cryoprecipitate

Transfusion Medicine | REVIEW ARTICLE

Cryoprecipitate: an outmoded treatment?

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

1Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK , and 2NHS 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.

Key words: bleeding, coagulopathy, cryoprecipitate, fibrinogen.

HISTORY

In 1964, Pool first described the preparation of cryoprecipitate

by centrifuging frozen plasma thawed at 0–4 ◦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, Addenbrooke’s Hospital,

Cambridge CB2 0QQ, UK.

Tel.: +44 01223 217128; fax: +44 01223 274871;

e-mail: [email protected]

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 2009–2010, 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

The normal fibrinogen level is 2–4 g L−1. Fibrinogen is the

primary substrate for the formation of a fibrin clot and is

required for platelet aggregation via interaction with the αIIbβ3

integrin on the platelet membrane (glycoprotein IIb/IIIa).

CONGENITAL HYPOFIBRINOGENAEMIA

Congenital fibrinogen deficiency is rare. Three genes encode the

Aα, Bβ and γ chains in the fibrinogen molecule; FGA, FGB

and FGG. Homozygous or double heterozygous inheritance of

gene mutations can result in a plasma fibrinogen concentration

<0·1 g L−1 (Sørensen & 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

(Sørensen & 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

© 2012 The AuthorsTransfusion Medicine © 2012 British Blood Transfusion Society 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 L−1 and 97% negative predic-

tive value when fibrinogen concentration is <4 g L−1 (bottom

of the physiological norm in pregnancy). Similarly, Simon et al.

(1997) showed 94·3% negative predictive value of fibrinogen

concentration less than 2·9 g L−1 predicting the occurrence of

post-partum haemorrhage. Although these findings are not

generalisable to all surgical patients as there are profound physio-

logical 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 <0·5 g L−1 (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 L−1),

predict post-operative bleeding, and has an overall odds ratio

of 2·0 for every 1 g L−1 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; O’Shaughnessy et al., 2004) recommends maintaining

fibrinogen above 1 g L−1 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

(Sørensen & 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 L−1 (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 1–2 g L−1 depending on clinical

setting.

There are two successful case reports of conservatively

managing splenic rupture in congenital afibrinogenaemia by

maintaining fibrinogen concentrate >1 g L−1 with cryoprecip-

itate infusion (Ehmann & al-Mondhiry, 1994). One small trial

compared the efficacy of cryoprecipitate with FFP for the cor-

rection 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 (2·1 g

fibrinogen) or 5 units of cryoprecipitate (2·7 g fibrinogen). An

insignificant trend to a greater increase in plasma fibrinogen

was observed with cryoprecipitate compared to FFP (20 vs 7%,

P = 0·27).

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 L−1 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 treat-

ment 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

Transfusion Medicine, 2012, 22, 315–320 © 2012 The AuthorsTransfusion Medicine © 2012 British Blood Transfusion Society

Cryoprecipitate: an outmoded treatment? 317

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

Product Volume (mL)

Fibrinogen

concentration

(g L−1)

Fibrinogen

administered

in one

adult dose (g)

4 units of fresh

frozen plasma

1000 3 3

2 pools of

cryoprecipitate

300 15 3·75

4 g fibrinogen

concentrate

200 (reconstituted) 20 4

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 L−1,

fibrinogen concentrate significantly reduced post-operative

blood loss and the 12 h post-operative total transfusion require-

ments 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 = 0·014) in

therapeutic fibrinogen concentrate increase and improved 7 day

survival following administration of 4 g fibrinogen concentrate

in patients with fibrinogen <1 g L−1 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 = 0·073). The mean fibrinogen concentration increase was

1·09 g L−1.

