A critical evaluation of cryoprecipitate for replacement of fibrinogen

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.

Abstract: Maintaining 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.

Summary

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.

Figures

Figure 1. Timeline of developments in treatment of haemophilia

Full text

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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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