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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. ispartof: Journal of Thrombosis and Haemostasis vol:16 issue:2 pages:209-219 ispartof: location:England status: published

B-cell lymphoblastic lymphoma (B-LBL) rarely occurs in the oral cavity (3.5% of all intra-oral malignant tumors). Few cases of B-LBL mandibular bone involvement have been reported.We report the case of a 30-year-old female patient presenting with a single swelling of the left mandibular region, having grown for several weeks. Maxillo-facial CT and MRI showed inflammation of soft tissues and muscles without initial signs of osteitis, thus noncontributive to the diagnosis. A biopsy allowed diagnosing an intra-oral bone lymphoblastic lymphoma. The patient was referred to the hematooncology unit for treatment.Jaw localization of non Hodgkin's lymphoma is rare. Clinical symptomatology and radiological signs are poorly contributive. The diagnosis relies on a histopathological analysis.

The vascular endothelium has been characterized in every organ system, and is described as a selective permeable barrier and as a dynamic and disseminated organ with endocrine function. These activities have been shown to result from the interactions of ligands with membrane-bound receptors as well as through specific junctional proteins and receptors that govern cell-cell interactions. The endothelial cells' movement (e.g., angiogenesis) has been hypothesized to occur following the release of stimuli that could promote the formation of new blood vessels. Angiogenesis has also been reported to be the continued expansion of the vascular tree in avascular regions, as a result of the sprouting of endothelial cells from existing vessels. Most commonly, angiogenesis has been characterized during wound healing and tumour growth. Herein we summarize and discuss the latest results from fundamental laboratory research aimed at proving a link between the proliferation of cancer and angiogenesis, as well as the new rationale around novel pro- and anti-angiogenic molecules.

In a previous work, we have compared two automated techniques for platelet-rich plasma using a thrombocounter or whole blood with the continuous flow instrument Auto-analyzer (AA). More recently, we have tested two instruments using whole blood: the first one, fully automated: Coulter S+; and the other one, semi-automated: Clay-Adams. In the present work, these 4 methods are compared to the phase contrast microscope technique, used as reference. The coefficients of variation ranged betweeen 2 and 13 per cent. The coefficients of correlation between the different methods were between 0.92 and 0.96. Platelet distribution curves for platelet volumes obtained in parallel with platelet-rich plasma and with whole blood in 30 controls, show that platelet population are not significantly different. These instruments count particles and, therefore, necessitate a calibration made by means of platelet standards. Different platelet standards have been studied: those containing latex particles seem to give better results than suspensions of human or animal platelets.

Acute venous thromboembolism (VTE) is a serious and potentially fatal disorder, which often complicates the course of hospitalized medical patients. This is particularly true for carriers of malignant diseases. While the introduction of thromboprophylactic measures has probably affected the occurrence of postoperative VTE, there is an increasing awareness of the importance of medical conditions in determining thromboembolic events. Simple and clinically relevant risk assessment models are available to facilitate VTE risk assessment in hospitalized medical patients. Their validation in prospective studies is in progress. Randomized controlled clinical trials have consistently documented the efficacy of heparins and fondaparinux for prevention of VTE in hospitalized medical patients with a minimal haemorrhagic risk. Recognition of the incidence and clinical importance of thrombosis will probably encourage more widespread use of antithrombotic prophylaxis in medical patients and especially in some particular types of malignancies.

SummaryLow-molecular-weight heparins (LMWHs) have become the corner stone of antithrombotic treatment but their administration protocol needs to be optimized for certain groups of patients. In this paper, we studied the influence of nadroparin treatment on clot formation process assessed by thromboelastography in patients with carotid artery disease undergoing angioplasty and stenting. Standard thromboelastography assays (in-TEM® and ex-TEM® ) and minimal TF-triggered thromboelastography assay in citrated whole blood were performed in normal volunteers (n=20), in patients with carotid artery disease receiving only antiplatelet treatment (n=30), and in patients undergoing angioplasty receiving nadroparin 5750 anti-Xa IU s.c. twice daily (n=60). Blood samples were collected four hours after a second injection of nadroparin. In a subgroup of LMWH-patients (n=18) blood samples were also obtained prior to first injection of LMWH. Antiplatelet treatment had no effect on any parameter of the thromboelastographic pattern. Nadroparin treatment resulted in significant prolongation of clotting time (CT) and clot formation time (CFT) and significantly reduced α-angle in minimal TF-triggered thromboelastography and 30–38% of nadroparin treated patients had thromboelastographic parameters beyond the normal maximum limit. In-TEM test revealed a significant prolongation of clotting time while ex-TEM was not modified, and 20 to 30% of the patients had thromboelastographic parameters beyond the normal maximum limit. Anti factor-Xa activity in platelet-poor plasma (PPP) was also measured, and statistical analysis showed that prolongation of CFT of minimal TF-triggered TEM was significantly correlated to the levels of anti-Xa activity in patients’ plasma (p=0.04; r2 =0.7). There was no statistical correlation for any other parameter in all tests. In conclusion, the present study shows that nadroparin treatment in patients with carotid artery disease undergoing endovascular procedures induces significant modification of the thrombus kinetics assessed by minimal TF-triggered whole blood thromboelastography. The clinical relevance of these findings has to be evaluated in future studies.

