Fibrinogen and Hemostasis

A Primary Hemostatic Target for the Management of Acquired Bleeding

Abstract

Fibrinogen plays several key roles in the maintenance of hemostasis. Its cleavage by thrombin and subsequent polymerization to form fibrin strands provides the structural network required for effective clot formation. During cases of acute blood loss, attempts to maintain circulating volume and tissue perfusion often involve the infusion of crystalloids, colloids, and red blood cells. Intravascular volume resuscitation, although vital, frequently results in dilution of the remaining clotting factors and onset of dilutional coagulopathy. In such cases, fibrinogen is the first coagulation factor to decrease to critically low levels. There currently is a lack of awareness among physicians regarding the significance of fibrinogen during acute bleeding and, at many centers, fibrinogen is not monitored routinely during treatment. We reviewed current studies that demonstrate the importance of considering fibrinogen replacement during the treatment of acquired bleeding across clinical settings. If depleted, the supplementation of fibrinogen is key for the rescue and maintenance of hemostatic function; however, the threshold at which such intervention should be triggered is currently poorly defined. Although traditionally performed via administration of fresh frozen plasma or cryoprecipitate, the use of lyophilized fibrinogen (concentrate) is becoming more prevalent in some countries. Recent reports relating to the efficacy of fibrinogen concentrate suggest that it is a viable alternative to traditional hemostatic approaches, which should be considered. The prospective study of fibrinogen supplementation in acquired bleeding is needed to accurately assess the range of clinical settings in which this management strategy is appropriate, the most effective method of supplementation and a comprehensive safety profile of fibrinogen concentrate used for such an approach.

In Brief

Published ahead of print September 29, 2011

Fibrinogen is a plasma protein critical to hemostasis and clot formation.¹ The blood plasma concentration of fibrinogen ranges between 1.5 and 4.0 g/L but it can be higher, particularly in certain conditions such as pregnancy.² Structurally, human fibrinogen comprises 2 outer D domains, which are both linked by a central E domain.³ Each D domain is made up of 3 polypeptide chains (α, β, and γ), which together form a coiled-coil configuration. These domains are linked at the N-terminus to the central E domain via a series of disulfide bonds.⁴ Thrombin cleavage occurs at specific amino-acid sequences present on the α and β polypeptide chains, removing the N-terminal peptides (fibrinopeptides) and exposing the polymerization sites (Fig. 1).³ Fibrin polymerization then occurs via noncovalent interaction of the exposed polypeptide chain with complementary binding sites present on the D domain of a neighboring molecule.³ Furthermore, recent preliminary data have suggested that fibrinogen may be heme associated and could play a role in carbon monoxide sensing.⁵

Figure 1: The thrombin cleavage of fibrinogen and polymerization of fibrin monomers to fibrin. A schematic representation of the thrombin cleavage of fibrinogen, followed by the polymerization of fibrin monomers to form fibrin strands is illustrated.

Studies from our laboratory and others have demonstrated the importance of thrombin generation and hemostatic activation for clot formation.^6–11 Functionally, fibrinogen molecules act during both cellular and fluid phases of coagulation. In the cellular phase, it facilitates the aggregation of platelets via binding of glycoprotein IIb/IIIa receptors on platelet surfaces. In the fluid phase, it is cleaved by thrombin to produce fibrin monomers, which polymerize to form the basis of the clot (Fig. 2).^4,12–14 Fibrinogen also plays other important roles, functioning in vivo as an acute phase reactant, helping modulate inflammatory cellular reactions and also increasing in plasma concentration after injury.

Figure 2: A fibrin blood clot: the constituent parts of a blood clot are shown (red blood cells, red; fibrin fibers, blue; platelet aggregates, purple). From John W. Weisel, PhD, University of Pennsylvania, with permission.

