The development of cryoprecipitate

In the 1940s, concentrated antihemophilic factor, created by means of the fractionation of plasma with ethanol, was developed by Edwin J. Cohn and used for treatment of hemophilia.^{Reference Cohn, Strong and Hughes27,Reference McMillan, Diamond and Surgenor28} Cryoprecipitate arrived in the 1960s, when investigations to create an improved, concentrated form of factor VIII (FVIII) revealed that thawing frozen plasma slowly at 1–10°C provided a product rich in FVIII, FXIII, and fibrinogen.^{Reference Nascimento, Goodnough and Levy21,Reference Kasper29}

Preparation and components of cryoprecipitate

Cryoprecipitate is prepared from fresh frozen plasma.^{Reference Eder and Sebok30} One unit of fresh frozen plasma from a single donor is thawed at 1–6°C and centrifuged to remove the supernatant. The remaining insoluble precipitate is resuspended in a small amount of plasma and refrozen at −18°C to form a single unit of cryoprecipitate.^{Reference Nascimento, Goodnough and Levy21} Typically, five single units from multiple donors are pooled into one bag before use.^{Reference Nascimento, Goodnough and Levy21} Cryoprecipitate may be prepooled, with pooling of units occurring at the central blood bank before freezing.^{Reference Nascimento, Goodnough and Levy21} Alternatively, units may be pooled by licensed centers upon thawing, either by the blood bank or at the patient's bedside, potentially leading to delayed treatment that may be unacceptable in an emergency setting.^{Reference Callum, Karkouti and Lin31} The best method of pooling (laboratory v. bedside) remains to be determined, and the reliability of the pooling process regarding the content of each pool and ensuring the full dose is administered have not been established.^{Reference Nascimento, Goodnough and Levy21,Reference Callum, Karkouti and Lin31}

In accordance with AABB (American Association of Blood Banks) guidance, cryoprecipitate should be thawed in a protective plastic overwrap in a water bath at 30–37°C.³² Once thawed, cryoprecipitate can be stored between 20 and 24°C, but must be administered within 6 hours (or within 4 hours if pooled after thawing).³² Although fibrinogen levels and von Willebrand factor (vWF) activity do not appear to be significantly affected by extended storage of thawed cryoprecipitate (up to 120 hours at ambient temperature), the levels of FVIII activity were significantly decreased.^{Reference Lokhandwala, O'Neal and Patel33,Reference Soundar, Reyes, Korte and Bracey34} Moreover, although some studies have not identified any bacterial contamination following extended storage, a recent report showed that, while bacterial growth was not observed in spiked, thawed cryoprecipitate samples after 4 hours, considerable proliferation was seen after 24 hours.^{Reference Lokhandwala, O'Neal and Patel33–Reference Ramirez-Arcos, Jenkins and Sheffield35}

Fibrinogen content per cryoprecipitate unit has been shown to vary, ranging from 183 to 611 mg/unit, potentially due to between-donor variability, and preparation and storage methods at different institutions.^{Reference Lee, Lee and Kim24} Cryoprecipitate also contains several other clotting factors, including FXIII (20–30% of levels found in plasma), FVIII, vWF (40–70%), fibronectin (20–25%), as well as albumin (5–8%), immunoglobulins G (5–8%), and M (1–2%), and platelet microparticles.^{Reference Callum, Karkouti and Lin31}

Cryoprecipitate dosing

As cryoprecipitate contains variable amounts of fibrinogen, dosing may provide variable amounts of fibrinogen repletion. The European Trauma Guidelines recommend an initial cryoprecipitate dose of 50 mg/kg (15–20 units for a 70 kg individual) in patients with significant bleeding following major trauma^{Reference Rossaint, Bouillon and Cerny4}; the AABB recommends 1 unit per 7–10 kg bodyweight to raise plasma fibrinogen by 50–75 mg/dL in patients with fibrinogen deficiency-associated bleeding³²; and the Australian National Blood Authority suggests a dose of 3–4 g in patients with critical bleeding.³⁶ The British Committee for Standards in Haematology (BCSH) suggests using 10 units with the aim of raising plasma fibrinogen by 100 mg/dL for management of disseminated intravascular coagulation.^{Reference Levi, Toh, Thachil and Watson37} A common adult dose is a pool of 10 single-unit bags or two pools of 5 units each, i.e., 10 units of cryoprecipitate.^{Reference Stanworth9,Reference Pantanowitz, Kruskall and Uhl38}

