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The glycocalyx is a carbohydrate-rich layer that lines the luminal side of the vascular endothelium. Its soluble components exist in a dynamic equilibrium with the bloodstream and play an important role in maintaining endothelial layer integrity. However, the glycocalyx can be easily damaged and is extremely vulnerable to insults from a variety of sources, including inflammation, trauma, haemorrhagic shock, hypovolemia and ischaemia-reperfusion. Damage to the glycocalyx commonly precedes further damage to the vascular endothelium. Preclinical research has identified a number of different factors capable of protecting or regenerating the glycocalyx. Initial investigations suggest that plasma may convey protective and regenerative effects. However, it remains unclear which exact components or properties of plasma are responsible for this protective effect. Studies have reported protective effects for several plasma proteins individually, including antithrombin, orosomucoid and albumin; the latter of which may be of particular interest, due to the high levels of albumin present in plasma. A further possibility is that plasma is simply a better intravascular volume expander than other resuscitation fluids. It has also been proposed that the protective effects are mediated indirectly via plasma resuscitation-induced changes in gene expression. Further work is needed to determine the importance of specific plasma proteins or other factors for glycocalyx protection, particularly in a clinical setting.

Severe trauma-related bleeding is associated with high mortality. Standard coagulation tests provide limited information on the underlying coagulation disorder. Whole-blood viscoelastic tests such as rotational thromboelastometry or thrombelastography offer a more comprehensive insight into the coagulation process in trauma. The results are available within minutes and they provide information about the initiation of coagulation, the speed of clot formation, and the quality and stability of the clot. Viscoelastic tests have the potential to guide coagulation therapy according to the actual needs of each patient, reducing the risks of over- or under-transfusion. The concept of early, individualized and goal-directed therapy is explored in this review and the AUVA Trauma Hospital algorithm for managing trauma-induced coagulopathy is presented.

Cardiac surgery involving cardiopulmonary bypass (CPB) is often associated with important blood loss, allogeneic blood product usage, morbidity, and mortality. Coagulopathy during CPB is complex, and the current lack of uniformity for triggers and hemostatic agents has led to a wide variability in bleeding treatment. The aim of this review is to provide a simplified picture of the data available on patients’ coagulation status at the end of CPB in order to provide relevant information for the development of tailored transfusion algorithms. A nonsystematic literature review was carried out to identify changes in coagulation parameters during CPB. Both prothrombin time and activated partial thromboplastin time increased during CPB, by a median of 33.3% and 17.9%, respectively. However, there was marked variability across the published studies, indicating these tests may be unreliable for guiding hemostatic therapy. Some thrombin generation (TG) parameters were affected, as indicated by a median increase in TG lag time of 55.0%, a decrease in TG peak of 17.5%, and only a slight decrease in endogenous thrombin potential of 7%. The most affected parameters were fibrinogen levels and platelet count/function. Both plasma fibrinogen concentration and FIBTEM maximum clot firmness decreased during CPB (median change of 36.4% and 33.3%, respectively) as did platelet count (44.5%) and platelet component (34.2%). This review provides initial information regarding changes in coagulation parameters during CPB but highlights the variability in the reported results. Further studies are warranted to guide physicians on the parameters most appropriate to guide hemostatic therapy.

Severe traumatic brain injury (sTBI) is often accompanied by coagulopathy and an increased risk of bleeding. To identify and successfully treat bleeding disorders associated with sTBI, rapid assessment of coagulation status is crucial. This retrospective study was designed to assess the potential role of whole-blood thromboelastometry (ROTEM®, Tem International, Munich, Germany) in patients with isolated sTBI (abbreviated injury scale [AIS]head ≥3 and AISextracranial <3). Blood samples were obtained immediately following admission to the emergency room of the Trauma Centre Salzburg in Austria. ROTEM analysis (EXTEM, INTEM, and FIBTEM tests) and standard laboratory coagulation tests (prothrombin time index [PTI, percentage of normal prothrombin time], activated partial thromboplastin time [aPTT], fibrinogen concentration, and platelet count) were compared between survivors and non-survivors. Out of 88 patients with sTBI enrolled in the study, 66 survived and 22 died. PTI, fibrinogen, and platelet count were significantly higher in survivors (p<0.005). Accordingly, aPTT was shorter in this group (p<0.0001). ROTEM analysis revealed shorter clotting times in extrinsically activated thromboelastometric test (EXTEM) and intrinsically activated thromboelastometric test (INTEM) (p<0.001), shorter clot formation times in EXTEM and INTEM (p<0.0001), and higher maximum clot firmness in EXTEM, INTEM, and FIBTEM (p<0.01) in survivors compared with non-survivors. Logistic regression analysis revealed extrinsically activated thromboelastometric test with cytochalasin D (FIBTEM) MCF and aPTT to have the best predictive value for mortality. According to the degree of coagulopathy, non-survivors received more RBC (p=0.016), fibrinogen concentrate (p=0.01), and prothrombin complex concentrate (p<0.001) within 24 h of arrival in the emergency room. ROTEM testing appeared to offer an early signal of severe life-threatening sTBI. Further studies are warranted to confirm these results and to investigate the role of ROTEM in guiding coagulation therapy.

