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1.  Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study 
BJA: British Journal of Anaesthesia  2009;102(6):785-792.
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.
PMCID: PMC2683341  PMID: 19411671
blood, coagulation; measurement techniques, thrombelastograph; surgery, cardiovascular; transfusion
2.  Time course of haemostatic effects of fibrinogen concentrate administration in aortic surgery 
BJA: British Journal of Anaesthesia  2013;110(6):947-956.
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.
PMCID: PMC3657602  PMID: 23388508
blood coagulation tests; cardiopulmonary bypass; fibrin; fibrinogen; plasma
3.  Impact of fibrinogen concentrate alone or with prothrombin complex concentrate (+/− fresh frozen plasma) on plasma fibrinogen level and fibrin-based clot strength (FIBTEM) in major trauma: a retrospective study 
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.
PMCID: PMC3852540  PMID: 24103457
Fibrinogen concentrate; Prothrombin complex concentrate; Fresh frozen plasma; Thromboelastometry (ROTEM)
4.  Fibrinogen concentrate administration attributes to significant reductions of blood loss and transfusion requirements in thoracic aneurysm repair 
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.
PMCID: PMC4067735  PMID: 24884627
Massive hemorrhage; Thoracic aortic aneurysm; Cardiopulmonary bypass; Dilutional coagulopathy; Hypofibrinogenemia
5.  Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy 
Critical Care  2011;15(2):R83.
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.
PMCID: PMC3219338  PMID: 21375741
6.  Effect of haematocrit on fibrin-based clot firmness in the FIBTEM test 
Blood Transfusion  2013;11(3):412-418.
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.
PMCID: PMC3729133  PMID: 23245708
cardiac surgery; fibrinogen; FIBTEM; haematocrit; thromboelastometry
7.  Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review 
Critical Care  2011;15(5):R239.
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.
PMCID: PMC3334790  PMID: 21999308
8.  The FIB-PPH trial: fibrinogen concentrate as initial treatment for postpartum haemorrhage: study protocol for a randomised controlled trial 
Trials  2012;13:110.
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.
Trial registration NCT01359878.
PMCID: PMC3434105  PMID: 22805300
Postpartum haemorrhage; Haemostasis; Blood transfusion; Fibrinogen concentrate; Obstetrics; Thrombelastography; Coagulation
9.  Functional Fibrinogen Assay Indicates That Fibrinogen is Critical in Correcting Abnormal Clot Strength Following Trauma 
Shock (Augusta, Ga.)  2013;39(1):45-49.
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.
PMCID: PMC3529156  PMID: 23247121
Functional Fibrinogen; TEG; Clot Strength; Trauma; Fibrinogen Concentrate; Platelets; Resuscitation
10.  Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM®)-guided administration of fibrinogen concentrate and prothrombin complex concentrate 
Critical Care  2010;14(2):R55.
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.
PMCID: PMC2887173  PMID: 20374650
11.  Theoretical modelling of fibrinogen supplementation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate 
BJA: British Journal of Anaesthesia  2014;113(4):585-595.
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.
PMCID: PMC4166889  PMID: 25064078
computer simulation; cryoprecipitate; drug dosage calculations; fibrinogen; plasma
12.  Administration of fibrinogen concentrate for refractory bleeding in massively transfused, non-trauma patients with coagulopathy: a retrospective study with comparator group 
BMC Anesthesiology  2014;14(1):109.
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.
PMCID: PMC4258800  PMID: 25489274
Anaemia; Bleeding; Clauss method; Fibrinogen concentrate; Goal directed therapy; Massive transfusion protocol; Thromboelastometry; ROTEM; Thromboelastography; TEG; FIBTEM; Transfusion
13.  Fresh Frozen Plasma in Pump Priming for Congenital Heart Surgery: Evaluation of Effects on Postoperative Coagulation Profiles Using a Fibrinogen Assay and Rotational Thromboelastometry 
Yonsei Medical Journal  2013;54(3):752-762.
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.
PMCID: PMC3635629  PMID: 23549826
Congenital heart disease; cardiopulmonary bypass; blood coagulation disorder; fresh frozen plasma
14.  Platelet Glycoproteins and Fibrinogen in Recovery from Idiopathic Sudden Hearing Loss 
PLoS ONE  2014;9(1):e86898.
