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Goal of this article is to select three molecules from all the candidates currently under clincial development and to present and comapre their characteristics. Dabigatran is a direct thrombin (FIIa) inhibitor, whereas Rivaroxaban and Apixaban are direct factor Xa (FXa) inhibitors. All three represent small molecules that reversibly, rapidly and directly bind to their target, the active center of the respective activated coagulation factor. Phase III data have been published for venous thromboembolism prophylaxis for each of these three drugs. Interestingly, VTE prophylaxis is initiated postoperatively with these products. Rivaroxaban currently holds the only accepted indication in Switzerland. For the indications VTE, atrial fibrillation and acute coronary syndrome promising phase III data have been or are in the process of being published. Monitoring is not necessary for any of these three new anticoagulants. [ABSTRACT FROM AUTHOR]

Objectives: Assessing urgency in ectopic pregnancies (ECP) remains controversial since the disorder covers a large clinical spectrum. Severe conditions such as acute abdomen or hemodynamic instability are mostly related to intra-abdominal blood loss diagnosed as free fluid (FF) on transvaginal sonography (TVS). The aims of the current study were to investigate the value of FF and to assess other potentially predictive parameters for judging urgency., Methods: Retrospective cohort analysis on prospectively collected cases of proven ECP (n = 343). Demographics, clinical and laboratory parameters, and findings on TVS and laparoscopy (LSC) were extracted from the digital patient file. FF on TVS and free blood (FB) in LSC were evaluated. Low urgency was defined as FB (LSC) < 100 ml and high urgency as FB (LSC) ≥ 300 ml. The best subset of variables for the prediction of FB was selected and predictors of urgency were evaluated using receiver operator characteristic (ROC) curves., Results: Clinical symptoms, age, β-HCG, hemoglobin (HB) preoperative, and FF were examined in multivariate analysis for the cutoff values of 100 ml and 300 ml. FF was the only independent predictor for low and high urgency; HB preoperative was only significant for high urgency offering marginal improvement. ROC analysis revealed FF as an excellent discriminatory parameter for defining low (AUC 0.837, 95% CI 0.794-0.879) and high urgency (AUC 0.902, 95 % CI 0.860-0.945)., Conclusion: Single assessment of FF on TVS is most valuable for judging urgency. However, the exact cutoff values for a low- and high-risk situation must still be defined., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: Thrombophilia testing is controversial, not least because of its high cost. Because comprehensive valid testing requires standardized blood collection close by the specialized laboratory, and interpretation of findings together with clinical data, often only part of the necessary laboratory analyses can be performed in remote central laboratories. Restrictive indications for testing, as have been recommended by previous reviews on the topic, have been based on incomplete analytics, studies with small case numbers, or short observation periods, and on an inappropriate, simple risk stratification for venous thromboembolism (VTE), further subdivided into provoked and unprovoked events., Methods: The authors reviewed four electronic databases for all peer-reviewed and in-press articles about thrombophilia, VTE, obstetric complications, and arterial thrombosis. After confirmation for relevance to the topic, 201 articles were accepted for inclusion in this article. This review summarizes the studies relevant to the evaluation of thrombophilic conditions, and their combination with each other and with clinical risk factors, to stratify individual risk for thromboembolism and obstetric complications., Results: Thrombophilia testing requires highly skilled personnel for laboratory analysis and interpretation. Clinical conditions that influence the results as well as special preanalytical, analytical, and postanalytical aspects must be considered if valid results are to be obtained. Tests involved include the natural anticoagulants antithrombin, protein C, and protein S; the procoagulants fibrinogen (dysfibrinogen), prothrombin (mutation G20210A), factor V (Leiden mutation), factor VIII/von Willebrand factor/blood group ABO, factor IX, and factor XI; the anti-phospholipid antibodies to detect an antiphospholipid syndrome and potentially additional uncertain thrombophilic conditions. The risks of thrombophilic conditions and clinical risk factors for VTE are cumulative or even supra-additive. Scores from thrombophilic conditions and other genetic and nongenetic risk factors permit estimation of risk for first and recurrent VTE. Therapeutic strategies can be derived from this risk stratification., Conclusions: Thrombophilia testing is indicated when the results have potential to influence the type and duration of treatment. Indications include certain patients after VTE; or patients without previous VTE but with positive family history regarding VTE or thrombophilia before major surgery, pregnancy, combined oral contraceptives, or hormone replacement therapy. Whether or not thrombophilia is present should help determine anticoagulation, hormonal contraception, or hormone replacement.

