A case of anaphylactic shock to human fibrinogen infusion during cardiac surgery.

Human fibrinogen (FIB) has been clinically proven to be considerably effective for the treatment of postoperative bleeding, with reported cases of allergic reactions to human FIB being rare. Here, we report a case of an anaphylactic shock in 27-year-old patients with rheumatic heart valve disease who received a human FIB infusion during mitral valve replacement, aortic valve replacement, and tricuspid valve-shaping surgery. The patients showed generalised profuse sweating, a barely noticeable skin rash, faint pulse, systolic pressure < 50 mmHg, and a heart rate of 71 beats/min. We share insights from a case of severe allergy to human FIB infusion during cardiac surgery, through which we have gained experience in the processes of diagnosing and treating. This report aims to provide a preliminary summary of the characteristics of this case to serve as a reference for fellow clinicians.

Budd-Chiari syndrome associated with congenital afibrinogenaemia reversed after orthotopic liver transplant.

A woman in her mid-20s, a known case of congenital afibrinogenaemia, presented with abdominal pain and distension. She was diagnosed with decompensated liver cirrhosis due to Budd-Chiari syndrome. She underwent deceased donor liver transplantation. Preoperatively, her serum fibrinogen level was undetectable and prothrombin time and international normalised ratio (INR) were unrecordable. Intraoperatively, she was given thromboelastography-guided human fibrinogen concentrate. Postoperatively, her fibrinogen, prothrombin time and INR normalised rapidly. This report summarises the rare occurrence of a complication of hypercoagulability (Budd-Chiari syndrome) in the setting of congenital hypocoagulability (congenital afibrinogenaemia). In this report, we discuss the simultaneous management of these two clinical problems and the curative role of liver transplantation.

How do I implement pathogen reduced Cryoprecipitated fibrinogen complex in a tertiary Hospital's blood Bank.

BACKGROUND: Kaiser-Permanente Los Angeles Medical Center (LAMC) is a 560 licensed bed facility that provides regional cardiovascular services, including 1200 open heart surgeries annually. In 2021, LAMC explored alternative therapies to offset the impact of pandemic-driven cryo AHF shortages, and implemented Pathogen Reduced Cryoprecipitated Fibrinogen Complex (also known as INTERCEPT Fibrinogen Complex or IFC). IFC is approved to treat and control bleeding associated with fibrinogen deficiency. Unlike cryo AHF, IFC has 5-day post-thaw shelf life with potential operational and clinical benefits. The implementation steps and the operational advantages to the LAMC Blood Bank are described. STUDY DESIGN AND METHODS: Eighteen months post-implementation, the institution reviewed their product implementation experience and compared IFC with cryo AHF with a retrospective review of transfusion service and cardiac post-op data. RESULTS: IFC significantly decreased product wastage rates and order-to-issue time. It did not significantly impact post-op product utilization or hospital length of stay (LOS) in cardiac surgery patients when compared with cryo AHF. DISCUSSION: Implementation of IFC provides improved product supply stability, shorter turnaround times, and reduced wastage.

Diaphragm reconstruction using a TachoSil patch as alternative to intrasellar packing for small focal diaphragm defects in pituitary surgery: a cohort study.

BACKGROUND: During pituitary surgery, CSF leaks are often treated by intrasellar packing, using muscle or fat grafts. However, this strategy may interfere with the interpretation of postoperative MRI and may impact the quality of resection in cases of second surgery, due to the existence of additional fibrous tissue. We present an alternative technique, using a diaphragm reconstruction with a heterologous sponge combining fibrinogen and thrombin (TachoSil), applied in selected patients with low-flow CSF leaks. This study investigates the surgical outcome of patients treated with this strategy. METHODS: From a cohort of 2231 patients treated from June 2011 to June 2023 by endoscopic endonasal approach for pituitary surgery, the surgical technique of diaphragm repair with TachoSil patch performed in 55 patients (2.6%) was detailed, and the rate of closure failure was analyzed at 6 months postoperatively. No intrasellar packing was used and sellar floor reconstruction was performed whenever possible. The rate of postoperative CSF leak was compared with that reported in three previous publications that also used the TachoSil patch technique. RESULTS: Patients were mostly women (F/M ratio: 1.2) with a median age of 53.6 years. Surgery was indicated for non-functioning adenomas, Cushing's disease, acromegaly, and Rathke's cleft cysts in 38/55 (69.1%), 6/55 (10.9%), 5/55 (9.1%) and 6/55 (10.9%) patients respectively. The rate of postoperative CSF leak was 1.8% (n = 1/55), which was not significantly different from that reported in the three cohorts from the literature (2.8%, p > 0.05). No postoperative meningitis was recorded. CONCLUSIONS: In highly selected patients with low-flow CSF leaks related to small focal diaphragm defects, diaphragm reconstruction using a TachoSil patch can be a safe and valuable alternative to intrasellar packing.

