 vs. 543/3230, P  < 0.001), including 10 patients diagnosed at time of splanchnic vein thrombosis presentation. Cirrhotic patients reported more recurrent thrombosis/clot progression (6/34) compared to noncirrhotic patients (3/64) (15.6 vs. 2.3 events/100-person-years; hazard ratio 4.7 (95% confidence interval 1.2-18.9), P  = 0.030) and other venous thromboembolism patients (2.6/100-person-years; hazard ratio 4.7, 95% confidence interval 2.1-10.7; P  < 0.001) with comparable major bleeding rates. All renal vein thrombosis were provoked including five malignant-related cases while three ovarian vein thrombosis occurred postpartum. No recurrent thrombotic or bleeding complications were reported in renal vein thrombosis and ovarian vein thrombosis. CONCLUSION: These rare intraabdominal venous thromboses are often provoked. Splanchnic vein thrombosis (SVT) patients with cirrhosis have a higher rate of thrombotic complications, while SVT without cirrhosis was associated with more malignancy. Given the concurrent comorbidities, careful assessment and individualized anticoagulation decision is needed.

DOAC-stop can remove direct oral anticoagulants and allow analysis by global coagulation assays.

INTRODUCTION: Activated charcoal based compounds such as DOAC-stop™ (DS) have been developed to remove direct oral anticoagulant (DOAC) interference in-vitro. However, few studies have used this approach with global coagulation assays (GCAs), such as thrombin generation assays, which are sensitive to the effect of DOACs. METHODS: Thrombin generation with and without thrombomodulin (TM) via the automated ST-Genesia system, and the overall haemostatic potential (OHP) assay, a spectrophotometric fibrin generation assay in which fibrin formation (triggered by small amounts of thrombin (overall coagulation potential, OCP)) and fibrinolysis (by the addition of thrombin and tissue plasminogen activator) were measured on (i) pooled normal plasma (PNP) spiked with varying amounts of rivaroxaban, apixaban, and dabigatran, and (ii) platelet poor plasma (PPP) from 21 non-anticoagulated adults, before and after DS addition. RESULTS: Following the addition of DS to spiked PNP without thrombomodulin, thrombin and velocity index increased by 21.9% and 42.6%, respectively, while ETP increased by 6.93%. A decrease in OCP (-10.6%) and OHP (-12.7%) was observed following DS. Similar changes were seen post-DS to plasma from non-anticoagulated patients. Also in this group, pre- and post-DS thrombin generation parameters showed high correlation, with the strongest observed for ETP (R2  = 0.94). There was a strong correlation for OHP parameters, with the closest seen with OCP (R2  = 0.96) and OHP (R2  = 0.95). CONCLUSION: DS causes some changes to the ETP and OHP assay, however, strong correlations were seen pre- and post-DS in all GCA parameters. These findings support the use of DS to facilitate GCA testing in anticoagulated individuals for evaluation of the underlying thrombotic state.

Clinical predictors of pulmonary embolism for inpatients: are computed tomography pulmonary angiograms being requested appropriately?

BACKGROUND: The heterogeneity of inpatient pulmonary embolism (PE) presentations may lead to computed tomography pulmonary angiograms (CTPA) being over-requested. Current clinical predictors for PE, including Wells criteria and Pulmonary Embolism Rule-out Criteria (PERC), have predominantly focussed on outpatient and emergency department populations. AIM: To determine the clinical indicators for ordering inpatient CTPA and the predictors of positive scans for PE. METHODS: Consecutive inpatient CTPA (performed >24 h after admission) from January 2017 to December 2017 were retrospectively reviewed. Variables including baseline characteristics, vital signs and risk factors for PE were extracted. RESULTS: A total of 312 CTPA was reviewed (average patient age 67 years; 46% male) and 36 CTPA were positive for PE (11.5%). The average time to inpatient CTPA request was 7 days. Clinical indicators associated with positive scans were hypoxia (odds ratio (OR) 2.4; 95% confidence interval (CI) 1.1-5.6), tachypnoea (OR 2.5; 95% CI 1.2-6.0), recent surgery or immobilisation (OR 2.7; 95% CI 1.2-6.4), S1Q3T3 pattern on electrocardiogram (ECG; OR 7.2; 95% CI 1.4-35.7) and right bundle branch block pattern on ECG (OR 4.7; 95% CI 1.6-13.1). Hypotension, fever and malignancy were not significant. Both PERC and Wells criteria had poor positive predictive value (12% and 27% respectively), but the negative predictive value for PERC and Wells was 100% and 95.8% respectively. CONCLUSION: Inpatient CTPA appear to be over-requested and can potentially be rationalised based on a combination of clinical predictors and Wells criteria and/or PERC rule. Further prospective studies are needed to develop accurate clinical decision tools targeted towards inpatients.