When acute hemorrhage occurs, the resulting blood loss and consumption of procoagulants combine to reduce the circulating concentration of multiple clotting factors. Derangement in common measures of coagulation (prothrombin time and activated partial thromboplastin time) can develop in cases of acute trauma, before administration of fluid therapy.¹⁵ Such derangements are associated with significantly increased mortality rates in trauma patients.¹⁵ The dilution of clotting factors during intravascular volume replacement can result in further coagulopathy; however, such hemostatic intervention is essential for the restoration of circulating volume and tissue perfusion. A prospective observation of plasma concentrations of clotting factors in patients undergoing major urologic or abdominal surgery (n = 60) showed that levels of prothrombin, factor V, factor VII and fibrinogen were all significantly reduced after blood loss and subsequent fluid replacement (red blood cells [RBCs] and colloids).¹⁶ Because of its relatively high initial plasma concentration, fibrinogen was the first clotting factor to decrease to critically low levels.¹⁶ In noncardiac major surgery, it has been shown that fibrinogen reaches plasma concentrations of 1 g/L when 142% (95% confidence interval [CI], 117 to 169%) of the circulating blood volume has been lost.¹⁶

The maintenance of hemostasis relies on a series of complex interactions between both the cellular and protein components of coagulation.¹⁷ Importantly, platelets play a key role in many of these interactions; the platelet surface is the primary site for thrombin generation,¹⁷ and platelets aggregate to form the primary hemostatic plug,¹⁸ as well as stabilizing clot formation.¹ Circulating platelet concentrations reduce in a similar manner to the observed depletion of clotting factors during major surgery.¹⁶ As such, the development of thrombocytopenia in critically bleeding patients is a significant challenge to hemostasis. In vitro analysis of platelet-poor plasma showed a positive correlation of viscoelastic measurements of clot strength with increasing fibrinogen concentration,¹ a result that was corroborated by a retrospective analysis of 904 thrombocytopenic patients. As such, the maintenance of fibrinogen concentrations is crucial in cases of thrombocytopenia.¹

The clinical relevance of plasma fibrinogen concentrations in bleeding patients is not widely recognized and, as a result, physicians may not routinely measure fibrinogen levels or consider supplementation options when treating major bleeding. In this review we will discuss the importance of fibrinogen in clot formation and the therapeutic approaches for replacing fibrinogen in acquired bleeding states.

ACUTE BLOOD LOSS AND MASSIVE TRANSFUSION COAGULOPATHY

In cases of acute blood loss, restoring circulatory volume is a primary objective often addressed with volume expanders such as crystalloids, colloids, or a combination of both.^19,20 The ideal volume expander has been the subject of significant debate; however, the administration of any volume expander will result in the reduction of platelets and plasma clotting factor concentrations.²¹ In such cases, the commonly observed change is dilutional thrombocytopenia, but continuing blood loss can lead to a more complex coagulopathy. Neither concentrates of RBCs or platelets contain enough plasma to supplement the depleted factors sufficiently to maintain hemostatic balance.¹⁶ Thus, continued consumption of clotting factors coupled with their dilution with volume expanders can lead to the development of dilutional coagulopathy.

The critical role of fibrinogen deficiency and fibrinolysis in cases of major bleeding is increasingly described.^1,22,23 The preoperative measurement of plasma fibrinogen concentration was found to be predictive of postoperative bleeding volume and transfusion requirements in a prospective observation of coronary bypass grafting surgical patients (n = 170).²⁴ In another example, a multivariate analysis of postpartum hemorrhage (n = 128) reported that fibrinogen concentration was the only hemostatic marker consistently associated with the occurrence of severe postpartum hemorrhage. It was concluded that the early measurement of fibrinogen was able to detect reductions in plasma fibrinogen concentration, allowing the risk of severe bleeding to be predicted. As such, monitoring of this kind is recommended during the management of obstetric-related bleeding events.²⁵

A greater understanding of the predictive value of plasma fibrinogen concentrations has led to the potential for laboratory-guided, prophylactic supplementation of coagulation factors in cases of elective procedures. Thus, in events when hemorrhage is likely, the onset of coagulopathy can be delayed and the extent of bleeding reduced. A recent prospective randomized controlled pilot study (n = 20) investigating prophylactic fibrinogen supplementation before coronary artery bypass grafting showed that postoperative bleeding was reduced by 32% in patients receiving 2 g fibrinogen concentrate preoperatively in comparison with the control group (565 ± 150 vs 830 ± 268 mL; P = 0.010), without any evidence of hypercoagulability.²⁶ Recognizing the emerging evidence, which highlights the importance of maintaining adequate plasma fibrinogen concentrations, European guidelines now include the administration of fibrinogen concentrate among their recommendations for the treatment of trauma-related, life-threatening hemorrhage; however, it should be noted that this recommendation is based upon the lowest level of evidence available to the guideline authors.^19,27

FIBRINOGEN REPLACEMENT

There are 3 main approaches to fibrinogen supplementation, which involve the infusion of fresh frozen plasma (FFP), cryoprecipitate, or fibrinogen concentrate.