Early viscoelastometric guided fibrinogen replacement combined with escalation of clinical care reduces progression in postpartum haemorrhage: a comparison of outcomes from two prospective observational studies.

BACKGROUND: Viscoelastometric haemostatic assays (VHA) give rapid information on coagulation status, allowing individualised resuscitation. METHODS: This paper compares outcomes from two observational studies of postpartum haemorrhage (PPH) in the same institution, before and after practice changed from fixed ratio empirical transfusion of coagulation products with laboratory coagulation testing to VHA-guided fibrinogen replacement incorporated into an enhanced PPH care bundle. In both studies, all blood samples were taken near 1000 mL qualitative blood loss (QBL). In Study One, QBL started once PPH was identified, and resuscitation with coagulation blood products was empirical or based on laboratory tests of coagulation. In Study Two, QBL started at delivery and VHA was used to guide fibrinogen replacement if FIBTEM A5 was <12 mm (Claus fibrinogen ≤2 g/L) or to withhold coagulation products if FIBTEM A5 was >12 mm. RESULTS: Improved PPH outcomes were observed in Study Two, with rates of measured blood loss ≥2500 mL, ≥4 units red blood cell (RBC) transfusion, fresh frozen plasma transfusion and ≥8 units of any blood product transfusion all reduced (P < 0.01). Clinically significant improvements occurred in women with fibrinogen ≤2 g/L at study entry, where the proportion of women who received ≥4 units RBC transfusion fell from 67% in Study One to 0% in Study Two (P = 0.0007). CONCLUSIONS: These results suggest that use of VHA as part of an early bundle of PPH care targeting fibrinogen ≤2 g/L with fibrinogen concentrate reduces PPH progression. The greatest benefit was seen when fibrinogen levels were ≤2 g/L at first testing.

Bleeding Reversal With Antifibrinolytics or Cryoprecipitate Following Thrombolysis for Acute Ischemic Stroke: A Case Series.

Patients who develop an intracerebral hemorrhage (ICH) following thrombolysis in acute ischemic stroke (AIS) have a mortality rate as high as 50%. Treatment options include blood products, such as cryoprecipitate, or antifibrinolytics, such as tranexamic acid (TXA) or ε-aminocaproic acid (EACA). Current guidelines recommend cryoprecipitate first-line despite limited data to support one agent over another. In addition, compared to antifibrinolytics, cryoprecipitate is higher in cost and requires thawing before use. This case series seeks to characterize the management of thrombolytic reversal at a single institution as well as provide additional evidence for antifibrinolytics in this setting. Patients were included for a retrospective review if they met the following criteria: presented between January 2011-January 2017, were >18 years of age, were admitted for AIS, received a thrombolytic, and received TXA EACA, or cryoprecipitate. Twelve patients met the inclusion criteria. Ten (83.3%) developed an ICH, one (8.3%) experienced gastrointestinal bleeding, and one (8.3%) had bleeding at the site of knee arthroscopy. Eleven patients received cryoprecipitate (median dose: 10 units), three received TXA (median dose: 1,000 mg), and one patient received EACA (13 g). TXA was administered faster than the first blood product at a mean time of 19 min and 137 min, respectively. Hemorrhagic expansion (N = 8, 66.67%) and inhospital mortality (N = 7, 58.3%) were high. While limited by its small sample size, this case series demonstrates significant variability in reversal strategies for thrombolysis-associated bleeding. It also provides additional evidence for the role of antifibrinolytics in this setting.

Long-Term Safety Analysis of a Fibrinogen Concentrate (RiaSTAP®/Haemocomplettan® P).