New direct oral anticoagulants (NOAC), inhibitors of factor IIa or Xa, are expected to be widely used for the treatment of venous thromboembolic disease, or in case of atrial fibrillation. Such anticoagulant treatments are known to be associated with haemorrhagic complications. Moreover, it is likely that such patients on long-term treatment with NOAC will be exposed to emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose management for optimal safety as regards the risk of bleeding in such emergency conditions. In this article, only dabigatran and rivaroxaban were discussed. For emergency surgery at risk of bleeding, we propose to dose the plasmatic concentration of drug. Levels inferior or equal to 30ng/mL for both dabigatran and rivaroxaban, should enable the realization of a high bleeding risk surgery. For higher concentration, it was proposed to postpone surgery by monitoring the evolution of the drug concentration. Action is then defined by the kind of NOAC and its concentration. If the dosage of the drug is not immediately available, proposals only based on the usual tests, PT and aPTT, also are presented. However, these tests do not really assess drug concentration or bleeding risk. In case of severe haemorrhage in a critical organ, it is proposed to reduce the effect of anticoagulant therapy using a nonspecific procoagulant drug (activated prothrombin concentrate, FEIBA, 30-50U/kg, or non-activated 4-factors prothrombin concentrates 50U/kg). For any other type of severe haemorrhage, the administration of such a procoagulant drug, potentially thrombogenic in these patients, will be discussed regarding concentration of NACO and possibilities for mechanical haemostasis.

Post-dural puncture headache (PDPH) is one of the most frequent complications of neuraxial anesthesia and analgesia. The objective is to determine risk factors of PDPH receiving a blood patch in the obstetric population.Between November 2009 and January 2013, 10914 women delivered in Port Royal maternity unit (Paris, France). The incidence of PDPH receiving a blood patch was calculated among those who received neuraxial analgesia or anesthesia for delivery. Then we performed a case-control study to identify risk factors for PDPH receiving a blood patch by comparing women who experienced PDPH receiving a blood patch with some women randomly selected by computer among those who delivered during the study period (4 controls for 1 case, univariate and multivariate analysis).Among the 10685 women who had neuraxial analgesia or anesthesia, 0.4% had a PDPH receiving a blood patch. In the univariate analysis, cervix dilatation ≥7 cm, lateral decubitus position during the neuraxial procedure and multiple punctures were significantly associated with PDPH receiving a blood patch, whereas maternal Body Mass Index, age, mode of delivery, performance at night and level of needle insertion were not. In the multivariate analysis, cervix dilatation ≥7 cm and multiple punctures significantly increased the risk of PDPH receiving a blood patch (odd ratios 6.5 [95% CI: 1.5-29.3] and 5.6 [95% CI: 2.2-14.0], respectively). Experience of the anesthesiologist was not associated with PDPH in both univariate and multivariate analysis.In the obstetric population, a cervix dilation ≥7 cm during labor and multiple punctures are independent risk factors for PDPH receiving a blood patch.

Summary. 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.

