Diagnostic Testing for von Willebrand Disease: Trends and Insights from North American Laboratories over the Last Decade.

Accurate diagnosis of von Willebrand disease (VWD) depends on the quality, precision, and variability of the laboratory assays. The North American Specialized Coagulation Laboratory Association (NASCOLA) is a provider of external quality assessment (EQA) for approximately 60 specialized coagulation laboratories in North America. In this report, NASCOLA EQA data from 2010 to 2021 are reviewed for trends in methodology and precision among various assays. In particular, recent ASH ISTH NHF WFH (American Society of Hematology, International Society on Thrombosis and Haemostasis, National Hemophilia Foundation, and World Hemophilia Federation) guidelines for diagnosis of VWD are reviewed in light of EQA data. In contrast to other geographic regions, laboratories in North America predominantly use three-assay screening panels (antigen, platelet-binding activity, and factor VIII [FVIII] activity) rather than four-assay panels (antigen, platelet-binding activity, FVIII activity, and collagen-binding activity). They also use latex immunoassays rather than chemiluminescence immunoassays, and the classic ristocetin cofactor (VWF:RCo) assay and monoclonal antibody (VWF:Ab) assay to assess VWF platelet-binding activity over newer recommended assays (VWF:GPIbM and VWF:GPIbR). Factors that may be influencing these North American practice patterns include lack of Food and Drug Administration approval of the VWF:GPIbM, VWF:GPIbR, collagen binding assays, and chemiluminescence methodologies, and the influence of the 2008 National Heart, Lung, and Blood Institute guidelines on laboratory practice. Lastly, systems-based solutions are urgently needed to improve the overall accuracy of laboratory testing for VWD by minimizing preanalytical variables and adopting assay standardization.

Effectiveness and safety of the direct oral anticoagulants in non-triple positive antiphospholipid syndrome without prior arterial thromboembolism.

Thrombotic antiphospholipid syndrome (TAPS) is an autoimmune disorder that manifests with venous thromboembolism (VTE) and/or arterial thromboembolism (ATE) in the presence of persistent antiphospholipid antibodies (aPLs). Recent trials have failed to demonstrate non-inferiority of the direct oral anticoagulants (DOACs) compared to vitamin K antagonists as anticoagulation in TAPS, but there is a subgroup of non-triple positive patients without prior ATE in who only limited data exists. The objective of this study was to assess the effectiveness and safety of DOACs in non-triple positive TAPS without prior ATE. We conducted a retrospective review of all non-triple positive TAPS patients without prior ATE who were anticoagulated with a DOAC at two tertiary care hospitals from January 2010 to July 2020. We assessed outcomes of VTE, ATE, major bleeding, and clinically relevant non-major bleeding (CRNMB). 50 patients were included in the analysis, encompassing 157.2 years of patient follow-up. There were no recurrent VTE, but one patient had a possible arterial thrombosis (0.64 events per 100 patient-years [95% confidence interval (CI 0.16-35.49)] as a transient ischemic attack (TIA) which occurred on reduced dose DOAC. There were no major bleeding events, but two patients had CRNMB (1.27 events per 100 patient-years [95% CI 1.5-46.0]), both as menorrhagia. DOACs were effective and safe as anticoagulation in non-triple positive TAPS patients without prior ATE with a low rate of recurrent thrombosis and bleeding. Larger, prospective controlled studies are required to confirm these findings prior to routine use of DOACs in this subgroup.

Diagnosis of von Willebrand disease: An assessment of the quality of testing in North American laboratories.

BACKGROUND: Laboratory diagnosis of von Willebrand Disease (VWD) is complex. Reliance on laboratory testing can be problematic as different VWD screening panels, assays and methodologies can produce analytic variability in test results. OBJECTIVES: To compare the degree of imprecision among the VWD assays and within the platelet binding activity (PBA) assays, to determine the consensus among the VWD assays for correct classification of sample results, and to determine consensus among laboratories' von Willebrand factor (VWF) multimer interpretations and final interpretations of the VWD panels. PATIENTS/METHODS: Proficiency testing results from the North American Specialized Coagulation Laboratory Association (NASCOLA) submitted by laboratories from 2010 to 2019 for all normal, type (T) 1 VWD and T2 VWD samples were analysed. RESULTS AND CONCLUSIONS: Imprecision was lowest for VWF antigen and highest for collagen binding activity (CBA) with median coefficient of variation (CV) of 12% (interquartile range (IQR) 7%) and 23% (IQR 21%) respectively. Within the VWF PBA assays, the gain-of-function mutant GP1b binding (VWF: GP1bM) methods had the least imprecision (CV 9%, IQR 10%). All assays, including the various PBA methods had excellent consensus. The majority of laboratories agreed that normal (median consensus-82%, IQR 16%) and T1 VWD (median consensus-100%, IQR 9%) samples had normal multimer distribution. Consensus among laboratories for final interpretations was excellent for normal samples (median 81%, IQR 8%), good for T1 VWD samples (median 59%, IQR 9%), and fair for T2 VWD samples (median 44%, IQR 21%). Consensus on final interpretation decreased as sample complexity increased.

