Alternative blood products in trauma.

PURPOSE OF REVIEW: Hemorrhage and trauma-induced coagulopathy cause significant morbidity and mortality in trauma patients. Although blood products are the cornerstone of resuscitation, these resources are scarce, necessitating alternatives. This review examines the use of alternative blood products in trauma as well as the literature supporting their use. RECENT FINDINGS: There is no single true blood product alternative. In recent years, there has been great progress in understanding trauma-induced pathophysiology and blood component alternatives. Products such as tranexamic acid and prothrombin complex concentrate have become well established and are frequently utilized in trauma centers, and many more alternatives are still undergoing further research and development. SUMMARY: Stabilization of hemorrhage and resuscitation is priority in trauma-induced coagulopathy treatment. Alternative products such as tranexamic acid, recombinant factors, prothrombic complex concentrate, fibrinogen concentrates, and desmopressin may also be considered based on the clinical context. Viscoelastic hemostatic assays such as rotational thromboelastometry and thromboelastography can help guide these efforts. Following initial stabilization, additional interventions such as iron supplementation, erythropoietin stimulating agents, and vitamin D may help with chronic sequela.

A low-dose therapy of fibrinogen supplement during perioperative period of total knee arthroplasty in an asymptomatic man with congenital dysfibrinogenemia: A case report.

RATIONALE: Congenital dysfibrinogenemia (CD) is a rare coagulation system disease that is often treated without unified management. Individualized treatment thereof presents clinicians with great challenges. PATIENT CONCERNS: A patient who was about to undergo total knee arthroplasty was found to have CD. DIAGNOSES: Coagulation screening revealed low fibrinogen, prolonged thrombin time, minor prolonged prothrombin time, and normal activated partial thromboplastin time were detected during admission, but no abnormal personal and family history findings were observed. Therefore, CD and hypofibrinogenemia were suspected. The gene sequencing confirmed the diagnosis of CD. INTERVENTIONS: The patient received plenty and low level of fibrinogen concentrate during 2 perioperative periods, respectively. OUTCOMES: Successful clinical outcomes were obtained using different treatment strategies. LESSONS: In contrast to prior case reports, this case illustrates the feasibility of low dosing of fibrinogen supplements within an asymptomatic patient in a selective operation. Changes in the level of fibrinogen and fibrin degradation product are of great importance for individualized treatment after supplementation.

Evaluation of Thromboelastography 6s prognostication of fibrinogen supplementation in pediatric cardiac surgery.

BACKGROUND: Implementation of point-of-care tests is recommended to provide tailored substitution during cardiac surgery. The measurement and substitution of fibrinogen have gained particular interest since it is the first coagulation factor to become depleted during cardiac surgery. However, the prognostic ability of thromboelastography (TEG) 6s has not been evaluated in pediatric patients. The aim of the present study was to describe patient characteristics of infants receiving fibrinogen substitution during cardiac surgery and evaluate the prognostic ability of TEG6s after weaning off cardiopulmonary bypass (CPB). METHODS: Infants undergoing congenital cardiac surgery with CPB were retrospectively included (n = 279) between January 2017 to July 2019. Patient and perioperative data were collected on the day of surgery until 6:00 AM the next morning. Hemostatic capacity was assessed with TEG6s. The efficacy of TEG-functional fibrinogen-maximal amplitude (TEG-FF-MA) measurements for the prediction of intraoperative bleeding, and thereby cryoprecipitate need, was evaluated by a sensitivity and specificity analysis. RESULTS: Among 174 children with TEG-FF-MA data, 147 (84%) received cryoprecipitate intraoperatively. Cryoprecipitate administration was associated with younger age 66 (10-132) versus 98 (45-204) days (p = .044), higher RACHS-1 classification, and intraoperative bleeding 21 (11-47) versus 5 (3-13) ml/kg (p < .001, mean difference 29 ml/kg [CI: 8-50]). Median TEG-FF-MA values were lower in transfused children 7.6 (5.3-11.0) versus 10.5 (7.3-13.4) mm (p = .004, mean difference - 2.4 mm [CI: -4.1 to - 0.73]). The volume of cryoprecipitate was associated with bypass time, TEG-FF-MA values, and in particular intraoperative bleeding volumes. A TEG-FF-MA threshold of 10.0 mm, resulted in sensitivity: 74%, specificity: 56%, positive predictive value: 80%, and a negative predictive value of 47% for the prediction of intraoperative bleeding (>10 ml/kg) and consequently a need of cryoprecipitate transfusion. CONCLUSION: Fibrinogen substitution in infants was associated with younger age and higher RACHS-1 category. The prognostic value of TEG6s was evaluated, and cryoprecipitate transfusion was related to TEG-FF-MA values, but also CPB-time, surgical complexity, and in particular excessive intraoperative bleeding. A clear-cut threshold for TEG-FF-MA is difficult to establish in infants undertaken congenital heart surgery.

Fibrinogen supplementation for the trauma patient: Should you choose fibrinogen concentrate over cryoprecipitate?

BACKGROUND: Trauma-induced coagulopathy is frequently associated with hypofibrinogenemia. Cryoprecipitate (Cryo), and fibrinogen concentrate (FC) are both potential means of fibrinogen supplementation. The aim of this study was to compare the outcomes of traumatic hemorrhagic patients who received fibrinogen supplementation using FC versus Cryo. METHODS: We performed a 2-year (2016-2017) retrospective cohort analysis of the American College of Surgeons Trauma Quality Improvement Program database. All adult trauma patients (≥18 years) who received FC or Cryo as an adjunct to resuscitation were included. Patients with bleeding disorders, chronic liver disease, and those on preinjury anticoagulants were excluded. Patients were stratified into those who received FC, and those who received Cryo. Propensity score matching (1:2) was performed. Outcome measures were transfusion requirements, major complications, hospital, and intensive care unit lengths of stay, and mortality. RESULTS: A matched cohort of 255 patients who received fibrinogen supplementation (85 in FC, 170 in Cryo) was analyzed. Overall, the mean age was 41 ± 19 years, 74% were male, 74% were white and median Injury Severity Score was 26 (22-30). Compared with the Cryo group, the FC group required less units of packed red blood cells, fresh frozen plasma, and platelets, and had shorter in-hospital and intensive care unit length of stay. There were no significant differences between the two groups in terms of major in-hospital complications and mortality. CONCLUSION: Fibrinogen supplementation in the form of FC for the traumatic hemorrhagic patient is associated with improved outcomes and reduced transfusion requirements as compared with Cryo. Further studies are required to evaluate the optimal method of fibrinogen supplementation in the resuscitation of trauma patients. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.

