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Journal ArticleDOI

A critical evaluation of cryoprecipitate for replacement of fibrinogen

01 Jun 2010-British Journal of Haematology (Br J Haematol)-Vol. 149, Iss: 6, pp 834-843

TL;DR: Wider availability and use of fibrinogen concentrate may improve the management of perioperative bleeding and further benefits may accrue from more rapid and accurate techniques for monitoring fibr inogen levels.

AbstractMaintaining the plasma fibrinogen concentration is important to limit excessive perioperative blood loss. This article considers the evidence for this statement, and questions the justification for using cryoprecipitate rather than virus-inactivated fibrinogen concentrate to support plasma fibrinogen levels. Haemophilia was historically treated with cryoprecipitate, but specific coagulation factor concentrates are now preferred. In contrast, primary fractions of allogeneic donor blood, including cryoprecipitate, are still commonly used to treat perioperative bleeding. When compared with cryoprecipitate and fresh-frozen plasma (FFP), freeze-dried fibrinogen concentrate offers standardized fibrinogen content, faster reconstitution and improved efficacy. Pasteurization and purification processes employed in the preparation of fibrinogen concentrate reduce the risk of pathogen transmission and immune-mediated complications, in comparison with cryoprecipitate and FFP. When all costs associated with administration are taken into consideration, the cost of fibrinogen concentrate is not substantially different to that of cryoprecipitate. In conclusion, wider availability and use of fibrinogen concentrate may improve the management of perioperative bleeding. Further benefits may accrue from more rapid and accurate techniques for monitoring fibrinogen levels. Clinical studies are needed to evaluate methods of measuring fibrinogen and assessing fibrin polymerization, and to define critical haemostatic plasma fibrinogen concentrations in different perioperative situations.

Topics: Cryoprecipitate (63%), Congenital afibrinogenemia (60%), Fibrinogen (54%), Fresh frozen plasma (54%), Fibrin (52%)

Summary (2 min read)

Introduction

  • In patients without pre-existing haemostatic disorders, coagulation defects that occur during surgery and/or massive haemorrhage are caused by loss, consumption and dilution of coagulation factors, collectively referred to as ‘dilutional coagulopathy’.
  • Some types of surgery disturb haemostasis in other ways: during cardiopulmonary bypass (CPB), interactions with the extracorporeal circuit activates the coagulation and fibrinolytic systems, resulting in platelet dysfunction, which is exacerbated by parallel induction of an inflammatory enzymatic cascade (Dietrich 2000).
  • Fibrinogen plays an important role in the coagulation process and clot stabilisation via its cleavage by thrombin to form fibrin polymers capable of binding factor XIII (Velik-Salchner, et al 2007), with consequent crosslinkage to form a robust fibrin network.
  • Alternatively, pasteurised human fibrinogen concentrates are available.
  • As initially stated almost a decade ago (Bevan 1999), the use of cryoprecipitate in the treatment of perioperative bleeding represents a double standard since it is contraindicated for the treatment of haemophilia, in preference for recombinant and pathogen-reduced plasma-fractionated products when available, on safety grounds.

Perioperative bleeding

  • Initially, whole blood was used in the management of perioperative bleeding, but this evolved to the use of blood components including red blood cells, FFP, cryoprecipitate and platelets.
  • Other ongoing developments include haemoglobin- or perfluorocarbon-based artificial oxygen carriers (Henkel-Honke and Oleck 2007).
  • During the era of whole-blood transfusion, thrombocytopenia was the first haemostatic abnormality observed during blood loss.
  • A further indication of the importance of fibrinogen comes from the observation that patients with high fibrinogen levels experience fewer bleeding complications than those with low levels (Blome, et al 2005, Fries, et al 2005, Pothula, et al 2004, Ucar, et al 2007a).
  • Based on this work, some current guidelines recommend transfusing fibrinogen concentrate in massive bleeding.

