Recombinant activated factor VII and prothrombin complex concentrates have different effects on bleeding and arterial thrombosis in the haemodiluted rabbit.

BACKGROUND: Recombinant activated factor VII (rFVIIa) is indicated in bleeding patients when a life-threatening haemorrhage occurs. Prothrombin complex concentrates (PCCs) are also used for this indication in several countries, without any evidence-based rationale. Our objective was to compare the efficacy and safety of PCC and rFVIIa in a model of bleeding and thrombosis in haemodiluted rabbits. METHODS: Forty-eight rabbits were randomly allocated into four groups: a control group and three treatment groups, in which animals were haemodiluted with hydroxyethyl starch 130/0.4 then administered either placebo, 160 µg kg(-1) rFVIIa, or 25 IU FIX kg(-1) PCC. The primary endpoint was hepatosplenic (HS) blood loss. Secondary endpoints were: (i) ear immersion bleeding time (IBT); (ii) thrombosis risk assessed by cyclic flow reductions (CFRs) of the carotid artery; and (iii) activated partial thromboplastin time (aPTT), and progress of thrombin activity. RESULTS: Haemodilution increased HS blood loss by 80% from 8 g (5-16) (control group) to 14 g (8-45) (placebo group) (P<0.01). HS blood loss was not different in animals receiving either rFVIIa [10 g (7-22)] or PCC [15 g (4-33)] (P<0.05) compared with the placebo group. Ear IBT was reduced with both rFVIIa and PCC. CFRs disappeared after haemodilution and were not restored with any treatment. Although PCC nearly doubled the total amount of thrombin generated, no significant change in the total amount of thrombin was seen in animals treated with rFVIIa. CONCLUSIONS: Neither rVIIa nor PCC reduced HS blood loss, whereas they both controlled the bleeding time, without increasing the thrombosis risk.

[Prevention of operational thromboembolic risk in plastic and aesthetic surgery. Analysis of cases, inquiries of practice and recommendations of professional practices]. / Prévention de la maladie thromboembolique périopératoire en chirurgie plastique et esthétique. Analyse de cas, enquête de pratique et recommandations de pratiques professionnelles.

SUBJECT: Thromboembolic accidents are a frightening complication of plastic and aesthetic surgery. The absence of recommendations for professional practices for the prevention of such accidents justified this work. The therapeutic practices of the surgeons were analysed and the results were then compared with those of the international literature. The analysis by a group of experts made it possible to establish recommendations for professional practices. MATERIAL AND METHODS: This work consisted in collecting, retrospectively, the therapeutic practices and the complications of 440 surgeons, concerning four types of interventions (abdominoplasty, mammoplasty, abdominal lift and liposuction), from 2006 to 2008, i.e., approximately 110.000 interventions. RESULTS: The intervention with the greatest risk is abdominoplasty with 0.9% of thromboembolic accidents; the intervention with the least risk is mammoplasty with 0.1% of accidents. The risk with the abdominal lift and liposuction of more than three zones is similar and intermediate with 06% of accidents. A protocol of prevention of thromboembolic accidents in plastic surgery is proposed.

Impact of preoperative maintenance or interruption of aspirin on thrombotic and bleeding events after elective non-cardiac surgery: the multicentre, randomized, blinded, placebo-controlled, STRATAGEM trial.

BACKGROUND: Patients receiving anti-platelet agents for secondary cardiovascular prevention frequently require non-cardiac surgery. A substantial proportion of these patients have their anti-platelet drug discontinued before operation; however, there is uncertainty about the impact of this practice. The aim of this study was to compare the effect of maintenance or interruption of aspirin before surgery, in terms of major thrombotic and bleeding events. METHODS: Patients treated with anti-platelet agents for secondary prevention and undergoing intermediate- or high-risk non-cardiac surgery were included in this multicentre, randomized, placebo-controlled, trial. We substituted non-aspirin anti-platelets with aspirin (75 mg daily) or placebo starting 10 days before surgery. The primary outcome was a composite score evaluating both major thrombotic and bleeding adverse events occurring within the first 30 postoperative days weighted by their severity (weights were established a priori using a Delphi consensus process). Analyses followed the intention-to-treat principle. RESULTS: We randomized 291 patients (n=145, aspirin group, and n=146, placebo group). The most frequent surgical procedures were orthopaedic surgery (52.2%), abdominal surgery (20.6%), and urologic surgery (15.5%). No significant difference was observed neither in the primary outcome score [mean values (SD)=0.67 (2.05) in the aspirin group vs 0.65 (2.04) in the placebo group, P=0.94] nor at day 30 in the number of major complications between groups. CONCLUSIONS: In these at-risk patients undergoing elective non-cardiac surgery, we did not find any difference in terms of occurrence of major thrombotic or bleeding events between preoperative maintenance or interruption of aspirin.

