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Society of Cardiovascular Anesthesiologists

Cardiovascular Anesthesiology Section Editor: Charles W. Hogue, Jr.

Perioperative Echocardiography and Cardiovascular Education Section Editor: Martin J. London

Hemostasis and Transfusion Medicine Section Editor: Jerrold H. Levy

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CME

Fibrinogen and Hemostasis: A Primary HemostaticTarget for the Management of Acquired BleedingJerrold H. Levy, MD, FAHA, Fania Szlam, MMSc, Kenichi A. Tanaka, MD, and Roman M. Sniecienski, MD

Fibrinogen plays several key roles in the maintenance of hemostasis. Its cleavage by thrombinand subsequent polymerization to form fibrin strands provides the structural networkrequired for effective clot formation. During cases of acute blood loss, attempts to maintaincirculating volume and tissue perfusion often involve the infusion of crystalloids, colloids, andred blood cells. Intravascular volume resuscitation, although vital, frequently results indilution 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 isa lack of awareness among physicians regarding the significance of fibrinogen during acutebleeding and, at many centers, fibrinogen is not monitored routinely during treatment. Wereviewed current studies that demonstrate the importance of considering fibrinogen replace-ment during the treatment of acquired bleeding across clinical settings. If depleted, thesupplementation of fibrinogen is key for the rescue and maintenance of hemostatic function;however, the threshold at which such intervention should be triggered is currently poorlydefined. Although traditionally performed via administration of fresh frozen plasma orcryoprecipitate, the use of lyophilized fibrinogen (concentrate) is becoming more prevalent insome countries. Recent reports relating to the efficacy of fibrinogen concentrate suggest that itis a viable alternative to traditional hemostatic approaches, which should be considered. Theprospective study of fibrinogen supplementation in acquired bleeding is needed to accuratelyassess the range of clinical settings in which this management strategy is appropriate, the mosteffective method of supplementation and a comprehensive safety profile of fibrinogenconcentrate used for such an approach. (Anesth Analg 2012;114:261–74)

Fibrinogen is a plasma protein critical to hemostasisand clot formation.1 The blood plasma concentrationof fibrinogen ranges between 1.5 and 4.0 g/L but it

can be higher, particularly in certain conditions such aspregnancy.2 Structurally, human fibrinogen comprises 2outer D domains, which are both linked by a central Edomain.3 Each D domain is made up of 3 polypeptidechains (�, �, and �), which together form a coiled-coilconfiguration. These domains are linked at the N-terminusto the central E domain via a series of disulfide bonds.4

Thrombin cleavage occurs at specific amino-acid sequencespresent on the � and � polypeptide chains, removing the

N-terminal peptides (fibrinopeptides) and exposing the po-lymerization sites (Fig. 1).3 Fibrin polymerization then occursvia noncovalent interaction of the exposed polypeptide chainwith complementary binding sites present on the D domain ofa neighboring molecule.3 Furthermore, recent preliminarydata have suggested that fibrinogen may be heme associatedand could play a role in carbon monoxide sensing.5

Studies from our laboratory and others have demonstratedthe importance of thrombin generation and hemostatic acti-vation for clot formation.6–11 Functionally, fibrinogen mol-ecules act during both cellular and fluid phases of coagula-tion. In the cellular phase, it facilitates the aggregation ofplatelets via binding of glycoprotein IIb/IIIa receptors onplatelet surfaces. In the fluid phase, it is cleaved by throm-bin to produce fibrin monomers, which polymerize to formthe basis of the clot (Fig. 2).4,12–14 Fibrinogen also playsother important roles, functioning in vivo as an acute phasereactant, helping modulate inflammatory cellular reactionsand also increasing in plasma concentration after injury.

When acute hemorrhage occurs, the resulting blood lossand consumption of procoagulants combine to reduce thecirculating concentration of multiple clotting factors. De-rangement in common measures of coagulation (prothrom-bin time and activated partial thromboplastin time) candevelop in cases of acute trauma, before administration offluid therapy.15 Such derangements are associated with

From the Department of Anesthesiology, Emory University School ofMedicine, Cardiothoracic Anesthesiology and Critical Care, Emory Health-care, Atlanta, Georgia.

Accepted for publication July 11, 2011.

Funding: Funded by Department of Anesthesiology at the Emory UniversitySchool of Medicine.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Jerrold H. Levy, MD, FAHA, Department ofAnesthesiology, Emory University School of Medicine, Cardiothoracic An-esthesiology and Critical Care, Emory Healthcare, Atlanta, GA. Addresse-mail [email protected].