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 kg−1 fibrinogen concentrate significantly

increased the plasma fibrinogen concentrate by 0·77 g L−1

compared with 0·16 g L−1 in patients who received 2·25 mL kg−1

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

transfusion requirement was significantly (P < 0·05) 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 = 0·34). In the second RCT, cardiac

surgery patients were randomly assigned to receive an infusion

of 2 g fibrinogen concentrate (approximately 29 mg kg−1) or no

infusion immediately before cardiac surgery. Plasma fibrinogen

increased by a mean of 0·6 g L−1 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 fibrino-

gen concentrate administration. Further trials are planned

or underway, for example in obstetric haemorrhage and

pre-hospital trauma patients. There are no prospective tri-

als 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 essen-

tial fibrinogen replacement with cryoprecipitate or fibrinogen

concentrate.

SAFETY

In terms of safety, both fibrinogen concentrate and cryoprecipi-

tate 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 prod-

ucts can be achieved by treatment with solvent/detergent or

methylene blue, which is primarily effective against enveloped

viruses. Methylene blue treatment significantly reduces fibrino-

gen 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 con-

tent of methylene blue plasma units. Currently, cryoprecipitate

available for adults in the UK is all derived from untreated

FFP (O’Shaughnessy 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,

© 2012 The Authors Transfusion Medicine, 2012, 22, 315–320Transfusion Medicine © 2012 British Blood Transfusion Society

318 L. Yang et al.

Tissues and Organs (SABTO) whose remit is to advise the UKGovernment and UK Health Departments.

In the Serious Hazards of Transfusion (SHOT) report for2010, 35 cases of transfusion associated dyspnoea were reportedand one was associated with cryoprecipitate use. None of the15 cases of TRALI were associated with cryoprecipitate and notransfusion transmitted infections were reported (Knowles &Cohen, 2011).

Thrombogenic risk of fibrinogen concentrate has been inves-tigated in a 22-year post-marketing surveillance programme(Dickneite et al., 2009). Nine reports of venous thrombosisevents were identified in patients with congenital or acquiredafibrinogenaemia. Although these patients most likely had othercoexisting risk factors, including the fibrinogen defect, an asso-ciation with fibrinogen concentrate administration could notbe excluded. However, a further systematic review of 10 clin-ical studies involving 298 patients revealed only one patientthat developed non-fatal venous thrombosis and pulmonaryembolism, to which fibrinogen concentrate may have con-tributed. Whilst a study has shown that fibrinogen increases thereactivity of platelets and may be a contributor to cardiovasculardisease (Schneider et al., 1999), on balance evidence suggests thatfibrinogen acts as a marker for cardiovascular event risk ratherthan as a mediator (Reinhart, 2003). Overall, from the availableevidence, the current risk of thrombogenicity with fibrinogenconcentrate is low.

ADMINISTRATION AND COST

At the time of massive bleeding speed of intervention is vital.Cryoprecipitate requires donor-recipient ABO compatibilityand thawing up to 45 min, although group A cryoprecipitatecan be given prior to a group being available in major bleedingand use of specific thawing apparatus can considerably reducethawing time. Infusion usually takes around 10–20 min. Inan on-going multicenter prospective observational study ofcoagulopathy in trauma the median length of time from hospitaladmission to cryoprecipitate administration was 103 min(Rourke et al., 2012). Another single centre retrospective reviewrevealed that during massive blood loss in 394 trauma patientscryoprecipitate was administered at a median of 4·5 h fromhospital admission (Nascimento et al., 2011).

Fibrinogen concentrate is stored at room temperature andABO compatibility is not an issue. It can be reconstituted in 5 minand administered rapidly. In spite of being able to administerfibrinogen concentrate much more rapidly compared withcryoprecipitate, measuring the plasma fibrinogen concentrationstill requires laboratory transfer of blood samples. Given that thefibrinogen concentration is usually measured by the derived orClauss method, turn-around-times from sampling to obtainingresults from the laboratory may be over an hour. Therefore,in the setting of major bleeding, there is increasing interestin 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

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 con-

centrate as the optimal source of fibrinogen replacement rather

than cryoprecipitate for patients with acquired hypofibrino-

genaemia 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 tri-

als there is a risk that fibrinogen concentrate use will further

increase in hospitals, but without full scrutiny of the effective-

ness, 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 L−1 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


Cryoprecipitate: an outmoded treatment? 319

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.

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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