Cryoprecipitate: The Current State of Knowledge
Jeannie L. Callum, Keyvan Karkouti, and Yulia Lin
Cryoprecipitate is a diverse product containing factor
VIII, von Willebrand factor, fibrinogen, fibronectin,
factor XIII, and platelet microparticles. The role of this
complex product in the management of hemostasis has
not been well studied (excluding patients with factor
VIII deficiency). There are insufficient data to determine
the clinical setting where this product might be
clinically efficacious despite its widespread use in
multiple different clinical scenarios. The best method
of pooling before transfusion has also not been
RYOPRECIPITATE WAS FIRST introduced
C in the mid 1960s as a method to concentrate
factor VIII. Cryoprecipitate provided a major
therapeutic advance for patients with congenital
factor VIII deficiency. Shortly thereafter, it was also
determined to be of benefit for patients with von
Willebrand disease and hypofibrinogenemia. Its use
today resembles little what Pool had intended it for.
The most common indication for the product today
is the replacement of fibrinogen in patients with
acquired hypofibrinogenemia and bleeding. The
diverse contents of this product have never been
fully elucidated, nor has its clinical efficacy been
determined in properly designed clinical studies.
This article reviews the medical literature on
cryoprecipitate published since its method of
production was first described in 1964. The authors
hope that you find its history and early research
interesting and that it spurs you on to contribute
further to our understanding of the role of
cryoprecipitate as a therapeutic treatment.
HISTORY
Judith Graham Pool (1919-1975) first described
the preparation of cryoprecipitate in 1964 while at
Stanford University.1 The frozen plasma was
thawed at 0°C to 4°C over 18 to 24 hours. The
product was then centrifuged for 20 minutes at
2000 × g with the refrigerated centrifuge set at
2°C.2 The supernatant plasma (termed ‘exhausted’
plasma) was removed by gravity drainage, leaving
only 10 to 15 mL of plasma. The product was then
refrozen at −20°C. In October of 1966, Bennett and
Dormandy3 reported on the successful use of
cryoprecipitate in 3 patients with von Willebrand
disease. In January of 1967, Barrett et al4 reported
on the successful use of cryoprecipitate in 7 patients
with hemophilia. Cryoprecipitate thus heralded a
Transfusion Medicine Reviews, Vol 23, No 3 (July), 2009: pp 177-188
thoroughly investigated to determine the optimal infu-
sion strategy (intralaboratory vs bedside). The most
common current indication for the use of this product is
hypofibrinogenemia in the setting of massive hemorr-
hage. There are insufficient data in the literature to
determine the efficacy, safety, and dosage in this
patient population. Despite 45 years of the use of this
product, we still have a lot to learn regarding the
optimal use of cryoprecipitate.
© 2009 Elsevier Inc. All rights reserved.
new lifestyle for patients with hemophilia. Its
introduction was not without substantial risk, with
many recipients subsequently exposed to HIV,
hepatitis B virus, and hepatitis C virus from this
pooled product.
The exhausted plasma, now termed cryosuper-
natant plasma, was immediately put to use. In
October of 1966, Bennett and Dormandy reported
on the successful use of exhausted plasma for a
patient with factor XI deficiency.3
MANUFACTURING PROCESS
The manufacturing process has changed little
since first described by Pool.1 Cryoprecipitate is
prepared by thawing 1 unit of frozen plasma or
fresh frozen plasma at 1°C to 6°C.5 After the
product is thawed and centrifuged at 5000 × g for 6
minutes, the supernatant is removed, leaving the
cold insoluble precipitate plus 5 to 15 mL of plasma
in the original bag. This residual material is
refrozen within 1 hour of thawing and stored at
−18°C or colder. The resulting product has a shelf-
life of 12 months. Methods of manufacturing may
vary slightly in different jurisdictions.
Factor VIII and von Willebrand factor (vWF)
represent only 5% of the total protein in cryopre-
cipitate.6 The final product however contains 40%
to 70% of the original factor VIII/vWF that was
present in the original plasma.6 Each unit also
From the Sunnybrook Health Sciences Centre and University
Health Network, Toronto, Ontario, Canada.
Address reprint requests to Jeannie L. Callum, BA, MD,
FRCPC, CTBS, B204, Sunnybrook Health Sciences Centre,
2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5.
E-mail: jeannie.callum@sunnybrook.ca
0887-7963/09/$ - see front matter
© 2009 Elsevier Inc. All rights reserved.
doi:10.1016/j.tmrv.2009.03.001
177
178
Table 1. Content of Cryoprecipitate
Substance Specifics
Fibrinogen Fibrinogen is a 340-kDa glycoprotein composed
of 3 pairs of protein chains interconnected by
disulfide bonds. This glycoprotein is
synthesized by the hepatocytes and has a
long half-life in the plasma of approximately 4
d.13 The diffusion phase half-life of fibrinogen
is 12 h, and therefore, cryoprecipitate
infusions every 12 h are recommended for
patients with congenital fibrinogen deficiency
where fibrinogen concentrates are not
available.14 In contrast to factor VIII,
fibrinogen activity remains stable with
recovery of fibrinogen at 87% after 24 h of
liquid storage, when compared to original
content at time of thawing.15 Fibrinogen is
converted to fibrin by thrombin.
