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Keywords:

  • cryoprecipitate;
  • fibrinogen concentrate;
  • congenital fibrinogen deficiency;
  • acquired fibrinogen deficiency;
  • perioperative bleeding

Summary

  1. Top of page
  2. Summary
  3. History of the development of blood products
  4. Current sources of fibrinogen
  5. The choice between cryoprecipitate and fibrinogen concentrate in therapy of congenital fibrinogen disorders
  6. The choice between cryoprecipitate and fibrinogen concentrate for the management of perioperative bleeding
  7. Conclusions
  8. Conflict of interest statements
  9. References

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.

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 stabilization 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 α2β3 integrin glycoprotein (GP)IIb/IIIa.

Cryoprecipitate is a good source of fibrinogen that is 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, pasteurized human fibrinogen concentrates are available. In Europe, fibrinogen concentrate is well established for treatment of congenital fibrinogen deficiency, and is increasingly used for acquired fibrinogen deficiency (i.e. the management of perioperative bleeding) (Bundesaertzekammer, 2009).

As initially stated a decade ago (Bevan, 1999), the use of cryoprecipitate in the treatment of perioperative bleeding represents a double standard because it is contraindicated for the treatment of haemophilia, in preference for recombinant and pathogen-reduced plasma-fractionated products when available, on safety grounds. The present article aims to explore: the historic reasons behind the discrepancy between treatment of acquired and hereditary bleeding disorders; the factors influencing the choice between cryoprecipitate and fibrinogen concentrate; and the potential for future improvements in perioperative bleeding management.

History of the development of blood products

  1. Top of page
  2. Summary
  3. History of the development of blood products
  4. Current sources of fibrinogen
  5. The choice between cryoprecipitate and fibrinogen concentrate in therapy of congenital fibrinogen disorders
  6. The choice between cryoprecipitate and fibrinogen concentrate for the management of perioperative bleeding
  7. Conclusions
  8. Conflict of interest statements
  9. References

Haemophilia

Haemophilia A and B are caused by deficiency of factors VIII and IX, respectively (Fig 1). The first successful treatment of perioperative bleeding in a haemophiliac using blood transfusion was reported as early as 1840, but modern transfusion history really began in 1900 when Landsteiner discovered ABO histocompatibility antigens (Starr, 2002).

image

Figure 1.  Timeline of developments in treatment of haemophilia.

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Figure 1 shows a timeline of developments in the treatment of haemophilia. In the 1940s and 1950s, transfusion for haemophilia involved the use of ‘antihaemophilic globulin’, a crude preparation of fibrinogen and factor VIII. This was followed by the development of cryoprecipitate (Pool et al, 1964; Pool & Shannon, 1965), which allowed an effective dose of factor VIII in a tolerable volume and led to a dramatic increase in life expectancy (Josephson & Abshire, 2006).

However, treatment with plasma-derived products brought infection with diseases such as hepatitis, with multiple transfusions increasing the risk of infection (Alter & Klein, 2008). In 1982, three cases of acquired immunodeficiency syndrome (AIDS) were observed among patients with haemophilia A in whom transfusion was the most likely source of infection. It is estimated that, tragically, around 90% of concentrate-treated patients with severe haemophilia were already infected with the human immunodeficiency virus (HIV) before the first case of AIDS was recognized in 1981 (Alter & Klein, 2008). Assays to screen blood for contamination with HIV were introduced in 1985, significantly reducing the risk of transfusion-transmitted HIV (Alter & Klein, 2008).

Although reduced by more rigorous donor screening and more sensitive viral detection tests, such as polymerase chain reaction testing for viral genomes, the residual risk of viral transmission by plasma-derived products drove the development of more purified preparations of factor VIII with better safety profiles (Poon, 1993). A method to produce virally-inactivated factor VIII concentrates was developed in 1985 (Heimburger, 2002). Most recently in the development of haemophilia A treatments, recombinant factor VIII products became available in the early 1990s. The World Federation of Haemophilia supports use of coagulation factor concentrates in preference to cryoprecipitate, because cryoprecipitate is not subjected to viral inactivation procedures (World Federation of Hemophilia, 2005).