Fresh Frozen Plasma

FFP contains all proteins present in human plasma, including albumin, immunoglobulins, and coagulation and fibrinolytic elements, which are at or below physiological concentrations (Table 1).²⁸ It is commonly transfused for the reversal of oral anticoagulation therapy,²⁹ but is also used for coagulation factor supplementation during acute bleeding.³⁰ Although extensively used during massive transfusion protocols, FFP preparations have been associated with the potential risk of pathogen transmission.^31,32 Commercially available plasma can be virally inactivated using 1 of 4 major treatment processes to minimize the risk of pathogen contamination: solvent-detergent (SD), methylene blue, amotosalen, or riboflavin. All 4 methods demonstrate effectiveness against common pathogens, including human immunodeficiency virus.³³ With the exception of SD-treated plasma, these methods are designed for small-volume use at blood banks,³³ and the availability of such plasmas is limited to certain regions and countries. Immunological reactions, including allergic reactions, and transfusion-related acute lung injury can also result from FFP administration.³²

Table 1: A Comparison of the Constituent Components of the Transfusion Options for Fibrinogen Supplementation

FFP contains approximately 2.0 g/L³⁴ of fibrinogen, but fibrinogen concentrations do vary between units; thus predicting the increase in patient plasma fibrinogen concentrations after transfusion is difficult.²⁸ When the in vivo fibrinogen concentration was measured in patients transfused with 30 mL/kg of FFP (approximating to 2.1 L of FFP for a 70-kg patient), a median increase of 1.0 g/L (range, 0.9 to 2.4 g/L) was observed.³⁵ Thus, large volumes of FFP are required to increase plasma fibrinogen concentrations in bleeding patients, increasing the risk of hypervolemia and transfusion-related circulatory overload.³⁶ FFP is used increasingly in situations such as massive transfusion coagulopathy; however, a recent systematic review of massive plasma transfusion found very-low-quality evidence that such treatment reduces the risk of patient death.³⁶

Cryoprecipitate

Cryoprecipitate is a human plasma concentrate that was first described in the 1960s.³⁷ It is manufactured from FFP, and the processes involved have changed little since it was first discovered. In short, the thawing (between 1°C and 6°C) and subsequent centrifugation of FFP is followed by the removal of the supernatant.³⁸ The remaining 5 to 15 mL of plasma is refrozen and can be stored in this way for up to 12 months.³⁸ According to recent testing, each unit of cryoprecipitate contains a median fibrinogen concentration of 388 mg (range, 120 to 796 mg), whereas the minimum requirements of the American Association of Blood Banks (AABB) is 150 mg per unit.³⁸ The typical concentrations of other constituents contained in each unit are displayed in Table 1.

Because cryoprecipitate contains higher concentrations of fibrinogen than does FFP, it is the therapy option often used for fibrinogen supplementation in the United States (US) and United Kingdom. However, the existing risk of immunological reactions and the transmission of infectious agents has led to its withdrawal in several European countries.³⁹ Cryoprecipitate is unsuitable for viral inactivation processes in its native form,⁴⁰ though plasma derivatives that have been pretreated with methylene blue or SD can be used for its production.³⁹ Unfortunately, such pretreatment processes can reduce the concentration of functional fibrinogen present.^39,40 As with FFP, cryoprecipitate requires blood type matching and thawing before infusion, delaying administration in time-critical situations.

Fibrinogen Concentrate

Fibrinogen concentrate is derived from human plasma and is stored at room temperature as a pasteurized, lyophilized powder.⁴¹ It does not require blood type matching or thawing; thus it is available immediately when required. It can be reconstituted in low-volume concentrations of up to 20 g/L.⁴¹ Doses as high as 6 g infused in as little as 1 to 2 minutes have been reported in critical bleeding.⁴² A summary of fibrinogen concentrates currently available is shown in Table 1. Commercially available fibrinogen concentrates are primarily licensed for the treatment of congenital fibrinogen deficiency across the US and Europe, and a license for the treatment of acquired bleeding has been granted for only 1 of these products in some European countries (Table 1).

