Recognizing the complexity of coagulation tests and currently used anticoagulants, we developed this illustrated review on bleeding assessment tools and common coagulation screening tests. Quantitative bleeding assessment tools (BATs) are available to standardize the bleeding history and improve the pretest probability prior to coagulation testing. We describe use of BATs and the principles, indications, and limitations of the prothrombin time (PT)/International Normalized Ratio, activated partial thromboplastin time (APTT), and 50:50 mix. Use of these tests to identify coagulation factor deficiencies, specific and nonspecific inhibitors, coagulopathy of liver disease, disseminated intravascular coagulation, and commonly used anticoagulant medications are reviewed. Current literature suggests that unnecessary coagulation testing is rampant. The PT and APTT have astoundingly low sensitivity (1.0%‐2.1%) for detection of clinically significant bleeding disorders. Thus, current guidelines recommend against the use of screening PT and APTT in preoperative patients undergoing noncardiac/vascular surgery.

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.

The risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear.Therefore, we conducted a systematic review and meta-analysis to estimate the incidence of recurrent VTE among women with COC-associated VTE, unprovoked

Background Patients with severe congenital hemophilia A (CHA) have a 25-40% lifetime risk of alloantibody (inhibitor) development to FVIII. Patients with acquired hemophilia A (AHA) spontaneously develop neutralizing autoantibodies to factor VIII. In both cases, patients require pro-hemostatic therapy with bypassing agents: recombinant factor VIIa (rFVIIa), activated prothrombin complex concentrate (aPCC) and more recently recombinant porcine factor VIII (rpFVIII). Anti-human FVIII (hFVIII) inhibitors typically bind to the A2 and C2 domains of the FVIII molecule. RpFVIII is an effective pro-hemostatic treatment for AHA and CHA given the immunologic difference in the A2 and C2 domains of the rpFVIII while maintaining sufficient hFVIII homology to act as an effective cofactor to human FIX in the intrinsic tenase. However, some anti-hFVIII antibodies cross-react with rpFVIII and may interfere with its hemostatic function. Cross-reacting antibodies were reported in 35% of subjects in a phase II/III trial prior to initiation of rpFVIII. Moreover, de novo rpFVIII inhibitors may develop during or after the treatment with rpFVIII and may affect its hemostatic function. Here we describe the largest case series to date on baseline cross-reactivity of rpFVIII inhibitors and post-treatment de novo inhibitor development in patients with CHA and AHA to address the paucity of published literature in this area. Aim First, we describe the frequency of baseline cross-reacting rpFVIII inhibitors in patients with AHA and CHA (with inhibitors) at our institution. Second, we describe the effect of baseline rpFVIII antibodies on FVIII recovery after treatment with rpFVIII. We also describe the frequency and timing of de novo rpFVIII inhibitor development after exposure to rpFVIII. Methods Institutional research ethics board approval was obtained. Electronic charts of patients admitted to our institution with AHA or CHA who underwent testing for rpFVIII inhibitors were reviewed retrospectively. RpFVIII inhibitor assay is performed in the special coagulation laboratory using the Nijmegen modified Bethesda assay. The patient sample is initially heat-treated at 57 Results Twenty-seven patients (7 CHA, 20 AHA) underwent testing for porcine inhibitors since assay availability in 2016. 61% (5/7 CHA, 11/20 AHA) of patients had a detectable rpFVIII inhibitor prior to exposure to rpFVIII; median titer 1.6 BU/ml (range 0.6-192). Eight patients with AHA with baseline cross-reacting inhibitors received rpFVIII. Of those, three achieved an initial FVIII recovery beyond 100% (132%, 148% and 177%) after approximately 100U/kg of rpFVIII and all three had very low anti-rpFVIII Bethesda titers (0.70, 0.85 and 0.9 BU/ml). Five patients did not achieve a FVIII recovery above 50% (46%, 46%, 40%, 36% and 0%) despite approximately 100U/kg of rpFVIII. Most patients who received rpFVIII were tested weekly for the duration of their treatment or hospital stay. Upon discharge, patients who were seen in clinic for follow up were tested for anti-hFVIII and anti-rpFVIII. Two AHA patients without a baseline inhibitor who received rpFVIII treatment developed a de novo inhibitor after 20 days (1 BU/ml) and 133 days (12 BU/ml), respectively. One AHA patient had a rise in baseline anti-rpFVIII titer after exposure to rpFVIII. Conclusion In conclusion, we found that 61% of patients with AHA and CHA tested for rpFVIII inhibitors had a detectable baseline cross-reacting inhibitor which is higher than previously described. Of those patients with a baseline inhibitor treated with rpFVIII, only 37.5% of patients had an appropriate rise in FVIII. Finally, 13% of patients without baseline inhibitors developed a de novo inhibitor after exposure to rpFVIII, an incidence comparable to previously published findings. Disclosures Pavenski: Bioverativ: Research Funding; Alexion: Honoraria, Research Funding; Octapharma: Research Funding; Shire: Honoraria; Ablynx: Honoraria, Research Funding. Teitel:BioMarin: Consultancy; CSL Behring: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Shire: Consultancy; Pfizer: Consultancy, Research Funding; Bayer: Consultancy, Research Funding. Sholzberg:Takeda: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding. OffLabel Disclosure: Recombinant porcine factor VIII is used to treated patients with congenital hemophilia A with allo inhibitors

