The Impact Factor measures the average number of citations received in a particular year by papers published in the journal during the two preceding years. SRJ is a prestige metric based on the idea that not all citations are the same. SJR uses a similar algorithm as the Google page rank; it provides a quantitative and qualitative measure of the journal's impact.
SNIP measures contextual citation impact by wighting citations based on the total number of citations in a subject field. Surgery and massive trauma are frequently associated with significant derangement of haemostatic capacity, caused by loss, consumption, endogenous inhibition by the protein C pathway , dilution of coagulation factors, and increased clot breakdown fibrinolysis.
Haemostatic therapy in patients without pre-existing haemostatic disorders aims to substitute key components clotting factors and other blood components by transfusion of allogeneic blood products, including fresh frozen plasma FFP , platelet concentrate PC , red blood cells RBC and, in some countries, cryoprecipitate or coagulation factor concentrates.
Most commonly, it is not a prophylactic administration of coagulation factors to supranormal levels but rather a correction of critically reduced coagulation factor activity or levels. Typically, standard preparation FFP contains 2. Concentrations are heterogeneous depending on the donor and mode of preparation.
Each vial of fibrinogen concentrate contains about 1. The concentrated dose of fibrinogen provided by fibrinogen concentrate could be preferable to FFP for restoring plasma fibrinogen levels because of its rapid availability no thawing , reduced volume faster infusion times and increased safety, and has recently been suggested to be more effective than administration of FFP.
In perioperative bleeding PCC containing activated coagulation factors factor eight bypassing activity is not routinely used. Clinical use of FFP in component therapy has increased over the past four decades. The benefits of any intervention should outweigh the risks: FFP has been associated with increased risk of morbidity and mortality. The evidence for the efficacy of fibrinogen concentrate was consistently positive with no negative effects reported. A Cochrane review assessed the use of fibrinogen concentrate in bleeding patients with the conclusion that it seems to reduce transfusion requirements but further studies are warranted to demonstrate its harms and benefits.
There are no factor concentrates currently available, e. After massive transfusion, replacement of these enzymes can only be achieved by FFP transfusion. According to evidence-based medicine methodology it would be rational to recommending that FFP should not be used outside clinical trials for fibrinogen and prothombin complex substitution until further data demonstrate the applicability of plasma to treat coagulopathy in bleeding patients.
Currently, 4 randomised controlled trials investigating the efficacy and safety of therapeutic plasma in comparison with other available choices of haemostatic therapy for fibrinogen supplementation are ongoing; no data have been released as yet. Reconstitution of these 3 allogeneic blood products results in dilution of erythrocytes, platelets and fibrinogen levels 9 ; adequate and timely correction of coagulopathy is not feasible.
Cost-effectiveness of a FFP ratio-driven transfusion protocol has not been investigated yet. There is a paucity of high-quality evidence reporting the clinical effectiveness of FFP in a perioperative or massive trauma setting, despite the long period of its usage. Controlled trials with robust blinding and randomisation procedures are warranted. Currently, FFP is overused, FFP is abused for volume replacement, adequate laboratory parameters for assessing the indication for haemostatic therapy are underused e.
An individualised, rational plasma transfusion behaviour with careful monitoring of indication, efficacy e. Final recommendations on when to use plasma and when coagulation factor concentrates are summarized in the table. ISSN: Previous article Next article. Issue 6. Pages August - September More article options. Clinical efficacy of fresh frozen plasma compared with coagulation factor concentrates for treating coagulopathy in patients with massive bleeding.
Download PDF. This item has received. Article information. Full Text. Perioperative indication for coagulation factor supplementation Surgery and massive trauma are frequently associated with significant derangement of haemostatic capacity, caused by loss, consumption, endogenous inhibition by the protein C pathway , dilution of coagulation factors, and increased clot breakdown fibrinolysis.
Alternatives for coagulation factor supplementation Typically, standard preparation FFP contains 2. Clinical routine despite poor efficacy Clinical use of FFP in component therapy has increased over the past four decades. The following table provides guidelines for selection of compatible FFP units:.
Often times, plasma is ordered prophylactically to rapidly correct an elevated INR in a patient receiving warfarin therapy prior to an invasive procedure. The INR results of nonbleeding patients, who were transfused with plasma only, were analyzed between Oct 25, and May 16, The longer the pre-transfusion INR, the greater the correction achieved with a single unit of plasma.