Current sources of fibrinogen

  • Today’s therapeutic options for supplementing plasma fibrinogen are FFP, cryoprecipitate and fibrinogen concentrate.
  • Other potential complications associated with the use of FFP include volume overload and transfusion-related acute lung injury (Stanworth 2007).
  • In afibrinogenaemia, homozygous or double heterozygous inheritance of lesions in the FGA, FGB or FGG genes encoding the paired Aα, Bβ and γ chains that form the hexameric fibrinogen molecule result in profound quantitative deficiency of fibrinogen (plasma concentration <0.1 g/L).
  • In terms of safety, cryoprecipitate retains, to a degree, the statistically low risk of pathogen transmission entailed by its single-donor origin.
  • For all these reasons, appropriately treated fibrinogen concentrate, if available, offers clear advantages over cryoprecipitate as therapy for inherited deficiencies and disorders of fibrinogen.

Efficacy

  • This is even more the case for cryoprecipitate (Danes, et al 2008), with no published studies specifically addressing the efficacy of cryoprecipitate in the management of perioperative bleeding.
  • In an observational study of 69 patients suffering from various forms of acquired severe hypofibrinogenaemia, most (62%) had consumptive hypofibrinogenaemia (Danes, et al 2008).
  • Furthermore, there was an association between plasma fibrinogen concentrations after treatment and 7-day patient survival.
  • This may reflect differences between the two study populations including underlying clinical conditions and proportion of paediatric patients.
  • There are no published studies comparing the efficacy of fibrinogen concentrate with cryoprecipitate.

Safety

  • In the past, nearly all patients with haemophilia who received factor VIII concentrates were exposed to transfusion-transmitted viruses, due to factor VIII being unable to withstand heating at 60°C during the standard pasteurisation process.
  • By 2002, four transplant-associated cases and 23 transfusion-transmitted symptomatic cases of WNV had been identified.
  • The use of methylene blue for viral inactivation of plasma was first described in 1991.
  • The authors proposed compensation for low fibrinogen content as the most plausible explanation for this increase.
  • Cryoprecipitate is not subject to the same postmarketing surveillance as fibrinogen concentrate, but has been associated with thrombotic events (Nizzi, et al 2002).

Cost and availability

  • Fibrinogen concentrate is often perceived as much more expensive than cryoprecipitate.
  • The true cost of cryoprecipitate may not be seen by operating theatre staff.

Conclusions

  • There is evidence that effective fibrinogen supplementation in patients with perioperative bleeding can: reduce blood loss, lower the requirement for transfusion of other blood components such as FFP and platelet concentrates, restore coagulation, and improve survival.
  • Where cryoprecipitate is still used, replacement with fibrinogen concentrate would offer improvements in efficacy and safety, bringing the standard of treatment for surgical patients in line with that offered to haemophilia patients.
  • Additional improvements to perioperative bleeding management may be attained by the introduction of more rapid and reliable tests for monitoring fibrinogen levels, and by clarification of the level of fibrinogen at which therapy should be initiated.
  • In congenital fibrinogen deficiencies, the argument for using current pathogenreduced fibrinogen concentrates as replacement therapy, in preference to cryoprecipitate, is very strong, although the current unlicensed status of this product in the UK is a significant impediment.

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A critical evaluation of cryoprecipitate for replacement
of brinogen
Benny Sørensen, David Bevan
To cite this version:
Benny Sørensen, David Bevan. A critical evaluation of cryoprecipitate for replacement of brinogen.
British Journal of Haematology, Wiley, 2010, 149 (6), pp.834. �10.1111/j.1365-2141.2010.08208.x�.
�hal-00552594�

For Peer Review
A critical evaluation of cryoprecipitate for replacement of
fibrinogen
Journal:
British Journal of Haematology
Manuscript ID:
BJH-2009-02003.R1
Manuscript Type:
Annotations
Date Submitted by the
Author:
25-Mar-2010
Complete List of Authors:
Sørensen, Benny; Center for Haemophilia and Thrombosis,
Department of Clinical Biochemistry
Bevan, David; Haemostasis Research Unit, Centre for Haemostasis
and Trombosis, Guy's and St Thomas NHS Trust Foundation &
King's College London School of Medicine
Key Words:
COAGULATION FACTORS, fibriogen, congentical fibrinogen
deficiency, cryprecipitate, mangement of perioperative bleeding
British Journal of Haematology