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. It was the needs of those wounded in war that led to advances in blood transfusion: blood storage was introduced during World War I; and fractionation of blood during World War II. Primary allogeneic blood components remain the mainstay of therapy for perioperative bleeding. At the same time, there is general agreement that transfusion of blood components, in particular plasma-rich blood components, should be avoided if possible (The Serious Hazards of Transfusion Steering Group 2004). Crystalloid and colloid solutions can be used to provide volume, and concentrates are available for replacement of coagulation factors (fibrinogen concentrate, factor XIII concentrate, and prothrombin complex concentrates containing three or four coagulation factors). Other ongoing developments include haemoglobin- or perfluorocarbon-based artificial oxygen carriers (Henkel-Honke & Oleck, 2007).

During the era of whole-blood transfusion, thrombocytopenia was the first haemostatic abnormality observed during blood loss. However, in the modern era of intravenous fluids and red cell concentrates, fibrinogen deficiency was the first defect observed (Hiippala et al, 1995). In a pig model of dilutional coagulopathy, even with moderate loss (35% of blood volume), the limited increase in fibrinogen synthesis cannot compensate for the concomitantly increased breakdown (Martini et al, 2005). Necessary fluid replacement using crystalloid and colloid solutions not only further reduces fibrinogen concentration by dilution, but colloids such as hydroxyethyl starch also impair fibrin polymerization (Fries et al, 2002; Innerhofer et al, 2002; Fenger-Eriksen et al, 2009a).

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). 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 [3·8 g/l; (Karlsson et al, 2008)]. Low preoperative levels of fibrinogen are associated with increased postoperative blood loss (Blome et al, 2005; Ucar et al, 2007b; Karlsson et al, 2008). In postpartum bleeding, low levels of fibrinogen are associated with severe bleeding, with a positive predictive value of 100% (Charbit et al, 2007). Based on this work, some current guidelines recommend transfusing fibrinogen concentrate in massive bleeding. Administration of fibrinogen is supported by recent studies including one prospective clinical trial (Fenger-Eriksen et al, 2009a, b).

In a porcine model of uncontrolled haemorrhage (induced by inflicting a standardized liver injury), administration of fibrinogen concentrate improved clot firmness and slowed down blood loss (Fries et al, 2005, 2006). In this model, fibrinogen concentrate was significantly more effective than platelet concentrate transfusion in the presence of thrombocytopenia [average platelet count = 30 × 109/l; (Velik-Salchner et al, 2007)]. Thus, substitution of fibrinogen may act at more than one level in clot formation, compensating for low thrombin generation and decreased platelet function. 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). Similarly, the number of platelets present may not be the limiting factor in clot formation if fibrinogen levels are high, as there are 40 000–80 000 copies of GPIIb/IIIa receptors on a single activated platelet (Kestin et al, 1993). This is supported by the observation that the effect of platelet-blocking substrates, such as clopidogrel, can be antagonized by increasing the concentration of fibrinogen (Li et al, 2001). In patients undergoing thoracoabdominal aortic aneurysm surgery, fibrinogen supplementation with concentrate was more effective than transfusion of FFP and platelet concentrate in achieving effective haemostasis and reducing postoperative bleeding (Rahe-Meyer et al, 2009a).

Current sources of fibrinogen

  1. Top of page
  2. Summary
  3. History of the development of blood products
  4. Current sources of fibrinogen
  5. The choice between cryoprecipitate and fibrinogen concentrate in therapy of congenital fibrinogen disorders
  6. The choice between cryoprecipitate and fibrinogen concentrate for the management of perioperative bleeding
  7. Conclusions
  8. Conflict of interest statements
  9. References

