Fibrinogen Replacement Therapy Research Articles

Physiopathology and treatment of critical bleeding: a literature review

Objectivesto develop the different factors involved in the physiopathology of trauma-induced coagulopathy, through a review of publications on the matter; as well as to assess the evidence available on the treatment of critical bleeding and the recommendations by clinical practice guidelines. Methodsa search has been conducted on the bibliography published about the physiopathology and treatment of critical bleeding in the PUBMED, BestPractice, UpToDate databases and the Cochrane Plus Library. The main key words used for this search were “early trauma induced coagulopathy”, “mechanisms of early trauma-induced coagulopathy”, “blood transfusion guidelines”, “massive transfusion guidelines” and “fibrinogen replacement therapy”. The most clinically relevant articles were selected for this review. Conclusionsthe physiopathology of the trauma-induced coagulopathy is a more complex matter and involves more factors than was initially assumed. The early treatment of the coa-gulopathy is critical for the initial management of the critical bleeding. However, the use of blood derivatives should be rational and based on homogeneous and high-quality scientific evidence.The main cornerstones for the treatment of critical bleeding are: fluid therapy, fibrinogen concentrate, prothrombin complex concentrate, plasma, erythrocyte or platelet concentrates, tranexamic acid, and calcium. Their administration should be assessed depending on the clinical condition of each patient.

Basic Principles of Rotational Thromboelastometry (ROTEM®) and the Role of ROTEM-Guided Fibrinogen Replacement Therapy in the Management of Coagulopathies.

Rotational thromboelastometry (ROTEM) is a viscoelastic method, which provides a graphical and numerical representation of induced hemostasis in whole blood samples. Its ability to quickly assess the state of hemostasis is used in the management of bleeding from a variety of causes. The separate activation of particular parts of hemocoagulation in INTEM, EXTEM, and FIBTEM tests allows for a more comprehensive and faster evaluation of the missing component of hemostasis followed by targeted therapy. One of the most common cause of coagulopathy is trauma-induced coagulopathy. Fibrinogen replacement therapy by ROTEM allows for the use of a standard dosage of fibrinogen, which has been shown to be successful in preventing dilutional coagulopathy following colloid and crystalloid replacement and excessive amount of allogeneic blood transfusions. The best reflection of fibrinogen activity is observed in the FIBTEM assay, where fibrinogen replacement therapy is recommended at an MCF (maximum clot firmness) of FIBTEM < 10 mm and FIBTEM A10 < 7 mm. ROTEM also plays an important role in the diagnostic and management of inherited fibrinogen disorders. These can be manifested by bleeding complications, where changes in the MCF parameter are the most useful tool for assessing the effectiveness of fibrinogen replacement therapy. ROTEM-guided bleeding management algorithms effectively reduce the number of transfusions, healthcare costs, and complications, leading to the improvement of patient safety and overall health.

Real-World Experience with a Human Fibrinogen Concentrate: Clinical Data from Adult and Pediatric Patients Requiring Fibrinogen for Bleeding Control and Prevention.

Human fibrinogen concentrate (Fibryga) received temporary approval for fibrinogen replacement therapy in France (2017), with subsequent full approval for congenital and acquired hypofibrinogenemia. We evaluated real-world use for on-demand treatment of bleeding and prophylaxis to enhance our knowledge on fibrinogen concentrate as an option for fibrinogen replacement. Data were retrospectively collected from adult and pediatric patients with fibrinogen deficiency. The primary end point was indication for fibrinogen concentrate use; the secondary end point was treatment success for on-demand treatment/perioperative prophylaxis. The study included 150 adult (median age, 62years; range, 18-94years) and 50 pediatric (median age, 3years; range, 0.01-17years) patients with acquired fibrinogen deficiency. Fibrinogen concentrate was administered to 47.3% for nonsurgical bleeding, 22.7% for surgical bleeding, and 30.0% for perioperative prophylaxis in adult patients, and to 4.0% for surgical bleeding and 96.0% for perioperative prophylaxis in pediatric patients. Cardiac surgeries accounted for 79.5%/75.0% perioperative prophylaxis and 82.4%/100.0% surgical bleeding cases in adult/pediatric patients, respectively. The mean±standard deviation (SD, median) total fibrinogen doses were 3.06±1.69g (32.61mg/kg), 2.09±1.36g (22.99mg/kg), and 2.36±1.25g (29.67mg/kg) for adult nonsurgical bleeding, surgical bleeding, and perioperative prophylaxis, respectively; doses of 0.75±0.35g (47.64mg/kg) and 0.83±0.62g (55.56mg/kg) were used for pediatric surgical bleeding and perioperative prophylaxis, respectively. Treatment success was 85.7%/97.1/93.3% in adults and 50.0%/87.5% in pediatrics for nonsurgical bleeding (adults only), surgical bleeding, and perioperative prophylaxis, respectively. Fibrinogen concentrate demonstrated favorable effectiveness and safety across the age groups. This study contributes to evidence supporting fibrinogen concentrate for bleeding control/prevention in real-world clinical practice, particularly for patients with acquired fibrinogen deficiency.