For Peer Review
Sørensen & Bevan Cryoprecipitate versus Fibrinogen concentrate
Page 1
A critical evaluation of cryoprecipitate for
replacement of fibrinogen
Benny Sørensen and David Bevan
Haemostasis Research Unit, Centre for Haemostasis and Thrombosis, Guy’s and St. Thomas’ NHS
Foundation & King’s College London School of Medicine, London, UK
Key words: Cryoprecipitate, fibrinogen concentrate, congenital fibrinogen deficiency,
acquired fibrinogen deficiency, perioperative bleeding
Word count: 4441 (excluding abstract, references, tables and figures)
Running short title: Cryoprecipitate versus Fibrinogen concentrate
Conflict of interest statements: Dr Benny Sørensen has participated in advisory
boards and/or received speaker honorariums from Novo Nordisk, Baxter, CSL
Behring, Bayer, Pentapharm, Biovitrum. Dr David Bevan has performed a CME
accredited talk on cryoprecipitate with unrestricted sponsorship provided by CSL
Behring. The Haemostasis Research Unit receives unrestricted research support from
Novo Nordisk, Grifols, CSL Behring, LFB, Baxter, Bayer, Octapharma.
Correspondence:
Benny Sørensen, E-mail: benny.sorensen@kcl.ac.uk
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For Peer Review
Sørensen & Bevan Cryoprecipitate versus Fibrinogen concentrate
Page 2
Summary
Maintaining the plasma fibrinogen concentration is important to limit excessive
perioperative blood loss. In this review, we consider the evidence for this statement,
and question the justification for using cryoprecipitate rather than virus-inactivated
fibrinogen concentrate to support plasma fibrinogen levels. Haemophilia was
historically treated with cryoprecipitate, but specific coagulation factor concentrates
are now preferred. In contrast, primary fractions of allogeneic donor blood, including
cryoprecipitate, are still commonly used to treat perioperative bleeding.
When compared with cryoprecipitate and fresh-frozen plasma (FFP), freeze-dried
fibrinogen concentrate offers standardised fibrinogen content, faster reconstitution
and improved efficacy. Pasteurisation and purification processes employed in the
preparation of fibrinogen concentrate reduce the risk of pathogen transmission and
immune-mediated complications, in comparison with cryoprecipitate and FFP. When
all costs associated with administration are taken into consideration, the cost of
fibrinogen concentrate is not substantially different to that of cryoprecipitate.
In conclusion, wider availability and use of fibrinogen concentrate may improve the
management of perioperative bleeding. Further benefits may accrue from more rapid
and accurate techniques for monitoring fibrinogen levels. Clinical studies are needed
to evaluate methods of measuring fibrinogen and assessing fibrin polymerisation,
and to define critical haemostatic plasma fibrinogen concentrations in different
perioperative situations.
Word count: 197
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Sørensen & Bevan Cryoprecipitate versus Fibrinogen concentrate
Page 3
Introduction
In patients without pre-existing haemostatic disorders, coagulation defects that occur
during surgery and/or massive haemorrhage are caused by loss, consumption and
dilution of coagulation factors, collectively referred to as ‘dilutional coagulopathy’.
Some types of surgery disturb haemostasis in other ways: during cardiopulmonary
bypass (CPB), interactions with the extracorporeal circuit activates the coagulation
and fibrinolytic systems, resulting in platelet dysfunction, which is exacerbated by
parallel induction of an inflammatory enzymatic cascade (Dietrich 2000). In liver
surgery, portal hypertension results in splenic platelet sequestration and
thrombocytopenia (Gorlinger 2006).
Current responses to severe perioperative bleeding include transfusion of allogeneic
blood products such as red blood cell concentrates, fresh frozen plasma (FFP),
platelets, and, in a few countries, cryoprecipitate. Transfusion of fibrinogen
concentrate is not yet a standard component of such protocols in either the UK or the
USA. In the past 5 years, several studies, which are reviewed below, have revealed
the importance of supplementing fibrinogen levels in correcting coagulopathy
associated with surgery. Fibrinogen plays an important role in the coagulation
process and clot stabilisation via its cleavage by thrombin to form fibrin polymers
capable of binding factor XIII (Velik-Salchner, et al 2007), with consequent cross-
linkage to form a robust fibrin network. In addition, it induces platelet activation and
aggregation by binding to the platelet fibrinogen receptor, the α
2
β
3
integrin
GPIIb/IIIa.
Cryoprecipitate is a good source of fibrinogen prepared by controlled thawing of
frozen plasma to precipitate high molecular weight proteins. These include factor
VIII, von Willebrand factor (vWF), and fibrinogen. The precipitated proteins are
separated by centrifugation, resuspended in a small volume of plasma (typically 10
20 mL) and stored frozen at -20°C (Poon 1993). In those countries that still use
cryoprecipitate, the current rationale is solely to provide fibrinogen. Although
cryoprecipitate is prepared as single units, these are pooled prior to administration –
a typical adult dose is 10 units (Stanworth 2007). Alternatively, pasteurised human
fibrinogen concentrates are available. In Europe, fibrinogen concentrate is well
established for treatment of congenital fibrinogen deficiency, and is increasingly
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Citations
More filters