Laboratory markers of severity across three COVID-19 outbreaks in Australia: has Omicron and vaccinations changed disease presentation?

COVID-19 has rapidly evolved since it was first discovered in December 2019. We aimed to retrospectively review our experience with COVID-19 infection across 2020-2022, focusing on differences in laboratory markers at presentation. Consecutive adult patients admitted to hospital with confirmed COVID-19 infection were retrospectively reviewed across three periods (29/3/2020-29/9/2020, 16/8/2021-13/10/2021 and 1/1/2022-31/1/2022), correlating with the lineages B.1.338, Delta (B.1.617.2) and Omicron (B.1.1.159), respectively. Laboratory findings of the first requested blood test within 24 h of presentation were recorded and correlated with patient outcome. The primary outcome was requirement for oxygen therapy at any point. Inflammatory markers, namely serum ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP) were significantly lower on presentation during 2022 compared to 2021, corresponding to a milder disease course. More than 80% of 2022 patients had received 2 or more vaccine doses and fully vaccinated patients displayed significantly lower inflammatory markers at presentation. Using 2022 data, a multivariate prediction model was constructed to predict for oxygen requirement, with c-statistic 0.86. Patients in 2022, corresponding with the Omicron variant, displayed a milder disease course, even in hospitalised patients, with the majority not requiring oxygen and lower inflammatory markers. We constructed a simple-to-use risk prediction model with c-statistic 0.86 which may identify individuals who can be safely managed as outpatients in the era of highly transmissible variants.

Management of venous thromboembolism in morbidly obese patients: a 10-year review.

Obesity is a known risk factor for venous thromboembolism (VTE) and poses a unique set of challenges in anticoagulation management. We report a 10-year experience of VTE management in morbidly obese patients. We conducted a retrospective analysis of VTE presentations to Northern Health, Victoria, Australia, from January 2011 to December 2020, with median follow-up of 44 months. Morbidly obese patients (defined as weighing > 120 kg) were compared to those ≤ 120 kg. Patients with active malignancy were excluded. 194 VTE cases with weight > 120 kg were compared to 2168 cases weighing ≤ 120 kg. Patients > 120 kg were more likely to present with unprovoked VTE (59.3% vs. 45.2%, p < 0.001) and major VTE (74.7% vs. 67.4%, p = 0.028). Overall, patients > 120 kg were more likely to develop VTE recurrence after anticoagulation cessation (7.80 vs. 3.92 per 100-patient-years, HR 1.97, 95%CI 1.29-3.00), while there were no significant differences in major bleeding or 30-day all-cause mortality. There were no significant differences in outcomes in patients > 120 kg treated with warfarin compared to direct oral anticoagulants (DOAC), or when comparing those treated with an uncapped (1 mg/kg BD) vs. capped (< 1 mg/kg) enoxaparin dosing regimen. Morbid obesity is associated with increased clot burden at presentation and VTE recurrence following anticoagulation cessation, without significant differences in bleeding compared to those ≤ 120 kg. There were no significant differences in morbidly obese patients' outcomes when treated with warfarin or DOAC, or when treated with an uncapped or capped enoxaparin dosing strategy. Larger randomised controlled trials evaluating the safety of DOACs and different enoxaparin dosing strategies in patients > 120 kg are warranted.

Overall haemostatic potential (OHP) assay can risk stratify for venous thromboembolism recurrence in anticoagulated patients.

