Comparative analysis of andexanet alfa and prothrombin complex concentrate in reversing anticoagulation by rivaroxaban ex vivo.

BACKGROUND: The comparative effectiveness of the specific antidote andexanet alfa vs the nonspecific therapy four-factor prothrombin complex concentrates (4F-PCCs) as reversal agents for direct factor Xa (FXa) inhibitors in severely bleeding patients is unclear. We hypothesised that specific reversal using andexanet alfa would be more effective than a high dose of PCC (50 IU kg-1) for reversing the FXa inhibitor rivaroxaban. METHODS: The reversal potential of andexanet alfa, various 4F-PCCs, and activated PCC was investigated ex vivo in human blood anticoagulated with rivaroxaban (37.5, 75, 150, and 300 ng ml-1) using a panel of coagulation parameters, including conventional coagulation assays, thrombin generation, and a newly developed viscoelastometric device. We simulated in vivo conditions of coagulation activation and fibrin formation using flow chamber experiments of thrombogenicity potential under arterial flow conditions. RESULTS: The 4F-PCCs normalised clotting profiles only at low rivaroxaban concentrations, whereas andexanet alfa and activated PCC significantly shortened clotting time at all rivaroxaban concentrations. Only andexanet alfa restored thrombin generation to baseline. Flow chamber results showed that various 4F-PCCs concentration-dependently restored clot formation. CONCLUSIONS: In contrast to thrombin generation measurements, haemostatic reversal of rivaroxaban using high-dose 4F-PCCs exhibited similar efficacy as andexanet alfa in flow chamber experiments. The haemostatic effects of 4F-PCCs and andexanet alfa in the context of bleeding patients taking FXa inhibitors requires further study.

Clinical guideline on reversal of direct oral anticoagulants in patients with life threatening bleeding.

BACKGROUND: Anticoagulation is essential for the treatment and prevention of thromboembolic events. Current guidelines recommend direct oral anticoagulants (DOACs) over vitamin K antagonists in DOAC-eligible patients. The major complication of anticoagulation is serious or life-threatening haemorrhage, which may necessitate prompt haemostatic intervention. Reversal of DOACs may also be required for patients in need of urgent invasive procedures. This guideline from the European Society of Anaesthesiology and Intensive Care (ESAIC) aims to provide evidence-based recommendations and suggestions on how to manage patients on DOACs undergoing urgent or emergency procedures including the treatment of DOAC-induced bleeding. DESIGN: A systematic literature search was performed, examining four drug comparators (dabigatran, rivaroxaban, apixaban, edoxaban) and clinical scenarios ranging from planned to emergency surgery with the outcomes of mortality, haematoma growth and thromboembolic complications. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to assess the methodological quality of the included studies. Consensus on the wording of the recommendations was achieved by a Delphi process. RESULTS: So far, no results from prospective randomised trials comparing two active comparators (e.g. a direct reversal agent and an unspecific haemostatic agent such as prothrombin complex concentrate: PCC) have been published yet and the majority of publications were uncontrolled and observational studies. Thus, the certainty of evidence was assessed to be either low or very low (GRADE C). Thirty-five recommendations and clinical practice statements were developed. During the Delphi process, strong consensus (>90% agreement) was achieved in 97.1% of recommendations and consensus (75 to 90% agreement) in 2.9%. DISCUSSION: DOAC-specific coagulation monitoring may help in patients at risk for elevated DOAC levels, whereas global coagulation tests are not recommended to exclude clinically relevant DOAC levels. In urgent clinical situations, haemostatic treatment using either the direct reversal or nonspecific haemostatic agents should be started without waiting for DOAC level monitoring. DOAC levels above 50 ng ml-1 may be considered clinically relevant necessitating haemostatic treatment before urgent or emergency procedures. Before cardiac surgery under activated factor Xa (FXa) inhibitors, the use of andexanet alfa is not recommended because of inhibition of unfractionated heparin, which is needed for extracorporeal circulation. In the situation of DOAC overdose without bleeding, no haemostatic intervention is suggested, instead measures to eliminate the DOACs should be taken. Due to the lack of published results from comparative prospective, randomised studies, the superiority of reversal treatment strategy vs. a nonspecific haemostatic treatment is unclear for most urgent and emergency procedures and bleeding. Due to the paucity of clinical data, no recommendations for the use of recombinant activated factor VII as a nonspecific haemostatic agent can be given. CONCLUSION: In the clinical scenarios of DOAC intake before urgent procedures and DOAC-induced bleeding, practitioners should evaluate the risk of bleeding of the procedure and the severity of the DOAC-induced bleeding before initiating treatment. Optimal reversal strategy remains to be determined in future trials for most clinical settings.