Effect of fibrinogen replacement therapy on bleeding outcomes and 1-year mortality in patients undergoing thoracic aortic surgery: a retrospective cohort study.

This study aimed to examine the effect of fibrinogen replacement therapy with cryoprecipitate or fibrinogen concentrate on bleeding outcomes and 1-year mortality in patients undergoing thoracic aortic surgery. We retrospectively studied 439 consecutive patients who underwent thoracic aortic surgery with cardiopulmonary bypass between January 1st, 2010 and December 31st, 2019 and identified patients who received cryoprecipitate or fibrinogen concentrate (the fibrinogen replacement group) and those who did not (the control group). Multivariate analyses were performed to examine the associations of fibrinogen replacement therapy with perioperative major bleeding (i.e., excessive hemorrhage or blood transfusion), re-exploration for bleeding, and 1-year mortality. There were 285 patients in the fibrinogen replacement group who received 2.2 ± 1.0g of concentrated fibrinogen amount and 154 patients in the control group. The incidence of major bleeding in the fibrinogen replacement group was less than that in the control group in patients with fibrinogen level < 150mg/dL during cardiopulmonary bypass (49.7% versus 74.6%, p = 0.0007, multivariate odds ratio; 0.33, 95% confidence intervals; 0.12-0.91, p = 0.03), but not in patients with fibrinogen level ≥ 150mg/dL (25.0% versus 29.6%, p = 0.51). No significant difference was found in re-exploration for bleeding (1.0% versus 1.3%, p = 1.00) or 1-year mortality (10.4% versus 5.3%, multivariate Cox proportional-hazard ratio; 1.03, 95% confidence intervals; 0.82-1.31, p = 0.74) between the fibrinogen replacement group and the control group. The results of this study indicate that 2-3g of fibrinogen replacement reduces the incidence of major bleeding in patients with hypofibrinogenemia during cardiopulmonary bypass in thoracic aortic surgery.

Kongenitalna afibrinogenemija kod novorođenčeta

Introduction: Congenital afibrinogenemia is a rare coagulation disorder characterized by a deficiency in the fibrinogen molecule. Fibrinogen is a hexameric glycoprotein consisting of a polypeptide chain encoded by FGB, FGA, and FGG and is required for normal hemostasis. Changes in FGA, FGB, and FGG may affect fibrinogen at different levels. As a result of these changes, fibrinogen cannot be detected in the blood. Clinical manifestations of such changes range from asymptomatic to life-threatening bleeding or thromboembolic events. Since it is an autosomal recessive disease, the risk is higher in children whose parents are related. Therefore, the disease is more common in regions where consanguineous marriage rates are high. Diagnosis is made by laboratory tests that show the absence of fibrinogen. These patients need to be treated with fibrinogen replacement therapy. Case presentation: This study reports the case of a newborn with congenital afibrinogenemia. The baby born from a first-degree consanguineous marriage was referred to our hospital due to bleeding and ecchymosis, and afibrinogenemia was diagnosed after coagulation tests were performed. Blood samples of the patient and his parents were sent to the Genetic Diseases Diagnosis Center for a genetic diagnosis of afibrinogenemia. A new homozygous mutation of FGB exon 7: c.1220c &gt; t (p.t407 m) (p.thr407 met) was identified in the patient. The patients' parents were heterozygous for the same mutation. Prophylaxis was not recommended for our patient who was asymptomatic in the follow-up. Conclusions: We present the case of a hemorrhagic neonatal patient diagnosed with congenital afibrinogenemia and emphasize that fibrinogen testing should be included in the evaluation of such patients. Furthermore, congenital fibrinogen disorders may be more severe when caused due to unknown specific mutation genes. Therefore, a more center-involved genetic analysis is required to identify undiagnosed fibrinogen and fibrinogen mutations.

Fibrinogen measurement by a novel point-of-care device with whole blood: comparison of values against Clauss method.

