Fibrinogen Supplementation Research Articles

A Randomized Controlled Trial Comparing Effectiveness of Different Fibrinogen Preparations in Restoring Clot Firmness.

Different preparations of fibrinogen concentrate are currently available. Two in vitro studies demonstrated the superiority of FibCLOT (LFB) in increasing clot firmness with respect to RiaSTAP (CSL Behring). The present trial involved a clinical model to test the hypothesis of superiority, with the increase in clot firmness as the primary end point. Forty cardiac surgery patients were randomly allocated to receive a dose of 30 mg/kg FibCLOT or RiaSTAP after protamine administration in the presence of microvascular bleeding and a FIBTEM maximum clot firmness (MCF) <10 mm. Viscoelastic parameters were measured before and after fibrinogen supplementation: FIBTEM MCF, EXTEM MCF, and EXTEM clotting time (CT). The mean increase in FIBTEM MCF was 4 ± 1.2 mm (mean and standard deviation) in the FibCLOT group and 4 ± 1.6 mm in the RiaSTAP group (P = 1.000); the mean decrease in CT was 11. 2 ± 12.2 (mean and standard deviation) seconds in the FibCLOT group and 14. 8 ± 13 seconds in the RiaSTAP group (P = .372). In both groups, fibrinogen supplementation induced a significant (P = .001) increase in the FIBTEM MCF and EXTEM CT. The proportions of patients who did not experience an increase of 4 mm in the RiaSTAP group and the FibCLOT group were not statistically significantly higher (35% vs 20%, respectively, relative risk 2.15, 95% confidence interval 0.52-9.00, P = .288). In contrast to previous in vitro studies, we found that the effect of FibCLOT on MCF and CT was not significantly greater than that of RiaSTAP in cardiac surgery patients. Further studies in other clinical settings are warranted.

Survey of pediatric massive transfusion protocol practice at United States level I trauma centers: An AABB Pediatric Transfusion Medicine Subsection study.

Trauma remains the leading cause of pediatric mortality in the United States. Although use of massive transfusion protocols (MTPs) in this population is widespread, optimal pediatric resuscitation is not well established. We sought to assess contemporary pediatric MTP practice in the United States. A web-based survey was designed by the Association for the Advancement of Blood & Biotherapies (AABB) Pediatric Transfusion Medicine Subsection and distributed to select American College of Surgeons (ACS) Level I Verified pediatric trauma centers. The survey assessed current MTP policy, implementation, and recent changes in practice. Response rate was 55% (22/40). Almost half of the respondents were from the South. The median RBC:plasma ratio was 1 (interquartile range 1-1.5). Protocolized fibrinogen supplementation was common while integration of antifibrinolytic therapy into MTPs was infrequent. Viscoelastic testing (VET) was available at most sites, 71% (15/21, one site did not respond), and was generally utilized on an ad-hoc basis. Roughly, a third of sites had changed their MTP in the past 3 years due to blood supply issues, and about a third reported having group O Whole Blood on-site. MTP practice is similar throughout the United States. Though fibrinogen supplementation is common-other emerging interventions such as antifibrinolytic therapy or utilization of routine viscoelastic testing-are not widespread. Pediatric transfusion medicine experts must continue to follow practice change, as contemporary large trials begin to characterize new supportive modalities to optimize resuscitation in pediatric trauma patients.

Fluid resuscitation in trauma: What you need to know.

There have been numerous changes in resuscitation strategies for severely injured patients over the last several decades. Certain strategies, such as aggressive crystalloid resuscitation, have largely been abandoned because of the high incidence of complications and worsening of trauma-induced coagulopathy. Significant emphasis has been placed on restoring a normal coagulation profile with plasma or whole blood transfusion. In addition, the importance of the lethal consequences of trauma-induced coagulopathy, such as hyperfibrinolysis, has been easily recognized by the use of viscoelastic testing, and its treatment with tranexamic acid has been extensively studied. Furthermore, the critical role of early intravenous calcium administration, even before blood transfusion administration, has been emphasized. Other adjuncts, such as fibrinogen supplementation with fibrinogen concentrate or cryoprecipitate and prothrombin complex concentrate, are being studied and incorporated in some of the institutional massive transfusion protocols. Finally, balanced blood component transfusion (1:1:1 or 1:1:2) and whole blood have become commonplace in trauma centers in North America. This review provides a description of recent developments in resuscitation and a discussion of recent innovations and areas for future investigation.