Antidote vs. unspecific hemostatic agents for the management of direct oral anticoagulant-related bleeding in trauma.

PURPOSE OF REVIEW: The advent of direct oral anticoagulants (DOACs) marks a significant milestone in anticoagulant treatment. However, DOACs can exacerbate bleeding, which is challenging for the treating clinician, especially when combined with traumatic injury. RECENT FINDINGS: In major bleeding associated with DOACs, rapid reversal of the anticoagulant effects is crucial. Recent observational and nonrandomized interventional trials have demonstrated the effectiveness of the specific antidotes andexanet alfa and idarucizumab as well as the unspecific prothrombin complex concentrates (PCCs) to counteract the anticoagulant effects of DOACs. The European Society of Anaesthesiology and Intensive Care guideline for severe perioperative bleeding and the European trauma guideline propose divergent recommendations for the use of andexanet alfa and PCC to obtain hemostasis in Factor Xa inhibitor-related bleeding. The conflicting recommendations are due to limited evidence from clinical studies and the potential increased risk of thromboembolic complications after the administration of andexanet. Regarding dabigatran-associated major bleeding, both guidelines recommend the specific reversal agent idarucizumab as first-line therapy. SUMMARY: Current guidelines recommend specific antidots and PCCs in DOAC-related major bleeding. Prospective randomized trials comparing specific vs. nonspecific hemostatic agents in the perioperative setting are needed to evaluate the effectiveness and safety of the hemostatic agents.

Direct oral anticoagulants in trauma patients.

PURPOSE OF REVIEW: Direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic events. Thus, trauma care providers are facing a steadily raising number of injured patients on DOACs. RECENT FINDINGS: Despite a predictable pharmacokinetic profile, the resulting plasma levels of trauma patients upon admission and bleeding risks remain uncertain. Therefore, recent guidelines recommend the measurement of DOAC plasma concentrations in injured patients. Alternatively, DOAC specific visco-elastic tests assays can be applied to identify DOAC patients at bleeding risk.Bleeding complications in trauma patients on DOACs are generally higher compared to nonanticoagulated subjects, but comparable to vitamin K antagonists (VKAs). In particular, a traumatic brain injury does not carry an increased risk of intracranial bleeding due to a DOAK intake compared to VKAs. Current studies demonstrated that up to 14% of patients with a hip fracture are on DOACs prior to surgery. However, the majority can be operated safely within a 24h time window without an increased bleeding rate.Specific antagonists facilitate rapid reversal of patients on DOACs. Idarucizumab for dabigatran, and andexanet alfa for apixaban and rivaroxaban have been approved for life threatening bleeding. Alternatively, prothrombin complex concentrate can be used. Dialysis is a potential treatment option for dabigatran and haemoabsorption with special filters can be applied in patients on FXa-inhibitors. SUMMARY: Current guidelines recommend the measurement of DOAC plasma levels in trauma patients. Compared to VKAs, DOACs do not carry a higher bleeding risk. DOAC specific antagonists facilitate the individual bleeding management.

Green Solvent-Based Antifouling Polymer Brushes Demonstrate Excellent Hemocompatibility.