Factor XIII (FXIII) is the final factor in the coagulation cascade. It converts soluble fibrin monomers into a stable fibrin clot, prevents premature degradation of fibrin, participates in wound healing, and helps prevent the loss of the endothelial barrier function. FXIII deficiency is believed to be rare, and this may explain why clinicians do not routinely take it into consideration. Congenital FXIII deficiency is a rare disease with a reported prevalence of 1 per million. However, the prevalence of acquired FXIII deficiency is much higher. Acquired forms have been described in patients with decreased hepatic or bone marrow synthesis, overconsumption and increased degradation by autoantibodies. This review offers guidance on how to suspect and diagnose FXIII deficiency in both the preoperative consultation and different surgical settings. We also analyze current scientific evidence in order to clarify when and why this clinical situation should be suspected, and how it may be treated.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug effect that occurs in 0.1&ndash;5% of heparin treated patients. Management of acute HIT currently involves (1) cessation of heparin exposure, and (2) inhibition of coagulation with an anticoagulant other than heparin. Several anticoagulants can be considered for the treatment of HIT. Anticoagulant monitoring, management of drug-induced adverse events including bleeding, and therapeutic dosing schedules in selected clinical settings represent challenges to the clinician treating HIT patients. Moreover, the fact that not all registered anticoagulants are approved for HIT in Switzerland further complicates the management of HIT. The present recommendations on the anticoagulant treatment of HIT in Switzerland have been elaborated by a panel of Swiss experts belonging to the Working Party Hemostasis (WPH) of the Swiss Society of Hematology (SGH-SSH). They are intended to support clinicians in their decision making when treating HIT patients.

Platelet quality in different platelet concentrates (PCs) has been the subject of several studies. Nonetheless, there is a lack of robust data on the correlation and agreement among platelet function tests as a prerequisite for the association of PC functionality in vitro with platelet function in vivo post PC transfusion. The purpose of our study was to correlate a larger panel of platelet function assays in PCs and to assess whether the methods agree sufficiently and can be used interchangeably. Twelve apheresis platelet concentrates in plasma (APC), 16 pooled platelet concentrates in plasma (PPC), and 12 PPC in T-sol (PPCA) were examined on days 1 and 4 after production. PCs were tested for platelet count, light transmission aggregation (LTA) induced by ADP, collagen, or TRAP; platelet ATP release induced by collagen; and spontaneous and ADP and TRAP-induced increase in CD62P and PAC1 expression measured by flow cytometry. All tests were performed in undiluted platelet-rich plasma, recalcified and mixed with an inhibitor of factor Xa and thrombin. Most platelet function parameters correlated significantly with each other, but agreement among methods was insufficient. A proper inverse correlation was observed between ADP-induced LTA and spontaneous platelet activation assessed by CD62P expression ( r  = -0.61, p  < 0.0001). Spontaneous CD62P correlated also significantly with spontaneous PAC1 ( r  = 0.69, p  < 0.0001) and inversely with TRAP-induced CD62P expression ( r  = -0.86, p  < 0.0001). We found significant correlations among all flow cytometric assays measuring platelet CD62P and PAC1 expression induced by ADP or TRAP. Subsequent Bland Altman analysis revealed insufficient agreement between methods. With one exception (collagen-induced LTA compared with TRAP-induced LTA, percentage error = 16%) the limits of agreement expressed as percentage error exceeded the chosen acceptable difference of 30%. In APC, platelet count was 41% and 44% higher, respectively, than in PPC and PPCA ( p  < 0.0001). Spontaneous CD62P and PAC1 expression were significantly greater, and ADP-induced aggregation and agonist-induced increase in CD62P and PAC1 were significantly lower in PPCA compared to APC and PPC on day 4 of storage. ADP and TRAP-induced CD62P and PAC1 activatability fell significantly during storage between day 1 and day 4 in APC and PPCA, but not in PPC. In conclusion, different platelet function tests capture different aspects of platelet function and do not correlate and agree sufficiently to be used interchangeably.