Trauma-induced dysfibrinogenemia: the von Clauss assay does not accurately measure fibrinogen levels after injury

AbstractTrauma patients who sustain severe tissue injury and hemorrhage often receive fibrinogen repletion to avert coagulopathy and achieve hemostasis. However, fibrinogen supplementation has not shown a benefit in trauma patients with coagulopathy. The von Clauss functional fibrinogen assay is the primary indication for fibrinogen transfusion. This assay, however, infers fibrinogen levels optically via in vitro clot formation time and does not directly measure the quantity or quality of plasma fibrinogen. We hypothesized that the Clauss fibrinogen activity assay does not accurately reflect true fibrinogen levels in severely injured patients. Here, we demonstrate normal baseline plasma fibrinogen levels as measured by mass spectrometry despite coagulopathic Clauss values in severely injured patients. This discrepancy is most significant in patients with coagulopathy (international normalized ratio of >1.3) or with high shock, and persists even after fibrinogen repletion. These data highlight the need to reevaluate clinical testing of fibrinogen activity and transfusion criteria for the critically injured, and indicate that correcting shock and the oxidative, inflammatory milieu of trauma may be more effective at improving fibrinogen activity. This trial was registered at www.ClinicalTrials.gov as #NCT01838863.

Heat stress–induced platelet dysfunction is associated with loss of fibrinogen and is improved by fibrinogen supplementation

IntroductionHeatstroke is a critical heat-related condition characterized by coagulopathy and multiple organ dysfunction. One of the most severe complications of heatstroke is disseminated intravascular coagulation. This condition manifests as excessive clot formation and bleeding that are primarily due to platelet depletion and dysfunction. Fibrinogen plays a crucial role in hemostasis because it links integrin αIIbβ3 on adjacent platelets, thereby promoting the platelet activation and aggregation necessary for clot formation. However, reduced fibrinogen levels may impair the formation of the initial platelet plug and increase the risk of bleeding. The current study explored the effect of fibrinogen on platelet dysfunction in a heatstroke model. Materials and methodsMale Wistar rats were subjected to heat stress, and subsequent changes in hemodynamic, biochemical, and coagulation parameters were analyzed. Platelet viability, aggregation, adhesion, spreading and fibrin clot retraction were assessed. ResultsThe rats with heatstroke exhibited a variety of clinical symptoms, including hypotension, tachycardia, multiple organ dysfunction, and coagulopathy. Platelet viability in the heatstroke group was comparable to that in the healthy control group. However, the heatstroke group exhibited significant reductions in plasma fibrinogen levels and platelet aggregation, adhesion, spreading, and fibrin clot retraction. Notably, fibrinogen supplementation markedly augmented the aggregation responses of platelets in the heatstroke group. The impairment of platelet adhesion, spreading, and fibrin clot retraction in the rats with heatstroke was partially ameliorated by fibrinogen supplementation. ConclusionsAn early use of fibrinogen replacement may serve as a therapeutic intervention to alleviate platelet hyporeactivity and prevent the complications in patients with heatstroke.

Effect of early hemostasis strategy on secondary post-traumatic sepsis in trauma hemorrhagic patients

IntroductionFibrinogen and platelet, as the two main components of hemostatic resuscitation, are frequently administered in traumatic massive hemorrhage patients. It is reasonable to infer that they may have an impact on post-traumatic sepsis as more and more recognition of their roles in inflammation and immunity. This study aims to determine the association between the fibrinogen/platelet transfusion ratio during the first 24 h after trauma and the risk of the post- traumatic sepsis. MethodsWe analyzed the data from the National Trauma Data Bank (NTDB). Subjects included the critically injured adult patients admitted to Level I/II trauma center from 2013 to 2017 who received fibrinogen and platelet supplementation and more than 10 units (about 4000 ml) packed red blood cells (pRBCs) during the first 24 h after trauma. Two parts of analyses were performed: (1) multivariable stepwise regression was used to determine the variables that influence the risk of post-traumatic sepsis; (2) propensity score matching (PSM), to compare the influences of different transfusion ratio between fibrinogen and platelet on the risk of sepsis and other outcomes after trauma. Results8 features were screened out by bi-directional multivariable stepwise logistic regression to predict the post-traumatic sepsis. They are age, sex, BMI, ISSabdomen, current smoker, COPD, Fib4h/24h and Fib/PLT24h. Fib/PLT24h was negatively related to sepsis (p < 0.05). A total of 1601 patients were included in the PSM cohort and grouped by Fib/PLT24h = 0.025 according to the fitting generalized additive model (GAM) model curve. The incidence of sepsis was significantly decreased in the high Fib/PLT group [3.3 % vs 9.4 %, OR = 0.33, 95 %CI (0.17–0.60)]; the length of stay in ICU and mechanical ventilation were both shortened as well [8 (IQR 2.00,17.00) vs 9 (IQR 3.00,19.25), p = 0.006 and 4 (IQR 2.00,10.00) vs 5 (IQR 2.00,14.00), p = 0.003, respectively. ConclusionsEarly and sufficient supplementation of fibrinogen was a convenient way contribute to reduce the risk of sepsis after trauma.