Medical devices are crucial for patient care, yet even the best biomaterials lead to infections and unwanted activation of blood coagulation, potentially being life-threatening. While hydrophilic polymer brushes are the best coatings to mitigate these issues, their reliance on fossil raw materials underscores the urgency of bio-based alternatives. In this work, we introduce polymer brushes of a green solvent-based monomer, prohibiting protein adsorption, bacterial colonization, and blood clot formation at the same level as fossil-based polymer brushes. The polymer brushes are composed of N,N-dimethyl lactamide acrylate (DMLA), can be polymerized in a controlled manner, and show strong hydrophilicity as determined by thermodynamic analysis of the surface tension components. The contact of various challenging protein solutions results in repellency on the poly(DMLA) brushes. Furthermore, the poly(DMLA) brushes completely prevent the adhesion and colonization of Escherichia coli. Remarkably, upon blood contact, the poly(DMLA) brushes successfully prevent the formation of a fibrin network and leukocyte adhesion on the surface. While showcasing excellent antifouling properties similar to those of N-hydroxypropyl methacrylamide (HPMA) polymer brushes as one of the best antifouling coatings, the absence of hydroxyl groups prevents activation of the complement system in blood. We envision the polymer brushes to contribute to the future of hemocompatible coatings.

The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition.

BACKGROUND: Severe trauma represents a major global public health burden and the management of post-traumatic bleeding continues to challenge healthcare systems around the world. Post-traumatic bleeding and associated traumatic coagulopathy remain leading causes of potentially preventable multiorgan failure and death if not diagnosed and managed in an appropriate and timely manner. This sixth edition of the European guideline on the management of major bleeding and coagulopathy following traumatic injury aims to advise clinicians who care for the bleeding trauma patient during the initial diagnostic and therapeutic phases of patient management. METHODS: The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma included representatives from six European professional societies and convened to assess and update the previous version of this guideline using a structured, evidence-based consensus approach. Structured literature searches covered the period since the last edition of the guideline, but considered evidence cited previously. The format of this edition has been adjusted to reflect the trend towards concise guideline documents that cite only the highest-quality studies and most relevant literature rather than attempting to provide a comprehensive literature review to accompany each recommendation. RESULTS: This guideline comprises 39 clinical practice recommendations that follow an approximate temporal path for management of the bleeding trauma patient, with recommendations grouped behind key decision points. While approximately one-third of patients who have experienced severe trauma arrive in hospital in a coagulopathic state, a systematic diagnostic and therapeutic approach has been shown to reduce the number of preventable deaths attributable to traumatic injury. CONCLUSION: A multidisciplinary approach and adherence to evidence-based guidelines are pillars of best practice in the management of severely injured trauma patients. Further improvement in outcomes will be achieved by optimising and standardising trauma care in line with the available evidence across Europe and beyond.

What is known in pre-, peri-, and post-procedural anticoagulation in micro-axial flow pump protected percutaneous coronary intervention?

Interest in the use of percutaneous left ventricular assist devices (p-LVADs) for patients undergoing high-risk percutaneous coronary intervention (PCI) is growing rapidly. The Impella™ (Abiomed Inc.) is a catheter-based continuous micro-axial flow pump that preserves haemodynamic support during high-risk PCI. Anticoagulation is required to counteract the activation of the coagulation system by the patient's procoagulant state and the foreign-body surface of the pump. Excessive anticoagulation and the effect of dual antiplatelet therapy (DAPT) increase the risk of bleeding. Inadequate anticoagulation leads to thrombus formation and device dysfunction. The precarious balance between bleeding and thrombosis in patients with p-LVAD support is often the primary reason that patients' outcomes are jeopardized. In this chapter, we will discuss anticoagulation strategies and anticoagulant management in the setting of protected PCI. This includes anticoagulant therapy with unfractionated heparin, direct thrombin inhibitors, DAPT, purge blockage prevention by bicarbonate-based purge solution, and monitoring by activated clotting time, partial thromboplastin time, as well as anti-factor Xa levels. Here, we provide a standardized approach to the management of peri-interventional anticoagulation in patients undergoing protected PCI.

Extended Coagulation Profiling in Isolated Traumatic Brain Injury: A CENTER-TBI Analysis.