Assessing the risk of recurrent venous thromboembolism (VTE), particularly when patients are anticoagulated, remains a major challenge largely due to the lack of biomarkers. Blood was sampled from adult VTE patients recruited between January 2018 and September 2020, while receiving therapeutic anticoagulation. Results were compared to 144 healthy subjects (34.7% male, median age 42 years). Overall haemostatic potential (OHP) assay, a spectrophotometric assay, was performed on platelet-poor plasma, in which fibrin formation (triggered by small amounts of thrombin (overall coagulation potential, OCP)) and fibrinolysis (by the addition of thrombin and tissue plasminogen activator (OHP)) are simultaneously measured. Results were obtained from 196 patients (52.6% male, mean age 57.1 years). Compared to healthy subjects, VTE patients displayed significantly higher OCP (39.6 vs 34.5 units, p < 0.001) and OHP (9.3 vs 6.4 units, p < 0.001) as well as lower overall fibrinolytic potential (75.6 v s81.1%, p < 0.001). All 16 VTE recurrences, including 11 unprovoked, occurred above an OCP cut-off of 40th percentile (recurrence rate 4.32/100 patient-years (100PY), 95% confidence interval (CI) 2.39-7.80, p = 0.002). Of 97 patients who subsequently discontinued anticoagulation, all unprovoked VTE recurrences (n = 9) occurred above the 40th OCP percentile (recurrence rate 9.10/100PY, 95% CI 4.74-17.49, p = 0.005) and the 40th OHP percentile (recurrence rate 8.46/100PY, 95% CI 4.40-16.25, p = 0.009). Our pilot study demonstrates that the OHP assay can detect a hypercoagulable and hypofibrinolytic state in anticoagulated VTE patients and may be able to risk stratify VTE recurrence, allowing for more individualised decision on long-term anticoagulation. Further larger prospective studies are required.

Thrombosis Risk Assessment in Myeloproliferative Neoplasm-Is There a Role for Viscoelastic Testing?

Philadelphia chromosome-negative myeloproliferative neoplasms include polycythemia vera, essential thrombocythemia, and myelofibrosis. They are associated with increased thrombotic events, and the primary goal of therapy, in particular those with polycythemia vera and essential thrombocythemia, is the prevention of thrombotic complications typically with antiplatelet therapy and/or cytoreduction. While several patient-, disease-, and genomic-related factors have been identified to influence thrombotic risks, there are no routine laboratory investigations to date that are sufficiently accurate to assess the underlying procoagulant state and predict the thrombotic risks. Conventional coagulation testing only measures time to clot formation and cannot reliably predict bleeding and thrombotic risks. Global coagulation assays such as thromboelastography, thrombin, and fibrin generation may provide a more thorough assessment of hemostatic function. Thromboelastography and thromboelastometry are viscoelastic tests which measure the mechanical properties of the hemostatic process, including the global dynamics of clot formation, stabilization, and dissolution. While viscoelastic testing is gaining traction in the investigations of coagulopathies and goal-directed blood product replacement in trauma and massive transfusion settings, the role of these assays in thrombosis is less well defined. Here, we provide a review of the current evidence of the role of viscoelastic testing in myeloproliferative neoplasm, particularly in the thrombotic risk assessment.

Overall Hemostatic Potential Assay Detects Risk of Progression to Post-Thrombotic Syndrome in Anticoagulated Patients following Deep Vein Thrombosis.

Deep vein thrombosis (DVT) frequently leads to post-thrombotic syndrome (PTS) which is challenging to predict and prevent. Identifying those at high risk of developing PTS may help to focus preventative strategies. Adults were recruited within 3 months of DVT diagnosis. Blood was sampled during the therapeutic anticoagulation phase. Overall hemostatic potential (OHP) assay, a spectrophotometric assay, was performed on platelet-poor plasma (PPP). In this assay, fibrin formation is triggered by small amounts of thrombin and termed the overall coagulation potential (OCP). Simultaneously, thrombin and tissue plasminogen activator are added to PPP and the resulting fibrin aggregation curve is the overall hemostatic potential (OHP). Fibrinolysis is expressed by the parameter overall fibrinolytic potential (OFP%). Patients were followed up at regular intervals. PTS was diagnosed if the Villalta score was ≥5 at least 3 months after the DVT diagnosis. Results were obtained from 190 patients (53.7% male, mean age 56.9 years). PTS developed in 62 (32.6%) patients. Patients with PTS displayed significantly higher median OCP (45.8 vs. 38.8 units, p = 0.010), OHP (12.8 vs. 9.2 units, p = 0.005) and significantly lower OFP (74.1 vs. 75.6%, p = 0.050). PTS patients had higher neutrophil/lymphocyte ratios (NLR) (2.3 vs. 1.9, p = 0.007). After multivariate analysis, proximal DVT location, history of varicose veins, NLR ≥ 2.6, OHP > 13.0 units and weight >108 kg were independent predictors for PTS. The c-statistic of the multivariate model was 0.77. This pilot study suggests that OHP testing while patients are still anticoagulated may assist in the prediction of PTS development and could assist in prognostication and targeting of preventative measures. However, larger prospective studies are needed to confirm these findings.

