Bleeding diathesis after aortic valve operation and ascending aorta replacement (AV–AA) is managed with fresh-frozen plasma (FFP) and platelet concentrates. The aim was to compare haemostatic effects of conventional transfusion management and FIBTEM (thromboelastometry test)-guided fibrinogen concentrate administration.
A blood products transfusion algorithm was developed using retrospective data from 42 elective patients (Group A). Two units of platelet concentrate were transfused after cardiopulmonary bypass, followed by 4 u of FFP if bleeding persisted, if platelet count was ≤100×103 µl−1 when removing the aortic clamp, and vice versa if platelet count was >100×103 µl−1. The trigger for each therapy step was ≥60 g blood absorbed from the mediastinal wound area by dry swabs in 5 min. Assignment to two prospective groups was neither randomized nor blinded; Group B (n=5) was treated according to the algorithm, Group C (n=10) received fibrinogen concentrate (Haemocomplettan® P/Riastap, CSL Behring, Marburg, Germany) before the algorithm-based therapy.
A mean of 5.7 (0.7) g fibrinogen concentrate decreased blood loss to below the transfusion trigger level in all Group C patients. Group C had reduced transfusion [mean 0.7 (range 0–4) u vs 8.5 (5.3) in Group A and 8.2 (2.3) in Group B] and reduced postoperative bleeding [366 (199) ml vs 793 (560) in Group A and 716 (219) in Group B].
In this pilot study, FIBTEM-guided fibrinogen concentrate administration was associated with reduced transfusion requirements and 24 h postoperative bleeding in patients undergoing AV–AA.
blood, coagulation; measurement techniques, thrombelastograph; surgery, cardiovascular; transfusion
There is currently a contrast between the demonstrated benefits of fibrinogen concentrate in correcting bleeding and reducing transfusion, and its perceived thrombogenic potential. This analysis evaluates the effects of fibrinogen concentrate on coagulation up to 12 days after administration during aortic surgery.
We performed a post hoc analysis of a prospective, randomized, double-blind, controlled trial of fibrinogen concentrate as first-line haemostatic therapy in aortic surgery. After cardiopulmonary bypass (CPB) and protamine administration, subjects with coagulopathic bleeding received fibrinogen concentrate or placebo. The placebo group received allogeneic blood products, including fresh-frozen plasma (FFP; n=32); the fibrinogen concentrate group received fibrinogen concentrate alone (FC; n=14), or fibrinogen concentrate followed by allogeneic blood products (FC+FFP; n=15). Plasma fibrinogen, fibrin-based clotting (ROTEM®-based FIBTEM assay), and peri- and postoperative haematological and coagulation parameters were compared.
Plasma fibrinogen and FIBTEM maximum clot firmness (MCF) decreased ∼50% during CPB but were corrected by FC or FC+FFP. At last suture, the highest values for plasma fibrinogen (360 mg dl−1) and FIBTEM MCF (22 mm) were within normal ranges—below the acute phase increases observed after surgery. In patients receiving only FFP as a source of fibrinogen, these parameters recovered marginally by last suture (P<0.001 vs FC and FC+FFP). All groups displayed comparable haemostasis at 24 h post-surgery. Fibrinogen concentrate did not cause alterations of other haemostasis parameters.
Fibrinogen concentrate provided specific, significant, short-lived increases in plasma fibrinogen and fibrin-based clot firmness after aortic surgery.
blood coagulation tests; cardiopulmonary bypass; fibrin; fibrinogen; plasma
Administration of fibrinogen concentrate, targeting improved maximum clot firmness (MCF) of the thromboelastometric fibrin-based clot quality test (FIBTEM) is effective as first-line haemostatic therapy in aortic surgery. We performed a post-hoc analysis of data from a randomised, placebo-controlled trial of fibrinogen concentrate, to investigate whether fibrinogen concentrate reduced transfusion requirements for patients with platelet counts over or under 100×109/L.
Material and methods
Aortic surgery patients with coagulopathic bleeding after cardiopulmonary bypass were randomised to receive either fibrinogen concentrate (n=29) or placebo (n=32). Platelet count was measured upon removal of the aortic clamp, and coagulation and haematology parameters were measured peri-operatively. Transfusion of allogeneic blood components was recorded and compared between groups.
After cardiopulmonary bypass, haemostatic and coagulation parameters worsened in all groups; plasma fibrinogen level (determined by the Clauss method) decreased by 43–58%, platelet count by 53–64%, FIBTEM maximum clot firmness (MCF) by 38–49%, FIBTEM maximum clot elasticity (MCE) by 43–54%, extrinsically activated test (EXTEM) MCF by 11–22%, EXTEM MCE by 25–41% and the platelet component of the clot by 23–39%. Treatment with fibrinogen concentrate (mean dose 7–9 g in the 4 groups) significantly reduced post-operative allogeneic blood component transfusion requirements when compared to placebo both for patients with a platelet count ≥100×109/L and for patients with a platelet count <100×109/L.
FIBTEM-guided administration of fibrinogen concentrate reduced transfusion requirements when used as a first-line haemostatic therapy during aortic surgery in patients with platelet counts over or under 100×109/L.
blood component transfusion; fibrinogen; haemostasis; cardiopulmonary bypass
Low plasma fibrinogen concentration is a predictor of poor outcome in major trauma patients. The role of fibrinogen concentrate for rapidly increasing fibrinogen plasma levels in severe trauma is not well defined.
In this retrospective study we included severe trauma patients treated with fibrinogen concentrate alone (FC group), fibrinogen concentrate with prothrombin complex concentrate (FC–PCC group) or fibrinogen concentrate with PCC and fresh frozen plasma (FC–PCC–FFP group). PCC was generally administered as the second step of intraoperative therapy, while FFP was only administered as a third step. All patients received ≥1 g fibrinogen concentrate within 24 hours. Plasma fibrinogen concentration and ROTEM parameters upon emergency room (ER) admission, intensive care unit (ICU) admission, and after 24 hours were analysed.