Timely fibrinogen replacement is key to treating critical hemorrhage. Measuring fibrinogen concentration by conventional laboratory tests requires centrifugation of blood samples and is often time-consuming. A point-of-care testing device (A&T, Yokohama, Japan), CG02N, has been available in Japan since 2011 to measure fibrinogen concentration without centrifugation. However, it has not been widely used as it requires dilution of blood samples using manual micropipetting. To further speed up and simplify the fibrinogen measurement, an improved device called FibCare (Atom Medical, Tokyo, Japan) was developed to avoid diluting blood samples. The purpose of this study is to verify the reliability of FibCare against laboratory measurement using the Clauss method. Fibrinogen concentrations with 60 sodium citrated whole blood samples were measured by both FibCare and Clauss methods in the laboratory. Measured values with the Clauss method were distributed in the 88-300mg/dL range. By comparing these results, a significant positive correlation was observed between the FibCare and Clauss method (Y = 12.402 + 0.982 X; R = 0.891; P < 0.01). The study indicated that FibCare allows accurate measurement of fibrinogen concentration and shows a possibility to contribute to optimal fibrinogen replacement therapy during critical hemorrhage.

Analysis of gene mutation spectrum and pharmacokinetics of fibrinogen infusion in 146 cases of congenital fibrinogen disorders

目的探讨先天性纤维蛋白原病的基因突变类型与分型、临床表现、实验室检查、诊断及纤维蛋白原替代治疗情况。方法对2003年4月至2020年11月就诊于中国医学科学院血液病医院的146例先天性纤维蛋白原病患者进行回顾性分析。结果146例患者中，男61例（41.8％），女85例（58.2％），就诊时中位年龄为33.5岁；共采集到98例患者的临床症状学信息，34例（34.7％）因出血症状而就诊，33例（33.7％）因手术前检查而确诊，55例（56.1％）患者至少有1次出血，42例（42.9％）无出血表现。纤维蛋白原活性（FIB∶C）与ISTH-BAT出血评分之间呈负相关（rs＝−0.412，P<0.001）。在56例患者中检出34种基因突变（包括新突变16种），其中84.1％为错义突变，FGA外显子2和FGG外显子8突变占全部突变位点的71.4％。无纤维蛋白原血症患者（7例）中位年龄为2（1～12）岁，ISTH-BAT评分为4分；异常纤维蛋白原血症患者（50例）中位凝血酶时间为28.5（19.2～36.6）s。输注纤维蛋白原后1 h、24 h的活性回收率（IVR）分别为（127.19±44.03）％、（101.78±43.98）％。输注纤维蛋白原后，FIB∶C明显提升，凝血酶时间及凝血酶原时间明显下降，用药24 h后凝血酶时间较基线平均下降（15.2±12.1）％。结论多数先天性纤维蛋白原缺乏症患者症状轻微或无症状；无纤维蛋白原血症患者出血症状较为严重，FIB∶C与出血程度之间存在负相关；基因检测有助于疾病分型诊断；FIB∶C/纤维蛋白原抗原（FIB∶Ag）比值<0.7可作为临床分型依据。凝血酶时间可作为异常纤维蛋白原血症诊断及纤维蛋白原替代治疗的疗效判定依据。

Role of fibrinogen concentrates for treatment of critical perioperative hemorrhage.

Acquired hypofibrinogenemia is a frequent cause of maintained bleeding in perioperative high-risk settings. Loss, consumption and dilution under resuscitation fluid therapy are the principal causes for fibrinogen depletion. Severe hypofibrinogenemia is frequently associated with an early bleeding complication that cannot be reliably avoided with high-ratio plasma transfusion strategies. Real-time monitoring with viscoelastic hemostatic assays is a useful tool for timely diagnosis and treatment of detected coagulopathies. Replenishment of fibrinogen in uncontrolled bleeding events is currently recommended by most published guidelines, suggesting treatment thresholds to maintain a minimum of 1.5 g/L plasma fibrinogen concentration for nonobstetrical hemorrhage. Fibrinogen concentrates, originally licensed for treatment of bleeding episodes in patients with congenital hypo-, dys- or afibrinogenemia disorders, are used in many clinical situations as supplementary therapy for the treatment of acquired hypofibrinogenemia. This review seeks to provide an overview of the most relevant topics associated to fibrinogen replacement therapy for critical perioperative hemorrhage highlighting currently available evidence on the risk/benefit profile of purified fibrinogen concentrates for this extended clinical indication.

Paper Diagnostic for Direct Measurement of Fibrinogen Concentration in Whole Blood.

