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BACKGROUND: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide. METHODS: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries. FINDINGS: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %). INTERPRETATION: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population. ispartof: THROMBOSIS RESEARCH vol:222 pages:31-39 ispartof: location:United States status: published

BACKGROUND The incidence of pulmonary embolism has been increasing, but its case-fatality rate is decreasing, suggesting a lesser severity of illness. The clinical importance of patients with pulmonary embolism isolated to the subsegmental vessels is unknown. OBJECTIVE To determine the rate of recurrent venous thromboembolism in patients with subsegmental pulmonary embolism managed without anticoagulation. DESIGN Multicenter prospective cohort study. (ClinicalTrials.gov: NCT01455818). SETTING Eighteen sites between February 2011 and February 2021. PATIENTS Patients with isolated subsegmental pulmonary embolism. INTERVENTION At diagnosis, patients underwent bilateral lower-extremity venous ultrasonography, which was repeated 1 week later if results were negative. Patients without deep venous thrombosis did not receive anticoagulant therapy. MEASUREMENTS The primary outcome was recurrent venous thromboembolism during the 90-day follow-up period. RESULTS Recruitment was stopped prematurely because the predefined stopping rule was met after 292 of a projected 300 patients were enrolled. Of the 266 patients included in the primary analysis, the primary outcome occurred in 8 patients, for a cumulative incidence of 3.1% (95% CI, 1.6% to 6.1%) over the 90-day follow-up. The incidence of recurrent venous thromboembolism was 2.1% (CI, 0.8% to 5.5%) and 5.7% (CI, 2.2% to 14.4%) over the 90-day follow-up in patients with single and multiple isolated subsegmental pulmonary embolism, respectively. No patients had a fatal recurrent pulmonary embolism. LIMITATION The study was restricted to patients with low-risk subsegmental pulmonary embolism. CONCLUSION Overall, patients with subsegmental pulmonary embolism who did not have proximal deep venous thrombosis had a higher-than-expected rate of recurrent venous thromboembolism. PRIMARY FUNDING SOURCE Heart and Stroke Foundation of Canada and French Ministry of Health Programme Hospitalier de Recherche Clinique.

Objective To determine the efficacy and safety of dalteparin postoperative bridging treatment versus placebo for patients with atrial fibrillation or mechanical heart valves when warfarin is temporarily interrupted for a planned procedure. Design Prospective, double blind, randomised controlled trial. Setting 10 thrombosis research sites in Canada and India between February 2007 and March 2016. Participants 1471 patients aged 18 years or older with atrial fibrillation or mechanical heart valves who required temporary interruption of warfarin for a procedure. Intervention Random assignment to dalteparin (n=821; one patient withdrew consent immediately after randomisation) or placebo (n=650) after the procedure. Main outcome measures Major thromboembolism (stroke, transient ischaemic attack, proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, peripheral embolism, or vascular death) and major bleeding according to the International Society on Thrombosis and Haemostasis criteria within 90 days of the procedure. Results The rate of major thromboembolism within 90 days was 1.2% (eight events in 650 patients) for placebo and 1.0% (eight events in 820 patients) for dalteparin (P=0.64, risk difference −0.3%, 95% confidence interval −1.3 to 0.8). The rate of major bleeding was 2.0% (13 events in 650 patients) for placebo and 1.3% (11 events in 820 patients) for dalteparin (P=0.32, risk difference −0.7, 95% confidence interval −2.0 to 0.7). The results were consistent for the atrial fibrillation and mechanical heart valves groups. Conclusions In patients with atrial fibrillation or mechanical heart valves who had warfarin interrupted for a procedure, no significant benefit was found for postoperative dalteparin bridging to prevent major thromboembolism. Trial registration Clinicaltrials.gov NCT00432796 .

Importance: Patients with atrial fibrillation (AF) who use a direct oral anticoagulant (DOAC) and request elective surgery or procedure present a common clinical situation yet perioperative management is uncertain. Objective: To investigate the safety of a standardized perioperative DOAC management strategy. Design, Setting, and Participants: The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study conducted at 23 clinical centers in Canada, the United States, and Europe enrolled and screened patients from August 1, 2014, through July 31, 2018. Participants (n = 3007) had AF; were 18 years of age or older; were long-term users of apixaban, dabigatran etexilate, or rivaroxaban; were scheduled for an elective surgery or procedure; and could adhere to the DOAC therapy interruption protocol. Interventions: A simple standardized perioperative DOAC therapy interruption and resumption strategy based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. The DOAC regimens were omitted for 1 day before a low-bleeding-risk procedure and 2 days before a high-bleeding-risk procedure. The DOAC regimens were resumed 1 day after a low-bleeding-risk procedure and 2 to 3 days after a high-bleeding-risk procedure. Follow-up of patients occurred for 30 days after the operation. Main Outcomes and Measures: Major bleeding and arterial thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack) and the proportion of patients with an undetectable or minimal residual anticoagulant level (

Background Parenteral anticoagulants and vitamin K antagonists (VKAs) have constituted the cornerstone of venous thromboembolism (VTE) treatment. Meanwhile, direct oral anticoagulants (DOACs) provide physicians with an alternative. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE observes real-world treatment practices. Objectives Describe initial anticoagulation (AC) treatment patterns in VTE patients who received parenteral AC, VKAs, and/or DOACs within ±30 days of diagnosis. Methods VTE patients were categorized into parenteral AC only, parenteral AC with transition to VKA, VKA only, parenteral AC with transition to DOAC, and DOAC only. Results A total of 9647 patients were initiated on AC treatment alone. 4781 (49.6%) patients received DOACs ± parenteral ACs; 3187 (33.0%), VKA ± parenteral ACs; and 1679 (17.4%) parenteral ACs alone. Rivaroxaban was the most frequently used DOAC (79.4%). DOACs were more frequently used in North America/Australia (58.1%), Europe (52.2%), and Asia (47.6%) than in Latin America (29.7%) and the Middle East/South Africa (32.5%). In patients with suspected VTE, most received parenteral AC monotherapy (67.7%). Patients with deep vein thrombosis were more likely to receive DOACs alone than those with pulmonary embolism with or without deep vein thrombosis (36.2% vs 25.9%). Active cancer patients received parenteral AC alone (58.9%), with 25.5% receiving DOAC ± parenteral AC and 12.8% parenteral AC and VKA. A total of 46.5% of pregnant patients received parenteral AC monotherapy, 34.0% were treated with VKA ± parenteral AC, and 19.5% received a DOAC (± parenteral AC). Conclusion AC treatment patterns vary by patient population, geographic region and site of VTE. Guidelines for AC therapy are not always adhered to.

Background The perioperative management of patients who take a direct oral anticoagulant (DOAC) for atrial fibrillation and require treatment interruption for an elective surgery/procedure is a common clinical scenario for which best practices are uncertain. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study is designed to address this unmet clinical need. We discuss the rationale for the PAUSE design and analysis plan as well as the rationale supporting the perioperative DOAC protocol. Methods PAUSE is a prospective study with three parallel cohorts, one for each DOAC, to assess a standardized but patient-specific perioperative management protocol for DOAC-treated patients with atrial fibrillation. The perioperative protocol accounts for DOAC type, patient's renal function and surgery/procedure-related bleeding risk. The primary study aim is to demonstrate the safety of the PAUSE protocol for the perioperative management of each DOAC. The secondary aim is to determine the effect of the pre-procedure interruption on residual anticoagulation when measured by the dilute thrombin time for dabigatran and anti-factor Xa levels for rivaroxaban and apixaban. The study hypothesis is that the perioperative management protocol for each DOAC is safe for patient care, defined by expected risks for major bleeding of 1% (80% power to exclude 2%), and for arterial thromboembolism of 0.5% (80% power to exclude 1.5%) in each DOAC group. Conclusion The PAUSE study has the potential to establish a standard-of-care approach for the perioperative management of DOAC-treated patients. The PAUSE management protocol is designed to be easily applied in clinical practice, as it is standardized and also patient specific.

Summary Background Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). Objective In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. Methods We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. Results Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05–1.45) and 1.25 (95% CI 1.05–1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07–1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose–response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. Conclusions In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.

Summary 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.

SummaryAcute deep venous thrombosis (DVT) causes leg pain. Elastic compression stockings (ECS) have potential to relieve DVT-related leg pain by diminishing the diameter of distended veins and increasing venous blood flow. It was our objective to determine whether ECS reduce leg pain in patients with acute DVT. We performed a secondary analysis of the SOX Trial, a multicentre randomised placebo controlled trial of active ECS versus placebo ECS to prevent the post-thrombotic syndrome.The study was performed in 24 hospital centres in Canada and the U.S. and included 803 patients with a first episode of acute proximal DVT. Patients were randomised to receive active ECS (knee length, 30–40 mm Hg graduated pressure) or placebo ECS (manufactured to look identical to active ECS, but lacking therapeutic compression). Study outcome was leg pain severity assessed on an 11-point numerical pain rating scale (0, no pain; 10, worst possible pain) at baseline, 14, 30 and 60 days after randomisation. Mean age was 55 years and 60% were male. In active ECS patients (n=409), mean (SD) pain severity at baseline and at 60 days were 5.18 (3.29) and 1.39 (2.19), respectively, and in placebo ECS patients (n=394) were 5.38 (3.29) and 1.13 (1.86), respectively. There were no significant differences in pain scores between groups at any assessment point, and no evidence for subgroup interaction by age, sex or anatomical extent of DVT. Results were similar in an analysis restricted to patients who reported wearing stockings every day. In conclusion, ECS do not reduce leg pain in patients with acute proximal DVT.

In the Original Article by Douketis et al. "The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study for Patients on a Direct Oral Anticoagulant who Need an Elective Surgery or Procedure: Design and Rationale (Thromb Haemost 2017;117:2415-2424; DOI: 10.1160/TH17-08-0553), the authors have identified two errors that they wish to correct: First, on page 2419, second paragraph, Clinical Outcomes subheading, the authors state that, "The primary clinical outcomes are arterial thromboembolism, comprising stroke (ischemic or haemorrhagic), systemic embolism or transient ischemic attack and major bleeding. The inclusion of "haemorrhagic stroke is incorrect as only ischemic strokes are included in their definition of an arterial thromboembolism outcome. The definitions of study outcomes are correctly indicated in Appendix A (pg. 2424) of the paper, where the authors state: "The second primary outcome is arterial thromboembolism, comprising (1) ischemic stroke, defined as any new focal neurologic deficit that persists for 24 hours or any new focal neurologic deficit of any duration that occurs with evidence of acute infarction on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain; (2) systemic embolism, defined as symptomatic embolism to upper or lower extremity or abdominal organ, confirmed intraoperatively or by objective imaging studies (e.g. CT angiography) and (3) transient ischemic attack, defined as symptomatic focal neurologic deficit (lasting typically 1 hour) that occurs with no evidence of acute infarction on CT/MRI of the brain. Second, the depiction of the pre-procedure interruption interval for dabigatran-treated patientswith a CrCl 50 mL/min is incorrect in Figure 1 (pg. 2418) of the paper, as the arrow should extend so it reflects 2 days off treatment (i.e., day -2 and day -1). The incorrect (currently published) version is shown below, with incorrect area shaded in red: (Figure Presented).