Journal ArticleDOI
TL;DR: These guidelines are intended to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthetists throughout Europe to integrate this knowledge into daily patient care wherever possible.
Abstract: The aims of severe perioperative bleeding management are three-fold. First, preoperative identification by anamesis and laboratory testing of those patients for whom the perioperative bleeding risk may be increased. Second, implementation of strategies for correcting preoperative anaemia and stabilisation of the macro- and microcirculations in order to optimise the patient’s tolerance to bleeding. Third, targeted procoagulant interventions to reduce the amount of bleeding, morbidity, mortality and costs. The purpose of these guidelines is to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthetists throughout Europe to integrate this knowledge into daily patient care wherever possible. The Guidelines Committee of the European Society of Anaesthesiology (ESA) formed a task force with members of scientific subcommittees and individual expert members of the ESA. Electronic databases were searched without language restrictions from the year 2000 until 2012. These searches produced 20 664 abstracts. Relevant systematic reviews with meta-analyses, randomised controlled trials, cohort studies, case-control studies and cross-sectional surveys were selected. At the suggestion of the ESA Guideline Committee, the Scottish Intercollegiate Guidelines Network (SIGN) grading system was initially used to assess the level of evidence and to grade recommendations. During the process of guideline development, the official position of the ESA changed to favour the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. This report includes general recommendations as well as specific recommendations in various fields of surgical interventions. The final draft guideline was posted on the ESA website for four weeks and the link was sent to all ESA members. Comments were collated and the guidelines amended as appropriate. When the final draft was complete, the Guidelines Committee and ESA Board ratified the guidelines.

820 citations


Journal ArticleDOI
TL;DR: First-line administration of coagulation factor concentrates combined with point-of-care testing was associated with decreased incidence of blood transfusion and thrombotic/thromboembolic events.
Abstract: INTRODUCTION Blood transfusion is associated with increased morbidity and mortality. We developed and implemented an algorithm for coagulation management in cardiovascular surgery based on first-line administration of coagulation factor concentrates combined with point-of-care thromboelastometry/impedance aggregometry. METHODS In a retrospective cohort study including 3,865 patients, we analyzed the incidence of intraoperative allogeneic blood transfusions (primary endpoints) before and after algorithm implementation. RESULTS Following algorithm implementation, the incidence of any allogeneic blood transfusion (52.5 vs. 42.2%; P < 0.0001), packed red blood cells (49.7 vs. 40.4%; P < 0.0001), and fresh frozen plasma (19.4 vs. 1.1%; P < 0.0001) decreased, whereas platelet transfusion increased (10.1 vs. 13.0%; P = 0.0041). Yearly transfusion of packed red blood cells (3,276 vs. 2,959 units; P < 0.0001) and fresh frozen plasma (1986 vs. 102 units; P < 0.0001) decreased, as did the median number of packed red blood cells and fresh frozen plasma per patient. The incidence of fibrinogen concentrate (3.73 vs. 10.01%; P < 0.0001) and prothrombin complex concentrate administration (4.42 vs. 8.9%; P < 0.0001) increased, as did their amount administered per year (179 vs. 702 g; P = 0.0008 and 162 × 10³ U vs. 388 × 10³ U; P = 0.0184, respectively). Despite a switch from aprotinin to tranexamic acid, an increase in use of dual antiplatelet therapy (2.7 vs. 13.7%; P < 0.0001), patients' age, proportion of females, emergency cases, and more complex surgery, the incidence of massive transfusion [(≥10 units packed red blood cells), (2.5 vs. 1.26%; P = 0.0057)] and unplanned reexploration (4.19 vs. 2.24%; P = 0.0007) decreased. Composite thrombotic/thromboembolic events (3.19 vs. 1.77%; P = 0.0115) decreased, but in-hospital mortality did not change (5.24 vs. 5.22%; P = 0.98). CONCLUSIONS First-line administration of coagulation factor concentrates combined with point-of-care testing was associated with decreased incidence of blood transfusion and thrombotic/thromboembolic events.