Fibrinogen concentrate treatment is recommended for acute bleeding episodes in adult and pediatric patients with congenital and acquired fibrinogen deficiency. Previous studies have reported a low risk of thromboembolic events (TEEs) with fibrinogen concentrate use; however, the post-treatment TEE risk remains a concern. A retrospective evaluation of RiaSTAP®/Haemocomplettan® P (CSL Behring, Marburg, Germany) post-marketing data was performed (January 1986-June 2022), complemented by a literature review of published studies. Approximately 7.45 million grams of fibrinogen concentrate was administered during the review period. Adverse drug reactions (ADRs) were reported in 337 patients, and 81 (24.0%) of these patients experienced possible TEEs, including 14/81 (17.3%) who experienced fatal outcomes. Risk factors and the administration of other coagulation products existed in most cases, providing alternative explanations. The literature review identified 52 high-ranking studies with fibrinogen concentrate across various clinical areas, including 26 randomized controlled trials. Overall, a higher number of comparative studies showed lower rates of ADRs and/or TEEs in the fibrinogen group versus the comparison group(s) compared with those that reported higher rates or no differences between groups. Post-marketing data and clinical studies demonstrate a low rate of ADRs, including TEEs, with fibrinogen concentrate treatment. These findings suggest a favorable safety profile of fibrinogen concentrate, placing it among the first-line treatments effective for managing intraoperative hemostatic bleeding.

Anti-infectious and anti-inflammatory effect of amniopatch in the treatment of spontaneous previable rupture of membranes.

Spontaneous previable rupture of membranes complicates approximately 0.4-0.7% of pregnancies and is associated with severe maternal and neonatal morbidity and mortality. Intra-amniotic inflammation is present in up to 94.4% of cases, most often caused by a bacterial infection. In comparison, the effectiveness of antibiotic therapy in its eradication reaches less than 17%. Inflammatory activity in the amniotic cavity disrupts the physiological development of the fetus with an increase in maternal, fetal, and neonatal inflammatory morbidity through the development of fetal inflammatory response syndrome, maternal chorioamnionitis, and neonatal sepsis. Amniopatch is an invasive therapeutic technique based on intra-amniotic administration of maternal hemoderivates in the form of thromboconcentrate and plasma cryoprecipitate to provide the temporary closure of the fetal membranes defect and secondary restitution of normohydramnios with correction of pressure-volume ratios. The supposed basis of this physical-mechanical action is the aggregation of coagulant components of amniopatch in the area of the defect with the formation of a valve cap. The background for the formulation of the hypothesis on the potential anti-infectious and anti-inflammatory action of non-coagulant components of amniopatch involved: i) clinical-academic and publishing outputs of the authors based on their many years' experience with amniopatch application in the treatment of spontaneous previable rupture of membranes (2008-2019), ii) the documented absence of clinically manifested chorioamnionitis in patients treated this way with a simultaneously reduced incidence of neonatal respiratory distress syndrome compared to expectant management (tocolysis, corticotherapy, antibiotic therapy). The non-coagulant components of plasma cryoprecipitate include mainly naturally occurring isohemagglutinins, albumin, and soluble plasma fibrinogen. Although these components of the amniopatch have not been attributed a significant therapeutic role, the authors assume that due to their opsonizing and aggregative properties, they can significantly participate in optimizing the intrauterine environment through the reduction in bacterial and cytokine charge in the amniotic fluid. The authors think these facts constitute a vital stimulus to future research-academic activity and, at the same time, an idea for reconsidering the therapeutic role of amniopatch as a tool for improving perinatal results of spontaneous previable ruptures of membranes.

Investigation of the appropriate viscosity of fibrinogen in repairing pleural defects using ventilation and anchoring in an ex vivo pig model.