Whereas, as many as 4 bags of plasma may be necessary to correct an INR of 1. When the INR is 1. Physicians performing invasive procedures want to avoid hemorrhagic complications and often regard a mild elevation of a coagulation test result as an indication to order plasma. The decision to prophylactically transfuse plasma is based on two unproven assumptions:.
An analysis of the Vitamin K dependent coagulation factors at different INR values clearly contradicts the first assumption. These results explain why a mildly elevated INR is not usually associated with spontaneous hemorrhage and does not increase the risk of bleeding during routine invasive procedures. Studies during the last 20 years in patients undergoing liver biopsies, bronchoscopic biopsies, renal biopsies, central line vein cannulation, thoracentesis and angiography have repeatedly demonstrated that INR and PTT are not predictive of hemorrhage.
While a patient with an INR of 1. However, it must be remembered that the risk of bleeding is greater if the platelet count is decreased, platelet function is abnormal, the patient has received antiplatelet medication, has experienced massive trauma or is undergoing extensive surgery. In view of this information, the common practice of prescribing plasma to correct a mildly elevated INR prior to an invasive procedure needs to be reevaluated.
It is usually not necessary or efficacious to correct an INR below 1. In summary, plasma transfusion has minimal effect on normalizing the INR in patients with mildly prolonged INRs for the following reasons:.
For elective surgery, the best strategy for warfarin reversal is to discontinue warfarin 3 to 5 days prior to the procedure. Patients presenting with minor bleeding may be treated by withholding the next dose of warfarin and giving oral Vitamin K. When vitamin K replacement therapy is used, its effect does not begin until hours after administration and is not complete until 36 hours. There was no significant difference between the FFP and 'pathogen-reduced' plasma groups.
Four comparator studies reported the effect of fibrinogen concentrate on blood loss Table 5. Three of these studies involved adults, of which one was an RCT involving the prophylactic administration of 2 g of fibrinogen concentrate prior to surgery [ 54 ].
The other two were comparator trials evaluating the post cardiopulmonary bypass administration of 7. Another RCT investigated the effect of fibrinogen concentrate administration and transfusion therapy guided by thromboelastography compared with 'standard allogeneic transfusion therapy' in children undergoing complex CV surgery [ 56 ].
Postoperative blood loss at 1, 6 and 24 hours by CTD was similar in both groups. Researchers in another seven noncomparator articles one retrospective observational study and six case studies observed a beneficial effect of fibrinogen concentrate on blood loss, with haemostasis frequently achieved after allogeneic transfusion therapies had failed [ 57 — 63 ]. The retrospective observational study of 43 patients comprising 39 adults, 8 of whom were excluded from analysis because of early death, and 4 newborns reported a significant decrease in median blood loss from 4, to 50 ml in the adult patients following administration of fibrinogen concentrate during serious haemorrhage [ 59 ].
A case report of a trauma patient suggested that 15 U of FFP would have been required to achieve haemostasis in place of the 5-g fibrinogen concentrate administered, which would have exposed the patient to the risk of volume overload as well as the risks associated with administration of any allogeneic blood product [ 60 ].
A total of 19 comparator studies reported 22 outcomes of the effect of FFP on allogeneic transfusion requirements [ 22 , 23 , 30 , 35 — 37 , 39 , 41 , 43 , 44 , 47 , 49 , 50 , 64 — 69 ]. These requirements were reported as intraoperative, postoperative or total studies in which the requirements were reported for the whole perioperative period. Of these studies, only five showed some benefit for FFP over the comparator group, with the majority of the studies finding no effect and two studies reporting an increase in allogeneic transfusion requirements in the groups receiving FFP Table 6.
Six of these showed no difference in the intraoperative [ 23 ], postoperative [ 23 , 35 , 36 , 47 ] or total [ 41 , 49 ] requirements requirements were measured as either RBC or any allogeneic product and excluded the study dose of FFP.
The study showed that transfusion requirements for RBC were significantly higher both intra- and postoperatively among those patients receiving FFP compared with patients administered HES. A further paediatric study also found that a greater proportion of patients in the FFP group required postoperative transfusions compared with those not receiving FFP [ 44 ].
