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Cryoprecipitate: The Current State of Knowledge

Jeannie L. Callum, Keyvan Karkouti, and Yulia Lin

Cryoprecipitate is a diverse product containing factor thoroughly investigated to determine the optimal infu-
VIII, von Willebrand factor, fibrinogen, fibronectin, sion strategy (intralaboratory vs bedside). The most
factor XIII, and platelet microparticles. The role of this common current indication for the use of this product is
complex product in the management of hemostasis has hypofibrinogenemia in the setting of massive hemorr-
not been well studied (excluding patients with factor hage. There are insufficient data in the literature to
VIII deficiency). There are insufficient data to determine determine the efficacy, safety, and dosage in this
the clinical setting where this product might be patient population. Despite 45 years of the use of this
clinically efficacious despite its widespread use in product, we still have a lot to learn regarding the
multiple different clinical scenarios. The best method optimal use of cryoprecipitate.
of pooling before transfusion has also not been © 2009 Elsevier Inc. All rights reserved.

RYOPRECIPITATE WAS FIRST introduced new lifestyle for patients with hemophilia. Its
C in the mid 1960s as a method to concentrate
factor VIII. Cryoprecipitate provided a major
introduction was not without substantial risk, with
many recipients subsequently exposed to HIV,
therapeutic advance for patients with congenital hepatitis B virus, and hepatitis C virus from this
factor VIII deficiency. Shortly thereafter, it was also pooled product.
determined to be of benefit for patients with von The exhausted plasma, now termed cryosuper-
Willebrand disease and hypofibrinogenemia. Its use natant plasma, was immediately put to use. In
today resembles little what Pool had intended it for. October of 1966, Bennett and Dormandy reported
The most common indication for the product today on the successful use of exhausted plasma for a
is the replacement of fibrinogen in patients with patient with factor XI deficiency.3
acquired hypofibrinogenemia and bleeding. The
diverse contents of this product have never been MANUFACTURING PROCESS
fully elucidated, nor has its clinical efficacy been The manufacturing process has changed little
determined in properly designed clinical studies. since first described by Pool.1 Cryoprecipitate is
This article reviews the medical literature on prepared by thawing 1 unit of frozen plasma or
cryoprecipitate published since its method of fresh frozen plasma at 1°C to 6°C.5 After the
production was first described in 1964. The authors product is thawed and centrifuged at 5000 × g for 6
hope that you find its history and early research minutes, the supernatant is removed, leaving the
interesting and that it spurs you on to contribute cold insoluble precipitate plus 5 to 15 mL of plasma
further to our understanding of the role of in the original bag. This residual material is
cryoprecipitate as a therapeutic treatment. refrozen within 1 hour of thawing and stored at
−18°C or colder. The resulting product has a shelf-
HISTORY life of 12 months. Methods of manufacturing may
Judith Graham Pool (1919-1975) first described vary slightly in different jurisdictions.
the preparation of cryoprecipitate in 1964 while at Factor VIII and von Willebrand factor (vWF)
Stanford University.1 The frozen plasma was represent only 5% of the total protein in cryopre-
thawed at 0°C to 4°C over 18 to 24 hours. The cipitate.6 The final product however contains 40%
product was then centrifuged for 20 minutes at to 70% of the original factor VIII/vWF that was
2000 × g with the refrigerated centrifuge set at present in the original plasma.6 Each unit also
2°C.2 The supernatant plasma (termed ‘exhausted’
plasma) was removed by gravity drainage, leaving From the Sunnybrook Health Sciences Centre and University
only 10 to 15 mL of plasma. The product was then Health Network, Toronto, Ontario, Canada.
refrozen at −20°C. In October of 1966, Bennett and Address reprint requests to Jeannie L. Callum, BA, MD,
Dormandy3 reported on the successful use of FRCPC, CTBS, B204, Sunnybrook Health Sciences Centre,
cryoprecipitate in 3 patients with von Willebrand 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5.
disease. In January of 1967, Barrett et al4 reported 0887-7963/09/$ - see front matter
on the successful use of cryoprecipitate in 7 patients © 2009 Elsevier Inc. All rights reserved.
with hemophilia. Cryoprecipitate thus heralded a doi:10.1016/j.tmrv.2009.03.001

Transfusion Medicine Reviews, Vol 23, No 3 (July), 2009: pp 177-188 177


Table 1. Content of Cryoprecipitate Table 1 (continued)