The pathomechanism and location of idiopathic sudden sensorineural hearing loss (ISSHL) is unclear. In a previous case-control study, we found elevated fibrinogen concentrations and a higher prevalence of T allele carriers of the glycoprotein (Gp) Ia C807T polymorphism in ISSHL patients.
127 patients with ISSHL (mean age 53.3 years, 48.8% females), who underwent a standard therapy with high dose steroids, pentoxifyllin and sterofundine over 8 days were included. We examined the influence of GpIa genotype and fibrinogen (BclI-, A312-, HaeIII-) genotype and fibrinogen plasma levels on hearing recovery after 8 weeks (change from baseline: 0 dB  =  no recovery, >0 to 10 dB = moderate recovery, >10 dB = good recovery). In a subsample of 59 patients with ISSHL, we further studied the association of platelet glycoprotein GpIa, Ib and IIIa densities on hearing recovery as well as the possible effect-modification of platelet glycoproteins on hearing recovery by plasma fibrinogen.
In univariate analysis, neither the GpIa genotype nor fibrinogen genotype (all p>0.1) but lower fibrinogen levels (p = 0.029), less vertigo (p = 0.002) and lower GpIIIa receptor density (p = 0.037, n = 59) were associated with hearing recovery. In multivariate analysis, fibrinogen significantly modified the effect of GPIa receptor density on good hearing recovery (effect-modification on multiplicative scale OR = 0.45 (95% confidence interval (0.21–0.94)), p = 0.03). GPIb receptor density below the mean was associated with a 2-fold increase in good hearing recovery both in patients with fibrinogen levels above (p = 0.04) as well as in patients with fibrinogen levels below the mean (p = 0.06). There was no indication for an effect-modification (p = 0.97).
The findings suggest a vascular/rheological origin of ISSHL with unique features of thrombosis in the inner ear artery that may include complex interrelationships among platelet glycoproteins and plasma fibrinogen.
PMCID: PMC3900659  PMID: 24466284
15.  Comparison of three point-of-care testing devices to detect hemostatic changes in adult elective cardiac surgery: a prospective observational study 
BMC Anesthesiology  2014;14:80.
Bleeding complications in cardiac surgery may lead to increased morbidity and mortality. Traditional blood coagulation tests are not always suitable to detect rapid changes in the patient's coagulation status. Point-of-care instruments such as the TEG (thromboelastograph) and RoTEM (thromboelastometer) have been shown to be useful as a guide for the clinician in the choice of blood products and they may lead to a reduction in the need for blood transfusion, contributing to better patient blood management.
The purpose of this study was to evaluate the ability of the TEG, RoTEM and Sonoclot instruments to detect changes in hemostasis in elective cardiac surgery with cardiopulmonary bypass and to investigate possible correlations between variables from these three instruments and routine hematological coagulation tests. Blood samples from thirty-five adult patients were drawn before and after surgery and analyzed in TEG, RoTEM, Sonoclot and routine coagulation tests. Data were compared using repeated measures analysis of variance and Pearson's test for linear correlation.
We found significant changes for all TEG variables after surgery, for three of the RoTEM variables, and for one variable from the Sonoclot. There were significant correlations postoperatively between plasma fibrinogen levels and variables from the three instruments.
TEG and RoTEM may be used to detect changes in hemostasis following cardiac surgery with CPB. Sonoclot seems to be less suitable to detect such changes. Variables from the three instruments correlated with plasma fibrinogen and could be used to monitor treatment with fibrinogen concentrate.
PMCID: PMC4179787  PMID: 25276093
Blood; Cardiac surgery; Cardiopulmonary bypass (CPB); Coagulation; Thromboelastography; Thromboelastometry
16.  Reduction of Fresh Frozen Plasma Requirements by Perioperative Point-of-Care Coagulation Management with Early Calculated Goal-Directed Therapy 
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.