BACKGROUND: Trauma-induced coagulopathy in traumatic brain injury (TBI) remains associated with high rates of complications, unfavorable outcomes, and mortality. The underlying mechanisms are largely unknown. Embedded in the prospective multinational Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, coagulation profiles beyond standard conventional coagulation assays were assessed in patients with isolated TBI within the very early hours of injury. METHODS: Results from blood samples (citrate/EDTA) obtained on hospital admission were matched with clinical and routine laboratory data of patients with TBI captured in the CENTER-TBI central database. To minimize confounding factors, patients with strictly isolated TBI (iTBI) (n = 88) were selected and stratified for coagulopathy by routine international normalized ratio (INR): (1) INR < 1.2 and (2) INR ≥ 1.2. An INR > 1.2 has been well adopted over time as a threshold to define trauma-related coagulopathy in general trauma populations. The following parameters were evaluated: quick's value, activated partial thromboplastin time, fibrinogen, thrombin time, antithrombin, coagulation factor activity of factors V, VIII, IX, and XIII, protein C and S, plasminogen, D-dimer, fibrinolysis-regulating parameters (thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor 1, antiplasmin), thrombin generation, and fibrin monomers. RESULTS: Patients with iTBI with INR ≥ 1.2 (n = 16) had a high incidence of progressive intracranial hemorrhage associated with increased mortality and unfavorable outcome compared with patients with INR < 1.2 (n = 72). Activity of coagulation factors V, VIII, IX, and XIII dropped on average by 15-20% between the groups whereas protein C and S levels dropped by 20%. With an elevated INR, thrombin generation decreased, as reflected by lower peak height and endogenous thrombin potential (ETP), whereas the amount of fibrin monomers increased. Plasminogen activity significantly decreased from 89% in patients with INR < 1.2 to 76% in patients with INR ≥ 1.2. Moreover, D-dimer levels significantly increased from a mean of 943 mg/L in patients with INR < 1.2 to 1,301 mg/L in patients with INR ≥ 1.2. CONCLUSIONS: This more in-depth analysis beyond routine conventional coagulation assays suggests a counterbalanced regulation of coagulation and fibrinolysis in patients with iTBI with hemostatic abnormalities. We observed distinct patterns involving key pathways of the highly complex and dynamic coagulation system that offer windows of opportunity for further research. Whether the changes observed on factor levels may be relevant and explain the worse outcome or the more severe brain injuries by themselves remains speculative.

The thrombotic risk of spaceflight: has a serious problem been overlooked for more than half of a century?

The first ever venous thrombotic condition associated with spaceflight, an internal jugular vein thrombus requiring anticoagulation, has recently been reported. Systematic investigation of space travel-associated thrombotic risk has not been conducted. Cellular, animal, and human studies performed in ground-based models and in actual weightlessness revealed influences of weightlessness and gravity on the blood coagulation system. However, human study populations were small and limited to highly selected participants. Evidence in individuals with medical conditions and older persons is lacking. Evidence for thrombotic risk in spaceflight is unsatisfactory. This issue deserves further study in heterogeneous, high risk populations to find prevention strategies and to enable safe governmental and touristic human spaceflight.

Reversing Rivaroxaban Anticoagulation as Part of a Multimodal Hemostatic Intervention in a Polytrauma Animal Model.

BACKGROUND: Life-threatening bleeding requires prompt reversal of the anticoagulant effects of factor Xa inhibitors. This study investigated the effectiveness of four-factor prothrombin complex concentrate in treating trauma-related hemorrhage with rivaroxaban-anticoagulation in a pig polytrauma model. This study also tested the hypothesis that the combined use of a low dose of prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate could improve its subtherapeutic effects. METHODS: Trauma (blunt liver injury and bilateral femur fractures) was induced in 48 anesthetized male pigs after 30 min of rivaroxaban infusion (1 mg/kg). Animals in the first part of the study received prothrombin complex concentrate (12.5, 25, and 50 U/kg). In the second part, animals were treated with 12.5 U/kg prothrombin complex concentrate plus tranexamic acid or plus tranexamic acid and fibrinogen concentrate. The primary endpoint was total blood loss postinjury. The secondary endpoints (panel of coagulation parameters and thrombin generation) were monitored for 240 min posttrauma or until death. RESULTS: The first part of the study showed that blood loss was significantly lower in the 25 U/kg prothrombin complex concentrate (1,541 ± 269 ml) and 50 U/kg prothrombin complex concentrate (1,464 ± 108 ml) compared with control (3,313 ± 634 ml), and 12.5 U/kg prothrombin complex concentrate (2,671 ± 334 ml, all P < 0.0001). In the second part of the study, blood loss was significantly less in the 12.5 U/kg prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate (1,836 ± 556 ml, P < 0.001) compared with 12.5 U/kg prothrombin complex concentrate plus tranexamic acid (2,910 ± 856 ml), and there were no early deaths in the 25 U/kg prothrombin complex concentrate, 50 U/kg prothrombin complex concentrate, and 12.5 U/kg prothrombin complex concentrate plus tranexamic acid and fibrinogen concentrate groups. Histopathologic analyses postmortem showed no adverse events. CONCLUSIONS: Prothrombin complex concentrate effectively reduced blood loss, restored hemostasis, and balanced thrombin generation. A multimodal hemostatic approach using tranexamic acid plus fibrinogen concentrate enhanced the effect of low doses of prothrombin complex concentrate, potentially reducing the prothrombin complex concentrate doses required for effective bleeding control.