Substance Specifics Substance Specifics

Fibrinogen Fibrinogen is a 340-kDa glycoprotein composed platelet membrane microparticle content.

of 3 pairs of protein chains interconnected by The platelet membrane microparticle
disulfide bonds. This glycoprotein is concentration of cryoprecipitate was 29-
synthesized by the hepatocytes and has a fold greater than the cryosupernant plasma
long half-life in the plasma of approximately 4 and 265-fold greater than the original plasma.
d.13 The diffusion phase half-life of fibrinogen Each clinical dose of cryoprecipitate (10
is 12 h, and therefore, cryoprecipitate units) contains approximately 4 × 109
infusions every 12 h are recommended for platelets in microparticle form. Whether the
patients with congenital fibrinogen deficiency platelet membrane microparticles retain
where fibrinogen concentrates are not hemostatic function after processing and
available.14 In contrast to factor VIII, freezing is unknown. Microparticles can play
fibrinogen activity remains stable with active roles in thrombosis, inflammation, and
recovery of fibrinogen at 87% after 24 h of vascular reactivity.22 We however need to
liquid storage, when compared to original further understand the concentration of
content at time of thawing.15 Fibrinogen is platelet microparticles in cryoprecipitate,
converted to fibrin by thrombin. their role in hemostasis, and their impact on
Factor VIII Factor VIII and vWF represent approximately 5% adverse reactions to the product
and vWF of the total protein in cryoprecipitate.6 vWF (alloimmunization and thrombosis).
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. contains approximately 100 to 250 mg of fibrino-
Factor XIII Factor XIII promotes clot stability by forming gen.7 The content of fibrinogen in current prepara-
covalent bonds between fibrin monomers
and by cross-linking alpha-2 antiplasmin,
tions of cryoprecipitate may be better than what was
fibrinogen, fibronectin, collagen, and other historically achieved, with recent testing yielding a
proteins to enhance the mechanical strength median of 388 mg per bag (range, 120-796 mg).8
of the fibrin clot and protect the clot from The minimum fibrinogen requirement by American
proteolytic degradation.16 Factor XIII
Association of Blood Banks (AABB) standards is
circulates in blood as a tetramer composed
of 2 A subunits (enzymatic portion) and 2 B
150 mg per bag.9 Each unit contains 30% to 50% of
subunits (carrier portion). The activated form the original fibrinogen in the source plasma.10
consists of 2 A subunits, with the 2 B carrier Other proteins in the concentrate include fibronec-
proteins removed.17 Cryoprecipitate contains tin (20%-25%), IgG (5%-8%), IgM (1%-2%), and
approximately 20% to 30% of the original albumin (5%-8%).6
factor XIII of plasma.10
Fibronectin Fibronectin is a dimeric α2-glycoprotein present
There is an increase in the factor VIII content of
at a concentration of 300 μg/mL in human cryoprecipitate if the donors are exercised for
plasma. It is thought to have opsonic activity 5 minutes on a bicycle before donation, but this fails
assisting with the phagocytosis of particulate to translate into a superior postinfusion in vivo
debris by the reticuloendothelial system.18
recovery of factor VIII due to rapid clearance of the
Human-derived factor VIII concentrates
(excluding the high purity preparations) and
‘exercise’ factor VIII.11 Factor VIII recovery is
cryoprecipitate are potential rich sources of improved by a higher donor factor VIII baseline
fibronectin at 2100-3600 μg/mL and 1500 level, continuously mixing blood during collection,
μg/mL, respectively.19 minimizing the time from donation of plasma to
Platelet The observation that antiplatelet antibodies can freezing, rapidly refreezing cryoprecipitate on dry
microparticles appear after the exposure to cryoprecipitate
prompted a search for platelet microparticles
ice, and limiting the duration of cryoprecipitate
in this blood component. 2 0 Platelet storage.12
microparticle content in plasma and Details regarding the specific contents of cryo-
cryoprecipitate are measured using an precipitate are presented in Table 1.
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 ABO-compatible cryoprecipitate is not required
whole blood. The process of preparing due to the small volume of plasma transfused,5
cryoprecipitate further concentrates the
although this may be important in patients receiving

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.