Hypofibrinogenaemia and hypocalcaemia in adult trauma patients receiving pre-hospital packed red blood cell transfusions: Potential for supplementary pre-hospital therapeutic interventions.

OBJECTIVE: To report the arrival ionised calcium (iCa) and fibrinogen concentrations in trauma patients treated with packed red blood cells by the road-based high-acuity response units of a metropolitan ambulance service. METHODS: A retrospective review of trauma patients treated with packed red blood cells by high-acuity response units between January 2012 and December 2016. Patients were identified from databases at southeast Queensland adult trauma centres, Pathology Queensland Central Transfusion Laboratory, Gold Coast University Hospital blood bank and the Queensland Ambulance Service. Patient characteristics, results of laboratory tests within 30 min of ED arrival were analysed. RESULTS: A total of 164 cases were analysed. The median injury severity score was 33.5 (interquartile range 22-41), with blunt trauma the commonest mechanism of injury (n = 128, 78.0%). Fifty-eight of the 117 patients (24.4%) with fibrinogen measured had a fibrinogen concentration ≤1.5 g/L; 79 of the 123 patients (64.2%) with an international normalised ratio (INR) measurement had an INR >1.2; 97 of 148 patients (63.8%) with an iCa measured, had an iCa below the Pathology Queensland reference range of 1.15-1.32 mmol/L. Arrival fibrinogen concentration ≤1.5 g/L and arrival iCa ≤1.00 were associated with in-hospital mortality with odds ratio 11.90 (95% confidence interval 4.50-31.65) and odds ratio 4.97 (95% confidence interval 1.42-17.47), respectively. CONCLUSIONS: Hypocalcaemia and hypofibrinogenaemia on ED arrival were common in this cohort. Future work should evaluate whether outcomes improve by correction of these deficits during the pre-hospital phase of trauma care.

Evaluation de Fibryga MC (concentré de fibrinogène humain): Déficit acquis en fibrinogène / Evaluation of fibrygatm (human fibrinogen concentrate): acquired fibrinogen deficiency

MANDAT: À la demande du fabricant Octapharma Canada Inc., l'Institut national d'excellence en santé et en services sociaux (INESSS) a procédé à l'évaluation du produit FibrygaMC, un concentré de fibrinogène humain. Ce produit est indiqué « pour le traitement d'épisodes de saignement aigus et la prophylaxie périopératoire chez les adultes et les enfants atteints d'afibrinogénémie ou d'hypofibrinogénémie congénitale ¼ ainsi que « comme traitement complémentaire durant la prise en charge de saignements sévères non contrôlés survenant au cours d'interventions chirurgicales chez les patients atteints d'un déficit acquis en fibrinogène ¼. La présente évaluation porte sur l'indication ciblant le déficit acquis en fibrinogène. DÉMARCHE D'ÉVALUATION: Une revue des données issues de la littérature et de celles fournies par le fabricant a été réalisée afin d'évaluer l'efficacité, l'innocuité et l'efficience du concentré de fibrinogène humain FibrygaMC. Des données contextuelles et expérientielles issues de la consultation d'experts sont également présentées. DIMENSIONS SOCIOCULTURELLE ET POPULATIONNELLE: Le déficit acquis en fibrinogène, aussi appelé hypofibrinogénémie acquise, est généralement causé par l'utilisation de facteurs de coagulation à la suite de saignements importants. L'hypofibrinogénémie acquise peut survenir de façon imprévisible chez les adultes et les enfants au cours d'interventions chirurgicales, de traumatismes importants, durant la période post-partum ou dans le cas de certaines maladies. Les cryoprécipités sont présentement utilisés pour compenser le déficit en fibrinogène. Ceux-ci sont produits par Héma-Québec en congelant et en décongelant du plasma et contiennent principalement du fibrinogène ainsi que d'autres facteurs de coagulation. Les besoins à combler pour le traitement de l'hypofibrinogénémie acquise en contexte chirurgical sont limités. Des options thérapeutiques permettant une administration plus rapide et sans aucun risque de transmission d'agents infectieux pourraient toutefois représenter un certain avantage par rapport à la situation actuelle. DÉLIBÉRATION SUR LA VALEUR THÉRAPEUTIQUE: Les membres du Comité scientifique de l'évaluation des médicaments aux fins d'inscription (CSEMI) sont unanimement d'avis que la valeur thérapeutique du concentré de fibrinogène FibrygaMC est reconnue comme traitement complémentaire durant la prise en charge de saignements sévères non contrôlés survenant au cours d'interventions chirurgicales chez les patients atteints d'un déficit acquis en fibrinogène. Motifs de la position unanime: Les membres sont d'avis que les résultats de l'étude canadienne FIBRES sont suffisants pour reconnaitre la non-infériorité du concentré de fibrinogène comparativement aux cryoprécipités dans la prise en charge des saignements liés à l'hypofibrinogénémie acquise en contexte de chirurgie cardiaque avec circulation extracorporelle. Les résultats de l'étude FORMA-05 appuient l'utilisation du concentré de fibrinogène dans des contextes chirurgicaux autres que la chirurgie cardiaque avec circulation extracorporelle. Les membres reconnaissent que le concentré de fibrinogène et les cryoprécipités partagent un profil d'effets indésirables similaire. Ils estiment par ailleurs que les risques de réactions transfusionnelles et de transmission d'agents infectieux inconnus associés aux cryoprécipités sont très faibles. Le concentré de fibrinogène représente une option thérapeutique de remplacement par rapport aux cryoprécipités, qui comblerait en partie le besoin de santé jugé faible pour le contexte de prise en charge de l'hypofibrinogénémie acquise en contexte chirurgical. Selon les membres du comité, les conclusions sur la valeur thérapeutique du concentré de fibrinogène s'appliquent aux conditions médicales où l'hypofibrinogénémie acquise est clairement démontrée. Délibération sur l'ensemble des critères: Les membres du Comité scientifique de l'évaluation des médicaments aux fins d'inscription (CSEMI) sont unanimement d'avis d'ajouter le concentré de fibrinogène FibrygaMC à la Liste des produits du système du sang du Québec comme traitement complémentaire durant la prise en charge de saignements sévères non contrôlés survenant au cours d'interventions chirurgicales chez les patients atteints d'un déficit acquis en fibrinogène. Motifs de la position unanime: Les membres reconnaissent une valeur thérapeutique non inférieure au concentré de fibrinogène par rapport aux cryoprécipités pour la prise en charge des saignements périopératoires chez les patients atteints d'hypofibrinogénémie acquise. Au prix soumis par le fabricant, le traitement par FibrygaMC est une option thérapeutique plus efficiente que les cryoprécipités actuellement distribués au Québec. Les membres soulignent que l'utilisation des cryoprécipités est associée à des pertes. Ils rappellent que le sang est une ressource précieuse et limitée dont l'utilisation doit être faite judicieusement par le système de soins. Toute réduction des pertes de produits sanguins devrait donc être valorisée. La distribution de FibrygaMC pour la prise en charge de l'hypofibrinogénémie acquise engendrerait une réduction des coûts estimée à 7,4 M$ sur le budget des établissements de santé au cours des trois prochaines années. Les membres sont d'avis que le concentré de fibrinogène a le potentiel de réduire les délais d'administration en contexte chirurgical si sa préparation est faite au bloc opératoire plutôt qu'à la banque de sang. Ils ajoutent toutefois que les conséquences d'une administration plus rapide du concentré de fibrinogène n'ont pas été investiguées. Recommandation de l'INESSS sur FibrygaMC: À la lumière des informations disponibles, l'INESSS recommande d'ajouter le concentré de fibrinogène FibrygaMC à la Liste des produits du système du sang du Québec comme traitement complémentaire durant la prise en charge de saignements sévères non contrôlés survenant au cours d'interventions chirurgicales chez les patients atteints d'un déficit acquis en fibrinogène.

