Variations and obstacles in the use of coagulation factor concentrates for major trauma bleeding across Europe: outcomes from a European expert meeting.

PURPOSE: Trauma is a leading cause of mortality, with major bleeding and trauma-induced coagulopathy (TIC) contributing to negative patient outcomes. Treatments for TIC include tranexamic acid (TXA), fresh frozen plasma (FFP), and coagulation factor concentrates (CFCs, e.g. prothrombin complex concentrates [PCCs] and fibrinogen concentrate [FCH]). Guidelines for TIC management vary across Europe and a clear definition of TIC is still lacking. METHODS: An advisory board involving European trauma experts was held on 02 February 2019, to discuss clinical experience in the management of trauma-related bleeding and recommendations from European guidelines, focusing on CFC use (mainly FCH). This review summarises the discussions, including TIC definitions, gaps in the guidelines that affect their implementation, and barriers to use of CFCs, with suggested solutions. RESULTS: A definition of TIC, which incorporates clinical (e.g. severe bleeding) and laboratory parameters (e.g. low fibrinogen) is suggested. TIC should be treated immediately with TXA and FCH/red blood cells; subsequently, if fibrinogen ≤ 1.5 g/L (or equivalent by viscoelastic testing), treatment with FCH, then PCC (if bleeding continues) is suggested. Fibrinogen concentrate, and not FFP, should be administered as first-line therapy for TIC. Several initiatives may improve TIC management, with improved medical education of major importance; generation of new and stronger data, simplified clinical practice guidance, and improved access to viscoelastic testing are also critical factors. CONCLUSIONS: Management of TIC is challenging. A standard definition of TIC, together with initiatives to facilitate effective CFC administration, may contribute to improved patient care and outcomes.

Institutionally Adopted Perioperative Blood Management Program Significantly Decreased the Transfusion Rate of Patients Having Primary Total Hip Replacement Surgery.

Perioperative transfusion in patients undergoing orthopedic surgery increases the number of postoperative complications. Thus, we have introduced an institution-tailored perioperative blood management program (PBM) to decrease the amount of blood transfused in patients going through primary total hip replacement (THR) surgery. We have conducted a before-after observational cohort study in two predetermined observational periods. Demographic and clinical data, ASA scores, laboratory parameters, features of surgical procedure, and anesthesia were registered. Parameters of perioperative fluid administration, transfusion rate, and postoperative complications were also assessed. One hundred patients in the first and 108 patients in the second observational period were enrolled. Eventhough the ratio of posttraumatic THR procedures increased (9% vs. 17%), the PBM protocol has been utilized effectively and a significant decrease in perioperative blood transfusion rate has been observed (61% vs. 21%). The abolishment of routine preoperative LMWH prophylaxis (90% vs. 16%), intraoperative use of tranexamic acid (10% vs. 84%), and the encouraged exploitation of our postoperative observational facility (5% vs. 39%) were abided by our colleagues. Patients still requiring transfusion had lower preoperative hemoglobin levels (129 vs. 147 g/l), scored higher in ASA (ASA III: 46% vs. 19%), and more often presented postoperative hypotension (40% vs. 7%), oliguria (23% vs. 5%), and infections (9% vs. 2%). We conclude that the individualized perioperative blood management protocol was successfully implemented and yielded a lower transfusion rate and better outcomes. Our study suggests that a partial, institution-tailored PBM program may be suitable and beneficial in countries where the modalities of perioperative blood management are limited.

FAD oxidizes the ERO1-PDI electron transfer chain: the role of membrane integrity.

The molecular steps of the electron transfer in the endoplasmic reticulum from the secreted proteins during their oxidation are relatively unknown. We present here that flavine adenine dinucleotide (FAD) is a powerful oxidizer of the oxidoreductase system, Ero1 and PDI, besides the proteins of rat liver microsomes and HepG2 hepatoma cells. Inhibition of FAD transport hindered the action of FAD. Microsomal membrane integrity was mandatory for all FAD-related oxidation steps downstream of Ero1. The PDI inhibitor bacitracin could inhibit FAD-mediated oxidation of microsomal proteins and PDI, but did not hinder the FAD-driven oxidation of Ero1. Our data demonstrated that Ero1 can utilize FAD as an electron acceptor and that FAD-driven protein oxidation goes through the Ero1-PDI pathway and requires the integrity of the endoplasmic reticulum membrane. Our findings prompt further studies to elucidate the membrane-dependent steps of PDI oxidation and the role of FAD in redox folding.