below. Counts et al 35 studied 27 massively approximately 5000 mL of surgical blood loss in

transfused trauma patients in 1979 and found no the absence of FFP or cryoprecipitate transfusion.
relationship between the number of ‘cryo’ poor A recent report from the US Army Combat
whole blood (84% of units transfused) and packed Support Hospital found that survivors of massive
RBCs (16% of units transfused) transfused and the trauma who had received at least 10 units of RBCs
fibrinogen level. Mannucci et al36 followed 127 and/or fresh whole blood had a higher fibrinogen
patients transfused in excess of 5 units of whole (determined as a calculated amount from total
blood to determine the relationship between plasma and cryoprecipitate transfusions) to RBC
coagulation parameters and units transfused. In ratio than nonsurvivors.33 It is unclear from their
the latter study, a fibrinogen below the normal range retrospective review whether this survival benefit
developed in 40% of patients transfused 5 to 9 units was attributable to ‘survivor bias’44 or cryopreci-
of whole blood and in 60% of patient transfused pitate/fresh frozen plasma administration. Survivor
more than 15 units. Based on their data, they bias in observational studies refers to a phenom-
recommended against indiscriminate use of cryo- enon where patients who live longer have a greater
precipitate without supporting laboratory data. In a probability to receive a certain treatment, and
study of 36 patients who had their fibrinogen hence, a retrospective report may yield a positive
measured every 12 units of whole blood during association between that treatment and survival. It
massive transfusion, microvascular bleeding is also unclear whether the 2 groups of patients
occurred in 4 of 4 patients with a fibrinogen level were similar in terms of baseline characteristics.
less than 0.5 g/L and in 2 of 10 patients with levels They nonetheless recommended that 10 units of
between 0.5 and 1.0 g/L (although both were also cryoprecipitate be administered with every 10
severely thrombocytopenic).37 It is unclear how RBCs transfused to improve survival of trauma
applicable these studies are to the current practice of patients with severe injury. Of particular note, no
using exclusively packed RBCs for transfusion. fibrinogen levels were reported in this study.33
The next group of reports describes massively There is considerable debate in the surgical
transfused trauma patients in the more current era of literature as to when and how cryoprecipitate should
packed RBC use. Three retrospective reviews be administered to massively bleeding patients.33,45
attempted to determine when coagulopathy devel- This debate is unlikely to be settled in the absence of
oped during massive transfusion, but each failed to a large, prospective, randomized trial of aggressive
report the fibrinogen levels.38-40 In a retrospective formula-driven cryoprecipitate transfusions (1:1
review of 28 massively transfused (more than 10 ratio of RBC to cryoprecipitate units) vs laboratory
units of packed RBCs in 24 hours) trauma patients driven triggers (ie, fibrinogen level) for product
who survived to have coagulation testing per- usage. Until such data are available, cryoprecipitate
formed, 21 (75%) had a fibrinogen less than 1.0 g/L should be used judiciously. Cryoprecipitate exposes
despite receiving a mean of 17 units of cryopreci- patients to large numbers of donors and therefore
pitate and 12 units of FFP.41 A similar retrospective increases the risk to known and emerging patho-
review of 45 trauma patients receiving in excess of gens. Given that FFP contains 2 g of fibrinogen per
50 units of packed RBCs found the fibrinogen level adult dose (4 units), a massively transfused patient
to be better preserved in survivors than nonsurvi- given adequate FFP to maintain international
vors (109.1 vs 70.8 μmol/L; P = .02), although normalized ratio (INR)/partial thromboplastin time
causality could not be determined.34 It is unclear if (PTT) within an appropriate range should only
hypofibrinogenemia is common or mitigated by rarely need extra fibrinogen in the form of
cryoprecipitate during massive transfusion due to cryoprecipitate. There is no evidence that higher
the almost complete lack of supporting literature. fibrinogen levels assist with the management of
Singbartl et al42 mathematically modeled the fall refractory hemorrhage in patients with fibrinogen
in fibrinogen level with surgical blood loss. They levels above 1.0 g/L.
estimated that a patient would reach the threshold
for fibrinogen replacement (1.0 g/L) after approxi- Cardiac Surgery
mately 4000 mL of surgical blood loss. The In Canada, the most common indication for
computer simulation of Hirchberg et al43 also cryoprecipitate transfusion is hemorrhage following
predicted a fibrinogen level less than 1.0 g/L after cardiac surgery.30 In this report, only 6% were

