The Transfusion Medicine Advisory Group (TMAG) of BC has prepared guidelines to provide physicians with current information on the appropriate use of cryoprecipitate plasma. These guidelines are available electronically on the British Columbia Provincial Coordinating Office web site (www.bloodlink.bc.ca [13]) and will be updated periodically. Prescribing physicians are responsible for referring to the most recent guidelines. 

How the guidelines were developed

These guidelines were developed to direct therapy but are not intended as a rigid prescription for cryoprecipitate use. The guidelines are based on a MEDLINE search using the key words “cryoprecipitate” plus “trials” or “randomized” or “guidelines” or “reviews.” The levels of evidence and grades of recommendations are based on standards developed by the US Agency for Healthcare Research and Quality (formerly the US Agency for Health Care Policy and Research)[1] (see Appendix A [14]). Because of the limited number of clinical trials completed, most of the recommendations are based on expert opinion—level IV evidence, grade C recommendation. These guidelines were reviewed by hematopathologists and clinicians, including hematologists and critical care physicians, and were subsequently approved by the Transfusion Medicine Advisory Group (see Appendix B [14]).

General considerations

Physicians contemplating the use of cryoprecipitate (see Table [15]), should keep in mind the following general considerations:
• In British Columbia, informed consent is required for the transfusion of cryoprecipitate.
• All routine coagulation parameters should be checked before ordering cryoprecipitate. This includes complete blood count (CBC), platelet count, international normalized ratio (INR), partial thromboplastin time (PTT), and fibrinogen.
• The Transfusion Medicine Laboratory Service should be made aware of the clinical diagnosis on the request form used to order cryoprecipitate. The reason for the transfusion should also be clearly and accurately recorded in the patient’s chart, and in any documentation that is used when administering cryoprecipitate.
• Cryoprecipitate should be given only after risks associated with transfusion of allogeneic blood products have been considered and only when the benefits outweigh the risks. 
• Alternative treatments or adjunctive agents should be used to minimize or to avoid the use of cryoprecipitate. For example, desmopressin (DDAVP), Humate P, fibrinogen concentrates, and antifibrinolytic agents may be appropriate in specific situations. 
• Most laboratories in British Columbia convert the prothrombin time (PT) to the international normalized ratio to facilitate comparison of results between laboratories. (Throughout the document, we have tried to use the INR where possible, as this is typically what is reported by laboratories.)

Clinical indications for use of cryoprecipitate

Clinical experience supports the use of cryoprecipitate in the following situations.
Hypodysfibrinogenemia. Reduced levels of fibrinogen activity can result from either a functional or qualitative defect (dysfibrinogenemia) or a quantitative deficiency, as is seen in massive transfusion or disseminated intravascular coagulation (DIC). Transfusion therapy with either frozen plasma (FP) or cryoprecipitate is usually indicated if fibrinogen levels are less than 1.0 g/L, and bleeding is present, although clinically significant bleeding can occur at higher levels. If fibrinogen levels are greater than 1.0 g/L in the setting of active bleeding secondary to DIC, then FP should be given instead of cryoprecipitate in order to address the multiple factor deficiencies typical of DIC. Cryoprecipitate may be considered as a substitute for FP when the required volume of plasma is relatively contraindicated and targeted fibrinogen replacement in a small volume is desirable.[2-4]
(Level IV evidence, grade C recommendation.)

von Willebrand (vWD) disease and hemophilia A (HA). The current practice in patients with mild (type 1) vWD disease or mild HA is to use desmopressin and/or antifibrinolytics or virus-inactivated factor VIII (F VIII) concentrate (e.g., Humate P), which contains both F VIII:C and von Willebrand factor multimers. Most hemophilia patients with F VIII:C deficiency are treated with F VIII:C concentrate, which is now a recombinant product and no longer derived from human plasma. Cryoprecipitate can be used by patients with vWD disease that is unresponsive to desmopressin and by hemophilia A patients in those locations where F VIII:C concentrates are not available. Every effort must be made to obtain the preferred recombinant factor concentrate for hemophiliacs before resorting to the use of cryoprecipitate.[2-6]
Dosing:
• vWD disease (as a second-line therapy—see above)
Adult: 10 to 12 units (bags) every 12 hours
Child: 1 unit (bag) per 6 kg of body weight every 12 hours 
• Hemophilia A (only as a second-line therapy—see above)
(Level IV evidence, grade C recommendation.)