361 citations


Journal ArticleDOI
TL;DR: Hemostatic therapy with fibrinogen concentrate in patients undergoing aortic surgery significantly reduced the transfusion of allogeneic blood products.
Abstract: BACKGROUND Fibrinogen is suggested to play an important role in managing major bleeding. However, clinical evidence regarding the effect of fibrinogen concentrate (derived from human plasma) on transfusion is limited. The authors assessed whether fibrinogen concentrate can reduce blood transfusion when given as intraoperative, targeted, first-line hemostatic therapy in bleeding patients undergoing aortic replacement surgery. METHODS In this single-center, prospective, placebo-controlled, double-blind study, patients aged 18 yr or older undergoing elective thoracic or thoracoabdominal aortic replacement surgery involving cardiopulmonary bypass were randomized to fibrinogen concentrate or placebo, administered intraoperatively. Study medication was given if patients had clinically relevant coagulopathic bleeding immediately after removal from cardiopulmonary bypass and completion of surgical hemostasis. Dosing was individualized using the fibrin-based thromboelastometry test. If bleeding continued, a standardized transfusion protocol was followed. RESULTS Twenty-nine patients in the fibrinogen concentrate group and 32 patients in the placebo group were eligible for the efficacy analysis. During the first 24 h after the administration of study medication, patients in the fibrinogen concentrate group received fewer allogeneic blood components than did patients in the placebo group (median, 2 vs. 13 U; P < 0.001; primary endpoint). Total avoidance of transfusion was achieved in 13 (45%) of 29 patients in the fibrinogen concentrate group, whereas 32 (100%) of 32 patients in the placebo group received transfusion (P < 0.001). There was no observed safety concern with using fibrinogen concentrate during aortic surgery. CONCLUSIONS Hemostatic therapy with fibrinogen concentrate in patients undergoing aortic surgery significantly reduced the transfusion of allogeneic blood products. Larger multicenter studies are necessary to confirm the role of fibrinogen concentrate in the management of perioperative bleeding in patients with life-threatening coagulopathy.

240 citations


Additional excerpts

  • ...Diabetes mellitus, n (%) 2 (7) 1 (3) Hypertension, n (%) 21 (72) 25 (78) Hyperlipidemia, n (%) 7 (24) 7 (22) Previous myocardial infarction, n (%) 9 (31) 6 (19) Previous heart operation, n (%) 5 (17) 2 (6) Smoking, n (%) 8 (28) 8 (25) Preoperative data FIBTEM MCF, mean ± SD, mm 18 ± 6....

    [...]