OBJECTIVE: Our previous study revealed that the viscosity of fibrinogen could influence the effectiveness of ventilation and anchoring (V/A) methods for controlling air leakages. Here, we examined the association between the viscosity of fibrinogen and effectiveness using an ex vivo pig model. METHODS: The fibrin glue used in this study was BOLHEAL® (KM Biologics Co., Ltd., Kumamoto, Japan). We prepared three types of fibrinogen with different viscosities (higher and lower than normal), including one without additives. Using an ex vivo pig model, a pleural defect was made, and the defect was repaired using three different viscosities of fibrinogen through the V/A method. We measured the rupture pressure at the repair site (N = 10) and histologically evaluated the depth of fibrin infiltration into the lung parenchyma at the repair sites. RESULTS: The median rupture pressure was 51.5 (40-73) cmH2O in Group 1 (lower viscosity), 47.0 (47-88) cmH2O in Group 2 (no change in viscosity), and 35.5 (25-61) cmH2O in Group 3 (higher viscosity). There was no statistically significant difference between Groups 1 and 2 (p = 0.819), but the rupture pressure was significantly higher in Group 2 than in Group 3 (p = 0.0136). Histological evaluation revealed deep infiltration of fibrin into the lung parenchyma in Groups 1 and 2, but no such infiltration was observed in the higher-viscosity group. CONCLUSIONS: The results of this experiment suggested that the V/A method using fibrin glue containing low-viscosity fibrinogen was more effective in controlling air leakage due to pleural defects.

Changes in use and outcomes after fibrinogen concentrate insurance coverage for critical obstetrical hemorrhage: a nationwide questionnaire survey in Japan.

Fibrinogen concentrate (FC) for acquired hypofibrinogenemia associated with critical obstetrical hemorrhage (COH) was covered by public medical insurance in September 2021 in Japan. We aimed to investigate changes in the policy of FC use and its effect on COH after insurance coverage. A primary survey covering September 2020 to August 2021 and a secondary survey covering September 2021 to August 2022 were conducted at 428 higher-level medical facilities. We investigated the policy of FC use in transfusion strategy and the maternal outcomes in COH. Among the hospitals that responded to both surveys, the number of facilities that use FC increased from 51.5 (101/196) to 78.6% (154/196) (P < 0.0001). The number of COH cases treated using FC increased from 14.3 to 24.3% (P < 0.0001) and that transfused with ≥ 10 units of red blood cells (RBCs) decreased from 36.8 to 29.8% (P = 0.001). The incidence of pulmonary edema reduced by 3.7-2.0% (P = 0.021), and transfusion-induced allergy by 1.9-0.7% (P = 0.008). No changes were observed in the incidence of thromboembolism, arterial embolization, or hysterectomy. The increased use of FC after insurance coverage led to changes in the transfusion strategy, which may be associated with decreases in transfusions of RBCs, pulmonary edema, and transfusion-induced allergies.

Rare bleeding disorders: Advances in management.

Inherited factor coagulation deficiencies and vascular bleeding disorders, associated with bleeding of various severity, are often classified as rare bleeding disorders (RBDs). These include inherited fibrinogen disorders, inherited platelet function disorders (IPFD) and hereditary haemorrhagic telangiectasia (HHT). In the last decades, there have been large increases in knowledge on the epidemiology, genetics, physiopathology, clinical features, and diagnosis of RBDs, but improvements in management have been more limited and remain challenging. The treatment mainstay of RBDs is based only on replacement of a few available coagulation factor concentrates or cryoprecipitates. There is growing interest in therapeutic agents that enhance coagulation or inhibiting anticoagulant pathways in RBDs. In severe IPFD, the optimal platelet transfusion strategy is not yet established. Moreover, data is scarce on the effectiveness and safety of desmopressin and/or antifibrinolytic drugs often used for milder IPFD treatment. The best fibrinogen replacement strategy (prophylaxis vs. on demand) in afibrinogenemia is still debated. Similarly, the optimal trough fibrinogen target level for treatment of acute bleeding, and the role of fibrinogen replacement during pregnancy in mild hypofibrinogenemia and dysfibrinogenemia, have not been properly evaluated. The therapeutic arsenal in HHT includes antifibrinolytics and a series of antiangiogenic agents whose potential efficacy has been tested in small studies or are under investigation for treatment of bleeding. However, there is need to address several issues, including the optimal dosing strategies, the potential emergent toxicity of longer-term use, and the impact of systemic antiangiogenic treatment on visceral arteriovenous malformations.

In silico study of combination thrombolytic therapy with alteplase and mutant pro-urokinase for fibrinolysis in ischemic stroke.