Reducing the hospital burden of heparin-induced thrombocytopenia: impact of an avoid-heparin program.

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction occurring in up to 5% of patients exposed to unfractionated heparin (UFH). We examined the impact of a hospital-wide strategy for avoiding heparin on the incidence of HIT, HIT with thrombosis (HITT), and HIT-related costs. The Avoid-Heparin Initiative, implemented at a tertiary care hospital in Toronto, Ontario, Canada, since 2006, involved replacing UFH with low-molecular-weight heparin (LMWH) for prophylactic and therapeutic indications. Consecutive cases with suspected HIT from 2003 through 2012 were reviewed. Rates of suspected HIT, adjudicated HIT, and HITT, along with HIT-related expenditures were compared in the pre-intervention (2003-2005) and the avoid-heparin (2007-2012) phases. The annual rate of suspected HIT decreased 42%, from 85.5 per 10 000 admissions in the pre-intervention phase to 49.0 per 10 000 admissions in the avoid-heparin phase ( ITALIC! P< .001). The annual rate of patients with a positive HIT assay decreased 63% from 16.5 to 6.1 per 10 000 admissions ( ITALIC! P< .001), adjudicated HIT decreased 79% from 10.7 to 2.2 per 10 000 admissions ( ITALIC! P< .001), and HITT decreased 91% from 4.6 to 0.4 per 10 000 admissions ( ITALIC! P< .001). Hospital HIT-related expenditures decreased by $266 938 per year in the avoid-heparin phase. To the best of our knowledge, this is the first study demonstrating the success and feasibility of a hospital-wide HIT prevention strategy.

Validity of Thromboelastometry for Rapid Assessment of Fibrinogen Levels in Heparinized Samples During Cardiac Surgery: A Retrospective, Single-center, Observational Study.

OBJECTIVE: To assess the validity of fibrinogen assay of rotational thromboelastometry (FIBTEM)-derived estimates of fibrinogen in samples collected during cardiopulmonary bypass in cardiac surgical patients by comparison to Clauss method fibrinogen concentration. DESIGN: Retrospective observational study. SETTING: Single university hospital center. PARTICIPANTS: Human participants. INTERVENTIONS: Retrospectively obtained laboratory assays including rotational thromboelastometry (ROTEM) and Clauss fibrinogen assay. MEASUREMENTS AND MAIN RESULTS: A retrospective review was performed of anesthesia records at a single university teaching hospital during a 1-year period. From paired samples taken near the end of cardiopulmonary bypass, fibrinogen concentrations (Clauss method) were compared with FIBTEM-derived measures of maximal clot firmness (MCF) and clot amplitude at 10 minutes (A10) using Spearman's rank correlation, linear regression, and receiver operating characteristic curve analysis. The study included 1,077 patients. Clauss fibrinogen was correlated strongly with FIBTEM amplitudes (r = 0.78 for MCF and A10; p<0.01). The correlation was related inversely to hemoglobin concentration (p<0.01). The area under the receiver operating characteristic curve was 0.95; the optimal FIBTEM A10 cutoff for diagnosis of a fibrinogen concentration of<1.5 g/L was ≤8 mm. CONCLUSIONS: The FIBTEM was a valid point-of-care method for estimating the fibrinogen concentration during cardiopulmonary bypass and may be used for prediction of hypofibrinogenemia before separation from the extracorporeal circuit.

Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial.

BACKGROUND: Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. METHODS: We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsberg's criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. FINDINGS: From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. INTERPRETATION: ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. FUNDING: Canadian Institutes of Health Research.

Evaluation of a novel transfusion algorithm employing point-of-care coagulation assays in cardiac surgery: a retrospective cohort study with interrupted time-series analysis.