MANDATE: At the request of the manufacturer, Octapharma Canada Inc., the Institut national d'excellence en santé et en services sociaux (INESSS) evaluated Fibryga™, a human fibrinogen concentrate. This product is indicated "for the treatment of acute bleeding episodes and perioperative prophylaxis in adult and pediatric patients with congenital afibrinogenemia and hypofibrinogenemia" and "as a complementary therapy during the management of uncontrolled severe bleeding in patients with acquired fibrinogen deficiency in the course of surgical interventions". The present evaluation concerns the indication involving acquired fibrinogen deficiency. EVALUATION PROCESS: Data from the scientific literature and those provided by the manufacturer were reviewed to document the efficacy, safety and cost-effectiveness of the human fibrinogen concentrate Fibryga™. Contextual and experiential data from the expert consultations are also presented. Lastly, INESSS performed a cost-effectiveness and budget impact analysis. SOCIOCULTURAL AND POPULATIONAL DIMENSIONS Acquired fibrinogen deficiency, also known as acquired hypofibrinogenemia, is usually caused by the consumptionof coagulation factors following major bleeding. Acquired hypofibrinogenemia can occur unpredictably in adults and children during surgical interventions, major trauma, during the postpartum period, and in certain diseases. Cryoprecipitate is currently used to compensate for fibrinogen deficiency. It is produced by Héma-Québec by freezing and thawing plasma and contains mainly fibrinogen and other coagulation factors. The need regarding the treatment of acquired hypofibrinogenemia in the surgical context is limited. However, therapeutic options that allow faster fibrinogen administration without the risk of transmitting infectious agents could offer a certain advantage over the current situation. DELIBERATION REGARDING THERAPEUTIC VALUE: The members of the Comité scientifique de l'évaluation des médicaments aux fins d'inscription (CSEMI) are of the unanimously opinion that the therapeutic value of the fibrinogen concentrate Fibryga™ is recognized when used as complementary therapy during the management of severe uncontrolled bleeding during surgical interventions in patients with acquired fibrinogen deficiency. Reasons for the unanimous position. The members feel that the results of the Canadian study FIBRES are sufficient to recognize the noninferiority of fibrinogen concentrate to cryoprecipitate in the management of bleeding related to acquired hypofibrinogenemia in the context of cardiac surgery with extracorporeal circulation. The results of the FORMA-05 study support the use of fibrinogen concentrate during surgery other than cardiac surgery with extracorporeal circulation. The members recognize that fibrinogen concentrate and cryoprecipitate have a similar adverse effect profile. They also feel that the risks of transfusion related reactions and transmission of unknown infectious agents associated with cryoprecipitate are very low. Fibrinogen concentrate represents an alternative therapeutic option to cryoprecipitate that would address, in part, the health need associated with the management of acquired hypofibrinogenemia in a surgical context, which is considered small. According to the committee members, the conclusions regarding the therapeutic value of fibrinogen concentrate also apply to the medical conditions in which ACQUIRED HYPOFIBRINOGENEMIA IS CLEARLY DEMONSTRATED. DELIBERATION regarding all the criteria: The members of the Comité scientifique de l'évaluation des médicaments aux fins d'inscription (CSEMI) are of the unanimously opinion that the fibrinogen concentrate Fibryga™ should be added to the Liste des produits du système du sang du Québec as complementary therapy during the management of severe uncontrolled bleeding during surgical interventions in patients with acquired fibrinogen deficiency. Reasons for the unanimous position: The members recognize the noninferior therapeutic value of fibrinogen concentrate relative to cryoprecipitate for the management of perioperative bleeding in patients with acquired hypofibrinogenemia. At the price submitted by the manufacturer, Fibryga™ is a more cost-effective treatment option than the cryoprecipitate currently distributed in Québec. The members note that the use of cryoprecipitate is associated with wastage. They stated that blood is a precious and limited resource that should be used judiciously by the healthcare system. Any reduction in blood product wastage should therefore be valued. Distributing Fibryga™ for the management of acquired hypofibrinogenemia would result in an estimated $7.4 million in cost savings in the health-care facility budget over the next 3 years. The members believe that fibrinogen concentrate has the potential to reduce administration times in surgical context if it is prepared in the operating room instead of the blood bank. However, they add that the impact of faster administration of fibrinogen concentrate has not been investigated. INESSS'S RECOMMENDATION CONCERNING FIBRYGA™: In light of the available data, INESSS recommends that the fibrinogen concentrate Fibryga™ be added to the Liste des produits du système du sang du Québec as complementary therapy during the management of severe uncontrolled bleeding during surgical interventions in patients with acquired fibrinogen deficiency.

