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Cancer-associated thrombosis (CT) is associated with a high risk of recurrent venous thromboembolic (VTE) events that require extended anticoagulation in patients with active cancer, putting them at risk of bleeding. The aim of the API-CAT study (NCT03692065) is to assess whether a reduced-dose regimen of apixaban (2.5 mg twice daily [bid]) is noninferior to a full-dose regimen of apixaban (5 mg bid) for the prevention of recurrent VTE in patients with active cancer who have completed ≥6 months of anticoagulant therapy for a documented index event of proximal deep-vein thrombosis and/or pulmonary embolism. API-CAT is an international, randomized, parallel-group, double-blind, noninferiority trial with blinded adjudication of outcome events. Consecutive patients are randomized to receive apixaban 2.5 or 5 mg bid for 12 months. The primary efficacy outcome is a composite of recurrent symptomatic or incidental VTE during the treatment period. The principal safety endpoint is clinically relevant bleeding, defined as a composite of major bleeding or nonmajor clinically relevant bleeding. Assuming a 12-month incidence of the primary outcome of 4% with apixaban and an upper limit of the two-sided 95% confidence interval of the hazard ratio <2.0, 1,722 patients will be randomized, assuming an up to 10% loss in total patient-years (β = 80%; α one-sided = 0.025). This trial has the potential to demonstrate that a regimen of extended treatment for patients with CT beyond an initial 6 months, with a reduced apixaban dose, has an acceptable risk of recurrent VTE recurrence and decreases the risk of bleeding., Competing Interests: I.M. reports an independent research grant to the sponsor (AP-HP) from BMS/Pfizer. I.M. has received a research grant from Leo Pharma, has been a speaker for BMS and Leo Pharma, and has participated in advisory boards for BMS and Bayer. G.A.: no disclosure was declared by the author. C.A. has received honoraria for lectures from Bayer, BKS, Pfizer, Sanofi, and Daiichi Sankyo, and has participated in advisory boards for Bayer, BMS, Pfizer, and Sanofi. C.B. has received consulting fees/honoraria from Bayer Healthcare, Daiichi Sankyo, and BMS. A.B. has nothing to disclose. M.C. reports research funding from BMS, Pfizer, and Leo Pharma, and honoraria from BMS, Pfizer, Sanofi, Bayer, Leo Pharma, Servier, and Valeo; all payments were made to the institution. C.C. has received consulting fees from Leo Pharma. A.T.C.: no disclosure was declared by the author. P.G. has received honoraria and support for attending meetings and/or travel from Leo Pharma and Bayer. M.V.H. reports grants from ZonMW Dutch Healthcare Fund, and grants and personal fees to the hospital from Boehringer Ingelheim, BMS/Pfizer, Bayer Healthcare, Aspen, and Daiichi Sankyo, all outside the submitted work. F.A.K. reports research grants from Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, MSD, The Netherlands Organization for Health Research and Development, Actelion, the Dutch Heart Foundation, and the Dutch Thrombosis Association, all outside the submitted work. J.J.L.-N. has received honoraria for: lectures from Bayer, Pfizer and Rovi; educational events from Leo Pharma; lectures and support for attending meetings and travel from Bayer, Boehringer Ingelheim, BMS, Pfizer, Leo Pharma, Rovi, and Sanofi; and advisory board participation from Pfizer and Techdow. A.M. has received honoraria from Bayer, BMS, Leo Pharma, Rovi, and Pfizer, and support for attending meetings and/or travel from Bayer and BMS, and has participated in a data safety monitoring board or an advisory board for Bayer, BMS, and Leo Pharma. D.M. has received consulting fees from Leo Pharma, Pfizer, and BMS, and honoraria and support for attending meetings and/or travel from Leo Pharma and Pfizer. O.M. has received consulting fees from AstraZeneca, Blueprint Medicines, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Ipsen, Merck Sharpe & Dohme, Pfizer, Roche, Servier, and Vifor Pharma, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Blueprint Medicines, Eli-Lilly, Pfizer, Roche, and support for attending meetings and/or travel from Amgen and Roche, and has participated on a data safety monitoring board or advisory board for Blueprint Medicines, Boehringer-Ingelheim; and holds stock or stock options in Amplitude Surgical and Ipsen Transgene. M.M. has received an unrestricted grant for research from Sanofi, Leo Pharma, and Rovi, consulting fees from Sanofi and Bristol, and honoraria for lectures from Sanofi and Pfizer. M.R. has received honoraria for lectures from Bayer, Pfizer, and Biomérieux. C.M.S. has participated in a data safety monitoring