BACKGROUND: Cardiac surgery requiring the use of cardiopulmonary bypass is frequently complicated by coagulopathic bleeding that, largely due to the shortcomings of conventional coagulation tests, is difficult to manage. This study evaluated a novel transfusion algorithm that uses point-of-care coagulation testing. METHODS: Consecutive patients who underwent cardiac surgery with bypass at one hospital before (January 1, 2012 to January 6, 2013) and after (January 7, 2013 to December 13, 2013) institution of an algorithm that used the results of point-of-care testing (ROTEM; Tem International GmBH, Munich, Germany; Plateletworks; Helena Laboratories, Beaumont, TX) during bypass to guide management of coagulopathy were included. Pre- and postalgorithm outcomes were compared using interrupted time-series analysis to control for secular time trends and other confounders. RESULTS: Pre- and postalgorithm groups included 1,311 and 1,170 patients, respectively. Transfusion rates for all blood products (except for cryoprecipitate, which did not change) were decreased after algorithm institution. After controlling for secular pre- and postalgorithm time trends and potential confounders, the posttransfusion odds ratios (95% CIs) for erythrocytes, platelets, and plasma were 0.50 (0.32 to 0.77), 0.22 (0.13 to 0.37), and 0.20 (0.12 to 0.34), respectively. There were no indications that the algorithm worsened any of the measured processes of care or outcomes. CONCLUSIONS: Institution of a transfusion algorithm based on point-of-care testing was associated with reduced transfusions. This suggests that the algorithm could improve the management of the many patients who develop coagulopathic bleeding after cardiac surgery. The generalizability of the findings needs to be confirmed.

Platelet dysfunction as measured by a point-of-care monitor is an independent predictor of high blood loss in cardiac surgery.

BACKGROUND: Excessive bleeding carries a heavy burden of illness in cardiac surgery. Although platelet dysfunction is considered to be an important cause, it is not routinely measured. Our objective was to explore the relationship between platelet dysfunction and blood loss in cardiac surgery. METHODS: In 100 consenting patients undergoing cardiac surgery requiring cardiopulmonary bypass, platelet function was measured before, during, and after bypass with a point-of-care device that compares platelet counts before and after exposure to an agonist. Clinicians were blinded to the results of testing. Patients whose calculated blood loss was part of the highest quartile for the cohort were classified as having had high blood loss. The independent relationship between platelet function and high blood loss was measured with the aid of multivariable Poisson regression modeling (with a robust error variance) that controlled for patients' overall risk of high blood loss. RESULTS: Calculated blood loss was negatively skewed with a median of 798 mL (25th and 75th percentiles of 380 and 1775 mL). Patients whose blood loss exceeded 1770 mL were classified as having had high blood loss, and 25 patients met this criterion. There was 1 death in the high blood loss group unrelated to hemorrhage. After adjusting for bleeding risk, each 10 × 10/L increase in collagen-activated functional platelet count during rewarming and postprotamine, respectively, was associated with a relative risk of 0.89 (95% confidence interval, 0.82-0.97; P = 0.006) and 0.87 (95% confidence interval, 0.78-0.98; P = 0.02) for high blood loss. CONCLUSIONS: Platelet dysfunction, as measured by a point-of-care method during rewarming and postprotamine, is independently associated with high blood loss in cardiac surgery. Additional studies are needed to determine whether the incorporation of this assay into blood management algorithms might help rationalize blood transfusion therapy, potentially reducing blood loss and improving clinical outcomes.

D-dimer diagnostics: can I use any D-dimer assay? Bridging the knowledge-to-action gap.

A State of the Art lecture titled "D-dimer Diagnostics: Can I use any D-dimer assay? Bridging the Knowledge-to-Action gap" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023, included in the session on the clinical impact of variability in commonly used coagulation assays. Here, we review the role of D-dimer, primarily in the outpatient diagnosis of patients with venous thromboembolism (VTE) when combined with clinical decision rules. We focus on the recent large management trials that have studied adjustments of VTE exclusion thresholds for D-dimer based on either prior clinical probability of VTE or patient age, and the resultant benefit of reduced imaging for VTE and improved diagnostic efficiency. In this context, we report on the significant variability between D-dimer results and the multiple D-dimer assays in use worldwide using data from international external quality assurance programs. This variability is particularly high at typical VTE exclusion thresholds. We discuss the potential clinical impact of D-dimer assay substitution on accuracy of diagnosis and risk stratification of patients with VTE. Finally, we summarize relevant new data on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress and outline future priorities urgently needed to harmonize D-dimer results and reporting that will require international collaboration among multiple stakeholders with an overall goal to close this knowledge-to-action gap.

