Patient values and preferences regarding thromboprophylaxis treatment appear to be highly variable. Participant responses may depend on their prior experience with the treatments or health outcomes considered as well as on the methods used for preference elicitation. It should be standard for clinical practice guidelines to conduct systematic reviews of patient values and preferences in the specific content area.

We previously showed that ␤ 2 -glycoprotein I (␤ 2 GPI)-dependent lupus anticoagulants (LAs) form bivalent antigen-antibody complexes with high affinity for phospholipids; these complexes are responsible for their in vitro anticoagulant effect. We now studied the role of these bivalent complexes in arterial thrombosis in the hamster. Three monoclonal antibodies (mAbs) raised against human ␤ 2 GPI were selected on the basis of their crossreactivity with hamster ␤ 2 GPI. Two of these, one with LA activity, 5H2, and one with only anticardiolipin properties, 11E8, were infused at 0 to 10 mg/kg prior to photochemically induced vessel damage. 5H2 promoted thrombus formation dose dependently, raising the thrombus size from 6.0 arbitrary units (AU) in controls (n ‫؍‬ 9) to 65.0 AU in the high-dose group (10 mg/kg, n ‫؍‬ 6, P ‫؍‬ .007). The LA ؊ mAb 11E8 and mAb 27A8, reactive with human ␤ 2 GPI exclusively, did not significantly promote thrombus formation. In a second set of experiments, intact mAb 5H2 was compared to its fragments. Intact mAb 5H2 at 3.3 mg/kg and the equimolar dose of F(ab) 2 fragments (2.2 mg/kg) promoted thrombus formation equally well (55.8 AU, n ‫؍‬ 8 and 62.5 AU, n ‫؍‬ 7, respectively); mAb 5H2-derived Fab fragments were inactive. Immunohistochemical analysis showed platelet-rich thrombi, with 5H2 or its F(ab) 2 fragments mainly bound to individual platelets. Our results indicate that bivalent immune complex formation plays an important role in the genesis of arterial thrombosis by certain antiphospholipid antibodies. Cellular activation via the Fc portion of these immune complexes, however, is not essential, because F(ab) 2 fragments of 5H2 still promote thrombus formation. (Blood. 2003;

To cite this article: Ingerslev J, Jankowski MA, Weston SB, Charles LA, the ReFacto Field Study Participants. Collaborative field study on the utility of a BDD factor VIII concentrate standard in the estimation of BDDr Factor VIII:C activity in hemophilic plasma using one-stage clotting assays. J Thromb Haemost 2004; 2: 623-8.Summary. Advances in production technologies of factor (F)VIII concentrates during the last two decades has resulted in very pure and safe products. In assessment of recombinant FVIII:C, inconsistent assay values are found comparing onestage assays with two-stage (e.g. amidolytic) methods. Such discrepancies have been quite prominent in the case of a Bdomain deleted recombinant FVIII (BDDrFVIII, ReFacto Ò ). In order to alleviate this assay variance, a product-specific reference standard [the ReFacto Laboratory Standard TM (RLS)], was established for laboratory use with either one-stage clotting or chromogenic substrate assays for the measurement of FVIII:C in ReFacto-containing patient samples. The primary objective of the current study was to assess, under field laboratory conditions, the accuracy and precision of the onestage clotting assay for the determination of FVIII:C in ReFacto-containing samples employing the new concentrate standard. A secondary goal was to assess whether use of the RLS would minimize the discrepancy between one-stage clotting and chromogenic substrate assays. Thirty-one clinical laboratories worldwide participated in the study of severe-hemophilic plasma (SHP) samples that had been spiked with ReFacto to target levels of 0.9, 0.6 and 0.2 IU mL )1. FVIII:C levels were determined against both the RLS and the local in-house plasma standard (IHS). The results showed good agreement between laboratories in FVIII:C levels obtained by one-stage clotting assays utilizing the RLS, and a good degree of accuracy was found compared with the intended target values. Consistent with previously published data, a discrepancy of approximately 30% was observed between one-stage clotting and chromogenic potencies when the IHS was used as the calibrator. The discrepancy between one-stage and chromogenic assay methodologies was significantly reduced when the RLS was employed as calibrator in the one-stage assay. In conclusion, the study demonstrates that accurate and precise FVIII:C results can be obtained for ReFacto-containing SHP samples by clinical laboratories using a product-specific standard in onestage clotting assays. In addition, the product-specific reference standard significantly reduced the discrepancy between the onestage clotting and the chromogenic substrate assay for ReFacto.