Early graft failure is a complex and challenging clinical condition faced by vascular surgeons performing infrainguinal bypass surgery. This case describes a patient with undiagnosed thrombocytosis undergoing urgent open revascularization for critical limb ischemia. The operative case was complicated by recurrent on-table acute thrombosis that was successfully managed with intravenous glycoprotein IIb/IIIa antagonism with eptifibatide. This is a novel case of its use for on-table salvage of an infrainguinal bypass graft. This case report outlines this challenging clinical problem and a novel use for glycoprotein IIb/IIIa antagonists.

SummaryThe anticoagulant effect of warfarin is influenced by variations in vitamin K intake. Concomitant use of daily low-dose oral vitamin K (LDVK) and warfarin may improve INR stability. We hypothesise that administration of LDVK improves INR control. To test this hypothesis we performed a multi-centre, placebo-controlled, randomised trial conducted at four university-affiliated hospitals in Canada. Patients on chronic warfarin therapy received oral vitamin K 150 mcg daily or a matching placebo for a total of six months after a one-month run in period. The primary outcome was a comparison of mean time in therapeutic range (TTR) in LDVK and placebo group during a six-month-period. The secondary outcome was number of INR excursions 4.5. There was no significant difference in the final TTR between the two groups (65.1 % vs 66 %, p =0.8). Mean TTR in both LDVK and placebo groups were statistically increased compared with prior to the study. The number of INR excursions were significantly decreased in the LDVK group (9.4 % and 5.4 %, absolute difference [pre- minus post-] = 4 %, 95 % CI, 2 to 6 %, p-value

• A subset of women enrolled in the REVERSE II study underwent a second, blinded assessment for signs of post-thrombotic syndrome (hyperpigmentation, edema, redness).

We describe the first sandwich enzyme-linked immunosorbent assay (ELISA) capable of recognizing both rat and human activated coagulation Factor XII (FXIIa). Increased plasma concentrations of FXIIa have been associated with adverse outcomes in several cardiovascular disease states. In humans, the FXIIa antigen in plasma is quantified by a direct sandwich ELISA employing an antibody (mAb 2/215) raised against its β-fragment (β-FXIIa), but this assay is unable to detect rat β-FXIIa antigen. Thus, experimental models are at present limited in their capacity to reveal mechanisms by which FXIIa might contribute to cardiovascular pathology. Consistent with overlap between human and rat FXIIa protein epitope sequences, Western blot analysis and ELISA demonstrate that another previously developed antibody against human FXIIa (mAb 201/9) detects β-FXIIa in both human and rat plasma, with no evidence for cross-reactivity with the FXII zymogen or FXIIa complexed with its endogenous inhibitor. The mAb 201/9 based ELISA identified similar elevations in FXIIa in plasma from rats and humans with chronic renal failure. The capacity of this ELISA to identify rat plasma FXIIa has potential application to a wide range of experimental models of human cardiovascular disease.

Introduction: The perioperative management of patients who are taking a direct oral anticoagulant (DOAC) for atrial fibrillation (AF) and require an elective surgery/procedure is uncertain. No studies have addressed the timing of perioperative DOAC interruption and resumption, and if perioperative heparin bridging and coagulation function testing are needed. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study hypothesized that a simple, standardized perioperative management strategy, based on DOAC-specific interruption and resumption intervals, that foregoes perioperative heparin bridging and coagulation function testing, is safe for patient care, with associated low rates of major bleeding (1%) and arterial thromboembolism (0.5%). We postulated that this management yields a high proportion of patients (>90%) with a minimal to no DOAC level at surgery/procedure. Methods: PAUSE is a prospective study with 3 parallel DOAC cohorts of patients with AF taking apixaban, dabigatran or rivaroxaban and requiring anticoagulant interruption for an elective surgery/procedure. Patients were managed using a standardized protocol based on DOAC pharmacokinetic properties, procedure-associated bleeding risk (Appendix 1) and creatinine clearance (CrCl). DOACs were interrupted for 1 day before and after surgery for a low bleed risk surgery and 2 days before and after a high bleed surgery; longer interruption was done in patients on dabigatran with a CrCl Results: We enrolled 3007 patients from 23 sites in Canada, the U.S. and Europe (Appendix 4). The patient characteristics were (Figure 2): mean age 72.5 years; 66.1% male; 33.5% high bleeding risk surgery/procedure, with 1257 patients in the apixaban cohort, 668 in the dabigatran cohort and 1082 in the rivaroxaban cohort (Table 1). DOAC interruption and resumption intervals are shown in Table 2. The 30-day postoperative rate (95% CI) of major bleeding was 1.35% (0-2.00) in the apixaban cohort, 0.90% (0-1.73) in the dabigatran cohort and 1.85% (0-2.65) in the rivaroxaban cohort; the rate (95% CI) of arterial thromboembolism was 0.16% (0-0.48) in the apixaban cohort, 0.6% (0-1.33) in the dabigatran cohort and 0.37% (0-0.82) in the rivaroxaban cohort (Table 3). There were 2541 (84.5%) patients with preoperative DOAC levels measured: a level Conclusions: In patients with AF who were taking a DOAC (apixaban, dabigatran, rivaroxaban) and required anticoagulant interruption for an elective surgery/procedure, using a standardized DOAC-specific perioperative management strategy was safe for patient care, with associated low rates of perioperative MB (90% overall; 98.8% at high bleeding risk) had a minimal or no residual DOAC level at the time of the surgery/procedure. PAUSE is the largest study, to date, that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care. Study Funding: CIHR (313156) and the H&S Foundation of Canada (G-14-0006136). Aniara-Hyphen Biomed (assays). Acknowledgments: We thank Drs. Walter Ageno, David Garcia, Lehana Thabane, Wendt Lim, Lori Linkins, William Ristevski, and Demetrios J. Sahlas. Also, Kayla Lucier, Grace Wang, Tara McDougall, and HRLMP and CRLB. Supported by CanVector and REDCap. Disclosures Douketis: Bayer: Other: Advisory Board; Janssen: Consultancy; BMS: Other: Advisory Board; Biotie: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; The Medicines Company: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Portola: Other: Advisory Board; Pfizer: Other: Advisory Board. Spyropoulos:Janssen Scientific Affairs, LLC: Consultancy. Carrier:Bayer: Honoraria; Leo Pharma: Research Funding; Pfizer: Honoraria; BMS: Honoraria, Research Funding. Vanassche:Bayer: Consultancy; Boehringer Ingelheim: Consultancy; BMS/Pfizer: Consultancy. Verhamme:Bayer: Honoraria, Research Funding; Medtronic: Honoraria; Portola: Honoraria; Boehringer Ingelheim: Honoraria; Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Shivakumar:Pfizer: Honoraria; Servier: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria. Gross:Pfizer: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria; Servier: Honoraria. Lee:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Servier: Honoraria; LEO Pharma: Consultancy, Research Funding; Bayer: Consultancy, Honoraria. Le Templier:BMS-pfizer: Honoraria. Wu:Leo Pharma: Honoraria; Pfizer: Honoraria; BMS-Pfizer: Honoraria. Coppens:Bayer: Honoraria, Other: Non-financial support, Research Funding; CSL Behring: Honoraria, Other: non-financial support, Research Funding; Uniqure BV: Research Funding. Arnold:Bristol Myers Squibb: Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding. Caprini:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Recovery Force: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizor: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Membership on an entity's Board of Directors or advisory committees. Summer:Octapharma: Honoraria. Schulman:Daiichi-Sankyo: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Boehringer-Ingelheim: Honoraria, Research Funding.

On behalf of the Hokusai VTE Cancer Investigators The treatment of cancer-associated venous thromboembolism (VTE) is challenging because these patients are at increased risk of both recurrent VTE and major bleeding. Low-molecular-weight heparin (LMWH) treatment is standard care for these patients, but requires daily subcutaneous injections. Guidelines recommend LMWH treatment for 6 months, but the risk-benefit beyond this time is uncertain. Direct oral anticoagulants are used for the treatment of VTE in patients without cancer, but their role in patients with cancer- associated VTE is uncertain. In this randomized, open-label non-inferiority trial, cancer patients with acute symptomatic or incidental VTE were assigned to receive LMWH for a minimum of 5 days followed by the oral factor Xa inhibitor edoxaban at a dose of 60 mg once daily (or 30 mg once daily in patients with a creatinine clearance of 30 to 50 ml per minute or a body weight below 60 kg), or subcutaneous dalteparin 200 units per kg once daily for one month followed by 150 units per kg thereafter. Patients received these regimens for up to 12 months. The primary outcome was the composite of the first recurrent VTE or major bleeding event during follow-up for 12 months. Secondary outcomes included recurrent VTE and major bleeding analyzed separately, and survival free of recurrent VTE or major bleeding. The study hypothesis was that edoxaban would be noninferior to dalteparin for the primary outcome with an upper 95% confidence interval [CI] for the hazard ratio below 1.5, and a two-sided alpha of 0.05. All outcomes were independently adjudicated by a committee without knowledge of treatment allocation. This committee also assessed the clinical severity of major bleeding events using categorical criteria defined a priori (categories 1 to 4). From July 2015 through December 2016 a total of 1050 patients were enrolled at 114 centers in 13 countries; 525 were randomized to edoxaban and 525 to dalteparin. At entry, pulmonary embolism with or without deep-vein thrombosis was present in 657 patients (63%) while the remainder had isolated deep-vein thrombosis. Of the 1050 patents, 706 (67%) had symptomatic VTE and the rest were incidental. Active cancer at entry was present in 97% of the patients and 53% had metastatic disease. 1046 patients were included in the modified-intention-to-treat analysis. The primary outcome occurred in 67 of 522 patients (12.8%) in the edoxaban group compared with 71 of 524 patients (13.5%) in the dalteparin group (hazard ratio with edoxaban, 0.97; 95% CI, 0.70 to 1.36; P = 0.0056 for noninferiority) for a risk difference (edoxaban minus dalteparin) of - 0.7% (95% CI, - 4.8 to 3.4). The difference in risk for recurrent VTE was -3.8 % (95% CI, -7.1 to -0.4), whereas the corresponding difference in risk for major bleeding was 3.1% (95% CI, 0.5 to 5.7). The frequencies of severe major bleeding events (categories 3 and 4) were similar during treatment with edoxaban or dalteparin (12 patients in each group respectively). Survival at 12 months free of recurrent VTE and major bleeding in the edoxaban and dalteparin groups was similar (55.0% and 56.5% respectively). Oral edoxaban for up to 12 months is noninferior to subcutaneous dalteparin for the treatment of cancer-associated VTE. Disclosures Raskob: BMS: Consultancy, Honoraria; Eli Lilly: Consultancy; Janssen: Consultancy; Johnson and Johnson: Consultancy; Pfizer: Consultancy, Honoraria; Portola: Consultancy; Boehringer-Ingelheim: Consultancy; Medscape: Honoraria; Bayer Healthcare: Consultancy; Daiichi Sankyo: Consultancy, Honoraria. Van Es:Daiichi Sankyo: Honoraria; Pfizer: Honoraria. Verhamme:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Bayer Healthcare: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy; Medscape: Honoraria; Leo: Honoraria, Research Funding; Sanofi Aventis: Research Funding; Medtronic: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carrier:Daiichi Sankyo: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Leo: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria. Di Nisio:Daiichi: Consultancy, Honoraria. Garcia:Daiichi Sankyo: Honoraria, Research Funding; BMS: Consultancy; Boehringer Ingelheim: Consultancy; Janssen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria; Medscape: Honoraria; Incyte: Consultancy, Honoraria, Research Funding. Grosso:Daiichi Sankyo: Employment. Kakkar:Daiichi Sankyo: Consultancy, Honoraria; Bayer Healthcare: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi SA: Consultancy, Honoraria; Verseon: Consultancy, Honoraria. Kovacs:Daiichi Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Bristol Myers Squibb: Research Funding. Mercuri:Daiichi Sankyo: Employment, Patents & Royalties: pending properties of edoxaban . Meyer:BMS Pfizer: Research Funding; Leo: Other: travel support; Stago: Other: travel support. Segers:Ionis: Research Funding; Daiichi Sankyo: Research Funding; Janssen: Research Funding. Shi:Daiichi Sankyo: Employment. Wang:Daiichi Sankyo: Honoraria. Yeo:Daiichi Sankyo: Honoraria, Research Funding; Bayer Healthcare: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Leo: Consultancy, Honoraria. Zhang:Daiichi Sankyo: Employment. Zwicker:Daiichi Sankyo: Honoraria; Quercegen Pharma: Research Funding; Parexel: Consultancy. Weitz:Daiichi-Sankyo: Consultancy, Honoraria; Ionis Pharmaceuticals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis Pharmaceuticals: Consultancy, Honoraria; Merck & Co., Inc.: Consultancy, Honoraria; Pfizer, Inc.: Consultancy, Honoraria; Portola Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Medscape: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy; Bayer HealthCare Pharmaceuticals: Consultancy, Honoraria. Büller:Daiichi Sankyo: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Portola: Consultancy; Medscape: Honoraria; Eli Lilly: Consultancy; Sanofi Aventis: Consultancy; Ionis: Consultancy.

