Major hemorrhage is a source of significant mortality and morbidity worldwide. Identification and characterization of coagulation impairment associated with major hemorrhage has suggested a key role ...for fibrinogen deficiency, however the optimum mode of replacement of fibrinogen remains unclear, and standardized major hemorrhage protocols may overlook context-dependent variations in individual patients' clotting derangement. Areas covered: This paper examines the current practice and evidence regarding the role of different modes of fibrinogen replacement in major hemorrhage in 3 distinct clinical settings: trauma, obstetric hemorrhage, and gastrointestinal hemorrhage with associated liver disease. A literature search was carried out electronically using Athens access to the National Health Service evidence health information resources, primarily PubMed and Google Scholar. Expert commentary: Two key questions need to be addressed. First, what is the role of concentrated fibrinogen (by comparison to no fibrinogen), and second, which concentrated source or product is more effective (or cost-effective)? Current practice and concept is derived largely from small pilot trials in the trauma setting, but results from larger studies are awaited. More comparative data on changes to clotting profiles in different groups of bleeding patients are needed to help delineate differences and guide interventional treatment studies.
Background
Some hospital patients may be at risk of or may present with major bleeding. Abnormalities of clotting (coagulation) are often recorded in these people, and the traditional management has ...been with transfusions of blood components, either to prevent bleeding (prophylactic) or to treat bleeding (therapeutic). There is growing interest in the use of targeted therapies with specific pro‐coagulant haemostatic (causing bleeding to stop and to keep blood within a damaged blood vessel) factor concentrates in place of plasma.
Objectives
To assess the effects and safety of pro‐coagulant haemostatic factors and factor concentrates in the prevention and treatment of bleeding in people without haemophilia.
Search methods
We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (2018, issue 3), MEDLINE (from 1948), Embase (from 1974), CINAHL (from 1938), PubMed (publications in process to 18 April 2018), PROSPERO, Transfusion Evidence Library (from 1950), LILACS (from 1980), IndMED (from 1985), KoreaMed (from 1934), Web of Science Conference Proceedings Citation Index (from 1990) and ongoing trial databases to 18 April 2018.
Selection criteria
We included RCTs that compared intravenous administration of a pro‐coagulant haemostatic factor concentrate, either with placebo, current best or standard treatment, or another pro‐coagulant haemostatic factor concentrate for prevention or treatment of bleeding. There was no restriction on the types of participants. We excluded studies of desmopressin, tranexamic acid and aminocaproic acid and use of pro‐coagulant haemostatic factors for vitamin K over‐anticoagulation.
Data collection and analysis
We followed standard Cochrane methodological procedures.
Main results
We identified 31 RCTs with 2392 participants and 22 ongoing trials. There were 13 therapeutic RCTs that randomised 1057 participants (range from 20 to 249 participants) and 18 prophylactic trials that randomised 1335 participants (range 20 to 479 participants). The pro‐coagulant haemostatic factor concentrate was fibrinogen in 23 trials, Factor XIII in seven trials and pro‐thrombin complex concentrates (PCC) in one trial.
Seventeen trials had industrial funding or support, eight studies either did not declare their funding or were unclear about their source of funding and six studies declared non‐industrial funding sources.
Certainty in the evidence and included study bias
Our certainty in the evidence, using GRADE criteria, ranged from very low to high across all outcomes. We assessed most outcomes as being of low certainty. Risks of bias were a concern in many of the RCTs; randomisation methodology was unclear in 15 RCTs, with allocation concealment unclear in 14 RCTs and at high risk of bias in five RCTs. The blinding status of outcome assessors was unclear in 13 RCTs and at high risk of bias in five RCTs, although most outcomes in these trials were objective and not prone to observer bias. Study personnel were often unblinded or insufficient information was available to assess their level of blinding (five RCTs were at unclear risk and seven at high risk of bias).
Primary outcomes
All‐cause mortality was reported by 21 RCTs, arterial thromboembolic events by 22 RCTs, and venous thromboembolic events by 21 RCTs.