Among 157 patients fulfilling the inclusion criteria, 83% were male; mean age was 44 years and median injury severity score (ISS) was 29. Standard coagulation tests reflected increasing severity of coagulopathy with increasing complexity of haemostatic therapy (highest severity in the FC–PCC–FFP group; p < 0.0001). Total 24-hour fibrinogen concentrate dose also increased with complexity of haemostatic therapy. Plasma fibrinogen concentration was maintained, with no significant difference between ER admission and ICU admission in all patient groups. FIBTEM clot firmness at 10 minutes (CA10) was similarly maintained, albeit with a small increase in the FC–PCC group. Fibrinogen concentration and FIBTEM CA10 were within the normal range in all groups at 24 hours. The ratio of fibrinogen concentrate to red blood cells (g:U) ranged between 0.7:1.0 and 1.0:1.0.
Fibrinogen concentrate therapy maintained fibrinogen concentration and FIBTEM CA10 during the initial phase of trauma care until ICU admission. After 24 hours, these parameters were comparable between the three groups and within the normal range for each of them. Further studies are warranted to investigate the effect of fibrinogen concentrate on clinical outcomes.
Fibrinogen concentrate; Prothrombin complex concentrate; Fresh frozen plasma; Thromboelastometry (ROTEM)
Repair of thoracic aortic aneurysm (TAA) is often associated with massive hemorrhage aggravated by dilutional coagulopathy with severe hypofibrinogenemia. Although only fresh frozen plasma (FFP) is available for acquired hypofibrinogenemia in Japan, the hemostatic effect of FFP has not been enough for dilutional coagulopathy in TAA surgery. There are increasing reports suggesting that fibrinogen concentrate may be effective in controlling perioperative bleeding and reducing transfusion requirements.
We retrospectively analyzed the hemostatic effect of fibrinogen concentrate compared with FFP in total 49 cases of elective TAA surgery. In 25 patients, fibrinogen concentrate was administered when the fibrinogen level was below 150 mg/dL at the cardiopulmonary bypass (CPB) termination. The recovery of fibrinogen level, blood loss, and transfused units during surgery were compared between cases of this agent and FFP (n = 24).
We observed rapid increases in plasma fibrinogen level and subsequent improvement in hemostasis by administration of fibrinogen concentrate after CPB termination. The average volume of total blood loss decreased by 64% and the average number of transfused units was reduced by 58% in cases of fibrinogen concentrate given, in comparison with cases of only FFP transfused for fibrinogen supplementation.
In patients showing severe hypofibrinogenemia during TAA surgery, timely administration of fibrinogen concentrate just after removal from CPB is effective for hemostasis, and therefore in reducing blood loss and transfused volumes.
Massive hemorrhage; Thoracic aortic aneurysm; Cardiopulmonary bypass; Dilutional coagulopathy; Hypofibrinogenemia
Thromboelastometry (TEM)-guided haemostatic therapy with fibrinogen concentrate and prothrombin complex concentrate (PCC) in trauma patients may reduce the need for transfusion of red blood cells (RBC) or platelet concentrate, compared with fresh frozen plasma (FFP)-based haemostatic therapy.
This retrospective analysis compared patients from the Salzburg Trauma Centre (Salzburg, Austria) treated with fibrinogen concentrate and/or PCC, but no FFP (fibrinogen-PCC group, n = 80), and patients from the TraumaRegister DGU receiving ≥ 2 units of FFP, but no fibrinogen concentrate/PCC (FFP group, n = 601). Inclusion criteria were: age 18-70 years, base deficit at admission ≥2 mmol/L, injury severity score (ISS) ≥16, abbreviated injury scale for thorax and/or abdomen and/or extremity ≥3, and for head/neck < 5.
For haemostatic therapy in the emergency room and during surgery, the FFP group (ISS 35.5 ± 10.5) received a median of 6 units of FFP (range: 2, 51), while the fibrinogen-PCC group (ISS 35.2 ± 12.5) received medians of 6 g of fibrinogen concentrate (range: 0, 15) and 1200 U of PCC (range: 0, 6600). RBC transfusion was avoided in 29% of patients in the fibrinogen-PCC group compared with only 3% in the FFP group (P< 0.001). Transfusion of platelet concentrate was avoided in 91% of patients in the fibrinogen-PCC group, compared with 56% in the FFP group (P< 0.001). Mortality was comparable between groups: 7.5% in the fibrinogen-PCC group and 10.0% in the FFP group (P = 0.69).
TEM-guided haemostatic therapy with fibrinogen concentrate and PCC reduced the exposure of trauma patients to allogeneic blood products.
Point-of-care thromboelastometry (ROTEM®) can be used to assess coagulation in whole blood. In the ROTEM® FIBTEM test, cytochalasin D eliminates the contribution of platelets to the whole blood clot; hence, only the remaining elements, including fibrinogen/fibrin, red blood cells and factor XIII, contribute to clot strength. We investigated the relationships between FIBTEM maximum clot firmness (MCF), whole blood fibrinogen concentration and plasma fibrinogen concentration to determine the impact of haematocrit on these parameters during cardiac surgery.
Materials and methods
The relationships between FIBTEM MCF and both whole blood fibrinogen concentration and plasma fibrinogen concentration (Clauss assay) were evaluated pre-operatively and after cardiopulmonary bypass/protamine administration in haematocrit-based subgroups.