Appropriate use of cryoprecipitate

Current guidelines for appropriate use of cryoprecipitate generally agree that it should be limited to hypofibrinogenemia treatment in clinical bleeding events; however, specific recommendations vary between guidelines. The European Trauma Guidelines recommend fibrinogen supplementation if plasma fibrinogen concentrations fall below 150–200 mg/dL, and suggest that cryoprecipitate may be used for treatment of bleeding accompanied by thromboelastometric signs of a functional fibrinogen deficit or a plasma fibrinogen level below the specified threshold.^{Reference Rossaint, Bouillon and Cerny4}

The Association of Anaesthetists of Great Britain and Ireland and the European Society of Anaesthesiology recommend cryoprecipitate for fibrinogen replacement in massive hemorrhage only in the absence of fibrinogen concentrate.^{Reference Thomas and Wee39,Reference Kozek-Langenecker, Afshari and Albaladejo40} Similarly, the Australian National Blood Authority guidelines indicate that cryoprecipitate may be used in critical bleeding requiring massive transfusion, if fibrinogen levels are not maintained above 100 mg/dL by fresh frozen plasma.³⁶ However, these guidelines also indicate that early cryoprecipitate administration may be warranted in major obstetric hemorrhage.³⁶

The BCSH guidelines for use of fresh frozen plasma, cryoprecipitate, and cryosupernatant note that cryoprecipitate is commonly used to enhance fibrinogen levels in dysfibrinogenemia and acquired hypofibrinogenemia in massive transfusion and disseminated intravascular coagulation, where plasma fibrinogen is below 100 mg/dL.^{Reference O'Shaughnessy, Atterbury and Bolton Maggs6} The related BCSH guidelines on management of massive blood loss recommend that cryoprecipitate should be given if fibrinogen cannot be maintained above this 100 mg/dL threshold using fresh frozen plasma, further noting that cryoprecipitate is rarely needed except in disseminated intravascular coagulation.^{Reference Stainsby, MacLennan, Thomas, Isaac and Hamilton41} Considering the treatment of disseminated intravascular coagulation, the BCSH recommend that severe hypofibrinogenemia (plasma fibrinogen below 100 mg/dL) that persists despite fresh frozen plasma replacement may be treated with fibrinogen concentrate or cryoprecipitate.^{Reference Levi, Toh, Thachil and Watson37}

In the United States, the AABB, American Red Cross, America's Blood Centers, and Armed Services Blood Program advise that cryoprecipitate is indicated for the control of bleeding associated with fibrinogen deficiency, FVIII, or FXIII deficiency only if recombinant or virus-inactivated FVIII or FXIII are unavailable, and for the control of uremic bleeding if all other modalities have failed.³² The American Society of Anesthesiologists Practice Guidelines for Perioperative Blood Transfusion and Adjuvant Therapies note that cryoprecipitate is rarely required for fibrinogen levels above 150 mg/dL, but is indicated when fibrinogen levels are below 80–100 mg/dL and accompanied by excessive microvascular bleeding, or in a massively transfused patient with excessive microvascular bleeding in whom fibrinogen levels cannot be rapidly assessed.⁴² Several of these guidelines are currently undergoing revision.