Role of extracorporeal membrane oxygenation in critically Ill COVID-19 patients and predictors of mortality.

The role of extracorporeal membrane oxygenation (ECMO) in the management of critically ill COVID-19 patients remains unclear. Our study aims to analyze the outcomes and risk factors from patients treated with ECMO. This retrospective, single-center study includes 17 COVID-19 patients treated with ECMO. Univariate and multivariate parametric survival regression identified predictors of survival. Nine patients (53%) were successfully weaned from ECMO and discharged. The incidence of in-hospital mortality was 47%. In a univariate analysis, only four out of 83 pre-ECMO variables were significantly different; IL-6, PCT, and NT-proBNP were significantly higher in non-survivors than in survivors. The Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score was significantly higher in survivors. After a multivariate parametric survival regression, IL-6, NT-proBNP and RESP scores remained significant independent predictors, with hazard ratios (HR) of 1.069 [95%-CI: 0.986-1.160], P = .016 1.001 [95%-CI: 1.000-1.001], P = .012; and .843 [95%-CI: 0.564-1.260], P = .040, respectively. A prediction model comprising IL-6, NT-proBNP, and RESP score showed an area under the curve (AUC) of 0.87, with a sensitivity of 87.5% and 77.8% specificity compared to an AUC of 0.79 for the RESP score alone. The present study suggests that ECMO is a potentially lifesaving treatment for selected critically ill COVID-19 patients. Considering IL-6 and NT-pro-BNP, in addition to the RESP score, may enhance outcome predictions.

Thromboembolic and Bleeding Events in COVID-19 Patients receiving Extracorporeal Membrane Oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a potential treatment option in critically ill COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) if mechanical ventilation (MV) is insufficient; however, thromboembolic and bleeding events (TEBE) during ECMO treatment still need to be investigated. METHODS: We conducted a retrospective, single-center study including COVID-19 patients treated with ECMO. Additionally, we performed a univariate analysis of 85 pre-ECMO variables to identify factors influencing incidences of thromboembolic events (TEE) and bleeding events (BE), respectively. RESULTS: Seventeen patients were included; the median age was 57 years (interquartile range [IQR]: 51.5-62), 11 patients were males (65%), median ECMO duration was 16 days (IQR: 10.5-22), and the overall survival was 53%. Twelve patients (71%) developed TEBE. We observed 7 patients (41%) who developed TEE and 10 patients (59%) with BE. Upper respiratory tract (URT) bleeding was the most frequent BE with eight cases (47%). Regarding TEE, pulmonary artery embolism (PAE) had the highest incidence with five cases (29%). The comparison of diverse pre-ECMO variables between patients with and without TEBE detected one statistically significant value. The platelet count was significantly lower in the BE group (n = 10) than in the non-BE group (n = 7) with 209 (IQR: 145-238) versus 452 G/L (IQR: 240-560), with p = 0.007. CONCLUSION: This study describes the incidences of TEE and BE in critically ill COVID-19 patients treated with ECMO. The most common adverse event during ECMO support was bleeding, which occurred at a comparable rate to non-COVID-19 patients treated with ECMO.

Global Characterisation of Coagulopathy in Isolated Traumatic Brain Injury (iTBI): A CENTER-TBI Analysis.

