A critical evaluation of cryoprecipitate for replacement of fibrinogen
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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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....
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...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....
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...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....
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...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)...
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...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....
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253 citations
253 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....
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References
77 citations
"A critical evaluation of cryoprecip..." refers background in this paper
...The development of inhibitory antibodies in response to treatment with fibrinogen has been reported in three cases of afibrinogenemia: two cases following the use of cryoprecipitate (Bronnimann, 1954; Ra’anani et al, 1991) and one case following treatment with Cohn fraction I (De Vries et al, 1961)....
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...The patient who received Cohn fraction I developed anaphylaxis and giant urticaria, and eventually died as a result of anaphylaxis following subsequent infusion with whole blood (De Vries et al, 1961)....
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77 citations
"A critical evaluation of cryoprecip..." refers background in this paper
...High fibrinogen levels may compensate for a low concentration of thrombin because it only takes a single thrombin molecule to cleave up to 1680 molecules of fibrinogen (Elodi & Varadi, 1979)....
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74 citations
"A critical evaluation of cryoprecip..." refers background in this paper
...Solvent/detergent-treated plasma has reduced activity of the anticoagulant protein S, and has been associated with deep vein thromboses when used to treat patients with thrombotic thrombocytopenic purpura (PLAS+SD ; VI Technologies, Melvin, NY, USA) (Flamholz et al, 2000)....
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72 citations
"A critical evaluation of cryoprecip..." refers background in this paper
...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 (Pothula et al, 2004; Blome et al, 2005; Fries et al, 2005; Ucar et al, 2007a)....
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...Low preoperative levels of fibrinogen are associated with increased postoperative blood loss (Blome et al, 2005; Ucar et al, 2007b; Karlsson et al, 2008)....
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70 citations
"A critical evaluation of cryoprecip..." refers background in this paper
...838 ª 2010 Blackwell Publishing Ltd, British Journal of Haematology, 149, 834–843 Aside from the risk of viral transmission, the same immunemediated risks associated with transfusion of plasma exist for cryoprecipitate (MacLennan & Barbara, 2006)....
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