deemed appropriate based on current guide- Factor XIII Deficiency

lines.14,46 In addition, there was wide variability Persons with congenital factor XIII deficiency
in the proportion of cardiac surgery patients have a tendency for severe bleeding, a risk for
transfused cryoprecipitate when individual hospital spontaneous abortion, and a high rate (25%-40%)
sites were compared (overall, 4.1%; range, 0.3%- of spontaneous intracranial hemorrhage.17 Virally
10.1%). Despite this common practice in cardiac inactivated, human-derived factor XIII concentrates
surgery, there are no clinical data to support its use are commercially available, and thus, cryoprecipi-
in this specific patient population. tate is obsolete in this clinical setting.57 In addition,
a recent study demonstrating that recombinant
Congenital Deficiencies of Fibrinogen factor XIII-A2, when combined with endogenous
Cryoprecipitate has been documented in case factor XIII-B subunits, has a half-life similar to that
reports to be effective in the prevention47,48 and of native factor XIII and appears to be safe and to
treatment47,49 of bleeding in the setting of con- result in no serious adverse events in patients with
genital deficiencies of fibrinogen. More recently, factor XIII deficiency.16
human-derived fibrinogen concentrates were
reported to be effective in the treatment of Von Willebrand Disease
congenital deficiencies of fibrinogen.50 Because Von Willebrand disease is a common inherited
fibrinogen concentrates undergo viral inactivation, bleeding disorder caused by the deficiency or
when available, they should be used rather than dysfunction of vWF affecting approximately 1%
cryoprecipitate in patients with congenital deficien- of the population, with most individuals having
cies of fibrinogen. only a mild bleeding disorder. Treatment of patients
with von Willebrand disease with human-derived
Iatrogenic Premature Rupture of virally inactivated blood products containing both
Amniotic Membranes VIII and vWF is the treatment of choice when
Iatrogenic preterm rupture of amniotic mem- bleeding occurs or must be prevented, and the
branes is a known complication of diagnostic response to desmopressin is considered suboptimal
amniocentesis and fetoscopy, with perinatal mor- or insufficient for hemostasis.58 The transition to
tality in pre-viable pregnancies approaching 50%.51 virally inactivated human-derived factor VIII/vWF
Serious sequelae may often be seen in surviving concentrates was due to the concerns regarding
infants, particularly pulmonary hypoplasia.52 Two transfusion-transmitted viral infections from cryo-
reports have evaluated the use of topical autologous precipitate. The use of cryoprecipitate for von
platelets and cryoprecipitate in the management of Willebrand disease should be restricted to emer-
iatrogenic preterm rupture of amniotic mem- gency therapy where factor VIII/vWF concentrates
branes.53,54 Membrane sealing and delivery of a are not immediately available and bleeding is
viable near-term infant was observed in 4 of 10 sufficiently severe to warrant the risks associated
cases. It is unclear whether this is an improvement with cryoprecipitate. Where cryoprecipitate is
over expectant management because no control required due to lack of availability of virally
group was used in these studies. Other investigators inactivated human-derived products, a dose of 8
have used fibrin sealants and observed similar to 10 units of cryoprecipitate appears to result in
perinatal outcomes.55 hemostasis and adequate postinfusion levels.59,60

Hepatic Failure Management of Hemorrhage Secondary to

In a very small crossover trial of 11 patients with Thrombolytic Therapy
coagulopathy secondary to liver disease, FFP was The primary effect of thrombolytic therapy on
found to be superior to cryoprecipitate in terms coagulation is a dose-dependent effect of the
of improvement in INR and PTT.56 Cryoprecipitate concentration of fibrinogen. Thrombolytic therapy
alone is inadequate for the treatment of the is used in the management of acute myocardial
coagulopathy seen in patients with hepatic infarction, stroke, and venous thromboembolism.
failure due to lack of key coagulation factors in At a dose of 150 mg of tissue-plasminogen
this product. activator, 25% of patients have a fibrinogen level