Fibrinogen concentrate: prophylactic trials with inactive comparator (nine RCTs)
The trials had heterogeneous clinical settings and outcome time points, so we did not pool the data. Compared to placebo, there was no evidence that prophylactic fibrinogen concentrate reduced all‐cause mortality (4 RCTs; 248 participants). Compared to inactive comparators there was low‐ to moderate‐quality evidence that prophylactic fibrinogen concentrate did not increase the risk of arterial or venous thromboembolic complications (7 RCTs; 398 participants).
Fibrinogen concentrate: prophylactic trials with active comparator (two RCTs)
There was no mortality or incidence of thromboembolic events in these two RCTs (with 57 participants).
Fibrinogen concentrate: therapeutic trials with inactive comparator (eight RCTs)
The trials had heterogeneous surgical settings and outcome time points, so we pooled data for subgroups only. Compared to an inactive comparator, there was no evidence (quality ranging from low to high) that fibrinogen concentrate reduced all‐cause mortality in actively bleeding participants (7 RCTs; 724 participants). Compared to inactive comparators there was no evidence that the use of fibrinogen concentrate in active bleeding increased arterial (7 RCTs; 607 participants) or venous (6 RCTs; 562 participants) thromboembolic events.
Fibrinogen concentrate: therapeutic trials with active comparator (four RCTs)
We did not pool the outcome data, as they were not measured at comparable time points. Compared to other active pro‐coagulant agents, there was no evidence (very low to moderate quality) that fibrinogen concentrate reduced all‐cause mortality in actively bleeding participants (4 RCTs; 220 participants). There was no evidence that fibrinogen concentrate increased the risk of arterial (3 RCTs; 126 participants) or venous (4 RCTs; 220 participants) thromboembolic events.
FactorXIII: Prophylactic trials with inactive comparator (six trials)
The trials were heterogeneous in their surgical settings and time points for outcome analysis, so we pooled data for subgroups only. Compared to an inactive comparator, there was no evidence that prophylactic Factor XIII reduced all‐cause mortality (5 RCTs; 414 participants). There was no evidence (very low to low quality) of a difference in the arterial or venous event rate between Factor XIII and inactive comparators (4 trials; 354 participants).
FactorXIII: therapeutic trials with inactive comparator (one trial)
There was no mortality or incidence of thromboembolic events in this trial.
Prothrombin complex concentrate (PCC): prophylactic trials with inactive comparator (one trial)
There was no evidence (moderate quality) that PCC reduced all‐cause mortality (1 trial; 78 participants). No thromboembolic complications were reported in this trial.
Authors' conclusions
The paucity of good‐quality comparable evidence precludes the drawing of conclusions for clinical practice. Further research is required to determine the risk‐to‐benefit ratio of these interventions. The sample sizes of future RCTs would need to be greatly increased to detect a reduction in mortality or thromboembolic events between treatment arms. To improve consistency in outcome reporting, the development of core outcome sets is essential and may help address a number of the limitations identified in this review.
Fibrinogen in traumatic haemorrhage Winearls, James; Reade, Michael C; McQuilten, Zoe ...
Current opinion in anaesthesiology,
2021-Aug-01, Volume:
34, Issue:
4
Journal Article
Recent advances in the understanding of the pathophysiological processes associated with traumatic haemorrhage and trauma-induced coagulopathy (TIC) have resulted in improved outcomes for seriously ...injured trauma patients. However, a significant number of trauma patients still die from haemorrhage. This article reviews the role of fibrinogen in normal haemostasis, the effect of trauma and TIC on fibrinogen levels and current evidence for fibrinogen replacement in the management of traumatic haemorrhage.
Fibrinogen is usually the first factor to reach critically low levels in traumatic haemorrhage and hypofibrinogenaemia after severe trauma is associated with increased risk of massive transfusion and death. It is postulated that the early replacement of fibrinogen in severely injured trauma patients can improve outcomes. There is, however, a paucity of evidence to support this, and in addition, there is little evidence to support or refute the effects of cryoprecipitate or fibrinogen concentrate for fibrinogen replacement.