Recombinant activated factor VII (rFVIIa) is currently not approved by Health Canada or the Food and Drug Administration for treating excessive blood loss in nonhemophiliac patients undergoing on-pump cardiac surgery, but is increasingly being used “off-label” for this indication. A Canadian Consensus Conference was convened to generate recommendations for rFVIIa use in on-pump cardiac surgery. Methods: The panel undertook a literature review of the use of rFVIIa in both cardiac and non-cardiac surgery. Appropriateness, timing, and dosage considerations were addressed for three cardiac surgery indications: prophylactic, routine, and rescue uses. Recommendationswere based on evidencefromtheliterature and derived by consensus following recognized grading procedures. The panel recommended against prophylactic or routine use of rFVIIa, as there is no evidence at this time that the benefits of rFVIIa outweigh its potential risks compared with standard hemostatic therapies. On the other hand, the panel made a weak recommendation (grade 2C) for the use of rFVIIa (one to two doses of 35–70 μg·kg-1) as rescue therapy for blood loss that is refractory to standard hemostatic therapies, despite the lack of randomized controlled trial data for this indication. In cardiac surgery, the risks and benefits of rFVIIa are unclear, but current evidence suggests that its benefits may outweigh its risks for rescue therapy in selected patients. Methodologically rigorous studies are needed to clarify its risk-benefit profile in cardiac surgery patients. Le facteur VII active recombinant (rFVIIa) n’est actuellement approuve ni par Sante Canada ni par la Food and Drug Administration (FDA) pour le traitement du saignement excessif chez les patients non-hemophiles subissant une chirurgie cardiaque avec circulation extra-corporelle (CEC); neanmoins, il est de plus en plus utilise de maniere ‘non conforme’ pour cette indication. Une Conference canadienne de consensus s’est reunie afin de rediger des recommandations quant a l’utilisation du rFVIIa lors de la chirurgie cardiaque avec CEC. Le panel a entrepris une revue de la litterature traitant de l’utilisation du rFVIIa en chirurgies cardiaque et non cardiaque. Des considerations quant a la justification, au moment de l’administration et a la posologie ont ete evaluees pour trois indications en chirurgie cardiaque: les utilisations prophylactique, de routine ou de sauvetage. Les recommandations, basees sur des donnees probantes tirees de la litterature, ont ete interpretees par un consensus suivant des procedures de gradation reconnues. Le panel s’est prononce contre une utilisation prophylactique ou de routine du rFVIIa, etant donne qu’il n’existe actuellement pas de preuve que les bienfaits du rFVIIa l’emportent sur les risques potentiels encourus en comparaison des therapies hemostatiques standard. En revanche, le panel a enonce une recommandation faible (note 2C) en faveur de l’utilisation du rFVIIa (une a deux doses de 35–70 μg·kg-1) comme therapie de sauvetage en cas de saignement refractaire aux therapies hemostatiques standard et ce, malgre le manque de donnees d’etudes randomisees controlees concernant cette indication. En chirurgie cardiaque, les risques et bienfaits du rFVIIa ne sont pas clairs; toutefois, les donnees actuelles suggerent que ses bienfaits pourraient contrebalancer ses risques dans les cas de therapie de sauvetage chez certains patients. Des etudes methodologiquement rigoureuses sont necessaires afin de clarifier le profil risque/benefice du rFVIIa pour les patients de chirurgie cardiaque.

L'accident vasculaire cerebral et l'accident ischemique transitoire chez les patients porteurs d'un foramen ovale permeable qui presentent un accident vasculaire cerebral cryptogenique. Contexte: Parmi les patients qui presentent un accident vasculaire cerebral (AVC) cryptogenique, 40% sont porteurs d'un foramen ovale permeable (FOP) qui peut etre a l'origine d'une embolie paradoxale au cerveau. Les differentes options therapeutiques sont: les antiplaquettaires, les anticoagulants, un dispositif percutane et la fermeture chirurgicale. Notre hypothese etait que le taux de recidive de l'accident ischemique transitoire (AIT) ou de l'AVC est different selon que le patient recoit l'un ou l'autre de ces traitements. Methodes: Il s'agit d'une etude prospective de tous les patients porteurs d'un FOP ayant subi un AVC ou un AIT cryptogenique depuis janvier 1997 et qui ont ete suivis jusqu'en juin 2003. Le choix du traitement etait individualise. Le critere d'evaluation principal etait la recidive d'AVC. Le critere d'evaluation secondaire etait compose de l'AVC, de l'AIT et du deces d'origine vasculaire. Resultats: Notre cohorte etait constituee de 121 patients dont 64 etaient des hommes (53%). L'âge median etait de 43 ans. Soixante-neuf pour cent ont consulte pour un AVC et 31% pour un AIT. Quarante pour cent avaient un ou plusieurs facteurs de risque vasculaires et 24% avaient un anevrisme septal auriculaire. Trente-quatre pour cent ont recu des antiplaquettaires, 17% ont ete anticoagules, 39% ont recu un dispositif percutane et 11% ont subi une occlusion chirurgicale. Au cours du suivi, 16 patients ont subi une recidive, soit un AVC chez 7 et un AIT chez 9. Neuf de ces patients etaient sous antiplaquettaires, 3 patients etaient anticoagules et 4 patients avaient recu un dispositif percutane. En comparant les quatre traitements, on note une tendance a observer plus d'AVC sous traitement antiplaquettaire (p = 0,072); la difference etait significative pour le critere d'evaluation compose (p = 0,012). La difference entre la fermeture et les traitements medicaux etait significative tant en ce qui concerne le critere d'evaluation principal (p = 0,014) que le critere d'evaluation secondaire (p = 0,008), en faveur de la fermeture. L'âge et l'evenement precedant l'etude predisait l'issue. Conclusion: Moins de recidives ont ete observees chez les patients qui ont subi une occlusion du FOP. Les complications de la chirurgie et de l'implantation d'un dispositif percutane etaient autolimitees.

In Canada, hydroxyethyl starch 264/0.45 (HES 264/0.45; molar weight 264 kDa, molar substitution 0.45) has largely replaced albumin as the colloidal fluid of choice for perioperative intravascular volume expansion. The maximum recommended dose of HES 264/0.45 is 28 mL/kg; however, there are no clinical data supporting this limit. In this study we compared the hemostatic effects of HES 264/0.45 versus 5% albumin in doses up to 45 mL/kg over 24 h during major reconstructive head and neck surgery. Fifty patients were randomized to receive HES 264/0.45 or 5% human albumin from the induction of anesthesia until 24 h thereafter. Both albumin and HES 264/0.45 effectively maintained physiologic variables in the perioperative and postoperative periods. The partial thromboplastin time and international normalized ratio were significantly increased in the HES 264/0.45 group compared with the albumin group after infusion of 30 mL/kg and 45 mL/kg (P0.05). Factor VIII activity and von Willebrand factor level were significantly reduced in the HES 264/0.45 group compared with the albumin group after infusion of 15 mL/kg, 30 mL/kg, and 45 mL/kg (P0.05). Significantly more subjects in the HES 264/0.45 group received allogeneic red blood cell transfusions (P0.02). We conclude that HES 264/0.45 infusions30 mL/kg over 24 h impair coagulation to a greater extent than albumin, possibly leading to more allogeneic transfusions.

SummaryPreliminary evidence suggests that use of antipsychotic drugs is associated with an increased risk of venous thromboembolism.To evaluate the relationship between antipsychotic or antidepressant drug use and venous thromboembolism among adults aged 65 years and older.Retrospective cohort study using linked health care administrative databases over a nine year period.The entire province of Ontario, Canada.Individuals aged 65 years and over exclusively prescribed either antipsychotic drugs (n = 22514), antidepressant drugs (n = 75649) or thyroid replacement hormones (33033), the referent control group. We excluded those with an antecedent history of cardiovascular disease, venous thromboembolism or cancer, as well as those dispensed warfarin before study entry.Diagnosis of deep vein thrombosis or pulmonary embolism.Relative to those prescribed thyroid hormones, neither anti-depressant (adjusted hazard ratio 1.02, 95% CI 0.91-1.14) nor anti-psychotic (adjusted hazard ratio 1.13, 95% CI 0.96-1.32) drug use was associated with an increased risk for deep vein thrombosis. Similar risk estimates were found for deep vein thrombosis or pulmonary embolism. In a sub-group analysis, only butyrophenone use was found to be associated with a slightly increased risk of deep vein thrombosis (adjusted HR 1.51, 95% CI 1.23-1.86) as well as deep vein thrombosis or pulmonary embolism (adjusted HR 1.43, 95% CI 1.18-1.74).In a large cohort of adults aged 65 years and older, neither antipsychotic or antidepressant drug use was associated with an increased risk of venous thromboembolism, with the exception of a slightly increased risk among those prescribed butyrophenones. Further data are required before use of these psychoactive drugs can be considered a risk factor for venous thromboembolism.