Recombinant Human HPS Protects Mice and Nonhuman Primates from Acute Liver Injury.

Acute liver injury shares a common feature of hepatocytes death, immune system disorders, and cellular stress. Hepassocin (HPS) is a hepatokine that has ability to promote hepatocytes proliferation and to protect rats from D-galactose (D-Gal)- or carbon tetrachloride (CCl4)-induced liver injury by stimulating hepatocytes proliferation and preventing the high mortality rate, hepatocyte death, and hepatic inflammation. In this paper, we generated a pharmaceutical-grade recombinant human HPS using mammalian cells expression system and evaluated the effects of HPS administration on the pathogenesis of acute liver injury in monkey and mice. In the model mice of D-galactosamine (D-GalN) plus lipopolysaccharide (LPS)-induced liver injury, HPS treatment significantly reduced hepatocyte death and inflammation response, and consequently attenuated the development of acute liver failure. In the model monkey of D-GalN-induced liver injury, HPS administration promoted hepatocytes proliferation, prevented hepatocyte apoptosis and oxidation stress, and resulted in amelioration of liver injury. Furthermore, the primary pharmacokinetic study showed natural HPS possesses favorable pharmacokinetics; the acute toxicity study indicated no significant changes in behavioral, clinical, or histopathological parameters of HPS-treated mice, implying the clinical potential of HPS. Our results suggest that exogenous HPS has protective effects on acute liver injury in both mice and monkeys. HPS or HPS analogues and mimetics may provide novel drugs for the treatment of acute liver injury.

Pathogen reduction of whole blood: Supplementing fibrinogen partly corrects clot formation in a massive transfusion model.

BACKGROUND: The use of whole blood (WB) to treat trauma patients is becoming more common. Similar to the treatment of individual components, pathogen inactivation (PI) technologies are available to treat WB. The impact of PI on WB function is not well understood. This study investigated the impact of PI of WB with riboflavin/ultraviolet (UV) light on its hemostatic function by modeling transfusion scenarios for trauma patients and assessing transfusion efficacy by rotational thromboelastometry (ROTEM). As fibrinogen is affected by PI of WB, the effect of fibrinogen supplementation commonly used in trauma patients was also analyzed in this model. STUDY DESIGN AND METHODS: Trauma transfusion scenarios were simulated by mixing untreated WB or WB treated with the Mirasol PI technology (riboflavin/UV) in different ratios with hemodiluted blood, and the thromboelasticity was monitored by ROTEM. The impact of supplementation with the fibrinogen concentrate RiaSTAP was investigated in this model. RESULTS: Pathogen-inactivated WB (PI-WB) showed decreased activity in the hemostatic profile compared to the untreated control. Hemodiluted blood at a hematocrit (hct) of 20%, which was reconstituted with PI-WB or untreated WB, exhibited increased alpha values, maximum clot firmness, and clot formation time. Simulating transfusion scenarios by blood replacement with PI-WB resulted in a significant difference in ROTEM parameters between reconstituted PI-treated and -untreated WB (p ≥ .05). The effect of PI treatment waned when PI-WB was enriched with fibrinogen. CONCLUSION: ROTEM investigations suggest that PI treatment has a negative impact on WB clot formation unless fibrinogen supplementation is used.

Therapeutic potential of fibrinogen γ-chain peptide-coated, ADP-encapsulated liposomes as a haemostatic adjuvant for post-cardiopulmonary bypass coagulopathy.

Fibrinogen γ-chain peptide-coated, adenosine 5'-diphosphate (ADP)-encapsulated liposomes (H12-ADP-liposomes) are a potent haemostatic adjuvant to promote platelet thrombi. These liposomes are lipid particles coated with specific binding sites for platelet GPIIb/IIIa and encapsulating ADP. They work at bleeding sites, facilitating haemostasis by promoting aggregation of activated platelets and releasing ADP to strongly activate platelets. In this study, we investigated the therapeutic potential of H12-ADP-liposomes on post-cardiopulmonary bypass (CPB) coagulopathy in a preclinical setting. We created a post-CPB coagulopathy model using male New Zealand White rabbits (body weight, 3 kg). One hour after CPB, subject rabbits were intravenously administered H12-ADP-liposomes with platelet-rich plasma (PRP) collected from donor rabbits (H12-ADP-liposome/PRP group, n = 8) or PRP alone (PRP group, n = 8). Ear bleeding time was greatly reduced for the H12-ADP-liposome/PRP group (263 ± 111 s) compared with the PRP group (441 ± 108 s, p < 0.001). Electron microscopy showed platelet thrombus containing liposomes at the bleeding site in the H12-ADP-liposome/PRP group. However, such liposome-involved platelet thrombi were not observed in the end organs after H12-ADP-liposome administration. These findings suggest that H12-ADP-liposomes could help effectively and safely consolidate platelet haemostasis in post-CPB coagulopathy and may have potential for reducing bleeding complications after cardiovascular surgery with CPB.

Impact of a Surgical Sealing Patch on Lymphatic Drainage After Axillary Dissection for Breast Cancer: The SAKK 23/13 Multicenter Randomized Phase III Trial.

BACKGROUND: Several studies and a meta-analysis showed that fibrin sealant patches reduced lymphatic drainage after various lymphadenectomy procedures. Our goal was to investigate the impact of these patches on drainage after axillary dissection for breast cancer. METHODS: In a phase III superiority trial, we randomized patients undergoing breast-conserving surgery at 14 Swiss sites to receive versus not receive three large TachoSil® patches in the dissected axilla. Axillary drains were inserted in all patients. Patients and investigators assessing outcomes were blinded to group assignment. The primary endpoint was total volume of drainage. RESULTS: Between March 2015 and December 2016, 142 patients were randomized (72 with TachoSil® and 70 without). Mean total volume of drainage in the control group was 703 ml [95% confidence interval (CI) 512-895 ml]. Application of TachoSil® did not significantly reduce the total volume of axillary drainage [mean difference (MD) -110 ml, 95% CI -316 to 94, p = 0.30]. A total of eight secondary endpoints related to drainage, morbidity, and quality of life were not improved by use of TachoSil®. The mean total cost per patient did not differ significantly between the groups [34,253 Swiss Francs (95% CI 32,625-35,880) with TachoSil® and 33,365 Swiss Francs (95% CI 31,771-34,961) without, p = 0.584]. In the TachoSil® group, length of stay was longer (MD 1 day, 95% CI 0.3-1.7, p = 0.009), and improvement of pain was faster, although the latter difference was not significant [2 days (95% CI 1-4) vs. 5.5 days (95% CI 2-11); p = 0.2]. CONCLUSIONS: TachoSil® reduced drainage after axillary dissection for breast cancer neither significantly nor relevantly.