Copyright © 2012 International Anesthesia Research SocietyDOI: 10.1213/ANE.0b013e31822e1853

February 2012 • Volume 114 • Number 2 www.anesthesia-analgesia.org 261

significantly increased mortality rates in trauma patients.15

The dilution of clotting factors during intravascular volumereplacement can result in further coagulopathy; however,such hemostatic intervention is essential for the restorationof circulating volume and tissue perfusion. A prospectiveobservation of plasma concentrations of clotting factors inpatients undergoing major urologic or abdominal surgery(n � 60) showed that levels of prothrombin, factor V, factorVII and fibrinogen were all significantly reduced afterblood loss and subsequent fluid replacement (red bloodcells [RBCs] and colloids).16 Because of its relatively highinitial plasma concentration, fibrinogen was the first clot-ting factor to decrease to critically low levels.16 In noncar-diac major surgery, it has been shown that fibrinogenreaches plasma concentrations of 1 g/L when 142% (95%confidence interval [CI], 117 to 169%) of the circulatingblood volume has been lost.16

The maintenance of hemostasis relies on a series ofcomplex interactions between both the cellular and proteincomponents of coagulation.17 Importantly, platelets play akey role in many of these interactions; the platelet surface isthe primary site for thrombin generation,17 and plateletsaggregate to form the primary hemostatic plug,18 as well asstabilizing clot formation.1 Circulating platelet concentra-tions reduce in a similar manner to the observed depletionof clotting factors during major surgery.16 As such, thedevelopment of thrombocytopenia in critically bleedingpatients is a significant challenge to hemostasis. In vitroanalysis of platelet-poor plasma showed a positive correla-tion of viscoelastic measurements of clot strength withincreasing fibrinogen concentration,1 a result that wascorroborated by a retrospective analysis of 904 thrombocy-topenic patients. As such, the maintenance of fibrinogenconcentrations is crucial in cases of thrombocytopenia.1

The clinical relevance of plasma fibrinogen concentrationsin bleeding patients is not widely recognized and, as a result,physicians may not routinely measure fibrinogen levels orconsider supplementation options when treating major bleed-ing. In this review we will discuss the importance of fibrino-gen in clot formation and the therapeutic approaches forreplacing fibrinogen in acquired bleeding states.

ACUTE BLOOD LOSS AND MASSIVETRANSFUSION COAGULOPATHYIn cases of acute blood loss, restoring circulatory volume isa primary objective often addressed with volume expand-ers such as crystalloids, colloids, or a combination ofboth.19,20 The ideal volume expander has been the subjectof significant debate; however, the administration of anyvolume expander will result in the reduction of plateletsand plasma clotting factor concentrations.21 In such cases,the commonly observed change is dilutional thrombocyto-penia, but continuing blood loss can lead to a morecomplex coagulopathy. Neither concentrates of RBCs orplatelets contain enough plasma to supplement the de-pleted factors sufficiently to maintain hemostatic balance.16

Thus, continued consumption of clotting factors coupledwith their dilution with volume expanders can lead to thedevelopment of dilutional coagulopathy.

The critical role of fibrinogen deficiency and fibrinolysis incases of major bleeding is increasingly described.1,22,23 Thepreoperative measurement of plasma fibrinogen concentra-tion was found to be predictive of postoperative bleedingvolume and transfusion requirements in a prospectiveobservation of coronary bypass grafting surgical patients(n � 170).24 In another example, a multivariate analysis ofpostpartum hemorrhage (n � 128) reported that fibrinogenconcentration was the only hemostatic marker consistentlyassociated with the occurrence of severe postpartum hemor-rhage. It was concluded that the early measurement of fibrino-gen was able to detect reductions in plasma fibrinogenconcentration, allowing the risk of severe bleeding to bepredicted. As such, monitoring of this kind is recommendedduring the management of obstetric-related bleeding events.25

A greater understanding of the predictive value ofplasma fibrinogen concentrations has led to the potentialfor laboratory-guided, prophylactic supplementation ofcoagulation factors in cases of elective procedures. Thus, in

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

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). FromJohn W. Weisel, PhD, University of Pennsylvania, with permission.

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262 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA

events when hemorrhage is likely, the onset of coagulopa-thy can be delayed and the extent of bleeding reduced. Arecent prospective randomized controlled pilot study (n �20) investigating prophylactic fibrinogen supplementationbefore coronary artery bypass grafting showed thatpostoperative bleeding was reduced by 32% in patientsreceiving 2 g fibrinogen concentrate preoperatively in com-parison 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 theimportance of maintaining adequate plasma fibrinogenconcentrations, European guidelines now include theadministration of fibrinogen concentrate among their rec-ommendations for the treatment of trauma-related, life-threatening hemorrhage; however, it should be noted thatthis recommendation is based upon the lowest level ofevidence available to the guideline authors.19,27

FIBRINOGEN REPLACEMENTThere are 3 main approaches to fibrinogen supplementa-tion, which involve the infusion of fresh frozen plasma(FFP), cryoprecipitate, or fibrinogen concentrate.