The study included 157 patients. The correlation coefficient rho between FIBTEM MCF and plasma fibrinogen concentration was 0.68 at baseline and 0.70 after protamine, while that between FIBTEM MCF and whole blood fibrinogen concentration was 0.74 at baseline and 0.72 after protamine (all P <0.001). In subgroup analyses based on haematocrit levels, pre-operative FIBTEM MCF and whole blood fibrinogen concentration were both significantly higher (P <0.05) for the lowest haematocrit subgroup, but plasma fibrinogen concentration was similar in all groups. After protamine, no significant differences were observed between the lowest haematocrit group and the other groups for any of the three parameters.
The effect of haematocrit on blood clotting is not reflected by plasma fibrinogen concentration, in contrast to FIBTEM MCF which incorporates the contribution of haematocrit to whole blood clot firmness. This effect does, however, appear to be negligible in haemodiluted patients.
cardiac surgery; fibrinogen; FIBTEM; haematocrit; thromboelastometry
Postpartum haemorrhage (PPH) is a major cause of maternal morbidity. Bleeding is caused by a combination of physical causes, such as failure of the uterus to contract or operations, and is made worse by impairment of the blood clotting system. A number of studies have shown that low levels of the blood clotting factor fibrinogen are associated with progression of bleeding, the need for invasive interventions and transfusions of red blood cells and fresh frozen plasma (FFP). This trial will investigate whether early infusion of fibrinogen concentrate during a major PPH, with the aim of correcting a low fibrinogen to a level that is normal for delivery, based on the Fibtem test, reduces the total number of allogeneic blood products (red blood cells, FFP, cryoprecipitate and platelets) transfused after study medication until discharge, compared to placebo.
This is a prospective, randomised, double-blind placebo controlled trial. Women will enter an observational phase and if their Fibtem levels fall they will be randomised in the interventional phase. A total of 60 women will be randomised and women are eligible for the trial if they meet all of the following inclusion criteria: age 18 years or over, gestation ≥24 + 0 weeks, haemorrhage of about 1500 ml and on-going bleeding without another complication or haemorrhage of about 1000 ml and caesarean section/uterine atony/placental abruption/placenta praevia/cardiovascular instability or microvascular oozing. Participants with a Fibtem A5 < 16 mm will be randomly allocated to receive either a bolus infusion of fibrinogen concentrate or placebo (isotonic saline). The dose of fibrinogen concentrate or placebo will be calculated based on the woman’s ideal body weight for height and the measured Fibtem A5 with the aim of increasing the Fibtem A5 to 23 mm.
The trial aims to provide evidence on the efficacy and safety of fibrinogen concentrate during acute bleeding in an obstetric setting.
ISRCTN ref: ISRCTN46295339 (01.07.2013); EudraCT: 2012-005511-11 (28.11.2012), UKCRN ref: 13940.
Postpartum haemorrhage; Blood transfusion; Fibrinogen concentrate; Fibtem
Haemostatic therapy in surgical and/or massive trauma patients typically involves transfusion of fresh frozen plasma (FFP). Purified human fibrinogen concentrate may offer an alternative to FFP in some instances. In this systematic review, we investigated the current evidence for the use of FFP and fibrinogen concentrate in the perioperative or massive trauma setting.
Studies reporting the outcome (blood loss, transfusion requirement, length of stay, survival and plasma fibrinogen level) of FFP or fibrinogen concentrate administration to patients in a perioperative or massive trauma setting were identified in electronic databases (1995 to 2010). Studies were included regardless of type, patient age, sample size or duration of patient follow-up. Studies of patients with congenital clotting factor deficiencies or other haematological disorders were excluded. Studies were assessed for eligibility, and data were extracted and tabulated.
Ninety-one eligible studies (70 FFP and 21 fibrinogen concentrate) reported outcomes of interest. Few were high-quality prospective studies. Evidence for the efficacy of FFP was inconsistent across all assessed outcomes. Overall, FFP showed a positive effect for 28% of outcomes and a negative effect for 22% of outcomes. There was limited evidence that FFP reduced mortality: 50% of outcomes associated FFP with reduced mortality (typically trauma and/or massive bleeding), and 20% were associated with increased mortality (typically surgical and/or nonmassive bleeding). Five studies reported the outcome of fibrinogen concentrate versus a comparator. The evidence was consistently positive (70% of all outcomes), with no negative effects reported (0% of all outcomes). Fibrinogen concentrate was compared directly with FFP in three high-quality studies and was found to be superior for > 50% of outcomes in terms of reducing blood loss, allogeneic transfusion requirements, length of intensive care unit and hospital stay and increasing plasma fibrinogen levels. We found no fibrinogen concentrate comparator studies in patients with haemorrhage due to massive trauma, although efficacy across all assessed outcomes was reported in a number of noncomparator trauma studies.
The weight of evidence does not appear to support the clinical effectiveness of FFP for surgical and/or massive trauma patients and suggests it can be detrimental. Perioperatively, fibrinogen concentrate was generally associated with improved outcome measures, although more high-quality, prospective studies are required before any definitive conclusions can be drawn.
After cardiac surgery with cardiopulmonary bypass (CPB), acquired coagulopathy often leads to post-CPB bleeding. Though multifactorial in origin, this coagulopathy is often aggravated by deficient fibrinogen levels.
To assess whether laboratory and thrombelastometric testing on CPB can predict plasma fibrinogen immediately after CPB weaning.
Patients / Methods
This prospective study in 110 patients undergoing major cardiovascular surgery at risk of post-CPB bleeding compares fibrinogen level (Clauss method) and function (fibrin-specific thrombelastometry) in order to study the predictability of their course early after termination of CPB. Linear regression analysis and receiver operating characteristics were used to determine correlations and predictive accuracy.