The risk of viral infection with fibrinogen concentrates is significantly reduced because of viral inactivation and removal processes.⁴³ This inherent viral reduction capacity also minimizes the risk of transmitting new emerging viruses.⁴³ Although fibrinogen concentrate is manufactured using human plasma from a large pool of donors, the production processes involved remove antibodies and antigens, largely mitigating the risk of immunological and allergic reactions resulting from its administration.³⁹ It should be noted that although this risk is much reduced, as with all blood products, fibrinogen concentrate administration will always have the theoretical potential for transmission of new emerging infectious agents.⁴⁴

Historically, the occurrence of thromboembolic events has been a concern surrounding the administration of clotting factor concentrates. With respect to fibrinogen concentrate specifically, there are currently no results from large prospective randomized controlled clinical trials on which any firm judgments can be based. Although an increase in the amount of available prospective data would provide valuable evidence for fully evaluating the thrombotic potential of fibrinogen concentrate, reviews of published clinical data and a recent pharmacovigilance report have demonstrated no significant thrombogenic concerns with fibrinogen concentrate.^45,46 Furthermore, a study of 151 separate infusions administered to 12 patients with congenital fibrinogen deficiencies showed that the supplementation of fibrinogen using fibrinogen concentrate for prophylaxis, as well as during bleeding episodes and surgery, was both efficient (with a median in vivo fibrinogen recovery of 59.8% [n = 8; range: 32.5 to 93.9]) and generally well tolerated.⁴⁷ In support of the clinical data, animal models of venous stasis have found that fibrinogen concentrates demonstrated no thrombogenic activity.^22,45 It should be noted, however, that the use of fibrinogen concentrate in patients exhibiting disseminated intravascular coagulation is potentially hazardous because of the risk of accelerated fibrin formation and should be avoided.⁴¹ Current opinion still remains divided regarding what constitutes the correct and appropriate administration of fibrinogen concentrate in the critical care setting.^44,48 Surveillance data may not provide reliable estimates of thrombotic adverse events, which can occur up to 3 months postsurgery at the doses used.⁴⁴ It is also important to consider that there is no current prospective comparison of the safety profiles of FFP, cryoprecipitate, and fibrinogen concentrate, when administered for fibrinogen supplementation.

CURRENT UNDERSTANDING OF FIBRINOGEN REPLACEMENT

Preclinical Data

In a porcine model of thrombocytopenia, fibrinogen concentrate was shown to better improve hemostatic function and survival times than platelet transfusion alone after blunt liver injury.²² A second porcine model of blunt liver trauma has compared bleeding and subject outcomes among animals receiving varying concentrations of fibrinogen concentrate. When compared with placebo, the administration of fibrinogen concentrate (70 or 200 mg/kg) after severe dilutional coagulopathy both significantly improved coagulation and attenuated blood loss.⁴⁹ Although the proper dosing cannot be determined from the studies involving nonhuman species, in vitro clinical data using human blood also demonstrate that increased fibrinogen concentration improves clot strength independently of platelet count.^1,50 Taken together, these results suggest that restoration of plasma fibrinogen concentrations using fibrinogen concentrate could be an effective hemostatic treatment in cases of acquired bleeding.

Clinical Data

Since fibrinogen supplementation in cases of major bleeding was established as a potentially useful treatment approach, the efficacy of fibrinogen concentrate has been assessed by many retrospective and some prospective studies. Its administration for the treatment of acquired bleeding has been studied in heterologous cohorts of patients across a range of critical care settings (summarized in Table 2).

Table 2: A Summary of Clinical Studies Detailing Fibrinogen Administration

Retrospective analyses (n = 30) of fibrinogen concentrate administration to treat acquired hypofibrinogenemia and life-threatening bleeding found it was effective in the management of such events,⁴⁶ improving laboratory coagulation measures and survival rates in unresponsive coagulopathy.⁵¹ Laboratory monitoring of plasma fibrinogen concentrations has shown significant increases after fibrinogen concentrate administration (median dose, 3.52 g [range: 0.5 to 8.0]; mean increase [± SD] in plasma fibrinogen, 1.09 [±0.68] g/L),⁵¹ with associated improvements in both prothrombin time and activated partial thromboplastin time.^51,52 Retrospective analysis of such laboratory coagulation measurements, in bleeding patients (n = 43) treated with fibrinogen concentrate, demonstrated that such improvements have led to reduced blood loss and lower requirements for RBCs (∼12 U vs ∼2 U), FFP (∼8 U vs ∼2 U), and platelets (∼2.5 U vs ∼0.5 U).⁵³ These blood-sparing effects indicate that fibrinogen concentrate could potentially challenge traditional hemostatic approaches using FFP and platelet concentrates.