PMCID: PMC3364099  PMID: 22670128
Thromboelastometry; Transfusion algorithms; Fibrinogen concentrate; Prothrombin complex concentrate; Transfusion-associated adverse events; Pharmacoeconomics
17.  Intraarticular Fibrinogen Does Not Reduce Blood Loss in TKA: A Randomized Clinical Trial 
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.
PMCID: PMC3889440  PMID: 23657879
18.  Can Plasma Fibrinogen Levels Predict Bleeding After Coronary Artery Bypass Grafting? 
Fibrinogen is the main biomarker for bleeding. To prevent excessive postoperative bleeding, it would be useful to identify high-risk patients before coronary artery bypass grafting (CABG).
In order to predicating bleeding after CABG, we sought to determine whether preoperative fibrinogen concentration was associated with the amount of bleeding following CABG.
Patients and Methods:
A total of 144 patients (mean age = 61.50 ± 9.42 years; 65.7% men), undergoing elective and isolated CABG, were included in this case-series study. The same anesthesia technique and medicines were selected for all the patients. In the ICU, the patients were assessed in terms of bleeding at 12 and 24 hours post-operation, amount of contingent blood products received, and relevant tests. Statistical tests were subsequently conducted to analyze the correlation between preoperative fibrinogen concentration and the amount of post-CABG bleeding.
The mean ± standard deviation of bleeding at 12 and 24 hours post-operation was 285.37 ± 280.27 and 499.31 ± 355.57 mL, respectively. The results showed that postoperative bleeding was associated with different factors whereas pre-anesthesia fibrinogen was not correlated with bleeding at 12 (P = 0.856) and 24 hours (P = 0.936) post-operation. There were correlations between the extra-corporal circulation time and bleeding at 12 hours post-operation (ρ = 0.231, P = 0.007) and bleeding at 24 hours post-operation (ρ = 0.218, P = 0.013).
Preoperative assessment of plasma fibrinogen levels failed to predict post-CABG bleeding.
PMCID: PMC4253797  PMID: 25478546
Hemorrhage; Coronary Artery Bypass; Fibrinogen
19.  Effects of fibrinogen concentrate after shock/resuscitation – A comparison between in vivo microvascular clot formation and thromboelastometry 
Critical care medicine  2013;41(11):e301-e308.
Dilutional coagulopathy after resuscitation with crystalloids/colloids clinically often appears as diffuse microvascular bleeding. Administration of fibrinogen reduces bleeding and increases maximum clot firmness (MCF), measured by thromboelastometry. Study objective was to implement a model where microvascular bleeding can be directly assessed by visualizing clot formation in microvessels, and correlations can be made to thromboelastometry.
Randomized animal study.
University research laboratory.
Male Syrian Golden hamsters.
Microvessels of Syrian Golden hamsters fitted with a dorsal window chamber were studied using videomicroscopy. After 50% hemorrhage followed by 1 hr of hypovolemia resuscitation with 35% of blood volume using a high molecular weight (MW) HES solution (Hextend®, Hospira, MW 670 kD) occurred. Animals were then treated with 250 mg/kg fibrinogen iv (Laboratoire français du Fractionnement et des Biotechnologies (LFB), Paris, France) or an equal volume of saline before venular vessel wall injuries were made by directed laser irradiation and the ability of microthrombus formation was assessed.
Measurements and main results
Thromboelastometric measurements of MCF were performed at the beginning and at the end of the experiment. Resuscitation with HES and sham treatment significantly decreased FIBTEM MCF from 32 ± 9 at baseline vs. 13 ± 5 mm after sham treatment (p < 0.001). Infusion of fibrinogen concentrate significantly increased MCF, restoring baseline levels (baseline 32 ± 9 mm; after fibrinogen administration 29 ± 2 mm).
In vivo microthrombus formation in laser injured vessels significantly increased in fibrinogen treated animals compared with sham (77% vs. 18%).
Fibrinogen treatment leads to increased clot firmness in dilutional coagulopathy as measured with thromboelastometry. At the microvascular level this increased clot strength, corresponds to an increased incidence of thrombus formation in vessels injured by focused laser irradiation.