Quantitative estimation of post-CPB Clauss fibrinogen from on-CPB fibrinogen was feasible with small bias (+0.19 g/l), but with poor precision and a percentage of error >30%. A clinically useful alternative approach was developed by using on-CPB A10 to predict a Clauss fibrinogen range of interest instead of a discrete level. An on-CPB A10 ≤10 mm identified patients with a post-CPB Clauss fibrinogen of ≤1.5 g/l with a sensitivity of 0.99 and a positive predictive value of 0.60; it also identified those without a post-CPB Clauss fibrinogen <2.0 g/l with a specificity of 0.83.
When measured on CPB prior to weaning, a FIBTEM A10 ≤10 mm is an early alert for post-CPB fibrinogen levels below or within the substitution range (1.5–2.0 g/l) recommended in case of post-CPB coagulopathic bleeding. This helps to minimize the delay to data-based hemostatic management after weaning from CPB.
The early detection of coagulopathy helps guide decisions regarding optimal transfusion management during cardiac surgery. This study aimed to determine whether rotational thromboelastometry (ROTEM) analysis during cardiopulmonary bypass (CPB) could predict thrombocytopenia and hypofibrinogenemia after CPB.
We analyzed 138 cardiac surgical patients for whom ROTEM tests and conventional laboratory tests were performed simultaneously both during and after CPB. An extrinsically activated ROTEM test (EXTEM), a fibrin-specific ROTEM test (FIBTEM) and PLTEM calculated by subtracting FIBTEM from EXTEM were evaluated. Correlations between clot amplitude at 10 min (A10), maximal clot firmness, platelet count, and fibrinogen concentrations at each time point were calculated. A receiver operating characteristic analysis with area under the curve (AUC) was used to assess the thresholds of EXTEM, PLTEM and FIBTEM parameters during CPB and for predicting thrombocytopenia and hypofibrinogenemia after weaning of CPB.
The A10 on EXTEM, PLTEM, and FIBTEM during CPB showed a good correlation with platelet counts (r = 0.622 on EXTEM and r = 0.637 on PLTEM; P < 0.0001 for each value) and fibrinogen levels (r = 0.780; P < 0.0001) after CPB. A10 on a FIBTEM threshold of 8 mm during the CPB predicted a fibrinogen concentration < 150 mg/dl (AUC = 0.853) after CPB. Additionally, the threshold level of A10 on EXTEM during CPB for predicting platelet counts < 100,000 /µl after CPB was 42 mm (AUC = 0.768).
EXTEM, PLTEM, and FIBTEM parameters during CPB may be useful for predicting thrombocytopenia and hypofibrinogenemia after weaning of CPB.
Cardiac surgery; Cardiopulmonary bypass; Coagulopathy; Thromboelastometry
Postoperative bleeding after heart operations is still a common finding, leading to allogeneic blood products transfusion. Fibrinogen and coagulation factors deficiency are possible determinants of bleeding. The experimental hypothesis of this study is that a first-line fibrinogen supplementation avoids the need for fresh frozen plasma (FFP) and reduces the need for any kind of transfusions.
Methods and Results
This was a single-center, prospective, randomized, placebo-controlled, double-blinded study. One-hundred sixteen patients undergoing heart surgery with an expected cardiopulmonary bypass duration >90 minutes were admitted to the study. Patients in the treatment arm received fibrinogen concentrate after protamine administration; patients in the control arm received saline solution. In case of ongoing bleeding, patients in the treatment arm could receive prothrombin complex concentrates (PCCs) and those in the control arm saline solution. The primary endpoint was avoidance of any allogeneic blood product. Patients in the treatment arm had a significantly lower rate of any allogeneic blood products transfusion (odds ratio, 0.40; 95% confidence interval, 0.19 to 0.84, P=0.015). The total amount of packed red cells and FFP units transfused was significantly lower in the treatment arm. Postoperative bleeding was significantly (P=0.042) less in the treatment arm (median, 300 mL; interquartile range, 200 to 400 mL) than in the control arm (median, 355 mL; interquartile range, 250 to 600 mL).
Fibrinogen concentrate limits postoperative bleeding after complex heart surgery, leading to a significant reduction in allogeneic blood products transfusions. No safety issues were raised.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01471730.
cardiopulmonary bypass; fibrinogen; hemorrhage; surgery
Haemorrhage remains a leading cause of morbidity and mortality in trauma patients. Fibrinogen is an essential endogenous component of haemostasis and the plasma level is associated with bleeding, transfusion and outcome. Fibrinogen concentrate is widely used to correct acquired hypofibrinogenaemia, recommended by several international guidelines for the treatment of trauma patients, but evidence is lacking regarding the treatment safety and efficacy.
We aim to assess the efficacy and safety of an immediate pre-emptive first-line treatment with fibrinogen concentrate in patients with trauma haemorrhage in need of haemostatic resuscitation.
This is a single-centre, randomized (1:1, active:placebo), placebo-controlled, double-blinded, investigator-initiated phase II trial. The trial population consists of 40 adult patients (>18 years) with traumatic, critical bleeding admitted to the Level 1 Trauma Centre at Rigshospitalet in Copenhagen, with immediate need for blood transfusion on arrival and an expected need for haemostatic resuscitation with multiple transfusions during the initial resuscitation. Patients will receive either pre-emptive administration of a bolus dose of 60–70 mg/kg fibrinogen concentrate (Riastap®) or placebo 0.9 % saline in equal volume to active treatment, both given as intravenous infusion blinded for the person administering the infusion.
The primary end point is the change in thrombelastograph (TEG®) functional fibrinogen maximum amplitude in millimetres at 15 min after the intervention. The follow-up period on safety events and mortality will be until day 30.
