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REVIEW ARTICLE
Department of Haematology, Addenbrookes Hospital, Cambridge, UK , and 2 NHS Blood and Transplant, John Radcliffe Hospital,
Oxford, UK
Received 15 June 2012; accepted for publication 15 August 2012
SUMMARY
Cryoprecipitate is an allogeneic blood product prepared from
human plasma. It contains factors VIII, von Willebrand factor
(vWF), fibrinogen, fibronectin and factor XIII. Its use was first
described in the 1960s for treatment of patients with factor
VIII deficiency. It has also been used to treat patients with
congenital hypofibrinogenaemia. Now, the most common use
of cryoprecipitate is fibrinogen replacement in patients with
acquired hypofibrinogenaemia and bleeding. Despite almost
50 years of use, evidence of efficacy is limited. This review
provides an overview of the history of cryoprecipitate use,
the current debates on the use of this product and future
developments.
HYPOFIBRINOGENAEMIA
Key words: bleeding, coagulopathy, cryoprecipitate, fibrinogen.
HISTORY
In 1964, Pool first described the preparation of cryoprecipitate
by centrifuging frozen plasma thawed at 04 C. Supernatant
plasma was removed and the remaining plasma was refrozen
as cryoprecipitate at 20 C (Pool et al., 1964). As a result
all plasma proteins remain in cryoprecipitate with factor VIII,
vWF and fibrinogen concentrated. The first successful use of
cryoprecipitate was in patients with von Willebrand disease in
1966 (Bennett & Dormandy, 1966). From 1967 cryoprecipitate
was used to successfully treat patients with haemophilia A
(factor VIII deficiency; Barrett et al., 1967). This was a pivotal
advance in the treatment of haemophilia. However, infection
risks with cryoprecipitate use were high due to multiple donor
exposure, particularly prior to the 1980s. As development of
more purified factor concentrates by pharmaceutical companies
CONGENITAL HYPOFIBRINOGENAEMIA
Congenital fibrinogen deficiency is rare. Three genes encode the
A, B and chains in the fibrinogen molecule; FGA, FGB
and FGG. Homozygous or double heterozygous inheritance of
gene mutations can result in a plasma fibrinogen concentration
<01 g L1 (Srensen & Bevan, 2010). Affected patients often
suffer from spontaneous bleeding, including mucosal, cerebral
and musculoskeletal haemorrhages. Pregnant women can suffer
early foetal loss. Hypofibrinogenaemia can also be associated
with unexplained thrombosis, which may be related to the role
of fibrin in binding thrombin.
Heterozygous inheritance of gene mutations associated
with afibrinogenaemia can result in hypofibrinogenaemia
and dysfibrinogenaemia. In dysfibrinogenaemia, the plasma
fibrinogen level is usually low, but sometimes can be normal
(Srensen & Bevan, 2010). This can result in poor wound
healing or bleeding after surgery and spontaneous thrombosis
(Girolami et al., 2012). Abnormal fibrin clot structure and
dysfunctional fibrinolysis can contribute to thrombogenesis in
doi: 10.1111/j.1365-3148.2012.01181.x
Product
4 units of fresh
frozen plasma
2 pools of
cryoprecipitate
4 g fibrinogen
concentrate
Volume (mL)
Fibrinogen
Fibrinogen administered
concentration
in one
(g L1 )
adult dose (g)
1000
300
15
375
200 (reconstituted)
20
317
SAFETY
In terms of safety, both fibrinogen concentrate and cryoprecipitate are plasma derived products and carry risks for transmission
of infectious diseases including new variant Creutzfeldt-Jakob
disease. Cryoprecipitate and fibrinogen concentrate are both
pooled products. Although cryoprecipitate can be administered
in single units, larger volumes may be required, thus exposing
recipients to multiple donors. Viral inactivation of both products can be achieved by treatment with solvent/detergent or
methylene blue, which is primarily effective against enveloped
viruses. Methylene blue treatment significantly reduces fibrinogen concentration, and it is of interest that the French agency
for the safety of health products (AFSSAPS, 2011) has decided to
withdraw methylene blue plasma for transfusion in France, due
to an increased number of severe allergic reactions compared
to other types of plasma and variability in the fibrinogen content of methylene blue plasma units. Currently, cryoprecipitate
available for adults in the UK is all derived from untreated
FFP (OShaughnessy et al., 2004). Cryoprecipitate derived from
methylene blue treatment is available for children under 16 years
of age, although guidance on defining age limits is currently
under review by the Advisory Committee on the Safety of Blood,
FUTURE DEVELOPMENT
Currently, there is interest in moving towards fibrinogen concentrate as the optimal source of fibrinogen replacement rather
than cryoprecipitate for patients with acquired hypofibrinogenaemia and major bleeding. However, there is a lack of
prospective trial data to inform effectiveness of replacement
by either source of fibrinogen. Arguably, without clinical trials there is a risk that fibrinogen concentrate use will further
increase in hospitals, but without full scrutiny of the effectiveness, safety and costs, as was the case for recombinant factor
VIIa, another even more expensive pro-coagulant product (Gill
et al., 2009).