The ability to diagnose and treat critically bleeding patients can save more than 2 million lives a year. Diagnosing hypofibrinogenemia is essential in these patients. Recently, with the development of new handheld diagnostics, fibrinogen concentration can be measured rapidly at the point of care. However, these diagnostics can only work with plasma and hence need blood cells to be separated before use. In this study, we demonstrate a handheld fibrinogen diagnostic that works with whole blood. The test works by (1) forming a premixed droplet of a whole blood sample and thrombin solution on a solid surface, (2) allowing it to clot, and (3) dropping a paper strip on top. The further that blood moves down the strip, the lower the fibrinogen concentration. The diagnostic can easily measure plasma fibrinogen concentrations below 1.6 g/L for blood samples with hematocrits between 40 and 50%. Furthermore, diluting blood samples not only increases the test's sensitivity but also eliminates the effect of hematocrit and thrombin inhibitors. The test can be completed in 3-4 min, making it suitable for diagnosing early hypofibrinogenemia and allowing for fibrinogen replacement therapy in critically bleeding patients.

Early Use of Fibrinogen Replacement Therapy in Postpartum Hemorrhage-A Systematic Review.

Fibrinogen levels drop early in postpartum hemorrhage (PPH), and low fibrinogen levels predict outcomes. There is increasing interest in replacing fibrinogen early in severe PPH and this systematic review's aim was to assess if early fibrinogen replacement therapy improves outcomes in severe PPH. We searched the following databases from inception to June 2019: CDSR and CENTRAL (The Cochrane Library), MEDLINE, Embase, CINAHL, PubMed, Transfusion Evidence Library, LILACS, Web of Science Conference Proceedings Citation Index-Science, ClinicalTrials.gov and the WHO International Clinical Trials Registry Portal. We included randomized (RCT) and well-designed controlled observational studies where fibrinogen replacement therapy was given early (within 90 minutes of bleeding) compared with standard protocol in pregnant women > 24 weeks' gestation who developed PPH, defined as estimated blood loss ≥500 mL up to 24 hours post-delivery. Two independent reviewers extracted and reviewed the data on the primary outcome of allogeneic blood transfusion at 24 hours after intervention and secondary outcomes including all-cause mortality, rate of thrombosis, and the need for surgical and non-surgical interventions. We identified 5 eligible studies: 2 completed (total of 299 women) RCTs comparing fibrinogen concentrate with placebo, and 3 ongoing RCTs. There was no completed study assessing cryoprecipitate transfusion. There was variation of: timings of intervention administration; severity of PPH; fibrinogen doses and use of tranexamic acid. There was insufficient evidence that early administration of fibrinogen in PPH reduces the need for allogeneic blood transfusion at 24 hours (risk ratio 0.83 (95% CI 0.54-1.26), P = 0.38) (2 trials, 299 participants) or improves other outcomes. Both studies were underpowered to answer our outcomes. There is a lack of evidence that early fibrinogen replacement therapy improves outcomes in PPH. Future studies are needed to address this, underpinned by data on the optimal fibrinogen dose, protocol-driven approaches versus targeted therapy, and cost-effectiveness of cryoprecipitate versus fibrinogen concentrate therapy in PPH.

Rapid, hand-held paper diagnostic for measuring Fibrinogen Concentration in blood

Critical bleeding causes over 2 million deaths a year. Early hypofibrinogenemia is a strong predictor of mortality in critically bleeding patients. The early replenishment of fibrinogen can significantly improve outcomes. However, over replenishment can also be dangerous. Furthermore, there is no rapid, cheap, hand-held diagnostic that can aid critically bleeding patients in fibrinogen replacement therapy. In this study, we have developed a hand-held paper diagnostic that measures plasma fibrinogen concentrations. The diagnostic has the potential to be used as a point of care device both inside and outside of hospital settings. It can vastly reduce the time to treatment for fibrinogen replacement therapy. The diagnostic is a two-step process. First, thrombin and plasma are added onto horizontially-orientated paper strips where the fibrinogen is converted into fibrin, drastically increasing the plasma’s hydrophobicity. Second, an aqueous blue dye is pipetted onto the strips and allowed to wick through the fibrin. The distance the blue dye wicks through the strip correlates precisely to the fibrinogen concentration. The diagnostic can provide results within a minute. It can distinguish low fibrinogen concentrations (ie. <2 g/L) from normal fibrinogen concentrations. It shows remarkable reproducibility between healthy individuals. It is unaffected by common blood conditions such as acidosis, blood alcohol, severe hypertriglyceridemia, severe haemolysis and warfarin administration. Finally, it is unaffected by humidity and can withstand cold temperatures.