Activated coagulation Factor XII (FXIIa) infusion increases peripheral resistance (TPR) and mean arterial pressure (MAP) of Brown Norway but not plasma kininogen deficient Brown Norway Katholiek (BNK) rats. FXIIa concentrations are elevated in hypertensive end-stage renal disease patients receiving conventional haemodialysis (CHD). Conversion to nocturnal haemodialysis (NHD) lowers peripheral resistance and MAP.To determine whether the plasma coagulation FXIIa-kallikrein-kinin axis contributes to the hypertension of chronic kidney disease (CKD).Plasma FXIIa and haemodynamic data were acquired in 11 CHD patients before and after 2 months of NHD. Cardiac and systemic haemodynamics of Brown Norway and BNK rats rendered hypertensive and uremic by 5/6 nephrectomy (NX) were determined before and after acute FXIIa inhibition.FXIIa was increased three-fold in CHD patients relative to control plasma (P0.05). After conversion to NHD, both ΔMAP and ΔTPR correlated with ΔFXIIa. In rats, plasma FXIIa was three-fold higher in both NX groups than respective SHAM controls (all P0.05), but MAP (147 ± 4 vs. 133 ± 2 mmHg; P0.05) and TPR (2.8 ± 0.2 vs. 2.3 ± 0.2 units; P0.05) were greater in Brown Norway NX (n = 16) than in BNK (n = 15) NX rats. FXIIa correlated with MAP only in Brown Norway NX, and plasma catecholamines were increased relative to SHAM only in Brown Norway NX (P0.05). In Brown Norway NX rats, FXIIa inhibitor infusion decreased MAP (-12 mmHg) and TPR (-0.5 Units) (both P0.05), and halved catecholamines (P0.05). No such changes occurred in BNK NX rats.FXIIa-kininogen mediated vasoconstriction contributes significantly to CKD hypertension in Brown Norway rats; this novel mechanism may be active in humans with CKD.

Background. The predominant renal elimination of low molecular weight heparin (LMWH) has raised concerns regarding the safety of therapeutic dose LMWH in patients with renal impairment, particularly those with Cockcroft Gault creatinine clearance (CrCl) Aims. To assess for tinzaparin accumulation in patients with venous thromboembolism (VTE) and varying degrees of renal impairment using serial trough anti-Xa level measurements. The degree of accumulation occurring in patients with CrCl Methods. Prospective multicenter cohort study of patients with objectively confirmed VTE treated with tinzaparin (Tinzaparin in Renal Insufficient Venous Thromboembolism (TRIVET) study; NCT00186745). Informed consent was obtained and the study approved by the ethics board at each site. Patients were stratified into 4 groups based on calculated CrCl (ml/min): >60, 30-60, 0.5 IU/mL which resulted in a predefined dose reduction. Bleeding and recurrent thrombotic events were recorded. Results. 148 patients were enrolled from 5 centers (Table 1). A total of 29 patients had CrCl 60 ml/min as the comparison, trough anti-Xa levels were significantly higher in CrCl Conclusion. Therapeutic dose tinzaparin is associated with higher mean trough anti-Xa levels in patients with CrCl Disclosures Lim: Pfizer: Honoraria; Leo Pharma: Honoraria, Research Funding. Crowther:Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Daichii: Honoraria; Daichii: Honoraria; Daichii: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Daichii: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AKP America: Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daichii: Honoraria; Alexion: Consultancy, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daichii: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria; Alexion: Consultancy, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Alexion: Consultancy, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Alexion: Consultancy, Speakers Bureau; Daichii: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; AKP America: Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: Honoraria; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daichii: Honoraria; Daichii: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Daichii: Honoraria; Celgene: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Celgene: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Alexion: Consultancy, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Ortho Clinical Diagnostics: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichii: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichii: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ortho Clinical Diagnostics: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daichii: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AKP America: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; AKP America: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Daichii: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Daichii: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Boehringer-Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Speakers Bureau; Bristol-Myers Squibb - Pfizer alliance: Honoraria; Alexion: Consultancy, Speakers Bureau; Daichii: Honoraria; Ortho Clinical Diagnostics: Honoraria; Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ortho Clinical Diagnostics: Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rodger:Boehringer Ingelheim: Research Funding; Canadian Agency for Drugs and Technologies in Health: Consultancy. Ribic:Leo Pharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

Neutrophil activation for adherent and nonadherent cells, as measured by flow cytometry, was not strongly dependent on material surface chemistry. We had hypothesized that material-induced neutrophil activation was an important parameter associated with material failure. All materials tested [cellophane, an acrylonitrile copolymer (AN69), Pellethane, nylon, polyethylene terephthalate, low density polyethylene, and polydimethylsiloxane] activated isolated human neutrophils, which were resuspended in plasma or serum, to similar extents based on L-selectin shedding, CD11b upregulation, and stimulation of the oxidative burst after 30-min exposure. Inhibition of complement activation by sCR1 unexpectedly had little effect if any on nonadherent neutrophils. However, neutrophil adhesion, but not the level of activation of the adherent cells, was strongly dependent on complement activation. Pretreatment with albumin did not inhibit adhesion or reduce neutrophil activation, but plasma pretreatment resulted in increased activation for nonadherent and adherent cells. More adhesion and a higher level of activation of adherent cells was observed following pretreatment with fibrinogen, a ligand of CD11b. Taken together these results suggest that upon contact with a material, neutrophil activation may occur though mechanisms that are not mediated by complement. For example, the presence of plasma proteins such as fibrinogen at the interface may trigger activation and the release of other activating agents. Although the material differences are small, the extent of activation may be significant and warrant further study of the mechanism and consequences of that activation.

SummaryThe HHLGGAKQAGDV (H12) sequence at the carboxyl termini of the γ chains and the RGD sequences in the Aα chains of human fibrinogen are potential recognition sites for the binding of soluble fibrinogen to glycoprotein IIb-IIIa (GPIIb-IIIa) on activated human platelets. Thus, addition of either H12 or RGD-containing peptides inhibits aggregation of and fibrinogen binding to human platelets. In contrast, we reported previously that RGDS had relatively little inhibitory effect on these functions of rabbit platelets. In the present study, we found that H12 inhibited ADP- and thrombin-induced aggregation of rabbit platelets in a dose-dependent manner. Specificity was demonstrated by the failure of the variant HHLGGAKQAGEV peptide to inhibit ADP-induced aggregation. Furthermore, flow cytometric analyses demonstrated that H12 inhibited the binding of FITC-fibrinogen to ADP-activated rabbit platelets in a dose-dependent manner. To examine the direct interaction of H12 with rabbit GPIIb-IIIa, we performed affinity chromatography by applying an octylglucoside extract of rabbit platelet proteins onto an affinity matrix containing the fibrinogen γ chain sequence. Proteins of ∼135 kDa and ∼95 kDa were specifically eluted by soluble H12, and the 95 kDa protein band was immunoblotted by anti-LIBS1, a monoclonal antibody against human GPIIIa. In control samples, no detectable protein from rabbit platelet lysates was eluted from an RGD affinity matrix by GRGDSP. Collectively, our results demonstrated that H12 inhibits aggregation of and fibrinogen binding to rabbit platelets by directly interacting with rabbit GPIIb-IIIa. These findings suggest that rabbit platelets would serve as a suitable thrombosis model for testing the efficacy of peptide mimetics derived from H12.

Background Asymptomatic deep vein thrombosis (DVT) occurs in up to 11% of medical inpatients. The incidence of asymptomatic DVT among patients with inflammatory bowel disease (IBD) is unknown but may be even higher. D-dimer is effective for DVT screening, but its utility has not been studied in the IBD population. Methods Hospitalized and ambulatory patients with IBD during flares were recruited between 2009 and 2011. Those with clinical symptoms of venous thromboembolism or previous venous thromboembolism were excluded. We determined the prevalence of DVT among asymptomatic subjects using lower extremity Doppler ultrasound and assessed the performance characteristics of the D-dimer in this high-risk study population. Results We enrolled 101 hospitalized and 49 ambulatory patients with IBD during active flares. There were no cases of proximal DVT detected by lower extremity Doppler ultrasound. The 95% confidence interval (CI) for the rate of proximal DVT was 0% to 2%. D-dimer was elevated in 60% of subjects without DVT, occurring more frequently among hospitalized than ambulatory subjects [89% versus 65%, P = 0.01; adjusted odds ratio (aOR), 4.16, 95% CI, 1.58-10.9]. Other predictors of elevated D-dimer were incremental decade in age (aOR, 1.97; 95% CI, 1.24-3.14); ulcerative colitis versus Crohn's disease diagnosis (aOR, 3.38; 95% CI, 1.29-8.84); and every 10-unit increase in C-reactive protein (aOR, 1.33; 95% CI, 1.09-1.62). Conclusion From this pilot study, there appears to be low prevalence of asymptomatic DVTs among patients with IBD during flares. The high prevalence of elevated D-dimer in DVT-negative patients limits its utility in IBD.

Contrary to a recent report [Rinder et al.: Blood 82:505, 1993], aspirin does inhibit the release of alpha-granule contents as well as inhibiting the release of dense granule contents by human platelets during ADP-induced aggregation in citrated platelet-rich plasma (PRP). Measurements were: percent release of 14C-serotonin from prelabeled platelets, radio-immunoassay of beta-thromboglobulin (beta TG), and expression on the platelet surface of the alpha-granule constituent, P-selectin, by flow cytometry. During the second phase of ADP-induced aggregation, 69.0 +/- 8.3% of beta TG and 54.1 +/- 4.6% of 14C-serotonin were released (mean +/- SEM, n = 13); aspirin treatment reduced these values to 6.0 +/- 1.2 and 1.0 +/- 0.3%, respectively. In contrast, incubation of platelets with ADP without stirring caused only 6.7 +/- 1.7% release of beta TG and 2.1 +/- 0.4% release of 14C-serotonin; these low values were not appreciably affected by aspirin. During ADP-induced primary aggregation in PRP anticoagulated with FPRCH2CI (PPACK), only 4.7 +/- 0.9% release of beta TG and no detectable release of 14C-serotonin occurred; aspirin had no effect. In both stirred and unstirred PRP, the thrombin receptor activating peptide, SFLLRN (50 microM), caused at least 75% release of the contents of both granules, which was partially inhibited by aspirin. Upon incubation of platelets with ADP (2-10 microM), the mean fluorescence intensity due to P-selectin was < 14% of that induced by SFLLRN. In this unstirred system used for flow cytometry, aspirin treatment caused no significant inhibition of P-selectin expression. Thus, under conditions in which ADP does not cause secondary aggregation (physiological Ca2+ concentration or unstirred citrated PRP) release of the contents of both types of granules is less than 7% and aspirin is not inhibitory; the P-selectin expression associated with this low percent release is also unaffected by aspirin. However, aspirin does strongly inhibit the extensive release of both alpha-granule and dense granule contents during ADP-induced secondary aggregation in citrated PRP.