BACKGROUND: Trauma-induced coagulopathy in patients with traumatic brain injury (TBI) is associated with high rates of complications, unfavourable outcomes and mortality. The mechanism of the development of TBI-associated coagulopathy is poorly understood. METHODS: This analysis, embedded in the prospective, multi-centred, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, aimed to characterise the coagulopathy of TBI. Emphasis was placed on the acute phase following TBI, primary on subgroups of patients with abnormal coagulation profile within 4 h of admission, and the impact of pre-injury anticoagulant and/or antiplatelet therapy. In order to minimise confounding factors, patients with isolated TBI (iTBI) (n = 598) were selected for this analysis. RESULTS: Haemostatic disorders were observed in approximately 20% of iTBI patients. In a subgroup analysis, patients with pre-injury anticoagulant and/or antiplatelet therapy had a twice exacerbated coagulation profile as likely as those without premedication. This was in turn associated with increased rates of mortality and unfavourable outcome post-injury. A multivariate analysis of iTBI patients without pre-injury anticoagulant therapy identified several independent risk factors for coagulopathy which were present at hospital admission. Glasgow Coma Scale (GCS) less than or equal to 8, base excess (BE) less than or equal to - 6, hypothermia and hypotension increased risk significantly. CONCLUSION: Consideration of these factors enables early prediction and risk stratification of acute coagulopathy after TBI, thus guiding clinical management.

Prehospital administration of blood and plasma products.

PURPOSE OF REVIEW: Posttraumatic bleeding following major trauma is life threatening for the patient and remains a major global health issue. Bleeding after major trauma is worsened by trauma-induced coagulopathy (TIC). TIC consists of acute trauma coagulopathy and resuscitation coagulopathy. The early diagnosis and management of prehospital TIC management are challenging. RECENT FINDINGS: Concepts for early diagnosis and management of civilian prehospital TIC management are evolving. The feasibility of prehospital blood component as well as coagulation factor transfusion has been proven. SUMMARY: Due to different national guidelines and regulations of blood component therapies there is a wide heterogeneity in concepts of prehospital damage control resuscitation. Tranexamic acid administration is widely accepted, whereas the transfusion of whole blood, blood components, or coagulations factors needs further examination in the civilian setting.

Fibrinogen Supplementation and Its Indications.

Adequate plasma levels of fibrinogen are essential for clot formation, and in severe bleeding, fibrinogen reaches a critically low plasma concentration earlier than other coagulation factors. Although the critical minimum concentration of fibrinogen to maintain hemostasis is a matter of debate, many patients with coagulopathic bleeding require fibrinogen supplementation. Among the treatment options for fibrinogen supplementation, fibrinogen concentrate may be viewed by some as preferable to fresh frozen plasma or cryoprecipitate. The authors review major studies that have assessed fibrinogen treatment in trauma, cardiac surgery, end-stage liver disease, postpartum hemorrhage, and pediatric patients. Some but not all randomized controlled trials have shown that fibrinogen concentrate can be beneficial in these settings. The use of fibrinogen as part of coagulation factor concentrate based therapy guided by point-of-care viscoelastic coagulation monitoring (ROTEM [rotational thromboelastometry] or TEG [thromboelastography]) appears promising. In addition to reducing patients' exposure to allogeneic blood products, this strategy may reduce the risk of complications such as transfusion-associated circulatory overload, transfusion-related acute lung injury, and thromboembolic adverse events. Randomized controlled trials are challenging to perform in patients with critical bleeding, and more evidence is needed in this setting. However, current scientific rationale and clinical data support fibrinogen repletion in patients with ongoing bleeding and confirmed fibrinogen deficiency.

Comparison of fresh frozen plasma vs. coagulation factor concentrates for reconstitution of blood: An in vitro study.