DUK114, the Drosophila orthologue of bovine brain calpain activator protein, is a molecular chaperone.

UK114, the goat liver tumour antigen, is a member of a widely distributed family of conserved low-molecular-mass proteins (YER057c/YjgF/UK114), the function of which is ill understood. To the various orthologues diverse functions have been ascribed, such as translation inhibition, regulation of purine repressor or calpain activation. Owing to a limited sequence similarity to Hsp90 (heat-shock protein 90), they have also been proposed to be molecular chaperones; however, this has never been tested. In the present paper, we report the cloning and characterization of the Drosophila orthologue, DUK114. In brief, DUK114 had no effect that would have qualified it as a calpain activator. In contrast, it proved to be a very potent molecular chaperone in in vitro assays. In a heat-aggregation test, it significantly decelerated the formation of citrate synthase aggregates. In a reverse assay, the recovery of the enzyme from urea- and heat-induced denatured states was accelerated almost 3-fold. On a molar basis, the chaperone activity of the 15-kDa DUK114 is comparable with that of Hsp90, the almost 6-times-larger archetypal molecular chaperone. In similar assays, DUK114 was ineffective with Drosophila calpain A or calpain B. To test for its chaperone activity in vivo, DUK114 was transfected into Schneider (S2) cells; after heat shock, the number of viable non-transfected cells started to increase after a lag time; in the presence of DUK114, cell proliferation started at once. Our work is the first experimental evidence that DUK114, and possibly other members of this family, are molecular chaperones.

Enhancement of complement-induced cell lysis: a novel mechanism for the anticancer effects of Hsp90 inhibitors.

Molecular chaperones (heat shock proteins, Hsp-s) play a pleiotropic role in immunological functions. Hsp-s participate in the presentation of peptide antigens, folding of several immunologically important proteins, such as the MHC, and in the maintenance of the activation-competent conformation of key signaling molecules (mostly serine/threonine and tyrosine kinases) of B and T cells activation. The most abundant cytoplasmic chaperone, Hsp90, is in the center of these processes. In recent years Hsp90 inhibitors emerged as very promising anticancer agents. Not surprisingly, Hsp90 inhibitors behave as immunosuppressants, and also cause an induction of superoxide production. Here we extend our previous data by showing the enhancement of complement-induced lysis of several types of tumor cells after Hsp90 inhibition. This novel mechanism may significantly contribute to the anticancer effects of Hsp90 inhibitors in vivo.

[Stress proteins in medicine]. / Stresszfehérjék az orvostudományban.

Stress proteins or in other words heat shock proteins form an ancient defense system of our cells. They are necessary to prevent the aggregation of damaged proteins and to help their refolding after stress. Stress protein-assisted remodeling of protein structure is an important step of many cellular processes, such as protein transport, signaling and protein degradation. Stress proteins have a key role in many diseases. Thus they 1. protect our cells against the deteriorating effects of ischemia/reperfusion in myocardiac infarcts or in stroke; 2. protect transplanted tissues and organs; 3. act against the multiple damage of chronic diseases such as diabetes, or neurodegenerative diseases (Alzheimer's and Parkinson's disease); 4. participate in the etiology of several autoimmune diseases; 5. their activation, and role in antigen presentation can be used as an anticancer-therapy; 6. stress proteins increase longevity, and lastly 7. stress proteins act as a buffer of phenotypically silent mutations and may contribute to the onset of "civilizational diseases" (cancer, atherosclerosis, diabetes, etc.). In this review the authors also summarize the existing stress protein-related pharmacological approaches to cure a large variety of diseases.