Trauma

The significant loss of blood volume associated with trauma-related bleeding often precipitates the “lethal triad” of acidosis, hypothermia, and coagulopathy. Coagulopathy in trauma patients results from the rapid depletion of circulating coagulation factors because of consumption and blood loss. Although acidemia, hypothermia, and subsequent dilution all interact to contribute to trauma-related coagulopathy, the interplay between these mechanisms is yet to be fully elucidated.⁵⁴ Importantly, trauma-related coagulopathy is a leading cause of mortality,^55,56 and is responsible for up to 40% of trauma-related deaths.¹⁹ In such cases, the need for effective and rapid hemostasis management is important, in addition to the rapid surgical control of bleeding. In cases of trauma-related massive bleeding, European transfusion guidelines recommend the primary restoration of circulating volume and secondary hemostatic measures via transfusion of blood products or pharmaceutical agents.^19,27 Recent military experience of trauma has strongly influenced transfusion practices in US trauma centers.^57,58 Several observational studies have suggested that transfusion of high ratios of FFP to RBCs (1:1) is key to improving survival rates in patients with major trauma.^59–61 Consequently, many civilian trauma centers are now adopting massive transfusion protocols, which include the transfusion of FFP in high volumes.⁶² Although this approach is not universally accepted,^63–65 and the complete restoration of circulating volume is not recommended in the US, it is becoming clear that the timely supplementation of coagulation factors during major trauma-related bleeding is important for the improvement of patient outcomes.⁶⁶ A retrospective review of battlefield trauma reported 252 patients receiving massive transfusion, in which the total amount of fibrinogen infused within all administered blood products (FFP, RBCs, and platelets) correlated with reductions in mortality.⁶⁷

There are increasing reports of fibrinogen replacement using concentrates administered as a first-line treatment of trauma. Brenni et al. detailed a case study in which fibrinogen concentrate was used in combination with RBCs as a primary hemostatic agent for the treatment of coagulopathy resulting from major abdominal trauma.⁶⁸ Coagulopathy was corrected without the use of allogeneic blood products, highlighting the potential efficacy and safety benefits of such management protocols. The coadministration of fibrinogen concentrate with other prohemostatic agents is an effective management protocol for trauma patients. A separate case study details the administration of fibrinogen concentrate, in combination with prothrombin complex concentrate (PCC), for the successful treatment of polytrauma.⁶⁹ The combined use of these coagulation factor concentrates, guided by point-of-care assessment (rotational thromboelastometry [ROTEM®; TEM Innovations GmbH, Munich, Germany]), eliminated the need for allogeneic factors (including FFP and platelet transfusion) and reduced the need for RBCs. A larger, retrospective analysis of a patient cohort with acquired bleeding (n = 131 total) receiving similar transfusion protocols adds weight to the conclusions drawn by these case studies.⁷⁰ Patients infused with fibrinogen concentrates (n = 128) and PCCs (n = 98), using ROTEM-guided goal-directed coagulation management, displayed favorable survival rates in relation to those predicted by the trauma injury severity score (TRISS).⁷⁰ A similar retrospective analysis compared a group of trauma patients (n = 80) receiving TEM-guided fibrinogen concentrate (median 6 g [range: 0 to 15 g]) and PCC administration (median 1200 U [range: 0 to 6600]) with trauma patients administered FFP in the absence of coagulation factor concentrates (n = 601, median 6 U [range: 2 to 51]).⁷¹ The need for RBC and platelet transfusion was avoided in 29% and 91% of fibrinogen-PCC patients, respectively, in comparison with 3% and 56%, respectively, in the FFP group. The study authors concluded that the TEM-guided administration of coagulation factor concentrates reduced the exposure level of trauma patients to allogeneic blood products; however, it should be noted that mortality rates between groups remained broadly comparable (7.5% vs.10.0% [fibrinogen-PCC versus FFP; P = 0.69]).