The synergistic advantage of combining tissue plasminogen activator (tPA) with pro-urokinase (proUK) for thrombolysis has been demonstrated in several in vitro experiments, and a single site proUK mutant (m-proUK) has been developed for better stability in plasma. Based on these studies, combination thrombolytic therapy with intravenous tPA and m-proUK has been suggested as a promising treatment for patients with ischemic stroke. This paper evaluates the efficacy and safety of the dual therapy by computational simulations of pharmacokinetics and pharmacodynamics coupled with a local fibrinolysis model. Seven dose regimens are simulated and compared with the standard intravenous tPA monotherapy. Our simulation results provide more insights into the complementary reaction mechanisms of tPA and m-proUK during clot lysis and demonstrate that the dual therapy can achieve a similar recanalization time (about 50 min) to tPA monotherapy, while keeping the circulating fibrinogen level within a normal range. Specifically, our results show that for all dual therapies with a 5 mg tPA bolus, the plasma concentration of fibrinogen remains stable at around 7.5 µM after a slow depletion over 50 min, whereas a rapid depletion of circulating fibrinogen (to 5 µM) is observed with the standard tPA therapy, indicating the potential advantage of dual therapy in reducing the risk of intracranial hemorrhage. Through simulations of varying dose combinations, it has been found that increasing tPA bolus can significantly affect fibrinogen level but only moderately improves recanalization time. Conversely, m-proUK doses and infusion duration exhibit a mild impact on fibrinogen level but significantly affect recanalization time. Therefore, future optimization of dose regimen should focus on limiting the tPA bolus while adjusting m-proUK dosage and infusion rate. Such adjustments could potentially maximize the therapeutic advantages of this combination therapy for ischemic stroke treatment.

Altered fibrin clot properties are associated with the progression of chronic kidney disease in atrial fibrillation.

INTRODUCTION: Formation of denser and resistant to lysis fibrin clot networks has been shown in chronic kidney disease (CKD) and atrial fibrillation (AF). We investigated whether such prothrombotic fibrin clot properties are associated with faster progression of CKD in AF patients. MATERIAL AND METHODS: We recruited 265 AF patients (men 49.1 %, median age of 64.0 years, median estimated glomerular filtration rate [eGFR] of 77.0 ml/min/1.73 m2), including 137 patients on non-vitamin K antagonist oral anticoagulants (NOACs) (51.7 %) and 109 patients (41.1 %) on vitamin K antagonists (VKAs). At baseline while off anticoagulation, we determined fibrin clot permeability (Ks), and clot lysis time (CLT), along with plasminogen activator inhibitor-1 (PAI-1), endogenous thrombin potential (ETP), and von Willebrand factor (vWF). The kidney function was assessed at baseline and after a median follow-up of 50.0 months. RESULTS: During follow-up, a median eGFR decreased by 8.0 (5.0-11.0) ml/min/1.73 m2, 1.8 ml/min/1.73 m2/year and this change correlated with age (R = 0.19, P = 0.002), Ks (R = 0.46, P < 0.0001), and CLT (R = -0.17, P = 0.005), but not ETP, fibrinogen, PAI-1 or vWF. A decrease in eGFR was lower in patients who used NOACs at baseline but not in those who started NOACs during follow-up (n = 101) as compared to the remaining patients. On multiple linear regression analysis, adjusted for age and fibrinogen, baseline Ks, eGFR, hypertension, and NOACs use independently predicted a decrease in eGFR. CONCLUSIONS: This study is the first to show that more compact fibrin clot networks may contribute to faster progression of CKD in AF, indicating novel kidney-related harmful effects of prothrombotic clot properties in humans.

Recurrence of macular edema in patients with branch retinal vein occlusion: a proteomic study.