Background/Objectives: Rivaroxaban, an oral anticoagulant, shows poor aqueous solubility, posing significant challenges to its bioavailability and therapeutic efficiency. The present study investigates the improvement of rivaroxaban’s solubility through the formation of different inclusion complexes with three cyclodextrin derivatives, such as β-cyclodextrin (β-CD), methyl-β-cyclodextrin (Me-β-CD), and hydroxypropyl-β-cyclodextrin (HP-β-CD) prepared by lyophilization in order to stabilize the complexes and improve dissolution characteristics of rivaroxaban. Methods: The physicochemical properties of the individual compounds and the three lyophilized complexes were analysed using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). Results: FTIR spectra confirmed the formation of non-covalent interactions between rivaroxaban and the cyclodextrins, suggesting successful encapsulation into cyclodextrin cavity. SEM images revealed a significant morphological transformation from the crystalline structure of pure rivaroxaban and cyclodextrins morphologies to a more porous and amorphous matrix in all lyophilized complexes. XRD patterns indicated a noticeable reduction in drug crystallinity, supporting enhanced potential of the drug solubility. TGA analysis demonstrated improved thermal stability in the inclusion complexes compared to the individual drug and cyclodextrins. Pharmacotechnical evaluation revealed that the obtained formulations (by comparison with physical mixtures formulations) possessed favorable bulk and tapped density values, suitable compressibility index, and good flow properties, making all suitable for direct compression into solid dosage forms. Conclusions: The improved cyclodextrins formulation characteristics, combined with enhanced dissolution profiles of rivaroxaban comparable to commercial Xarelto® 10 mg, highlight the potential of both cyclodextrin inclusion and lyophilization technique as synergistic strategies for enhancing the solubility and drug release of rivaroxaban.

Transfusion therapy is associated with increased morbidity, mortality and costs. Conventional coagulation tests (CCT) are weak bleeding predictors, poorly reflecting coagulation in vivo. Thromboelastometry (ROTEM) provides early identification of coagulation disorders and can guide transfusion therapy by goals, reducing blood components transfusion. The aim of this study is to describe coagulation profile of critically ill patients using ROTEM and evaluate the association between CCT and thromboelastometry. This is a retrospective, observational study conducted in medical-surgical intensive care unit (ICU). Adult patients (≥18 years) admitted to ICU between November 2012 and December 2014, in whom ROTEM analyses were performed for bleeding management were included in this study. The first ROTEM and CCT after ICU admission were recorded simultaneously. Additionally, we collected data on blood components transfusion and hemostatic agents immediately after laboratory tests results. The study included 531 patients. Most ROTEM tests showed normal coagulation profile [INTEM (54.8%), EXTEM (54.1%) and FIBTEM (53.3%)] with divergent results in relation to CCT: low platelet count (51.8% in INTEM and 55.9% in EXTEM); prolonged aPTT (69.9% in INTEM and 63.7% in EXTEM) and higher INR (23.8% in INTEM and 27.4% in EXTEM). However 16,7% of patients with normocoagulability in ROTEM received platelet concentrates and 10% fresh frozen plasma. The predominant ROTEM profile observed in this sample of critically ill patients was normal. In contrast, CCT suggested coagulopathy leading to a possibly unnecessary allogenic blood component transfusion. ROTEM test may avoid inappropriate allogeneic blood products transfusion in these patients.

What's known Purified human fibrinogen concentrate (HFC) has been used for fibrinogen replacement in acquired bleeding across a number of clinical settings including surgery, trauma and major obstetric hemorrhage. The randomized, controlled, FORMA‐05 study compared efficacy and safety of HFC and cryoprecipitate for hemostasis in surgical bleeding during major abdominal surgery. HFC maintained overall hemostatic efficacy with noninferiority to cryoprecipitate, with coagulation factor levels maintained throughout surgery. What's new This subanalysis of the FORMA‐05 study examined the changes in coagulation parameters during and after surgery in patients receiving HFC versus cryoprecipitate. Seven patients experienced thromboembolic events (TEEs), all of whom were on cryoprecipitate. Of these, two patients had deep vein thromboses (DVT), with higher fibrinogen, FIBTEM A20, and platelet levels, which persisted perioperatively. The five patients who developed pulmonary embolism (PE) had slightly higher preoperative von Willebrand factor (VWF) levels, which increased disproportionately following cryoprecipitate administration and postoperatively. Clinical implications Study results indicated a procoagulant status in patients experiencing DVT, and a disproportionate intra‐ and postoperative increase in VWF for patients experiencing PE. Larger studies in more diverse surgical settings should consider recording coagulation factor levels to gain a better understanding of how coagulation factor levels relate to TEEs.