Two studies that compared FFP with 'pathogen-reduced' plasma showed no differences between groups in the total requirements for allogeneic transfusion [ 22 , 65 ]. There were another two noncomparator studies one prospective and one retrospective reporting the effect of FFP on allogeneic transfusion requirements [ 53 , 70 ]. The volume of intraoperatively transfused FFP was inversely associated with the postoperative administration of allogeneic products in one paediatric study [ 70 ].
The effect of fibrinogen concentrate on allogeneic transfusions was assessed in five comparator trials, four of which showed a reduction in requirements as a result of the intervention [ 26 , 54 — 56 , 71 ] Table 6. A third study reported lower postoperative RBC requirements in the fibrinogen concentrate group compared with the control group that received saline , with no difference found for intraoperative RBC requirements [ 71 ].
The fourth study, a RCT of children undergoing CV surgery, found a significant reduction in postoperative and total FFP requirements in the fibrinogen concentrate group compared with the control group [ 56 ]. The intervention group received less than half the amount of FFP than the control group No differences were seen in the amount of intra-, post- or perioperative RBC administered.
A fifth study reported no difference in the amount of postoperative allogeneic products administered to the group that had received a prophylactic dose of 2 g of fibrinogen concentrate prior to surgery compared with the control group no fibrinogen concentrate [ 54 ]. Four retrospective noncomparator studies provided evidence for a reduction in allogeneic transfusion requirements following administration of fibrinogen concentrate, with a further five case studies also suggesting a reduction as a result of the intervention [ 57 — 62 , 72 — 74 ].
One of the noncomparator studies that presented data derived from CV surgery patients reported that 35 of 39 patients did not receive any further intraoperative FFP or PC after administration of fibrinogen concentrate the remaining four patients received PC [ 72 ].
In addition, in the postoperative period, only 11 of 39 patients required additional transfusions, whereas in another sizable study of trauma patients, only 6 of the patients who received fibrinogen concentrate were administered intraoperative FFP, and only 12 of received FFP in the first 24 hours after admission to the emergency room [ 73 ]. The other two noncomparator studies demonstrated a reduction in allogeneic transfusions, with one reporting a drop in transfusion of RBC from 6 U to 3 U after administration of fibrinogen concentrate [ 74 ] and the other reporting significantly fewer allogeneic transfusions in the 24 hours after administration of the fibrinogen concentrate than in the 24 hours prior to administration [ 59 ].
We found 32 comparator studies involving FFP reporting results from 40 time points over periods ranging from 6 hours to 10 years [ 3 , 4 , 28 , 31 — 34 , 38 — 40 , 42 , 66 — 69 , 75 — 93 ] Table 7.
Eight studies compared the effect of FFP with no FFP, of which, three showed no effect of the intervention on survival trauma with nonmassive transfusion [ 79 ], hepatectomy for hepatocellular carcinoma [ 40 ] and CV surgery [ 84 ] , and five reported reduced survival for patients receiving FFP trauma [ 77 ], traumatic brain injury [ 78 ], liver transplantation [ 82 ], liver resection for colorectal metastases [ 88 ] and hepatectomy for hepatocellular carcinoma [ 92 ].
In the trauma study, the investigators found a dose-dependent correlation between FFP transfusion and mortality, with each unit of FFP given increasing the risk of death by 3. The effect of FFP on patient mortality has largely been reported in the form of articles exploring the impact of different FFP:RBC ratios, of which we found 19 such studies.
Sixteen studies reported the impact of FFP:RBC ratios in trauma patients, typically by comparing a prospective cohort that received a 'transfusion protocol' with a historical cohort that received treatment prior to implementation of the protocol [ 3 , 4 , 28 , 31 — 34 , 66 — 68 , 80 , 81 , 85 — 87 , 89 — 91 ].
In general, outcomes were favourable for patients who received more FFP than for those who received less FFP, though the exact ratio needed to achieve an improvement in the survival rate was not consistent. Ten noncomparator studies also reported on the effect of FFP on survival [ 94 — ]. Furthermore, FFP administration was associated with a 2. Higher levels of FFP were also reported to improve survival in two trauma studies [ 97 , 99 ]. Only three fibrinogen concentrate studies, one retrospective comparator study and two retrospective noncomparator studies [ 26 , 73 , ] Table 7 , were suitable for inclusion in this section of the review.