BACKGROUND: Branch retinal vein occlusion (BRVO) is a common retinal vascular disease leading to severe vision loss and blindness. This study aimed to investigate and reveal the pathophysiological mechanisms underlying macular edema (ME) recurrence in patients with BRVO through a proteomic approach. METHODS: We detected proteins in the aqueous humor of 14 untreated, four refractory, and four post-operative patients with BRVO-ME and 12 age-matched cataract controls using four-dimensional label-free proteomic and bioinformatics analyses. RESULTS: In total, 84 proteins exhibited significant differential expression between the BRVO and control samples (fold change [FC] ≥ 1.2 and adjusted p-value < 0.05). Compared to the control group, 43 and 41 proteins were upregulated and downregulated, respectively, in the BRVO group. These proteins were involved in cell adhesion, visual perception, retina homeostasis, and platelet activation. Several significantly enriched signaling pathways included complement and coagulation cascades and platelet activation. In the protein-protein interaction networks generated using the search tool for retrieval of interacting genes (STRING), the fibrinogen alpha chain and fibrinogen beta chain constituted a tightly connected cluster. Many common protein expression trends, such as the fibrinogen alpha chain and fibrinogen beta chain, were observed in both the recurrent and refractory groups. Differentially expressed proteins in the two groups were involved in complement activation, acute-phase response, platelet activation, and platelet aggregation. Important signaling pathways include the complement and coagulation cascades, and platelet activation. Protein-protein interaction analysis suggested that the fibrinogen alpha chain and fibrinogen beta chain constituted a tightly connected cluster. The expression of some differentially expressed proteins shared by the BRVO and the recurrent and refractory groups was reversed in the post-operative group. CONCLUSIONS: Our study is the first to analyze the proteomics of recurrent, refractory, and post-operative groups treated for BRVO-ME, and may potentially provide novel therapeutic interventions for the recurrence of ME.

Management of pregnancy and delivery in congenital fibrinogen disorders: communication from the ISTH SSC Subcommittee on Factor XIII and Fibrinogen.

Congenital fibrinogen disorders (CFDs) are a heterogeneous group of rare congenital quantitative and/or qualitative fibrinogen deficiencies. The spectrum of molecular anomalies is broad, leading to several subtypes of fibrinogen disorders (ie, afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia). Pregnancy in women with CFDs is a high-risk clinical situation, with an increased tendency for miscarriages, bleeding, and thrombosis. Even though it is well established that management of such pregnancies requires a multidisciplinary approach involving specialists (hematologists and maternal/fetal medicine experts with expertise in the management of inherited bleeding disorders), specific guidelines are lacking. In this International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee communication, we aim to propose an expert consensus opinion with literature evidence where available on the strategy for management of pregnancy, delivery, and puerperium in CFDs.

Empiric Cryoprecipitate Transfusion in Patients with Severe Hemorrhage: Results from the US Experience in the International CRYOSTAT-2 Trial.

BACKGROUND: Hypofibrinogenemia has been shown to predict massive transfusion and is associated with higher mortality in severely injured patients. However, the role of empiric fibrinogen replacement in bleeding trauma patients remains controversial. We sought to determine the effect of empiric cryoprecipitate as an adjunct to a balanced transfusion strategy (1:1:1). STUDY DESIGN: This study is a subanalysis of patients treated at the single US trauma center in a multicenter randomized controlled trial. Trauma patients (more than 15 years) were eligible if they had evidence of active hemorrhage requiring emergent surgery or interventional radiology, massive transfusion protocol (MTP) activation, and received at least 1 unit of blood. Transfer patients, those with injuries incompatible with life, or those injured more than 3 hours earlier were excluded. Patients were randomized to standard MTP (STANDARD) or MTP plus 3 pools of cryoprecipitate (CRYO). Primary outcomes included all-cause mortality at 28 days. Secondary outcomes were transfusion requirements, intraoperative and postoperative coagulation laboratory values, and quality-of-life measures (Glasgow outcome score-extended). RESULTS: Forty-nine patients (23 in the CRYO group and 26 in the STANDARD group) were enrolled between May 2021 and October 2021. Time to randomization was similar between groups (14 vs 24 minutes, p = 0.676). Median time to cryoprecipitate was 41 minutes (interquartile range 37 to 48). There were no differences in demographics, arrival physiology, laboratory values, or injury severity. Intraoperative and ICU thrombelastography values, including functional fibrinogen, were similar between groups. There was no benefit to CRYO with respect to post-emergency department transfusions (intraoperative and ICU through 24 hours), complications, Glasgow outcome score, or mortality. CONCLUSIONS: In this study of severely injured, bleeding trauma patients, empiric cryoprecipitate did not improve survival or reduce transfusion requirements. Cryoprecipitate should continue as an "on-demand" addition to a balanced transfusion strategy, guided by laboratory values and should not be given empirically.