Journal ArticleDOI
TL;DR: Results show that fibrinogen concentrate is associated with a reduction or even total avoidance of allogeneic blood product transfusion, and represents an important option for the treatment of coagulopathic bleeding; further studies are needed to determine precise dosing strategies and thresholds for fibr inogen supplementation.
Abstract: Fibrinogen plays a critical role in achieving and maintaining hemostasis and is fundamental to effective clot formation. There is increasing awareness of the important role of fibrinogen as a key target for the treatment and prevention of acquired bleeding. Fibrinogen is the first coagulation factor to fall to critically low levels (<1.0 g/L) during major hemorrhage (normal plasma fibrinogen levels range from 2.0 to 4.5 g/L), and current guidelines recommend maintaining the plasma fibrinogen level above 1.5 g/L. Fibrinogen supplementation can be achieved using plasma or cryoprecipitate; however, there are a number of safety concerns associated with these allogeneic blood products and there is a lack of high-quality evidence to support their use. Additionally, there is sometimes a long delay associated with the preparation of frozen products for infusion. Fibrinogen concentrate provides a promising alternative to allogeneic blood products and has a number of advantages: it allows a standardized dose of fibrinogen to be rapidly administered in a small volume, has a very good safety profile, and is virally inactivated as standard. Administration of fibrinogen concentrate, often guided by point-of-care viscoelastic testing to allow individualized dosing, has been successfully used as hemostatic therapy in a range of clinical settings, including cardiovascular surgery, postpartum hemorrhage, and trauma. Results show that fibrinogen concentrate is associated with a reduction or even total avoidance of allogeneic blood product transfusion. Fibrinogen concentrate represents an important option for the treatment of coagulopathic bleeding; further studies are needed to determine precise dosing strategies and thresholds for fibrinogen supplementation.

219 citations


Journal ArticleDOI
TL;DR: 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 fibinogen concentrate used for such an approach.
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.

213 citations


Cites background from "A critical evaluation of cryoprecip..."

  • ...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....

    [...]

  • ...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....

    [...]

  • ...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....

    [...]

  • ...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)...

    [...]

  • ...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....

    [...]


References
More filters

Journal ArticleDOI
TL;DR: Fresh‐frozen plasma (FFP), cryoprecipitate and cryosupernatant plasma are very limited and should not be used to reverse warfarin anticoagulation in the absence of severe bleeding, and PRP may be used as an alternative to FFP.
Abstract: The indications for transfusing fresh-frozen plasma (FFP), cryoprecipitate and cryosupernatant plasma are very limited. When transfused they can have unpredictable adverse effects. The risks of transmitting infection are similar to those of other blood components unless a pathogen-reduced plasma (PRP) is used. Of particular concern are allergic reactions and anaphylaxis, transfusion-related acute lung injury, and haemolysis from transfused antibodies to blood group antigens, especially A and B. FFP is not indicated in disseminated intravascular coagulation without bleeding, is only recommended as a plasma exchange medium for thrombotic thrombocytopenic purpura (for which cryosupernatant is a possible alternative), should never be used to reverse warfarin anticoagulation in the absence of severe bleeding, and has only a very limited place in prophylaxis prior to liver biopsy. When used for surgical or traumatic bleeding, FFP and cryoprecipitate doses should be guided by coagulation studies, which may include near-patient testing. FFP is not indicated to reverse vitamin K deficiency for neonates or patients in intensive care units. PRP may be used as an alternative to FFP. In the UK, PRP from countries with a low bovine spongiform encephalopathy incidence is recommended by the Departments of Health for children born after 1 January 1996. Arrangements for limited supplies of single donor PRP of non-UK origin are expected to be completed in 2004. Batched pooled commercially prepared PRP from donors in the USA (Octaplas) is licensed and available in the UK. FFP must be thawed using a technique that avoids risk of bacterial contamination. Plastic packs containing any of these plasma products are brittle in the frozen state and must be handled with care.