Factor VIII Factor VIII and vWF represent approximately 5%
and vWF of the total protein in cryoprecipitate.6 vWF
performs 2 major functions in primary
hemostasis: it mediates the adhesion of
platelets to exposed subendothelium, and it
stabilizes coagulation factor VIII in the plasma.
Factor XIII Factor XIII promotes clot stability by forming
covalent bonds between fibrin monomers
and by cross-linking alpha-2 antiplasmin,
fibrinogen, fibronectin, collagen, and other
proteins to enhance the mechanical strength
of the fibrin clot and protect the clot from
proteolytic degradation.16 Factor XIII
circulates in blood as a tetramer composed
of 2 A subunits (enzymatic portion) and 2 B
subunits (carrier portion). The activated form
consists of 2 A subunits, with the 2 B carrier
proteins removed.17 Cryoprecipitate contains
approximately 20% to 30% of the original
factor XIII of plasma.10
Fibronectin Fibronectin is a dimeric α2-glycoprotein present
at a concentration of 300 μg/mL in human
plasma. It is thought to have opsonic activity
assisting with the phagocytosis of particulate
debris by the reticuloendothelial system.18
Human-derived factor VIII concentrates
(excluding the high purity preparations) and
cryoprecipitate are potential rich sources of
fibronectin at 2100-3600 μg/mL and 1500
μg/mL, respectively.19
Platelet The observation that antiplatelet antibodies can
microparticles appear after the exposure to cryoprecipitate
prompted a search for platelet microparticles
in this blood component. 2 0 Platelet
microparticle content in plasma and
cryoprecipitate are measured using an
antibody to glycoprotein IIb. 2 1 The
microparticle content of plasma prepared
from platelet-rich plasma was greater than
that of plasma prepared directly from
whole blood. The process of preparing
cryoprecipitate further concentrates the
CALLUM ET AL
Table 1 (continued)
Substance Specifics
platelet membrane microparticle content.
The platelet membrane microparticle
concentration of cryoprecipitate was 29-
fold greater than the cryosupernant plasma
and 265-fold greater than the original plasma.
Each clinical dose of cryoprecipitate (10
units) contains approximately 4 × 109
platelets in microparticle form. Whether the
platelet membrane microparticles retain
hemostatic function after processing and
freezing is unknown. Microparticles can play
active roles in thrombosis, inflammation, and
vascular reactivity.22 We however need to
further understand the concentration of
platelet microparticles in cryoprecipitate,
their role in hemostasis, and their impact on
adverse reactions to the product
(alloimmunization and thrombosis).
contains approximately 100 to 250 mg of fibrino-
gen.7 The content of fibrinogen in current prepara-
tions of cryoprecipitate may be better than what was
historically achieved, with recent testing yielding a
median of 388 mg per bag (range, 120-796 mg).8
The minimum fibrinogen requirement by American
Association of Blood Banks (AABB) standards is
150 mg per bag.9 Each unit contains 30% to 50% of
the original fibrinogen in the source plasma.10
Other proteins in the concentrate include fibronec-
tin (20%-25%), IgG (5%-8%), IgM (1%-2%), and
albumin (5%-8%).6
There is an increase in the factor VIII content of
cryoprecipitate if the donors are exercised for
5 minutes on a bicycle before donation, but this fails
to translate into a superior postinfusion in vivo
recovery of factor VIII due to rapid clearance of the
‘exercise’ factor VIII.11 Factor VIII recovery is
improved by a higher donor factor VIII baseline
level, continuously mixing blood during collection,
minimizing the time from donation of plasma to
freezing, rapidly refreezing cryoprecipitate on dry
ice, and limiting the duration of cryoprecipitate
storage.12
Details regarding the specific contents of cryo-
precipitate are presented in Table 1.
PREPARATION PRETRANSFUSION
ABO-compatible cryoprecipitate is not required
due to the small volume of plasma transfused,5
although this may be important in patients receiving
CRYOPRECIPITATE 179

large volumes of cryoprecipitate relative to their red CLINICAL STUDIES

blood cell (RBC) mass. Mollison's 11th edition Massive Hemorrhage
recommends giving neonates ABO-compatible
cryoprecipitate.10 A positive direct antiglobulin There are numerous clinical settings where
test and hemolysis have only rarely been reported in administration of cryoprecipitate has been used as
patients receiving non–ABO-compatible cryopre- a therapeutic treatment (Table 2). One of the most
cipitate.23 Rh compatibility need not be considered common indications is massive transfusion. There
when selecting this product for transfusion. The are a considerable number of review articles on
product should be thawed in a plastic ‘over bag’ at when to give fresh frozen plasma (FFP) and
30°C to 37°C for no more than 15 minutes using an cryoprecipitate to a trauma patient with active
approved temperature-controlled water bath. Alter- hemorrhage, but few clinical studies to support such
natively, the product can be thawed with an recommendations.31-34 Many studies relate to the
approved microwave device. Once thawed, the use of whole blood and are therefore of no use in
product should be infused immediately. If not used today's world of packed RBCs.35-37 These retro-
immediately, it can be stored at 20°C to 24°C and spective case series are small and mainly present
must be used within 4 to 6 hours24,25 depending on data showing the fibrinogen levels after the FFP is
the jurisdiction. The Canadian Standards allow for administered. With few exceptions, the authors
storage for up to 24 hours as long as the intended recommend aggressive, early use of FFP, platelets,
use is for fibrinogen replacement and the system and cryoprecipitate. However, there is very little
remains closed. 26 For pooling, cryoprecipitate published on the rate of coagulopathic bleeding in
should be mixed with 10 to 15 mL of 0.9% sodium the setting of hypofibrinogenemia to know whether
chloride injection to ensure complete removal of all a low laboratory value is of any clinical signifi-
the material from each bag. If pooled, the product cance. There is even less known about the possible
must be used within 4 hours. The product cannot be benefit of cryoprecipitate in this clinical setting.