Fresh Frozen PlasmaFFP contains all proteins present in human plasma, includingalbumin, immunoglobulins, and coagulation and fibrinolyticelements, which are at or below physiological concentrations(Table 1).28 It is commonly transfused for the reversal of oralanticoagulation therapy,29 but is also used for coagulationfactor supplementation during acute bleeding.30 Althoughextensively used during massive transfusion protocols, FFPpreparations have been associated with the potential risk of

pathogen transmission.31,32 Commercially available plasmacan be virally inactivated using 1 of 4 major treatmentprocesses to minimize the risk of pathogen contamination:solvent-detergent (SD), methylene blue, amotosalen, or ribo-flavin. All 4 methods demonstrate effectiveness against com-mon pathogens, including human immunodeficiency virus.33

With the exception of SD-treated plasma, these methods aredesigned for small-volume use at blood banks,33 and theavailability of such plasmas is limited to certain regions andcountries. Immunological reactions, including allergic reac-tions, and transfusion-related acute lung injury can also resultfrom FFP administration.32

FFP contains approximately 2.0 g/L34 of fibrinogen, butfibrinogen concentrations do vary between units; thuspredicting the increase in patient plasma fibrinogen con-centrations after transfusion is difficult.28 When the in vivofibrinogen concentration was measured in patients trans-fused with 30 mL/kg of FFP (approximating to 2.1 L of FFPfor a 70-kg patient), a median increase of 1.0 g/L (range, 0.9to 2.4 g/L) was observed.35 Thus, large volumes of FFP arerequired to increase plasma fibrinogen concentrations inbleeding patients, increasing the risk of hypervolemia andtransfusion-related circulatory overload.36 FFP is used in-creasingly in situations such as massive transfusion coagu-lopathy; however, a recent systematic review of massiveplasma transfusion found very-low-quality evidence thatsuch treatment reduces the risk of patient death.36

CryoprecipitateCryoprecipitate is a human plasma concentrate that wasfirst described in the 1960s.37 It is manufactured from FFP,and the processes involved have changed little since it was

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

Coagulationfactor

FFP, relative content (%)in comparison withnormal plasma28,34

Cryoprecipitate, relativecontent (%) in comparison

with normal plasma: per singledonor unit (20–50 mL)38

Fibrinogen concentrates

Riastap™d/Haemocomplettan P/HS�e

(per 50-mL vial) (CSLBehring, Marburg, Germany)

Clottafact�f

(LFB-biomedicaments)(per 100-mL vial)

(LFB-biomedicaments,Paris, France)

Fibrinogen 2.0 mg/mL (0.9–3.2)34b 388 mgc (range: 120–796 mg) 18–26 mg/mL �15 mg/mLFII 90 (72–108)34b — — —FV 88 (72–108)34b — — —FVII 90 (59–120)34b — — —FVIII 53 (32–92)34b — — —FIX 68 (45–87)34b — — —FX 88 (72–108)34b — — —FXI 10028 — — —FXII 8328 — — —FXIII 10028 20%–30% — —Antithrombin III 10028 — — —VWF 8028c — — —FVIII and VWFa — 40%–70% — —Fibronectin — 20%–25% — —IgG — 5%–8% — —IgM — 1%–2% — —Albumin — 5%–8% 8–14 mg/mL —L-arginine — — 7.5–13.2 mg/mL —Sodium chloride — — 4–7 mg/mL —Sodium citrate — — 1–2 mg/mL —

F � factor; FFP � fresh frozen plasma; Ig � immunoglobulin; VWF � Von Willebrand factor.a Reported jointly. b Median (reported range). c With some loss of high molecular weight multimers, particularly if solvent/detergent treated. d Licensed inEuropean countries and the United States for congenital fibrinogen deficiency. e Licensed in Austria, Brazil, Bulgaria, Germany, the Czech Republic, Hungary,Kuwait, the Netherlands, Portugal, Romania, Switzerland, Taiwan, and Turkey for acquired bleeding. fLicensed in France for acquired bleeding.

Fibrinogen Management in Acquired Bleeding


first discovered. In short, the thawing (between 1°C and 6°C)and subsequent centrifugation of FFP is followed by theremoval of the supernatant.38 The remaining 5 to 15 mL ofplasma is refrozen and can be stored in this way for up to 12months.38 According to recent testing, each unit of cryopre-cipitate contains a median fibrinogen concentration of 388 mg(range, 120 to 796 mg), whereas the minimum requirements ofthe American Association of Blood Banks (AABB) is 150 mgper unit.38 The typical concentrations of other constituentscontained in each unit are displayed in Table 1.