749 citations


Journal ArticleDOI
TL;DR: Point-of-care coagulation monitoring using TEG resulted in fewer transfusions in the postoperative period, and this data support the use of TEG in an algorithm to guide transfusion therapy in complex cardiac surgery.
Abstract: Transfusion therapy after cardiac surgery is empirically guided, partly due to a lack of specific point-of-care hemostasis monitors. In a randomized, blinded, prospective trial, we studied cardiac surgical patients at moderate to high risk of transfusion. Patients were randomly assigned to either a thromboelastography (TEG)-guided transfusion algorithm (n 5 53) or routine transfusion therapy (n 5 52) for intervention after cardiopulmonary bypass. Coagulation tests, TEG variables, mediastinal tube drainage, and transfusions were compared at multiple time points. There were no demographic or hemostatic test result differences between groups, and all patients were given prophylactic antifibrinolytic therapy. Intraoperative transfusion rates did not differ, but there were significantly fewer postoperative and total transfusions in the TEG group. The proportion of patients receiving freshfrozen plasma (FFP) was 4 of 53 in the TEG group compared with 16 of 52 in the control group (P , 0.002). Patients receiving platelets were 7 of 53 in the TEG group compared with 15 of 52 in the control group (P , 0.05). Patients in the TEG group also received less volume of FFP (36 6 142 vs 217 6 463 mL; P , 0.04). Mediastinal tube drainage was not statistically different 6, 12, or 24 h postoperatively. Point-of-care coagulation monitoring using TEG resulted in fewer transfusions in the postoperative period. We conclude that the reduction in transfusions may have been due to improved hemostasis in these patients who had earlier and specific identification of the hemostasis abnormality and thus received more appropriate intraoperative transfusion therapy. These data support the use of TEG in an algorithm to guide transfusion therapy in complex cardiac surgery. Implications: Transfusion of allogeneic blood products is common during complex cardiac surgical procedures. In a prospective, randomized trial, we compared a transfusion algorithm using point-of-care coagulation testing with routine laboratory testing, and found the algorithm to be effective in reducing transfusion requirements. (Anesth Analg 1999;88:312‐9)

735 citations


Journal ArticleDOI
TL;DR: It is concluded that deficiency of fibrinogen develops earlier than any other hemostatic abnormality when plasma-poor RCCs are used for the replacement of major blood loss.
Abstract: The purpose of this study was to assess the change of platelet and fibrinogen concentrations and the change of activities of prothrombin and factors V and VII when major surgical blood loss was replaced with plasma-poor red cell concentrates (RCCs) and colloid plasma substitutes. Sixty patients were studied. The average blood loss was 65% +/- 41% of the calculated blood volume (CBV). Blood loss was monitored carefully and replaced without delay to ensure stable blood volume. Blood samples were obtained at the induction of anesthesia and at the end of the recovery room period, or before the patient was given fresh frozen plasma. In addition, a platelet count was determined after each 20% blood loss. The results were converted to relative values, and simple linear regression with logarithmic transformation was applied. The initial platelet concentration was 257 +/- 89 x 10(3)/mm3 and the extrapolation of the regression line intercepted the critical level of 50 x 10(3)/mm3 at 230% (confidence interval 169%-294%) blood loss. The initial fibrinogen concentration was 3.7 +/- 1.1 g/L and the hemostatically significant level of 1.0 g/L was already reached at 142% (117%-169%) blood loss (r2 = 0.90). Activities of prothrombin and coagulation factors V and VII reached their critical levels at 201% (160%-244%), 229% (167%-300%), and 236% (198%-277%) blood loss, respectively. We conclude that deficiency of fibrinogen develops earlier than any other hemostatic abnormality when plasma-poor RCCs are used for the replacement of major blood loss.

601 citations


"A critical evaluation of cryoprecip..." refers background in this paper

  • ...However, in the modern era of intravenous fluids and red cell concentrates, fibrinogen deficiency was the first defect observed (Hiippala et al, 1995)....

    [...]