To detect a difference in the change from baseline to the 15-minute post-randomization measurement of 6–8 mm in TEG® functional fibrinogen maximum amplitude with a power of 0.90 and alpha of 0.05, we require 19 patients in each group. We have chosen to include 40 patients, 20 evaluable patients in each randomization group in case of attrition, in the present trial.
Patients considered to be included in the trial will temporarily have a compromised consciousness because of the acute, critical bleeding related to trauma, so scientific guardians will co-sign the informed consent form. Next of kin and the patients’ general practitioner or the patients will co-sign as soon as possible.
This trial will test whether immediate pre-emptive fibrinogen concentrate administered to adult trauma patients as first-line treatment of trauma haemorrhage will increase the clot strength as evaluated by thrombelastography, transfusion requirements and survival in patients receiving haemostatic resuscitation according to current standard of care.
EudraCT no. 2014-003978-16 (22/1 2015); ClinicalTrials.gov: NCT02344069. Registered on 14 January 2015. Trial protocol version 4.2 (23-12-2014).
Trauma; Haemorrhage; Fibrinogen; Haemostatic Resuscitation; Thrombelastography
Postpartum haemorrhage (PPH) remains a leading cause of maternal mortality worldwide. In Denmark 2% of parturients receive blood transfusion. During the course of bleeding fibrinogen (coagulation factor I) may be depleted and fall to critically low levels, impairing haemostasis and thus worsening the ongoing bleeding. A plasma level of fibrinogen below 2 g/L in the early phase of postpartum haemorrhage is associated with subsequent development of severe haemorrhage. Use of fibrinogen concentrate allows high-dose substitution without the need for blood type crossmatch. So far no publications of randomised controlled trials involving acutely bleeding patients in the obstetrical setting have been published. This trial aims to investigate if early treatment with fibrinogen concentrate reduces the need for blood transfusion in women suffering severe PPH.
In this randomised placebo-controlled double-blind multicentre trial, parturients with primary PPH are eligible following vaginal delivery in case of: manual removal of placenta (blood loss ≥ 500 ml) or manual exploration of the uterus after the birth of placenta (blood loss ≥ 1000 ml). Caesarean sections are also eligible in case of perioperative blood loss ≥ 1000 ml. The exclusion criteria are known inherited haemostatic deficiencies, prepartum treatment with antithrombotics, pre-pregnancy weight <45 kg or refusal to receive blood transfusion. Following informed consent, patients are randomly allocated to either early treatment with 2 g fibrinogen concentrate or 100 ml isotonic saline (placebo). Haemostatic monitoring with standard laboratory coagulation tests and thromboelastography (TEG, functional fibrinogen and Rapid TEG) is performed during the initial 24 hours.
Primary outcome is the need for blood transfusion. To investigate a 33% reduction in the need for blood transfusion, a total of 245 patients will be included. Four university-affiliated public tertiary care hospitals will include patients during a two-year period. Adverse events including thrombosis are assessed in accordance with International Conference on Harmonisation (ICH) good clinical practice (GCP).
A widespread belief in the benefits of early fibrinogen substitution in cases of PPH has led to increased off-label use. The FIB-PPH trial is investigator-initiated and aims to provide an evidence-based platform for the recommendations of the early use of fibrinogen concentrate in PPH.
Postpartum haemorrhage; Haemostasis; Blood transfusion; Fibrinogen concentrate; Obstetrics; Thrombelastography; Coagulation
The appropriate strategy for trauma-induced coagulopathy management is under debate. We report the treatment of major trauma using mainly coagulation factor concentrates.
This retrospective analysis included trauma patients who received ≥ 5 units of red blood cell concentrate within 24 hours. Coagulation management was guided by thromboelastometry (ROTEM®). Fibrinogen concentrate was given as first-line haemostatic therapy when maximum clot firmness (MCF) measured by FibTEM (fibrin-based test) was <10 mm. Prothrombin complex concentrate (PCC) was given in case of recent coumarin intake or clotting time measured by extrinsic activation test (EXTEM) >1.5 times normal. Lack of improvement in EXTEM MCF after fibrinogen concentrate administration was an indication for platelet concentrate. The observed mortality was compared with the mortality predicted by the trauma injury severity score (TRISS) and by the revised injury severity classification (RISC) score.
Of 131 patients included, 128 received fibrinogen concentrate as first-line therapy, 98 additionally received PCC, while 3 patients with recent coumarin intake received only PCC. Twelve patients received FFP and 29 received platelet concentrate. The observed mortality was 24.4%, lower than the TRISS mortality of 33.7% (P = 0.032) and the RISC mortality of 28.7% (P > 0.05). After excluding 17 patients with traumatic brain injury, the difference in mortality was 14% observed versus 27.8% predicted by TRISS (P = 0.0018) and 24.3% predicted by RISC (P = 0.014).
ROTEM®-guided haemostatic therapy, with fibrinogen concentrate as first-line haemostatic therapy and additional PCC, was goal-directed and fast. A favourable survival rate was observed. Prospective, randomized trials to investigate this therapeutic alternative further appear warranted.
Fibrinogen concentrate is increasingly considered as a hemostatic agent for trauma patients experiencing bleeding. Placing a venous access is sometimes challenging during severe hemorrhage. Intraosseous access may be considered instead. Studies of intraosseous infusion of coagulation factor concentrates are limited. We investigated in vivo recovery following intraosseous administration of fibrinogen concentrate and compared the results with intravenous administration.
This study was performed on 12 pigs (mean [SD] body weight, 34.1 [2.8] kg). Following controlled blood loss (35 mL/kg) and fluid replacement with balanced crystalloid solution, intraosseous (n = 6) administration of fibrinogen concentrate (80 mg per kilogram of bodyweight) in the proximal tibia was compared with intravenous (n = 6) administration of the same dose (fibrinogen infusion time approximately 5 minutes in both groups). The following laboratory parameters were assessed: blood cell count, prothrombin time index, activated partial thromboplastin time, and plasma fibrinogen concentration (Clauss assay). Coagulation status was also assessed by thromboelastometry.