Clot-associated prothrombinase and thrombin activities may contribute to thrombus extension after thrombolytic and anticoagulant treatment. We studied prothrombin activation after adding human purified prothrombin to human clot. By using two different drugs with an exclusive direct anti-activated factor X activity (DX9065a) or anti-activated factor II activity (r-hirudin), we tried to determine whether clot-bound thrombin and prothrombinase could be inhibited in our experimental system when human purified prothrombin was added. Standard clots were prepared from platelet-poor human plasma after addition of calcium. We measured clot-bound thrombin or free thrombin using a direct simple chromogenic assay. In parallel, prothrombin fragment 1 + 2 measurement was used to monitor prothrombin activation. For this, two protocols were used. We introduced the direct inhibitors before starting the activation process (protocol A) or at the time of the activation process (protocol B). We found a direct correlation between thrombin generation and prothrombin fragment 1 + 2 with an increase of thrombin activity on clots and in the incubation mixtures when clots were incubated in human purified pothrombin alone. Two protocols were used: in the first, clots were pre-incubated in presence of drugs before adding prothrombin; and in the second, clots were incubated in the presence of prothrombin and drugs. Prothrombin activation was not inhibited when clots were incubated with r-hirudin and consequently thrombin generation still occurred. However, added r-hirudin blocks thrombin activity on the clots and in the incubation mixture, but does not prevent prothrombin activation, as shown by the increase of prothrombin fragment 1 + 2. In contrast, DX9065a did not suppress clot-bound thrombin. However, DX9065a blocks prothrombin activation whichever protocol was used. The results show that hirudin is a poor inhibitor of thrombin generation in contrast to DX9065a. On the other hand, DX9065a cannot inhibit thrombin bound to clot in contrast to hirudin.

Thromboembolic disorders continue to be a major cause of morbidity and mortality, resulting in an increased need for anticoagulant therapy. In recent years, new anticoagulant drugs have been developed at a rapid pace, prompted by the recognition of many undesirable properties of currently used agents, and by a greater knowledge of the active enzymatic sites of clotting factors. Furthermore, the structure of a thrombus is better understood, so that newer drugs can inhibit thrombin or Factor Xa not only on the surface of a thrombus, as in the case of heparin, but also the fibrin-bound thrombin or Factor Xa within the thrombus. These agents are usually small molecules synthesized on the basis of their inhibition of specific active sites in the respective coagulation factors. They possess many improved characteristics, such as greater efficacy and safety, oral administration, reliable pharmacokinetics, less need for laboratory monitoring and minimal interactions with other drugs and diet. Prominent among these are lepuridin (Refludan, Pfizer), fondaparinux (Arixtra, Sanofi-Synthelabo) and ximelagatran (Exanta, Astra Zeneca). However, these new drugs are still far from fulfilling the desired objectives. Most of them possess some but not all of the needed properties. Furthermore, many do not have specific antidotes for immediate reversal of their pharmacologic actions, and all are much more costly than conventional agents. Development of newer agents with properties closer to that of the ideal drug remains a challenge.

Several haemostasis point-of-care (POC) monitors are now available in the operating theatre. Two of these are widely used; the Coaguchek® and the thromboelastograph (TEG), but they have been developed in very different ways. Bedside-activated partial thromboplastin time and prothrombin time performed with the Coaguchek monitor seem to be reliable and have been used to build algorithms for transfusion decision making. They have been developed in close collaboration with haemostasis groups and therefore gain a benefit from these links. Conversely, TEG provides very important information except it has never been validated. The number of collaborative studies with biologists has to increase in order to implement the use of TEG in the routine practice.

Assess the efficacy and safety of tranexamic acid administration for the prevention and/or the treatment of postpartum haemorrhage.Systematic review with meta-analysis.Systematic review of the literature with the aim of identifying prospective, randomised, controlled trials that assessed the effect of tranexamic acid on peripartum blood loss and transfusion requirement in three clinical contexts: (i) prevention of post-partum haemorrhage in case of elective caesarean section, (ii) prevention of post-partum haemorrhage in case of vaginal delivery, (iii) treatment of post-partum haemorrhage.Prophylactic administration of tranexamic acid reduced blood loss (mean difference for intraoperative blood loss: -177.9mL, IC 95%: -189.51 to -166.35, total blood loss: -183.94, IC 95%: -198.29 to -169.60), and the incidence of severe post-partum haemorrhage (OR: 0.49, IC 95%: 0.33 to 0.74). None of the published trials assessed the effect of tranexamic acid on blood products administration or transfusion requirement. Only one study assessed and reported the efficacy of tranexamic acid when administered as a treatment for postpartum haemorrhage. A significant reduction in blood loss was reported within 30 minutes after randomisation (P=0.03) and confirmed after 6 hours (median: 170mL (58-323) vs 221mL (110-543), P=0.04). None of the included studies adequately studied the incidence of side effects after tranexamic acid administration.Although tranexamic acid administration seemed to significantly reduce blood loss and the incidence of severe post-partum haemorrhage, further prospective trials are needed to confirm the efficacy and safety of tranexamic administration in the treatment of postpartum haemorrhage. Those studies should assess the pharmacokinetic profile and the safety of this drug in pregnant women.