board for the API-CAT study. K.S. has received personal fees from Roche, BMS, and MSD, and institutional fees from Amgen. S.S. has received honoraria for lectures from Bayer, BMS, Pfizer, Angelini, Janssen-Cilag, and Roche, and support for attending meetings and/or travel from BMS. A.T. has received consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, and participated on an advisory board for Bayer and Pfizer. P.V. is co-holder of the Bayer Chair in Cardiovascular Medicine at the University of Leuven. He has received consulting fees from Bayer, Daiichi Sankyo, Portola, and Anthos Pharmaceuticals, and honoraria from Bayer, Daiichi Sankyo, BMS, Pfizer, Boehringer, and Leo Pharma. E.V. has contracts for consulting in statistics with Pfizer, Novartis, Boehringer, Hexacath, Amgen, and Abbott. He has received fees for consulting in statistics from Pfizer, Novartis, Boehringer, Hexacath, Amgen, and Abbott, and honoraria for lectures on statistics from Amgen. T.-F.W. has received a research grant from Leo Pharma, and has participated in advisory boards for Pfizer and Servier. G.M. is deceased. S.L. has received grants from Leo Pharma, grants and consulting fees from Bayer Healthcare, and speaker fees from BMS, Pfizer, Merck Serono. The other authors report no conflicts of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

With current clinical practice, postoperative venous thromboembolism (VTE) risk is not only well controlled, but it is steadily decreasing, especially in orthopaedic surgery, thanks to fast-track and day case procedures, new surgical techniques, and potent antithrombotic agents. Thromboprophylaxis is becoming increasingly adapted to these patients. Aspirin is also extensively prescribed in total hip replacement and total knee replacement procedures in the United States and Australia. Mechanical prophylaxis is sometimes applied alone but most often combined with anticoagulant agents. However, large evidence-based studies are still needed to confirm these optimistic tendencies. In the meantime, physicians have to keep strong control over the VTE risk to prevent the reappearance of pulmonary embolism after admission to the surgical wards., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Surgical bleeding has been decreasing steadily for the last 20 years, but there are still some hemorrhagic procedures occurring in scheduled surgical settings and emergency procedures. The interest in potent hemostatic agents has recently focused on fibrinogen concentrates. A weak historical rationale based on the rapid decrease in fibrinogen concentration in the bleeding patient and several uncontrolled studies have prompted the use of fibrinogen concentrates in emergency units and in operating theaters. Very few positive randomized studies are available to confirm the usefulness of fibrinogen concentrates. The largest most recent double-blind studies are even negative. As recent guidelines recommend early and liberal use of fibrinogen concentrates in massive bleeding patients, this review reports the most important facts and studies on efficacy and raises some questions about safety., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Rivaroxaban and apixaban are selective direct inhibitors of free and prothrombinase-bound factor Xa (FXa). Surprisingly prothrombin time (PT) is little sensitive to clinically relevant changes in drug concentration, especially with apixaban. To investigate this pharmacodynamic discrepancy we have compared the kinetics of FXa inhibition in strictly identical conditions (pH 7.48, 37 °C, 0.15 M). KI values of 0.74 ± 0.03 and 0.47 ± 0.02 nM and kon values of 7.3 ± 1.6 10(6) and 2.9 ± 0.6 10(7) M(-1) s(-1) were obtained for apixaban and rivaroxaban, respectively. To investigate if these constants rationalise the inhibitor pharmacodynamics, we used numerical integration to evaluate impact of FXa inhibition on thrombin generation assay (TGA) and PT. Simulation predicted that in TGA triggered with 20 pM tissue factor, 100 ng/ml apixaban or rivaroxaban increased 1.8- or 3.0-fold the lag time and 1.4- or 2.0-fold the time to peak, whilst decreasing 1.2- or 3.1-fold the maximum thrombin and 1.7- or 3.5-fold the endogenous thrombin potential. These numbers were consistent with those obtained through the corresponding TGA triggered in plasma spiked with apixaban or rivaroxaban. Simulated PT ratios were also consistent with the corresponding plasma PT: markedly less sensitive to apixaban than to rivaroxaban. Analogous differences in TGA and PT were obtained irrespective of the drug amount added. We concluded that kon values for FXa of apixaban and rivaroxaban rationalise the unexpected lower sensitivity of PT and TGA to the former.