Maize- or potato-derived hydroxyethyl starches: is there any thromboelastometric difference?

BACKGROUND: Hydroxyethyl starches (HES) could differ with regard to the origin, and the influence on the coagulation of the raw material is unknown. This study compared the effects of a new potato-derived HES with a maize-derived HES and two crystalloid solutions. METHODS: Whole blood from 10 healthy individuals was diluted by 20% and 40% using either non-balanced potato-derived HES 130/0.42/6:1, non-balanced maize-derived HES 130/0.4/9:1, isotonic saline or Ringer's lactate solution. Samples were analysed by thromboelastometry ROTEM(®) : Coagulation was initiated by acid ellagic [intrinsic thromboelastometry (INTEM)] or tissue factor (extrinsic thromboelastometry) with and without cytochalasin to determine the functional component of fibrinogen [cytochalasin-d-modified thromboelastometry (FIBTEM)]. Platelet count and fibrinogen activity were measured. RESULTS: No effect of raw material was found as no difference was detected among the HES solutions. Whatever the solution, progressive haemodilution impaired haemostasis in a dose-dependant manner: For INTEM, the clot formation time was increased up to 308% and the maximum clot firmness (MCF) was decreased down to 49%. As dilution increased, initiation of coagulation was also impaired. Thromboelastometric alterations were more severe with HES than with crystalloids, especially regarding fibrin polymerization explorations: MCF of FIBTEM was considerably reduced from 12[10-14] to 2[2-3] mm (P<0.05). Fibrinogen activity and platelet count were reduced by dilution in a dose-dependant manner and decreased similarly in all groups. CONCLUSION: Maize- and potato-derived HES have similar effects on coagulation. Both the starch preparations tested lead to more severe haemostatic defects than crystalloids, and impairment of fibrin polymerization appears to be a leading determinant of this coagulopathy.

Andexanet alfa for the reversal of factor Xa inhibitors.

INTRODUCTION: Andexanet alfa is a recombinant modified factor Xa protein that has been developed to reverse factor Xa inhibitors. Since May 2018, the FDA has approved its utilization in patients treated with apixaban and rivaroxaban in case of life-threatening or uncontrolled bleeding. On 28 of February 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a conditional marketing authorization for andexanet alfa in Europe. Area covered: The authors provide an overview of andexanet alfa development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial ANNEXA as well as current limitations related to andexanet alfa are also discussed. Expert opinion: Although phase I and II studies have proven that andexanet alfa can be effective in reversing the effect of factor Xa inhibitors, its efficacy in major bleeding patients has only been shown for apixaban and rivaroxaban, without any comparator group. Well-designed studies comparing the efficacy and safety of andexanet alfa to other reversal strategies are required to confirm preliminary data. The benefit of andexanet alfa in specific settings needs to be investigated and its use in clinical practice needs to be facilitated by the implementation of international guidelines.

Prothrombin complex concentrates: a brief review.

Prothrombin complex concentrates are haemostatic blood products containing four vitamin K-dependent clotting factors (II, VII, IX and X). They are a useful, reliable and fast alternative to fresh frozen plasma for the reversal of the effects of oral anticoagulant treatments (vitamin K antagonists). They are sometimes used for factor II or factor X replacement in patients with congenital or acquired deficiencies. They are widely prescribed in Europe. Several retrospective and prospective studies have demonstrated their efficacy in normalizing coagulation and in helping to control life-threatening bleeding. Few side-effects, mainly thromboembolic events, have been reported. The link between these events and prothrombin complex concentrate infusion has, however, often been brought into question. The use of prothrombin complex concentrates in new promising indications such as the management of massive bleeding requires prospective studies providing a high level of evidence in a high-risk setting.

Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians.

Click to hear Dr Baglin's perspective on the role of the laboratory in treatment with new oral anticoagulants SUMMARY: One of the key benefits of the direct oral anticoagulants (DOACs) is that they do not require routine laboratory monitoring. Nevertheless, assessment of DOAC exposure and anticoagulant effects may become useful in various clinical scenarios. The five approved DOACs (apixaban, betrixaban, dabigatran etexilate, edoxaban and rivaroxaban) have different characteristics impacting assay selection and the interpretation of results. This article provides an updated overview on (i) which test to use (and their advantages and limitations), (ii) when to assay DOAC levels, (iii) how to interpret the results relating to bleeding risk, emergency situations and perioperative management, and (iv) what is the impact of DOACs on routine and specialized coagulation assays. Assays for anti-Xa or anti-IIa activity are the preferred methods when quantitative information is useful, although the situations in which to test for DOAC levels are still debated. Different reagent sensitivities and variabilities in laboratory calibrations impact assay results. International calibration standards for all specific tests for each DOAC are needed to reduce the inter-laboratory variability and allow inter-study comparisons. The impact of the DOACs on hemostasis testing may cause false-positive or false-negative results; however, these can be minimized by using specific assays and collecting blood samples at trough concentrations. Finally, prospective clinical trials are needed to validate the safety and efficacy of proposed laboratory thresholds in relation to clinical decisions. We offer recommendations on the tests to use for measuring DOACs and practical guidance on laboratory testing to help patient management and avoid diagnostic errors.

Epidemiology of venous thromboembolism after lower limb arthroplasty: the FOTO study.

BACKGROUND: In view of recent substantial changes in the management of orthopedic surgery patients, a study was performed in order to update data on the epidemiology of venous thromboembolism (VTE) in patients undergoing lower limb arthroplasty according to contemporary practise. METHODS: We performed a prospective observational study of a cohort of consecutive patients hospitalized for total hip or knee replacement in June 2003. The primary study outcome was the incidence of symptomatic VTE at 3 months. All events were adjudicated by an independent critical event committee. RESULTS: Data from 1080 patients (mean age 68.0 years) were available; 63.2% were undergoing total hip replacement and 36.8% total knee replacement. Pharmacological thromboprophylaxis was administered for a mean time of 36 days. Injectable antithrombotics were used in more than 99% of patients, irrespective of the type of surgery. The incidence of the primary study outcome was 1.8% (20 events; 95% CI: 1.0-2.6%). The incidences were 1.3% and 2.8% in hip and knee surgery patients, respectively. There were two pulmonary embolisms, both in knee surgery patients; neither was fatal. Thirty-five per cent of VTEs occurred after hospital discharge. An age of at least 75 years and the absence of ambulation before hospital discharge were the only significant (P < 0.05) predictors of VTE. The rate of clinically significant bleeding was 1.0% and the rate of death was 0.9%. CONCLUSIONS: The incidence of symptomatic VTE after lower limb arthroplasty is low, even if there is still a need to improve thromboprophylaxis, notably in patients undergoing knee arthroplasty.

Recombinant activated factor VII efficacy and safety in a model of bleeding and thrombosis in hypothermic rabbits: a blind study.