refrozen. Cryoprecipitate has been reported in the The first series of reports in the literature relate to
United Kingdom to be ‘lumpy’ and occasionally the infusion of whole blood and are described
occluding blood giving sets.27 Upon investigation,
this abnormal behavior of the product was found to Table 2. Reported Clinical Uses of Cryoprecipitate (see text for
be due to improper storage of cryoprecipitate in the details on efficacy)
refrigerator after pooling. Clinical setting Indication
Pooling of cryoprecipitate within the transfusion
Surgical bleeding Massive hemorrhage/
laboratory is estimated to occur in approximately transfusion
20% of laboratories in the United Kingdom.28 Very Hemorrhage post cardiac
little is known about the rate of pooling in other surgery
jurisdictions. To pool cryoprecipitate in the Eur- Topical use as a fibrin glue
Acquired hypofibrinogenemia Treatment of hemorrhage
opean Union, the blood facility must have a license
secondary to thrombolytic
under the European Union Blood Directive and be therapy
subject to regular inspections. Hence, many blood Management of bleeding due
facilities have discontinued pooling.29 The pool to snake envenomation
must have a unique identifier traceable to the original Obstetrics Iatrogenic premature rupture
of amniotic membranes
donor unit numbers. It is preferable to pool in an
Amniotic fluid embolism
approved biosafety cabinet to ensure maintenance of (for plasma opsonic activity)
sterility throughout the pooling process. Certainly, Congenital fibrinogen Prevention and treatment
pooling at the bedside requires additional time as deficiency of bleeding ⁎
multiple bags will need to be spiked, diluted with Congenital Factor Prevention and treatment
XIII deficiency of bleeding ⁎
saline, mixed, and then serially infused. Cryopreci-
Von Willebrand disease Prevention and treatment
pitate is most commonly administered in the setting of bleeding ⁎
of major hemorrhage after cardiac surgery and Uremia Prevention and treatment
trauma,30 and hence, lack of pooling within the of bleeding
blood transfusion service may lead to delays in ⁎ Only where human-derived, virally inactivated, or recombi-
transfusion due to competing bedside priorities. nant products are unavailable.
180
below. Counts et al 35 studied 27 massively
transfused trauma patients in 1979 and found no
relationship between the number of ‘cryo’ poor
whole blood (84% of units transfused) and packed
RBCs (16% of units transfused) transfused and the
fibrinogen level. Mannucci et al36 followed 127
patients transfused in excess of 5 units of whole
blood to determine the relationship between
coagulation parameters and units transfused. In
the latter study, a fibrinogen below the normal range
developed in 40% of patients transfused 5 to 9 units
of whole blood and in 60% of patient transfused
more than 15 units. Based on their data, they
recommended against indiscriminate use of cryo-
precipitate without supporting laboratory data. In a
study of 36 patients who had their fibrinogen
measured every 12 units of whole blood during
massive transfusion, microvascular bleeding
occurred in 4 of 4 patients with a fibrinogen level
less than 0.5 g/L and in 2 of 10 patients with levels
between 0.5 and 1.0 g/L (although both were also
severely thrombocytopenic).37 It is unclear how
applicable these studies are to the current practice of
using exclusively packed RBCs for transfusion.
The next group of reports describes massively
transfused trauma patients in the more current era of
packed RBC use. Three retrospective reviews
attempted to determine when coagulopathy devel-
oped during massive transfusion, but each failed to
report the fibrinogen levels.38-40 In a retrospective
review of 28 massively transfused (more than 10
units of packed RBCs in 24 hours) trauma patients
who survived to have coagulation testing per-
formed, 21 (75%) had a fibrinogen less than 1.0 g/L
despite receiving a mean of 17 units of cryopreci-
pitate and 12 units of FFP.41 A similar retrospective
review of 45 trauma patients receiving in excess of
50 units of packed RBCs found the fibrinogen level
to be better preserved in survivors than nonsurvi-
vors (109.1 vs 70.8 μmol/L; P = .02), although
causality could not be determined.34 It is unclear if
hypofibrinogenemia is common or mitigated by
cryoprecipitate during massive transfusion due to
the almost complete lack of supporting literature.