Obstetrical and postpartum complications in women with hereditary fibrinogen disorders: A systematic literature review

Hereditary fibrinogen disorders (HFD) are rare quantitative or qualitative fibrinogen anomalies, including afibrinogenaemia (A), hypofibrinogenaemia (H), dysfibrinogenaemia (D) and hypodysfibrinogenaemia (HD). As fibrinogen plays an essential role in pregnancy, we addressed the issue of obstetrical and postpartum complications in women with HFD. A systematic literature review, restricted to English manuscripts, was conducted according to the PRISMA guidelines. We searched through the MEDLINE database for English articles, published from January 1985 until November 2018, focusing on pregnancy in A, H, D and HD. A total of 198 articles were identified, 15 articles were added from other sources. Overall, 213 articles were screened and 54 were included in the final analysis. A total of 188 pregnancies from 70 women were analysed. About half of pregnancies resulted in miscarriage; more specifically in 15 (42.9%), 36 (46.8%), 27 (42.9%) and 4 (30.8%) of A, H, D and HD patients, respectively. Preterm complications were also frequent (33.5%). Metrorrhagia, mainly in the first trimester, was observed in 21.7% of the pregnancies. Placenta abruption was reported in 5 (14.3%), 4 (5.2%), 5 (7.9%) and 1 (7.7%) of A, H, D and HD, respectively. A total of 24 (12.7%) deliveries were complicated by postpartum thrombotic events (3.2%) or postpartum haemorrhage (9.6%). A fibrinogen replacement therapy was introduced in 30% of pregnancies, as prophylaxis (81.1%) or on demand (18.9%). These results suggest that women with HFD are at high risk of obstetrical and postpartum complications. Prospective international registries may allow to identify more precisely the incidence of obstetrical and postpartum adverse outcomes and their management.

Fibrinogen Concentrate Vs Cryoprecipitate in Pseudomyxoma Peritonei Surgery: Interim Results from a Prospective, Randomized, Controlled Phase 2 Study

Introduction: Pseudomyxoma peritonei (PMP) is a rare entity that usually results from a perforated primary appendiceal tumor. The established intervention for PMP is cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (Sugarbaker procedure). Acquired fibrinogen deficiency and clinically-relevant bleeding are common complications of this surgery; maintaining adequate plasma fibrinogen concentration during the procedure may help control hemostasis. We present data from the planned interim analysis of FORMA-05, a study comparing the hemostatic efficacy and safety of cryoprecipitate, the standard fibrinogen replacement therapy, with that of a new highly purified, double virus-inactivated human fibrinogen concentrate (Fibryga; Octapharma).Methods: FORMA-05 is a prospective, single center, randomized, controlled phase 2 study in patients with acquired fibrinogen deficiency undergoing cytoreductive surgery for PMP. The study aims to enroll up to 55 patients. Individuals who required intraoperative fibrinogen supplementation (predicted intraoperative blood loss ≥2 L without fibrinogen supplementation) were randomized to preemptively receive fibrinogen concentrate (Fibryga; 4 g) or cryoprecipitate (2 pools, 5 units each). Further doses of fibrinogen concentrate or cryoprecipitate up to 24 h postoperatively were to be administered if the thromboelastometry FIBTEM A20 parameter decreased to ≤12 mm. The primary endpoint was a composite of intraoperative efficacy (assessed by the surgeon and anesthesiologist at the end of surgery) and postoperative efficacy (assessed by the hematologist 24 h after the end of surgery), graded using an objective four-point scale and adjudicated by an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC).Results: This planned interim analysis included 23 patients in the per-protocol set, 10 who received fibrinogen concentrate and 13 who received cryoprecipitate. During surgery, a mean of 6.4 g (SD ±2.8) of fibrinogen concentrate (85±36 mg/kg bw) and 3.9 (SD ±1.7) pools of 5 units of cryoprecipitate were administered per patient, respectively. 100% of patients in both groups were adjudicated as having achieved ‘treatment success’, with 95% CIs of 69.2-100% for the fibrinogen concentrate group and 75.3-100% for the cryoprecipitate group. Intraoperative hemostatic efficacy, as assessed by the surgeon and anesthesiologist, was judged to be ‘excellent’ or ‘good’ for 90.0% of the patients who received fibrinogen concentrate and 76.9% of those who received cryoprecipitate (IDMEAC: 90.0% vs 61.5%). Postoperative hemostatic efficacy was deemed by the hematologist and IDMEAC to be ‘excellent’ for all 23 patients. Preemptive infusion was initiated 0.5 h earlier with fibrinogen concentrate than with cryoprecipitate (2.0 vs. 2.5 h; p<0.001). Overall, intraoperative fibrinogen concentrate administration led to a mean increase of 3.1 mm in FIBTEM A20 vs 0.6 mm with cryoprecipitate (p=0.0544). A significantly higher mean increase in fibrinogen concentration was obtained with administration of fibrinogen concentrate than with cryoprecipitate (0.7 g/L vs 0.3 g/L, respectively; p=0.0127).Intraoperative blood loss did not differ significantly between groups, with 1,291 mL (SD ±319) and 1,429 mL (SD ±486) for the fibrinogen concentrate and cryoprecipitate groups, respectively (p=0.446). A median of 1 unit of red blood cells was administered intraoperatively, with no units administered during the first 24 h postoperatively in each group. No transfusion of fresh frozen plasma or platelet concentrates was given. The occurrence of adverse events (AEs) appeared comparable between the two groups, with 29 in 10/11 patients (90.9%) in the fibrinogen concentrate group and 44 in 12/13 patients (92.3%) in the cryoprecipitate group. There were 2 serious AEs in the fibrinogen concentrate group, while there were 9 in the cryoprecipitate group (including 2 thromboembolic events [TEEs]). No AEs were assessed as related to study drug administration.Conclusions: In this interim analysis, fibrinogen concentrate was at least as efficacious as cryoprecipitate with no related AEs and no TEEs in the treatment of bleeding related to acquired fibrinogen deficiency in patients undergoing cytoreductive surgery for PMP. The latest data from the final analysis of this study will also be presented, which corroborate these findings. DisclosuresRoy:Octapharma AG: Other: Investigator fees. Solomon:Octapharma AG: Employment. Kruzhkova:Octapharma AG: Employment. Knaub:Octapharma AG: Employment. Mohamed:Octapharma AG: Other: Investigator fees.