Because cryoprecipitate contains higher concentra-tions of fibrinogen than does FFP, it is the therapy optionoften used for fibrinogen supplementation in the UnitedStates (US) and United Kingdom. However, the existingrisk of immunological reactions and the transmission ofinfectious agents has led to its withdrawal in severalEuropean countries.39 Cryoprecipitate is unsuitable forviral inactivation processes in its native form,40 thoughplasma derivatives that have been pretreated with meth-ylene blue or SD can be used for its production.39

Unfortunately, such pretreatment processes can reducethe concentration of functional fibrinogen present.39,40

As with FFP, cryoprecipitate requires blood type match-ing and thawing before infusion, delaying administra-tion in time-critical situations.

Fibrinogen ConcentrateFibrinogen concentrate is derived from human plasma andis stored at room temperature as a pasteurized, lyophilizedpowder.41 It does not require blood type matching orthawing; thus it is available immediately when required. Itcan be reconstituted in low-volume concentrations of up to20 g/L.41 Doses as high as 6 g infused in as little as 1 to 2minutes have been reported in critical bleeding.42 A sum-mary of fibrinogen concentrates currently available isshown in Table 1. Commercially available fibrinogen con-centrates are primarily licensed for the treatment of con-genital fibrinogen deficiency across the US and Europe, anda license for the treatment of acquired bleeding has beengranted for only 1 of these products in some Europeancountries (Table 1).

The risk of viral infection with fibrinogen concentrates issignificantly reduced because of viral inactivation andremoval processes.43 This inherent viral reduction capacityalso minimizes the risk of transmitting new emergingviruses.43 Although fibrinogen concentrate is manufac-tured using human plasma from a large pool of donors, theproduction processes involved remove antibodies and an-tigens, largely mitigating the risk of immunological andallergic reactions resulting from its administration.39 Itshould be noted that although this risk is much reduced, aswith all blood products, fibrinogen concentrate administra-tion will always have the theoretical potential for transmis-sion of new emerging infectious agents.44

Historically, the occurrence of thromboembolic eventshas been a concern surrounding the administration ofclotting factor concentrates. With respect to fibrinogenconcentrate specifically, there are currently no results fromlarge prospective randomized controlled clinical trials onwhich any firm judgments can be based. Although anincrease in the amount of available prospective data would

provide valuable evidence for fully evaluating the throm-botic potential of fibrinogen concentrate, reviews of pub-lished clinical data and a recent pharmacovigilance reporthave demonstrated no significant thrombogenic concernswith fibrinogen concentrate.45,46 Furthermore, a study of151 separate infusions administered to 12 patients withcongenital fibrinogen deficiencies showed that the supple-mentation of fibrinogen using fibrinogen concentrate forprophylaxis, as well as during bleeding episodes andsurgery, was both efficient (with a median in vivo fibrino-gen recovery of 59.8% [n � 8; range: 32.5 to 93.9]) andgenerally well tolerated.47 In support of the clinical data,animal models of venous stasis have found that fibrinogenconcentrates demonstrated no thrombogenic activity.22,45 Itshould be noted, however, that the use of fibrinogenconcentrate in patients exhibiting disseminated intravascu-lar coagulation is potentially hazardous because of the riskof accelerated fibrin formation and should be avoided.41

Current opinion still remains divided regarding whatconstitutes the correct and appropriate administration offibrinogen concentrate in the critical care setting.44,48

Surveillance data may not provide reliable estimates ofthrombotic adverse events, which can occur up to 3months postsurgery at the doses used.44 It is also impor-tant to consider that there is no current prospectivecomparison of the safety profiles of FFP, cryoprecipitate,and fibrinogen concentrate, when administered for fi-brinogen supplementation.

CURRENT UNDERSTANDING OFFIBRINOGEN REPLACEMENTPreclinical DataIn a porcine model of thrombocytopenia, fibrinogen con-centrate was shown to better improve hemostatic functionand survival times than platelet transfusion alone afterblunt liver injury.22 A second porcine model of blunt livertrauma has compared bleeding and subject outcomesamong animals receiving varying concentrations of fibrino-gen concentrate. When compared with placebo, the admin-istration of fibrinogen concentrate (70 or 200 mg/kg) aftersevere dilutional coagulopathy both significantly improvedcoagulation and attenuated blood loss.49 Although theproper dosing cannot be determined from the studiesinvolving nonhuman species, in vitro clinical data usinghuman blood also demonstrate that increased fibrinogenconcentration improves clot strength independently ofplatelet count.1,50 Taken together, these results suggest thatrestoration of plasma fibrinogen concentrations using fi-brinogen concentrate could be an effective hemostatic treat-ment in cases of acquired bleeding.

Clinical DataSince fibrinogen supplementation in cases of major bleed-ing was established as a potentially useful treatment ap-proach, the efficacy of fibrinogen concentrate has beenassessed by many retrospective and some prospectivestudies. Its administration for the treatment of acquiredbleeding has been studied in heterologous cohorts ofpatients across a range of critical care settings (summarizedin Table 2).

