Transfusion Medicine

REVIEW ARTICLE

Cryoprecipitate: an outmoded treatment?

L. Yang,1 S. Stanworth2 & T. Baglin1
1

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.

progressed, the use of cryoprecipitate to replace factor VIII in

haemophilia patients declined.
Today, cryoprecipitate is largely used to replace fibrinogen in
acquired fibrinogen deficiency. In UK, there has been a steady
increase in the use of cryoprecipitate since 1999 (Knowles &
Cohen, 2011). In 20092010, 120 311 pools of cryoprecipitate
were issued from UK blood transfusion laboratories (Knowles
& Cohen, 2011). This amount of usage is concerning given the
known risks associated with human-derived blood products and
the lack of evidence supporting its efficacy. In many European
countries cryoprecipitate is not recommended due to the risk of
transmission of infectious disease and fibrinogen concentrate is
the preferred treatment for fibrinogen deficiency.

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

Correspondence: Dr Trevor Baglin, Cambridge University Hospitals

NHS Trust, Department of Haematology, Addenbrookes Hospital,
Cambridge CB2 0QQ, UK.
Tel.: +44 01223 217128; fax: +44 01223 274871;
e-mail: trevor.baglin@addenbrookes.nhs.uk
2012 The Authors
Transfusion Medicine 2012 British Blood Transfusion Society

The normal fibrinogen level is 24 g L1 . Fibrinogen is the

primary substrate for the formation of a fibrin clot and is
required for platelet aggregation via interaction with the IIb 3
integrin on the platelet membrane (glycoprotein IIb/IIIa).

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

316 L. Yang et al.

patients with dysfibrinogenaemia. Fibrinogen replacement to a
normal plasma level is sufficient to treat bleeding abnormalities
in both afibrinogenaemia and hypofibrinogenaemia patients.
Treatment of thrombosis requires conventional anticoagulant
therapy.

PREDICTIVE VALUE OF FIBRINOGEN IN BLEEDING

Assessment of the predictive value of differing fibrinogen
concentrations has only been described in a few studies of
major bleeding after trauma and surgery. Other relevant factors
for bleeding include dilution and consumption of coagulation
factors, activation of the fibrinolytic system and abnormal fibrin
polymerisation (Fries & Martini, 2010). Infusion of colloids
during blood loss, in particular hydroxyethyl starch (HES) can
also disturb fibrin polymerisation. Hypothermia and acidosis;
both common consequences of trauma, and severe blood loss
reduced plasma fibrinogen level in animal models (Martini,
2007; Martini & Holcomb, 2007).
It has been reported in obstetric patients that a low plasma
fibrinogen concentration is associated with increased bleeding
(Charbit et al., 2007). This study demonstrated 100% positive
predictive value for severe post-partum haemorrhage when the
fibrinogen concentration is <2 g L1 and 97% negative predictive value when fibrinogen concentration is <4 g L1 (bottom
of the physiological norm in pregnancy). Similarly, Simon et al.
(1997) showed 943% negative predictive value of fibrinogen
concentration less than 29 g L1 predicting the occurrence of
post-partum haemorrhage. Although these findings are not
generalisable to all surgical patients as there are profound physiological changes in the coagulation system at the end of pregnancy,
it suggests that even a near normal fibrinogen concentration may
be predictive of post-operative bleeding in some settings. This
is largely in contrast to previous studies carried out in major
trauma patients, where increased bleeding was observed with a
fibrinogen level of <05 g L1 (Ciavarella et al., 1987).
In cardiothoracic surgery, mechanisms of bleeding are
complicated by the use of cardiopulmonary bypass (CPB), in
which non-physiological changes in flow patterns lead to platelet
and clotting-factor activation, consumption and dilution,
together with activation of the inflammatory cascades (Besser
& Klein, 2010). It is reported that pre-operative fibrinogen
concentrations above the (perceived) normal range (>2 g L1 ),
predict post-operative bleeding, and has an overall odds ratio
of 20 for every 1 g L1 decrease in fibrinogen concentration
(Karlsson et al., 2008). Different strategies for fibrinogen
replacement are likely to apply for these patients suffering from
bleeding compared with those in obstetric and trauma cases.