Singbartl et al42 mathematically modeled the fall
in fibrinogen level with surgical blood loss. They
estimated that a patient would reach the threshold
for fibrinogen replacement (1.0 g/L) after approxi-
mately 4000 mL of surgical blood loss. The
computer simulation of Hirchberg et al43 also
predicted a fibrinogen level less than 1.0 g/L after
CALLUM ET AL
approximately 5000 mL of surgical blood loss in
the absence of FFP or cryoprecipitate transfusion.
A recent report from the US Army Combat
Support Hospital found that survivors of massive
trauma who had received at least 10 units of RBCs
and/or fresh whole blood had a higher fibrinogen
(determined as a calculated amount from total
plasma and cryoprecipitate transfusions) to RBC
ratio than nonsurvivors.33 It is unclear from their
retrospective review whether this survival benefit
was attributable to ‘survivor bias’44 or cryopreci-
pitate/fresh frozen plasma administration. Survivor
bias in observational studies refers to a phenom-
enon where patients who live longer have a greater
probability to receive a certain treatment, and
hence, a retrospective report may yield a positive
association between that treatment and survival. It
is also unclear whether the 2 groups of patients
were similar in terms of baseline characteristics.
They nonetheless recommended that 10 units of
cryoprecipitate be administered with every 10
RBCs transfused to improve survival of trauma
patients with severe injury. Of particular note, no
fibrinogen levels were reported in this study.33
There is considerable debate in the surgical
literature as to when and how cryoprecipitate should
be administered to massively bleeding patients.33,45
This debate is unlikely to be settled in the absence of
a large, prospective, randomized trial of aggressive
formula-driven cryoprecipitate transfusions (1:1
ratio of RBC to cryoprecipitate units) vs laboratory
driven triggers (ie, fibrinogen level) for product
usage. Until such data are available, cryoprecipitate
should be used judiciously. Cryoprecipitate exposes
patients to large numbers of donors and therefore
increases the risk to known and emerging patho-
gens. Given that FFP contains 2 g of fibrinogen per
adult dose (4 units), a massively transfused patient
given adequate FFP to maintain international
normalized ratio (INR)/partial thromboplastin time
(PTT) within an appropriate range should only
rarely need extra fibrinogen in the form of
cryoprecipitate. There is no evidence that higher
fibrinogen levels assist with the management of
refractory hemorrhage in patients with fibrinogen
levels above 1.0 g/L.
Cardiac Surgery
In Canada, the most common indication for
cryoprecipitate transfusion is hemorrhage following
cardiac surgery.30 In this report, only 6% were
CRYOPRECIPITATE
deemed appropriate based on current guide-
lines.14,46 In addition, there was wide variability
in the proportion of cardiac surgery patients
transfused cryoprecipitate when individual hospital
sites were compared (overall, 4.1%; range, 0.3%-
10.1%). Despite this common practice in cardiac
surgery, there are no clinical data to support its use
in this specific patient population.
Congenital Deficiencies of Fibrinogen
Cryoprecipitate has been documented in case
reports to be effective in the prevention47,48 and
treatment47,49 of bleeding in the setting of con-
genital deficiencies of fibrinogen. More recently,
human-derived fibrinogen concentrates were
reported to be effective in the treatment of
congenital deficiencies of fibrinogen.50 Because
fibrinogen concentrates undergo viral inactivation,
when available, they should be used rather than
cryoprecipitate in patients with congenital deficien-
cies of fibrinogen.
Iatrogenic Premature Rupture of
Amniotic Membranes
Iatrogenic preterm rupture of amniotic mem-
branes is a known complication of diagnostic
amniocentesis and fetoscopy, with perinatal mor-
tality in pre-viable pregnancies approaching 50%.51
Serious sequelae may often be seen in surviving
infants, particularly pulmonary hypoplasia.52 Two
reports have evaluated the use of topical autologous
platelets and cryoprecipitate in the management of
iatrogenic preterm rupture of amniotic mem-
branes.53,54 Membrane sealing and delivery of a
viable near-term infant was observed in 4 of 10
cases. It is unclear whether this is an improvement
over expectant management because no control
group was used in these studies. Other investigators
have used fibrin sealants and observed similar
perinatal outcomes.55
Hepatic Failure
In a very small crossover trial of 11 patients with
coagulopathy secondary to liver disease, FFP was
found to be superior to cryoprecipitate in terms
of improvement in INR and PTT.56 Cryoprecipitate
alone is inadequate for the treatment of the
coagulopathy seen in patients with hepatic
failure due to lack of key coagulation factors in
this product.