Background Cocaine consumption has been associated with thrombosis of coronary and peripheral arteries. Since cocaine has been found to induce platelet activation in vitro, we sought to establish whether cocaine induced platelet activation in vivo. Methods and Results Chronically instrumented, conscious dogs were infused with cocaine (1 mg/kg), norepinephrine (0.2 to 0.4 mg/kg), or saline intravenously over 1 minute. Activated canine platelets were identified in whole blood collected from an indwelling aortic catheter by flow cytometric detection of the binding of a monoclonal antibody directed against the activation-dependent antigen P-selectin. Infusion of cocaine resulted in an elevation of mean arterial pressure (91±3 to 128±7 mm Hg [ P P P =NS) in mean arterial pressure followed norepinephrine infusion (100±5 to 137±13 mm Hg [ P P P P Conclusions Intravenous cocaine induces activation of individual circulating platelets; this effect is not reproduced by infusion of norepinephrine at doses sufficient to exert similar hemodynamic effects. The delay in detection of activated platelets after treatment with cocaine may result from the adhesion and subsequent detachment of activated platelets; alternatively, cocaine metabolites, rather than the drug itself, may induce platelet activation.

Background Among patients with acquired cardiovascular disease taking oral vitamin K antagonist medications, time within therapeutic range (TTR) is considered poor when below 60%. To date, however, there are no data about anticoagulation control in adults with congenital heart disease (CHD). This is concerning given that they represent an emerging and growing population of cardiac patients with specific management considerations. Objectives In a sample of adults with CHD taking oral vitamin K antagonist medications, we investigated (i) TTR and (ii) socio-demographic and medical factors associated with lower anticoagulation control. Methods In this retrospective study, the following were study inclusion criteria: age ≥ 18 years, diagnosis of CHD, prescribed oral vitamin K antagonist medication, followed in the thrombosis clinic at least once between January 2005 and December 2010, and adequate frequency of recording of INR values. We documented medical and socio-demographic background, indication for anticoagulation therapy, international normalised ratio (INR) values, and TTR; data were recorded through December 2013. Results We identified 119 eligible patients (49% male; mean age = 39 ± 17 years; mean follow up duration = 4 ± 2.3 years). Defect complexity was categorised as simple (n = 29; 24%), moderate (n = 46, 39%) or great (n = 44; 37%). Specific indications for oral anticoagulation were cardiac arrhythmias (n = 60; 51%), prior thrombus/emboli event (n = 30; 25%), mechanical valves (n = 24; 20%), and other (n = 5; 4%). Twenty-three patients (19%) had a documented psychiatric disorder and 21 patients (18%) had a history of medication non-adherence. Of 71 patients with known educational attainment, 45 (38%) had earned college or university degrees. Of 119 study patients, the mean TTR was 49 ± 19% (range: 0–89%); 82 patients (69%) had poor anticoagulation control (TTR Conclusions Among our study cohort of adults with CHD, patients were within therapeutic INR range only half of the time and more than two-thirds of patients had poor anticoagulation control. Poorer anticoagulation control was observed in patients with moderate defect complexity, with mechanical valves, and with a documented history of medication non-adherence. Future investigation into the clinical outcomes of sub-optimal INR control as well as the potential role of novel oral anticoagulant agents is encouraged.

By inducing BK (bradykinin)-stimulated adrenomedullary catecholamine release, bolus injection of the β-fragment of activated plasma coagulation Factor XII (β-FXIIa) transiently elevates BP (blood pressure) and HR (heart rate) of anaesthetized, vagotomized, ganglion-blocked, captopril-treated bioassay rats. We hypothesized that intravenous infusion of β-FXIIa into intact untreated rats would elicit a qualitatively similar vasoconstrictor response. BN (Brown Norway) rats received for 60 min either: (i) saline (control; n=10); (ii) β-FXIIa (85 ng/min per kg of body weight; n=9); or (iii) β-FXIIa after 2ADX (bilateral adrenalectomy; n=9). LV (left ventricular) volume and aortic BP were recorded before (30 min baseline), during (60 min) and after (30 min recovery) the infusion. TPR (total peripheral resistance) was derived from MAP (mean arterial pressure), SV (stroke volume) and HR. Saline had no haemodynamic effects. β-FXIIa infusion increased its plasma concentration 3-fold in both groups. In adrenally intact rats, β-FXIIa infusion increased MAP by 6% (5±2 mmHg) and TPR by 45% (0.50±0.12 mmHg/ml per min), despite falls in SV (−38±8 μl) and HR [−18±5 b.p.m. (beats/min)] (all P

Carbohydrate moieties on leukocytes adhere to activated platelets via P- selectin under static binding condition studies. We characterize polymorphonuclear cell (PMN) surface interactions with surface adherent platelets and the PMNs response, under physiologic flow conditions corresponding to a shear of 100 s-1, in an in vitro flow chamber. Fluorescent labeled PMNs with red blood cells were drawn through a transparent flow channel and visually quantitated over 30 minutes, interacting with a confluent monolayer of activated, shear-spread platelets expressing P-selectin. PMN adhesion was saturable (2,250 +/- 350/mm2), and time and cation (Ca2+, Mg2+) dependent, and PMNs did not bind to the experimental surface in the absence of a platelet monolayer. P-selectin antibodies completely abolished PMN adhesion in a concentration-dependent manner with half inhibition at 70 micrograms/mL. Antibodies to a putative P-selectin receptor CD15 (80H5 and MMA) maximally inhibited PMN adhesion by 73% and 10%, respectively. Adherent PMNs appeared morphologically activated and flow cytometric analysis of adherent PMNs confirmed activation because CD11b and CD18 surface expression was upregulated (100% and 27%, respectively), whereas L-selectin was downregulated (55%) compared with control nonadherent PMNs. In the presence of the metabolic inhibitor sodium azide (0.02% and 0.1%) there was a 23% +/- 9% and 51% +/- 3% decrease, respectively, in PMN adhesion at 100 s-1. Thus, P-selectin is required for PMN adhesion to a pathophysiologic surface of activated adherent platelets at physiologic shear rates. Furthermore, a secondary step involving PMN activation after platelet binding appears necessary for complete (irreversible) adhesion to occur. This unique flow cell provides a model to explore, under controlled conditions, biologic mechanisms and ligands involved in leukocyte-platelet binding that play important roles in PMN localization at sites of thrombosis and vascular injury.

While the physiologic role of platelet microparticles may include a stable, physical dispersion of concentrated surface procoagulant activity the mechanism(s) of platelet vesiculation remains unknown. We demonstrate using flow cytometric methods a central role for the beta 3 integrin glycoprotein (GP) IIb-IIIa complex and its ligand tetrapeptide Arg-Gly-Asp-Ser (RGDS) binding site in platelet vesiculation. Time- and calcium-dependent vesiculation of platelets in response to ADP, collagen, thrombin, phorbol myristate acetate, and the thrombin peptide SFLLRN were dramatically inhibited, in a concentration-dependent manner, by monoclonal antibodies to GPIIb-IIIa (A2A9, 7E3, PAC1) and RGDS. Complete inhibition with A2A9 and RGDS occurred at 7.5 micrograms/ml and 75 microM, respectively, while control antibodies and a mock peptide had no effect. Platelet vesiculation requires intact GPIIb-IIIa and is fully supported by the intracellular pool of GPIIb-IIIa alone since de-complexing of this heterodimer by calcium chelation completely abolished microparticle formation in response to collagen (no alpha-granule release) but not to thrombin or SFLLRN. A central role for GPIIb-IIIa is supported by the near total inability of Glanzmann's thrombasthenic (type I) platelets to vesiculate in response to thrombin, ADP, collagen, and phorbol 12-myristate 13-acetate. This extends the biologic roles of GPIIb-IIIa to include platelet vesiculation and suggests that one or all of its binding ligands play a role.

We have identified and biochemically characterized an antigen, 8A3, which is expressed on activated T lymphoblasts and activated platelets. Monoclonal antibodies to 8A3 were raised against the primitive lymphoid/myeloid cell line KG1a and additionally bound to the erythroleukemia-derived cell line HEL, whilst exhibiting little or no reactivity with a panel of other hematopoietic cell lines. The 8A3 antigen was expressed on poorly differentiated T-cell leukemias and on phytohemagglutinin-activated T-cells maintained in interleukin-2 (7,000 sites/cell). This antigen, though not detected on resting platelets, was expressed on thrombin-activated platelets (2,000 sites/platelet). Antibodies to 8A3 identified polypeptides of Mr 170,000 and 150,000 in lysates of surface-iodinated KG1a cells, T lymphoblasts, and activated platelets under both reducing and nonreducing conditions. However, peptide mapping and susceptibily to glycosidases indicated that the 8A3 antigen was a monomeric glycoprotein of Mr 170,000 which contained two N-linked endoglycosidase H-sensitive glycans, and that the Mr 150,000 structure was derived from it by proteolytic degradation. The 8A3 antigen was not detectably phosphorylated in KG1a cells in vivo, nor did immune complexes containing it exhibit kinase activity in vitro. Structural and serologic characteristics of the 8A3 antigen indicate that it is different from other previously described leukocyte activation antigens including transferrin receptors, interleukin-2 receptors, members of the integrin family of adhesion molecules, or “restricted” members of the leukocyte-common antigen/CD45 cluster. Furthermore, the 8A3 antigen does not appear to be related to the other previously described activation-specific platelet molecule, GMP140/PADGEM. This antibody may be useful in monitoring T-cell activation status in some clinical situations and in characterizing clinically relevant activation-associated platelet membrane alterations.

Background: PNH is an acquired hematopoietic stem cell disorder leading to a partial or absolute deficiency of all glycophosphatidyl-inositol (GPI)-linked proteins. The classical approach to diagnosis of PNH by cytometry involves the loss of at least two GPI-linked antigens on RBCs and neutrophils. While flow assays are more sensitive and specific than complement-mediated lysis or the Hams test, they suffer from several drawbacks. Bacterial aerolysin binds to the GPI moiety of cell surface GPI-linked molecules and causes lysis of normal but not GPI-deficient PNH cells. FLAER is an Alexa488-labeled inactive variant of aerolysin that does not cause lysis of cells. Our goals were to develop a FLAER-based assay to diagnose and monitor patients with PNH and to improve detection of minor populations of PNH clones in other hematologic disorders. Methods: In a single tube assay, we combined FLAER with CD45, CD33, and CD14 allowing the simultaneous analysis of FLAER and the GPI-linked CD14 structure on neutrophil and monocyte lineages. Results: Comparison to standard CD55 and CD59 analysis showed excellent agreement. Because of the higher signal to noise ratio, the method shows increased sensitivity in our hands over single (CD55 or CD59) parameter analysis. Using this assay, we were able to detect as few as 1% PNH monocytes and neutrophils in aplastic anemia, that were otherwise undetectable using CD55 and CD59 on RBC’s. We also observed abnormal FLAER staining of blast populations in acute leukemia. In these cases, the neutrophils stained normally with FLAER, while the gated CD33bright cells failed to express normal levels of CD14 and additionally showed aberrant CD45 staining and bound lower levels of FLAER. Conclusion: FLAER combined with multiparameter flow cytometry offers an improved assay for diagnosis and monitoring of PNH clones and may have utility in detection of unsuspected myeloproliferative disorders. q 2007 Clinical Cytometry Society Key terms: FLAER; PNH; multiparameter flow cytometry; hematologic abnormalities