THE ROLE OF FIBRINOGEN REPLACEMENT:

CLINICAL EXPERIENCE
The British Committee for Standards in Haematology
(BCSH; OShaughnessy et al., 2004) recommends maintaining

Transfusion Medicine, 2012, 22, 315320

fibrinogen above 1 g L1 to minimise bleeding. Current

available concentrated sources for fibrinogen replacement are
cryoprecipitate or fibrinogen concentrate. In the absence of a
concentrated source, large volumes of fresh frozen plasma (FFP)
are required for adequate fibrinogen supplementation, thus
exposing the patient to fluid overload and transfusion related
acute lung injury (TRALI). High quality randomised controlled
trials (RCTs) to evaluate the role of plasma transfusion have
never been undertaken and arguably what evidence exists from
RCTs indicates a lack of evidence for efficacy of prophylactic
and therapeutic FFP use (Stanworth et al., 2004; Yang
et al., 2012).
Current specifications for cryoprecipitate in the UK require
that 75% of units contain at least 140 mg of fibrinogen
(Srensen & Bevan, 2010). A single unit of cryoprecipitate
is prepared from a single unit of thawed FFP after harvesting
the cryosupernatant plasma following centrifugation. However,
instead of issuing cryoprecipitate in single units it can now be
prepared as a small pool from multiple donors. Five single units
are typically pooled into one bag (or one pool) before issue.
Fibrinogen concentration in cryoprecipitate is dependent on
inter-donor variability, but the typical fibrinogen concentration
is approximately 15 g L1 (Stinger et al., 2008). The often
quoted recommended adult dose is currently two pools (or
10 single units) of cryoprecipitate, to variably increase the
plasma fibrinogen level by 12 g L1 depending on clinical
setting.
There are two successful case reports of conservatively
managing splenic rupture in congenital afibrinogenaemia by
maintaining fibrinogen concentrate >1 g L1 with cryoprecipitate infusion (Ehmann & al-Mondhiry, 1994). One small trial
compared the efficacy of cryoprecipitate with FFP for the correction of coagulopathy associated with liver disease (French et
al., 2003). In the cross over trial, 11 patients admitted to the
intensive care unit with coagulopathy attributable to hepatic
failure were randomised to receive either 4 units of FFP (21 g
fibrinogen) or 5 units of cryoprecipitate (27 g fibrinogen). An
insignificant trend to a greater increase in plasma fibrinogen
was observed with cryoprecipitate compared to FFP (20 vs 7%,
P = 027).
Fibrinogen concentrate is provided in powder form and
stored at room temperature. It can be rapidly reconstituted and
administered within 5 min. ABO compatibility is not required.
Approximately 4 g of fibrinogen are often administered in one
adult dose of fibrinogen concentrate (Table 1).
Evidence for fibrinogen concentrate use is also very
limited. A few case reports described treatment of bleeding
by maintaining fibrinogen concentrate above 1 g L1 using
fibrinogen concentrate after splenic trauma in young patients
with congenital afibrinogenaemia (Ehmann & al-Mondhiry,
1994; Shima et al., 1997). A retrospective study showed that
fibrinogen concentrate is effective and well tolerated for treatment in patients with congenital fibrinogen deficiency (Kreuz
et al., 2005). Understandably, the lack of RCTs for congenital
hypofibrinogenaemia may be attributable to the rarity of the
2012 The Authors
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Cryoprecipitate: an outmoded treatment?

Table 1. The volume, concentration and amount of fibrinogen
administered in an adult dose.