All tested laboratory parameters were comparable between the intraosseous and intravenous groups at baseline, hemodilution, and 30 minutes after fibrinogen concentrate administration. In vivo recovery of fibrinogen was also similar in the two groups (89% [23%] and 91% [22%], respectively). There were no significant between-group differences in any of the thromboelastometric parameters. Histologic examination indicated no adverse effects on the tissue surrounding the intraosseous administration site.
This study suggests that intraosseous administration of fibrinogen concentrate results in a recovery of fibrinogen similar to that of intravenous administration. The intraosseous route of fibrinogen concentrate could be a valuable alternative in situations where intravenous access is not feasible or would be time consuming.
LEVEL OF EVIDENCE
Prospective, randomized, therapeutic feasibility study in an animal model, level V.
Intraosseous access; fibrinogen concentrate; traumatic hemorrhage; hemostatic therapy; pigs
Thrombelastography (TEG) is emerging as the standard in the management of acute coagulopathies in injured patients. While TEG is sensitive in detecting abnormalities in clot strength, one short-coming is differentiating between fibrinogen and platelet contributions to clot integrity. Current American algorithms suggest platelet transfusion, while European guidelines suggest fibrinogen concentrates for correcting low clot strength. Therefore, we hypothesized that a TEG-based functional fibrinogen assay would assess the contribution of fibrinogen and platelets to clot strength, and provide insight to transfusion priorities.
Blood samples were obtained from trauma patients on arrival to the emergency department or who were admitted to the SICU (n=68). Citrated Kaolin TEG, FF, and von Clauss fibrinogen levels (plasma-based clinical standard) were measured. Correlations were assessed using linear regression models. In vitro studies were also performed with adding fibrinogen concentrates to blood collected from healthy volunteers (n=10). FF and citrated Kaolin TEG parameters were measured.
FF strongly correlated with von Clauss fibrinogen levels (R2=0.87) and clot strength (R2=0.80). The mean fibrinogen contribution to clot strength was 30%; however, there was a direct linear relationship with fibrinogen level and % fibrinogen contribution to clot strength (R2=0.83). Traditional TEG parameters associated with fibrinogen activity (α-angle and k-time) had significantly lower correlations with FF (R2=0.70 and 0.35). Furthermore, platelet count only had a moderate correlation to clot strength (R2=0.51). The addition of fibrinogen concentrate in in vitro studies increased clot strength (MA) (60.44±1.48 to 68.12±1.39) and percent fibrinogen contribution to clot strength (23.8±1.8% to 37.7±2.5%).
FF can be performed rapidly with TEG, and correlates well with the standard von Clauss fibrinogen assay. Both fibrinogen and platelet contribution of clot strength can be derived from FF. Moreover, FF had a stronger correlation to clot strength and increased levels were directly associated with increased % contribution to clot strength. In vitro studies also demonstrated an increase in FF, clot strength, and percent fibrinogen contribution to clot strength with the addition of fibrinogen concentrate. These data suggest fibrinogen should be addressed early in trauma patients manifesting the acute coagulopathy of trauma.
Functional Fibrinogen; TEG; Clot Strength; Trauma; Fibrinogen Concentrate; Platelets; Resuscitation
In this prospective study, the effects of fresh frozen plasma (FFP) included in pump priming for congenital heart surgery in infants and children on post-bypass coagulation profiles were evaluated.
Materials and Methods
Either 20% albumin (50-100 mL) or FFP (1-2 units) was added to pump priming for patients randomly allocated into control or treatment groups, respectively. Hematologic assays, including functional fibrinogen level, and rotational thromboelastometry (ROTEM®) were measured before skin incision (baseline), after weaning from cardiopulmonary bypass (CPB) and heparin reversal, and at 24 hours (h) in the intensive care unit (ICU).
All the baseline measurements were comparable between the control and treatment groups of infants and children. After heparin reversal, however, significantly higher fibrinogen levels and less reduced ROTEM parameters, which reflect clot formation and firmness, were demonstrated in the treatment groups of infants and children. At 24 h in the ICU, hematologic assays and ROTEM measurements were comparable between the control and treatment groups of infants and children. Transfusion requirements, excluding FFP in pump prime, and postoperative bleeding were comparable between the control and treatment groups of infants and children.
Although clinical benefits were not clearly found, the inclusion of FFP in pump priming for congenital heart surgery in infants and children was shown to improve the hemodilution-related hemostatic dysfunction immediately after weaning from CPB and heparin reversal.