181
Factor XIII Deficiency
Persons with congenital factor XIII deficiency
have a tendency for severe bleeding, a risk for
spontaneous abortion, and a high rate (25%-40%)
of spontaneous intracranial hemorrhage.17 Virally
inactivated, human-derived factor XIII concentrates
are commercially available, and thus, cryoprecipi-
tate is obsolete in this clinical setting.57 In addition,
a recent study demonstrating that recombinant
factor XIII-A2, when combined with endogenous
factor XIII-B subunits, has a half-life similar to that
of native factor XIII and appears to be safe and to
result in no serious adverse events in patients with
factor XIII deficiency.16
Von Willebrand Disease
Von Willebrand disease is a common inherited
bleeding disorder caused by the deficiency or
dysfunction of vWF affecting approximately 1%
of the population, with most individuals having
only a mild bleeding disorder. Treatment of patients
with von Willebrand disease with human-derived
virally inactivated blood products containing both
VIII and vWF is the treatment of choice when
bleeding occurs or must be prevented, and the
response to desmopressin is considered suboptimal
or insufficient for hemostasis.58 The transition to
virally inactivated human-derived factor VIII/vWF
concentrates was due to the concerns regarding
transfusion-transmitted viral infections from cryo-
precipitate. The use of cryoprecipitate for von
Willebrand disease should be restricted to emer-
gency therapy where factor VIII/vWF concentrates
are not immediately available and bleeding is
sufficiently severe to warrant the risks associated
with cryoprecipitate. Where cryoprecipitate is
required due to lack of availability of virally
inactivated human-derived products, a dose of 8
to 10 units of cryoprecipitate appears to result in
hemostasis and adequate postinfusion levels.59,60
Management of Hemorrhage Secondary to
Thrombolytic Therapy
The primary effect of thrombolytic therapy on
coagulation is a dose-dependent effect of the
concentration of fibrinogen. Thrombolytic therapy
is used in the management of acute myocardial
infarction, stroke, and venous thromboembolism.
At a dose of 150 mg of tissue-plasminogen
activator, 25% of patients have a fibrinogen level
182
less than 0.7 g/L.61 In contrast, 87% of patients
administered streptokinase have a fibrinogen level
less than 0.5 g/L at 90 minutes.62 Additional effects
of these agents include the anticoagulant effects of
fibrin degradation products, depletion of factors V
and VIII, and antiplatelet effects.63 It has been
recommended to treat the hypofibrinogenemia and
hemorrhage complicating thrombolytic therapy
with 10 units (adult patients) of cryoprecipitate.63
Most bleeding episodes are from sites of arterial
puncture for vascular procedure, and if such a
procedure is required, meticulous care should be
taken to prevent postprocedure bleeding.64
Topical Fibrin Glue
The use of cryoprecipitate as a fibrin glue has
been superseded by the use of virally inactivated
human-derived fibrin sealant products. The clinical
trial data to support the use of topical cryoprecipitate
are limited.65 Even the data to support virally
inactivated, human-derived fibrin sealants are
limited. A meta-analysis of 12 methodologically
poor trials including 624 patients found only a
modest benefit of these agents in surgical settings to
reduce allogeneic transfusion (odds ratio, 0.40; 95%
confidence interval [CI], 0.26-0.61).66 A Cochrane
review by the same authors of 14 small trials of
fibrin sealants found a reduction in allogeneic
transfusion (odds ratio, 0.46; 95% CI, 0.32-0.68).
Of note, the use of fibrin sealants only reduced the
risk of transfusion by 0.56 RBC units (95% CI, 0.29-
0.84 units) and the volume of blood loss by 134 mL
per patient (95% CI, 51-127 mL).67 It is debatable
whether a reduction of a half of a RBC unit is
clinically relevant. In addition, a large, randomized,
controlled, clinical trial in patients requiring liver
resection found no benefit of the topical application
of virally inactivated, human-derived fibrin sea-
lants.68 Cryoprecipitate should not be used topically
for the prevention or treatment of hemorrhage due to
the complete absence of data to support its use and
the availability of safer alternatives.
Uremic Bleeding
The etiology of uremic bleeding is multifactorial,
including impaired platelet-platelet interaction,
impaired platelet–vessel wall interaction, accumu-
lation of guanidinosuccinic acid leading to exces-
sive nitric oxide formation by endothelial cells,
administration of antiplatelet agents, and use of
heparin during hemodialysis.69 In addition, correc-
CALLUM ET AL
tion of anemia is known to correct the bleeding
time abnormalities in patients with uremia, impli-
cating anemia as a potential contributor to the
hemorrhagic diathesis seen in these patients.70
Presumably, cryoprecipitate was initially studied
to determine if it would improve platelet function
by the administration of vWF. Janson et al71
administered cryoprecipitate to 6 patients with
uremia and a median bleeding time of 18 minutes
(range, 16-20 minutes). Four hours postadministra-
tion of 10 units of cryoprecipitate, the bleeding time
was found to be a median of 9.5 minutes (range, 6-
12 minutes). By 24 hours postadministration, the
bleeding time had returned to baseline. None of the
patients had active bleeding. In contrast, Triulzi and
Blumberg72 administered 10 units of cryoprecipi-
tate to 5 patients with uremia and bleeding times in
excess of 15 minutes and found an improvement in
bleeding time in only 2 patients. Numerous
alternate strategies are available for the prevention
and treatment of uremic type bleeding including
dialysis, erythropoietin, RBC transfusion, desmo-
pressin (DDAVP), and conjugated estrogens, and as
such, cryoprecipitate is rarely used in the preven-
tion or treatment of uremic bleeding.