Today’s therapeutic options for supplementing plasma fibrinogen are FFP, cryoprecipitate and fibrinogen concentrate. FFP is the most widely available source of fibrinogen, but it has several significant drawbacks, such as extended administration time, transfusion-related complications and questionable efficacy (Stanworth, 2007). Blood group matching is required and, as FFP is stored at −20°C, thawing time needs to be taken into account. High volumes are needed for effective fibrinogen supplementation as the concentration in FFP is low (typically around 2·5 g/l (O’Shaughnessy et al, 2004), although this is variable). These factors all contribute to extending the time for administering FFP, a clear disadvantage in the setting of massive haemorrhage. Also, the low concentration limits the extent to which the fibrinogen level can be raised. FFP is not typically subjected to viral inactivation procedures, so there are risks of viral transmission. Treatment with methylene blue or solvent–detergent can be employed, but this can reduce the level of fibrinogen in the end-product (particularly in the case of methylene-blue treatment, where the reduction is around 30%) (Cardigan et al, 2009). Other potential complications associated with the use of FFP include volume overload and transfusion-related acute lung injury (TRALI) (Stanworth, 2007). Perhaps the most notable consideration with FFP, however, is the lack of robust evidence supporting its efficacy (Stanworth, 2007; Heim et al, 2009).

Cryoprecipitate contains a higher concentration of fibrinogen than FFP, typically around 15 g/l (Stinger et al, 2008). However, it shares many of the disadvantages of FFP. The risk of viral transmission is similar to that with FFP, the fibrinogen concentration is variable, and blood group matching is needed (Danes et al, 2008). Time is also required for thawing cryoprecipitate. The product was withdrawn from most European countries some years ago, on the basis of safety concerns, though it remains available in the UK and the USA. Cryoprecipitate is unsuitable for pathogen reduction steps, but it can be produced from plasma that has undergone treatment with methylene blue or psoralen/ultraviolet light. However, as previously mentioned, these methods can reduce functional fibrinogen content.

In contrast to FFP and cryoprecipitate, viral inactivation steps are routinely included in the manufacturing process for fibrinogen concentrate, therefore the risk of viral transmission is minimal (Groner, 2008). The concentration of fibrinogen is standardized, and the administration volume is low (Fenger-Erikson et al, 2009c). The administration time is short as there is no requirement for thawing (Rahe-Meyer et al, 2009a). Fibrinogen concentrate has been shown to be effective and well tolerated, in a variety of clinical settings. The risk of thrombosis has been shown in a 22-year pharmacovigilance study to be low (Dickneite et al, 2008).

The choice between cryoprecipitate and fibrinogen concentrate in therapy of congenital fibrinogen disorders

  1. Top of page
  2. Summary
  3. History of the development of blood products
  4. Current sources of fibrinogen
  5. The choice between cryoprecipitate and fibrinogen concentrate in therapy of congenital fibrinogen disorders
  6. The choice between cryoprecipitate and fibrinogen concentrate for the management of perioperative bleeding
  7. Conclusions
  8. Conflict of interest statements
  9. References

In addition to its important role in perioperative bleeding, fibrinogen supplementation is also indicated for congenital deficiencies. Inherited disorders that result in fibrinogen deficiency and/or aberrant function are rare but challenging therapeutic problems.

In afibrinogenaemia, homozygous or double heterozygous inheritance of lesions in the FGA, FGB or FGG genes, which encode the paired Aα, Bβ and γ chains that form the hexameric fibrinogen molecule, results in profound quantitative deficiency of fibrinogen (plasma concentration <0·1 g/l). This results in an episodic, sometimes life-threatening bleeding disorder. Replacement of fibrinogen is required to treat spontaneous bleeding (mucosal, cerebral, musculoskeletal, ovarian); to prevent bleeding after surgery (including poor wound healing); and in pregnancy, including prevention of early fetal loss. Afibrinogenaemia can also be associated with thrombosis, an unexplained complication possibly connected to the role of fibrin in binding and localizing thrombin. There is marked heterogeneity in the frequency of these symptoms, but prophylactic fibrinogen replacement is clearly indicated in some individuals and is favoured by a long half-life of infused fibrinogen. The median plasma elimination half-life of Haemocomplettan® P (CSL Behring, Marburg, Germany) is 2·7 d (range: 2·5–3·7), with a median clearance of 0·91 ml/h/kg (range; 0·84–1·22) (Kreuz et al, 2005).