Thrombolysis and percutaneous transluminal angioplasty represent the cornerstone of the pharmacologic treatment of and the interventional approach to patients with myocardial infarction (MI). They are very effective. However, they are hampered by some critical limitations. Therefore, alternatives to standard thrombolytic therapy have been developed. Platelet glycoprotein (GP) IIb/IIIa blockade is under investigation and seems very attractive. This review will focus on the use of GP IIb/IIIa antagonists and thrombin inhibitors as adjunctive therapies to the thrombolytic treatment of patients with acute MI.

Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.

New oral anticoagulants which specifically inhibit factor Xa (FXa) or thrombin (FIIa) do not require routine laboratory monitoring. However, they induce a state of hypocoagulation and increase the risk of bleeding. In some clinical situations, such as emergency surgery, hemorrhagic episodes, or recurrent stroke, coagulation monitoring may be useful. A significant number of publications have reported uncontrollable hemorrhagic complications and deaths in patients treated with these new anticoagulants. The selection of the most appropriate clotting assay is based on the drug used and the availability of the test. The new anticoagulants influence all global clot-based tests. Prothrombin time and partial thromboplastin time measured before and after treatment are considered as qualitative tests since they are not specific. Specific anti-Xa and anti-IIa assays are available and results can be expressed in nanogram per milliliter of plasma using calibrated plasmas containing well-established amounts of drug. The fact that there is no specific antidote to reverse the anticoagulant action of the new anticoagulants can impair management of hemorrhagic complications; clinical experience is still limited. Pro-hemostatic treatment with non-activated or activated prothrombin complexes (FEIBA(®)), or as a last recourse with FVIIa concentrates (NovoSeven(®)), has been used with variable results. Some suggestions for the management of patients with bleeding have been published but there is still little clinical evidence for these interventions.

The current issues debate will bring together experts around the themes of self-sufficiency (in its national and European aspects) and of needs in cellular blood products. The point of view of the manufacturer and prescribers of blood products will be confronted.

The management of massive bleeding has improved, thanks to high-quality blood components and new transfusion strategies. However, it remains controversial and, despite a huge body of literature, randomised control trials are still lacking. However, the therapeutic approach has also evolved, requiring earlier and more active management. If a 'no delay' management is well recognized, its modes are still discussed. Immediate delivery of blood products with ratios close to 1:1:1 for RBC units/fresh frozen plasma/platelet concentrates, through massive transfusion protocol using blood packs, has been advocated, but yet this approach is not evidence-based. Secondly, a targeted strategy to provide fibrinogen concentrates is under evaluation. Tranexamic acid is effective in trauma patients. Recombinant factor VIIa should only be used on a compassionate basis.

Studies on the pharmacological and pharmacodynamic properties of heparins are complicated by the heterogeneity of heparin preparations. It is important to consider the molecular weight distribution, which may differ from one preparation to another. Molecules with a molecular weight ranging from about 2000 to 5000D are abundant in low molecular weight heparins (LMWHs), while they are present at a very low concentration in standard heparin. The clinical relevance of this difference is not fully understood. Recent work from our laboratory demonstrates that factor VII activation to factor VIIa in vitro is significantly inhibited by heparins. This is another aspect of some importance in understanding the mechanism of action of heparins. The bioavailability and plasma clearance of anti-Xa activity are well documented. In contrast, clear results regarding the bioavailability of anti-IIa activity are still missing. Recent data indicate that the anti-Xa activity of different molecules of heparin does not increase in parallel with the molecular weight of the heparin chain. In contrast, the anti-IIa activity of different molecules of heparin increases in parallel with the molecular weight. This could explain why activated partial-thromboplastin time is less prolonged with LMWHs than with standard heparin. There is growing evidence that anti-Xa activity contributes to the antithrombotic effect of heparins, although it is generally accepted that anti-IIa activity plays a major role. There have been 3 important findings from recent work on the pharmacology of heparins: i) heparin at a very low dose has thrombopoietic activity; ii) in hip surgery, the incidence of heparin-induced thrombocytopenia is significantly lower in patients receiving subcutaneous LMWHs for 2 weeks compared with patients receiving unfractionated heparin; and iii) the risk of osteoporosis with long term treatment with LMWHs seems lower than with standard heparin.