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

condition. In acquired hypofibrinogenaemia, which is common,

there is some data including observational studies and two
small RCTs that suggest fibrinogen concentrate can improve
coagulation and reduce blood loss. A single centre retrospective
audit showed that in patients with a fibrinogen level <2 g L1 ,
fibrinogen concentrate significantly reduced post-operative
blood loss and the 12 h post-operative total transfusion requirements for packed red cells, FFP and platelets (Fenger-Eriksen
et al., 2009). Patients had a variety of underlying conditions,
including obstetric complications, neonates with bleeding
during surgery for congenital heart disease, cardiothoracic
surgery, intra-abdominal surgery, trauma and post-operative
pharyngeal bleeding. A recent prospective observational study
(Danes et al., 2008) showed a significant trend (P = 0014) in
therapeutic fibrinogen concentrate increase and improved 7 day
survival following administration of 4 g fibrinogen concentrate
in patients with fibrinogen <1 g L1 and were acutely unwell
suffering from sepsis, upper gastrointestinal tract haemorrhage,
gynaecological diseases and trauma. This trend was observed
when chronic cases, such as haematological malignancy and
hepatic insufficiency were included, but it was not significant
(P = 0073). The mean fibrinogen concentration increase was
109 g L1 .
Two RCTs assessing fibrinogen concentrate use in patients
undergoing surgery have shown positive results (Fenger-Eriksen
et al., 2009; Karlsson et al., 2009). One trial (Fenger-Eriksen et al.,
2009) assessed the efficacy of fibrinogen concentrate therapy in
bleeding patients undergoing radical cystectomy who received
intra-operative fluid replacement with HES. The other (Karlsson
et al., 2009) was a pilot RCT assessing prophylactic infusion of
fibrinogen concentrate in patients before cardiac surgery. Both
studies were of small sample size enrolling 20 patients in each
trial. The radical cystectomy study showed that intra-operative
infusion of 45 mg kg1 fibrinogen concentrate significantly
increased the plasma fibrinogen concentrate by 077 g L1
compared with 016 g L1 in patients who received 225 mL kg1
normal saline. Patients in the fibrinogen replacement group
had significantly improved clot firmness as measured by
thromboelastometry (ROTEM). The post-operative bleeding
rate was not reported. Within 48 h post-operatively, red cell
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317

transfusion requirement was significantly (P < 005) lower in

the fibrinogen replacement group (2 of 10) compared with the
control group (8 of 10). However, the total peri-operative red
cell transfusion requirements were not significantly different
between the two groups (P = 034). In the second RCT, cardiac
surgery patients were randomly assigned to receive an infusion
of 2 g fibrinogen concentrate (approximately 29 mg kg1 ) or no
infusion immediately before cardiac surgery. Plasma fibrinogen
increased by a mean of 06 g L1 in the fibrinogen replacement
group. Fibrinogen infusion reduced the 12 h total post-operative
blood loss by 32% (565 150 vs 830 268 mL). No adverse
effects attributable to the study product were identified from
both these trials. One patient in the fibrinogen group (Karlsson
et al., 2009) developed a small subclinical peripheral pulmonary
embolus, coincidentally detected by CT. The authors concluded
that this was likely due to existing risks in this patient rather
than an increased risk from fibrinogen administration.
In summary, the limited clinical study data have suggested
improved clinical outcomes in selected patients after fibrinogen concentrate administration. Further trials are planned
or underway, for example in obstetric haemorrhage and
pre-hospital trauma patients. There are no prospective trials comparing the efficacy of cryoprecipitate with fibrinogen
concentrate in peri-operative bleeding. In clinical practice, it
is expected that fibrinogen requirements may be higher in
actively bleeding patients compared with hypofibrinogenaemia
patients requiring prophylaxis, and it may be necessary to
replace additional coagulation factors with plasma after essential fibrinogen replacement with cryoprecipitate or fibrinogen
concentrate.

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,

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318 L. Yang et al.