Amniotic Fluid Embolism
Amniotic fluid embolism is a rare complication of
pregnancy with an incidence of 1 in 20 646
pregnancies.73 The syndrome has a very high
mortality rate estimated to be between 26% and
61%, with most women dying within the first
hour.73,74 Cryoprecipitate has been used as a last
resort to replace depleted fibronectin (plasma opsonic
activity) with success reported in 2 case reports.75,76
Snake Bites
Snake envenomation can result either in hema-
tologic or neurologic toxicity. The primary hema-
tologic toxicity is the rapid consumption of
fibrinogen, resulting in acute coagulopathy. A
large series of 38 patients with North American
pit viper envenomation found 58% to have
hypofibrinogenemia, although none required cryo-
precipitate.77 Cryoprecipitate has been used suc-
cessfully for the management of the profound
coagulopathy after snake bites from the African
Bush Viper,78 Sochurek's saw-scaled viper,79 tiger
snake,80 Gaboon viper,81 and Bothrops asper.82
CRYOPRECIPITATE
Fibronectin Replacement
Deficiency of fibronectin has been observed in
patients after major surgery, trauma, burns, and
sepsis.83 It has been hypothesized that a deficiency
in fibronectin impairs the reticuloendothelial sys-
tem from clearing particulate debris in the circula-
tion resulting in the accumulation of fibrin
microaggregates, collagenous debris, and immune
complexes. These latter complexes have been
postulated to contribute to the multiorgan dysfunc-
tion seen in critically ill patients.19 In addition,
fibronectin also binds to Staphylococcus aureus and
may be important in its phagocytosis.84 In early
studies, low fibronectin concentrations have been
correlated with increased infection rates and poorer
survival in trauma patients.85,86 Infusion of cryo-
precipitate in a small crossover study of 14 trauma
and surgical patients resulted in an immediate
reversal of fibronectin deficiency and correction of
opsonic activity of plasma.83 After infusion, the
recovery of fibronectin is approximately 50% and
the half-life is 17 to 25 hours.19 Whether such
replacement is clinically relevant is, however, yet to
be determined.
CLINICAL GUIDELINES FOR THE USE
OF CRYOPRECIPITATE
The British Committee for Standards in Haema-
tology, Blood Transfusion Task Force published
guidelines for the use of cryoprecipitate in 2004.46
Cryoprecipitate was considered appropriate if the
fibrinogen was less than 1.0 g/L in the setting of
severe bleeding and/or disseminated intravascular
coagulation. This same recommendation was reit-
erated in the British Committee for Standards in
Haematology, Blood Transfusion Task Force guide-
lines on the management of massive blood loss in
2006.87 The College of American Pathologists'
guideline published in 1994 recommended that the
use of cryoprecipitate be reserved for patients with
clinical bleeding or planned invasive procedures in
patients with a fibrinogen level less than 1.0 g/L.14
Comprehensive cryoprecipitate guidelines were
published in the British Columbia Medical Journal
(Canada).88 This document advises on the use of
cryoprecipitate for hypodysfibrinogenemia when
recombinant or virally inactivated concentrates are
not available for von Willebrand disease, hemophi-
lia A, factor XIII deficiency, and thrombolytic-
related hemorrhage. The use of cryoprecipitate in
183
trauma was recently addressed in a review article by
Ketchum et al,31 recommending against prophy-
lactic cryoprecipitate administration in trauma
patients in the absence of hypofibrinogenemia.
They argue that FFP administration should be
adequate to prevent severe hypofibrinogenemia.
The fibrinogen cutoff of 1.0 g/L is reiterated in
all cryoprecipitate guidelines, although such a
cutoff does not reference a clinical study.14,46,87,88
This cutoff is likely based primarily on expert
opinion, although a study by Ciavarella et al37 of 36
massively transfused patients observed no micro-
vascular bleeding in patients with fibrinogen levels
in excess of 1.0 g/L.
The use of cryoprecipitate for the management
of uremic bleeding was detailed in an evidence-
based guideline on uremic bleeding in 2007.89
Cryoprecipitate was considered a reasonable ther-
apeutic option in uremic patients at high risk for
bleeding or actively bleeding, although they do
state, “The response in uremic patients can be
unpredictable.” Other therapeutic options recom-
mended in this evidence-based review included
dialysis, erythropoietin, desmopressin (DDAVP),
and conjugated estrogens.
DOSAGE RECOMMENDATIONS FOR THE USE
OF CRYOPRECIPITATE
One unit of FFP contains 0.5 g of fibrinogen;
thus, a standard adult dose of 4 units is equivalent to
2 g of fibrinogen. In contrast, 1 unit of cryopreci-
pitate contains 0.25 g of fibrinogen, giving the
content of 8 units of cryoprecipitate similar to that
of 4 units of FFP.31 The primary benefit of
administering fibrinogen as cryoprecipitate is that
the total volume of a single adult dose is 100 mL,
compared to 1000 mL for FFP.