Efficacy of cryoprecipitate

Risks of cryoprecipitate use

Although the adverse-event rate with cryoprecipitate is difficult to quantify precisely, one hemovigilance study of adverse transfusion events reported a rate of 6.57 events per 10,000 units administered.^{Reference Robillard, Nawej and Jochem50} This is considerably lower than rates reported for all other blood components evaluated, including for fresh frozen plasma (28.84 events per 10,000 units).^{Reference Robillard, Nawej and Jochem50} In a UK retrospective observational study of 89 patients between October 2010 and September 2011, there were no reports of acute adverse transfusion reactions following cryoprecipitate infusion,^{Reference Idris, Hadjinicolaou, Sweeney, Winthrop, Balendran and Besser51} and the Serious Hazards of Transfusion report published in 2011 reported only one serious acute transfusion reaction (urticaria and a sudden drop in cardiac output) in the United Kingdom.^{Reference Bolton-Maggs52} Furthermore, the specific risk of transfusion-related acute lung injury has been estimated at 1 in 317,000 units of cryoprecipitate administered, compared with 1 in 81,000 units for fresh frozen plasma/cryosupernatant.^{Reference Chapman, Stainsby and Jones26}

In a small, randomized controlled pilot study in children after cardiac surgery, Galas et al. found no significant differences between fibrinogen concentrate and cryoprecipitate arms in percentage of patients experiencing clinical complications (acute myocardial infarction, stroke, acute kidney injury requiring dialysis, septic shock, reoperation, peripheral artery occlusion, deep venous thrombosis) up to 7 days after surgery or hospital discharge.^{Reference Galas, de Almeida and Fukushima43} No adverse events were observed in either group. In a randomized, controlled feasibility trial in adult trauma patients, Curry et al. observed no increase in thrombotic events in the cryoprecipitate arm, and no acute or nonacute transfusion reactions were attributed to cryoprecipitate.^{Reference Curry, Rourke and Davenport44} Seven serious adverse events were recorded in the cryoprecipitate arm (three incidents of sepsis, one multiorgan failure, and three events classified as “other”), v. 11 events in the standard therapy arm. No severe bleeding events were described in the Galas et al. and Curry et al. studies.^{Reference Galas, de Almeida and Fukushima43,Reference Curry, Rourke and Davenport44}

In a large, prospective cohort study of patients with blunt trauma (N = 1,175), cryoprecipitate administration was independently associated with a 4.4% lower risk of developing multiorgan failure (hazard ratio, 0.956; p = 0.01 [95% confidence interval, 0.923–0.989]) per unit transfused.^{Reference Watson, Sperry and Rosengart8} In contrast, fresh frozen plasma was associated with a 2.1% increased risk of multiorgan failure for each transfused unit. In addition, no significant dose–response relationship was observed for cryoprecipitate transfusion and the increased risk of multiorgan failure or acute respiratory distress syndrome.^{Reference Watson, Sperry and Rosengart8}

Intraoperative cryoprecipitate transfusion was independently associated with biliary complications following liver transplantation (relative risk, 3.46; p < 0.001) in a retrospective analysis.^{Reference Liu, Fan and Wang25} Randomized controlled studies are needed to determine the safety and role of cryoprecipitate in liver transplantation.

Until recently, cryoprecipitate has been considered unsuitable for pathogen reduction, so there is a small risk of viral transmission associated with this product. Cryoprecipitate can be produced from plasma subjected to viral reduction or inactivation (e.g., by means of methylene blue treatment); however, this can reduce fibrinogen content by up to 40%.^{Reference Cardigan, Philpot, Cookson and Luddington53} As 1 unit of cryoprecipitate is produced from 1 unit of fresh frozen plasma, the risk of adverse events per unit is assumed to be similar for both products. However, as cryoprecipitate is usually administered as a pooled dose of approximately 10 units from multiple donors, the risk of viral transmission per dose is actually higher compared with fresh frozen plasma.^{Reference Callum, Karkouti and Lin31} In 2017, the manufacture of a pathogen-reduced cryoprecipitate was announced; this product should reduce the risks of viral transmission previously associated with cryoprecipitate.⁵⁴

Galas et al. observed no significant difference between fibrinogen concentrate and cryoprecipitate groups regarding the median length of mechanical ventilation, length of intensive care unit (ICU) stay and vasopressor requirement.^{Reference Galas, de Almeida and Fukushima43} Curry et al. noted that patients in the standard therapy arm remained in the ICU for 7 days longer on average, but no difference was observed in total hospital stay between the treatment arms.^{Reference Curry, Rourke and Davenport44}