Ahmed Al Bahrani Transfusion Medicine Fellow McMaster University May 7, 2009

1. CRYOPRECIPITATE USE IN 25 CANADIAN HOSPITALS: COMMONLY USED OUTSIDE OF THE PUBLISHED GUIDELINESEdward C Alport, Jeannie L Callum, Susan Nahirniak, Bernie Eurich, and Heather A. HumeTRANSFUSION 2008; 48:2122-2127 Ahmed Al Bahrani Transfusion Medicine Fellow McMaster University May 7, 2009

2. Background Over the past few decades, the principle of evidence based decision making has become widely accepted. When there is good evidence , care maps and practice guidelines are easy to implement.

3. The clinical indications of cryo transfusion have changed over the last 15 years due to: Advances in transmissible disease testing. Better understanding of the coagulation system Evolution of alternative products. Use in complex conditions where it is difficult to perform randomized trials and led to wide variation in clinical practice.

4. The current primary uses of cryo are for fibrinogen replacement in acquired hypofibrinogenemia or as empiric therapy in a bleeding patient. • Apart from the historical uses of cryoprecipitate as factor VIII concentrate for hemophilia and vWD, there is no prospective studies demonstrating evidence-based outcomes for the use of cryo.

5. Previous study suggest 24 - 61 % of cryo use is inappropriate, as defined by current practice guidelines. Monthly blood component disposition reports submitted to CBS by Canadian Hospitals suggest that there is considerable interhospital variation in cryoprecipitate use in Canada. Data for 4 month period (April 1,2005-July 31, 2005): 11,500 cryo units and 109,000 PRBC units were issued.

6. Ratio of Cryo : PRBC is 11:100 but with wide variation from 3:100 to 30:100 among individual institution. This observation prompted a joint effort of Canadian Blood Services and selected Canadian Hospitals to conduct a prospective audit of Cryoprecipitate Use.

7. MATERIAL AND METHODS The hospital receiving 80 % of the issues of Cryo from CBS were identified. 31 major hospital across Canada were considered. Prospective 2 month audit of cryoprecipitate use in these hospital. Hospitals agree to participate were asked to provide information for each cryoprecipitate transfusion event between March 6, 2006 and May 5, 2006.

8. Hospital demographic information included: Number of acute care beds. Number of RBC units transfused. Number of cardiac surgical procedures ( defined as more 3 hours scheduled operating room times).

9. Information required for each Cryo transfusion: Patient demographic and clinical information ( age, sex, diagnosis, clinical services) Lab information ( Hb, Platelet count, PT ,PTT ,Creat., Pre and post transfusion fibrinogen level) Transfusion data ( No. of Cryo. units transfused, No. of cryo transfusion events, total number of blood components used in the 12 hr before and after cryo. infusion) (The number of cryo. units transfused per 100 RBC units transfused was calculated for each hospital)

10. Criteria of cryo. transfusion was developed from CBS and other published guidelines: Likely appropriate: fibrinogen level taken within 6 hr before or 6 hr after transfusion was not more than 1 g/L. Likely inappropriate: fibrinogen level within 6 hr before transfusion was more than 1 g/L and post transfusion fibrinogen level was either more than 1 g/L or not performed. Undetermined appropriateness: No pre transfusion fibrinogen level was performed and post transfusion fibrinogen level was more than 1g/L or not performed.

11. RESULTS 25 of the 31 identified hospitals agreed to participate. 6 hospitals in one province declined to participate ( require ethic board approval) The 25 institutions were designated by letter A to Y. 23/25 tertiary care, university-affiliated institutions. Hospital size range from 177-2089 acute care beds.

12. Transfusion guidelines for cryo were in place at 16 of the 25 hospital. • 3 sites required physician approval for release of the products. • Intraoperative point of care testing for fibrinogen level was available only in 3 sites.

13. Overall, 4370 units of cryoprecipitate were transfused in the 25 institutions. 7036 units of cryo. were issued to hospital by CBS. This represent 62 % of the cryoprecipitate units issued to hospitals by CBS during the audit period. The 4370 units transfused represent 603 transfusion events in 453 different patients. 32 % of cryo. transfusion events were given to pediatric patients ( less than 16 years old)

16. 24 % of the cryo. transfusion events were considered to be appropriate with pre transfusion fibrinogen levels < 1g/L in 19 % , and post transfusion fibrinogen levels < 1g/L in another 5 %. 34 % were considered to be inappropriate. 42 % appropriateness could not be determined.

17. Hospitals with transfusion guidelines or physician approval process had higher rates of appropriateness when compared to institutions without guidelines. Cardiac surgery represent 45 % of all cryoprecipitate transfusions.