PMCID: PMC4109711  PMID: 23978812
Dilutional coagulopathy; fibrinogen polymerization; laser injury; thrombus formation; hemorrhagic shock; colloid resuscitation
20.  Blood transfusion and the anaesthetist: management of massive haemorrhage 
Anaesthesia  2010;65(11):1153-1161.
Hospitals must have a major haemorrhage protocol in place and this should include clinical, laboratory and logistic responses.Immediate control of obvious bleeding is of paramount importance (pressure, tourniquet, haemostatic dressings).The major haemorrhage protocol must be mobilised immediately when a massive haemorrhage situation is declared.A fibrinogen < 1 g.l−1 or a prothrombin time (PT) and activated partial thromboplastin time (aPTT) of > 1.5 times normal represents established haemostatic failure and is predictive of microvascular bleeding. Early infusion of fresh frozen plasma (FFP; 15−1) should be used to prevent this occurring if a senior clinician anticipates a massive haemorrhage.Established coagulopathy will require more than 15−1 of FFP to correct. The most effective way to achieve fibrinogen replacement rapidly is by giving fibrinogen concentrate or cryoprecipitate if fibrinogen is unavailable.1:1:1 red cell:FFP:platelet regimens, as used by the military, are reserved for the most severely traumatised patients.A minimum target platelet count of 75 × 109.l−1 is appropriate in this clinical situation.Group-specific blood can be issued without performing an antibody screen because patients will have minimal circulating antibodies. O negative blood should only be used if blood is needed immediately.In hospitals where the need to treat massive haemorrhage is frequent, the use of locally developed shock packs may be helpful.Standard venous thromboprophylaxis should be commenced as soon as possible after haemostasis has been secured as patients develop a prothrombotic state following massive haemorrhage.
PMCID: PMC3032944  PMID: 20963925
21.  Use of prothrombin complex concentrate for excessive bleeding after cardiac surgery 
Prothrombin complex concentrates (PCCs) are sometimes used as ‘off label’ for excessive bleeding after cardiopulmonary bypass (CPB). The main objective of this study was to retrospectively evaluate the clinical and biological efficacy of PCC in this setting.
We reviewed the charts of all patients who had undergone cardiac surgery under CPB in our institution for 2 years. Patients treated for active bleeding with haemostatic therapy were identified. Chest tube blood loss was quantified postoperatively in the first 24 h. Coagulation parameters were recorded at intensive care unit admission and in the patient's first 24 h. Thromboembolic complications were also ascertained.
Seventy-seven patients out of the 677 studied (11.4%) were included: PCC was solely administered in 24 patients (group I), fresh frozen plasma in 26 (group II) and both in 27 (group III). The mean dose of PCC was 10.0 UI/kg ± 3.5 for group I vs 14.1 UI/kg ± 11.2 for group III (P = 0.09). Initial blood loss in the first hour was different between the three groups (P = 0.05): 224 ± 131 ml for group I, 369 ± 296 ml for group II and 434 ± 398 ml for group III. Only group I vs group III presented a significant difference (P = 0.02). Variations of blood loss over time were no different according to the treatment groups (P = 0.12). Reductions in blood loss expressed in percentage showed no difference between the three groups after 2 h: 54.5% (68.6–30.8) for group I; 45.0% (81.6–22.2) for group II; 57.6 (76.0–2.1) for group III; (P = 0.89). Re-exploration for bleeding involved 1 patient in group I (4%), 2 in group II (8%) and 10 in group III (37%) (P = 0.002). Except for fibrinogen, variations of prothrombin time, activated partial thromboplastin time and platelets with time were not different according to the treatment groups. Cerebral infarction occurred in one patient in group II.
Administration of low-dose of PCC significantly decreased postoperative bleeding after CPB.
PMCID: PMC3422937  PMID: 22623627
Prothrombin complex concentrates; Bleeding; Cardiopulmonary bypass; Thromboembolic complications
22.  von Willebrand factor interaction with the glycoprotein IIb/IIa complex. Its role in platelet function as demonstrated in patients with congenital afibrinogenemia. 
Journal of Clinical Investigation  1986;77(4):1272-1277.