The important role fibrinogen plays in haemostasis and effective clot formation is clear. A number of pilot trials have investigated different strategies for fibrinogen replacement in severe trauma. These trials have formed the basis of several large-scale phase III trials, which, cumulatively will provide a firm evidence base to harmonise worldwide clinical management of severely injured trauma patients with major haemorrhage.
Although COVID-19 has been reported to be associated with high rates of venous thromboembolism (VTE), the risk of VTE and bleeding after hospitalization for COVID-19 remains unclear, and the optimal ...hospital VTE prevention strategy is not known. We collected retrospective observational data on thrombosis and bleeding in 303 consecutive adult patients admitted to the hospital for at least 24 hours for COVID-19. Patients presenting with VTE on admission were excluded. Data were collected until 90 days after admission or known death by using medical records and an established national VTE network. Maximal level of care was ward based in 78% of patients, with 22% requiring higher dependency care (12% noninvasive ventilation, 10% invasive ventilation). Almost all patients (97.0%) received standard thromboprophylaxis or were already receiving therapeutic anticoagulation (17.5%). Symptomatic image-confirmed VTE occurred in 5.9% of patients during index hospitalization, and in 7.2% at 90 days after admission (23.9% in patients requiring higher dependency care); half the events were isolated segmental or subsegmental defects on lung imaging. Bleeding occurred in 13 patients (4.3%) during index hospitalization (1.3% had major bleeding). The majority of bleeds occurred in patients on the general ward, and 6 patients were receiving treatment-dose anticoagulation, highlighting the need for caution in intensifying standard thromboprophylaxis strategies. Of 152 patients discharged from the hospital without an indication for anticoagulation, 97% did not receive thromboprophylaxis after discharge, and 3% received 7 days of treatment with low molecular weight heparin after discharge. The rate of symptomatic VTE in this group at 42 days after discharge was 2.6%, highlighting the need for large prospective randomized controlled trials of extended thromboprophylaxis after discharge in COVID-19.
•The rate of symptomatic VTE in patients after hospitalization for COVID-19 was 2.6% at 42 days after discharge.•Bleeding is a significant cause of morbidity in addition to thrombosis in patients admitted with COVID-19.
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The widespread use of the antifibrinolytic agent, tranexamic acid (TXA), interferes with the quantification of fibrinolysis by dynamic laboratory assays such as clot lysis, making it difficult to ...measure fibrinolysis in many trauma patients. At the final stage of coagulation, factor (F)XIIIa catalyzes the formation of fibrin–fibrin and fibrin–α2-antiplasmin (α2AP) cross-links, which increases clot mechanical strength and resistance to fibrinolysis.
Here, we developed a method to quantify fibrin–fibrin and fibrin–α2AP cross-links that avoids the challenges posed by TXA in determining fibrinolytic resistance in conventional assays.
Fibrinogen alpha (FGA) chain (FGA–FGA), fibrinogen gamma (FGG) chain (FGG–FGG), and FGA–α2AP cross-links were quantified using liquid chromatography–mass spectrometry (LC–MS) and parallel reaction monitoring in paired plasma samples from trauma patients prefibrinogen and postfibrinogen replacement. Differences in the abundance of cross-links in trauma patients receiving cryoprecipitate (cryo) or fibrinogen concentrate (Fg-C) were analyzed.
The abundance of cross-links was significantly increased in trauma patients postcryo, but not Fg-C transfusion (P < .0001). The abundance of cross-links was positively correlated with the toughness of individual fibrin fibers, the peak thrombin concentration, and FXIII antigen (P < .05).
We have developed a novel method that allows us to quantify fibrin cross-links in trauma patients who have received TXA, providing an indirect measure of fibrinolytic resistance. Using this novel approach, we have avoided the effect of TXA and shown that cryo increases fibrin–fibrin and fibrin–α2AP cross-linking when compared with Fg-C, highlighting the importance of FXIII in clot formation and stability in trauma patients.