Risk stratification for pregnancy-associated venous thromboembolism: Potential role for global coagulation assays.

Risk assessment for venous thromboembolism in pregnancy and the puerperium is currently limited to stratifying clinical surrogate risk factors without high-quality evidence. While the absolute risk of pregnancy-associated venous thromboembolism is low for the vast majority of women, associated morbidity and mortality remains significant. As guidelines for thromboprophylaxis vary widely, some women may be under- or over-anticoagulated, contributing to poor outcomes. New global coagulation assays provide a holistic view of coagulation and may have the potential to detect hypercoagulability in pregnancy, unlike clinically available coagulation assays. However, there are major technical challenges to overcome before global coagulation assays can be realistically proposed as an adjunct to risk assessment for pregnancy-associated venous thromboembolism. This review summarises the literature and controversies in the prediction and prevention of pregnancy-associated venous thromboembolism and outlines the new tools in haematology that may assist in our future understanding of hypercoagulability in pregnancy.

Impaired Fibrinolytic Potential Predicts Oxygen Requirement in COVID-19.

Abnormal coagulation and fibrinolysis contributes to the respiratory distress syndrome in COVID-19. We aimed to explore the association of impaired fibrinolytic potential with disease severity and oxygen requirement in hospitalized patients. Adults admitted to hospital with confirmed COVID-19 infection between 1-31 January 2022 were included, corresponding to the first Omicron outbreak in Melbourne, Victoria. The first citrated plasma sample requested within 24 h of the patient's presentation was obtained and analyzed by the overall hemostatic potential (OHP) assay, a spectrophotometric assay in which fibrin formation (triggered by small amounts of thrombin (OCP)) and fibrinolysis (by the addition of thrombin and tissue plasminogen activator (OHP and OFP%)) were simultaneously measured. There were 266 patients (median 72 years, 52.9% male), of which 49.6% did not require oxygen therapy. COVID-19 severity and requirement for oxygen was significantly associated with higher OCP, OHP, and lower OFP%. Vaccinated individuals compared with non-vaccinated individuals had significantly lower OHP (16.5 vs. 23.1, p = 0.015) and higher OFP (72.0% vs. 65.1%, p = 0.005), as well as significantly lower AST, ferritin, LDH, CRP, and D-dimer. A multivariate model containing OHP was constructed with the outcome of oxygen requirement, with c-statistic of 0.85 (95%CI 0.81-0.90). In this pilot study, we show a significant correlation between OHP results and requirement for oxygen supplementation in hospitalized patients during a period dominated by the Omicron variant. The results were incorporated into a multivariate model that predicted for oxygen requirement, with high discriminative ability.

A ten-year review of the impact of the transition from warfarin to direct oral anticoagulant - Has venous thromboembolism treatment become safer?

BACKGROUND: The introduction of direct oral anticoagulants (DOAC) has resulted in a paradigm shift in the management of venous thromboembolism (VTE). We evaluate the impact of the transition to DOAC, over the last decade, on overall VTE clinical outcomes including in first unprovoked major VTEs. METHOD: A retrospective analysis of all VTE admissions in non-cancer patients from January 2011 to December 2020 at Northern Health, Victoria, Australia. "Warfarin era" included events that occurred between January 2011 and December 2014 and "DOAC era" from January 2016. RESULTS: There were 2687 cases involving 2508 patients (45.9 % males; median age 63 years). 98 % were symptomatic and 1261 events (47 %) were unprovoked. 1003 events occurred during the warfarin era (79 % warfarin, 6 % DOAC) and 1479 during the DOAC era (18 % warfarin, 70 % DOAC). While recurrent thrombosis during the acute phase of treatment was comparable, there were fewer recurrences during the long-term preventative phase of treatment in the DOAC era compared to warfarin era (HR 0.602, 95 % CI: 0.393-0.924, p0.020). Clinically significant bleeding events were lower in the DOAC era (HR 0.623, 95 % CI: 0.395-0.985, p = 0.043). A subanalysis of first unprovoked major VTE events (n = 602) demonstrated a significant reduction in recurrent VTE during the long-term preventative phase of treatment in the DOAC era (HR 0.296, 95 % CI: 0.097-0.901, p = 0.032) with no difference in clinically significantly bleeding rates (HR 0.529, 95 % CI 0.219-1.280, p = 0.158) between the eras. CONCLUSION: Treatment outcomes for VTE appear to have improved over time with reduced rate of thrombotic and clinically significant bleeding complications in the DOAC era.