less than 0.7 g/L.61 In contrast, 87% of patients tion of anemia is known to correct the bleeding
administered streptokinase have a fibrinogen level time abnormalities in patients with uremia, impli-
less than 0.5 g/L at 90 minutes.62 Additional effects cating anemia as a potential contributor to the
of these agents include the anticoagulant effects of hemorrhagic diathesis seen in these patients.70
fibrin degradation products, depletion of factors V Presumably, cryoprecipitate was initially studied
and VIII, and antiplatelet effects.63 It has been to determine if it would improve platelet function
recommended to treat the hypofibrinogenemia and by the administration of vWF. Janson et al71
hemorrhage complicating thrombolytic therapy administered cryoprecipitate to 6 patients with
with 10 units (adult patients) of cryoprecipitate.63 uremia and a median bleeding time of 18 minutes
Most bleeding episodes are from sites of arterial (range, 16-20 minutes). Four hours postadministra-
puncture for vascular procedure, and if such a tion of 10 units of cryoprecipitate, the bleeding time
procedure is required, meticulous care should be was found to be a median of 9.5 minutes (range, 6-
taken to prevent postprocedure bleeding.64 12 minutes). By 24 hours postadministration, the
bleeding time had returned to baseline. None of the
Topical Fibrin Glue patients had active bleeding. In contrast, Triulzi and
The use of cryoprecipitate as a fibrin glue has Blumberg72 administered 10 units of cryoprecipi-
been superseded by the use of virally inactivated tate to 5 patients with uremia and bleeding times in
human-derived fibrin sealant products. The clinical excess of 15 minutes and found an improvement in
trial data to support the use of topical cryoprecipitate bleeding time in only 2 patients. Numerous
are limited.65 Even the data to support virally alternate strategies are available for the prevention
inactivated, human-derived fibrin sealants are and treatment of uremic type bleeding including
limited. A meta-analysis of 12 methodologically dialysis, erythropoietin, RBC transfusion, desmo-
poor trials including 624 patients found only a pressin (DDAVP), and conjugated estrogens, and as
modest benefit of these agents in surgical settings to such, cryoprecipitate is rarely used in the preven-
reduce allogeneic transfusion (odds ratio, 0.40; 95% tion or treatment of uremic bleeding.
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 Amniotic Fluid Embolism
transfusion (odds ratio, 0.46; 95% CI, 0.32-0.68). Amniotic fluid embolism is a rare complication of
Of note, the use of fibrin sealants only reduced the pregnancy with an incidence of 1 in 20 646
risk of transfusion by 0.56 RBC units (95% CI, 0.29- pregnancies.73 The syndrome has a very high
0.84 units) and the volume of blood loss by 134 mL mortality rate estimated to be between 26% and
per patient (95% CI, 51-127 mL).67 It is debatable 61%, with most women dying within the first
whether a reduction of a half of a RBC unit is hour.73,74 Cryoprecipitate has been used as a last
clinically relevant. In addition, a large, randomized, resort to replace depleted fibronectin (plasma opsonic
controlled, clinical trial in patients requiring liver activity) with success reported in 2 case reports.75,76
resection found no benefit of the topical application
of virally inactivated, human-derived fibrin sea-
lants.68 Cryoprecipitate should not be used topically Snake Bites
for the prevention or treatment of hemorrhage due to Snake envenomation can result either in hema-
the complete absence of data to support its use and tologic or neurologic toxicity. The primary hema-
the availability of safer alternatives. tologic toxicity is the rapid consumption of
fibrinogen, resulting in acute coagulopathy. A
Uremic Bleeding large series of 38 patients with North American
The etiology of uremic bleeding is multifactorial, pit viper envenomation found 58% to have
including impaired platelet-platelet interaction, hypofibrinogenemia, although none required cryo-
impaired platelet–vessel wall interaction, accumu- precipitate.77 Cryoprecipitate has been used suc-
lation of guanidinosuccinic acid leading to exces- cessfully for the management of the profound
sive nitric oxide formation by endothelial cells, coagulopathy after snake bites from the African
administration of antiplatelet agents, and use of Bush Viper,78 Sochurek's saw-scaled viper,79 tiger
heparin during hemodialysis.69 In addition, correc- snake,80 Gaboon viper,81 and Bothrops asper.82