Background
N8‐GP (turoctocog alfa pegol; Esperoct®, Novo Nordisk A/S, Bagsvaerd, Denmark) is a glycoPEGylated human recombinant factor VIII with a half‐life of ~1.6‐fold of standard FVIII products. ...pathfinder2 (NCT01480180) was a multi‐national, open‐label trial of N8‐GP in previously treated adolescent and adult patients with severe hemophilia A.
Objective
We report end‐of‐trial efficacy and safety of N8‐GP from pathfinder2.
Methods
pathfinder2 main phase and extension phase part 1 results have been previously reported. During extension phase part 2, patients could switch from N8‐GP prophylaxis 50 IU/kg every fourth day (Q4D) or 75 IU/kg once weekly (Q7D), depending on bleeding status. Extension phase part 2 collected long‐term safety and efficacy data for all regimens until trial end (first patient in main phase, 30 January 2012; trial end, 10 December 2018).
Results
Overall, 186 patients were exposed to N8‐GP for up to 6.6 years (median 5.4 years). The estimated annualized bleeding rate (ABR) was 2.14 (median 0.84) for the Q4D prophylaxis arm and 1.31 (median 1.67) for the Q7D prophylaxis arm. Nearly 30% of patients experienced zero bleeds throughout the entire duration of the trial, the hemostatic response was 83.2% across all treatment arms, and patient‐reported outcomes were maintained or slightly improved. No safety concerns were detected.
Conclusion
Data from the completed pathfinder2 trial, one of the largest and longest‐running clinical trials to investigate treatment of severe hemophilia A, demonstrate the efficacy and safety of N8‐GP in previously treated adolescent and adult patients.
In many patients referred with significant bleeding phenotype, laboratory testing fails to define any hemostatic abnormalities. Clinical practice with respect to diagnosis and management of this ...patient cohort poses significant clinical challenges. We recommend that bleeding history in these patients should be objectively assessed using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool. Patients with increased bleeding assessment tool scores should progress to hemostasis laboratory testing. To diagnose bleeding disorder of unknown cause (BDUC), normal complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen, von Willebrand factor function, coagulation factors VIII, IX, and XI, and platelet light transmission aggregometry should be the minimum laboratory assessment. In some laboratories, additional specialized hemostasis testing may be performed to identify other rare causes of bleeding. We recommend that patients with a significant bleeding phenotype but normal laboratory investigations should be registered with a diagnosis of BDUC in preference to other terminology. Global hemostatic tests and markers of fibrinolysis demonstrate variable abnormalities, and their clinical significance remains uncertain. Targeted genomic sequencing examining candidate hemostatic genes has a low diagnostic yield. Underlying BDUC should be considered in patients with heavy menstrual bleeding since delays in diagnosis often extend to many years and negatively impact quality of life. Treatment options for BDUC patients include tranexamic acid, desmopressin, and platelet transfusions.
Background: There is currently a lack of formal training in leadership skills, particularly during GP training. This study aimed to explore the current training and practical opportunities which ...exist, specifically exploring the views of GP trainees and trainers. Methods: An electronic questionnaire was sent to 266 GP trainees and trainers in south-east Scotland. Questions focused on respondents' experience of leadership-specific training and opportunities to engage with leadership roles. Results: There were a total of 76 respondents (28.6% response rate). Response rate was 19.0% in trainees and 34.6% in trainers. A majority of respondents (80.0%) were established GPs. Of those who had received training in leadership, most (72.1%) underwent this after qualifying as a GP. Respondents identified a range of leadership roles within and outside the practice covering clinical and non-clinical areas. Most were interested in future leadership roles (46.7% moderately interested; 28% very interested). More time, training opportunities and the presence of GP role models were motivating factors in terms of participants' readiness to take on future leadership roles. Conclusions: Signposting trainees, trainers and general practitioners to leadership opportunities and training would be relatively easy but addressing a lack of motivating factors at a local level is essential. The effectiveness of such training and opportunities for experiential learning in leadership roles requires further research.
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