The effect of fibrinogen concentrate on perioperative bleeding in transurethral resection of the prostate: a double-blind placebo-controlled and randomized study.

Essentials Perioperative bleeding during prostate surgery is still a common morbidity. Anticoagulant and antiplatelet medications contribute to the risk of hemorrhage and prolonged hospital stay. Multiple pharmacological agents have been proposed, but none of them have been widely accepted. It is crucial to find a safe and effective modality to reduce hemorrhage. SUMMARY: Background Hemorrhage during transurethral resection of the prostate (TUR-P) has always been a concern. Several studies have shown preoperative administration of fibrinogen concentrate to have promising results in reducing hemorrhage in cardiac surgery. Objectives To investigate the hemostatic effect of fibrinogen concentrate administration on reducing the amount of bleeding during TUR-P in patients with benign prostatic hyperplasia. Methods Sixty men with benign prostatic hyperplasia, who were chosen to undergo TUR-P, entered this prospective randomized double-blind placebo-controlled study. The participants were randomly assigned to two groups: treatment (n = 31) and placebo (n = 29). They received an infusion of 2 g of fibrinogen concentrate (treatment group) or normal saline (placebo group) before surgery. Data regarding the amount of bleeding, the operation and complications were recorded and analyzed. Results No difference was observed in bleeding between the fibrinogen and placebo groups during (521 mL versus 557 mL, respectively) and after (291 mL versus 341 mL, respectively) surgery. This lack of difference was also seen in operation time (43 min versus 42 min), irrigating fluid volume used during (17 L versus 19 L) and after (29 L versus 28 L) surgery, and resected adenoma volume (19 g versus 19 g). The mean blood pressure was also similar in both groups as a confounding factor for the amount of bleeding. Conclusion Preoperative administration of fibrinogen concentrate had no significant influence on intraoperative and postoperative bleeding in TUR-P surgery.

The Real-World Treatment of Hemorrhages Associated With Dabigatran and Rivaroxaban: A Multicenter Evaluation.

PURPOSE: Adoption of the target-specific oral anticoagulants (TSOACs) has been slow; accordingly, lack of guidance for emergent reversal confounded by the need for "direct" reversal agents has contributed significantly to warfarin entrenchment in the medical community. The purpose of this analysis is to provide real-world experiences regarding the management of the hemorrhaging patient secondary to dabigatran and rivaroxaban. METHODS: Retrospective review of patients admitted with a hemorrhage secondary to dabigatran or rivaroxaban were evaluated. Descriptive statistics were utilized for analysis. RESULTS: Four hundred forty-four patients were screened for inclusion into the study; notably, 419 (94%) of the patients were excluded because the bleed was secondary to warfarin therapy. Of those included in this analysis (n = 25), gastrointestinal bleeding accounted for 21 events (84%), followed by intracranial (n = 2; 8%) and epistaxis (n = 2; 8%). Two patients (8%) expired during admission and 6 patients (24%) expired within 6 months after discharge from the hospital. Three (12%) minor bleeds, 7 (28%) major bleeds, and 15 (60%) life-threatening bleeds were identified. Minor bleeds required careful monitoring, supportive care, and cessation of anticoagulation therapy, whereas increasing severity required multiple interventions with prothrombin complex concentrate, recombinant activated factor 7, fresh frozen plasma, packed red blood cells, cryoprecipitate, and platelets. CONCLUSION: The approach to the management of bleeding events borne from TSOACs has proven to be very heterogeneous. In the midst of this observation period, these facilities developed protocols, which created a stratification of bleeds and a more regimented approach to managing them. Although bleeding is less with new agents, the creation of pathways/algorithms for the management of TSOACs and education regarding clinical decision-making may be beneficial for the expeditious and appropriate management when these events arise.

Fibrinogen and prothrombin complex concentrate in trauma coagulopathy.

BACKGROUND: Coagulopathy after injury contributes to hemorrhage and death. Treatment with specific coagulation factors could decrease hemorrhage and mortality. Our aim was to compare fibrinogen and prothrombin complex concentrate (PCC) in a rabbit model of hemorrhagic shock. MATERIALS AND METHODS: New Zealand white rabbits were anesthetized. Blood was withdrawn to a mean arterial pressure (MAP) of 30-40 mm Hg for 30 min. Animals were resuscitated with lactated Ringer to a MAP of 50-60 mm Hg and randomized to receive 100 mg/kg of fibrinogen, PCC 25 IU/kg, or lactated Ringer. A liver injury was created. A MAP of 50-60 mm Hg was maintained for 60 min. The primary outcome was blood loss, and secondary outcomes were fluid administered and coagulopathy as measured by plasma-based tests. RESULTS: There were eight animals in each group. Median blood loss was significantly higher in the fibrinogen group, at 122 mL (95% confidence interval [CI], 75-194), when compared with that in the control group, 35 mL (95% CI, 23-46; P value = 0.001), and the PCC group, 26 mL (95% CI, 4-54; P value = 0.002). Resuscitation fluid requirement was highest in the fibrinogen group, at 374 mL (95% CI, 274-519), and lowest in the PCC group, at 238 mL (95% CI, 212-309) (P = 0.01). Plasma-based coagulation tests were not different among groups. CONCLUSIONS: In a rabbit model, PCC did not have a significant effect on blood loss. Fibrinogen increased blood loss and fluid requirements.

Fibrinogen concentrate improves survival during limited resuscitation of uncontrolled hemorrhagic shock in a Swine model.