F XIII deficiency. Hereditary deficiency of factor XIII is an extremely rare condition. In 2006, the Canadian Hemophilia Registry (www.fhs.mcmaster.ca/chr/2006 [16]) identified only 41 cases. Hemostasis may be achieved with levels as low as 2% to 3%. Compared with the half-life of other coagulation factors, the half-life of F XIII is very long (9 to 10 days). Plasma-derived F XIII concentrate (Fibrogammin P) is licensed and available in Canada through the Special Access Programme for use in patients with F XIII deficiency, but is not stocked in all regional blood centres. Because of the rarity of F XIII deficiency, specific factor concentrate is usually not readily available in emergent situations, and it is in these situations that cryoprecipitate can and should be used.[7]
Dosing:
• 1 unit (bag) per 10 kg of body weight every 7 to 14 days
(Level IV evidence, grade C recommendation.)

Management of bleeding related to thrombolytic therapy. Cryoprecipitate can be used to manage intracranial bleeding in patients during or after administration of tissue plasminogen activator (tPA).[8] Randomized controlled clinical trials of cyroprecipitate versus placebo for treatment of tPA-related bleeding are not available. However, various guidelines as well as articles in peer-reviewed journals suggest using the following clinical algorithm:
• Discontinue tPA administration with the onset of signs or symptoms of intracranial hemorrhage.
• Order stat lab studies: INR, PTT, platelet count, fibrinogen level.
• Consider administration of 10 units (bags) of cryoprecipitate.
• Consider administration of platelet concentrate if a drug-induced (e.g., ASA-induced) platelet dysfunction is likely.
• Consider neurosurgical evaluation.[9]
(Level IV evidence, grade C recommendation.)

Inappropriate uses for cryoprecipitate

The use of cryoprecipitate is not recommended in the following situations.

Fibrin glue. Allogeneic or autologous cryoprecipitate has been used to prepare fibrin glue.[10,11] To make this hemostatic product, cryoprecipitate is mixed with a commercial source of thrombin (usually bovine thrombin). Homemade fibrin sealants have used bovine thrombin preparations that contain bovine F V. A number of patients have developed antibodies to the bovine F V, resulting in potentially serious clinical sequelae whose management may be confounded by erroneous results in laboratory tests of coagulation.[12] To avoid this complication, the use of commercially manufactured fibrin sealant preparations containing human thrombin (e.g., Tisseel) is preferred.
(Level III and IV evidence, grade B and C recommendation.)

Sepsis. Cryoprecipitate has been used in septic patients to replace fibronectin.[13] Fibronectin is thought to function as the major opsonin for macrophage clearance of circulating noncellular debris. In early, uncontrolled studies, infusion of cryoprecipitate in critically ill septic patients resulted in improved renal and pulmonary function and changes in peripheral hemodynamics. However, subsequent controlled studies failed to confirm any benefit. [14]
(Level IV evidence, grade A recommendation.)

Competing interests
None declared.

Dr Droubatchevskaia is a hematopathologist at St. Paul’s Hospital in Vancouver, British Columbia. Dr Wong is a hematopathology resident in the Department of Pathology and Laboratory Medicine at the University of British Columbia. Dr Chipperfield is regional medical leader, Blood Transfusion Medicine, Vancouver Coastal Health, and a clinical assistant professor in the Department of Pathology and Laboratory Medicine at UBC. Dr Wadsworth is a hematopathologist at Children’s and Women’s Health Centre of BC, a clinical professor in the Department of Pathology and Laboratory Medicine at UBC and is chair of the Transfusion Medicine Advisory Group of BC. Dr Ferguson is the medical director of BC Biomedical Laboratories Ltd., and an assistant clinical professor in the Department of Pathology and Laboratory Medicine at UBC.