Objective Inflammation may play a role in pathogenesis of venous thromboembolism, but the nature of this relationship is not yet understood. The objective of this study was to assess whether inflammation marker levels measured at diagnosis of deep venous thrombosis (DVT) and change in levels during the first month after DVT are associated with anatomic extent of DVT and severity of venous signs and symptoms at baseline and 1 month. Methods The BioSOX study is a biomarker substudy of the Compression Stockings to Prevent the Post-Thrombotic Syndrome (SOX) trial, a multicenter, randomized controlled trial that included patients with a first, acute, symptomatic, proximal DVT. Blood samples were collected from participants at baseline and 1 month, and C-reactive protein (CRP), intercellular adhesion molecule 1, interleukin (IL)-6, and IL-10 were measured by established assays. Linear regression was used to assess the association between continuous log-transformed baseline biomarker levels and anatomic extent of DVT, classified as iliac or common femoral DVT vs femoral or popliteal DVT (reference). Proportional odds ordinal logistic regression models were used to analyze the association between biomarker level and Villalta score (as a measure of severity of venous signs and symptoms) at baseline and 1 month. Results Among 717 patients, 60.2% were male, and the mean age was 55.2 years. There was a significant association between more extensive DVT (common femoral or iliac) and levels of CRP and IL-6 at DVT diagnosis. Median (interquartile range) CRP level was 11.6 mg/L (3.84-39.5) in patients with common femoral or iliac DVT vs 6.86 mg/L (3.11-22) in patients with popliteal or femoral DVT, and median IL-6 level was 6.36 pg/mL (1.09-14.37) vs 4.40 pg/mL (2.35-8.27), respectively. These differences were statistically significant in linear regression analyses. In addition, compared with those in the lowest quartile, each higher quartile of baseline CRP concentration was associated with an odds ratio of 2.89 (1.93-4.33) for having a more severe Villalta category at baseline and 1.98 (1.28-3.08) for having a more severe Villalta category 1 month after DVT. Higher baseline levels of IL-6 were associated with Villalta severity category at baseline (odds ratio, 2.40 [1.61-3.59]). Change in biomarker levels during the first month after DVT was not strongly associated with the 1-month Villalta score. Conclusions Levels of CRP and IL-6 at DVT diagnosis were associated with thrombotic disease burden, as measured by DVT extent, and severity of DVT symptoms and signs. Further studies are required to more fully elucidate the role of inflammation in DVT and its clinical course.

Warfarin remains the most commonly used oral anticoagulant. Its efficacy is closely correlated with the time in therapeutic range (TTR) of the international normalized ratio (INR). Excellent anticoagulant management systems can achieve TTRs in excess of 80%: however, in day-to-day clinical practice TTR values in the range of 50 to 60% are more commonly seen. Strategies to increase TTR are widely sought; one such intervention is the daily administration of low dose vitamin K (VK) administered to reduce variations in VK intake and thus reduce fluctuations in the INR due to such variability. In this multicentre, blinded, randomized controlled trial we allocated patients on chronic warfarin therapy to receive either 0.150 mg of daily oral VK, or matching placebo. After a one month “run in period” to allow adjustment of the warfarin dose, patients were followed for a maximum of 9 months (mean 6 months), their INR was determined, their TTR calculated and their mean warfarin dose calculated. A total of 253 patients were enrolled at 4 clinical centres between Aug 19, 2010 and Aug 30, 2013; 18 (9 in each group) were excluded from this analysis due to inadequate follow-up data, mostly as a result of withdrawal from the study during the run in period. Of the 117 analyzable patients allocated to VK, 66 were male (average age 66.9 yrs). Of the 118 analyzable patients allocated to placebo 59 were male (average age 65.7 yrs). Indications for warfarin were similar between the two groups, as was the frequency of renal insufficiency and the presence of cancer. Patients allocated to placebo were more likely to report a history of bleeding (7% vs 3%). Mean TTR over the 6 months prior to enrollment to the study was 54.6% in the placebo group, and 51.8% in the VK group. Mean TTR over an average follow-up of 6 months after completion of the 1 month run-in period was 66% in the placebo group, and 65.1% in the VK group. We conclude that inclusion in this study resulted in a statistically (and likely clinically) significant improvement in the TTR. The improvement in the TTR we observed appeared to be predominately as a result of attentive clinical management, rather than administration of VK. Our findings do not support the use of daily, low dose oral vitamin K administered in an effort to improve TTR. Disclosures Crowther: Portola: Consultancy; Leo: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; AKP America: Consultancy; Heart and Stroke Foundation: Career Investigator award Other; Celgene: Honoraria; Shire: Honoraria; CSL Behring: Honoraria. Lazo Langer:Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Leo Pharma: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Alexion: Research Funding; Daichii Sankyo: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Yeo:Bayer: Honoraria. Schulman:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer HealthCare: Consultancy, Honoraria, Research Funding.

BACKGROUND There are limited data on dosing of enoxaparin in patients with renal disease due to the routine exclusion of this population in clinical trials. To account for the potentially delayed drug elimination in these patients, we developed guidelines for adjusting enoxaparin dosing based on anti-Xa monitoring. OBJECTIVE To evaluate anti-Xa level monitoring, resulting from the standards of practice as set out by our hospital's guidelines for enoxaparin dosing in renally impaired patients. METHODS A total of 72 separate acute coronary syndrome patient admissions were retrospectively reviewed. All patients had anti-Xa levels taken and creatinine clearance values RESULTS The average trough anti-Xa level at the once- and twice-daily doses was 0.40 and 0.72 IU/mL, respectively. With twice-daily dosing, only 6% of the trough concentrations were in the target range of 0.2–0.3 IU/mL compared with 36% with once-daily dosing. Of the 22 patients who had a change of dosing frequency from twice to once daily, 5% of trough anti-Xa levels were ≤0.5 IU/mL with twice-daily versus 68% with once-daily dosing. CONCLUSIONS Although the relationship between anti-Xa activity, efficacy, and adverse effects has not been definitively established, anti-Xa levels can assist with dosing of enoxaparin in renally impaired patients. Our hospital guidelines are effective in adjusting dosing to reach target anti-Xa levels.

The objective of this study was to determine the feasibility of device closure of patent foramen ovale (PFO) for presumed paradoxical emboli without echocardiographic guidance or balloon sizing and the clinical outcome after device closure. Closure of the PFO has been proposed as an alternative to anticoagulation in patients with presumed paradoxical emboli. At present, most centers perform device closure with transesophageal echocardiographic guidance and balloon sizing of the defect. Between May 1998 and April 2002, 92 consecutive patients underwent device closure for a PFO using fluoroscopic monitoring only. Procedural success and major complications were recorded. Follow-up outcomes were recurrence rate and residual atrial shunting on transthoracic echocardiography. All patients (mean age, 45 +/- 13 years; 52% male) had successful device deployment using either the CardioSeal (n = 78) and Amplatzer (n = 14) PFO occluders with no major complications. Mean procedure time and fluoroscopy time was 27 +/- 13 and 6 +/- 4 min, respectively. One patient had a residual shunt on echocardiography at 1 year. Cumulative event-free survival for recurrence of paradoxical embolus at 1 year was 97.3% +/- 1.8%. This study provides a basis for device closure of PFO becoming a safe, day-case procedure, resulting in a low rate of residual shunting and recurrent thromboembolic events.

Elevation of plasma homocyst(e)ine level is an independent risk factor for arterial and venous thrombosis. We studied the degree to which hyperhomocyst(e)inemia contributes to the development of venous thromboembolism, using a retrospective case-control study design.Cases were individuals with objectively confirmed venous thromboembolism and no history of atherosclerosis seen at the Toronto Hospital Thrombosis Clinic, Toronto, Ontario, between January 1, 1996, and July 31, 1998. Three controls were matched for every case according to sex and age within 5 years and were derived from a large community cohort. All subjects underwent assessment for fasting plasma homocyst(e)ine levels. Hyperhomocyst(e)inemia was defined as a fasting total homocyst(e)ine concentration above the 95th percentile control value.Seventy cases and 210 matched controls were included. Men and women were equally represented, and most were younger than 60 years. Among cases with venous thromboembolism, the mean (+/- SD) plasma homocyst(e)ine level was significantly higher than in controls (13.0 +/- 6.9 micromol/L vs 9.0 +/- 4.8 micromol/L, respectively; P.001). Sixteen (23%) of 70 cases had hyperhomocyst(e)inemia compared with 10 (5%) of 210 controls (odds ratio, 5.9; 95% confidence interval [CI], 2.5-13.8). Among subjects aged 60 years or younger, the odds ratio was 4.9 (95% CI, 1.4-16.4), while for those aged 60 years or older, it was 7.3 (95% CI, 2.2-24.0). Even with the exclusion of cases showing abnormal renal function or low serum vitamin B12 or folate levels, the odds ratio remained significantly elevated at 3.3 (95% CI, 1.1-10.0).We found that fasting hyperhomocyst(e)inemia is a significant risk factor for venous thromboembolic disease in patients at a thrombosis clinic. Given the magnitude of effect and consistency across these studies, it is likely that homocyst(e)ine plays a causative role in the development of venous thrombosis, and it should be considered in the workup for venous thromboembolism.

Background The post-thrombotic syndrome (PTS) is a frequent complication of deep venous thrombosis (DVT). Identifying predictors of PTS is important to counsel DVT patients on their expected prognosis and to identify patients who may benefit from closer monitoring or preventive strategies. Objective In a secondary analysis of the SOX Trial, we aimed to identify predictors of developing PTS during 2 years follow-up after a first episode of proximal DVT. Methods The study cohort consisted of participants in the SOX Trial, a multicenter (24 centres in Canada and U.S.) randomized placebo controlled trial of active elastic compression stockings vs. placebo stockings worn for 2 years after a first, symptomatic proximal DVT. PTS, the primary study endpoint, was diagnosed at or after the 6 month visit based on patient-reported pain and swelling of ≥ 1 month duration that were typical in character, i.e. worse at end of day or after prolonged sitting/standing and improved after rest/leg elevation (Ginsberg criteria). Cumulative incidences of PTS were compared in subgroups defined by sex, age category, body mass index (BMI) category, anatomic extent of index DVT, type of DVT (cancer-associated, secondary risk factor-associated, unprovoked) and 1-month Villalta score category (score 0-4: none; 5-9, mild; 10-14, moderate; >14, severe), using Cox regression. Losses to follow-up, withdrawals and deaths were censored as of last date of follow-up. Results are presented as cumulative incidence by 750 days follow-up and hazard ratios (HR) with 95% confidence intervals (CI). Results Among the 803 participants in the SOX Trial, 60% were male, mean age was 55.1 years, and 87% were out-patients. In analyses adjusted for intervention group (i.e. allocation to active vs. placebo stockings), iliac vein DVT (HR 2.26 [95% CI 1.12, 4.53]; reference category: popliteal DVT) and Villalta score category at 1 month after DVT (score 5-9, HR 2.74 [95% CI 1.62, 4.64]; score 10-14, HR 5.81[95% CI 2.99, 11.29]; score >14, HR 7.59 [95% CI 3.31, 17.44]; reference category: score Conclusions In a large prospective cohort of patients with proximal DVT who were participants in the SOX Trial, Villalta score category (which reflects severity of venous symptoms and signs) at 1 month after DVT was strongly predictive of development of PTS during 2 years follow-up. This confirms a similar finding that we first observed in the VETO cohort study (Kahn SR et. al., Annals Intern Med 2008). More extensive DVT was also associated with PTS. Patients with these risk factors may benefit from closer monitoring after proximal DVT, and in the case of iliac vein DVT, from more aggressive strategies to treat acute DVT. Disclosures: No relevant conflicts of interest to declare.