Despite the need for effective and safe thromboprophylactic drugs for patients with renal impairment, clinical trial data on anticoagulant agents are limited in this population. The study aim was to assess in the real-world setting the use of the once-daily 1.5 mg reduced dosage regimen of fondaparinux available for this context. In this prospective cohort study, patients with a creatinine clearance (CrCl) of 20-50 ml/minute, undergoing total hip (THR) or knee (TKR) replacement or hip fracture surgery (HFS) received fondaparinux thromboprophylaxis. Main clinical outcomes were bleeding (major/clinically relevant non-major), symptomatic venous thromboembolism (VTE) and death. Overall, 442 patients (353 women; median age: 82 years; 39.4% in ASA class ≥3; mean ± SD CrCl: 39.0 ± 8.0 ml/minute; 78% with additional risk factors for bleeding), undergoing THR (43.7%), TKR (27.6%), or HFS (28.7%) received fondaparinux 1.5 mg for a mean ± SD duration of 16.0 ± 12.5 days. At postoperative day 10, the rates (95% confidence interval) of major bleeding, clinically relevant bleeding and symptomatic VTE were 4.5% (2.8-6.9), 0.5% (0.1-1.6) and 0.5% (0.05-1.62), respectively; no fatal bleeding, bleeding into a critical organ, pulmonary embolism or proximal deep-vein thrombosis occurred. Corresponding rates at one month were 5.2%, 0.7% and 0.7%. One-month mortality was 2.3% (0.9-3.6). This large clinical prospective study provides for the first time, under conditions reflecting "real-world" routine clinical practice, data on the bleeding and VTE risks of thromboprophylaxis with fondaparinux 1.5 mg after major orthopaedic surgery in renally impaired patients. It shows that these patients constitute a very elderly and fragile population.

As a potent anticoagulant agent, fondaparinux exposes a risk of bleeding. An effective way to reverse its effects is needed. It was the objective to study efficacy and safety of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect of fondaparinux in a rabbit model of bleeding and thrombosis. In anaesthetised and ventilated rabbits, the Folts model was applied: a stenosis (75%) and an injury were carried out on the carotid artery, inducing thrombosis. Blood flow decreased as thrombus size increased until the pressure gradient was such that the thrombus was released and local blood flow was suddenly restored. This is known as a cyclic flow reduction (CFR). After the first CFR, rabbits were randomised into three groups: control (saline and saline after 1 minute), fondaparinux (fondaparinux [3 mg.kg-1] and saline), PCC (fondaparinux and PCC [40 UI.kg-1]). Then CFRs were recorded over 20 minutes. The following were measured: ear immersion bleeding time (BT), haemoglobin blood level (Hb1) and thrombelastometric parameters (ROTEM®). Finally, a hepatosplenic section was performed; 15 minutes later, the amount of blood loss was recorded as primary endpoint and Hb2 was measured. Blood loss was increased with fondaparinux and normalised with PCC. Regarding ROTEM® INTEM, fondaparinux increased clotting time and clotting formation time. PCC normalised these parameters. EXTEM and FIBTEM tests were not modified. Regarding safety, PCC did not increase CFRs. PCC reduced bleeding without increasing thrombosis and was effective to reverse the haemorrhagic effect of fondaparinux in this rabbit model.

Combined antiplatelet agents (cAPA), aspirin plus clopidogrel, increase the risk of bleeding. We hypothesised that recombinant activated FVIIa (rFVIIa), which normalises thrombin generation in platelet-rich plasma from patients treated with cAPA, could limit this bleeding risk. It was the objective of this study to investigate the efficacy and safety of rFVIIa compared to placebo, in a bleeding and thrombosis model in rabbits treated with aspirin and clopidogrel. New-Zealand rabbits, randomised into two groups (Placebo1, n=36 ; cAPA, n=34), were anaesthetised, ventilated and monitored for blood pressure, temperature and carotid blood flow. The Folts model was applied to a carotid artery. Cyclic flow reductions (CFR) were recorded over a first 20-min period (Obs1). Each rabbit was then randomly assigned into one of three subgroups (Placebo2, 40μg/kg rFVIIa, 160 μg/kg rFVIIa) and CFR were monitored for a second 20-min period (Obs2). Ear bleeding time (BT) was measured at the end of each period. Hepatosplenic (HS) section was performed at the end of the experiment and HS blood loss defines the primary endpoint. Secondary endpoints were thrombosis (CFR), prothrombin time, platelet aggregation, and thrombin generation. Non- parametric statistical tests were used (p<0.05). cAPA significantly increased HS blood loss, BT and suppressed CFR compared to Placebo1 (p<0.05). rFVIIa injection did not modify HS blood loss, BT or CFR rate in Placebo1 rabbits nor in cAPA animals. These effects were unaffected by either rFVIIa dose. rFVIIa accelerated thrombin generation but had no effect on platelet aggregation in citrated platelet-rich plasma. rFVIIa did not modify HS blood loss associated with cAPA in rabbits.