Testing for the lupus anticoagulant: the good, the bad, and the ugly.

Lupus anticoagulant (LA) represents 1 of the laboratory criteria for classification of patients as having definite antiphospholipid syndrome (APS). The other 2 laboratory criteria are anticardiolipin antibodies and anti-beta2-glycoprotein I antibodies. At least 1 of these antiphospholipid antibody (aPL) tests need to be positive, with evidence of persistence, together with evidence of at least 1 clinical criterion for APS, before a patient can be classified as having definite APS. LA and other aPL assays are also important for diagnosis or exclusion of APS, as well as for risk stratification, with triple-positive patients carrying the greatest risk. Whereas LA is identified through "uncalibrated" clot-based assays, the other aPL assays (anticardiolipin and anti-beta2-glycoprotein I antibodies) represent immunological assays, identified using calibrated solid-phase methods. Because LA is identified using clot-based assays, it is subject to considerable preanalytical and analytical issues that challenge accurate detection or exclusion of LA. In this narrative review, we take a look at the good, the bad, and the ugly of LA testing, primarily focusing on the last 10 years. Although harmonization of LA testing as a result of International Society on Thrombosis and Haemostasis guidance documents and other international activities has led to improvements in LA detection, many challenges remain. In particular, several anticoagulants, especially direct oral anticoagulants and also vitamin K antagonists, given as therapy to treat the pathophysiological consequences of aPL, especially thrombosis, interfere with LA assays and can generate false-positive or false-negative LA findings. Overcoming these diagnostic errors will require a multifaceted approach with clinicians and laboratories working together.

The historical origins of modern international normalized ratio targets.

Prothrombin time (PT) and its derivative international normalized ratio (INR) are frequently ordered to assess the coagulation system. Plasma transfusion to treat incidentally abnormal PT/INR is a common practice with low biological plausibility and without credible evidence, yet INR targets appear in major clinical guidelines and account for the majority of plasma use at many institutions. In this article, we review the historical origins of INR targets. We recount historical milestones in the development of the PT, discovery of vitamin K antagonists (VKAs), motivation for INR standardization, and justification for INR targets in patients receiving VKA therapy. Next, we summarize evidence for INR testing to assess bleeding risk in patients not on VKA therapy and plasma transfusion for treating mildly abnormal INR to prevent bleeding in these patients. We conclude with a discussion of the parallels in misunderstanding of historic PT and present-day INR testing with lessons from the past that might help rationalize plasma transfusion in the future.

Implementation of the YEARS algorithm to optimise pulmonary embolism diagnostic workup in the emergency department.

BACKGROUND: Excessive use of CT pulmonary angiography (CTPA) to investigate pulmonary embolism (PE) in the emergency department (ED) contributes to adverse patient outcomes. Non-invasive D-dimer testing, in the context of a clinical algorithm, may help decrease unnecessary imaging but this has not been widely implemented in Canadian EDs. AIM: To improve the diagnostic yield of CTPA for PE by 5% (absolute) within 12 months of implementing the YEARS algorithm. MEASURES AND DESIGN: Single centre study of all ED patients >18 years investigated for PE with D-dimer and/or CTPA between February 2021 and January 2022. Primary and secondary outcomes were the diagnostic yield of CTPA and frequency of CTPA ordered compared with baseline. Process measures included the percentage of D-dimer tests ordered with CTPA and CTPAs ordered with D-dimers <500 µg/L Fibrinogen Equivalent Units (FEU). The balancing measure was the number of PEs identified on CTPA within 30 days of index visit. Multidisciplinary stakeholders developed plan- do-study-act cycles based on the YEARS algorithm. RESULTS: Over 12 months, 2695 patients were investigated for PE, of which 942 had a CTPA. Compared with baseline, the CTPA yield increased by 2.9% (12.6% vs 15.5%, 95% CI -0.06% to 5.9%) and the proportion of patients that underwent CTPA decreased by 11.4% (46.4% vs 35%, 95% CI -14.1% to -8.8%). The percentage of CTPAs ordered with a D-dimer increased by 26.3% (30.7% vs 57%, 95% CI 22.2% 30.3%) and there were two missed PE (2/2695, 0.07%). IMPACT: Implementing the YEARS criteria may safely improve the diagnostic yield of CTPAs and reduce the number of CTPAs completed without an associated increase in missed clinically significant PEs. This project provides a model for optimising the use of CTPA in the ED.