In men with hypercholesterolemia, lowering serum cholesterol level by a three-month simvastatin treatment is accompanied by a marked reduction of thrombin generation both at basal conditions in venous blood and after activation of hemostasis by microvascular injury. Once blood cholesterol became reduced, adding aspirin to simvastatin did not enhance dampening of thrombin formation.

Objective-Homocysteine (Hcy) is a risk factor for thrombosis. We investigated a hypothesis that the clot permeability and its resistance to fibrinolysis is associated with plasma total Hcy (tHcy) in human subjects. Methods and Results-We studied healthy men not taking any medication (nϭ76), male patients with advanced coronary artery disease (CAD) taking low-dose aspirin (nϭ33), men with diabetes mellitus diagnosed recently (median hemoglobin A 1c 7.65%; nϭ16), and patients with isolated hypercholesterolemia (Ͼ7.0 mmol/L; nϭ15). We assessed clot permeability and turbidimetric lysis time as the determinants of fibrin clot structure. In a regression model, including age and fibrinogen, plasma tHcy was an independent predictor of clot permeation and fibrinolysis time in healthy subjects (R 2 ϭ0.88, PϽ0.0001 and R 2 ϭ0.54, PϽ0.0001, respectively). In CAD patients, tHcy and fibrinogen were stronger predictors of the permeation coefficient (R 2 ϭ0.84; PϽ0.0001) than was fibrinogen alone (R 2 ϭ0.66; PϽ0.0001), whereas tHcy was the only predictor of lysis time (R 2 ϭ0.69; PϽ0.0001). Elevated tHcy levels observed after methionine load were not associated with any of the fibrin clot properties. In patients with diabetes or hypercholesterolemia, the influence of Hcy on permeation and, to a lesser extent, on the lysis time was obscured by dominant effects of glucose and cholesterol. In 20 asymptomatic men with hyperhomocysteinemia treated with folic acid, reduction in tHcy levels resulted in increased clot permeability (Pϭ0.0002) and shorter lysis time (PϽ0.0001). Conclusions-Our results indicate that plasma tHcy predicts clot permeation and susceptibility to fibrinolysis in healthy men and CAD patients. Our data are consistent with a mechanism of thrombosis in hyperhomocysteinemia, which involves modification of fibrinogen by Hcy-thiolactone.

No abstract

Background— Optimal management of heart failure requires accurate assessment of prognosis. Many prognostic models are available. Our objective was to identify studies that evaluate the use of risk prediction models for mortality in ambulatory patients with heart failure and describe their performance and clinical applicability. Methods and Results— We searched for studies in Medline, Embase, and CINAHL in May 2012. Two reviewers selected citations including patients with heart failure and reporting on model performance in derivation or validation cohorts. We abstracted data related to population, outcomes, study quality, model discrimination, and calibration. Of the 9952 studies reviewed, we included 34 studies testing 20 models. Only 5 models were validated in independent cohorts: the Heart Failure Survival Score, the Seattle Heart Failure Model, the PACE (incorporating peripheral vascular disease, age, creatinine, and ejection fraction) risk score, a model by Frankenstein et al, and the SHOCKED predictors. The Heart Failure Survival Score was validated in 8 cohorts (2240 patients), showing poor-to-modest discrimination ( c -statistic, 0.56–0.79), being lower in more recent cohorts. The Seattle Heart Failure Model was validated in 14 cohorts (16 057 patients), describing poor-to-acceptable discrimination (0.63–0.81), remaining relatively stable over time. Both models reported adequate calibration, although overestimating survival in specific populations. The other 3 models were validated in a cohort each, reporting poor-to-modest discrimination (0.66–0.74). Among the remaining 15 models, 6 were validated by bootstrapping ( c -statistic, 0.74–0.85); the rest were not validated. Conclusions— Externally validated heart failure models showed inconsistent performance. The Heart Failure Survival Score and Seattle Heart Failure Model demonstrated modest discrimination and questionable calibration. A new model derived from contemporary patient cohorts may be required for improved prognostic performance.

Abstract:Extracorporeal membrane oxygenation (ECMO) is used as a salvage therapy in refractory acute respiratory distress syndrome (ARDS). Although technological progress in the ECMO systems improved the survival rate, prognosis is still significantly worsened by acute kidney injury (AKI), particularly if renal replacement therapy (RRT) is required. There are no exact guidelines recommending which techniques of ECMO and continuous RRT (CRRT) should be used for management of AKI coexisting with respiratory or circulatory failure, and how to combine them. The aim of this review is to describe methods of CRRT and ECMO simultaneous application, and to present advantages of various technical approaches versus possible complications.