Impact of early and empirical cryoprecipitate administration on the transfusion requirements in trauma patients with hemorrhagic shock

Abstract BACKGROUND: Fibrinogen is the earliest coagulation factor falling to the critical levels in severely bleeding trauma patients. Early fibrinogen supplementation in these patients has been recommended to improve the patient outcomes. However, its role in reducing the overall transfusion requirement remains equivocal. AIMS: This study aimed to evaluate the effect of early cryoprecipitate (CRYO) administration on the transfusion requirement and the coagulation assays in trauma patients with hemorrhagic shock. SETTINGS AND DESIGN: An interventional study was conducted in two phases at level I trauma center. During the 1st phase (Group I), patients received blood components in accordance with current practices, whereas in the 2nd phase (Group II), patients received an additional CRYO (pool of 6 units) empirically within 90 min of admission. METHODS: Demographics, clinical, injury characteristics, transfusion requirements, blood counts, and coagulation assays were assessed for both the study groups. STATISTICAL ANALYSIS: The comparative analysis was done for blood component utilization and coagulations assays (prothrombin time, activated partial thromboplastin time, and fibrinogen levels) in both study groups. RESULTS AND CONCLUSIONS: A total of 50 patients in Group I and 51 patients in Group II were recruited. Demographics, clinical, injury characteristics, and laboratory investigations were comparable, except for heart rate, blood pressure, and injury scores. Significant reductions in red blood cell and platelet transfusions were observed, whereas the fresh-frozen plasma transfusions remained unaffected. The results of coagulation assays at 18–24 h were similar for both groups. Although no significant differences in fibrinogen levels were observed despite CRYO administration, decreased requirement for transfusions indicated an improved hemostasis in CRYO group.

Precision medicine in hemostasis: a review of prothrombin complex concentrates and the role of viscoelastic tests in tailoring therapy

This review explores the role of precision medicine in the management of bleeding disorders and anticoagulation therapy, with a focus on the use of visco-elastic tests such as Thromboelastography (TEG) and Rotational Thromboelastometry (ROTEM). These tests provide real-time, dynamic insight into a patient's coagulation status, guiding the choice between three-factor prothrombin complex concentrate (PCC3) and four-factor PCC (PCC4), as well as the use of activated four-factor PCC (FEIBA). The specific ROTEM tests, INTEM and EXTEM, further enhance our understanding of the intrinsic and extrinsic coagulation pathways. Moreover, the use of tranexamic acid (TXA) and fibrinogen, guided by these visco-elastic tests, has shown promise in trauma patients. TXA has been associated with survival benefit when administered immediately or within 3 hours of injury. Fibrinogen, a key factor in clot formation, can be monitored and supplemented as needed to optimize hemostasis. In conclusion, the practice of precision medicine, with the aid of TEG and ROTEM, offers the potential to enhance the safety and efficacy of PCC therapy, TXA administration, and fibrinogen supplementation. These tools are invaluable in tailoring therapy to the specific needs of each patient, potentially optimizing patient outcomes and minimizing the risk of adverse events.