Quality of anticoagulant control and patient experience associated with long-term warfarin in Canadian patients with non-valvular atrial fibrillation: A multicentre, prospective study.

BACKGROUND: Despite the fact that direct oral anticoagulants (DOACs) are favoured over warfarin for stroke prevention in patients with non-valvular atrial fibrillation (NVAF), physicians need to maintain competence in using and monitoring warfarin since many patients have contraindications or other barriers to using DOACs. Unlike DOACs, warfarin therapy requires regular blood testing to ensure that it is within a target range to ensure efficacy and safety. There is limited real-world data on the adequacy of warfarin control and the cost and burden of monitoring warfarin therapy in Canadian NVAF patients. OBJECTIVES: In a large cohort of Canadian patients with NVAF on warfarin we assessed time in therapeutic range (TTR), determinants of TTR, process of care, direct costs, health related quality of life and loss of work time and productivity related to warfarin therapy. METHODS: Five hundred and fifty one patients with NVAF, either newly initiated or stable on warfarin were prospectively enrolled across 9 Canadian provinces from primary care practices and anticoagulant clinics. Participating physicians provided baseline demographic and medical information. Patients completed diaries for 48 weeks, capturing information about International Normalized Ratio (INR) test results, test locations, process of INR monitoring, direct costs of travel, health-related quality of life and work productivity measures. TTR was estimated using linear interpolation of INR results and linear regression used to investigate associations between TTR and factors (defined a priori). RESULTS: Four hundred and eighty (87.1%) patients had complete follow-up with an overall TTR of 74.4% based on 7,175 physician-reported INR values from 501 patients. 88% of this cohort were monitored through routine medical care (RMC). The average number of INRs per patient during the 48-week period was 14.1 (standard deviation (SD) = 8.3) tests with a mean duration of 23.8 (SD = 11.1) days between tests. We did not find a relationship between TTR and age, sex, presence of major comorbidities, patient's province of residence or rural vs. urban residence. 12% of patients monitored through anticoagulant clinics had significantly better TTR than patients monitored through RMC (82% vs. 74%; 95% confidence interval: -13.8, -1.2; p = 0.02). Health related quality of life utility values were high and remained consistent throughout the study. The majority of patients reported no impact on either work productivity or impairment of regular activities due to being on long-term warfarin treatment. CONCLUSIONS: We showed excellent overall TTR in an observed Canadian cohort, with monitoring through a dedicated anticoagulant clinic being associated with a statistically and clinically significant improvement in TTR. The burden of warfarin therapy on patients' health related quality of life or daily work and activities was low.

Illustrated State-of-the-Art Capsules of the ISTH 2023 Congress.

This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) took place in person in Montréal, Canada, from June 24-28, 2023. The conference, held annually, highlighted cutting-edge advances in basic, translational, population and clinical sciences relevant to the Society. As for all ISTH congresses, we offered a special, congress-specific scientific theme; this year, the special theme was immunothrombosis. Certainly, over the last few years, COVID-19 infection and its related thrombotic and other complications have renewed interest in the concepts of thromboinflammation and immunothrombosis; namely, the relationship between inflammation, infection and clotting. Other main scientific themes of the Congress included Arterial Thromboembolism, Coagulation and Natural Anticoagulants, Diagnostics and Omics, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostatic System in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. Among other sessions, the program included 28 State-of-the-Art (SOA) sessions with a total of 84 talks given by internationally recognized leaders in the field. SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the Congress.

Coagulation test understanding and ordering by medical trainees: Novel teaching approach.