Journal ArticleDOI
TL;DR: Findings indicate that a simple fibrinogen measurement can anticipate the risk of severe bleeding in PPH.
Abstract: Summary. Background: Postpartum hemorrhage (PPH) is a major source of maternal morbidity. Objectives: This study's objective was to determine whether changes in hemostasis markers during the course of PPH are predictive of its severity. Patients and methods: We enrolled 128 women with PPH requiring uterotonic prostaglandin E2 (sulprostone) infusion. Two groups were defined (severe and non-severe PPH) according to the outcome during the first 24 hours. According to our criteria, 50 of the 128 women had severe PPH. Serial coagulation tests were performed at enrollment (H0), and 1, 2, 4 and 24 hours thereafter. Results: At H0, and through H4, women with severe PPH had significantly lower fibrinogen, factor V, antithrombin activity, protein C antigen, prolonged prothrombin time, and higher D-dimer and TAT complexes than women with non-severe PPH. In multivariate analysis, from H0 to H4, fibrinogen was the only marker associated with the occurence of severe PPH. At H0, the risk for severe PPH was 2.63-fold higher for each 1 gL−1 decrease of fibrinogen. The negative predictive value of a fibrinogen concentration >4 gL−1 was 79% and the positive predictive value of a concentration ≤2 gL−1 was 100%. Conclusion: These findings indicate that a simple fibrinogen measurement can anticipate the risk of severe bleeding in PPH.

534 citations


"A critical evaluation of cryoprecip..." refers background in this paper

  • ...Thus, the threshold level for treatment may be substantially higher than the ‘historical’ 1 g/l, particularly in patients suffering from postpartum bleeding [4 g/l; (Charbit et al, 2007)] or excessive blood loss during cardiac surgery [3Æ8 g/l; (Karlsson et al, 2008)]....

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  • ...In postpartum bleeding, low levels of fibrinogen are associated with severe bleeding, with a positive predictive value of 100% (Charbit et al, 2007)....

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  • ...In a study of postpartum haemorrhage (PPH), fibrinogen concentrations less than 2 g/l had a 100% positive predictive value for severe PPH (Charbit et al, 2007)....

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Journal ArticleDOI
TL;DR: In patients with combat-related trauma requiring massive transfusion, the transfusion of an increased fibrinogen: RBC ratio was independently associated with improved survival to hospital discharge, primarily by decreasing death from hemorrhage.
Abstract: Background: To treat the coagulopathy of trauma, some have suggested early and aggressive use of cryoprecipitate as a source of fibrinogen. Our objective was to determine whether increased ratios of fibrinogen to red blood cells (RBCs) decreased mortality in combat casualties requiring massive transfusion. Methods: We performed a retrospective chart review of 252 patients at a U.S. Army combat support hospital who received a massive transfusion (≥10 units of RBCs in 24 hours). The typical amount of fibrinogen within each blood product was used to calculate the fibrinogen-to-RBC (F:R) ratio transfused for each patient. Two groups of patients who received either a low (<0.2 g fibrinogen/RBC Unit) or high (≥0.2 g fibrinogen/RBC Unit) F:R ratio were identified. Mortality rates and the cause of death were compared between these groups, and logistic regression was used to determine if the F:R ratio was independently associated with survival. Results: Two-hundred and fifty-two patients who received a massive transfusion with a mean (SD) ISS of 21 (±10) and an overall mortality of 75 of 252 (30%) were included. The mean (SD) F:R ratios transfused for the low and high groups were 0.1 grams/Unit (±0.06), and 0.48 grams/Unit (±0.2), respectively (p < 0.001). Mortality was 27 of 52 (52%) and 48 of 200 (24%) in the low and high F:R ratio groups respectively (p < 0.001). Additional variables associated with survival were admission temperature, systolic blood pressure, hemoglobin, International Normalized Ratio (INR), base deficit, platelet concentration and Combined Injury Severity Score (ISS). Upon logistic regression, the F:R ratio was independently associated with mortality (odds ratio 0.37, 95% confidence interval 0.171-0.812, p = 0.013). The incidence of death from hemorrhage was higher in the low F:R group, 23/27 (85%), compared to the high F:R group, 21/48 (44%) (p < 0.001). Conclusions: In patients with combat-related trauma requiring massive transfusion, the transfusion of an increased fibrinogen: RBC ratio was independently associated with improved survival to hospital discharge, primarily by decreasing death from hemorrhage. Prospective studies are needed to evaluate the best source of fibrinogen and the optimal empiric ratio of fibrinogen to RBCs in patients requiring massive transfusion.

386 citations


"A critical evaluation of cryoprecip..." refers background in this paper

  • ...Cryoprecipitate contains a higher concentration of fibrinogen than FFP, typically around 15 g/l (Stinger et al, 2008)....

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