There are some other considerations with this trend. First, it
has usually been accepted that a plasma fibrinogen level of above
1 g L1 should be maintained for haemostasis, however, there
is little evidence to support this threshold and recent studies
suggest higher fibrinogen thresholds may be more appropriate
in patients with acquired hypofibrinogenaemia and additional
coagulopathy. This suggests that the previously accepted critical
level of fibrinogen threshold is not the critical level. Second,
replacement of fibrinogen by cryoprecipitate may be associated
with specific practical difficulties, unlike fibrinogen concentrate.
For example, the concentration of fibrinogen differs between
units and timely administration is constrained by the need for
controlled thawing and transport to patients from blood banks.
More research is required to investigate the appropriate
fibrinogen thresholds required for haemostasis, for example in
patients undergoing cardiothoracic surgery using CPB, and to
determine the true association between hypofibrinogenaemia
and clinical outcome.
SUMMARY
Cryoprecipitate is still commonly used for replacement of
fibrinogen. Fibrinogen replacement in congenital fibrinogen
deficiency is gradually moving away from cryoprecipitate
use and fibrinogen concentrate is becoming the preferred
2012 The Authors
Transfusion Medicine 2012 British Blood Transfusion Society
REFERENCES
Afshari, A., Wikkelso, A., Brok, J., Moller, A.M.
& Wetterslev, J. (2011) Thrombelastography
(TEG) or thromboelastometry (ROTEM)
to monitor haemotherapy versus usual
care in patients with massive transfusion.
Cochrane Database of Systematic Reviews, 3,
CD007871.
AFSSAPS: Agence francaise de securite
sanitaire des produits de sante. (2011)
LAfssaps recommande larret progressif
de lutilisation du plasma therapeutique
traite par le bleu de methyl`ene. [Online].
Available: http://www.ansm.sante.fr/var/
ansm_site/storage/original/application/592
9de2c69988c350f277e5053a5b64b.pdf
(Accessed April 2012).
Barrett, K.E., Israels, M.C. & Burn, A.M. (1967)
The effect of cryoprecipitate concentrate
in patients with classical haemophilia. The
Lancet, 1, 191192.
Bennett, E. & Dormandy, K. (1966) Pools
cryoprecipitate and exhausted plasma in
the treatment of von Willebrands disease
and factor-XI deficiency. The Lancet, 2,
731732.
Besser, M.W. & Klein, A.A. (2010) The
coagulopathy of cardiopulmonary bypass.
Critical Reviews in Clinical Laboratory
Sciences, 47, 197212.
Charbit, B., Mandelbrot, L., Samain, E. et al.
(2007) The decrease of fibrinogen is an
early predictor of the severity of postpartum
hemorrhage. Journal of Thrombosis and
Haemostasis, 5, 266273.
Ciavarella, D., Reed, R.L., Counts, R.B., Baron,
L., Pavlin, E., Heimbach, D.M. & Carrico,
C.J. (1987) Clotting factor levels and the
risk of diffuse microvascular bleeding in the
massively transfused patient. British Journal
of Haematology, 67, 365368.
Danes, A.F., Cuenca, L.G., Bueno, S.R.,
Mendarte Barrenechea, L. & Ronsano, J.B.
(2008) Efficacy and tolerability of human
fibrinogen concentrate administration to
patients with acquired fibrinogen deficiency
and active or in high-risk severe bleeding.
Vox Sanguinis, 94, 221226.
Dickneite, G., Pragst, I., Joch, C. & Bergman,
G.E. (2009) Animal model and clinical evidence indicating low thrombogenic potential of fibrinogen concentrate
CONFLICT OF INTEREST
T. B. has received an honorarium for participating in an advisory
board for CSL Behring. All authors contributed to writing the
review and identifying and reviewing the source material.
319
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