Hypofibrinogenaemia and dysfibrinogenaemia (usually associated with hypofibrinogenaemia, but sometimes with a normal plasma level) is caused by heterozygous inheritance of genes associated with afibrinogenaemia, and a wide variety of other mutations. Bleeding and/or poor wound healing usually follows surgical challenge, but venous and arterial thrombosis can occur spontaneously. In dysfibrinogenaemia, abnormal fibrin clot structure and delayed or disordered fibrinolysis can contribute to thrombogenesis. Simply elevating the plasma fibrinogen is enough to prevent bleeding and normalize wound healing, but effective treatment of thrombosis also requires suppression of endogenous synthesis and/or secretion of the thrombogenic dysfibrinogen. Many variants of dysfibrinogen are associated with hypofibrinogenaemia due to impaired hepatocytic secretion of the mutant protein.

Transfusion strategies and dose calculations in fibrinogen replacement and prophylaxis demand an infusion product that delivers a known, standardized content of fibrinogen. This is difficult to achieve with cryoprecipitate, in which fibrinogen content varies widely between samples (manual pooling before infusion may add to this variability). In contrast, freeze-dried fibrinogen concentrate provides a known quantity of fibrinogen (900–1400 mg per vial).

In terms of safety, cryoprecipitate retains, to a degree, the statistically low risk of pathogen transmission entailed by its single-donor origin. However, a mini-pool of 10–12 units has to be assembled to make a single effective dose of fibrinogen, and in an inherited disorder, cumulative exposure obviates this advantage compared to large pool-derived fibrinogen concentrates treated with standard pathogen-reduction methods. For all these reasons, appropriately treated fibrinogen concentrate, if available, offers clear advantages over cryoprecipitate as therapy for inherited deficiencies and disorders of fibrinogen.

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). These inhibitors reduced the recovery and half-life of fibrinogen so that continuous infusion was required to maintain haemostasis. 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).

The choice between cryoprecipitate and fibrinogen concentrate for the management of perioperative bleeding

  1. Top of page
  2. Summary
  3. History of the development of blood products
  4. Current sources of fibrinogen
  5. The choice between cryoprecipitate and fibrinogen concentrate in therapy of congenital fibrinogen disorders
  6. The choice between cryoprecipitate and fibrinogen concentrate for the management of perioperative bleeding
  7. Conclusions
  8. Conflict of interest statements
  9. References

Efficacy

There is a clear consensus that treatment with FFP is inappropriate in cases of severe fibrinogen deficiency as it contains insufficient concentrations of fibrinogen (Chowdhury et al, 2004; Danes et al, 2008). Although scientific evidence regarding the clinical efficacy of fibrinogen concentrate is limited, 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.

There is evidence for the efficacy and safety of fibrinogen concentrate in congenital fibrinogen deficiency (Rodriguez et al, 1988; Kreuz et al, 2005; Aygoren-Pursun et al, 2007), and data on its use in patients with acquired deficiencies in a variety of surgical settings is beginning to emerge (Heindl et al, 2005; Danes et al, 2008; Fenger-Eriksen et al, 2008, 2009b; Haas et al, 2008; Weinkove & Rangarajan, 2008; Rahe-Meyer et al, 2009a,b). In an observational study of 69 patients suffering from various forms of acquired severe hypofibrinogenaemia, most (62%) had consumptive hypofibrinogenaemia (Danes et al, 2008). After a median dose of 4 g of fibrinogen concentrate, a mean absolute increase of 1·09 g/l of plasma fibrinogen was measured. Coagulation parameters, prothrombin and activated partial thromboplastin time, were significantly improved (P < 0·001) at 24 and 72 h after fibrinogen concentrate administration (Danes et al, 2008). Furthermore, there was an association between plasma fibrinogen concentrations after treatment and 7-d patient survival. In another retrospective study of 43 patients, a similar increase in fibrinogen levels (1·01 g/l) was achieved with half the average dose of fibrinogen (Fenger-Eriksen et al, 2008). 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. The specification for cryoprecipitate in the UK requires that 75% of units contain at least 140 mg of fibrinogen, in other words, there can be wide variation in fibrinogen content between units (O’Shaughnessy et al, 2004). This confounds dose calculations in comparative studies.