The purpose of this study was to evaluate the effect of fibrinogen concentrate, as a hemostatic agent, on limited resuscitation of uncontrolled hemorrhagic shock. We use a swine model of hemorrhagic shock with free bleeding from a 4-mm aortic tear to test the effect of adding a one-time dose of fibrinogen concentrate given at the onset of limited fluid resuscitation. Immature female swine were anesthetized and subjected to catheter hemorrhage and aortic tear to induce uniform hemorrhagic shock. Animals (n = 7 per group) were then randomized to receive (i) no fluid resuscitation (neg control) or (ii) limited resuscitation in the form of two boluses of 10 mL/kg of 6% hydroxyethyl starch solution given 30 min apart (HEX group), or (iii) the same fluid regimen with one dose of 120-mg/kg fibrinogen concentrate given with the first hydroxyethyl starch bolus (FBG). Animals were then observed for a total of 6 h with aortic repair and aggressive resuscitation with shed blood taking place at 3 h. Survival to 6 h was significantly increased with FBG (7/8, 86%) versus HEX (2/7, 29%) and neg control (0/7, 0%) (FBG vs. HEX, Kaplan-Meier log-rank P = 0.035). Intraperitoneal blood loss adjusted for survival time was increased in HEX (0.4 mL/kg per minute) when compared with FBG (0.1 mg/kg per minute, P = 0.047) and neg control (0.1 mL/kg per minute, P = 0.041). Systemic and cerebral hemodynamics also showed improvement with FBG versus HEX. Fibrinogen concentrate may be a useful adjunct to decrease blood loss, improve hemodynamics, and prolong survival during limited resuscitation of uncontrolled hemorrhagic shock.

Systemic treatments for the prevention of venous thrombo-embolic events in paediatric cancer patients with tunnelled central venous catheters.

BACKGROUND: Venous thrombo-embolic events (VTEs) occur in 2.2% to 14% of paediatric cancer patients and cause significant morbidity and mortality. The malignant disease itself, the cancer treatment and the presence of central venous catheters (CVCs) increase the risk of VTE. OBJECTIVES: The primary objective of this review was to investigate the effects of preventive systemic treatments in paediatric cancer patients with tunnelled CVCs on (a)symptomatic VTE. Secondary objectives of this review were to investigate adverse effects of systemic treatments for the prevention of (a)symptomatic VTE in paediatric cancer patients with tunnelled CVCs; and to investigate the effects of systemic treatments in the prevention of (a)symptomatic VTE with CVC-related infection in paediatric cancer patients with tunnelled CVCs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 8 2012), MEDLINE (1966 to August 2012) and EMBASE (1966 to August 2012). In addition, we searched reference lists from relevant articles and conference proceedings of the International Society for Paediatric Oncology (SIOP) (from 2006 to 2011), the American Society of Clinical Oncology (ASCO) (from 2006 to 2011), the American Society of Hematology (ASH) (from 2006 to 2011) and the International Society of Thrombosis and Haematology (ISTH) (from 2006 to 2011). We scanned the International Standard Randomised Controlled Trial Number (ISRCTN) Register and the National Institute of Health (NIH) Register for ongoing trials (www.controlled-trials.com) (August 2012), and we contacted the authors of eligible studies if additional information was required. SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing systemic treatments to prevent venous thrombo-embolic events (VTEs) in paediatric cancer patients with tunnelled CVCs with a control intervention or no systemic treatment. For the description of adverse events, cohort studies were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, extracted data and performed risk of bias assessment of included studies. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: Three RCTs and three CCTs (including 1291 children) investigated the prevention of VTE (low molecular weight heparin (LMWH) n = 134, antithrombin (AT) supplementation n = 37, low-dose warfarin n = 31, cryoprecipitate and/or fresh frozen plasma (FFP) supplementation n = 240, AT supplementation and LMWH n = 41). AT, cryoprecipitate and FFP were supplemented only in cases of AT or fibrinogen deficiency. Of the six included RCTs/CCTs, five investigated the prevention of VTE compared with no intervention (n = 737), and one CCT compared AT supplementation and LMWH with AT supplementation (n = 71). All studies had methodological limitations, and clinical heterogeneity between studies was noted.We found no significant effects of systemic treatments compared with no intervention in preventing (a)symptomatic VTE and no differences in adverse events (such as major and/or minor bleeding; none of the studies reported thrombocytopenia, heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia with thrombosis (HITT), death as a result of VTE, removal of CVC due to VTE, CVC-related infection, and post-thrombotic syndrome (PTS)) between experimental and control groups. Two studies with comparable participant groups and interventions were included for meta-analyses (n = 182). In the experimental group, 1/68 (1.5%) children were diagnosed with symptomatic VTE, as were 4/114 (3.5%) in the control group (best case scenario: risk ratio (RR) 0.65, 95% confidence interval (CI) 0.09 to 4.78). These studies also evaluated asymptomatic CVC-related VTE: In the experimental group, 22/68 (32.4%) were diagnosed with asymptomatic VTE, as were 35/114 (30.7%) in the control group (best case scenario: RR 1.02, 95% CI 0.40 to 2.55). Heterogeneity was substantial for this analysis: I(2) = 73%.The attribution of LMWH to AT supplementation resulted in a significant reduction in symptomatic VTE (Fisher's exact test, two-sided P = 0.028) without bleeding complications; asymptomatic VTE, thrombocytopenia, HIT, HITT, death as a result of VTE, removal of CVC due to VTE, CVC-related infection and PTS were not assessed.Four cohort studies were included for the evaluation of adverse events. Three studies provided information on bleeding episodes: One participant developed an ischaemo-haemorrhagic stroke. One study provided information on other adverse events: None occurred. AUTHORS' CONCLUSIONS: We found no significant effects of systemic treatments compared with no intervention in preventing (a)symptomatic VTE in paediatric oncology patients with CVCs. However, this could be a result of the low number of included participants, which resulted in low power. In one CCT, which compared one systemic treatment with another systemic treatment, we identified a significant reduction in symptomatic VTE with the addition of LMWH to AT supplementation.All studies investigated the prevalence of major and/or minor bleeding episodes, and none found a significant difference between study groups. None of the studies reported thrombocytopenia, HIT, HITT, death as a result of VTE, removal of CVC due to VTE, CVC-related infection or PTS among participants.On the basis of currently available evidence, we are not able to give recommendations for clinical practise. Additional well-designed international RCTs are needed to further explore the effects of systemic treatments in preventing VTE. Future studies should aim for adequate power with attainable sample sizes. The incidence of symptomatic VTE is relatively low; therefore, it might be necessary to select participants with thrombotic risk factors or to investigate asymptomatic VTE instead.