Management of Major Obstetric Haemorrhage using ROTEM Point-of-Care Haemostasis Analysers Can Reduce Blood Product usage Without Increasing Fibrinogen Replacement Therapy

Major obstetric haemorrhage (MOH) is a leading cause of maternal death and morbidity, with the majority of deaths occurring within four hours of delivery. Therefore, prompt identification of women at risk of MOH is crucial for the rapid assessment and management of blood loss to urgently restore haemodynamic stability. Furthermore, as the rate of blood loss during MOH can increase rapidly in the time when laboratory results are awaited, the management of MOH could benefit from point-of-care coagulation testing by the ROTEM analyser which has a quicker turnaround time compared to standard laboratory coagulation tests. A number of studies indicate that ROTEM-based management of MOH has resulted in a significant reduction in massive transfusions and decreased transfusion of concentrated red cells (CRC) and fresh frozen plasma (FFP) due to a reduction in total blood loss. Several reports which have linked MOH to the depletion of fibrinogen reserves indicate that the reduction in CRC and FFP transfusions is largely due to an increase in early fibrinogen replacement therapy which corrects hypofibrinogenemia. This short report discusses preliminary findings on the impact of ROTEM point-of-care haemostasis analyser on the transfusion of various blood products to obstetric women experiencing MOH at the Royal Gwent Hospital in South wales. The number of blood products transfused following decisions based on the ROTEM analyser measurements (ROTEM group) was compared to historical transfusion data before the ROTEM analyser became available (Pre-ROTEM group). Blood product transfusion in the Pre-ROTEM group was guided by measurements of standard laboratory coagulation tests in conjunction with the established major haemorrhage protocols at the time. The findings indicate that the ROTEM analyser was effective in managing MOH at point-of-care and led to a reduction in the transfusion of CRC, FFP and platelets. However, contrary to published studies, the reduction in blood product usage was not accompanied by an increase in fibrinogen replacement transfusion therapy, suggesting that the ROTEM’s FIBTEM assay accurately quantified fibrinogen levels based on fibrin-clot firmness to enable an early diagnosis of hypofibrinogenemia. Early establishment of the absence of hypofibrinogenemia helped to prevent unnecessary transfusion of fibrinogen concentrate in this study. These findings support the adoption of routine use of ROTEM analysers at point-of-care on labour wards to manage MOH and reduce fibrinogen replacement therapy. The ease of use and rapidity of ROTEM tests could enable departure from globally directed correction of coagulopathy during MOH to a more focussed and precise target transfusion therapy, which will ultimately reduce blood product wastage (including fibrinogen concentrate) whilst minimising transfusion-associated side effects such as alloimmunisation, circulatory overload and dilutional coagulopathy.

Do we need cryoprecipitate in the era of fibrinogen concentrate and other specific factor replacement options?

