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Home , AABB, Cryoprecipitate, Cryosupernatant, Dysfibrinogenemia, Whole blood

Nadejda Droubatchevskaia, MD, Michelle P. Wong, MD, Kate M. Chipperfield, MD, FRCPC, Louis D. Wadsworth, MB, ChB, FRCPC, FRCPath, David J. Ferguson, MD, FRCPC

Guidelines for transfusion

A new document from the Advisory Group describes appropriate use of cryoprecipitate plasma.

ABSTRACT: The literature shows he Transfusion Medicine Ad - tologists and critical care physicians, there is often inappropriate use visory Group (TMAG) of BC and were subsequently approved by the of products, including cryo - T has prepared guidelines to pro- Transfusion Medicine Advisory Group precipitate plasma, because of in - vide physicians with current informa- (see Appendix B). adequate education of physicians. tion on the appropriate use of cryopre- Guidelines for cryoprecipitate trans- General considerations cipitate plasma. These guidelines are fusion have been developed by the available electronically on the British Physicians contemplating the use of Transfusion Medicine Advisory Group Table Columbia Provincial Coordinating cryoprecipitate (see ), should of British Columbia to educate clini- Office web site (www.blood keep in mind the following general cians and address transfusion prac- link.bc.ca) and will be updated period- considerations: tices in the province. These guide- ically. Prescribing physicians are • In British Columbia, informed con- lines are based on a MEDLINE responsible for referring to the most sent is required for the transfusion of search and consultation with hema- recent guidelines. cryoprecipitate. to pathologists and clinicians. At pre- • All routine parameters sent, transfusion of cryoprecipitate How the guidelines is indicated for hypofibrinogen emia/ were developed Dr Droubatchevskaia is a hema topatholo - , von Willebrand gist at St. Paul’s Hospital in Vancouver, These guidelines were developed to disease, hemophilia A, factor XIII British Columbia. Dr Wong is a hemato - direct therapy but are not intended as a deficiency, and management of pathology resident in the Department of rigid prescription for cryoprecipitate related to thrombolytic Pathology and Laboratory Medicine at the use. The guidelines are based on a therapy. Cryoprecipitate should not University of British Columbia. Dr Chip- MEDLINE search using the key be used to prepare glue or to perfield is regional medical leader, Blood words “cryoprecipitate” plus “trials” treat sepsis. Transfusion Medicine, Vancouver Coastal or “randomized” or “guidelines” or Health, and a clinical assistant professor in “reviews.” The levels of evidence and the Department of Pathology and Labora- grades of recommendations are based tory Medicine at UBC. Dr Wadsworth is a on standards developed by the US hematopathologist at Children’s and Wo - Agency for Healthcare Research and men’s Health Centre of BC, a clinical pro- Quality (formerly the US Agency for 1 fessor in the Department of Pathology and Health Care Policy and Research) (see Laboratory Medicine at UBC and is chair of Appendix A). Because of the limited the Transfusion Medicine Advisory Group number of clinical trials completed, of BC. Dr Fer guson is the medical director most of the recommendations are based of BC Bio medical Laboratories Ltd., and an on expert opinion—level IV evidence, assistant clinical professor in the Depart- grade C recommendation. These guide- ment of Path ology and Laboratory Medi- lines were reviewed by hematopathol- cine at UBC. ogists and clinicians, including hema-