Essentials Accurate determination of anticoagulant plasma concentration is important in clinical practice. We studied the accuracy and consistency of anti-Xa assays for rivaroxaban in a multicentre study. In a range between 50 and 200 μg L -1 , anti-Xa activity correlated well with plasma concentrations. The clinical value might be limited by overestimation and intra- and inter-individual variation., Summary: Background Determining the plasma level of direct oral anticoagulants reliably is important in the work-up of complex clinical situations. Objectives To study the accuracy and consistency of anti-Xa assays for rivaroxaban plasma concentration in a prospective, multicenter evaluation study employing different reagents and analytical platforms. Methods Rivaroxaban 20 mg was administered once daily to 20 healthy volunteers and blood samples were taken at peak and trough levels (clinicaltrials.gov NCT01710267). Anti-Xa activity was determined in 10 major laboratories using different reagents and analyzers; corresponding rivaroxaban plasma concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). Findings Overall Pearson's correlation coefficient of anti-Xa levels and HPLC-MS results was 0.99 for Biophen ® Heparin (95% CI, 0.99, 0.99), Biophen ® DiXaI (95% CI, 0.99, 0.99) and STA ® anti-Xa liquid (95% CI, 0.99, 1.00). Correlation was lower in rivaroxaban concentrations below 50 μg L -1 and above 200 μg L -1 . The overall bias of the Bland-Altman difference plot was 14.7 μg L -1 for Biophen Heparin, 17.9 μg L -1 for Biophen DiXal and 19.0 μg L -1 for STA anti-Xa liquid. Agreement between laboratories was high at peak level but limited at trough level. Conclusions Anti-Xa activity correlated well with rivaroxaban plasma concentrations, especially in a range between 50 and 200 μg L -1 . However, anti-Xa assays systematically overestimated rivaroxaban concentration as compared with HPLC-MS, particularly at higher concentrations. This overestimation, coupled with an apparent interindividual variation, might affect the interpretation of results in some situations., (© 2017 International Society on Thrombosis and Haemostasis.)

Objectives: Factor V (FV) plays an important role in coagulation. As no purified concentrate is available to restore critical FV levels, the main blood product used to replace FV is plasma. The aim of the present in vitro study was to compare the efficacy of the different available plasma products on the reversal of moderate and severe FV deficiency as assessed by ROTEM® and FV levels., Methods: Five different plasma products (6 batches of each) were compared to determine their effectiveness in replacing FV in plasma moderately or severely deficient in FV. Effectiveness was measured using the ROTEM® EXTEM clotting time (CT) and a factor V assay., Results: FFP, plasma frozen within 24 hours (FP24), Octaplas (solvent/detergent treated pooled plasma), as well as Octaplas and FP24 thawed and stored for 5 days (Octaplas TP and TP), were all used for in vitro replacement of FV. TP was significantly less effective at reversing a prolonged EXTEM CT and FV levels in FV deficient plasma than other tested products. There were no significant differences in EXTEM CT between Octaplas and Octaplas TP, while factor V activity was significantly lower in the Octaplas TP. There was no significant difference between Octaplas and FFP for EXTEM CT or FV activity., Conclusions: Octaplas and Octaplas TP appear to have an equivalent ability to improve the EXTEM CT and could be considered as a treatment alternative to FFP in patients with FV deficiency., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Plasma fibrinogen concentration is important for coagulopathy assessment, and is most commonly measured using the Clauss method. Several factors, including device type and reagent, have been shown to affect results. The study objective was to evaluate performance and repeatability of the Clauss method and to assess differences between measurements performed during and after cardiopulmonary bypass (CPB), by testing plasma samples from patients undergoing cardiac surgery with CPB. Samples were collected from 30 patients before surgery, approximately 20 minutes before weaning from CPB, and 5 minutes after CPB and protamine. Fibrinogen concentration was determined using the Clauss method at six quality-controlled specialised laboratories, according to accredited standard operating procedures. Regarding within-centre agreement for Clauss measurement, mean differences between duplicate measurements were between 0.00 g/l and 0.15 g/l, with intervals for 95% limits of agreement for mean Bland-Altman differences up to 1.3 g/l. Regarding between-centre agreement, some mean differences between pairs of centres were above 0.5 g/l. Differences of up to ~2 g/l were observed with individual samples. Increased variability was observed between centres, with inter-class correlation values below 0.5 suggesting only fair agreement. There were no significant differences in fibrinogen concentration before weaning from CPB and after CPB for most centres and methods. In conclusion, considerable differences exist between Clauss-based plasma fibrinogen measured using different detection methods. Nevertheless, the similarity between measurements shortly before weaning from CPB and after CPB within centres suggests that on-pump measurements could provide an early estimation of fibrinogen deficit after CPB and thus guidance for haemostatic therapy.