Supplemental fibrinogen restores thrombus formation in cardiopulmonary bypass-induced platelet dysfunction ex vivo

BackgroundMajor cardiac surgery related blood loss is associated with increased postoperative morbidity and mortality. Platelet dysfunction is believed to contribute to post-cardiopulmonary bypass (CPB)-induced microvascular bleeding. We hypothesised that moderately hypothermic CPB induces platelet dysfunction and that supplemental fibrinogen can restore in vitro thrombus formation. MethodsBlood from 18 patients, undergoing first-time elective isolated aortic valve surgery was drawn before CPB, 30 min after initiation of CPB, and after CPB and protamine administration, respectively. Platelet aggregation was quantified by optical aggregometry, platelet activation by flow-cytometric detection of platelet surface expression of P-selectin, annexin V, and activated glycoprotein IIb/IIIa, thrombus formation under flow and effect of supplemental fibrinogen (4 mg ml−1) on in vitro thrombogenesis. ResultsPost-CPB adenosine–diphosphate and TRAP-6-induced aggregation decreased by 40% and 10% of pre-CPB levels, respectively (P<0.0001). Although CPB did not change glycoprotein IIb/IIIa receptor expression, it increased the percentage of unstimulated P-selectin (1.2% vs 7%, P<0.01) positive cells and annexin V mean fluorescence intensity (15.5 vs 17.2, P<0.05), but decreased percentage of stimulated P-selectin (52% vs 26%, P<0.01) positive cells and annexin V mean fluorescence intensity (508 vs 325, P<0.05). Thrombus area decreased from 6820 before CPB to 5230 after CPB (P<0.05, arbitrary units [a.u.]). Supplemental fibrinogen increased thrombus formation to 20 324 and 11 367 a.u. before CPB and after CPB, respectively (P<0.001), thereby restoring post-CPB thrombus area to levels comparable with or higher than pre-CPB baseline. ConclusionsSingle valve surgery using moderately hypothermic CPB induces partial platelet dysfunction. Thrombus formation was restored in an experimental study design by ex vivo supplementation of fibrinogen.

The Use of Extracorporeal Circulation to Facilitate the Resection of a Large Retroperitoneal Sarcoma With Major Vessel Involvement: A Single-Center Review of 20 Cases

To describe the introduction of extracorporeal corporeal oxygenation (ECMO) to facilitate the surgical resection of large retroperitoneal sarcomas involving major vessels and to report preliminary outcomes. A case series. At a tertiary university hospital and state sarcoma center. Patients undergoing retroperitoneal sarcoma resection requiring inferior vena cava (IVC) reconstruction between June 2018 and March 2022. ECMO for retroperitoneal tumor resection requiring IVC reconstruction. A total of 20 patients underwent ECMO-assisted retroperitoneal sarcoma resection and IVC reconstruction. The median age was 60.5 years (IQR 48-69); 15 women and 5 men. The median procedure and ECMO durations were 10.8 hours (IQR 8.5-12.4 hours) and 2.2 hours (IQR 62-218 minutes), respectively. The median intensive care unit and hospital lengths of stay were 4 days (IQR 3-5 days) and 21 days (IQR 14-31 days), respectively. All 20 patients received packed cell transfusions (median 8 per patient [IQR 4-14]); 11 patients required fresh frozen plasma, 6 required platelets, and 11 required fibrinogen supplementation. One patient required recombinant activated factor VII. Sixteen patients experienced acute kidney injury, with 12 patients progressing to chronic kidney disease. Three patients were required to return to the operating room within 7 days, with no returns within the first 24 hours. There was no in-hospital or 30-day mortality. Survival at 3 years was 84%. ECMO for resecting large retroperitoneal tumor resection was introduced successfully and facilitated satisfactory outcomes for many patients who might otherwise have been considered too high risk.

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

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). 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. 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 (>10ml/kg) and consequently a need of cryoprecipitate transfusion. 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?

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. 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. 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. 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. Therapeutic/Care Management; Level III.

Platelet dysfunction after trauma: From mechanisms to targeted treatment.

Platelet dysfunction after trauma: From mechanisms to targeted treatment.

Which injured patients with moderate fibrinogen deficit need fibrinogen supplementation?