VOL. 49 NO. 8, OCTOBER 2007 BC MEDICAL JOURNAL 441 Guidelines for cryoprecipitate transfusion

should be checked before ordering apy with either frozen plasma (FP) or py—see above) cryoprecipitate. This includes com- cryoprecipitate is usually indicated if Adult: 10 to 12 units (bags) every 12 plete blood count (CBC), levels are less than 1.0 g/L, hours count, international normalized ratio and bleeding is present, although clin- Child: 1 unit (bag) per 6 kg of body (INR), partial thromboplastin time ically significant bleeding can occur at weight every 12 hours (PTT), and fibrinogen. higher levels. If fibrinogen levels are • Hemophilia A (only as a second-line • The Transfusion Medicine Laborato- greater than 1.0 g/L in the setting of therapy—see above) ry Service should be made aware of active bleeding secondary to DIC, then (Level IV evidence, grade C recom- the clinical diagnosis on the re quest FP should be given instead of cryo- mendation.) form used to order cryoprecipitate. precipitate in order to address the mul- F XIII deficiency. The reason for the transfusion should tiple factor deficiencies typical of Hereditary defi- also be clearly and accurately record- DIC. Cryo precipitate may be consid- ciency of factor XIII is an extremely ed in the patient’s chart, and in any ered as a substitute for FP when the rare condition. In 2006, the Canadian documentation that is used when required volume of plasma is relative- Hemophilia Registry (www.fhs.mc administering cryoprecipitate. ly contraindicated and targeted fibrino- master.ca/chr/2006) identified only 41 • Cryoprecipitate should be given only gen replacement in a small volume cases. Hemostasis may be achieved 2-4 after risks associated with transfu- is desirable. with levels as low as 2% to 3%. Com- sion of allogeneic blood products (Level IV evidence, grade C recom- pared with the half-life of other coag- have been considered and only when mendation.) ulation factors, the half-life of F XIII the benefits outweigh the risks. is very long (9 to 10 days). Plasma- von Willebrand (vWD) disease and • Alternative treatments or adjunctive derived F XIII concentrate (Fibro - hemophilia A (HA). agents should be used to minimize The current prac- gammin P) is licensed and available in or to avoid the use of cryoprecipi- tice in patients with mild (type 1) Canada through the Special Access tate. For example, vWD disease or mild HA is to use Programme for use in patients with F (DDAVP), Humate P, fibrinogen desmopressin and/or antifibrinolytics XIII deficiency, but is not stocked in concentrates, and antifibrinolytic or virus-inactivated factor VIII (F VIII) all regional blood centres. Because of agents may be appropriate in specif- concentrate (e.g., Humate P), which the rarity of F XIII deficiency, specif- ic situations. contains both F VIII:C and von Wille- ic factor concentrate is usually not • Most laboratories in British Colum- brand factor multimers. Most hemo- readily available in emergent situa- bia convert the prothrombin time philia patients with F VIII:C deficien- tions, and it is in these situations that (PT) to the international normalized cy are treated with F VIII:C cryoprecipitate can and should be 7 ratio to facilitate comparison of re - concentrate, which is now a recombi- used. Dosing: sults between laboratories. (Through- nant product and no longer derived out the document, we have tried to from human plasma. Cryoprecipitate • 1 unit (bag) per 10 kg of body weight use the INR where possible, as this can be used by patients with vWD dis- every 7 to 14 days is typically what is reported by lab- ease that is unresponsive to desmo- (Level IV evidence, grade C recom- oratories.) pressin and by hemophilia A patients mendation.) in those locations where F VIII:C con- Clinical indications for use Management of bleeding related to centrates are not available. Every effort of cryoprecipitate thrombolytic therapy. must be made to obtain the preferred Cryoprecipi- Clinical experience supports the use recombinant factor concentrate for tate can be used to manage intracranial of cryoprecipitate in the following sit- hemophiliacs before resorting to the bleeding in patients during or after 2-6 uations. use of cryoprecipitate. administration of tissue plasminogen . Dosing: 8 Reduc ed activator (tPA). Randomized con- levels of fibrinogen activity can result • vWD disease (as a second-line thera- trolled clinical trials of cyroprecipitate from either a functional or qualitative defect (dysfibrinogenemia) or a quanti- number of bags of = [(plasma volume in mL ϫ % increase in F VIII: C needed)/100] tative deficiency, as is seen in massive cryoprecipitate 80 transfusion or disseminated intravascu- lar coagulation (DIC). Trans fusion ther-

442 BC MEDICAL JOURNAL VOL. 49 NO. 8, OCTOBER 2007 Guidelines for cryoprecipitate transfusion

Table. Characteristics of four frozen plasma products.