Effect of Preoperative Therapeutic Plasma Exchange With Albumin Replacement Before Kidney Transplant on Intraoperative Coagulation Measured By the Thrombelastograph (TEGR 6s): A Case Report.

Anesthesiologists should be aware of the coagulation implications of therapeutic plasma exchange (TPE) with albumin replacement for desensitization of kidney transplant (KT) recipients. We describe a case where the final preoperative TPE was performed with albumin. A TEGR 6s demonstrated defects in fibrinogen component to clot strength. With surgical oozing noted and the fibrinogen defect, cryoprecipitate was administered. Thereafter, fibrinogen contribution to clot strength normalized, coinciding with clinical hemostasis. With the increased use of TPE to reduce antibodies in KT recipients, visco-elastic testing may assist in the identification of coagulation defects when plasma is not used as replacement fluid.

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.

Uso de concentrados de fibrinógeno para el tratamiento de la hipofibrinogenemia adquirida / Use of Fibrinogen Concentrates for the Treatment of Acquired Hypofibrinogenemia

Resumen Introducción: Un adecuado manejo del sangrado debe incluir la correcta valoración y eventual reposición de fibrinógeno. Las fuentes tradicionales de este elemento hemostático incluyen el plasma fresco congelado y los crioprecipitados. Los concentrados liofilizados de fibrinógeno humano (CFH) son una alternativa terapéutica novedosa en el mercado chileno. Objetivo: Este estudio describe el curso clínico de los primeros pacientes en nuestra institución requirentes de CFH, dentro de un algoritmo de reposición hemostática por metas. Materiales y Método: Serie de pacientes con hipofibrinogenemia secundaria a sangrado perioperatorio severo, en los que se utilizó CFH como método de reposición de fibrinógeno. Se utilizó tromboelastometría para definir dosis. Se registraron variables demográficas, operatorias, complicaciones y seguimiento hasta los 3 meses. Resultados: Se utilizaron CFH en 18 pacientes. La mediana de edad fue 40,7 (56,5-63) años y dos tercios de los pacientes fueron de sexo masculino. Fallecieron 5 pacientes de la serie. Todos los pacientes requirieron manejo posoperatorio en una unidad de cuidados intensivos. Ocho pacientes fueron sometidos a cirugía cardiaca. El uso de hemocomponentes y concentrados liofilizados fue heterogéneo, pero en todos los casos su uso fue determinado por tromboelastometría. Ningún paciente fue reintervenido a causa de sangrado posoperatorio. Conclusión: El uso de concentrados de fibrinógeno humano dentro de un algoritmo de manejo de sangrado guiado por tromboelastometría, es un recurso hemostático factible en la realidad nacional. El impacto clínico de esta intervención requiere una subsiguiente evaluación basada en la evidencia.

Introduction: An adequate bleeding management should include a proper assessment of fibrinogen values and consequent replacement. Traditional sources for this hemostatic element include fresh frozen plasma and cryoprecipitates. Lyophilized human fibrinogen concentrates are a novel therapeutic alternative for the chilean market. Aim: This study aims to describe the clinical course of the first patients in our institution receiving fibrinogen concentrates, included in a goal directed hemostatic management algorithm. Materials and Method: Case series of patients with hypofibrinogenemia secondary to severe perioperative bleeding, in which fibrinogen concentrate was used for fibrinogen replacement. Thromboelastometry was used to define dose regimens. Demographic and surgical variables, complications and follow-up up to 3 months were registered. Results: Fibrinogen concentrate was used in 18 patients. Median age was 40.7 (56.5-63) years, and two thirds of the patients were male. Five patients died. All of the cases required postoperative intensive care. Eight patients underwent cardiac surgery. There was a heterogenic use of blood derived products and lyophilized concentrates, but in all cases its use was guided by thromboelastometry. No patients needed a secondary exploration due to bleeding. Conclusion: The use of human fibrinogen concentrate included in a bleeding management algorithm is a feasible hemostatic resource in the chilean current situation. The clinical impact of this intervention requires further evidence-based evaluation.