Background: Coagulation testing provides a prime opportunity to make an impact on the reduction of unnecessary laboratory test ordering, as there are clear indications for testing. Despite the prothrombin time/international normalized ratio and activated partial thromboplastin time being validated for specific clinical indications, they are frequently ordered as screening tests and often ordered together, suggesting a gap in understanding of coagulation. Methods: Based on a needs assessment, we developed an online educational module on coagulation for trainees, incorporating education on testing cost, specificity, and sensitivity. Fifty participating resident physicians and medical students completed a validated premodule quiz, postmodule quiz after completion of the module, and a latent quiz 3 to 6 months after to assess longer-term knowledge retention. Trainees provided responses regarding their subjective laboratory test-ordering practices before and after module completion. Results: The median premodule quiz score was 67% (n = 50; range, 24%-86%) with an increase of 24% to a median postmodule quiz score of 91% (n = 50; range, 64%-100%). There was evidence of sustained knowledge acquisition with a latent quiz median score of 89% (n = 40; range, 67%-100%). Trainees were more likely to consider the sensitivity, specificity, and cost of laboratory investigations before ordering them following completion of the educational module. Conclusions: Using the expertise of medical educators and incorporating trainee feedback, we employed a novel approach to the teaching of coagulation to maximize its approachability and clinical relevance. We found sustained knowledge retention regarding coagulation and appropriate coagulation test ordering, and a subjective change to trainee ordering habits following participation in our educational intervention.

Pseudo Heparin Resistance After Pulmonary Endarterectomy: Role of Thrombus Production of Factor VIII.

Pulmonary endarterectomy (PEA) is the main treatment for chronic thromboembolic pulmonary hypertension (CTEPH). Postoperative unfractionated heparin dosing can be monitored by activated partial thromboplastin time (APTT) or by anti-factor Xa activity (anti-Xa). In pseudo heparin resistance, APTT response to heparin is blunted due to elevated Factor VIII (FVIII) which can underestimate anticoagulation. We examined possible pseudo heparin resistance after PEA and assessed the impact of FVIII. APTT response to heparin before and after operation was determined in 13 PEA patients anticoagulated with unfractionated heparin. APTT and anti-Xa concordance was analyzed from paired postoperative samples, and antithrombin, fibrinogen and FVIII levels were measured. Single-cell RNA sequencing was used to characterize FVIII gene expression in PEA specimens of 5 patients. APTT response to heparin was blunted after PEA. APTT and anti-Xa were discordant in 36% of postoperative samples and most common discordant patterns were subtherapeutic APTT with therapeutic (16%) or supratherapeutic (11%) anti-Xa. Overall, APTT underestimated anticoagulation relative to anti-Xa in one-third of the samples. FVIII levels were elevated before surgery, increased substantially 1 and 3 days (median 4.32 IU/mL) after PEA, and were higher in discordant than concordant samples. Single-cell RNA sequencing showed FVIII gene expression in PEA specimen endothelial cells. Pseudo heparin resistance is common after PEA likely due to highly elevated postoperative FVIII levels indicating that anti-Xa reflects postoperative heparinization better than APTT in these patients. FVIII production by the pulmonary artery endothelium may participate in local prothrombotic processes important for CTEPH pathogenesis.

Safety of idarucizumab in the reversal of dabigatran at six tertiary care Ontario hospitals.

BACKGROUND: Idarucizumab, a monoclonal antibody fragment that reverses the anticoagulant effect of dabigatran, was approved for use in Canada in 2016. OBJECTIVE: Our objective was to assess the safety of idarucizumab among patients who received the drug within the first 3 years of its use in Canada. PATIENTS/METHODS: We performed a retrospective health records review of all idarucizumab use, excluding use in those <18 years of age, between May 16, 2016, and August 1, 2019, at six Ontario tertiary care hospitals. The primary outcome was mortality. The secondary outcomes were in-hospital arterial thrombotic event (ATE), in-hospital venous thromboembolism (VTE), length of hospital stay, and length of critical care stay. RESULTS: A total of 85 patients received idarucizumab during the study period for the following indications: 37 (43.5%) for spontaneous bleeding, 28 (32.9%) for traumatic bleeding, 11 (12.9%) for emergency surgeries/procedures, 5 (5.9%) for elective surgeries/procedures, and 4 (4.7%) for other indications. Nineteen patients (22.4%; 95% confidence interval [CI], 14.8%-32.3%) did not survive their hospitalization. During hospitalization, two patients (2.4%; 95% CI, 0.7%-8.2%) had ATE, and three patients (3.5%; 95% CI, 1.2%-9.9%) had VTE. The median length of stay was 8 (interquartile range [IQR], 2.5-13) days in hospital and 3 (IQR, 2-5) days in critical care. CONCLUSIONS: Compared with clinical trial data, we found a numerically higher rate of mortality and similar rate of ATE and VTE among patients treated with idarucizumab in the real world.