BACKGROUND: Recombinant activated factor VII (rFVIIa) is increasingly used to secure hemostasis in hemorrhagic situations in trauma and surgical patients. Hypothermia is often observed in these clinical settings. OBJECTIVE: To study the efficacy and safety of rFVIIa in hypothermia in a rabbit model of bleeding and thrombosis. METHODS: Sixty-nine rabbits were anesthetized, ventilated and monitored for blood pressure, temperature and carotid flow. The Folts model was used: 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 arterial blood flow was suddenly restored. This is known as a cyclic flow reduction (CFR). After counting baseline CFRs during a 20-min period (P1), rabbits were randomized blindly to one of four groups: normothermic (NT) placebo or rFVIIa (150 microg kg(-1)), hypothermic (HT) (34 degrees C) placebo or rFVIIa. Then CFRs were recorded over a second period (P2). At the end of the experiment, a hepato-splenic section was performed and the amount of blood loss was recorded. After each period, the following were measured: ear immersion bleeding time (BT), hemoglobin, platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT) and fibrinogen. RESULTS: Hypothermia increased BT and blood loss. These effects were reversed by rFVIIa. In NT rabbits, rFVIIa shortened BT but did not reduce blood loss. rFVIIa-treated rabbits bled similarly regardless of temperature. The incidence of CFRs was higher in treated than placebo animals regardless of temperature. rFVIIa decreased PT and aPTT without modifying platelet count or fibrinogen level. CONCLUSION: Hemostatic efficacy of rFVIIa was maintained in hypothermia. However, the number of CFRs was higher in the rFVIIa-treated group than in the placebo groups, whether for NT or HT rabbits.

A randomized study comparing the efficacy and safety of nadroparin 2850 IU (0.3 mL) vs. enoxaparin 4000 IU (40 mg) in the prevention of venous thromboembolism after colorectal surgery for cancer.

BACKGROUND: The optimal thromboprophylactic dosage regimen of low-molecular-weight heparins in high-risk general surgery remains debatable. OBJECTIVES: We performed a randomized, double-blind study to compare the efficacy and safety of nadroparin 2850 IU (0.3 mL) and enoxaparin 4000 IU (40 mg) in the prevention of venous thromboembolism (VTE) after colorectal surgery for cancer. PATIENTS AND METHODS: Patients undergoing resection of colorectal adenocarcinoma were randomized to receive once daily either 2850 IU nadroparin or 4000 IU enoxaparin s.c. for 9 +/- 2 days. The primary efficacy outcome was the composite of deep vein thrombosis (DVT) detected by bilateral venography or documented symptomatic DVT or pulmonary embolism up to day 12. The main safety outcome was major bleeding. A blinded independent committee adjudicated all outcomes. RESULTS: Out of 1288 patients analyzed, efficacy was evaluable in 950 (73.8%) patients. The VTE rate was 15.9% (74/464) in nadroparin-treated patients and 12.6% (61/486) in enoxaparin-treated patients, a relative risk of 1.27 (95% confidence interval; CI: 0.93-1.74) that did not met the criterion for non-inferiority of nadroparin. The rate of proximal DVT was comparable in the two groups (3.2% vs. 2.9%, respectively), but that of symptomatic VTE was lower in nadroparin-treated patients (0.2% vs. 1.4%). There was significantly (P = 0.012) less major bleeding in nadroparin- than in enoxaparin-treated patients (7.3% vs. 11.5%, respectively). CONCLUSION: Compared with those receiving enoxaparin 4000 IU, patients treated with nadroparin 2850 IU showed a higher incidence of asymptomatic distal DVT, but a lower incidence of symptomatic VTE. Nadroparin treatment was safer in terms of bleeding risk.

Early ambulation and prevention of post-operative thrombo-embolic risk.

The prevention of post-operative risk of venous thrombo-embolism (VTE) is of fundamental importance, but preventive methods have progressed with the introduction of direct oral anticoagulants (DOAC), the development of ambulatory surgery and enhanced recovery programs (ERP) after surgery. Surgery is, inherently a trigger for venous thrombo-embolic disease, as is prolonged immobilization. However, the risk of VTE is very low following ambulatory surgery, especially in this selected population. ERP, consists of a set of measures to optimize the patient's peri-operative management while reducing length of stay, costs and morbidity and mortality; one measure is the encouragement of early ambulation. This will undoubtedly have an impact on the incidence of VTE and lessen the need for prolonged thrombo-prophylaxis.

Venous thromboembolism and mortality after hip fracture surgery: the ESCORTE study.