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 pasteurization process. The same is true for fibrinogen. In 1985, CSL Behring (then called Behringwerke), invented a pasteurization process using stabilizers to protect fragile proteins (Heimburger, 2002). A sterile filtration step also removed pathogens (Fig 2). As a result, the fibrinogen concentrate available today has a superior viral safety over cryoprecipitate, despite being plasma-derived. The overall reduction of titres during the production of fibrinogen concentrate is shown for some representative viruses in Table I (Groner, 2008).

image

Figure 2.  Schematic of production of pasteurized fibrinogen concentrate from frozen plasma.

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Table I.   Mean reduction of virus titres during the production of Haemocomplettan® P/Riastap (CSL Behring, Marburg, Germany) (Groner, 2008).
VirusMean reduction of titre (log10)
  1. *Model virus for hepatitis C virus.

  2. †Model virus for human parvovirus B19.

Human immunodeficiency virus≥9·6
Bovine viral diarrhoea virus*≥11·2
Herpes simplex virus 1≥9·1
Hepatitis A virus≥7·6
Canine parvovirus†6·1

The introduction of viral testing of plasma has greatly reduced the risk of viral transmission with cryoprecipitate. It has been estimated that in the UK, where FFP is not manufactured from first-time or lapsed donors, the residual risks from a single unit of FFP are 1 in 10 million for HIV, 1 in 50 million for hepatitis C virus and 1 in 1·2 million for hepatitis B virus (Williamson et al, 2003). However, in the absence of pathogen inactivation processes, the potential remains for contamination of plasma with an emerging, potentially lethal agent, for example variant Creutzfeld-Jakob disease (vCJD) in the UK, and West Nile virus (WNV) in the USA. The first case of possible transmission of vCJD as a result of transfusion was reported in 2004 (Pincock, 2004). Countermeasures taken to minimize the risk of vCJD transmission by transfusion, such as the use of leucocyte-depleted blood components and sourcing of FFP for neonates and children born after 1 January 1996 from outside the UK (O’Shaughnessy et al, 2004), increase the cost of blood products. By 2002, four transplant-associated cases and 23 transfusion-transmitted symptomatic cases of WNV had been identified. A test to detect genomic material of WNV was developed very rapidly, and transfusion-related transmission of WNV has been very rare since the implementation of testing in 2003 (Alter & Klein, 2008).

There are two main methods available for viral inactivation of plasma: treatment with solvent/detergent or methylene blue. However, at present, cryoprecipitate available in the UK is all derived from untreated FFP (O’Shaughnessy et al, 2004). The use of methylene blue for viral inactivation of plasma was first described by Lambrecht et al (1991). Reactive oxygen species that are generated when methylene blue is exposed to visible light inactivate viruses. However, it is well documented that methylene blue treatment also reduces coagulation factor levels, with fibrinogen one of the factors most sensitive to depletion. Compared with cryoprecipitate derived from untreated plasma, the loss of fibrinogen in methylene blue-inactivated cryoprecipitate ranged from 18% to 41% (Aznar et al, 2000; Hornsey et al, 2000; Seghatchian & Krailadsiri, 2001). A retrospective analysis of blood product use before and after the introduction of methylene blue-inactivated plasma in a University hospital in Spain found that the demand for plasma and cryoprecipitate increased across all diagnostic categories (Atance et al, 2001). The authors proposed compensation for low fibrinogen content as the most plausible explanation for this increase. No loss of coagulation factors is associated with solvent/detergent treatment of plasma, but there have been batch withdrawals due to possible contamination with parvovirus B19 (O’Shaughnessy et al, 2004). Both the methylene-blue and solvent/detergent methods of inactivation are primarily effective against enveloped viruses. Therefore, agents that are inactivated by pasteurization or removed by filtration during the processing of fibrinogen concentrates may still be transmitted by cryoprecipitate prepared from virally-inactivated plasma.