BACKGROUND: Many trauma centres have adopted the administration of fixed ratios of packed red blood cells (PRBCs), platelet concentrates and fresh frozen plasma (FFP) for bleeding patients. However, the haemostatic efficacy of this concept is not well proven. OBJECTIVE: Our objective was to characterise the haemostatic profile of different ratios (2 : 1 : 1, 1 : 1 : 1 and 1 : 1 : 2) of PRBCs, platelet concentrates and FFP in comparison with coagulation factor concentrates (fibrinogen and/or prothrombin complex concentrate). DESIGN: An in vitro study. SETTING: Research laboratories of the department of transfusion medicine, Linz, Austria. MATERIALS: Whole blood donations from a total of 20 male volunteers. INTERVENTION: Reconstitution of blood at different ratios of PRBCs, platelet concentrates and FFP or coagulation factor concentrates. MAIN OUTCOME MEASURES: Cell count, conventional and thromboelastometric coagulation parameters, single coagulation factor activities as well as endogenous thrombin potential. RESULTS: Fibrinogen levels and haematocrit were lower in the FFP group at any ratio compared with the concentrate-based groups (P < 0.0001). Reconstitution of blood with FFP at different ratios resulted in haematocrit or fibrinogen levels that were borderline with regard to recommended substitution triggers (haematocrit 41 ±â€Š2% and fibrinogen 1.5 ±â€Š0.3 g l at the 2 : 1 : 1 ratio vs. 21 ±â€Š1% and 2.1 ±â€Š0.4 g l respectively at the 1 : 1 : 2 ratio). Compared with FFP at any ratio, maximum clot firmness showed higher values in the groups using fibrinogen concentrate (P < 0.0001), whereas endogenous thrombin potential revealed higher values in the groups using prothrombin complex concentrate (P < 0.0001). CONCLUSION: Use of coagulation factor concentrates for the reconstitution of blood allows for delivery of a higher haematocrit and a higher fibrinogen content compared with FFP. However, prothrombin complex concentrate might result in an unnecessary excess of thrombin generation. Clinical studies are warranted to further investigate these in vitro findings.

Evaluation of combined idarucizumab and prothrombin complex concentrate treatment for bleeding related to dabigatran in a lethal porcine model of double trauma.

BACKGROUND: Idarucizumab (IDA) is approved for emergency reversal of dabigatran; prothrombin complex concentrates (PCCs) are recommended in the absence of specific antidote. The combined effects of IDA and PCC in trauma-related bleeding are unknown. The efficacy and safety of combined IDA + PCC were assessed in a lethal porcine model of double trauma under dabigatran anticoagulation. STUDY DESIGN AND METHODS: Male pigs (n = 28) received oral dabigatran etexilate (30 mg/kg bid) for 3 days; a non-dabigatran control group (n = 7) received placebo. On Day 4, dabigatran-treated animals were randomized 1:1:1:1 to receive placebo + placebo (dabigatran-treated control), IDA + PCC (60 mg/kg + 50 IU/kg), PCC + IDA, or IDA + IDA. Trauma was induced at t = 0 (bilateral femur fractures and blunt liver injury) and t = 60 minutes (second blunt liver injury). Study treatment was administered 15 minutes after each trauma. Animals were monitored for 5 hours or until death. RESULTS: Total blood loss in IDA + PCC, PCC + IDA, and IDA + IDA was 1673 ± 370, 1981 ± 361, and 1417 ± 135 mL, respectively, with 100% survival at 5 hours. Blood loss in dabigatran-treated controls was 4427 ± 162 mL with 100% mortality. With IDA + IDA, plasma coagulation parameters and thrombin generation were similar to non-dabigatran control group levels after the second dose and remained stable over time. In the IDA + PCC and PCC + IDA groups, thrombin generation and d-dimer levels after the second dose were higher than with IDA + IDA. No thromboembolic complications were found. CONCLUSION: IDA and PCC are effective in treating trauma-related bleeding with dabigatran anticoagulation. IDA is preferable for emergency reversal of dabigatran, but PCC may be valuable when the anticoagulant is unknown.

Plasma-derived Factor X therapy for treatment of intracranial bleeding in a patient with Factor X deficiency: a case report.