Cryoprecipitate was first used in the 1960s as a source of factor VIII (FVIII) for the treatment of bleeding in haemophilia A. Although still used in some countries for this purpose, its main use now is as a concentrated source of fibrinogen, commonly administered as part of major haemorrhage therapy for patients with uncontrolled bleeding. Fibrinogen is recognized as the first clotting protein to fall to clinically significant low levels during major haemorrhage, and there has been a recent explosion of interest around the potential importance of fibrinogen replacement therapy in this setting. This has led many to question the relative benefits of cryoprecipitate as compared to fibrinogen concentrate. This review will explore whether cryoprecipitate, in the era of specific factor concentrates, is an outmoded treatment. Cryoprecipitate is manufactured from frozen plasma after controlled thawing. It is not only a rich source of FVIII and fibrinogen but also contains von Willebrand Factor (VWF), FXIII and fibronectin. In UK, cryoprecipitate is available as single donor units or as pools of 5 units and requires thawing before transfusion. Variability in clotting factor levels in blood donors means that the fibrinogen concentration in cryoprecipitate may vary. With the exception of donor screening and viral testing at the time of donation, no viral reduction steps are taken during manufacture. Fibrinogen concentrate is an alternative concentrated source of fibrinogen but is not licensed in every country for acquired bleeding. It is a plasma‐derived product manufactured from pooled plasma. Many view fibrinogen concentrate as a superior product to cryoprecipitate with reasons including: standardization of production–vials contain a known fibrinogen concentration; lyophilization making it easily portable and not requiring storage or thawing in blood bank; viral inactivation; a consideration for the UK is a likely lower risk for vCJD transmission. Gram for gram, fibrinogen concentrate is four times the cost of cryoprecipitate. The UK haemophilia centre doctors organisation (UKHCDO) recommends the use of single‐factor agents above pooled blood components for replacement therapy in inherited bleeding conditions, where possible, for many of these reasons. But what about cryoprecipitate as therapy for acquired bleeding where patients develop a complex coagulopathy affecting multiple coagulation and fibrinolytic factors? Might cryoprecipitate therapy confer an advantage? Theoretically, higher concentrations of VWF, FVIII and FXIII might promote more rapid primary and secondary haemostasis. Clinical efficacy for the two products in observational studies and one RCT has been reported to be similar, where increases in fibrinogen blood levels are comparable. However, no study has yet been large enough to look at comparative clinical efficacy or indeed safety. In the era of single‐factor concentrates, cryoprecipitate may seem outdated, but at present–in particular in relation to therapy for major haemorrhage–insufficient evidence is available which confirms or refutes it place in major haemorrhage therapy.

Thromboelastometry guided fibrinogen replacement therapy in cardiac surgery: a retrospective observational study

This retrospective, observational study compared the impact of a point-of-care rotational thromboelastometry (ROTEM®) method versus conventional bleeding management in terms of postoperative (24-h) blood loss, intraoperative and postoperative (24-h) transfusion requirement and length of stay in the postoperative intensive care unit (ICU) in patients undergoing cardiac surgery. Forty consecutive patients undergoing cardiac surgery under ROTEM®-guided hemostatic management were enrolled; the control population included 40 selected patients undergoing similar interventions without ROTEM® monitoring. Significantly more patients in the thromboelastometry group versus the control group received fibrinogen (45 vs 10%; p<0.0001), while fewer received a transfusion (40 vs 72.5%; p<0.0033). Compared with control group patients, those in the thromboelastometry group had less postoperative bleeding (285 vs 393mL; p<0.0001), a shorter time from cardiopulmonary bypass discontinuation to skin suture (79.3 vs 92.6min; p=0.0043) and a shorter stay in the ICU (43.7 vs 52.5h; p=0.0002). In our preliminary experience, ROTEM®-guided bleeding management was superior to conventional management of bleeding in patients undergoing complex cardiac surgery with cardiopulmonary bypass in terms of reduced postoperative blood loss, transfusion requirement, and length of ICU stay.

Hémorragie cérébrale fatale en cours d’induction d’une leucémie aiguë lymphoblastique

Intracerebral hemorrhage (ICH) remains a cause of death in hematologic malignancies. Asparaginase represents a key agent in the treatment of acute lymphoblastic leukemia (ALL). The toxicity of asparaginase includes coagulopathy such as thrombotic or bleeding tendency. We report a case of fatal cerebral hemorrhage in a 12-year-old girl treated for ALL. Cerebral hemorrhage occurred after three injections of L-asparaginase. The patient presented with hypofibrinogenemia (0.36g/L), associated with thrombocytopenia (24,000/mm3). Despite maximal medical and surgical treatment (platelets and fresh-frozen plasma transfusions, red blood cells transfusion, fibrinogen replacement therapy, and craniotomy discharge), the patient died. L-asparaginase is well known for its prothrombotic action. By inhibiting the synthesis of fibrinogen and factors V, VII, VIII, and IX, it causes an increased risk of bleeding, including intracranial bleeding. Predictive scores for ICH onset have been established but there is no consensus on the management of coagulation disorders induced by L-asparaginase. It is recommended to check fibrinogen and antithrombin (AT) blood values in order to substitute them if they drop to <1g/L for fibrinogen and <60% for AT. The management of asparaginase-induced ICH does not differ from that of ICH of other origin. The risk of death is high, and surgical treatment has not proven superior to medical therapy in terms of mortality rates and 6-month survival. Further studies are needed to define consensus guidelines for coagulation disorders induced by asparaginase and also to define the specific management in cases of ICH in childhood hematological malignancies.