Congenital heart disease; cardiopulmonary bypass; blood coagulation disorder; fresh frozen plasma
Higher levels of fibrinogen, a critical element in hemostasis, are associated with increased postoperative survival rates, especially for patients with massive operative blood loss. Fibrinogen deficiency after surgical management of intracranial tumors may result in postoperative intracranial bleeding and severely worsen patient outcomes. However, no previous studies have systematically identified factors associated with postoperative fibrinogen deficiency. In this study, we retrospectively analyzed data from patients who underwent surgical removal of intracranial tumors in Beijing Tiantan Hospital date from 1/1/2013to12/31/2013. The present study found that patients with postoperative fibrinogen deficiency experienced more operative blood loss and a higher rate of postoperative intracranial hematoma, and they were given more blood transfusions, more plasma transfusions, and were administered larger doses of hemocoagulase compared with patients without postoperative fibrinogen deficiency. Likewise, patients with postoperative fibrinogen deficiency had poorer extended Glasgow Outcome Scale (GOSe), longer hospital stays, and greater hospital expenses than patients without postoperative fibrinogen deficiency. Further, we assessed a comprehensive set of risk factors associated with postoperative fibrinogen deficiency via multiple linear regression. We found that body mass index (BMI), the occurrence of postoperative intracranial hematoma, and administration of hemocoagulasewere positively associated with preoperative-to-postoperative plasma fibrinogen consumption; presenting with a malignant tumor was negatively associated with fibrinogen consumption. Contrary to what might be expected, intraoperative blood loss, the need for blood transfusion, and the need for plasma transfusion were not associated with plasma fibrinogen consumption. Considering our findings together, we concluded that postoperative fibrinogen deficiency is closely associated with postoperative bleeding and poor outcomes and merits careful attention. Practitioners should monitor plasma fibrinogen levels in patients with risk factors for postoperative fibrinogen deficiency. In addition, postoperative fibrinogen deficiency should be remediated as soon as possible to reduce postoperative bleeding, especially when postoperative bleeding is confirmed.
We aimed to create a theoretical tool to model the effect of three haemostatic agents containing fibrinogen (therapeutic plasma, cryoprecipitate, and fibrinogen concentrate) on the patient's plasma fibrinogen level.
A mathematical model was developed step-wise. The relationship between the amount of haemostatic agent and plasma fibrinogen level was plotted for each agent. A fibrinogen concentration simulator (FCSamount) was developed, where the amount of haemostatic agent was calculated from patient characteristics, agent characteristics, and target plasma fibrinogen level. Refinements were introduced so that (i) FCSamount would account for in vivo fibrinogen recovery, (ii) circulatory volume would not increase ad infinitum with increasing amounts, and (iii) red blood cells would be included in the simulation if haematocrit decreased below a certain level. A second FCS (FCSlevel) was created to calculate fibrinogen levels resulting from specified amounts of haemostatic agents.
Fibrinogen concentration in haemostatic agents has a critical impact on their ability to increase patients' fibrinogen levels. If the target plasma fibrinogen level approaches the concentration of the fibrinogen source, the required amounts increase exponentially; it is impossible to achieve a target above the concentration of the fibrinogen source.
We successfully developed two theoretical tools answering the questions: ‘How much therapeutic plasma, cryoprecipitate, or fibrinogen concentrate would be needed to achieve a specified target fibrinogen level?’ and ‘What would be the resultant fibrinogen level for a specified amount of haemostatic agent?’ The current tools are not intended for clinical application, but they are potentially useful for educational purposes.
computer simulation; cryoprecipitate; drug dosage calculations; fibrinogen; plasma
•We analyzed mental stress, fibrinogen, and CVD within an integrated framework.•Fibrinogen is not a positive mediator between mental stress and CVD.•The higher the fibrinogen response to mental stress is, the lower the risk of CVD, assessed by detectable HS-CTnT levels.
Plasma fibrinogen is considered as a positive mediator between mental stress and cardiovascular disease because it is an acute-phase protein released in response to mental stress and a coagulation factor. However those three factors have never been studied together within a single integrated framework, using cardiac troponin T as a marker of cardiovascular risk.
491 disease-free men and women aged 53–76 were tested for fibrinogen levels before, immediately after, and following recovery from standardized mental stress tasks. We measured plasma cardiac troponin T using a high-sensitivity assay (HS-CTnT) and coronary calcification using electron-beam dual-source computed tomography.
The average fibrinogen concentration increased by 5.1% (s.d. = 7.3) in response to stress and then tended to return to baseline values. People with higher baseline fibrinogen values had smaller increases (blunted responses) following the stress task (P = 0.001), and people with higher stress responses showed better recovery (P < 0.001). In unadjusted analyses, higher baseline fibrinogen was associated with higher chances of having detectable HS-CTnT (P = 0.072) but, conversely, higher fibrinogen response was associated with lower chances of having detectable HS-CTnT (P = 0.007). The adjustment for clinical, inflammatory, and haemostatic factors, as well as for coronary calcification eliminated the effect of baseline fibrinogen, whereas the negative association between fibrinogen response and HS-CTnT remained robust: the odds of detectable HS-CTnT halved for each 10% increase in fibrinogen concentration due to stress (OR = 0.49, P = 0.007, 95% CI = 0.30–0.82).
Greater fibrinogen responses to mental stress are associated with lower likelihood of detectable high-sensitivity troponin T plasma concentration. A more dynamic fibrinogen response appears to be advantageous for cardiovascular health.
Stress; Psychological; Fibrinogen; Troponin T; Atherosclerosis; Allostasis
This retrospective, single centre study was conducted to investigate the efficacy of fibrinogen concentrate (FBNc) in decreasing blood requirements and reaching optimal fibrinogen level, in non-trauma, massively transfused, bleeding patients with coagulopathy.
Over a 3-years period, all patients for whom a massive transfusion protocol was activated and had received ≥4 units of allogeneic blood components within a ≤4 h period, were included. Patients were classified according to whether they received FBNc or achieved an optimal fibrinogen level of ≥2 g/L within 24 h after FBNc administration.
Seventy-one patients received 2 [2,4] g of FBNc (FBNc group) and 72 did not (comparator group). FBNc was administered after transfusing 5 [5,9] blood component units, 3 [2,6] hours after massive transfusion protocol activation. Linear regression analysis showed that SOFA (AOR 0.75 [95% CI:0.08-1.43]) and admission fibrinogen level (AOR -2.7 [95% CI:-4.68 – -0.78]), but not FBNc administration, were independently associated with total transfused units. There was a significant inverse relation between both admission and target fibrinogen levels, and total transfused components. Logistic regression showed a direct relationship between admission fibrinogen level and achieving a target level ≥2 g/L (AOR 3.29 [95% CI;1.95-5.56]). No thromboembolic events associated with FBNc were observed.