Evaluation of recombinant activated factor VII, prothrombin complex concentrate, and fibrinogen concentrate to reverse apixaban in a rabbit model of bleeding and thrombosis.

BACKGROUND: As all anticoagulants, apixaban exposes to a bleeding risk, thus an effective way to reverse its effects is needed. Objectives were to study efficacy and safety of recombinant activated factor VII (rFVIIa), prothrombin complex concentrate (PCC), and fibrinogen concentrate (Fib) to reverse apixaban in a rabbit model of bleeding and thrombosis. METHODS: After a dose-ranging study to assess the minimal amount of apixaban increasing bleeding, 63 anaesthetized rabbits were randomized into 5 groups: control (saline), apixaban (apixaban and saline), rFVIIa (apixaban and rFVIIa), PCC (apixaban and PCC) and fibrinogen (apixaban and Fib). The Folts model was applied: a stenosis and an injury were carried out on the carotid artery, inducing thrombosis detected as cyclic flow reductions (CFRs) within 20 min. A number of parameters were recorded through ear immersion bleeding time (BT), clotting times (CT), thrombelastography, and thrombin generation time (TGT). Ultimately, a hepatosplenic section was performed to evaluate as primary endpoint the blood loss in 15 min. RESULTS: Apixaban increased blood loss (11.6 ± 3 g vs. 8.3 ± 3 g for control, p < 0.0003), lengthened BT, the prothrombin time (PT), thrombelastographic CT and decreased thrombin generation. Only rFVIIa reduced BT yet failed to improve blood loss. PCC and rFVIIa both shortened the PT, CT in thrombelastographic, and lag time in TGT. Fib improved clot firmness, enhanced thrombin generation but increased bleeding. Regarding safety, neither rFVIIa, PCC, nor Fib increased CFRs. CONCLUSION: rFVIIa, PCC, and Fib failed to reverse apixaban-induced bleeding. They only improved several laboratory parameters.

2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Actualización del Documento Sevilla / The 2013 Seville Consensus Document on alternatives to allogenic blood transfusion. An update on the Seville Document

La transfusión de sangre alogénica (TSA) no es inocua, y como consecuencia han surgido múltiples alternativas a la misma (ATSA). Existe variabilidad respecto a las indicaciones y buen uso de las ATSA. Dependiendo de la especialidad de los médicos que tratan a los pacientes, el grado de anemia, la política transfusional, la disponibilidad de las ATSA y el criterio personal, estas se usan de forma variable. Puesto que las ATSA tampoco son inocuas y pueden no cumplir criterios de coste-efectividad, la variabilidad en su uso es inaceptable. Las sociedades españolas de Anestesiología y Reanimación (SEDAR), Hematología y Hemoterapia(SEHH), Farmacia Hospitalaria (SEFH), Medicina Intensiva y Unidades Coronarias(SEMICYUC), Trombosis y Hemostasia (SETH) y Transfusiones Sanguíneas (SETS) han elaborado un documento de consenso para el buen uso de la ATSA. Un panel de expertos de las 6sociedades ha llevado a cabo una revisión sistemática de la literatura médica y elaborado el 2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Solo se contempla las ATSA dirigidas a disminuir la transfusión de concentrado de hematíes. Se definen las ATSA como toda medida farmacológica y no farmacológica encaminada a disminuir la transfusión de concentrado de hematíes, preservando siempre la seguridad del paciente. La cuestión principal que se plantea en cada ítem se formula, en forma positiva o negativa, como: “La ATSA en cuestión reduce/no reduce la tasa transfusional». Para formular el grado de recomendación se ha usado la metodología Grades of Recommendation Assessment, Development and Evaluation (GRADE) (AU)

Since allogeneic blood transfusion (ABT) is not harmless, multiple alternatives to ABT (AABT) have emerged, though there is great variability in their indications and appropriate use. This variability results from the interaction of a number of factors, including the specialty of the physician, knowledge and preferences, the degree of anemia, transfusion policy, and AABT availability. Since AABTs are not harmless and may not meet cost-effectiveness criteria, such variability is unacceptable. The Spanish Societies of Anesthesiology (SEDAR), Hematology and Hemotherapy (SEHH), Hospital Pharmacy (SEFH), Critical Care Medicine (SEMICYUC), Thrombosis and Hemostasis (SETH)and Blood Transfusion (SETS) have developed a Consensus Document for the proper use of AABTs. A panel of experts convened by these 6 Societies have conducted a systematic review of the medical literature and have developed the 2013 Seville Consensus Document on Alternatives to Allogeneic Blood Transfusion, which only considers those AABT aimed at decreasing the transfusion of packed red cells. AABTs are defined as any pharmacological or non-pharmacological measure aimed at decreasing the transfusion of red blood cell concentrates, while preserving patient safety. For each AABT, the main question formulated, positively or negatively, is: “Does this particular AABT reduce the transfusion rate or not? “All the recommendations on the use of AABTs were formulated according to the Grades of Recommendation Assessment, Development and Evaluation(GRADE) methodology (AU)

The evaluation of the effectiveness of Tachosil in the treatment of lymphorrhea of the postoperative wound in the selected group of patients, after vascular reconstructive surgeries--preliminary report.