Frozen plasma Fresh-frozen plasma Cryoprecipitate plasma plasma (from collection) (from collection) (cryo) (cryo-poor plasma)

Whole blood is centrifuged at Whole blood is processed Plasma is frozen for 24 hours, Plasma is frozen for 24 hours, high speed, allowing separa- through a cell separator to and then thawed at 1°– 6°C and then thawed at 1°– 6°C tion of plasma, red blood cells obtain plasma. Plasma is until insoluble proteins precip- until insoluble proteins precip- (RBCs), and the buffy coat frozen within 8 hours of col- itate. The pack is centrifuged itate. The pack is centrifuged layer (, white blood lection and is designated as to obtain the cryoprecipitate. to obtain the supernatant. cells, some RBCs and plasma). fresh-frozen plasma (FFP). In The cryoprecipitate is then The supernatant, or cryo-poor Plasma is frozen within 24 general, 1 unit of FFP from refrozen for storage. plasma, is then refrozen for hours of collection and is des- apheresis collection is equiva- storage. ignated as frozen plasma (FP). lent to approximately 2 units Once thawed, the product It is prepared for use by thaw- of FP from whole blood collec- should be transfused immedi- Once thawed, the product Preparation ing at 37°C, a process that can tion. The two products can be ately, with completion of should be transfused immedi- take up to 30 minutes. used interchangeably. transfusion within 4 hours of ately, with completion of issuing product. transfusion within 4 hours of Once thawed, the product Once thawed, the product issuing product. should be transfused immedi- should be transfused immedi- ately, with completion of ately, with completion of transfusion within 4 hours of transfusion within 4 hours of issuing product. issuing product.

Contains all of the coagulation Contains all of the coagulation Contains FVIII:C, von Is deficient in high molecular factors, including the labile factors, including the labile Willebrand factor (vWF), fib- weight vWF multimers and factors (FV and FVIII:C). For factors (FV and FVIII:C). rinogen, FXIII, and fibronectin. FVIII:C. product prepared within 24 Cryoprecipitate has the fol- hours of collection, FVIII:C lev- lowing factor activities: els are less than those found 91 IU of FVIII: C per bag, in fresh-frozen plasma pre- 113 IU of vWF per bag, and Factors pared within 8 hours of collec- 150 mg of fibrinogen per bag. tion, but levels are still at or above 0.50 IU/mL. FP can be used for coagulation factor replacement except for isolat- ed or severe FVIII deficiency.

Each bag = 1 unit Each bag = 1 unit Each bag = 1 unit (5–15 mL) Each bag = 1 unit (>100 mL) Volume (200 – 250 mL) (100 – 600 mL)

Typical adult dose of plasma is Typical adult dose of plasma is Typical adult dose of cryo is Typically 1.0–1.5 times plasma 10–15 mL/kg body weight. 10–15 mL/kg body weight. 1 unit/5 kg body weight, up to volume exchange is a total dose of 10 units (bags). performed per plasma The pediatric dose of plasma The pediatric dose of plasma exchange (PLEX) run. is 10–15 mL/kg body weight. is 10–15 mL/kg body weight. The pediatric dose is 1 unit/5–10 kg body weight or Indicated as replacement fluid Infusion rate is over 2–3 Infusion rate is over 2–3 5–10 mL/kg. in PLEX for thrombotic throm- Dose hours, or as required. hours, or as required. bocytopenic . Will raise fibrinogen by Will raise factor levels by Will raise factor levels by 0.5 g/L, assuming there is no 25%, assuming there is no 25%, assuming there is no ongoing consumption/loss of ongoing consumption/loss of ongoing consumption/loss of fibrinogen. factors. factors.