The College of American Pathologists' guideline
published in 1994 recommended a dose of 1
cryoprecipitate unit per 5 kg of body weight.14
The AABB physician handbook states that 1 unit
will increase the fibrinogen by 5 to 10 mg/dL (0.05-
0.1 g/L) in an average sized adult.25 The AABB
Technical Manual, 15th Edition recommends the
use of the following calculation5:
1. Blood volume = weight (kg) × 70 mL/kg
2. Plasma volume = blood volume × (1-hematocrit)
3. mg of fibrinogen required = (desired fibrino-
gen − current fibrinogen in mg/dL) × plasma
volume divided by 100 mL/dL
184
4. Bags of cryoprecipitate required = mg of
fibrinogen divided by 250 mg.
Cryoprecipitate should be administered through
a 170- to 260-μm standard blood tubing.5
STANDARDS FOR CRYOPRECIPITATE USE
The AABB Standards, 25th Edition states that
“Cryoprecipitate AHF shall be prepared by a method
known to separate the cold insoluble portion from
fresh frozen plasma and result in a minimum of
150 mg of fibrinogen and 80 IU of coagulation factor
VIII.”9 The Canadian Standards for Transfusion
Medicine (version 2) recommend the use of ABO-
compatible cryoprecipitate, with a policy required for
situations where ABO-compatible cryoprecipitate is
not available.90 In addition, the product should be
thawed in a protective overbag at 30°C to 37°C in an
approved warming device.90 The Canadian Stan-
dards Association Z902-04 are consistent with the
AABB and Canadian Society for Transfusion
Medicine (CSTM) standards.26 The Council of
Europe Recommendation, 12th Edition require
that a unit of cryoprecipitate contain a minimum of
140 mg of fibrinogen and 70 IU of factor VIII.91
UTILIZATION OF CRYOPRECIPITATE
In Canada (excluding Quebec) in the fiscal year
2007-2008, 42 585 units of cryoprecipitate were
issued to hospitals with a population of approxi-
mately 25 million (excluding Quebec). Thus, the
transfusion rate in Canada is 1.7 units per 1000
people annually.
The use of cryoprecipitate in the UK is remark-
ably similar to Canada. For the years 1999-2000,
2000-2001, and 2001-2002, the UK Transfusion
Services issued 94 114, 95 456, and 88 253 units of
cryoprecipitate, respectively, for a population of 59
million (1.5 units per 1000 people annually).
APPROPRIATENESS OF CRYOPRECIPITATE USE
Reports on the misuses of cryoprecipitate date as
far back as 1975.92 In this letter to the editor,
cryoprecipitate was documented to be used as a
routine treatment for all patients with hemophilia,
including those patients with factor IX deficiency.
This report also surveyed 38 colleagues, and only 9
were aware that cryoprecipitate was not an appro-
priate treatment for factor IX deficiency.
Three reports have retrospectively reviewed the
use of cryoprecipitate in hospitals.30,93,94 An audit
CALLUM ET AL
of cryoprecipitate use in Australia documented that
only 38% of 64 cryoprecipitate transfusions were
given for hypofibrinogenemia (fibrinogen b1.0
g/L).93 A report from the United States, also
published in 2003, reviewed the use of cryopreci-
pitate in 51 patients and found 76% to be appropriate
when different appropriateness criteria were
applied.93 This group considered cryoprecipitate
appropriate for fibrinogen less than 1.0 g/L, tissue
plasminogen activator–related hemorrhage, trans-
fusion of 10 or more RBC units irrespective of the
fibrinogen level, uremic bleeding, topical use, and
von Willebrand disease. Only 52% of all cryopre-
cipitate transfusions in this report were administered
for fibrinogen levels less than 1.0 g/L. A recent
report from Canada detailing 4370 units of cryo-
precipitate transfused to 453 patients found only
24% to be appropriate with a pretransfusion
fibrinogen level less than 1.0 g/L. Of note, in 42%
of cryoprecipitate transfusions in this report, the
appropriateness could not be determined due to
complete lack of fibrinogen testing, which is in itself
inappropriate.30 There are 3 major impediments to
improving the appropriateness of the use of
cryoprecipitate: (1) inability to obtain rapid results
for the fibrinogen for a bleeding patient in many
hospitals; (b) competing bedside priorities in a
massively bleeding patient that prevents frequent
laboratory testing; and (c) the length of time
required to prepare cryoprecipitate results in the
product being ordered without fibrinogen levels.