Severe Thrombotic Complications in Congenital Afibrinogenemia: A Pathophysiological and Management Dilemma.

Congenital afibrinogenemia (CA) is a disease characterized by a complex pathophysiology, involving both the procoagulant and fibrinolytic systems, as well as platelet activity. Although hemorrhagic diathesis represents the most frequent clinical presentation of this disorder, severe thrombotic events can occur. It is not yet clear if these events are strictly related to the disease itself or to the fibrinogen replacement therapy. Different hypotheses on the pathophysiological mechanisms have been proposed. It is well known that fibrinogen/fibrin has a role in the downregulation of thrombin generation in plasma. In the absence of circulating fibrinogen, this "antithrombin" activity is missing and plasma thrombin levels rise; this excess of thrombin could promote clotting of the infused fibrinogen, initiating the thrombotic process. Furthermore, the observation of impaired plasmin generation in the plasma of CA patients has raised the hypothesis of a fibrinolytic system deficiency. We report the case of a CA male patient who at the age of 36 years experienced an arterial thrombosis in his left lower limb. Despite an aggressive medical treatment with low-molecular-weight heparin, fibrinolytic and antiplatelet agents, the arterial thrombosis progressed to the obstruction of the whole left arterial district and the patient underwent the amputation of the left lower limb. This case demonstrates the complexity of pathophysiology and clinical management of a "so-called" bleeding disorder as CA.

What Is the Biological and Clinical Relevance of Fibrin?

As our knowledge of the structure and functions of fibrinogen and fibrin has increased tremendously, several key findings have given some people a superficial impression that the biological and clinical significance of these clotting proteins may be less than earlier thought. Most strikingly, studies of fibrinogen knockout mice demonstrated that many of these mice survive to weaning and beyond, suggesting that fibrin(ogen) may not be entirely necessary. Humans with afibrinogenemia also survive. Furthermore, in recent years, the major emphasis in the treatment of arterial thrombosis has been on inhibition of platelets, rather than fibrin. In contrast to the initially apparent conclusions from these results, it has become increasingly clear that fibrin is essential for hemostasis; is a key factor in thrombosis; and plays an important biological role in infection, inflammation, immunology, and wound healing. In addition, fibrinogen replacement therapy has become a preferred, major treatment for severe bleeding in trauma and surgery. Finally, fibrin is a unique biomaterial and is used as a sealant or glue, a matrix for cells, a scaffold for tissue engineering, and a carrier and/or a vector for targeted drug delivery.

Clinical efficacy of fresh frozen plasma compared with coagulation factor concentrates for treating coagulopathy in patients with massive bleeding

Critical bleeding causes over 2 million deaths a year. Early hypofibrinogenemia is a strong predictor of mortality in critically bleeding patients. The early replenishment of fibrinogen can significantly improve outcomes. However, over replenishment can also be dangerous. Furthermore, there is no rapid, cheap, hand-held diagnostic that can aid critically bleeding patients in fibrinogen replacement therapy. In this study, we have developed a hand-held paper diagnostic that measures plasma fibrinogen concentrations. The diagnostic has the potential to be used as a point of care device both inside and outside of hospital settings. It can vastly reduce the time to treatment for fibrinogen replacement therapy. The diagnostic is a two-step process. First, thrombin and plasma are added onto horizontially-orientated paper strips where the fibrinogen is converted into fibrin, drastically increasing the plasma’s hydrophobicity. Second, an aqueous blue dye is pipetted onto the strips and allowed to wick through the fibrin. The distance the blue dye wicks through the strip correlates precisely to the fibrinogen concentration. The diagnostic can provide results within a minute. It can distinguish low fibrinogen concentrations (ie. <2 g/L) from normal fibrinogen concentrations. It shows remarkable reproducibility between healthy individuals. It is unaffected by common blood conditions such as acidosis, blood alcohol, severe hypertriglyceridemia, severe haemolysis and warfarin administration. Finally, it is unaffected by humidity and can withstand cold temperatures.