These studies highlight the potentially useful combination of modern, real-time, coagulation monitoring with the administration of clotting factor concentrates capable of rapidly increasing the plasma concentrations of procoagulants in a goal-directed fashion. Currently, evidence, which demonstrates the efficacy of this approach, is restricted to case studies and retrospective analyses. There are concerns that highlight the limitations in study design that are inherent in such retrospective analyses, and care should be taken regarding the strength of conclusions that can be drawn on the basis of their results.⁷² It is clear that though promising, further prospective studies are required to better establish the dosing efficacy and safety of this approach.

Perioperative Bleeding

Fibrinogen concentrate is now used across a range of surgical settings to maintain patient hemostasis and control bleeding. There follows an overview of recent studies that examines the efficacy of fibrinogen concentrate administered perioperatively.

Cardiovascular and Vascular Surgery

Cardiovascular and vascular surgical procedures are often accompanied by excessive bleeding.^73–75 Perioperative bleeding is a serious problem that can lead to increases in both morbidity and mortality rates.^76,77 The effective management of such bleeding is the key to improved patient outcomes, and a variety of approaches are now available to physicians.⁷⁸ Increasing numbers of both prospective and retrospective studies allow analysis of the impact of coagulation management in surgical procedures typically associated with excessive hemorrhage.

A retrospective study investigating mortality rates in patients (n = 128) undergoing ruptured abdominal aortic aneurysm repair found a significant reduction in mortality rates (15% vs 39%; P < 0.03) in patients receiving RBC:FFP ratio of ≤2:1 (high FFP cohort) in comparison with those receiving >2:1 ratios (low FFP cohort).⁷⁹ These results suggest that high volumes of FFP can effectively aid hemostatic function and improve patient outcomes during high-risk procedures. Fibrinogen concentrate may also be of benefit during such procedures. A study comparing both retrospective and prospective data investigated the use of fibrinogen concentrate during aortic valve and ascending aorta surgery. Eight of 10 patients (prospective group) receiving fibrinogen concentrate before surgery required no transfusion of RBCs during cardiopulmonary bypass or within the subsequent 24 hours. In comparison, 41 of 42 patients (retrospective group) receiving conventional hemostatic therapy did require RBC transfusion within the same period (P < 0.05).⁷⁴ A follow-up study evaluated prospective fibrinogen replacement using concentrates in 6 patients as an initial treatment of postbypass bleeding during thoracoabdominal aortic aneurysm repair in comparison with a retrospective cohort of patients receiving no prophylaxis (n = 20).⁸⁰ The need for transfusion of allogeneic blood products was reduced in patients receiving fibrinogen concentrate in comparison with those who did not (2.5 ± 4.3 U vs 16.4 ± 4.8 U), as was both the amount of bleeding during the following 24 hours, and the average length of treatment in the intensive care unit.⁸⁰ These preliminary data have led to the initiation of a prospective randomized clinical trial to further elucidate the potential of fibrinogen concentrate in this setting (ClinicalTrials.gov identifier number NCT00701142).

A retrospective analysis (n = 39) of fibrinogen concentrate infusion after cardiopulmonary bypass showed it to be an effective method of increasing the plasma fibrinogen concentration (mean dose [±SD]: 6.5 [±1.6]; absolute increase: 1.7 [±0.5] g/L).⁴² As was mentioned previously, serious intraoperative bleeding was treated successfully using rapid fibrinogen concentrate infusion in some cases (∼6 g in 1 to 2 minutes). The study authors concluded that the use of fibrinogen concentrate contributed to the correction of bleeding after surgery.⁴²

Noncardiovascular Surgery

Patients undergoing orthopedic surgery are at risk of significant bleeding and developing dilutional coagulopathy, which may be influenced by the solution used for intravascular volume replacement.^21,81,82 A prospective study compared patients receiving colloids (either hydroxyethyl starch [HES] [n = 19] or a modified gelatin solution [n = 21]) with those receiving Ringer's lactate solution (n = 21) for volume replacement during major orthopedic surgery, and examined coagulation variables using ROTEM.⁸² Fibrinogen polymerization was significantly impaired in patients receiving colloid rather than crystalloid. Different HES solutions variably impede fibrinogen polymerization, resulting in reduced clot firmness. The administration of fibrinogen concentrate led to the restoration and maintenance of clot firmness, even during continued blood loss and further colloid administration.⁸²