Tissues and Organs (SABTO) whose remit is to advise the UK
Government and UK Health Departments.
In the Serious Hazards of Transfusion (SHOT) report for
2010, 35 cases of transfusion associated dyspnoea were reported
and one was associated with cryoprecipitate use. None of the
15 cases of TRALI were associated with cryoprecipitate and no
transfusion transmitted infections were reported (Knowles &
Cohen, 2011).
Thrombogenic risk of fibrinogen concentrate has been investigated in a 22-year post-marketing surveillance programme
(Dickneite et al., 2009). Nine reports of venous thrombosis
events were identified in patients with congenital or acquired
afibrinogenaemia. Although these patients most likely had other
coexisting risk factors, including the fibrinogen defect, an association with fibrinogen concentrate administration could not
be excluded. However, a further systematic review of 10 clinical studies involving 298 patients revealed only one patient
that developed non-fatal venous thrombosis and pulmonary
embolism, to which fibrinogen concentrate may have contributed. Whilst a study has shown that fibrinogen increases the
reactivity of platelets and may be a contributor to cardiovascular
disease (Schneider et al., 1999), on balance evidence suggests that
fibrinogen acts as a marker for cardiovascular event risk rather
than as a mediator (Reinhart, 2003). Overall, from the available
evidence, the current risk of thrombogenicity with fibrinogen
concentrate is low.

ADMINISTRATION AND COST

At the time of massive bleeding speed of intervention is vital.
Cryoprecipitate requires donor-recipient ABO compatibility
and thawing up to 45 min, although group A cryoprecipitate
can be given prior to a group being available in major bleeding
and use of specific thawing apparatus can considerably reduce
thawing time. Infusion usually takes around 1020 min. In
an on-going multicenter prospective observational study of
coagulopathy in trauma the median length of time from hospital
admission to cryoprecipitate administration was 103 min
(Rourke et al., 2012). Another single centre retrospective review
revealed that during massive blood loss in 394 trauma patients
cryoprecipitate was administered at a median of 45 h from
hospital admission (Nascimento et al., 2011).
Fibrinogen concentrate is stored at room temperature and
ABO compatibility is not an issue. It can be reconstituted in 5 min
and administered rapidly. In spite of being able to administer
fibrinogen concentrate much more rapidly compared with
cryoprecipitate, measuring the plasma fibrinogen concentration
still requires laboratory transfer of blood samples. Given that the
fibrinogen concentration is usually measured by the derived or
Clauss method, turn-around-times from sampling to obtaining
results from the laboratory may be over an hour. Therefore,
in the setting of major bleeding, there is increasing interest
in using near patient testing, such as the thromboelastography
(TEG) and ROTEM to assess bleeding and guide management.
Reduced clot strength as measured by TEG has been shown to

Transfusion Medicine, 2012, 22, 315320

be associated with low fibrinogen level in paediatric cardiac

surgery (Moganasundram et al., 2010). TEG and ROTEM
are being increasingly used in trauma settings (Schochl et al.,
2010, 2011; Tauber et al., 2011). TEG can be useful in guiding
and reducing transfusion requirements following cardiac and
liver transplantation surgery although many hospitals use local,
non-validated policies to guide transfusion in actively bleeding
patients (Afshari et al., 2011).
In terms of cost, the net cost of fibrinogen concentrate is
higher. The current cost of one pool of cryoprecipitate is 180; so
one adult dose costs 360. One 1 g vial of fibrinogen concentrate
currently costs approximately 400, or approximately 1600 per
gram rise for fibrinogen concentrate. It should be noted that
there are also uncertain but higher indirect costs of preparation,
thawing, processing and administration of all blood components
including cryoprecipitate.

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
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Cryoprecipitate: an outmoded treatment?

product. Similar trends may be developing for patients with
acquired hypofibrinogenaemia. RCTs are required to establish
the optimal source for replacement of fibrinogen and the size
of benefit in improving outcomes of patients when fibrinogen
supplementation is administered.

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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.

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2012 The Authors

Transfusion Medicine 2012 British Blood Transfusion Society

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