We have studied three afibrinogenemic patients, who had only trace amounts of plasma and platelet fibrinogen as measured by radioimmunoassay, and demonstrate here that the residual aggregation observed in their platelet-rich plasma is dependent upon von Willebrand factor (vWF) binding to the platelet membrane glycoprotein (GP)IIb/IIIa complex. The abnormality of aggregation was more pronounced when ADP, rather than thrombin, collagen, or the combination of ADP plus adrenaline was used to stimulate platelets. With all stimuli, nevertheless, the platelet response was completely inhibited by a monoclonal antibody (LJP5) that is known to block vWF, but not fibrinogen binding to GPIIb/IIIa. Addition of purified vWF to the afibrinogenemic plasma resulted in marked increase in the rate and extent of aggregation, particularly when platelets were stimulated with ADP. This response was also completely blocked by LJP5. Addition of fibrinogen, however, restored normal aggregation even in the presence of LJP5, a finding consistent with the knowledge that antibody LJP5 has no effect on platelet aggregation mediated by fibrinogen binding to GPIIb/IIIa. Two patients gave their informed consent to receiving infusion of 1-desamino-8-D-arginine vasopressin (DDAVP), a vasopressin analogue known to raise the vWF levels in plasma by two- to fourfold. The bleeding time, measured before and 45 min after infusion, shortened from greater than 24 min to 12 min and 50 s in one patient and from 16 min to 9 min and 30 s in the other. Concurrently, the rate and extent of ADP-induced platelet aggregation improved after DDAVP infusion. The pattern, however, reversed to baseline levels within 4 h. The concentration of plasma vWF increased after DDAVP infusion, but that of fibrinogen remained at trace levels. We conclude that vWF interaction with GPIIb/IIIa mediates platelet-platelet interaction and may play a role in primary hemostasis.
PMCID: PMC424474  PMID: 3007578
23.  Prognostic significance of preoperative fibrinogen in patients with colon cancer 
AIM: To investigate the prognostic significance of preoperative fibrinogen levels in colon cancer patients.
METHODS: A total of 255 colon cancer patients treated at the Affiliated Tumor Hospital of Xinjiang Medical University from June 1st 2005 to June 1st 2008 were enrolled in the study. All patients received radical surgery as their primary treatment method. Preoperative fibrinogen was detected by the Clauss method, and all patients were followed up after surgery. Preoperative fibrinogen measurements were correlated with a number of clinicopathological parameters using the Student t test and analysis of variance. Survival analyses were performed by the Kaplan-Meier method and Cox regression modeling to measure 5-year disease-free survival (DFS) and overall survival (OS).
RESULTS: The mean preoperative fibrinogen concentration of all colon cancer patients was 3.17 ± 0.88 g/L. Statistically significant differences were found between preoperative fibrinogen levels and the clinicopathological parameters of age, smoking status, tumor size, tumor location, tumor-node-metastasis (TNM) stage, modified Glasgow prognostic scores (mGPS), white blood cell (WBC) count, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and carcinoembryonic antigen (CEA) levels. Univariate survival analysis showed that TNM stage, tumor cell differentiation grade, vascular invasion, mGPS score, preoperative fibrinogen, WBC, NLR, PLR and CEA all correlated with both OS and DFS. Alpha-fetoprotein (AFP) and body mass index correlated only with OS. Kaplan-Meier analysis revealed that both OS and DFS of the total cohort, as well as of the stage II and III patients, were higher in the hypofibrinogen group compared to the hyperfibrinogen group (all P < 0.05). In contrast, there was no significant difference between OS and DFS in stage I patients with low or high fibrinogen levels. Cox regression analysis indicated preoperative fibrinogen levels, TNM stage, mGPS score, CEA, and AFP levels correlated with both OS and DFS.
CONCLUSION: Preoperative fibrinogen levels can serve as an independent prognostic marker to evaluate patient response to colon cancer treatment.