A prospective, placebo-controlled, randomized study (n = 20) of patients undergoing elective radical cystectomy investigated the ability of fibrinogen concentrate to restore hemostasis in patients experiencing excessive blood loss.⁸³ Patients received HES for volume replacement when required as part of the established blood replacement regimen; treatment with fibrinogen concentrate was triggered once 30% volume dilution had occurred. In comparison with placebo, fibrinogen supplementation significantly improved both whole blood clot firmness and the rate of clot formation. Additionally, the requirement for postoperative transfusion of RBCs was significantly reduced.⁸³

Obstetric Hemorrhage

Obstetric hemorrhage remains a major cause of mortality and morbidity associated with childbirth.^84,85 The increase in uterine arterial bloodflow during labor means that massive obstetric hemorrhage (>1500 mL) can rapidly result in life-threatening blood loss, occurring in approximately 0.67% of all deliveries.⁸⁶ Such events require volume resuscitation and allogeneic transfusion; however, this approach can contribute to coagulopathy because of further dilution of coagulation factors. A review of 6 cases of severe obstetric hemorrhage suggested that the addition of fibrinogen concentrate to traditional therapies was effective in the treatment of peripartum blood loss associated with hypofibrinogenemia.⁸⁷ Fibrinogen administration in combination with other blood products can control bleeding even during continuing consumption and hemodilution.

These initial studies detail potential mechanisms by which severe obstetric hemorrhage could be both predicted and attenuated. However, it should be noted that there is currently little published evidence conclusively showing fibrinogen concentrate to be effective in preventing obstetric bleeding. Further prospective studies are needed to elucidate the full potential of this treatment option.

RECOMMENDED TRIGGER CONCENTRATIONS FOR FIBRINOGEN

Fibrinogen Detection Assays

Quantitative fibrinogen detection can be performed immunologically, measuring both functional and nonfunctional fibrinogen molecules. Functional assays that measure fibrinogen-dependent clot formation are used most often and utilize spectroscopic or viscoelastic detection. The Clauss method is a frequently used functional fibrinogen assay, whereby diluted citrated plasma is activated with thrombin and the time-to-clot formation is recorded spectroscopically.⁴¹ Viscoelastic detection is performed using whole blood. When tested this way, the blood is housed in a cup (maintained at 37°C) and a pin is suspended within the sample. The cup and pin are oscillated in relation to each other and any subsequent impedance to this oscillation provides a measure of clot formation.⁸⁸ Point-of-care testing using viscoelastic measures of clot strength (TEG®; Hemonetics®, Braintree, MA, or ROTEM) allow patient-specific, rapid, and guided supplementation of depleted coagulation elements.^69,70,89,90 The extent of fibrin polymerization in whole blood can be estimated by inhibiting platelet-fibrin(ogen) interactions on the TEG-based Functional Fibrinogen Test or ROTEM-based FIBTEM. The latter is commonly used in European countries to titrate the dosing of fibrinogen concentrates.^69,70,89

When deciding which functional test is most appropriate for fibrinogen detection, several considerations must be made. One advantage of using viscoelastic testing for fibrinogen determination is the inherent variability of Clauss-based fibrinogen assays. Clauss-based fibrinogen measurements may be falsely decreased in the presence of direct thrombin inhibitors,⁹¹ and falsely increased in the presence of HES solutions.⁹² In general, the turbidimetric (optical) detection method is affected more than mechanical detections by these agents.⁹³ However, it should be noted that the viscoelastic methodology described has not been prospectively validated for the measurement of fibrinogen-dependent clot formation during acute bleeding. It is not universally available, and furthermore, recent evidence suggests that the measurement of fibrinogen levels using FIBTEM can vary after hemostatic therapy, depending upon the type of coagulometer being used.⁹³