RISKS ASSOCIATED WITH
CRYOPRECIPITATE USE
Per unit, cryoprecipitate has the same risk of viral
transmission as a unit of RBC or FFP; however,
given that an adult dose of the product is 8 to 16
units, this product has a greater risk of transmission
per dose. In hemovigilance reports, adverse event
rates for cryoprecipitate are rarely reported. In a
report from the hemovigilance program in Quebec,
Canada, the rate of all adverse events from
cryoprecipitate in 2001 was 6 per 10 000.95
Cryoprecipitate has rarely been reported to be
associated with hemolysis secondary to anti-A/B,
febrile and allergic reactions, respiratory distress,
and thrombosis.23,96 Reports on reactions to cryo-
precipitate have been limited to case reports23,97 and
small case series.20,96
Fatal thrombosis has been reported in a single
case of a 28-year-old man with acute lymphocytic
CRYOPRECIPITATE
leukemia on L -asparaginase chemotherapy. 98
Because of L-asparaginase, his fibrinogen level
decreased to 0.7 g/L, and the patient developed
mucocutaneous bleeding. He was administered 10
units of cryoprecipitate on day 1 and 6 units on day
2. On day 3, the patient developed acute abdominal
pain, which was found on laparotomy to be due to a
mesenteric thrombosis. The levels of anti-thrombin
III, protein C, and protein S were all low at the time
of thrombosis. Thrombosis secondary to L-aspar-
aginase has been reported to occur in 1% to 3% of
patients with acute lymphocytic leukemia, and
therefore, the role of cryoprecipitate in the causality
of this thrombosis is unclear.99
ALTERNATIVES TO CRYOPRECIPITATE
Human-derived fibrinogen concentrates are
available and have primarily been evaluated in
patients with hemorrhagic complications from
congenital hypofibrinogenemia and afibrinogen-
emia.50 One fibrinogen concentrate (Haemocom-
plettan P, ZLB Behring, Germany) is a pooled,
human-derived plasma product that undergoes
multiple inactivation steps to reduce the risk of
viral transmission: donor screening for transmissi-
ble diseases (including parvovirus B19 nucleic acid
testing) and heat treatment (20 hours at 60°C). A
report detailing 151 infusions in 12 patients with
hypofibrinogenemia or dysfibrinogenemia evalu-
ated both the safety and efficacy of this product.50
Overall, 2 patients had adverse events. The first
patient had an anaphylactic reaction on the 56th
infusion, with no reactions with further treatments.
The second adverse reaction was a deep vein
thrombosis with a nonfatal pulmonary embolism
after a femoral fracture. Fibrinogen concentrates
have also been used successfully to treat implanta-
tion bleeds in the first trimester of pregnancy in
patients with congenital afibrinogenemia.100 Non–
heat-treated fibrinogen concentrates administered
in Japan before 1988 were associated with an
estimated 10 000 cases of hepatitis C virus
infections.101 Factor VIII deficiency, von Will-
ebrand disease, and congenital factor XIII defi-
ciency should be managed with either virally
inactivated human-derived products or where
available, recombinant products.
FUTURE RESEARCH
There is a distinct lack of knowledge regarding
the use of cryoprecipitate in many clinical scenar-
185
ios. The following are clinical questions that still
need to be answered so that evidence-based care
can be used when it comes to the transfusion
of cryoprecipitate:
1. The role of formula-driven cryoprecipitate
transfusion in massive transfusion: There is
currently a trend toward abandoning coagula-
tion monitoring in the setting of acute trauma
and providing component therapy in a 1:1 ratio
with RBCs. This literature comes primarily
from military experience and is retrospective.
There is an urgent need for a prospective
randomized trial in the setting of acute trauma
to determine the optimal cryoprecipitate trans-
fusion strategy in this patient population.
2. The role of cryoprecipitate in the management
of hemorrhage after cardiac surgery: Cur-
rently, this is one of the most common
indications for the transfusion of cryoprecipi-
tate, with little data to support or refute its use.
Prospective trials are clearly needed evaluat-
ing the therapeutic benefit of this product in
this patient population.
3. The dosage of cryoprecipitate necessary to
replete hypofibrinogenemia: The literature on
the incremental rise in fibrinogen level per
dose of cryoprecipitate used is limited to case
series and needs to be validated in larger
prospective clinical trials.
4. The impact of pooling on the speed of
cryoprecipitate delivery to the patient: Cryo-
precipitate is generally transfused in the
setting of massive hemorrhage, where there
are few resources at the bedside to pool this
product. A small randomized trial is needed of
pooled vs unpooled cryoprecipitate to deter-
mine which results in less delay in transfusion.
In addition, the need to assess the reliability of
the pooling process within the laboratory and
at the bedside to ensure that each bag is
properly emptied and that the patient receives
a complete dose. We may be doing a
considerable disservice to our patients by
failing to perform this task in a controlled
laboratory environment.
5. An assessment of the contents of cryoprecipi-
tate with modern laboratory instrumentation:
Most of the published literature dates from the
pre-1970s era, and we need to determine if the
current content of fibrinogen, factor VIII,
186
vWF , fibronectin, factor XIII, and platelet
microparticles is similar to that seen when the
product was first introduced. We need to
understand interdonor variability so that the
content of a pool of 10 units of cryoprecipitate
can be predicted with better accuracy.
6. The role of fibronectin in the management of
patients with septic shock or amniotic fluid
embolism: Fibronectin currently accounts for
25% of the total protein content of cryopreci-
pitate. It would be extremely useful to under-
stand if the fibronectin content is therapeutic in
any disease process. Other than a few case
reports of use in amniotic fluid embolism,
there has been little recent research on the role
of fibronectin as a clinical treatment option.
7. The role of platelet microparticles: Cryopre-
cipitate has an extremely high concentration
of platelet microparticles, and there is a need
to further clarify whether such microparticles
have a role in hemostasis, vascular function,
or inflammation. We also need to clarify their
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