The present study investigates the co-crystallization process of rivaroxaban (RIV), a poorly water-soluble potent oral anticoagulant, with niacinamide (NIA), a highly soluble and pharmaceutically acceptable co-crystal former, in two different molar ratios (1:1 and 1:2). The aim was to enhance the physicochemical and biopharmaceutical properties of rivaroxaban such as dissolution rate and aqueous solubility, by forming stable co-crystals through a solvent evaporation technique. The resulting co-crystals (RIV-NIA, 1:1 co-crystallization compound, F1 and RIV-NIA, 1:2 co-crystallization compound, F3) were characterized using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), powder X-ray diffraction (XRD) and thermal analysis, which confirmed the formation of a new rivaroxaban–niacinamide co-crystalline phase. In vitro dissolution studies confirmed a significant enhancement in the dissolution rate of the two obtained co-crystals. These findings suggest that stoichiometric variation plays an important role in co-crystal performance and in improving solubility compared with the pure drug. Also, the obtained results suggest that niacinamide is an effective coformer for improving the dissolution and physicochemical properties of rivaroxaban.

Thrombelastography (TEG)/thromboelastometry (ROTEM) devices measure viscoelastic clot strength as clot amplitude (A). Transformation of clot amplitude into clot elasticity (E with TEG; CE with ROTEM) is sometimes necessary (eg, when calculating platelet component of the clot). With TEG, clot amplitude is commonly transformed into shear modulus (G; expressed in Pa or dyn/cm2) as follows: G = (5000 × A)/(100 – A). Use of the constant “5000” stems from Hartert's 50-year-old calculation of G for a normal blood clot. We question the value of calculating G as follows: (1) It may be questioned whether TEG/ROTEM analysis enable measurement of elasticity because viscosity may also contribute to clot amplitude. (2) It has been suggested that absolute properties of a blood clot cannot be measured with TEG/ROTEM analysis because the strain amplitude applied by the device is uncontrolled and changes during the course of coagulation. (3) A review of the calculation of G using Hartert's methods and some updated assumptions suggests that the value of 5000 is unreliable. (4) Recalculation of G for the ROTEM device yields a different value from that with Hartert TEG, indicating a degree of inaccuracy with the calculations. (5) Shear modulus is simply a multiple of E/CE and, because of the unreliability of G in absolute terms, it provides no additional value versus E/CE. The TEG and ROTEM are valuable coagulation assessment tools that provide an evaluation of the viscoelastic properties of a clot, not through measuring absolute viscoelastic forces but through continuous reading of the clot amplitude relative to an arbitrary, preset scale.

The standard method of assessment of platelet function is represented by light transmission aggregometry (LTA), performed in citrated platelet-rich plasma (PRP). With LTA, decrease and subsequent post-cardiopulmonary bypass (CPB) recovery of platelet function have been reported during cardiac surgery. Multiple electrode aggregometry (MEA) may be used as point-of-care method to monitor perioperative changes in platelet function. Since MEA assesses macroaggregation which is influenced by the plasmatic levels of unbound calcium, citrate may be inadequate as anticoagulant for MEA. We used citrate and heparin for MEA samples, to see with which anticoagulant the intraoperative decrease and postoperative recovery in platelet function previously described with other aggregometric methods in cardiac surgery may be observed with MEA. Blood was obtained from 60 patients undergoing routine cardiac surgery and the samples were collected in standard tubes containing unfractionated heparin (50 U/mL) or trisodium citrate (3.2%). The samples were obtained before CPB, at 30 minutes on CPB, end of CPB and on the first postoperative day. MEA was performed using the Multiplate® analyzer. Collagen (COLtest, 100 μg/mL) and TRAP-6 (thrombin receptor activating peptide, TRAPtest, 1mM/mL) were used as aggregation agonists. Platelet aggregometric response decreased significantly during CPB. Platelet aggregation assessed using TRAP-6 as agonist on heparinized blood significantly correlated with the duration of CPB (r = -0.41, p = 0.001, 2-tailed Pearson test). The aggregometric analysis performed on the first postoperative day showed a significant recovery in platelet activity in the samples containing heparin (increase from 30 ± 22 U to 46 ± 27 U for the COLtest and from 70 ± 34 U to 95 ± 32 U for the TRAPtest, p < 0.001, Student's t-test), while no significant recovery of platelet function could be established in the MEA measurements performed with citrated blood. The choice of blood sample anticoagulant used for impedance aggregometry influenced the platelet aggregation response. Postoperative platelet function recovery was only detected in the heparinized samples. Heparin seems to be better suited than citrate for the analysis of impedance aggregometry in heart surgery.