Plasma Angiotensin Converting Enzyme 2 (ACE2) Activity in Healthy Controls and Patients with Cardiovascular Risk Factors and/or Disease.

Angiotensin converting enzyme 2 (ACE2) is an endogenous negative regulator of the renin-angiotensin system, a key factor in the development of cardiovascular disease (CVD). ACE2 is also used by SARS-CoV-2 for host cell entry. Given that COVID-19 is associated with hypercoagulability, it is timely to explore the potential relationship between plasma ACE2 activity and the coagulation profile. In this cross-sectional study, ACE2 activity and global coagulation assays (GCA) including thromboelastography, thrombin, and fibrin generation were measured in adult healthy controls (n = 123; mean age 41 ± 17 years; 35% male) and in patients with cardiovascular risk factors and/or disease (n = 258; mean age 65 ± 14 years; 55% male). ACE2 activity was significantly lower in controls compared to patients with cardiovascular risk factors and/or disease (median 0.10 (0.02, 3.33) vs. 5.99 (1.95, 10.37) pmol/mL/min, p < 0.001). Of the healthy controls, 48% had undetectable ACE2 activity. Controls with detectable ACE2 had lower maximum amplitude (p < 0.001). In patients with cardiovascular risk factors and/or disease, those in the 3rd tertile were older and male (p = 0.002), with a higher Framingham grade and increased number of cardiovascular risk factors (p < 0.001). In conclusion, plasma ACE2 activity is undetectable to very low in young healthy controls with minimal clinically relevant associations to GCA. Patients with cardiovascular risk factors and/or disease have increased plasma ACE2 activity, suggesting that it may be an important biomarker of endothelial dysfunction and atherosclerosis.

The Need for Individualized Risk Assessment in Cardiovascular Disease.

Cardiovascular disease remains the leading cause of death in the era of modern medicine despite major advancements in this field. Current available clinical surrogate markers and blood tests do not adequately predict individual risk of cardiovascular disease. A more precise and sophisticated tool that can reliably predict the thrombosis and bleeding risks at an individual level is required in order for clinicians to confidently recommend early interventions with a favorable risk-benefit profile. Critical to the development of this tool is the assessment and understanding of Virchow's triad and its complex interactions between hypercoagulability, endothelial dysfunction and vessel flow, a fundamental concept to the development of thrombosis. This review explores the pathophysiology of cardiovascular disease stemming from the triad of factors and how individualized risk assessment can be improved through the multimodal use of tools such as global coagulation assays, endothelial biomarkers and vessel flow assessment.

Global coagulation assays in hypercoagulable states.

Thrombosis is one of the major global causes of morbidity and mortality, and predicting the risk of thrombotic and cardiovascular complications remains one of the key challenges in modern medicine. Conventional coagulation testing does not provide sufficient information, primarily because they measure the time to start of blood clotting and do not evaluate total thrombin generation. Possible adjunctive tools that may be helpful are global coagulation assays, which includes the assessment of the final products of the coagulation cascade, namely thrombin and fibrin. Whilst these assays have been more widely investigated in bleeding states, their role in thrombotic disorders is less established. We have previously investigated the use of assays such as thromboelastography, calibrated automated thrombogram and overall haemostatic potential assay in several hypercoagulable states including cardiovascular disease, haematological disorders and influence of hormone status as well as healthy controls. We provide a review of the use and limitations of global coagulation assays in healthy controls as well as hypercoagulable conditions.