There were no deaths reported in either arm of the fibrinogen concentrate studies included elsewhere in this review. In the retrospective comparator study, there was no significant difference in day mortality between groups. The other study, which reported the effect of fibrinogen concentrate administration to trauma patients, observed significantly reduced mortality compared with the mortality predicted by Trauma Injury Severity Score TRISS and by revised injury severity classification RISC [ 73 ].
Eleven comparator studies reported the effect of FFP on patients' hospital LOS [ 3 , 24 , 39 , 40 , 66 , 67 , 69 , 77 , 79 , 81 , 87 ], with only one reporting a benefit for FFP [ 24 ] Table 8. Of the three retrospective noncomparator studies involving FFP, administration was significantly associated with an increased or prolonged ICU stay in two [ 98 , ], but it was not correlated with LOS in the third [ ]. Hospital LOS was reported in one noncomparator study in which surgical patients were analysed.
All three fibrinogen concentrate studies reporting LOS showed significant reductions in the time spent in the ICU of 11 hours [ 55 ], 78 hours [ 26 ] and 36 hours [ 56 ] for patients in the intervention group compared with those in the control FFP group. Hospital LOS was also reported in these three studies. One observed a significantly reduced hospital LOS for patients in the fibrinogen concentrate group compared with the control group 21 days versus 32 days, respectively [ 56 ].
The other two studies found no difference in hospital LOS between patients in the intervention and control groups [ 26 , 55 ].
Eleven FFP comparator studies reported plasma fibrinogen levels pre- and postadministration or in relation to a control [ 22 , 23 , 30 , 38 , 41 , 43 , 44 , 49 , 64 , , ] Table 9. It is difficult to compare most of the results directly because they differ widely in the way in which they were reported.
For instance, some studies compared plasma fibrinogen levels pre- and postadministration, whereas others compared the difference in levels between groups at certain time points. To further complicate matters, many comparisons were made between groups of patients receiving different doses or formulations of FFP and did not compare the effect of FFP against a non plasma product. A positive effect was seen for the FFP group in five studies [ 23 , 30 , 38 , 41 , 43 ] whereas the control group had higher levels in two [ 44 , ].
Four studies assessed the effect of FFP versus a non blood product. Two found significantly higher plasma fibrinogen levels postadministration in the FFP group than in the control group [ 23 , 41 ]. Intraoperative plasma fibrinogen levels were maintained at the preoperative level of 2.
In the study of adults undergoing CV surgery, plasma fibrinogen levels fell from a baseline value of 2. A third study reported significantly reduced levels from baseline values throughout the operative period, with no significant differences between the two study groups at any point despite the administration of ml of FFP to one group [ 49 ]. The fourth study reported significantly lower plasma fibrinogen levels compared with baseline in the FFP group, but not in the control group [ ].
Chowdhury and colleagues [ ] reported the effect on plasma fibrinogen levels of two different doses of FFP The first 10 patients received the lower dose, and the next 12 patients received the higher dose. There was no significant difference between the two groups postadministration, and plasma fibrinogen levels were not significantly higher postadministration than preadministration in either group. Five noncomparator studies reported the effect of FFP on plasma fibrinogen levels.
Two indicated a benefit from FFP [ 53 , 70 ], whilst three found that FFP was associated with lower plasma fibrinogen levels [ 51 , , ]. Plasma fibrinogen levels following administration of fibrinogen concentrate were reported in four comparator studies [ 26 , 54 , 55 , 71 ] Table 9. In all studies, plasma fibrinogen levels were significantly higher postadministration in the fibrinogen concentrate group than in the control group which received FFP in two studies. Increases in plasma fibrinogen levels postadministration ranged from 0.
Importantly, plasma fibrinogen levels were not significantly higher in the fibrinogen concentrate group than in the control group at the next assessment point 6 to 24 hours later. A further 13 noncomparator studies presented data on the effect of fibrinogen concentrate on plasma fibrinogen levels, all of which also showed an increase in plasma fibrinogen levels after the intervention [ 59 — 62 , 72 — 74 , , — ].