Treatment Thresholds and Dosing of Fibrinogen

Although there are increasing data on the importance of plasma fibrinogen levels to prevent profuse bleeding, the threshold levels for transfusing either cryoprecipitate or fibrinogen concentrates have not been agreed on universally because of a lack of prospective evidence or consistent observations across different clinical settings. There has been some concern over iatrogenic hyperfibrinogenemia because increased plasma fibrinogen concentrations have been linked to an increased risk of coronary heart disease and myocardial infarction.⁹⁴ However, a study by Reinhart demonstrated that fibrinogen is a marker rather than a mediator of coronary heart disease.⁹⁵

The revised European trauma guidelines published in 2010 recommend a trigger fibrinogen concentration of 1.5 to 2.0 g/L,²⁷ which was increased from below 1.0 g/L in earlier guidelines.⁹⁶ This change is in agreement with other in vitro evidence that concentrations larger than 2.0 g/L are required to produce effective clot formation.⁵⁰ Importantly, fibrinogen concentrations can vary among patients, as well as during incidences of acquired bleeding. Although the target plasma fibrinogen concentration that should be reached in a bleeding patient is not known, and the optimum dose of fibrinogen has not been established by dose-ranging trials, bleeding increases for each 1.0 g/L decrease in plasma fibrinogen in parturients.²⁵ In vitro viscoelastic analysis of whole blood shows clot strength increases linearly up to a fibrinogen concentration of 3.0 g/L, with a minimum threshold of 2.0 g/L required for the optimal rate of clot formation.^50,97

Because of the large variability in fibrinogen concentrations among bleeding patients, increasing fibrinogen levels should be individualized and based upon both the level of bleeding and the plasma fibrinogen concentration.⁴¹ An initial dose of 10 U of cryoprecipitate, or 2.0 to 4.0 g of fibrinogen concentrate is recommended for a 70-kg patient,⁴¹ with subsequent administration dependent upon an individual's bleeding status. For fibrinogen concentrates, the required dose can be estimated as follows^41,74:

Thus, administration of 3 g of fibrinogen concentrate in a 70-kg patient approximates to an overall increase in plasma fibrinogen concentration of 1.0 g/L (assuming 0.04 L/kg plasma volume). Predicting the increase in plasma fibrinogen concentrations that will result after cryoprecipitate administration is troublesome, because of the wide variation in fibrinogen concentration between units.³⁹

SUMMARY

Fibrinogen is critical for effective clot formation, and its monitoring and guided supplementation in the treatment of major bleeding is increasingly recognized. A growing number of reports note the importance of fibrinogen replacement in the treatment of massive bleeding across a broad range of clinical settings.^{1,22,42,51,68–70,74,80,82,87,98} Available sources of fibrinogen for supplementation include FFP, cryoprecipitate, and fibrinogen concentrates. Coagulation factor concentrates offer potential advantages over allogeneic blood products, such as decreased immunogenic and infectious complications, as well as rapid availability. Studies of the efficacy and safety of fibrinogen supplementation during acute bleeding has been most often retrospective or performed in prospective trials with limited participant numbers owing to ethical and practical constraints. This must be considered when evaluating the evidence on the administration of fibrinogen in bleeding patients. As such, further prospective, randomized controlled studies on the use of fibrinogen concentrate are essential to help define the breadth of clinical settings in which fibrinogen supplementation may be beneficial. Additional evidence would also help further define optimal trigger concentrations and doses for fibrinogen supplementation.

RECUSE NOTE

Jerrold H. Levy is section Editor of Hemostasis and Transfusion Medicine for Anesthesia & Analgesia. This manuscript was handled by Steve Shafer, Editor-in-Chief, and Dr. Levy was not involved in any way with the editorial process or decision.

DISCLOSURES

Name: Jerrold H. Levy.

Contribution: Performed literature search and manuscript preparation, oversaw ongoing revisions and corrections.

Conflict of Interest: Dr. Levy receives research support from CSI Behring.

Name: Fania Szlam.

Contribution: Reviewed manuscript, added additional information and references.

Conflict of Interest: This author has no conflict to declare.

Name: Kenichi A. Tanaka, MD.

Contribution: Reviewed manuscript, added additional information and references.

Conflict of Interest: Dr. Tanaka receives research support from CSL Behring and Octapharma.

Name: Roman M. Sniecienski, MD.

Contribution: Reviewed manuscript, added additional information, references, and developed figures for manuscript.

Conflict of Interest: This author has no conflict to declare.

This manuscript was handled by: Steven L. Shafer, MD.