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13 apy: A physician’s handbook. 8th ed. versus placebo for treatment of tPA- nectin. Fibronectin is thought to Bethesda, MD: AABB Press; 2005:28, related bleeding are not available. function as the major opsonin for 43, 94-99. However, various guidelines as well as macrophage clearance of circulating 7. Israels SJ. Factor XIII deficiency. Emedi- articles in peer-reviewed journals sug- noncellular debris. In early, uncon- cine web site. www.emedicine.com/ gest using the following clinical algo- trolled studies, infusion of cryoprecip- ped/topic3040.htm (accessed 13 Octo- rithm: itate in critically ill septic patients ber 2006). • Discontinue tPA administration resulted in improved renal and pul- 8. Levine MN, Goldhaber SZ, Gore JM, et with the onset of signs or symptoms monary function and changes in al. Hemorrhagic complications of throm- of . peripheral hemodynamics. However, bolytic therapy in the treatment of • Order stat lab studies: INR, PTT, subsequent controlled studies failed to 14 and venous throm- platelet count, fibrinogen level. confirm any benefit. boembolism. Chest 1995;108(4 suppl): • Consider administration of 10 units (Level IV evidence, grade A recom- 291S-301S. (bags) of cryoprecipitate. mendation.) 9. Pantanowitz L, Kruskall MS, Uhl L. Cryo- • Consider administration of platelet Competing interests precipitate. Patterns of use. Am J Clin concentrate if a drug-induced (e.g., None declared. Pathol 2003;119:874-881. ASA-induced) platelet dysfunction 10. Shiono N, Koyama N, Watanabe Y, et al. is likely. 9 References Application of cryoprecipitate as a hema - • Consider neurosurgical evaluation. 1. United States Department of Health tostatic glue. J Cardiovasc Surg (Torino) (Level IV evidence, grade C recom- and Human Services. Agency for Health 1998;39:609-612. mendation.) Care Policy and Research. Acute Pain 11. Milne AA, Murphy WG, Reading SJ, et al. Inappropriate uses for Management: Operative or Medical A randomised trial of fibrin sealant in cryoprecipitate Procedures and Trauma. Rockville, MD: peripheral vascular surgery. Vox Sang AHCPR, 1993:107. Clinical practice 1996;70:210-212. The use of cryoprecipitate is not rec- guide line No. 1, AHCPR publication No. 12. Streiff MB, Ness PM. Acquired FV ommended in the following situations. 92-0023. inhibitors: A needless iatrogenic com - Fibrin glue. 2. O’Shaughnessy DF, Atterbury C, Bolton plication of bovine exposure. Allogeneic or autolo- Maggs P, et al. British Committee for Transfusion 2002;42:18-26. gous cryoprecipitate has been used 10,11 Standards in Haematology, Blood Trans- 13. Poon MC. Cryoprecipitate: Uses and to prepare fibrin glue. To make this fusion Task Force. Guidelines for the use alternatives. Transfus Med Rev 1993;7: hemo static product, cryoprecipitate is of fresh-frozen plasma, cryoprecipitate 180-192. mixed with a commercial source of and cryosupernatant. Br J Haematol 14. Hesselvik F, Brodin B, Carlsson C, et al. thrombin (usually bovine thrombin). 2004:126:11-28. Cryoprecipitate infusion fails to improve Homemade fibrin sealants have used 3. Practice guidelines for blood component organ function in septic shock. Crit Care bovine thrombin preparations that therapy: A report by the American Soci- Med 1987;15:475-483. contain bovine F V. A number of pa - ety of Anesthesiologists Task Force on tients have developed antibodies to the Blood Component Therapy. Anesthesiol- bovine F V, resulting in potentially ogy 1996;84:732-747. serious clinical sequelae whose man- 4. Practice parameter for the use of fresh- agement may be confounded by erro- frozen plasma, cryoprecipitate, and neous results in laboratory tests of 12 platelets. Fresh-Frozen Plasma, Cryopre- coagulation. To avoid this complica- cipitate, and Platelets Administration tion, the use of commercially manu- Practice Guidelines Development Task factured fibrin sealant preparations Force of the College of American Pathol- containing human thrombin (e.g., Tis- ogists. JAMA 1994;271:777-781. seel) is preferred. 5. Petrides M, Stack G (eds). Practical Guide (Level III and IV evidence, grade B and to Transfusion Medicine. Bethesda, MD: C recommendation.) AABB Press; 2001:158-160. Sepsis. 6. Gottschall J (ed). ther- Cryoprecipitate has been used in septic patients to replace fibro -