BackgroundIn severely injured patients, fibrinogen supplementation is recommended when fibrinogenemia is < 1.5 g L−1, but some teams have suggested to use higher thresholds (fibrinogenemia < 2.0 g L−1 or FIBTEM clot amplitude at 5 min (A5) values < 11 mm). The goal of this study was to specify in patients with a moderate fibrinogen deficit (MFD) whether some admission characteristics would be associated with fibrinogen administration at 24 h.MethodsProspective analysis of retrospectively collected data from a trauma registry (01/2011–12/2019). MFD-C was defined by a fibrinogenemia 1.51–1.99 g L−1 or the corresponding FIBTEM-A5 values (MFD-A5) that were determined from linear regression and ROC curve analysis. Administration of fibrinogen were described according to the following admission parameters: shock index (SI) > 1, hemoglobin level < 110 g L−1 (HemoCue®), and base deficit > 5 mEq L−1. Data are expressed as count (%), median [IQR].Results1076 patients were included in the study and 266 (27%) had MFD-C, among them, 122/266 (46%) received fibrinogen. Patients with MFD-C who received fibrinogen were more severely injured (ISS: 27 [19–36] vs. 24 [17–29]) and had more impaired vital signs (base deficit: 5.4 [3.6–7.8] vs. 3.8 [2.0–6.0]). Linear regression analysis found a positive correlation between fibrinogen level and FIBTEM-A5 (r: 0.805). For a fibrinogen level < 1.5 g L−1 and < 2.0 g L−1, FIBTEM-A5 thresholds were 6 mm (sensitivity 85%, specificity 83%, AUC: 0.934) and 9 mm (sensitivity 84%, specificity 69%, AUC: 0.874), respectively. MFD-A5 values (185 (27%) patients) were defined as a FIBTEM-A5 between 7 and 9 mm. More than 50% of MFD-C patients presenting a SI > 1, a hemoglobin level < 110 g L−1, or a base deficit > 5.0 mEq L−1 received fibrinogen. The relative risk [95% CI] for fibrinogen administration (SI > 1) were 1.39 [1.06–1.82] for MFD-C, and 2.17 [1.48–3.19] for MFD-A5. Results were not modified after adjustment on the ISS.ConclusionsWe have shown in this study an association between shock parameters and fibrinogen administration. Further studies are needed to determine how these parameters may be used to guide fibrinogen administration in trauma patients with MFD.

Fibrinogen and Bleeding in Adult Cardiac Surgery: A Review of the Literature

Background: Fibrinogen is a substrate for blood clots formation. In cardiac surgery, a number of different mechanisms lead to a decrease in fibrinogen levels and consequent impaired haemostasis. Patients undergoing cardiac surgery are therefore frequently exposed to blood loss and allogeneic blood transfusion, which are risk factors associated with morbidity and mortality. Thus, particular efforts in fibrinogen management should be made to decrease bleeding and the need for blood transfusion. Therefore, fibrinogen remains an active focus of investigations from basic science to clinical practice. This review aims to summarise the latest evidence regarding the role of fibrinogen and current practices in fibrinogen management in adult cardiac surgery. Methods: The PubMed database was systematically searched for literature investigating the role and disorders of fibrinogen in cardiac surgery and diagnostic and therapeutic procedures related to fibrinogen deficiency aimed at reducing blood loss and transfusion requirements. Clinical trials and reviews from the last 10 years were included. Results: In total, 146 articles were analysed. Conclusion: The early diagnosis and treatment of fibrinogen deficiency is crucial in maintaining haemostasis in bleeding patients. Further studies are needed to better understand the association between fibrinogen levels, bleeding, and fibrinogen supplementation and their impacts on patient outcomes in different clinical settings.

Pathogen Reduced Cryoprecipitate and Fibrinogen Concentrate Have Delayed Resuscitation of Simulated Dilutional Coagulopathy in a Microfluidic Model of Bleeding When Compared to Cryoprecipitate