In massively transfused, non-trauma patients with coagulopathy and refractory bleeding, late administration of low FBNc dosage was not associated with decreased blood transfusion or increased post-infusion fibrinogen level. Given that both fibrinogen upon admission and target fibrinogen levels were associated with decreased blood transfusion, earlier administration and higher doses of FBNc could be needed.
Anaemia; Bleeding; Clauss method; Fibrinogen concentrate; Goal directed therapy; Massive transfusion protocol; Thromboelastometry; ROTEM; Thromboelastography; TEG; FIBTEM; Transfusion
Massive bleeding and transfusion of packed red blood cells (PRBC), fresh frozen plasma (FFP) and platelets are associated with increased morbidity, mortality and costs.
Patients and Methods
We analysed the transfusion requirements after implementation of point-of-care (POC) coagulation management algorithms based on early, calculated, goal-directed therapy with fibrinogen concentrate and prothrombin complex concentrate (PCC) in different perioperative settings (trauma surgery, visceral and transplant surgery (VTS), cardiovascular surgery (CVS) and general and surgical intensive care medicine) at 3 different hospitals (AUVA Trauma Centre Salzburg, University Hospital Innsbruck and University Hospital Essen) in 2 different countries (Austria and Germany).
In all institutions, the implementation of POC coagulation management algorithms was associated with a reduction in the transfusion requirements for FFP by about 90% (Salzburg 94%, Innsbruck 88% and Essen 93%). Furthermore, PRBC transfusion was reduced by 8.4–62%. The incidence of intraoperative massive transfusion (≥10 U PRBC) could be more than halved in VTS and CVS (2.56 vs. 0.88%; p < 0.0001 and 2.50 vs. 1.06%; p = 0.0007, respectively). Platelet transfusion could be reduced by 21–72%, except in CVS where it increased by 115% due to a 5-fold increase in patients with dual antiplatelet therapy (2.7 vs. 13.7%; p < 0.0001).
The implementation of perioperative POC coagulation management algorithms based on early, calculated, goal-directed therapy with fibrinogen concentrate and PCC is associated with a reduction in the transfusion requirements for FFP, PRBC and platelets as well as with a reduced incidence of massive transfusion. Thus, the limited blood resources can be used more efficiently.
Thromboelastometry; Transfusion algorithms; Fibrinogen concentrate; Prothrombin complex concentrate; Transfusion-associated adverse events; Pharmacoeconomics
Supplemental digital content is available in the text.
Fibrinogen plays a key role in hemostasis and is the first coagulation factor to reach critical levels in bleeding patients. Current European guidelines on the management of traumatic or perioperative bleeding recommend fibrinogen supplementation at specific threshold levels. Whole blood viscoelastic tests provide fast evaluation of fibrin deficits. Fast measurement of plasma fibrinogen concentration is not yet available. We investigated a method to rapidly determine whole blood fibrinogen concentration using standard Clauss assays and a steel ball coagulometer and provide an estimate of the “plasma-equivalent” fibrinogen concentration within minutes by adjustment of the measured whole blood fibrinogen concentration with a quickly measureable hemoglobin-derived hematocrit.
The feasibility of this approach was tested with a Clauss assay using multiple porcine fresh blood samples obtained during in vivo bleeding, hemodilution, and after treatment with hemostatic therapy. Two different Clauss assays were then tested using multiple human volunteers’ blood samples diluted in vitro and supplemented with fibrinogen concentrate. Comparative measurements with fibrin-based thromboelastometry tests were performed.
Regression and Bland-Altman analyses of derived “plasma-equivalent” fibrinogen and measured plasma fibrinogen concentration was excellent in porcine and human blood samples, especially in the ranges relevant to traumatic or perioperative bleeding.
Fast whole blood fibrinogen measurements could be considered as an alternative to plasma fibrinogen measurement for acute bleeding management in trauma and perioperative care settings. Further studies are needed to prove this concept and determine the turnaround times for its clinical application in emergency departments and operating theaters.
Blood coagulation tests; clinical laboratory techniques; fibrinogen; pigs
Bleeding remains an ongoing concern after total knee arthroplasty (TKA). Intraarticular application of human fibrinogen with a topical thrombin has been described to stop diffuse bleeding in knee arthroplasty.
It was hypothesized that the use of human fibrinogen as a topical agent would result in a reduction of bleeding and transfusions required after TKA; secondary end points included comparison of early clinical results including pain scores and range of motion (ROM) at 6 weeks and complications after surgery.
Two hundred patients undergoing TKA were randomized into a double-blind clinical trial to receive either intraarticular fibrinogen 2 minutes before tourniquet release or no such treatment. Postoperative hemoglobin and hematocrit levels, drain output, and transfusion requirements were recorded and blood loss was calculated. Clinical outcomes and adverse events were tracked prospectively. Descriptive analysis was performed using a two-sample t-test.
There were no differences in calculated blood loss between the fibrinogen and the control groups; the mean postoperative drain output was 780 ± 378 mL in the fibrinogen group compared with 673 ± 301 mL in the control group (p = 0.029), but the hemoglobin drop at Day 2 was 3.47 ± 1.53 g/L in the fibrinogen group and 3.84 ± 1.24 g/Ll in the control group (p = 0.051). There were no differences in in transfusions, early ROM, visual analog pain scores, or complications between the groups.
The use of fibrinogen in TKA did not lead to a significant reduction of blood loss or transfusions in primary TKA for osteoarthritis. Given the lack of benefits and the costs this procedure adds to TKA, its routine use cannot be justified during primary TKA for osteoarthritis.
Level of Evidence
Level I, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.