Delay in collecting coagulation test results from a central laboratory is one of the critical issues to efficiently control haemostasis during surgery. The aim of this multicenter study was to compare the performance of a point-of-care (POC) device (CoaguChek Pro DM) with the central laboratory-based coagulation testing during haemorrhagic surgery. For this purpose, 93 patients undergoing major surgical procedure were prospectively included in three centers. Blood was drawn from all patients before surgical incision and from most patients during surgical procedure after a blood loss of 25% or more was observed. When expressed in activity percentage, POC-based prothrombin time (PT) was in good agreement with central laboratory test result with coefficient of correlation in the range from 0.711 to 0.960 in the three centers. Comparison was less conclusive when PT was expressed in seconds or as the patient-to-control ratio and for activated partial thromboplastin time, with significantly shorter clotting times and lower ratios obtained on the POC device. On-site PT (in activity percentage) monitoring would have induced no significant change in fresh frozen plasma (FFP) transfusion in patients when compared to central laboratory monitoring. Test results were obtained in less than 5 minutes when performed using the POC device versus a median turnaround time of 88 minutes (range: 29-235 minutes) when blood collection tubes were sent to the central laboratory. These results suggest that, in providing a rapid answer, POC-based monitoring of PT (in percentage) using the CoaguChek device could be validly used in patients undergoing haemorrhagic surgical procedures.

Haemostatic properties of aprotinin could be associated with an increased risk of thrombosis. A randomized, blinded study was conducted to consider the potential thrombogenicity of aprotinin, using the Folts' model on femoral arteries in 12 pigs. The flow variations were measured by a pulsed Doppler in anaesthetised animals. Ear immersion bleeding time was performed. During the first part of the study, a stenosis was performed successively on both femoral arteries, each for a period of 30 min, without prior injury, to assess the integrity of the vessel, and to check that the arteries did not develop cyclic flow reductions (CFR), permanent cessation of flow (PCF) or partial thrombosis, when a stenosis is applied. Then the clamp was released and a bolus of placebo (saline), or aprotinin (4 millions KIU, followed by a continuous infusion of 1 million KIU.h-1), was administered. At the end of the bolus, the second part of the study began. Stenosis was applied to the arteries. If CRF, PCF, or partial thrombosis were observed without prior injury then the infused drug (aprotinin or saline) was considered a prothrombotic drug, and the opposite artery was studied. For each animal, right and left femoral artery segments were fixed and studied (morphologic study). Eighteen arteries were studied. In the aprotinin group, 6 arteries out of 8 developed an unexpected thrombosis, as compared with only 2 out of 10 arteries in the control group (p = 0.02). The morphologic study confirmed the occurrence of thrombosis in 4 out of 7 arteries in the aprotinin group, as compared with only 1 out of 9 in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the comparative antithrombotic properties of clopidogrel, an analogue of ticlopidine, and aspirin, using the Folts' model on femoral arteries in 22 pigs. On each animal, clopidogrel or aspirin were used to treat the thrombotic process on the left femoral artery and to prevent this process on the right femoral artery. Sequentially: an injury and stenosis were carried out on the left femoral artery; the thrombotic process was monitored with a Doppler during a 30-min observation period for cyclic flow reductions or permanent cessation of flow; after the first cyclic flow reduction occurred, clopidogrel (5 mg kg-1) or aspirin (2.5, 5, 100 mg kg-1) were injected intravenously; if cyclic flow reductions were abolished, epinephrine (0.4 micrograms kg-1 min-1) was injected to try to restore cyclic flow reductions and/or permanent cessation of flow; then injury and stenosis were applied on the right femoral artery. Before and after injection of clopidogrel or aspirin, ear immersion bleeding times and ex-vivo platelet aggregation were performed. Clopidogrel (n = 7) abolished cyclic flow reductions were efficiently prevented, even for two injuries. Basal bleeding time (5 min 28) was lengthened (> 15 min, 30 min after clopidogrel and remained prolonged even after 24 h). ADP-induced platelet aggregation was inhibited (more than 78%). Comparatively, aspirin had a moderate and no dose-dependent effect. Aspirin 2.5 mg kg-1 (n = 6) abolished cyclic flow reductions in 2 animals, CFR reoccurred spontaneously in one animal and epinephrine restored it in a second animal.(ABSTRACT TRUNCATED AT 250 WORDS)