Six retrospective observational studies showed mean increases in plasma fibrinogen levels, ranging from 0. There is a relative paucity of high-quality evidence reporting the outcome of administration of FFP in a perioperative or massive trauma setting, despite the long period of its usage. Also, few high-quality trials were identified that reported the outcome of administration of fibrinogen concentrate perioperatively, and none assessed the intervention during massive trauma.
Controlled trials with robust blinding and randomisation procedures are the gold standard when assessing the efficacy and safety of interventions.
However, the low number of RCTs conducted for each intervention may reflect the difficulties in designing and implementing such trials in bleeding patients who are in potentially life-threatening situations.
Despite there being fewer fibrinogen concentrate comparator studies than FFP comparator studies 5 versus 52, respectively , the nature of the comparison must also be considered. Many FFP studies assessed outcomes against a control group that received a different dosage or formulation of FFP reflecting the widely held assumption that 'standard' FFP is efficacious in these situations. Therefore, the low number of comparator trials for fibrinogen concentrate still provided useful evidence and allowed valuable comparisons to be made between the intervention and a non blood control, as well as a direct comparison with FFP.
Whilst observations can be made about the relative efficacies of FFP and fibrinogen concentrate in the perioperative setting, it is notable that, despite a number of noncomparator studies of fibrinogen concentrate in the trauma setting with one recent study involving patients , there are no comparator studies involving the use of fibrinogen concentrate in patients with haemorrhage due to massive trauma.
This lack of evidence highlights a need for more research in this area so that the efficacy of fibrinogen concentrate can be assessed in this clinical setting.
The majority of studies included in this review were observational in nature and as such could be subject to bias, particularly in studies in which researchers were looking for associations between outcomes and different dosages of an intervention. Most of the studies did not report whether they had performed an assessment of, or had controlled for, bias when calculating the effect of the intervention in question. Bias may have occurred by a number of mechanisms.
First, a selection bias may have been in effect because the most resources were directed towards the patients deemed most likely to survive. Second, in other studies, the less-well patients may have received more of an intervention because they were more ill.
Third, the studies may have had a survival bias where patients in the worst condition died too quickly to receive a high dose of the intervention, so, by default, the patients with a poor prognosis were preferentially included in the low-dose groups.
It is possible that the intervention group had a prognosis different from that of the comparison group regardless of the amount of the intervention administered, post hoc ergo propter hoc. The use of fibrinogen concentrate as a haemostatic intervention in the management of perioperative bleeding is still in its early years.
Therefore, in the current literature, there may be a publication bias towards studies demonstrating the successful use of a product rather than those reporting failure. Our systematic literature search identified 70 FFP and 21 fibrinogen concentrate publications reporting the effects of the intervention on a number of outcomes of interest.
Figure 2 summarises the results of all studies in our review with a comparator group for each intervention by reported outcome and also as a combined total of all outcomes. In contrast, the evidence for the efficacy of fibrinogen concentrate was far more consistent, with no negative outcomes reported for any measure Figure 2b.
Fibrinogen concentrate was shown to reduce blood loss, reduce allogeneic transfusion requirements, reduce ICU and hospital LOS and increase plasma fibrinogen levels in over two-thirds of reported outcomes. Importantly, the control was FFP in three of the studies, thus providing some evidence that fibrinogen concentrate is more efficacious than FFP across a range of clinical outcomes in the perioperative setting. Summary of efficacy outcomes from comparator trials.
Numbers represent number of outcomes. This finding is in agreement with the meta-analysis performed by Murad and colleagues [ 5 ]. This temporal aspect of FFP administration was highlighted in a recent publication which found that patients who received an early high FFP:RBC ratio were in less severe shock and less likely to die early from uncontrollable haemorrhage than were those patients in the low FFP:RBC ratio group, who never achieved a high ratio [ ].
The survival advantage associated with the higher FFP:RBC ratios currently being lauded in the literature may be due partly to selection, whereby patients in such studies die with a low FFP:RBC ratio, not because of a low ratio.
Fibrinogen deficiency manifests early in bleeding patients. It is possible that an improvement in survival rates at higher FFP:RBC ratios was due in part to earlier supplementation of plasma fibrinogen in the resuscitation effort and not to a benefit of FFP per se. The fibrinogen concentrate studies identified were typically small, with a mean of only 10 patients per arm. Consequently, there were almost no deaths reported in either group, making a robust assessment of any survival benefit following the administration of fibrinogen concentrate early or late virtually impossible.