Aside from the risk of viral transmission, the same immune-mediated risks associated with transfusion of plasma exist for cryoprecipitate (MacLennan & Barbara, 2006). These risks include anaphylactic or anaphyloid reactions, allergic reactions, haemolysis, and TRALI. However, the non-specific allergic reactions associated with FFP transfusion are rarely seen with cryoprecipitate as only a small volume of plasma is used to resuspend the cryoprecipitated proteins (Ahrons et al, 1970; Reese et al, 1975). TRALI is believed to be caused by donor leucocyte antibodies, which are produced mainly as a result of pregnancy. Although it is under-diagnosed (Wallis, 2003), not least because the same clinical features are seen in acute lung injury resulting from other causes such as sepsis, trauma and shock, TRALI is a common cause of transfusion-related death. The UK National Blood Service announced its decision not to supply FFP from female blood donors in an effort to reduce the risk of TRALI in 2003. A recent summary of 10 years of haemovigilance reports of TRALI in the UK suggested that this policy has been effective in reducing the incidence of TRALI due to FFP (Chapman et al, 2008). However, the report also found that, although low, the risk from cryoprecipitate seems to have increased (from 4·3 cases per 106 cryoprecipitate components issued from 1999 to 2004 to 9·6 cases per 106 from 2004 to 2006). This could be because there is now a greater proportion of female donor plasma being used to prepare cryoprecipitate (Chapman et al, 2008).

A further safety concern in the management of perioperative bleeding is the risk of a thrombogenic event occurring. 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). Increased fibrinogen levels are associated with increased risk of coronary heart disease and myocardial infarction (MI). However, there is evidence to suggest that, in this instance, fibrinogen is acting as a marker rather than a mediator (Reinhart, 2003). For example, there is no increased risk of MI in people with fibrinogen gene polymorphisms that result in high fibrinogen levels (Reinhart, 2003). There have been nine reports of thromboembolic events in patients with congenital or acquired afibrinogenaemia during postmarketing surveillance of a fibrinogen concentrate (Dickneite et al, 2008). Although the patients had additional risk factors in most of the cases, a causal relationship could not be definitely excluded. Nonetheless, fibrinogen concentrate appears to have a very low risk of thrombogenicity, corresponding to one case report for every 13 655 treatments of 8 g (Dickneite et al, 2008). Thrombin generation in plasma is inhibited by formation of fibrin (hence fibrin has been referred to as antithrombin I), and increased thrombin generation in afibrinogenaemic patients can be normalized by fibrinogen supplementation (Korte & Feldges, 1994; Mosesson, 2003). Cryoprecipitate is not subject to the same postmarketing surveillance as fibrinogen concentrate, but has been associated with thrombotic events (Nizzi et al, 2002). Administration of cryoprecipitate to substitute fibrinogen could cause thrombosis as a result of supraphysiological levels of other proteins present in the precipitate (e.g. VWF).

Cost and availability

Fibrinogen concentrate is often perceived as much more expensive than cryoprecipitate. However, the true cost of cryoprecipitate may not be seen by operating theatre staff. Savings are made with fibrinogen concentrate as there is no need for compatibility testing or thawing and administration is simpler, meaning the net cost is not necessarily higher (Weinkove & Rangarajan, 2008). Cryoprecipitate is not available in most European countries (Haas et al, 2008) but is still used in the US and the UK whereas fibrinogen concentrate is far more widely available than cryoprecipitate in Central Europe. These factors naturally affect treatment decisions.

Future improvements in management of perioperative bleeding

General uptake of fibrinogen concentrate in place of cryoprecipitate for the management of perioperative bleeding would bring about the benefits described above and summarized in Table II. There is also scope for further improvement through clarification of critical fibrinogen levels and more rapid and reliable diagnostic tests.

Table II.   Attributes to consider when choosing between cryoprecipitate and fibrinogen concentrate for the management of perioperative bleeding.
AttributeCryoprecipitateFibrinogen concentrate
  1. MB, methylene blue; SD, solvent/detergent; TRALI, transfusion-related lung injury.

  2. *In Haemocomplettan® P/Riastap only.