UNLABELLED: Lymphorrhea of a postoperative wound after vascular reconstructive surgeries does not occur frequently but it accounts for a major complication. It should be brought to attention that during the intraoperative period it is impossible to diagnose any damages within the lymphatic system of the operated area. Additionally, the treatment of lymphorrhea with thermal abrasion does not usually bring the desired outcome. Therefore, the extended time of the postoperative wound treatment with the lymphatic drainage constitutes a standard method in such cases. The aim of the study was to evaluate the effectiveness of Tachosil surgical patch in the treatment of lymphorrhea of the postoperative wound in a selected group of patients who have undergone vascular reconstructive surgeries. Additionally, the aim of the study was to analyze the results and draw conclusions pertaining to the validity and effectiveness of the treatment with the use of Tachosil surgical patch. MATERIAL AND METHODS: The observed group included 10 patients with lymphorrhea developed during the postoperative period. 6 of the observed patients have undergone the vascular reconstructive surgery with the implantation of the vascular prosthesis (distal femoropopliteal reconstruction bridge - 3 patients; iliofemoral reconstruction bridge - 1 patient; angioplasty of the common femoral artery (CFA) with the use of the prosthetic patch - 1 patient; the implantation of the bifurcated (type Y) aortofemoral prosthesis - 1 patient). The remaining patients in the observed group have undergone the restoration of patency of the CFA. Additionally, 1 patient has undergone the resection of the pseudo aneurysm in the distal part of the iliofemoral prosthesis. The vascular reconstructive surgery required the denudation and isolation of the common femoral artery from the surrounding tissue as a step 1. The persisting lymphorrhea of the postoperative wound, in the volume of more than 200 ml per day during the first 3 postoperative days, indicated the necessity for the inguinal wound revision. In addition, Tachosil surgical patch was applied at that time. The drain was placed over Tachosil patch. RESULTS: Complete stop of lymphorrhea was shorter by 4.87 days in patients treated with the use of Tachosil in comparison to control group. These patients also had an average hospitalization time shorter by 3.88 days than patients in the control group. CONCLUSIONS: Early intervention in the cases of lymphorrhea of the postoperative wound allows planning and conducting successful treatment. The use of Tachosil surgical patch in the treatment of lymphorrhea of the postoperative wound shortens the treatment and hospitalization periods. The use of Tachosil in the treatment of postoperative lymphorrhea appeared to be significantly more effective than the standard drainage method of treatment. Results obtained through this study pave the way for the research on other possible applications of Tachosil in the cases of lymphorrhea after vascular reconstructive surgeries.

Collagen sealant patch to reduce lymphatic drainage after lymph node dissection.

BACKGROUND: Seroma formation is a frequent complication following radical lymph node dissection (RLND) in patients with metastatic melanoma. Several strategies have been used to prevent fluid accumulation and thereby reduce the duration of postoperative drainage, including fibrin sealants. METHODS: This was a prospective, single-center study in which consecutive patients undergoing surgical treatment of stage III metastatic melanoma by axillary or ilio-inguinal RLND were randomized to receive standard treatment plus fibrinogen/thrombin-coated collagen sealant patch (CSP) or standard treatment alone. The primary endpoint of the study was postoperative duration of drainage. RESULTS: A total of 70 patients underwent axillary (n = 47) or ilio-inguinal (n = 23) RLND and received CSP plus standard treatment (n = 37) or standard treatment alone (n = 33). Mean duration of drainage was significantly reduced in the CSP group compared with standard treatment (ITT analysis: 20.1 ± 5.1 versus 23.3 ± 5.1 days; p = 0.010). The percentage of patients drainage-free on day 21 was significantly higher in the CSP group compared with the standard treatment group (86% versus 67%; p = 0.049). CONCLUSIONS: Use of the tissue sealant resulted in a significant reduction in duration of drainage. Further studies are warranted to confirm these results in different and selected types of lymphadenectomy.

[Coagulation management of trauma patients with unstabile circulation : establishment of a hemoglobin-oriented standard operating procedure]. / Gerinnungsmanagement beim kreislaufinstabilen Polytraumapatienten : Erarbeitung einer hämoglobinorientierten "standard operating procedure"

INTRODUCTION: Massive hemorrhage is the leading cause of death in the first few hours following multiple trauma, therefore, early and aggressive treatment of clotting disorders and surgical intervention to stop the bleeding are of utmost importance. However, commonly performed clotting tests have a considerable latency of at least 30-45 min, whereas hemoglobin (Hb) levels can be tested very quickly. If a multiple trauma patient has already received fluid resuscitation, a certain relationship may be observed between the hemoglobin value and the development of clotting disturbances. Hence, hemoglobin may be a useful and rapidly available parameter for guiding the initial treatment of clotting disturbances in multiple trauma patients. METHODS: A Hb-guided algorithm has been developed to initiate initial clotting therapy. The algorithm contains three stages of different aggressive clotting therapy with fibrinogen, prothrombin complex concentrate (PCC), factor VIIa, tranexamic acid and desmopressin, depending on the first Hb value measured. For admission Hb levels > 5.5 mmol/l (≈8.8 g/dl) coagulation therapy is managed on the basis of the laboratory tests and if in doubt 2 g fibrinogen is administered. For admission Hb levels between 5.5 mmol/l (≈8.8 g/dl) and 4 mmol/l (≈6.5 g/dl) 2-4 g fibrinogen and 2,500-3,000 IU PCC are administered and tranexamic acid and desmopressin administration should be considered. For admission Hb levels < 4 mmol/l (≈6.5 g/dl) 4-6 g fibrinogen, 3,000-5,000 IU PCC and 1 mg factor VIIa should be administered and tranexamic acid and desmopression should be considered. All drugs mentioned should be stored in a special "coagulation box" in the hospital pharmacy and this box is brought immediately to the patient on demand. In addition to the use of clotting factors, infusions should be performed with balanced crystalloids and transfusions with an RBC/FFP ratio of 2:1-1:1. To assess the efficiency of the algorithm the routinely measured clotting parameters at trauma bay admission were compared with intensive care unit (ICU) admission and the standardized mortality ratio (SMR) was calculated. RESULTS: During a 6-month investigation period 71 severe multiple trauma patients were admitted to the trauma center and 19 patients were treated using the coagulation box of which 13 required massive transfusions. The routinely used clotting parameters markedly improved between admission to the trauma bay and ICU admission: Quick 61% versus 97% (p < 0.001), partial prothromboplastin time (PTT) 50 s versus 42 s (not significant), fibrinogen 1.7 g/l versus 2.15 g/l (not significant). Of the 19 patients 11 (58%) survived. The revised injury severity classification (RISC) predicted a survival rate of 40%, which corresponds to an SMR of 0.69, thus implying a higher survival rate than predicted. CONCLUSIONS: The Hb-driven algorithm, in combination with the coagulation box and the early use of clotting factors, may be a simple and effective tool for improving coagulopathy in multiple trauma patients.