REVIEW ARTICLE


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REVIEW ARTICLE


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Retrospective analyses (n � 30) of fibrinogen concen-trate administration to treat acquired hypofibrinogenemiaand life-threatening bleeding found it was effective in themanagement of such events,46 improving laboratory coagu-lation measures and survival rates in unresponsive coagu-lopathy.51 Laboratory monitoring of plasma fibrinogenconcentrations has shown significant increases after fi-brinogen concentrate administration (median dose, 3.52 g[range: 0.5 to 8.0]; mean increase [� sd] in plasma fibrino-gen, 1.09 [�0.68] g/L),51 with associated improvements inboth prothrombin time and activated partial thromboplas-tin time.51,52 Retrospective analysis of such laboratorycoagulation measurements, in bleeding patients (n � 43)treated with fibrinogen concentrate, demonstrated thatsuch improvements have led to reduced blood loss andlower requirements for RBCs (�12 U vs �2 U), FFP (�8 Uvs �2 U), and platelets (�2.5 U vs �0.5 U).53 Theseblood-sparing effects indicate that fibrinogen concentratecould potentially challenge traditional hemostatic ap-proaches using FFP and platelet concentrates.

TraumaThe significant loss of blood volume associated withtrauma-related bleeding often precipitates the “lethal triad”of acidosis, hypothermia, and coagulopathy. Coagulopathyin trauma patients results from the rapid depletion ofcirculating coagulation factors because of consumption andblood loss. Although acidemia, hypothermia, and subse-quent dilution all interact to contribute to trauma-relatedcoagulopathy, the interplay between these mechanisms isyet to be fully elucidated.54 Importantly, trauma-relatedcoagulopathy is a leading cause of mortality,55,56 and isresponsible for up to 40% of trauma-related deaths.19 Insuch cases, the need for effective and rapid hemostasismanagement is important, in addition to the rapid surgicalcontrol of bleeding. In cases of trauma-related massivebleeding, European transfusion guidelines recommend theprimary restoration of circulating volume and secondaryhemostatic measures via transfusion of blood products orpharmaceutical agents.19,27 Recent military experience oftrauma has strongly influenced transfusion practices in UStrauma centers.57,58 Several observational studies have sug-gested that transfusion of high ratios of FFP to RBCs (1:1) iskey to improving survival rates in patients with majortrauma.59–61 Consequently, many civilian trauma centersare now adopting massive transfusion protocols, whichinclude the transfusion of FFP in high volumes.62 Althoughthis approach is not universally accepted,63–65 and thecomplete restoration of circulating volume is not recom-mended in the US, it is becoming clear that the timelysupplementation of coagulation factors during majortrauma-related bleeding is important for the improvementof patient outcomes.66 A retrospective review of battlefieldtrauma reported 252 patients receiving massive transfu-sion, in which the total amount of fibrinogen infused withinall administered blood products (FFP, RBCs, and platelets)correlated with reductions in mortality.67

There are increasing reports of fibrinogen replacementusing concentrates administered as a first-line treatment oftrauma. Brenni et al. detailed a case study in whichfibrinogen concentrate was used in combination with RBCsTa

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REVIEW ARTICLE


as a primary hemostatic agent for the treatment of coagu-lopathy resulting from major abdominal trauma.68 Coagu-lopathy was corrected without the use of allogeneic bloodproducts, highlighting the potential efficacy and safetybenefits of such management protocols. The coadministra-tion of fibrinogen concentrate with other prohemostaticagents is an effective management protocol for traumapatients. A separate case study details the administration offibrinogen concentrate, in combination with prothrombincomplex concentrate (PCC), for the successful treatment ofpolytrauma.69 The combined use of these coagulation fac-tor concentrates, guided by point-of-care assessment (rota-tional thromboelastometry [ROTEM�; TEM InnovationsGmbH, Munich, Germany]), eliminated the need for allo-geneic factors (including FFP and platelet transfusion) andreduced the need for RBCs. A larger, retrospective analysisof a patient cohort with acquired bleeding (n � 131 total)receiving similar transfusion protocols adds weight to theconclusions drawn by these case studies.70 Patients infusedwith fibrinogen concentrates (n � 128) and PCCs (n � 98),using ROTEM-guided goal-directed coagulation manage-ment, displayed favorable survival rates in relation to thosepredicted by the trauma injury severity score (TRISS).70 Asimilar retrospective analysis compared a group of traumapatients (n � 80) receiving TEM-guided fibrinogen concen-trate (median 6 g [range: 0 to 15 g]) and PCC administration(median 1200 U [range: 0 to 6600]) with trauma patientsadministered FFP in the absence of coagulation factorconcentrates (n � 601, median 6 U [range: 2 to 51]).71 Theneed for RBC and platelet transfusion was avoided in 29%and 91% of fibrinogen-PCC patients, respectively, in com-parison with 3% and 56%, respectively, in the FFP group.The study authors concluded that the TEM-guided admin-istration of coagulation factor concentrates reduced theexposure level of trauma patients to allogeneic bloodproducts; however, it should be noted that mortality ratesbetween groups remained broadly comparable (7.5%vs.10.0% [fibrinogen-PCC versus FFP; P � 0.69]).