Impaired fibrinogen function, one component of trauma-associated coagulopathy, is highly associated with increased mortality in patients with severe traumatic bleeding. Fibrinogen replacement is crucial for improving outcomes in bleeding patients. The two most common clinically-used hemostatic adjuncts for fibrinogen supplementation are fibrinogen concentrates (FibCon) and cryoprecipitate (Cryo), yet which of these products provides better hemostatic resuscitation remains controversial. Where FibCon is predominantly a source of fibrinogen, Cryo contains additional factors which may enhance hemostatic efficacy, such as FVIII and FXIII (inherent to clot strength and fibrin crosslinking) and von Willebrand factor (VWF, important for platelet adhesion and aggregation). Cryo poses more logistical challenges than FibCon, as Cryo is a frozen product that requires thawing (20 minutes) prior to use, and has a shelf life of 4-6 hours post thaw. FibCon is lyophilized, and can be reconstituted and used within 10 minutes, but with a cost roughly 3 times that of Cryo, use of FibCon can be cost-prohibitive. Ultimately, in the setting of hemostatic resuscitation, every minute matters and each minute delay in blood product transfusion is associated with a 5% increase in mortality. Moreover, Cryo is associated with an increased risk of transfusion transmitted infection (TTI).Thus, there is a need for an immediately available and safe fibrinogen source for use in hemostatic resuscitation.Pathogen reduction (PR) of blood products renders any nucleic acid-containing source replication incompetent via crosslinking using psoralens and ultraviolet light. PR was recently adapted for use with cryoprecipitate, yielding a novel hemostatic adjunct - pathogen reduced cryoprecipitated fibrinogen complex, or PR-Cryo FC. We have previously shown PR-Cryo FC stored out to 10 days performs similarly to Cryo and FibCon in current standard assays used to assess hemostatic function. However, as primary hemostasis is dictated by physiologically relevant flow conditions, we wanted to determine if PR of cryoprecipitate altered its hemostatic function during resuscitation of dilutional coagulopathy using a microfluidic model of hemorrhage.Healthy human whole blood (WB), Cryo, FibCon, and PR-Cryo FC were stained with fluorescent antibodies specific for VWF, CD41, fibrinogen, and FXIII. Stained WB was diluted 3:7 in 0.9% NaCl to induce dilutional coagulopathy (dWB). dWB was resuscitated 1:5 with stained adjuncts (Cryo:dWB, FibCon:dWB, or PR-Cryo FC:dWB) and perfused at three different shear rates (150, 500, 3500 1/s) through a microfluidic model of hemorrhage (a lumen that “bleeds” through an injury site into a collagen/tissue factor-coated extravascular space). Occlusion of the injury site was defined as the point at which clot formation sealed the injury site for > 3 minutes. The time from initial perfusion to occlusion was defined as the bleeding time (BT, seconds). If no seal was formed, the assay was stopped at 20 minutes, and the assay given a BT of 1200 seconds. Real-time phase and fluorescent images of the injury site were acquired. Data was extracted from real-time phase and fluorescent images using MATLAB.Both FibCon:dWB and PR-Cryo FC:dWB had significantly increased BT compared to Cryo:dWB at low shear (150 1/s). PR-Cryo FC:dWB had significantly increased BT compared to Cryo:dWB at medium shear (500 1/s), and at high shear (3500 1/s) there were no significant differences in BT between hemostatic adjuncts. However, kinetic analysis at high shear revealed there was a significant delay in clot formation and accumulation in the injury site, such that by 5 minutes, Cryo:dWB had filled 75% of the injury site and FibCon:dWB and PR-Cryo FC:dWB had only filled 50% of the injury site. Real-time fluorescent image analysis showed that both FibCon:dWB and PR-Cryo FC:dWB had reduced VWF deposition at the injury site compared to Cryo:dWB, and this led to a delays in platelet recruitment. FibCon has less VWF than Cryo, which would explain the delayed VWF deposition and platelet recruitment. In contrast, PR-Cryo FC and Cryo have similar amounts of VWF, suggesting that VWF from PR-Cryo FC has limited binding to the collagen-coated injury site, and as PR-Cryo FC:dWB phenocopies FibCon:dWB during clot formation at high shear, this suggests that pathogen reduction of Cryo may impair early VWF mediated capture of platelets at high shear. DisclosuresSpinella: Secure Transfusion Services: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cerus Corporation: Consultancy, Research Funding.

Fibrinogen Replacement in Haemostatic Resuscitation: Dose, Laboratory Targets and Product Choice.

Fibrinogen is a key coagulation protein that is necessary for the formation of stable clots. Fibrinogen levels have been reported to be one of the first to fall during major haemorrhage reflecting consumption, dilution and fibrinogenolysis. Its role in acquired major haemorrhage, both in relation to the contribution it plays to the coagulopathy of major bleeding that can exacerbate bleeding and how effective fibrinogen supplementation can be at improving clinical outcomes, has received a great deal of attention over the last 10 - 15 years. This commentary focuses on just three of the more recent publications from the last 5 years that provide some of the evidence behind how we can think about fibrinogen as a haemostatic treatment for acquired major haemorrhage and how we can use the laboratory thresholds to guide therapy.