In this review, we examined relevant outcomes of interest by analysing the literature regarding one of two interventions: FFP and fibrinogen concentrate. However, haemostatic support during surgery or massive trauma is rarely achieved by the administration of one product alone; therefore, the majority of the studies included in this review involved the administration of other products, particularly RBC, but also PC, cryoprecipitate, prothrombin complex concentrate, tranexamic acid, aprotinin and others.
The influence of coadministered products on the outcomes of interest was not studied in this review, though the potential for an impact should be considered when drawing any conclusions regarding the impact of each intervention on these outcomes, particularly in studies where cryoprecipitate was administered, as this would provide a more concentrated dose of fibrinogen than FFP alone.
In this review, we found inconsistent and contradictory evidence concerning the efficacy of FFP. Furthermore, the findings of this review are in line with other published work, where FFP has particularly been associated with an increased risk of mortality when used during nonmassive transfusion [ 5 ].
Although the risk of viral and bacterial transmission by FFP exists, it is very low. The introduction of nucleic acid screening for known infectious diseases has led to the transmission of infectious diseases being rare [ ]. Furthermore, several strategies have been employed successfully to reduce many of the risks associated with 'standard' FFP, such as the introduction of different formulations of plasma for example, SD-FFP and photochemical treatment FFP, lyophilised and others , the use of leucocyte-depleted plasma and restricting the use of FFP from female donors [ 9 ].
Half of all outcomes analysed in this review indicated that FFP had no effect, positive or negative, and it could be argued that administration of FFP is worthwhile on the basis of the possibility that it might be efficacious and at worst will effect no change in clinical parameters.
Nonetheless, when the potential risks associated with FFP, however rare, are considered in the context of the efficacy findings in this study, in which fewer than one-third of the reported outcomes favoured FFP over the comparator, the continued use of the product should be questioned in an approach that weighs risk versus benefit.
There was consistent evidence that fibrinogen concentrate improved the outcomes studied in this review. Furthermore, no study reported a negative effect versus a comparator on any outcome measure included in this review. In terms of the risks involved with fibrinogen concentrate, there is a low risk of AEs such as allergic reactions, and, in rare cases, administration of fibrinogen concentrate has been associated with thromboembolic events [ , ].
A number of preclinical studies have provided evidence supporting the safety and tolerability of fibrinogen concentrate, and preclinical models, including one of venous stasis, have shown no evidence of thrombosis formation in treated animals, demonstrating the low thrombogenic potential of the product [ , — ]. In addition, a pharmacosurveillance report and systematic review of thrombotic events in clinical studies of patients with both congenital and acquired afibrinogenaemia showed no significant safety concerns associated with fibrinogen concentrate Haemocomplettan P; CSL Behring, Marburg, Germany use in perioperative bleeding situations with regard to thrombogenicity [ ].
Over a year pharmacosurveillance period, nine thrombotic events possibly related to the administration of fibrinogen concentrate were reported seven of which were in patients with congenital fibrinogen deficiency at an incidence of 3. However, further safety studies employing rigorous methods intended to detect conditions such as deep vein thrombosis are still required to confirm the findings from the preclinical and pharmacosurveillance studies.
Among the trials included in this review [ 26 , 54 — 63 , 71 — 74 , , — ], there was a low incidence of the predefined safety outcomes thrombotic events, ALI, TACO, infections [bacterial contamination and viral transmission] and MOF. Furthermore, there was a low frequency of AEs of any nature in the 17 fibrinogen concentrate studies in which AEs were reported Table Of the remaining three AEs, one case of 'jitter and snoring respiration' was reported by nursing staff, though the patient was judged to be alert with normal respiration upon the arrival of the attending physician; one patient complained of attacks of shivering 24 hours after fibrinogen concentrate administration [ 59 ]; and one patient who received massive transfusion of a variety of haemostatic products had subsequent acute renal failure [ ].
This review presents a consistent picture of the efficacy of fibrinogen concentrate and supports the safety of the product, with a low incidence of thrombotic events reported in the included studies.
However, this evidence was derived from a small number of studies with a low number of patients in each arm. Whilst published studies support the efficacy and safety of fibrinogen concentrate during surgical procedures, more trials reporting outcomes from a greater number of patients are needed to reinforce these findings.
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