Background Acute deep venous thrombosis (DVT) is associated with leg pain and discomfort. Elastic compression stockings (ECS) have the potential to improve DVT-related leg pain by reducing the diameter of distended veins, increasing venous blood flow and reducing venous hypertension. To date, however, the effect of ECS on DVT-related leg pain has not been studied. In the SOX Trial, a randomized trial of active ECS vs. placebo ECS to prevent the post-thrombotic syndrome, we measured leg pain intensity at baseline and at several time-points during follow-up. Objective In a secondary, non-prespecified analysis of the SOX Trial, to determine whether active ECS, compared with placebo (sham) stockings, are effective to reduce leg pain associated with acute proximal DVT. Methods We did a multicenter (24 centres in Canada and U.S.) randomized placebo controlled trial of active ECS vs. placebo ECS after a first, symptomatic proximal DVT. Active ECS were knee length, 30-40 mm Hg (Class II) graduated ECS. Placebo ECS were manufactured to appear identical to active ECS but lacked therapeutic compression. Study stockings were worn on the DVT-affected leg daily and continued for up to 2 years. Exclusion criteria were >10 days since DVT diagnosis, not planned to be treated with anticoagulants, known peripheral arterial disease or limb phlegmasia, anticipated lifespan < 6 months, inability of patient or caregiver to apply ECS, thrombolysis to treat DVT, geographically inaccessible for follow-up visits or unable to give informed consent. Leg pain intensity was assessed on a 10-point Visual Analog Scale (0, no pain; 10, worst possible pain) via patient self-report at baseline, 14 days, 1 month and 60 days after randomization. We compared mean pain scores at each time point in the active ECS vs. placebo ECS groups using t-tests. We repeated this analysis, restricted to patients who reported daily stockings use at the 1 month visit (the first visit at which frequency of stocking use was assessed). We conducted pre-specified subgroup analyses by age, sex, and extent of DVT. Results are presented as mean difference (95% confidence interval [CI]) in pain intensity score between groups. All statistical tests were 2-sided and significance was set at P Results 410 patients were randomized to active ECS and 396 to placebo ECS. One and 2 patients, respectively, were found to be ineligible soon after randomization and excluded from the analysis. Mean time from DVT diagnosis to randomization was 4.7 days. Baseline characteristics were similar in the 2 groups (60% male, mean age 55.1 years, highest proximal extent of DVT was iliac or femoral vein in 70% and popliteal vein in 30%, 87% were out-patients). Pain scores diminished over time in both groups. There were no differences between groups in pain scores at any time-point (Table), and no evidence for subgroup interaction by age category, sex or anatomical extent of DVT (not shown). Conclusions In a large randomized placebo-controlled trial in patients with symptomatic proximal DVT, leg pain improved at each follow-up visit to a similar degree in patients randomized to active ECS and placebo ECS, and we did not find evidence for benefit of active ECS to reduce pain associated with acute proximal DVT. As our first follow-up assessment was 14 days after DVT, we were unable to evaluate if active ECS had a beneficial or detrimental effect on pain scores during the first 2 weeks after DVT. Disclosures: No relevant conflicts of interest to declare.

Introduction The post thrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT). It is not understood why up to 50% of DVT patients develop PTS despite optimal anticoagulation. In the Bio-SOX Study, we investigated whether markers of inflammation, one of the putative pathophysiologic processes leading to PTS, are of value in predicting the development of PTS in DVT patients. Objective To assess whether markers of inflammation measured at three time points after DVT diagnosis are predictors of risk of PTS. Methods The Bio-SOX is a sub-study of the SOX Trial, a multicenter, randomized controlled trial of elastic compression stockings for the prevention of PTS. Eight hundred and three patients with a first, symptomatic, proximal DVT were randomly allocated to receive active or placebo stockings to be worn daily, starting within 2 weeks of DVT diagnosis. During the SOX trial we prospectively collected blood samples from participants at baseline, one and six months. We measured plasma concentrations of C-reactive protein (CRP), interleukin (IL)-6, IL-10 and intercellular adhesion molecule (ICAM)-1 using validated established methods. Differences between median biomarker levels in PTS positive and negative patients (as defined by the Villalta scale applied over time starting at the 6 month visit) were assessed using the Wilcoxon rank-sum test. Multivariable logistic regression models were used to calculate crude and adjusted odds ratios (OR) of PTS by biomarker levels. Results Among study patients, 60.1% were male and mean age was 55.1 years. There were 334 cases of Villalta-defined PTS during follow up, with no significant difference in incidence between the active and placebo stockings groups. Median values of biomarkers between cases and noncases of PTS showed statistically significant differences in CRP and IL-6 at one and six months, ICAM-1 at all time points, and IL-10 at six months post DVT (Figure 1). Table 2 summarizes crude and adjusted ORs for PTS, using the median as a cut-off value. ICAM-1 was associated with PTS at all time points, IL-10 at six months, and CRP at 1 month post DVT, though this association was attenuated after adjustment. Conclusion The Bio-SOX Study is the first large scale prospective study we are aware of that evaluated the predictive role of biomarkers measured at baseline and relevant time points after acute DVT in the development of PTS. Findings suggest that inflammation plays an important role in PTS development. Among the studied biomarkers, ICAM-1 appeared to be most strongly associated with PTS development. ICAM-1 is an endothelial- and leukocyte-associated transmembrane protein important in stabilizing cell-cell interactions and facilitating leukocyte endothelial transmigration. Its expression and secretion by activated endothelial cells is induced by thrombin. Future therapeutic trials should be aimed at targeting this pathway. Disclosures: No relevant conflicts of interest to declare.

Abstract 393 Background: The post-thrombotic syndrome (PTS) is a burdensome, costly complication of deep venous thrombosis (DVT). Investigating strategies to prevent PTS is important, as treatments for PTS are limited. To date, randomized trials of elastic compression stockings (ECS) to prevent PTS were small, single-center, none used a placebo control and results are conflicting. Objective: To determine whether ECS, compared with inactive (placebo) stockings, are effective to prevent PTS in patients with proximal DVT. Methods: We conducted a multicenter (24 centres, Canada and U.S.) randomized placebo controlled trial of active ECS (A-ECS) vs. placebo ECS (P-ECS) to prevent PTS after a first, symptomatic proximal DVT. A-ECS were knee length 30–40 mm Hg (Class II) graduated ECS. P-ECS were manufactured to look identical to A-ECS but lacked therapeutic compression. Stockings were mailed directly to patients and worn on the DVT-affected leg daily for up to 2 years. Patients did not wear their stockings at study follow-up visits (1, 6, 12, 18 and 24 months) to maintain study personnel blinding. The primary study outcome, PTS, was diagnosed at or after the 6 month visit using the Ginsberg measure (leg pain and swelling of 3 1 month duration and typical in character: worse end of day or after prolonged sitting/standing and improved after rest/leg elevation). All PTS diagnoses were confirmed by the local study physicians. Secondary outcomes were incidence and severity of PTS using the Villalta scale, venous ulcers, VTE recurrence and death from VTE. A sample size of 800 patients was targeted based on a hypothesized cumulative incidence of the primary outcome of 30% in P-ECS vs. 20% in A-ECS, 2-tailed a of 0.05 and 80% power, and anticipated 25% rate of death/withdrawal/lost-to-follow-up. Using a modified intent to treat approach, we performed a time-to-event analysis using a Cox proportional hazards model adjusted for center to calculate hazard ratios (HR) and 95% confidence intervals (CI) to compare rates of the primary outcome in A-ECS vs. P-ECS. A similar time-to-event analysis was performed for Villalta PTS (Villalta score ≥ 5 at or after the 6 month visit). Results: From 2004–2010, 398 patients were randomized to A-ECS and 408 to P-ECS. 3 patients found to be ineligible soon after randomization were excluded from the analysis. Median time from DVT diagnosis to randomization was 4 days. Baseline features were similar in the 2 groups; overall, 60% were male, mean age was 55 years, and most proximal extent of DVT was iliac or femoral vein in 70% and popliteal vein in 30% of patients. The cumulative incidence of PTS (primary outcome) by 750 days was 14.8% in A-ECS vs. 12.3% in P-ECS ( Figure ) (HRadj 1.17; 95% CI 0.75–1.81; p=0.49). The cumulative incidence of Villalta PTS (secondary outcome) was 52.1% in A-ECS vs. 52.2% in P-ECS (HRadj 0.96; 95% CI 0.78–1.19; p=0.69). Additional outcomes were also similar in the two intervention groups ( Table ). Rates of loss to follow-up (5.5% vs. 5.4%) and withdrawal (8.3% vs. 9.1%) were similar in A-ECS and P-ECS. Overall, ∼70% of patients in both groups continued the intervention throughout study follow-up, and of these, >80% of patients in both groups reported use for ≥ 3 days per week. Conclusions: In a large randomized placebo-controlled trial, ECS did not prevent the occurrence of PTS after a first proximal DVT and did not influence the severity of PTS or rate of recurrent VTE. The reported benefits of ECS to prevent PTS in some prior studies could be due, at least in part, to bias from open-label design. Whether ECS may be of benefit to manage symptoms of established PTS should be evaluated in future studies. Active ECS (n = 397) Placebo ECS (n = 406) Villalta severity category * None (score 181 (51.9%) 182 (50.8%) Mild (5-9) 114 (32.6%) 116 (32.4%) Moderate (10-14) 30 (8.6%) 37 (10.3%) Severe (>14 or ulcer) 24 (6.9%) 23 (6.4%) Ipsilateral leg ulcer 16 ulcers in 16 patients 17 ulcers in 16 patients Recurrent VTE 45 events in 33 patients 44 events in 38 patients Recurrent ipsilateral DVT 18 events in 16 patients 17 events in 17 patients Death 36 (9.0%) 36 (9.1%) Death due to PE 0 0 Serious adverse event due to ECS 0 0 Adverse event due to ECS # 7 8 * Highest Villalta score at or after 6-month visit. Missing for 48 patients in each group; # leg rash or itching. Download : Download high-res image (26KB) Download : Download full-size image Disclosures: Kahn: NIH: Research Funding; Canadian Institutes for Health Research: Research Funding; Sigvaris: Research Funding.