Fibronectin Replacement trauma was recently addressed in a review article by

Deficiency of fibronectin has been observed in Ketchum et al,31 recommending against prophy-
patients after major surgery, trauma, burns, and lactic cryoprecipitate administration in trauma
sepsis.83 It has been hypothesized that a deficiency patients in the absence of hypofibrinogenemia.
in fibronectin impairs the reticuloendothelial sys- They argue that FFP administration should be
tem from clearing particulate debris in the circula- adequate to prevent severe hypofibrinogenemia.
tion resulting in the accumulation of fibrin The fibrinogen cutoff of 1.0 g/L is reiterated in
microaggregates, collagenous debris, and immune all cryoprecipitate guidelines, although such a
complexes. These latter complexes have been cutoff does not reference a clinical study.14,46,87,88
postulated to contribute to the multiorgan dysfunc- This cutoff is likely based primarily on expert
tion seen in critically ill patients.19 In addition, opinion, although a study by Ciavarella et al37 of 36
fibronectin also binds to Staphylococcus aureus and massively transfused patients observed no micro-
may be important in its phagocytosis.84 In early vascular bleeding in patients with fibrinogen levels
studies, low fibronectin concentrations have been in excess of 1.0 g/L.
correlated with increased infection rates and poorer The use of cryoprecipitate for the management
survival in trauma patients.85,86 Infusion of cryo- of uremic bleeding was detailed in an evidence-
precipitate in a small crossover study of 14 trauma based guideline on uremic bleeding in 2007.89
and surgical patients resulted in an immediate Cryoprecipitate was considered a reasonable ther-
reversal of fibronectin deficiency and correction of apeutic option in uremic patients at high risk for
opsonic activity of plasma.83 After infusion, the bleeding or actively bleeding, although they do
recovery of fibronectin is approximately 50% and state, “The response in uremic patients can be
the half-life is 17 to 25 hours.19 Whether such unpredictable.” Other therapeutic options recom-
replacement is clinically relevant is, however, yet to mended in this evidence-based review included
be determined. dialysis, erythropoietin, desmopressin (DDAVP),
and conjugated estrogens.
The British Committee for Standards in Haema- One unit of FFP contains 0.5 g of fibrinogen;
tology, Blood Transfusion Task Force published thus, a standard adult dose of 4 units is equivalent to
guidelines for the use of cryoprecipitate in 2004.46 2 g of fibrinogen. In contrast, 1 unit of cryopreci-
Cryoprecipitate was considered appropriate if the pitate contains 0.25 g of fibrinogen, giving the
fibrinogen was less than 1.0 g/L in the setting of content of 8 units of cryoprecipitate similar to that
severe bleeding and/or disseminated intravascular of 4 units of FFP.31 The primary benefit of
coagulation. This same recommendation was reit- administering fibrinogen as cryoprecipitate is that
erated in the British Committee for Standards in the total volume of a single adult dose is 100 mL,
Haematology, Blood Transfusion Task Force guide- compared to 1000 mL for FFP.
lines on the management of massive blood loss in The College of American Pathologists' guideline
2006.87 The College of American Pathologists' published in 1994 recommended a dose of 1
guideline published in 1994 recommended that the cryoprecipitate unit per 5 kg of body weight.14
use of cryoprecipitate be reserved for patients with The AABB physician handbook states that 1 unit
clinical bleeding or planned invasive procedures in will increase the fibrinogen by 5 to 10 mg/dL (0.05-
patients with a fibrinogen level less than 1.0 g/L.14 0.1 g/L) in an average sized adult.25 The AABB
Comprehensive cryoprecipitate guidelines were Technical Manual, 15th Edition recommends the
published in the British Columbia Medical Journal use of the following calculation5:
(Canada).88 This document advises on the use of
cryoprecipitate for hypodysfibrinogenemia when 1. Blood volume = weight (kg) × 70 mL/kg
recombinant or virally inactivated concentrates are 2. Plasma volume = blood volume × (1-hematocrit)
not available for von Willebrand disease, hemophi- 3. mg of fibrinogen required = (desired fibrino-
lia A, factor XIII deficiency, and thrombolytic- gen − current fibrinogen in mg/dL) × plasma
related hemorrhage. The use of cryoprecipitate in volume divided by 100 mL/dL