Background Although combined oral contraceptives (COC) are considered a transient risk factor for venous thromboembolism (VTE), the risk of recurrence after discontinuation of anticoagulation is unclear. Few studies have focused on the risk of recurrence in this group; studies report variable results and are limited by small sample size. The risk of recurrence appears to be low, but this could relate to the young age of affected women. Deciphering the absolute VTE recurrence risk after a COC-associated VTE is crucial in helping clinicians and patients decide if anticoagulation could be discontinued after the initial treatment period. Objectives The objectives of this systematic review and meta-analysis are to estimate the incidence of recurrent VTE among women with COC-associated VTE, compared with women with unprovoked VTE. Methods We searched the following databases: Cochrane Central Register of Controlled Trial, Cochrane Database of Systematic Reviews, Embase Classic +Embase, and Medline ALL, all from the OvidSP platform, from the database's inception to July 2020. Additional studies were identified by screening citations from included studies. Prospective cohort studies, randomized controlled trials (RCTs), and meta-analyses of prospective cohort studies or RCTs were reviewed by two authors for study inclusion (Figure 1). Studies were included if women had objectively confirmed COC-associated VTE, received a minimum of three months of anticoagulation, discontinued COC prior to or at time of discontinuation of anticoagulation, time of follow-up began after anticoagulation was stopped, and recurrent VTE data was available. Studies were excluded if patients were systematically treated with an alternative pharmacologic agent intended to reduce the risk of recurrent VTE such as aspirin. Authors of identified papers were contacted for additional data on critical variables. If there were multiple publications from a cohort, the study with the longest follow up was included. Two authors extracted study data and assessed included studies for risk of bias using the Newcastle Ottawa Scale. Meta-analysis was done using a random effects Poisson regression model. Heterogeneity was assessed using the I-squared measure. Results Our systematic review included 19 studies with a total of 1,537 women (5,828 patient years of follow up) with an index COC-associated VTE, and 1,974 women (7,798 patient years of follow up) with an index unprovoked VTE. Authors contributed additional unpublished data in 16 of the 19 studies. Overall, studies were at low risk of bias, with a mean of 7 stars (out of a possible 9) in the Newcastle Ottawa Scale. Among the 19 studies, the incidence rate of VTE recurrence in women with COC-associated VTE was 1.22 per patient year (95% confidence interval (CI) 0.94 to 1.59, I 2 = 6.4%, 95% prediction interval (PI) 0.81 to 1.85) (Figure 2). The incidence rate of VTE recurrence in women with an index unprovoked VTE not associated with COC was 3.89 per patient year (95% CI 2.98 to 5.07, I 2 =74.2%, 95% PI 1.37 to 11.03). The unadjusted incidence rate ratio of recurrent VTE comparing women with COC-associated events to women with unprovoked events was 0.34 (95% CI 0.26 to 0.45, I 2 = 2.6%, 95% PI 0.26 to 0.46). Only three studies had age-adjusted comparisons, but each with a different effect measure so they could not be combined, with a relative risk ratio 0.4 (95% CI 0.2 to 0.8) (also adjusted for site of VTE and congenital thrombophilia) (Eischer 2014), a hazard ratio of 0.11 (95% CI 0.01 to 0.85) (Kearon 2019), and an incidence rate ratio of 1 (95% CI 0.3 to 3.2) (Le Moigne 2013). Conclusions The estimated risk of VTE recurrence after a COC-associated VTE is low, and is lower compared to women with unprovoked VTE, however this comparison may be confounded by age. With only a minority of studies providing age adjusted analyses, the true difference remains unknown. Our meta-analysis is strengthened by the substantial contribution of unpublished data from individual study authors. This can help to guide clinicians and patient shared decision-making on the duration of anticoagulation. Figure 1 Figure 1. Disclosures Le Gal: LEO Pharma: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Bayer: Honoraria; Aspen: Honoraria; Sanofi: Honoraria. Schulman: Boehringer-Ingelheim: Research Funding; Octapharma: Research Funding. Skeith: CSL Behring: Research Funding; Leo Pharma: Honoraria; Sanofi: Honoraria.