SummaryExposure to streptokinase (SK) elicits anti-SK antibodies (Abs), which inhibit fibrinolysis and induce platelet aggregation. The mechanism of the latter is not fully understood, although it seems to involve platelet binding by a plasminogen streptokinase and anti-SK ternary complex. Anti-SK Abs were purified by affinity chromatography from serum of patients having received SK for acute myocardial infarction (AMI), and were shown to be of the IgG type. Their effects were studied with (i) human platelets in citrated plasma in the presence of SK or acetylated plasminogen-SK activator complex (APSAC), and (ii) in washed platelets, resuspended in Tyrode buffer after lowering the ionic strength, in the presence of APSAC (which provides both SK and plasminogen). An antibody concentration-response curve was obtained, showing a plateau in the presence of 0.1 mg/ml IgG. By increasing the concentration of APSAC, we obtained a unimodal response curve, the optimal concentration of APSAC being 0.05 U/ml. Aggregation was suppressed by chelating calcium with EDTA, blocking fibrinogen binding by the synthetic peptide Arg-Gly-Asp-Ser (RGDS), and raising intraplatelet cAMP with Iloprost (a prostacyclin analogue). Aggregation required the interaction of the anti-SK Ab Fc domain with the platelet Fc-gamma receptor type II, also known as CD32, since: (i) it was blocked by the monoclonal antibody IV-3 directed against CD32, (ii) it did not occur with F(ab)’2 fragments, which block the response to the intact IgG. The clinical relevance of these platelet-activating anti-SK antibodies remains to be determined. Two factors might influence clinical outcome: (i) the amount and type of pre-existing anti-SK Abs; (ii) the known interindividual variability of the platelet response to binding and activation by IgG involving the CD32 molecule.

Rare inherited bleeding disorders include fibrinogen disorders, and deficiencies of factors II (prothrombin), V, VII, X, XI, XIII, and combined V+VIII, and combined vitamin K-dependent factors, with general population prevalence rates between 1/500,000 and 1/2,000,000. These inherited disorders, transmitted as autosomal recessive traits, are characterized by a heterogeneous clinical presentation (asymptomatic, mild, moderate or severe bleeding tendency); this variability is more important for deficiencies with factor levels ranging from 5 to 50%. Individual bleeding risk assessment before an invasive procedure or during peri-partum period remains difficult, although an essential step to decide whether a substitution with clotting factor is necessary or not. Because there is a poor correlation between factor activity levels and the severity of bleeding symptoms, factor correction before an invasive procedure should not be based on factor level only, but physicians must also take into account the patient phenotype as well as the haemorrhagic risk of the procedure.

The study objective was to evaluate the potential increase in fatal bleeding risk related to curative anticoagulation of asymptomatic deep venous thromboses diagnosed by routine ultrasound screening after total hip/knee replacement or hip fracture using data from a comprehensive literature review.Rates of venous thromboembolic and bleeding events occurring with recommended prophylaxis, and rates of iatrogenic bleeding risk induced by curative anticoagulation were extracted from randomized clinical trials, diagnosis codes at discharge, electronic databases, and observational studies. The fatal events rate was calculated for pulmonary embolism, major bleeding with prophylaxis, and iatrogenic bleeding from curative anticoagulation by multiplying the mean rate by its case-fatality rate. Fatal event rates were evaluated for 10,000 total hip or knee replacements and for 10,000 hip fractures.For 10,000 patients undergoing total hip or knee replacement, five fatal pulmonary embolisms and two fatal bleedings are expected, despite recommended extension of thromboprophylaxis. Curative anticoagulation of asymptomatic venous thrombosis would add nine fatal bleedings, 8/9 related to distal thrombosis care. For 10,000 patients undergoing hip fracture surgery, six fatal pulmonary embolisms and 23 fatal bleedings are expected. Curative anticoagulation of asymptomatic venous thrombosis would add 16 fatal bleedings, 14/16 related to distal thrombosis care.Curative anticoagulation of asymptomatic distal deep vein thromboses, leads to more fatal bleeding compared to avoidable fatal pulmonary embolism. These findings strengthen recommendations against routine ultrasound screening for asymptomatic distal deep vein thrombosis.