PMCID: PMC4093707  PMID: 25024612
Fibrinogen; Colon cancer; Clinicopathological parameters; Relationship; Prognosis
24.  Activated coagulation time vs. intrinsically activated modified rotational thromboelastometry in assessment of hemostatic disturbances and blood loss after protamine administration in elective cardiac surgery: analysis from the clinical trial (NCT01281397) 
Excessive bleeding after cardiopulmonary bypass (CPB) is risk factor for adverse outcomes after elective cardiac surgery (ECS). Although many different point-of-care devices to diagnose hemostatic disturbances after CPB are available, the best test is still unclear. The study aim was to compare the accuracy of hemostatic disorder detection between two point-of-care devices.
We enrolled 148 patients (105 male and 43 female) undergoing ECS in a prospective observational study. Rotational thromboelastometry (TEM, with InTEM test), and Activated coagulation time (ACT) measurement were performed 15 min after protamine administration. The cohort group was divided into two subgroups according to occurrence of excessive postoperative bleeding. Endpoints were defined in two ways: as total amount of chest tube output (CTO) and blood product transfusion requirements.
Total amount of CTO value of 1507,50 mL presented 75th percentile of distribution, thus cut-off value for bleeder category. InTEM parameters, but not ACT, correlated significantly with CTO. InTEM parameters with the strongest correlation to CTO were tested for accuracy in predicting excessive postoperative bleeding using ROC analysis. InTEM A 10 value of 38 mm, InTEM A 20 value of 49 mm and InTEM A 30 value of 51 mm delineated bleeding tendency. Patients with total amount of CTO exceeding 75th percentile were more frequently transfused with fresh frozen plasma (51.4% vs. 9.9%, p < 0.001), fibrinogen concentrate (21.6% vs. 2.7%, p = 0.001) and platelet concentrate (13.5% vs. 0.9%, p = 0.004).
Our study showed that InTEM test, but not ACT is useful in prediction of bleeding tendency after protamine administration following weaning from CPB. InTEM test could be used as a first line test in screening of possible hemostatic disorder following protamine administration.
PMCID: PMC4283124  PMID: 25231271
Rotational thromboelastometry; Hemorrhage; Cardiac surgery; Activating coagulation time; Transfusion; Bleeding management
25.  Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre observational study 
Critical Care  2014;18(2):R52.
Exsanguination due to trauma-induced coagulopathy is a continuing challenge in emergency trauma care. Fibrinogen is a crucial factor for haemostatic competence, and may be the factor that reaches critically low levels first. Early fibrinogen substitution is advocated by a number of authors. Little evidence exists regarding the indications for fibrinogen supplementation in the acute phase. This study aims to estimate the prevalence of hypofibrinogenaemia in a multi-center trauma population, and to explore how initial fibrinogen concentration relates to outcome. Also, factors contributing to low fibrinogen levels are identified.
Patients arriving in hospital less than 180 minutes post-injury requiring full trauma team activation in four different centers were included in the study. Time from injury, patient demographics, injury severity scores (ISS) and 28 days outcome status were recorded. Initial blood samples for coagulation and blood gas were analyzed. Generalized additive regression, piecewise linear regression, and multiple linear regression models were used for data analyses.
Out of 1,133 patients we identified a fibrinogen concentration ≤1.5g/L in 8.2%, and <2 g/L in 19.2%. A non-linear relationship between fibrinogen concentration and mortality was detected in the generalized additive and piecewise linear regression models. In the piecewise linear regression model we identified a breakpoint for optimal fibrinogen concentration at 2.29 g/L (95% confidence interval (CI): 1.93 to 2.64). Below this value the odds of death by 28 days was reduced by a factor of 0.08 (95% CI: 0.03 to 0.20) for every unit increase in fibrinogen concentration. Low age, male gender, lengthened time from injury, low base excess and high ISS were unique contributors to low fibrinogen concentrations on arrival.
Hypofibrinogenaemia is common in trauma and strongly associated with poor outcome. Below an estimated critical fibrinogen concentration value of 2.29 g/L a dramatic increase in mortality was detected. This finding indicates that the negative impact of low fibrinogen concentrations may have been previously underestimated. A number of clinically identifiable factors are associated with hypofibrinogenaemia. They should be considered in the management of massively bleeding patients. Interventional trials with fibrinogen substitution in high-risk patients need to be undertaken.
PMCID: PMC4056526  PMID: 24666991

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