20. DISCUSSION Cryoprecipitate is generally considered appropriate for patients with bleeding and significant hypofibrinogenemia ( fibrinogen less than or equal 0.8-1.0 g/L) There is no randomized controlled clinical trials evaluating the efficacy of cryo. have ever been performed.

21. In this study, only 24 % of requests were within the scope of these recommendation, whereas 76 % of cryoprecipitate transfusions were likely inappropriate or of undetermined appropriateness. • Comparison of the number of units of cryoprecipitate per 100 units RBC transfused by each institution showed significant variation in practice ( mean 9 per 100 RBC, range 2 to 27 units).

22. The single most common indication for cryoprecipitate was cardiac surgery (45.4 % of events), of which only 6 % had hypofibrinogenemia documented before or after administration of cryoprecipitate. Large variation in practice was observed with appropriate use per hospital ranging from 0- 100 % of transfusion.

23. This results are comparable to a large audit of cryoprecipitate use in Australia reported in 2003 ( only 38 % of 64 cryoprecipitate transfusions were appropriate when the same criteria was applied). Other previous studies suggest 24 to 61 % of cryoprecipitate use is inappropriate as defined by current practice guidelines.

24. Cryoprecipitate is prepared by thawing 1 unit of FFP at 1-6 C. After it is thawed, the supernatant plasma is removed, which leaves the cold-precipitated protein plus 10-15 ml of plasma in the bag. • This material is then refrozen at – 18 C or colder within 1 hour and has a shelf life of one year.

25. Each bag of cryoprecipitate contains 80 to 120 units of factor VIII, 150-250 mg of fibrinogen, and about 20 - 30 % of factor XIII. • 40 - 70 % of the VWF present in the initial unit of FFP is recovered in the cryoprecipitate.

26. The use of cryo for VWD has been replaced with the use of desmopressin or virally inactivated human-derived factor VIII/vWF concentrate. The use of cryo as a fibrin glue has largely been superseded by the use of virally inactivated human derived fibrin sealants. The use cryo for the prevention and treatment of uremic bleeding are limited.

27. Congenital factor XIII deficiency is rare and a commercial factor XIII concentrate is available for use in such patients. • The use of cryo for hemophilia A is also replaced by DDAVP and commercial recombinant factor VIII concentrate.

28. The use of cryo should be balanced with the potential adverse effects. • Cryo is administered in a dosage of 1 unit per 5-10 kg of body wt and therefore a typical adult dose results in as exposure to 8-12 donors.

29. Physician awareness should be made of the potential risks of this product. Practice guidelines for cryo have been available in the medical literature since the mid- 1990. In this study, there is association between the use of guidelines or an approval process and better compliance with published guidelines.

30. Obstacles to appropriate use: Inadequate laboratory resources to allow for rapid measurement of the fibrinogen level. Unstable clinical situations precluding measurement of the fibrinogen level. Lack of physician knowledge regarding this component. It is difficult to convince many clinicians that cryo. is unnecessary in different clinical situations because supporting scientific literature is lacking.

31. Low fibrinogen levels occur in well recognized clinical settings: • DIC • Massive transfusion • Cardiac surgery • Thus, fibrinogen serum level is a routine test and should be available with a short turnaround time. • Cryoprecipitate should only be used as a replacement product for a documented fibrinogen deficiency.

32. Each unit of cryoprecipitate contains 0.25 g of fibrinogen in 10-15 ml plasma. • 8 units of cryoprecipitate contains 2 g of fibrinogen in 80-120 ml of plasma. • 4 units of FFP contain 2 g of fibrinogen. • In a bleeding patient with significant coagulopathy, 4 units of FFP will replace the coagulation factors and provide a fibrinogen dosage equivalent to that of 8 units of cryo.

33. Evaluation • Limitation of this study: • Limited clinical data collected preventing in depth analysis of clinical outcomes. • Inadequate number of pediatric sites. • Data were collected by transfusion services preventing combined analysis of hypofibrinogenemia in the presence or absence of bleeding.

34. Evaluation • Recording of clinical outcomes or bleeding status were not included in the evaluation. • In 42 % of infusion there was no monitoring of fibrinogen levels and therefore we do not know which of these were appropriate.

35. Evaluation • Strength of this study • Large number of hospitals surveyed. • Large number of cryoprecipitate transfusion events evaluated. • This is the largest cross sectional analysis of the use of cryoprecipitate that has been reported.

36. Conclusion • Cryoprecipitate is generally considered appropriate for patients with bleeding and significant hypofibrinogenemia ( fibrinogen less than or equal 0.8-1.0 g/L) • Further studies are required: • To determine the impact of cryoprecipitate on clinical outcomes ( bleeding and mortality). • To study the impact of turnaround time of fibrinogen results and transfusion guidelines on appropriateness of use.

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