These studies highlight the potentially useful combina-tion of modern, real-time, coagulation monitoring with theadministration of clotting factor concentrates capable ofrapidly increasing the plasma concentrations of procoagu-lants in a goal-directed fashion. Currently, evidence, whichdemonstrates the efficacy of this approach, is restricted tocase studies and retrospective analyses. There are concernsthat highlight the limitations in study design that areinherent in such retrospective analyses, and care should betaken regarding the strength of conclusions that can bedrawn on the basis of their results.72 It is clear that thoughpromising, further prospective studies are required tobetter establish the dosing efficacy and safety of thisapproach.

Perioperative BleedingFibrinogen concentrate is now used across a range ofsurgical settings to maintain patient hemostasis and controlbleeding. There follows an overview of recent studies thatexamines the efficacy of fibrinogen concentrate adminis-tered perioperatively.

Cardiovascular and Vascular SurgeryCardiovascular and vascular surgical procedures are oftenaccompanied by excessive bleeding.73–75 Perioperativebleeding is a serious problem that can lead to increases inboth morbidity and mortality rates.76,77 The effective man-agement of such bleeding is the key to improved patientoutcomes, and a variety of approaches are now available tophysicians.78 Increasing numbers of both prospective andretrospective studies allow analysis of the impact of coagu-lation management in surgical procedures typically associ-ated with excessive hemorrhage.

A retrospective study investigating mortality rates inpatients (n � 128) undergoing ruptured abdominal aorticaneurysm repair found a significant reduction in mortalityrates (15% vs 39%; P � 0.03) in patients receiving RBC:FFPratio of �2:1 (high FFP cohort) in comparison with thosereceiving �2:1 ratios (low FFP cohort).79 These resultssuggest that high volumes of FFP can effectively aidhemostatic function and improve patient outcomes duringhigh-risk procedures. Fibrinogen concentrate may also beof benefit during such procedures. A study comparing bothretrospective and prospective data investigated the use offibrinogen concentrate during aortic valve and ascendingaorta surgery. Eight of 10 patients (prospective group)receiving fibrinogen concentrate before surgery requiredno transfusion of RBCs during cardiopulmonary bypass orwithin the subsequent 24 hours. In comparison, 41 of 42patients (retrospective group) receiving conventional he-mostatic therapy did require RBC transfusion within thesame period (P � 0.05).74 A follow-up study evaluatedprospective fibrinogen replacement using concentrates in 6patients as an initial treatment of postbypass bleedingduring thoracoabdominal aortic aneurysm repair in com-parison with a retrospective cohort of patients receiving noprophylaxis (n � 20).80 The need for transfusion of alloge-neic blood products was reduced in patients receivingfibrinogen concentrate in comparison with those who didnot (2.5 � 4.3 U vs 16.4 � 4.8 U), as was both the amountof bleeding during the following 24 hours, and the averagelength of treatment in the intensive care unit.80 Thesepreliminary data have led to the initiation of a prospectiverandomized clinical trial to further elucidate the potentialof fibrinogen concentrate in this setting (ClinicalTrials.govidentifier number NCT00701142).

A retrospective analysis (n � 39) of fibrinogen concen-trate infusion after cardiopulmonary bypass showed it tobe an effective method of increasing the plasma fibrinogenconcentration (mean dose [�sd]: 6.5 [�1.6]; absolute in-crease: 1.7 [�0.5] g/L).42 As was mentioned previously,serious intraoperative bleeding was treated successfullyusing rapid fibrinogen concentrate infusion in some cases(�6 g in 1 to 2 minutes). The study authors concluded thatthe use of fibrinogen concentrate contributed to the correc-tion of bleeding after surgery.42

Noncardiovascular SurgeryPatients undergoing orthopedic surgery are at risk of signifi-cant bleeding and developing dilutional coagulopathy, whichmay be influenced by the solution used for intravascularvolume replacement.21,81,82 A prospective study comparedpatients receiving colloids (either hydroxyethyl starch [HES]