Introduction: Rivaroxaban (RXA) is licensed for prophylaxis of venous thromboembolism after major orthopaedic surgery of the lower limbs. Currently, no test to quantify RXA in plasma has been validated in an inter-laboratory setting. Our study had three aims: to assess i) the feasibility of RXA quantification with a commercial anti-FXa assay, ii) its accuracy and precision in an inter-laboratory setting, and iii) the influence of 10mg of RXA on routine coagulation tests., Methods: The same chromogenic anti-FXa assay (Hyphen BioMed) was used in all participating laboratories. RXA calibrators and sets of blinded probes (aim ii.) were prepared in vitro by spiking normal plasma. The precise RXA content was assessed by high-pressure liquid chromatography-tandem mass spectrometry. For ex-vivo studies (aim iii), plasma samples from 20 healthy volunteers taken before and 2 - 3hours after ingestion of 10mg of RXA were analyzed by participating laboratories., Results: RXA can be assayed chromogenically. Among the participating laboratories, the mean accuracy and the mean coefficient of variation for precision of RXA quantification were 7.0% and 8.8%, respectively. Mean RXA concentration was 114±43μg/L .RXA significantly altered prothrombin time, activated partial thromboplastin time, factor analysis for intrinsic and extrinsic factors. Determinations of thrombin time, fibrinogen, FXIII and D-Dimer levels were not affected., Conclusions: RXA plasma levels can be quantified accurately and precisely by a chromogenic anti-FXa assay on different coagulometers in different laboratories. Ingestion of 10mg RXA results in significant alterations of both PT- and aPTT-based coagulation assays., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: DMSO is routinely infused together with hematopoietic cells in patients undergoing myeloablative therapy and was recently found to inhibit smooth muscle cells proliferation and arterial thrombus formation in the mouse by preventing tissue factor (TF), a key activator of the coagulation cascade. This study was designed to investigate whether DMSO prevents platelet activation and thus, whether it may represent an interesting agent to be used on drug eluting stents., Methods and Results: Human venous blood from healthy volunteers was collected in citrated tubes and platelet activation was studied by cone and platelet analyzer (CPA) and rapid-platelet-function-assay (RPFA). CPA analysis showed that DMSO-treated platelets exhibit a lower adherence in response to shear stress (-15.54+/-0.9427%, n=5, P<0.0001 versus control). Additionally, aggregometry studies revealed that DMSO-treated, arachidonate-stimulated platelets had an increased lag phase (18.0%+/-4.031, n=9, P=0.0004 versus control) as well as a decreased maximal aggregation (-6.388+/-2.212%, n=6, P=0.0162 versus control). Inhibitory action of DMSO could be rescued by exogenous thromboxane A2 and was mediated, at least in part, by COX-1 inhibition., Conclusions: Clinically relevant concentrations of DMSO impair platelet activation by a thromboxane A2-dependent, COX-1-mediated effect. This finding may be crucial for the previously reported anti-thrombotic property displayed by DMSO. Our findings support a role for DMSO as a novel drug to prevent not only proliferation, but also thrombotic complications of drug eluting stents., (Copyright 2009 Elsevier Inc. All rights reserved.)