4. Bags of cryoprecipitate required = mg of of cryoprecipitate use in Australia documented that

fibrinogen divided by 250 mg. only 38% of 64 cryoprecipitate transfusions were
given for hypofibrinogenemia (fibrinogen b1.0
Cryoprecipitate should be administered through g/L).93 A report from the United States, also
a 170- to 260-μm standard blood tubing.5 published in 2003, reviewed the use of cryopreci-
pitate in 51 patients and found 76% to be appropriate
STANDARDS FOR CRYOPRECIPITATE USE when different appropriateness criteria were
The AABB Standards, 25th Edition states that applied.93 This group considered cryoprecipitate
“Cryoprecipitate AHF shall be prepared by a method appropriate for fibrinogen less than 1.0 g/L, tissue
known to separate the cold insoluble portion from plasminogen activator–related hemorrhage, trans-
fresh frozen plasma and result in a minimum of fusion of 10 or more RBC units irrespective of the
150 mg of fibrinogen and 80 IU of coagulation factor fibrinogen level, uremic bleeding, topical use, and
VIII.”9 The Canadian Standards for Transfusion von Willebrand disease. Only 52% of all cryopre-
Medicine (version 2) recommend the use of ABO- cipitate transfusions in this report were administered
compatible cryoprecipitate, with a policy required for for fibrinogen levels less than 1.0 g/L. A recent
situations where ABO-compatible cryoprecipitate is report from Canada detailing 4370 units of cryo-
not available.90 In addition, the product should be precipitate transfused to 453 patients found only
thawed in a protective overbag at 30°C to 37°C in an 24% to be appropriate with a pretransfusion
approved warming device.90 The Canadian Stan- fibrinogen level less than 1.0 g/L. Of note, in 42%
dards Association Z902-04 are consistent with the of cryoprecipitate transfusions in this report, the
AABB and Canadian Society for Transfusion appropriateness could not be determined due to
Medicine (CSTM) standards.26 The Council of complete lack of fibrinogen testing, which is in itself
Europe Recommendation, 12th Edition require inappropriate.30 There are 3 major impediments to
that a unit of cryoprecipitate contain a minimum of improving the appropriateness of the use of
140 mg of fibrinogen and 70 IU of factor VIII.91 cryoprecipitate: (1) inability to obtain rapid results
for the fibrinogen for a bleeding patient in many
UTILIZATION OF CRYOPRECIPITATE hospitals; (b) competing bedside priorities in a
In Canada (excluding Quebec) in the fiscal year massively bleeding patient that prevents frequent
2007-2008, 42 585 units of cryoprecipitate were laboratory testing; and (c) the length of time
issued to hospitals with a population of approxi- required to prepare cryoprecipitate results in the
mately 25 million (excluding Quebec). Thus, the product being ordered without fibrinogen levels.
transfusion rate in Canada is 1.7 units per 1000
people annually. RISKS ASSOCIATED WITH
The use of cryoprecipitate in the UK is remark- CRYOPRECIPITATE USE
ably similar to Canada. For the years 1999-2000, Per unit, cryoprecipitate has the same risk of viral
2000-2001, and 2001-2002, the UK Transfusion transmission as a unit of RBC or FFP; however,
Services issued 94 114, 95 456, and 88 253 units of given that an adult dose of the product is 8 to 16
cryoprecipitate, respectively, for a population of 59 units, this product has a greater risk of transmission
million (1.5 units per 1000 people annually). per dose. In hemovigilance reports, adverse event
rates for cryoprecipitate are rarely reported. In a
APPROPRIATENESS OF CRYOPRECIPITATE USE report from the hemovigilance program in Quebec,
Reports on the misuses of cryoprecipitate date as Canada, the rate of all adverse events from
far back as 1975.92 In this letter to the editor, cryoprecipitate in 2001 was 6 per 10 000.95
cryoprecipitate was documented to be used as a Cryoprecipitate has rarely been reported to be
routine treatment for all patients with hemophilia, associated with hemolysis secondary to anti-A/B,
including those patients with factor IX deficiency. febrile and allergic reactions, respiratory distress,
This report also surveyed 38 colleagues, and only 9 and thrombosis.23,96 Reports on reactions to cryo-
were aware that cryoprecipitate was not an appro- precipitate have been limited to case reports23,97 and
priate treatment for factor IX deficiency. small case series.20,96
Three reports have retrospectively reviewed the Fatal thrombosis has been reported in a single
use of cryoprecipitate in hospitals.30,93,94 An audit case of a 28-year-old man with acute lymphocytic