BACKGROUND: Factor X (FX) deficiency (FXD) is an extremely rare autosomal recessive hereditary hematologic disorder, affecting approximately one in 1,000,000 of the general population. CASE REPORT: This case report describes an infant with hereditary severe FXD who presented with a spontaneous, life-threatening intracranial hemorrhage and was treated with the first licensed plasma-derived FX (pdFX) concentrate. On admission, laboratory assays showed severe coagulopathy of unknown cause; the patient was empirically treated using a multimodal hemostatic approach with prothrombin complex concentrate, fresh-frozen plasma, and tranexamic acid. Subsequent single-factor coagulation and genetic analyses confirmed the hereditary FXD diagnosis, and the therapeutic regimen was changed to a targeted regimen of 250 IU pdFX daily. Based on careful monitoring of the coagulation profile, pdFX administration frequency was increased to twice daily, followed by a reduction to once every 18 hours. The patient was discharged after 7 weeks of hospitalization in good clinical condition and now receives prophylactic pdFX three times weekly.

Prothrombin Complex Concentrate-induced Disseminated Intravascular Coagulation Can Be Prevented by Coadministering Antithrombin in a Porcine Trauma Model.

BACKGROUND: The risk of thromboembolic complications with prothrombin complex concentrates (PCCs) appears low when used for reversal of vitamin K antagonists but might be different in other indications (e.g., trauma). A difference in risk could arise from the plasma ratio of pro- versus anticoagulant proteins. This study used a porcine trauma model to investigate combined treatment with PCC and antithrombin. The hypothesis was that antithrombin can modulate prothrombotic effects and prevent adverse events of PCC. METHODS: Nine treatment groups (n = 7 per group) were included: control (placebo), PCC (50 IU/kg), PCC plus antithrombin (three groups, with antithrombin doses of 12.5, 25, or 50 IU/kg), fibrinogen concentrate (100 mg/kg) plus PCC, fibrinogen concentrate plus PCC plus antithrombin dose of 50 IU/kg, tranexamic acid (15 mg/kg) plus fibrinogen concentrate plus PCC, and tranexamic acid plus fibrinogen concentrate plus PCC plus antithrombin dose of 50 IU/kg. In each group, bilateral femur fractures and thorax contusion were followed 60 min later by blunt liver injury. Study treatment was then administered, and animals were subsequently observed for 210 min. RESULTS: Total blood loss (mean ± SD) was statistically significantly lower in all three PCC plus antithrombin groups (PCC plus antithrombin dose of 50 IU/kg, 672 ± 63 ml; PCC plus antithrombin dose of 25 IU/kg, 535 ± 72 ml; and PCC plus antithrombin dose of 12.5 IU/kg, 538 ± 50 ml) than in the PCC group (907 ± 132 ml), which in turn had statistically significantly reduced bleeding versus the control group (1,671 ± 409 ml). Signs of disseminated intravascular coagulation were apparent with PCC monotherapy, and early deaths occurred with fibrinogen concentrate plus PCC, attributable to pulmonary emboli. Antithrombin was protective against both of these effects: signs of disseminated intravascular coagulation were absent from the PCC plus antithrombin groups, and there were no early deaths in the group with fibrinogen concentrate plus PCC plus antithrombin dose of 50 IU/kg. CONCLUSIONS: According to this trauma model, 50 IU/kg PCC increases the risk of disseminated intravascular coagulation and other thromboembolic complications, most notably when coadministered with fibrinogen concentrate. The addition of antithrombin appears to reduce this risk.

Antifouling Microparticles To Scavenge Lipopolysaccharide from Human Blood Plasma.

Currently, one of the most promising treatments of lipopolysaccharides (LPS)-induced sepsis is based on hemofiltration. Nevertheless, proteins rapidly adsorbed on the artificial surface of membranes which leads to activation of coagulation impairing effective scavenging of the endotoxins. To overcome this challenge, we designed polymer-brush-coated microparticles displaying antifouling properties and functionalized them with polymyxin B (PMB) to specifically scavenge LPS the most common endotoxin. Poly[( N-(2-hydroxypropyl) methacrylamide)- co-(carboxybetaine methacrylamide)] brushes were grafted from poly(glycidyl methacrylate) microparticles using photoinduced single-electron transfer living radical polymerization (SET-LRP). Notably, only parts-per-million of copper catalyst were necessary to achieve brushes able to repel adsorption of proteins from blood plasma. The open porosity of the particles, accessible to polymerization, enabled us to immobilize sufficient PMB to selectively scavenge LPS from blood plasma.