Immunological reactionsRisk of ABO incompatibility, TRALI and severe anaphylaxis, albeit low because resuspended in small volume of plasma.Negligible risk of immunological reactions because purification steps during preparation remove donor antibodies
Risk of viral/pathogen transmissionUsually not virally inactivated. Viral inactivation using MB or SD not as effective as pasteurizationManufacturing process includes pasteurization* and filtration steps that minimize the risk
Accuracy of dosingInconsistent fibrinogen content between units. Reduced fibrinogen content in cryoprecipitate from MB-treated plasmaStandardized fibrinogen content
Number of units/vials required to provide 4 g dose29 units (based on 140 mg/unit)4 vials
Reconstituted volume of 4 g doseApproximately 375 ml (based on 15 g/l)200 ml
Time to administrationMust first be thawed in a water bathCan be reconstituted rapidly
CostPerceived to be cheaper than fibrinogen concentrateCost-effective and overall cost may be similar to cryoprecipitate
AvailabilityNot available in many European countries. Mainly used in UK and USAMore widely available than cryoprecipitate in most European countries

Although fibrinogen levels of around 1 g/l are widely cited as a threshold for triggering supplementation, dating back to the late 1980s (Ciavarella et al, 1987), the optimal value for this is not clear (O’Shaughnessy et al, 2004; Stainsby et al, 2006). The critical threshold may vary with the clinical situation and patient characteristics, for example, normal fibrinogen levels increase with age (Oswald et al, 1983; Balleisen et al, 1985; Laharrague et al, 1993; Ishikawa et al, 1997; Coppola et al, 2000). Several authors consider a threshold of 1 g/l to be too low when blood loss is continuing (Haas et al, 2008). In an in vitro study, there was no clot formation at <0·5 g/l fibrinogen and at 0·75 g/l only weak clots were formed (Nielsen et al, 2005). 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).

Point-of-care monitoring may further improve the management of patients with peri-operative bleeding. Certainly, evidence is growing that haemostasis management guided by thromboelastographic techniques is associated with a lower requirement for allogeneic transfusions (Shore-Lesserson et al, 1999; Royston & von Kier, 2001; Kozek-Langenecker, 2007; Spalding et al, 2007). Recently, assays that specifically measure the contribution of fibrinogen to clot formation by inhibiting platelets have been developed for both available point-of-care systems – the TEG® Coagulation Analyzer, Haemoscope Corporation, Niles, IL, USA and the ROTEM® Whole Blood Haemostasis Analyser, Pentapharm GmbH, Munich, Germany. These methods provide faster results than the standard laboratory tests and also offer greater accuracy. The Clauss method for measuring fibrinogen may give falsely high fibrinogen levels if colloids have been used for volume replacement because they impair fibrin polymerization (Hiippala, 1995; Mardel et al, 1998; Fries et al, 2002; Innerhofer et al, 2002; Mittermayr et al, 2007).

Conclusions

  1. Top of page
  2. Summary
  3. History of the development of blood products
  4. Current sources of fibrinogen
  5. The choice between cryoprecipitate and fibrinogen concentrate in therapy of congenital fibrinogen disorders
  6. The choice between cryoprecipitate and fibrinogen concentrate for the management of perioperative bleeding
  7. Conclusions
  8. Conflict of interest statements
  9. References

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 pathogen-reduced 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.

Conflict of interest statements

  1. Top of page
  2. Summary
  3. History of the development of blood products
  4. Current sources of fibrinogen
  5. The choice between cryoprecipitate and fibrinogen concentrate in therapy of congenital fibrinogen disorders
  6. The choice between cryoprecipitate and fibrinogen concentrate for the management of perioperative bleeding
  7. Conclusions
  8. Conflict of interest statements
  9. References

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.

References

  1. Top of page
  2. Summary
  3. History of the development of blood products
  4. Current sources of fibrinogen
  5. The choice between cryoprecipitate and fibrinogen concentrate in therapy of congenital fibrinogen disorders
  6. The choice between cryoprecipitate and fibrinogen concentrate for the management of perioperative bleeding
  7. Conclusions
  8. Conflict of interest statements
  9. References
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