leukemia on L -asparaginase chemotherapy. 98 ios. The following are clinical questions that still
Because of L-asparaginase, his fibrinogen level need to be answered so that evidence-based care
decreased to 0.7 g/L, and the patient developed can be used when it comes to the transfusion
mucocutaneous bleeding. He was administered 10 of cryoprecipitate:
units of cryoprecipitate on day 1 and 6 units on day
2. On day 3, the patient developed acute abdominal 1. The role of formula-driven cryoprecipitate
pain, which was found on laparotomy to be due to a transfusion in massive transfusion: There is
mesenteric thrombosis. The levels of anti-thrombin currently a trend toward abandoning coagula-
III, protein C, and protein S were all low at the time tion monitoring in the setting of acute trauma
of thrombosis. Thrombosis secondary to L-aspar- and providing component therapy in a 1:1 ratio
aginase has been reported to occur in 1% to 3% of with RBCs. This literature comes primarily
patients with acute lymphocytic leukemia, and from military experience and is retrospective.
therefore, the role of cryoprecipitate in the causality There is an urgent need for a prospective
of this thrombosis is unclear.99 randomized trial in the setting of acute trauma
to determine the optimal cryoprecipitate trans-
ALTERNATIVES TO CRYOPRECIPITATE fusion strategy in this patient population.
Human-derived fibrinogen concentrates are 2. The role of cryoprecipitate in the management
available and have primarily been evaluated in of hemorrhage after cardiac surgery: Cur-
patients with hemorrhagic complications from rently, this is one of the most common
congenital hypofibrinogenemia and afibrinogen- indications for the transfusion of cryoprecipi-
emia.50 One fibrinogen concentrate (Haemocom- tate, with little data to support or refute its use.
plettan P, ZLB Behring, Germany) is a pooled, Prospective trials are clearly needed evaluat-
human-derived plasma product that undergoes ing the therapeutic benefit of this product in
multiple inactivation steps to reduce the risk of this patient population.
viral transmission: donor screening for transmissi- 3. The dosage of cryoprecipitate necessary to
ble diseases (including parvovirus B19 nucleic acid replete hypofibrinogenemia: The literature on
testing) and heat treatment (20 hours at 60°C). A the incremental rise in fibrinogen level per
report detailing 151 infusions in 12 patients with dose of cryoprecipitate used is limited to case
hypofibrinogenemia or dysfibrinogenemia evalu- series and needs to be validated in larger
ated both the safety and efficacy of this product.50 prospective clinical trials.
Overall, 2 patients had adverse events. The first 4. The impact of pooling on the speed of
patient had an anaphylactic reaction on the 56th cryoprecipitate delivery to the patient: Cryo-
infusion, with no reactions with further treatments. precipitate is generally transfused in the
The second adverse reaction was a deep vein setting of massive hemorrhage, where there
thrombosis with a nonfatal pulmonary embolism are few resources at the bedside to pool this
after a femoral fracture. Fibrinogen concentrates product. A small randomized trial is needed of
have also been used successfully to treat implanta- pooled vs unpooled cryoprecipitate to deter-
tion bleeds in the first trimester of pregnancy in mine which results in less delay in transfusion.
patients with congenital afibrinogenemia.100 Non– In addition, the need to assess the reliability of
heat-treated fibrinogen concentrates administered the pooling process within the laboratory and
in Japan before 1988 were associated with an at the bedside to ensure that each bag is
estimated 10 000 cases of hepatitis C virus properly emptied and that the patient receives
infections.101 Factor VIII deficiency, von Will- a complete dose. We may be doing a
ebrand disease, and congenital factor XIII defi- considerable disservice to our patients by
ciency should be managed with either virally failing to perform this task in a controlled
inactivated human-derived products or where laboratory environment.
available, recombinant products. 5. An assessment of the contents of cryoprecipi-
tate with modern laboratory instrumentation:
FUTURE RESEARCH Most of the published literature dates from the
There is a distinct lack of knowledge regarding pre-1970s era, and we need to determine if the
the use of cryoprecipitate in many clinical scenar- current content of fibrinogen, factor VIII,

vWF , fibronectin, factor XIII, and platelet possible role in the development of HLA and
microparticles is similar to that seen when the platelet antibodies and the acute infusional
product was first introduced. We need to adverse events.
understand interdonor variability so that the 8. The incidence of adverse events reported to
content of a pool of 10 units of cryoprecipitate national hemovigilance programs: It would
can be predicted with better accuracy. be very useful to understand the incidence of
6. The role of fibronectin in the management of adverse events associated with the use of
patients with septic shock or amniotic fluid cryoprecipitate. A logical starting point would
embolism: Fibronectin currently accounts for be to utilize reports to National reporting
25% of the total protein content of cryopreci- systems, such as the Transfusion Transmitted
pitate. It would be extremely useful to under- Injury Surveillance System (Canada) and the
stand if the fibronectin content is therapeutic in Serious Hazards of Transfusion (SHOT)
any disease process. Other than a few case reporting system (United Kingdom).
reports of use in amniotic fluid embolism, 9. The possible clinical role of virally inactivated
there has been little recent research on the role pooled fibrinogen products: There is a need to
of fibronectin as a clinical treatment option. determine the feasibility and effectiveness of
7. The role of platelet microparticles: Cryopre- fibrinogen concentrates in the management of
cipitate has an extremely high concentration hypofibrinogenemia secondary to hemorrhage
of platelet microparticles, and there is a need and massive transfusion. Such products are
to further clarify whether such microparticles potentially safer and logistically easier to
have a role in hemostasis, vascular function, administer due to the time and logistics
or inflammation. We also need to clarify their required to thaw and pool cryoprecipitate.

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