ClinicalTrials.gov

[n � 19] or a modified gelatin solution [n � 21]) with thosereceiving Ringer’s lactate solution (n � 21) for volume re-placement during major orthopedic surgery, and examinedcoagulation variables using ROTEM.82 Fibrinogen polymer-ization was significantly impaired in patients receiving colloidrather than crystalloid. Different HES solutions variably im-pede fibrinogen polymerization, resulting in reduced clotfirmness. The administration of fibrinogen concentrate led tothe restoration and maintenance of clot firmness, even duringcontinued blood loss and further colloid administration.82

A prospective, placebo-controlled, randomized study(n � 20) of patients undergoing elective radical cystectomyinvestigated the ability of fibrinogen concentrate to restorehemostasis in patients experiencing excessive blood loss.83

Patients received HES for volume replacement when re-quired as part of the established blood replacement regi-men; treatment with fibrinogen concentrate was triggeredonce 30% volume dilution had occurred. In comparisonwith placebo, fibrinogen supplementation significantly im-proved both whole blood clot firmness and the rate of clotformation. Additionally, the requirement for postoperativetransfusion of RBCs was significantly reduced.83

Obstetric HemorrhageObstetric hemorrhage remains a major cause of mortalityand morbidity associated with childbirth.84,85 The increasein uterine arterial bloodflow during labor means thatmassive obstetric hemorrhage (�1500 mL) can rapidlyresult in life-threatening blood loss, occurring in approxi-mately 0.67% of all deliveries.86 Such events require vol-ume resuscitation and allogeneic transfusion; however, thisapproach can contribute to coagulopathy because of furtherdilution of coagulation factors. A review of 6 cases of severeobstetric hemorrhage suggested that the addition of fi-brinogen concentrate to traditional therapies was effectivein the treatment of peripartum blood loss associated withhypofibrinogenemia.87 Fibrinogen administration in com-bination with other blood products can control bleedingeven during continuing consumption and hemodilution.

These initial studies detail potential mechanisms bywhich severe obstetric hemorrhage could be both predictedand attenuated. However, it should be noted that there iscurrently little published evidence conclusively showingfibrinogen concentrate to be effective in preventing obstet-ric bleeding. Further prospective studies are needed toelucidate the full potential of this treatment option.

RECOMMENDED TRIGGER CONCENTRATIONSFOR FIBRINOGENFibrinogen Detection AssaysQuantitative fibrinogen detection can be performed immu-nologically, measuring both functional and nonfunctionalfibrinogen molecules. Functional assays that measurefibrinogen-dependent clot formation are used most oftenand utilize spectroscopic or viscoelastic detection. TheClauss method is a frequently used functional fibrinogenassay, whereby diluted citrated plasma is activated withthrombin and the time-to-clot formation is recorded spec-troscopically.41 Viscoelastic detection is performed usingwhole blood. When tested this way, the blood is housed ina cup (maintained at 37°C) and a pin is suspended within

the sample. The cup and pin are oscillated in relation toeach other and any subsequent impedance to this oscilla-tion provides a measure of clot formation.88 Point-of-caretesting using viscoelastic measures of clot strength (TEG�;Hemonetics�, Braintree, MA, or ROTEM) allow patient-specific, rapid, and guided supplementation of depletedcoagulation elements.69,70,89,90 The extent of fibrin polym-erization in whole blood can be estimated by inhibitingplatelet-fibrin(ogen) interactions on the TEG-based Func-tional Fibrinogen Test or ROTEM-based FIBTEM. The latteris commonly used in European countries to titrate thedosing of fibrinogen concentrates.69,70,89

When deciding which functional test is most appropri-ate for fibrinogen detection, several considerations must bemade. One advantage of using viscoelastic testing forfibrinogen determination is the inherent variability ofClauss-based fibrinogen assays. Clauss-based fibrinogenmeasurements may be falsely decreased in the presence ofdirect thrombin inhibitors,91 and falsely increased in thepresence of HES solutions.92 In general, the turbidimetric(optical) detection method is affected more than mechanicaldetections by these agents.93 However, it should be notedthat the viscoelastic methodology described has not beenprospectively validated for the measurement of fibrinogen-dependent clot formation during acute bleeding. It is notuniversally available, and furthermore, recent evidencesuggests that the measurement of fibrinogen levels usingFIBTEM can vary after hemostatic therapy, dependingupon the type of coagulometer being used.93

Treatment Thresholds and Dosing of FibrinogenAlthough there are increasing data on the importance ofplasma fibrinogen levels to prevent profuse bleeding, thethreshold levels for transfusing either cryoprecipitate orfibrinogen concentrates have not been agreed on univer-sally because of a lack of prospective evidence or consistentobservations across different clinical settings. There hasbeen some concern over iatrogenic hyperfibrinogenemiabecause increased plasma fibrinogen concentrations havebeen linked to an increased risk of coronary heart diseaseand myocardial infarction.94 However, a study by Reinhartdemonstrated that fibrinogen is a marker rather than amediator of coronary heart disease.95