1. P-selectin (PADGEM, GMP140, or CD62) a member of lectin-like adhesive proteins is expressed on the surface of activated degranulated canine platelets and is the calcium-dependent receptor for leukocyte adhesion. 2. The electrophoretic mobility of P-selectin, by Western blot analysis and immunoprecipitation from radiolabeled membranes of canine and human platelets, was similar or identical and immunocytochemical studies localized P-selectin in internal vesicles similar to the alpha granule localization in human platelets. 3. Two antibodies to human P-selectin KC4.1 and AC1.2 crossreacted with canine platelets whose surface binding, in response to agonists thrombin, calcium ionophore (A23187), phorbol esters and ADP, was similar. 4. Anti-P-selectin antibodies in conjunction with crossreacting anti-GPIIb/IIIa antibodies (A2A9, 7E3, RUU-PL7F12) enables the analysis of activated platelets, platelet-derived microparticles and platelet-leukocyte interactions in canine models by flow cytometry.

There is a lack of consensus on how to best monitor therapy with the direct thrombin inhibitor argatroban. Currently, the most commonly used test is the activated partial thromboplastin time (aPTT). However, it has limited reliability, as it is easily affected by other factors, and the target is unclear in patients whose baseline values are abnormal. The ecarin chromogenic assay (ECA) reaction time is strongly correlated with plasma argatroban concentrations (r2 = 0.9994), and thus, can be used for direct quantification of argatroban concentrations. Moreover, the ECA is unaffected by low levels of prothrombin and fibrinogen, making it a more reliable and accurate test. Our institution developed a unique dosing and monitoring protocol for argatroban therapy incorporating the use of nomograms to dose argatroban and the ECA to monitor argatroban concentrations. The purpose of this study was to evaluate the ability of our current argatroban protocol to achieve and maintain ECA levels within the desired target range of 0.2 to 0.5 mcg/mL, validate the safety and efficacy of an ECA-based nomogram, and determine the relationship between argatroban concentrations and aPTT values. We conducted a prospective observational study of all patients receiving argatroban at the University Health Network (UHN) from September 1, 2007 to May 15, 2008. The UHN consists of three tertiary care hospitals in Toronto, Canada. The argatroban protocol consists of an initial infusion rate and two dose titration nomograms, one based on the ECA and the other based on the aPTT (for dose adjustment when the ECA result was unavailable during evenings and weekends). The recommended initial infusion rate was 1 mcg/kg/min, with a lower rate of 0.5 mcg/kg/min reserved for patients with liver dysfunction and/or an increased risk of bleeding. Both ECA levels and aPTT values were measured 6 hours after the initiation of argatroban and any change in rate. The primary outcome measures were the proportion of patients who achieved argatroban concentrations within the target range after the first level, the number of rate changes required to achieve target levels, and the proportion of time spent in the target range in the first 24, 48 and 72 hours. Secondary outcome measures included the proportion of patients who developed a thrombotic event or major bleed, as well as the correlation between argatroban concentrations and aPTT values. A total of 33 patients were enrolled. Protocol violations in the initial dosing and titration of argatroban led to the exclusion of 6 patients from all primary outcome analyses. Of the patients with ECA levels available at the initial rate, 35% of all patients had levels in the target range with the first ECA level. This proportion increased to 54% for patients started at 1 mcg/kg/min. The mean number of rate changes required to achieve levels in the target range was 1.15 and the mean time was 21.7 hours. The proportion of time spent in the target range in the first 72 hours was 78%. Two patients (6%) had thrombotic events during argatroban therapy with levels in the target range, and 1 patient (3%) who had previously bled prior to argatroban therapy had a confirmed major bleed. The correlation co-efficient between ECA levels and aPTT using 125 data points was 0.2475. In conclusion, our institution’s argatroban protocol enabled the majority of patients to achieve target argatroban concentrations in a timely manner, and resulted in safe and effective anticoagulation. Most patients could be started at a dose of 1 mcg/kg/min. The aPTT is poorly correlated with argatroban concentrations, we recommend using the ECA to more directly quantify argatroban concentrations and to dose and monitor argatroban therapy.

A strong link between asparaginase-containing (ase +) chemotherapy regimens and venous thrombotic events (VTE) has been established for pediatric acute lymphoblastic leukemia (ALL), but this association has not been studied in adult ALL. We recently adopted as our first-line therapy for adult ALL a treatment protocol (DFCI 00–01) that employs weekly high-dose ase throughout a 27 week intensification phase. We reviewed the records of 92 adult patients consecutively accrued at Princess Margaret Hospital (from Jan 2000 to Dec 2003) for venous thrombotic events (VTE). Median age at diagnosis of ALL was 41±17 y, or 19±3 y for those who presented after a history of pediatric ALL (n=6), and 42±16 y for adults who presented with de novo ALL (n=86). Thirty-five (37%) were female, 59 (63%) male. Twenty-four (26%) were Philadelphia-chromosome positive; 71% of these received regimens containing imatinib. At least 1 symptomatic, radiologically confirmed VTE was seen in 19 patients (21%), with 3 (3%) diagnosed prior to any antileukemic therapy. Overall survival (OS) versus thrombosis-free survival (TFS) is illustrated in the Kaplan-Meier curve below. Median time to VTE was 94±92 d [95% CI]. Average age of patients with VTE was 44 ±15y; no events were observed in patients with a prior pediatric history of ALL. The sites of VTE were: 10/22 (46%) in the lower extremities, 5/22 (23%) propagating from central venous access catheters (CVAC), 4/22 (18%) as pulmonary emboli (2 in isolation), and 3/22 (14%) CNS (2 cerebral venous sinus and 1 retinal venous thrombus). The first antileukemic regimen administered was DFCI 00–01 ± imatinib in 79/92 (86%), HyperCVAD ± imatinib in 7 (8%), an unclassified ase+ regimen in 1 (1%), or an unclassified asparaginase-excluding (ase−) regimen in 5 (5%). A significant difference in the rate of ase-dependent VTE was observed when all regimens (1° or subsequent) were counted, with 18 VTE during 103 ase+ regimens (17.5%), versus only 1 VTE in 32 ase− regimens (3.1%), [p=0.04]. Median time to VTE in DFCI 00-01was 109±98d, most often occurring during the intensification phase. The odds ratio for VTE with any T-cell subtype of ALL compared to any B-cell subtype was 4.6 [p=0.0043]. Conclusions : A high, significant VTE rate (~18%) was observed in adults with ALL undergoing ase+ antileukemic therapy, nearly 6X the rate observed either prior to treatment or during ase− regimens (~3%). Ase is thus strongly associated with VTE, warranting improved surveillance and antithrombotic prophylaxis. Risk factors (underlying thrombophilias, leukemic subtypes) similarly deserve further study. Figure Figure

Contemporary evidence suggests thromboprophylaxis in medical oncology patients may be effective, however, according to global surveys, is greatly underutilized despite the substantial risk of venous thromboembolism (VTE). To date, routine thromboprophylaxis of medical oncology inpatients has not been evaluated at a cancer care institution. Not equally common in all types of cancer, VTE is thought to present a higher risk in selected solid tumours of the CNS, lung, gastrointestinal and genitourinary tracts. Recommendations from the Sixth ACCP Consensus Conference on Antithrombotic Therapy include implementing institution-specific VTE prophylaxis guidelines for high-risk patients. The objectives of this study are to develop and implement targeted VTE prophylaxis guidelines for high-risk solid tumour inpatients during admission to a medical oncology ward and to evaluate the impact on prescribing practice. The study is a prospective, observational, before and after chart review with retrospective validation. VTE prophylaxis guidelines were developed through literature review and expert consensus. The results presented are the baseline pre-phase data over 14 weeks. Of nearly 240 charts assessed for eligibility criteria, 92 (39%) were stratified as high-risk according to the developed guidelines based on tumour site. Seventy-two of those patients identified as high-risk were followed prospectively to determine the baseline rates of thromboprophylaxis and venographically confirmed symptomatic VTE. Retrospective validation of results was performed in all 237 patients. Current results of the pre-phase revealed appropriate VTE prophylaxis with a low-molecular weight heparin based on the proposed guidelines in three eligible patients (5.3%). A total of 13 eligible patients (19%) received any form of pharmacological or non-pharmacological prophylaxis. The rate of symptomatic VTE was 11% (n = 10) among high-risk patients of which five patients developed pulmonary embolus (PE), four patients presented with deep vein thrombosis (DVT) and one patient developed portal vein thrombosis. Among non high-risk patients, the rate of symptomatic VTE was significantly lower at 3% (n = 5), among which three patients presented with PE and two patients developed DVT. In both groups, pulmonary embolus was the most common manifestation of VTE. No clinically significant bleeding occurred during prophylaxis. The rate of symptomatic VTE among the highly selected at-risk medical oncology population at this institution was substantially different than the non high-risk population and is in accordance with the literature. This study presents new data on the rates of symptomatic VTE and thromboprophylaxis for medical oncology patients in a hospital setting. The rate of VTE prophylaxis of 5.3% seen in the pre-phase appears unacceptably low given that appropriate pharmacological intervention may potentially reduce the VTE rate by as much as 50% as suggested by relevant literature. As such, implementation of VTE prophylaxis guidelines at this cancer care center is ongoing.

Background Some of the benefit of statins for the prevention of cardiovascular disease may be due to their antithrombotic properties. Little is known about the effect of these drugs on the development of deep vein thrombosis. Materials and Methods We conducted a retrospective cohort study over an 8-year period by linking Ontario provincial health care administrative databases covering more than 1.4 million Ontario residents aged 65 years or older. We excluded those with a documented history of atherosclerosis, venous thromboembolism, or cancer within 36 months prior to study enrollment, as well as those prescribed warfarin sodium within 12 months before enrollment. In the primary cohort, we evaluated the subsequent risk of deep vein thrombosis (DVT) among men and women prescribed thyroid replacement therapy, nonstatin lipid-lowering agents, or statins. A second cohort of women only was evaluated in a similar fashion, but estrogen use was added as a third comparison drug group. Results There were 125 862 men and women in the primary cohort. After adjusting for age; sex; prior hospitalization; newly diagnosed cancer; or prescribed aspirin, warfarin, or estrogen, statin users (n = 77 993) had an associated decreased risk of DVT relative to those prescribed thyroid replacement therapy (n = 35 978) (adjusted hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.69-0.87). Compared with thyroid replacement therapy, users of nonstatin lipid-lowering agents (n = 11 891) did not seem to be at lower risk for deep vein thrombosis (HR, 0.97; 95% CI, 0.79-1.18). In the secondary cohort of 89 508 women, after adjusting for age, prior hospitalization, newly diagnosed cancer, or prescribed aspirin or warfarin, estrogen users (n = 29 165) had an associated increased risk for DVT compared with those receiving thyroid replacement therapy (n = 22 118) (HR, 1.16; 95% CI, 1.01-1.33), while statin users had an associated decreased risk (HR, 0.68; 95% CI, 0.59-0.79). Nonstatin lipid-lowering agents (n = 5155) were not associated with a reduced risk of DVT compared with thyroid replacement therapy (HR, 0.84; 95% CI, 0.63-1.12). Conclusion Among selected individuals aged 65 years or older, statins were associated with a 22% relative risk reduction in the risk of DVT. A randomized clinical trial is needed to evaluate the efficacy of statins for the primary and secondary prevention of DVT.