First-Line Administration of Fibrinogen Concentrate in the Bleeding Trauma Patient: Searching for Effective Dosages and Optimal Post-Treatment Levels Limiting Massive Transfusion-Further Results of the RETIC Study.

Fibrinogen supplementation is recommended for treatment of severe trauma hemorrhage. However, required dosages and aimed for post-treatment fibrinogen levels remain a matter of discussion. Within the published RETIC study, adult patients suffering trauma-induced coagulopathy were randomly assigned to receive fibrinogen concentrate (FC) as first-line (n = 50) or crossover rescue (n = 20) therapy. Depending on bodyweight, a single dose of 3, 4, 5, or 6 g FC was administered and repeated if necessary (FibA10 < 9 mm). The dose-dependent response (changes in plasma fibrinogen and FibA10) was analyzed. Receiver operating characteristics (ROC) analysis regarding the need for massive transfusion and correlation analyses regarding fibrinogen concentrations and polymerization were performed. Median FC single doses amounted to 62.5 (57 to 66.66) mg·kg−1. One FC single-dose sufficiently corrected fibrinogen and FibA10 (median fibrinogen 213 mg·dL−1, median FibA10 11 mm) only in patients with baseline fibrinogen above 100 mg·dL−1 and FibA10 above 5 mm, repeated dosing was required in patients with lower baseline fibrinogen/FibA10. Fibrinogen increased by 83 or 107 mg·dL−1 and FibA10 by 4 or 4.5 mm after single or double dose of FC, respectively. ROC curve analysis revealed post-treatment fibrinogen levels under 204.5 mg·dL−1 to predict the need for massive transfusion (AUC 0.652; specificity: 0.667; sensitivity: 0.688). Baseline fibrinogen/FibA10 levels should be considered for FC dosing as only sufficiently corrected post-treatment levels limit transfusion requirements.

How I treat dysfibrinogenemia

AbstractCongenital dysfibrinogenemia (CD) is caused by structural changes in fibrinogen that modify its function. Diagnosis is based on discrepancy between decreased fibrinogen activity and normal fibrinogen antigen levels and is confirmed by genetic testing. CD is caused by monoallelic mutations in fibrinogen genes that lead to clinically heterogenous disorders. Most patients with CD are asymptomatic at the time of diagnosis, but the clinical course may be complicated by a tendency toward bleeding and/or thrombosis. Patients with a thrombosis-related fibrinogen variant are particularly at risk, and, in such patients, long-term anticoagulation should be considered. Management of surgery and pregnancy raise important and difficult issues. The mainstay of CD treatment remains fibrinogen supplementation. Antifibrinolytic agents are part of the treatment in some specific clinical settings. In this article, we discuss 5 clinical scenarios to highlight common clinical challenges. We detail our approach to establishing a diagnosis of CD and discuss strategies for the management of bleeding, thrombosis, surgery, and pregnancy.

Pediatric Fibrinogen PART II-Overview of Indications for Fibrinogen Use in Critically Ill Children.

Bleeding is frequently seen in critically ill children and is associated with increased morbidity and mortality. Fibrinogen is an essential coagulation factor for hemostasis and hypofibrinogenemia is an important risk factor for bleeding in pediatric and adult settings. Cryoprecipitate and fibrinogen concentrate are often given to critically ill children to prevent bleeding and improve fibrinogen levels, especially in the setting of surgery, trauma, leukemia, disseminated intravascular coagulopathy, and liver failure. The theoretical benefit of fibrinogen supplementation to treat hypofibrinogenemia appears obvious, yet the evidence to support fibrinogen supplementation in children is sparce and clinical indications are poorly defined. In addition, it is unknown what the optimal fibrinogen replacement product is in children and neonates or what the targets of treatment should be. As a result, there is considerable variability in practice. In this article we will review the current pediatric and applicable adult literature with regard to the use of fibrinogen replacement in different pediatric critical care contexts. We will discuss the clinical indications for fibrinogen supplementation in critically ill children and the evidence to support their use. We summarize by highlighting current knowledge gaps and areas for future research.