BACKGROUND: Recent changes in the management of hip fracture surgery patients may have modified the epidemiology of postoperative complications. OBJECTIVES: We performed an observational study of a cohort of patients undergoing hip fracture surgery to update the epidemiological data on this population. The primary study outcome was the incidence of confirmed symptomatic venous thromboembolism (VTE) [defined as deep vein thrombosis, pulmonary embolism (PE), or both] at 3 months. Overall mortality at 1, 3 and 6 months was also evaluated. PATIENTS/METHODS: Consecutive patients aged at least 18 years hospitalized in French public or private hospitals (531 centers) undergoing hip fracture surgery were recruited prospectively during 2 months in 2002 and a follow-up at 6 months. Predictive factors for VTE at 3 months and for death at 6 months were also analyzed. RESULTS: Data from 6860 (97.3%) of the 7019 recruited patients were included in the analysis. The median age was 82 years. Low molecular weight heparins were administered perioperatively in 97.6% of patients; 69.5% received this treatment for at least 4 weeks. The actuarial rate of confirmed symptomatic VTE at 3 months was 1.34% (85 events, 95% CI: 1.04-1.64). There were 16 PEs (actuarial rate: 0.25%), three of which were fatal. Overall, 1006 (14.7%) patients were dead at 6 months. Cardiovascular disease was the most frequent cause of death (270 patients; 26.8%). CONCLUSIONS: The current rate of postoperative VTE is low, but overall mortality remains high. Indeed, hip fracture patients belong to a vulnerable group of old people with comorbid diseases and a high risk of postoperative morbidity and mortality. An interdisciplinary approach could be the challenge to improve short and long-term outcome.

[Massive haemorrhage after dorsal decompressive laminectomy]. / Hémorragie massive après laminectomie dorsale décompressive.

We describe a case of a massive haemorrhage after dorsal decompressive laminectomy. The biological syndrome was at first a disseminated intravascular coagulation (DIC), rapidly complicated by a secondary fibrinolysis. The usual treatment of DIC with plasma and platelet transfusion failed to control bleeding and the patient underwent four repeat operations for relapsing rapidly evolving paraplegia. Aprotinine treatment stopped the haemorrhage. The vertebral metastasis causing spinal compression proved to be of prostatic origin.

[Prevention of venous thromboembolism in surgery and obstetrics]. / Prévention de la maladie thromboembolique veineuse périopératoire et obstétricale.

The French Society of anaesthesiology and intensive care has chosen a high level methodology to issue professional Recommendations on perioperative and obstetrical venous thromboembolism prophylaxis. In addition with a short review on mechanical and pharmacological prophylaxis, all surgical and obstetrical settings have been studied. The initiation and duration of prophylaxis have been particularly debated in close relation with the level of surgical risk. A large group of experts has been involved in this process. More than 150 other experts have participated in the reading process. Didactic tables have been added to help the prescription.

Multimodal assessment of non-specific hemostatic agents for apixaban reversal.

BACKGROUND: Non-specific hemostatic agents, namely activated prothrombin complex concentrate (aPCC), PCC and recombinant activated factor (F) VII (rFVIIa), can be used, off-label, to reverse the effects of FXa inhibitors in the rare cases of severe hemorrhages, as no approved specific antidote is available. We have evaluated the ability of aPCC, PCC and rFVIIa to reverse apixaban. METHODS: Healthy volunteer whole blood was spiked with therapeutic or supra-therapeutic apixaban concentrations and two doses of aPCC, PCC or rFVIIa. Tests performed included a turbidimetry assay for fibrin polymerization kinetics analysis, scanning electron microscopy for fibrin network structure observation, thrombin generation assay (TGA), thromboelastometry, prothrombin time and activated partial thromboplastin time. RESULTS: aPCC generated a dense clot constituting thin and branched fibers similar to those of a control without apixaban, increased fibrin polymerization velocity and improved quantitative (endogenous thrombin potential and peak height) as well as latency (clotting and lag times) parameters. Adding PCC also improved the fibrin and increased quantitative parameters, but fibrin polymerization kinetics and latency parameters were not corrected. Finally, rFVIIa improved latency parameters but failed to restore the fibrin network structure, fibrin polymerization velocity and quantitative parameters. CONCLUSION: aPCC was more effective than PCC or rFVIIa in reversing in vitro the effects of apixaban. aPCC rapidly triggered the development of an apparently normal fibrin network and corrected latency and quantitative parameters, whereas PCC or rFVIIa had only a partial effect.

Aprotinin could promote arterial thrombosis in pigs: a prospective randomized, blind study.

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)