The revised European trauma guidelines published in 2010recommend a trigger fibrinogen concentration of 1.5 to 2.0g/L,27 which was increased from below 1.0 g/L in earlierguidelines.96 This change is in agreement with other in vitroevidence that concentrations larger than 2.0 g/L are requiredto produce effective clot formation.50 Importantly, fibrinogenconcentrations can vary among patients, as well as duringincidences of acquired bleeding. Although the target plasmafibrinogen concentration that should be reached in a bleedingpatient is not known, and the optimum dose of fibrinogen hasnot been established by dose-ranging trials, bleeding increasesfor each 1.0 g/L decrease in plasma fibrinogen in parturi-ents.25 In vitro viscoelastic analysis of whole blood shows clotstrength increases linearly up to a fibrinogen concentration of3.0 g/L, with a minimum threshold of 2.0 g/L required for theoptimal rate of clot formation.50,97

Because of the large variability in fibrinogen concentra-tions among bleeding patients, increasing fibrinogen levels

REVIEW ARTICLE


should be individualized and based upon both the level ofbleeding and the plasma fibrinogen concentration.41 Aninitial dose of 10 U of cryoprecipitate, or 2.0 to 4.0 g offibrinogen concentrate is recommended for a 70-kg pa-tient,41 with subsequent administration dependent upon anindividual’s bleeding status. For fibrinogen concentrates,the required dose can be estimated as follows41,74:

Fibrinogen dose � desired increase (g/L) �

plasma volume (L).

Thus, administration of 3 g of fibrinogen concentrate in a70-kg patient approximates to an overall increase in plasmafibrinogen concentration of 1.0 g/L (assuming 0.04 L/kgplasma volume). Predicting the increase in plasma fibrino-gen concentrations that will result after cryoprecipitateadministration is troublesome, because of the wide varia-tion in fibrinogen concentration between units.39

SUMMARYFibrinogen is critical for effective clot formation, and itsmonitoring and guided supplementation in the treatmentof major bleeding is increasingly recognized. A growingnumber of reports note the importance of fibrinogen re-placement in the treatment of massive bleeding across abroad range of clinical settings.1,22,42,51,68–70,74,80,82,87,98

Available sources of fibrinogen for supplementation in-clude FFP, cryoprecipitate, and fibrinogen concentrates.Coagulation factor concentrates offer potential advantagesover allogeneic blood products, such as decreased immu-nogenic and infectious complications, as well as rapidavailability. Studies of the efficacy and safety of fibrinogensupplementation during acute bleeding has been mostoften retrospective or performed in prospective trials withlimited participant numbers owing to ethical and practicalconstraints. This must be considered when evaluating theevidence on the administration of fibrinogen in bleedingpatients. As such, further prospective, randomized con-trolled studies on the use of fibrinogen concentrate areessential to help define the breadth of clinical settings inwhich fibrinogen supplementation may be beneficial. Ad-ditional evidence would also help further define optimaltrigger concentrations and doses for fibrinogensupplementation.

RECUSE NOTEJerrold H. Levy is section Editor of Hemostasis and Transfu-sion Medicine for Anesthesia & Analgesia. This manuscript washandled by Steve Shafer, Editor-in-Chief, and Dr. Levy was notinvolved in any way with the editorial process or decision.

DISCLOSURESName: Jerrold H. Levy.Contribution: Performed literature search and manuscriptpreparation, oversaw ongoing revisions and corrections.Conflict of Interest: Dr. Levy receives research support from CSIBehring.Name: Fania Szlam.Contribution: Reviewed manuscript, added additional infor-mation and references.Conflict of Interest: This author has no conflict to declare.

Name: Kenichi A. Tanaka, MD.Contribution: Reviewed manuscript, added additional infor-mation and references.Conflict of Interest: Dr. Tanaka receives research support fromCSL Behring and Octapharma.Name: Roman M. Sniecienski, MD.Contribution: Reviewed manuscript, added additional infor-mation, 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.

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Nominations Sought for FAER Mentoring Excellence in Research Award

FAER is seeking nominations for the annual FAER Mentoring Excellence in Research Award. This award was created to ensure that the value of outstanding mentors is recognized and to encourage, develop, and retain these valuable individuals in our specialty. The FAER Mentoring Excellence in Research Award recognizes mentorship rather than scientific accomplishment. Nominees must have mentored anesthesiologists or scientists who have worked in the U.S. and contributed significantly to the practice. The award is focused on the successful development of mentees, not the professional accomplishments of the mentor. Nominees should be superior mentors, seen as supporting the future of the specialty. An overview of the award and the nomination process and a nomination form are posted on FAER’s website at faer.org/about/MentorResearchAward.html. The nomination form and supporting materials are due by March 31. Please submit all nomination materials by email to Mary Schrandt at [email protected].

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