Even with unfractionated heparin or derivates, the reversal of pharmacologic anticoagulation is crucial in anticoagulated patients developing a life-threatening bleeding or scheduled for an emergency procedure. The antagonisation of unfractionated heparin is well codified: each milligram of protamine sulfate antagonizes 100 IU of heparin. Measurement of thrombin time reflects the anti-IIa effect of heparin and has to be monitored immediately and 1hour after the injection of protamine. The required dose of protamine sulfate depends on dosage and time of LMWH administration, although no clinical study supports these data. To date, there is no effective antidote for new anticoagulants (fondaparinux and other pentasaccharides, direct thrombin inhibitors, direct anti-Xa inhibitors). Some preliminary studies suggest the effectiveness of recombinant activated factor VII for pentasaccharides and activated or not Prothrombin Complex Concentrates and recombinant activated factor VII for oral anti-Xa and anti-IIa agents. Therefore, while the characteristics of these new anticoagulants could increase the comfort and improve the compliance, their development needs to ascertain the lack of increase in bleeding complications and the need for a safe and effective antidote.

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.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.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.

Retinal venous circulation is characterized by the combination of a low flow state and a high vascular resistance, which would make it particularly dependent on blood viscosity. Erythrocyte aggregation is the chief determinant of blood viscosity at low shear rates. Recent studies have demonstrated increased erythrocyte aggregation in many systemic vascular disorders and also in retinal vein occlusion.To assess the possible role of abnormal hemorheologic findings in the pathogenesis of central retinal vein occlusion (CRVO), the authors retrospectively studied erythrocyte aggregation and hematocrit and fibrinogen levels in 33 patients with CRVO and without any known risk factors (diabetes, hypertension, smoking, hyperlipidemia, cardiovascular disease, glaucoma). Erythrocyte aggregation was assessed with a light back-scattering method. Results were compared with those of a group of 33 age- and sex-matched controls.Eleven (33%) of the 33 patients with CRVO had abnormal hemorheologic findings. Erythrocyte aggregation was highly significantly increased in the CRVO group when compared with the control group (P0.0001), as was the hematocrit level (P0.05). In addition, the proportion of patients with abnormal blood rheologic tests was greater (50%) in the subgroup of patients who initially had nonischemic CRVO that worsened into an ischemic CRVO during the follow-up.These data suggest that abnormal hemorheologic findings could affect the pathogenesis of CRVO, and perhaps be predictive of an aggravation. The latter hypothesis needs to be confirmed in a larger, prospective study.

Cutaneous necrosis is a rare complication of vitamin K antagonist therapy. It presents as cutaneous hemorrhagic necrosis and usually occurs at the start of treatment. We describe an atypical case of recurrent skin necrosis after two years of treatment with fluindione.A 70-year old woman with a history of venous thromboembolism and obesity presented with a large haemorrhagic necrosis of the abdominal wall. She had been treated with fluindione for two years. Genetic protein C deficiency was discovered. Resumption of vitamin K antagonist therapy was followed by recurrence of skin necrosis despite concomitant administration of heparin. Treatment with vitamin K antagonists could not be continued.This observation is unusual due to the late onset of skin necrosis. The condition usually begins shortly after initiation of vitamin K antagonist therapy, generally between the third and the sixth day of treatment. It is due to a transient hypercoagulable state in patients with protein C deficiency or, in rare cases, protein S deficiency. This late-onset skin necrosis, occurring many years after initiation of anticoagulant therapy, may be explained by a sudden worsening of pre-existing protein C deficiency due to infectious and iatrogenic factors.

Direct oral anticoagulants (DOAs), inhibitors of factor IIa or Xa, are expected to replace vitamin K antagonists in most of their indications. It is likely that patients on long-term treatment with DOAs will be exposed to elective or emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose perioperative management for optimal safety as regards the risk of bleeding and thrombosis. DOAs may increase surgical bleeding, they have no validated antagonists, they cannot be monitored by simple, standardised laboratory assays, and their pharmacokinetics vary significantly from patient to patient. Although DOAs differ in many respects, the proposals in the perioperative setting need not be specific to each. For procedures with low risk of haemorrhage, a therapeutic window of 48 h (last administration 24h before surgery, restart 24h after) is proposed. For procedures with medium or high haemorrhagic risk, we suggest stopping DOAs 5 days before surgery to ensure complete elimination of the drug in all patients. The treatment should be resumed only when the risk of bleeding has been controlled. In patients with a high risk of thrombosis (e.g. those in atrial fibrillation with an antecedent of stroke), bridging with heparin (low molecular weight, or unfractionated if the former is contraindicated) is proposed. In emergency, the procedure should be postponed for as long as possible (minimum 1-2 half-lives) and non-specific anti-haemorrhagic agents, such as recombinant human activated factor VIIa, or prothrombin concentrates, should not be given for prophylactic reversal, due to their uncertain benefit-risk.