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Appendix A

US Agency for Healthcare Policy and Research guidelines for defining the types of evidence and the grading recom- mendations. Levels of evidence Grades of recommendations Ia Evidence obtained from the meta-analysis of ran- A Required at least one randomized controlled trial as domized controlled trials. part of a body of literature of overall good quality Ib Evidence obtained from at least one randomized and consistency addressing the specific recommen- controlled trial. dations (evidence levels Ia, Ib). IIa Evidence obtained from at least one well-designed B Requires availability of well-conducted clinical stud- controlled study without randomization. ies but no randomized clinical trials on the topic of IIb Evidence obtained from at least one other type of recommendations (evidence levels IIa, IIb, III). well-designed quasi-experimental study. C Requires evidence obtained from expert committee III Evidence obtained from well-designed non-experi- reports or opinions and/or clinical experiences of mental descriptive studies, such as comparative respected authorities. Indicates an absence of direct- studies, correlation studies and case studies. ly applicable clinical studies of good quality (evi- IV Evidence obtained from expert committee reports dence level IV). or opinions and/or clinical experiences of respect- ed authorities.

Appendix B

The Transfusion Medical Advisory Group advises the BC Ministry of Health. It is composed of transfusion medicine experts who meet regularly to discuss pertinent transfusion-related issues and to endorse transfusion initiatives that will improve the Canadian health care system. Members Ms Sheila Armstrong, Administrator, Provincial Dr Randell Moore, Anesthesiologist, St. Paul’s Laboratory Coordinating Office Hospital, Vancouver, BC Dr Brian Berry, Director Hematopathology and Dr Doug Morrison, Director, Transfusion Medicine, Transfusion Medicine, Vancouver Island Health— Royal Columbian Hospital, New Westminster, BC South Island, Victoria, BC Dr David Pi, Director, Provincial Blood Coordinating Dr Mark Bigham, Medical Officer, Canadian Blood Office, Vancouver, BC Services—BC and Yukon Centre Ms Pam Quibell, Charge Technologist—Transfusion Dr Kate M. Chipperfield, Regional Medical Leader, Services, Northern Health, Prince George, BC Blood Transfusion Medicine, Vancouver Coastal Mr Lyle Unrau, Customer Service Rep, Canadian Health, Vancouver, BC Blood Services—BC and Yukon Centre Dr Jason Doyle, Director, Transfusion Services— Dr Louis D. Wadsworth, Executive Medical Director, Interior Health, Kelowna, BC Provincial Health Services Authority (PHSA) Ms Shelley Feenstra, Regional Blood Transfusion Corporate—Lab Services, Vancouver, BC (Chair) Clinician—Vancouver Coastal Health, Vancouver, Ms Maureen Wyatt, Assistant Charge Technologist, BC Interior Health, Kelowna, BC Dr David Ferguson, Medical Director, BC Biomedical Mr Ed Yee, Regional Director, Canadian Blood Laboratories Ltd., Surrey, BC Services—BC and Yukon Centre Dr Gershon Growe, Canadian Blood Services—BC and Dr Wilson Yeung, Hematopathologist, St. Paul’s Yukon Centre Hospital, Vancouver, BC Ms Donna Miller, Chair, Nursing Resource Group, Royal Jubilee Hospital, Victoria, BC

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