Approchons-nous de la fin du cryoprécipité en Ontario?

Jeannie Callum, BA, MD, FRCPC
Directrice du Service de médecine transfusionnelle, Centre des sciences de la santé de Kingston

En octobre 2019, les résultats de l’essai FIBRES ont été simultanément publiés dans JAMA et à la séance plénière de la réunion annuelle de l’AABB1. La conduite de l’essai FIBRES a été un exploit majeur pour les technologistes des banques de sang hospitalières et les équipes de chirurgie cardiaque de 11 hôpitaux du Canada. L’essai a démontré que le concentré de fibrinogène n’était pas inférieur au cryoprécipité pour atteindre l’hémostase en cas de saignement lié à une chirurgie cardiaque et qu’il affichait un profil d’innocuité semblable. Dans l’analyse des sous-groupes, on a constaté une meilleure maîtrise des hémorragies avec le concentré de fibrinogène qu’avec le cryoprécipité chez les patients qui subissaient une intervention chirurgicale non urgente. C’était une avancée importante vers des produits sanguins à teneur réduite en agents pathogènes, transition qui avait été soutenue lors de la conférence consensuelle de Toronto sur la réduction des agents pathogènes en 20072. De fait, la Société canadienne du sang a fait avancer le Canada d’un autre pas dans ce parcours important vers la sécurité cette année (2022) avec le lancement de concentrés plaquettaires à teneur réduite en agents pathogènes.

So where are we almost 30 months later after the publication of the FIBRES trial in the transition to a safer fibrinogen replacement product? Ontario turned on a dime after the FIBRES trial was published, with the number of cryoprecipitate units issued 8 weeks later in January 2020 already in half. In February of 2022, only 148 units or approximately 15 adult doses were issued to the remaining 12 hospitals in Ontario still ordering cryoprecipitate as a fibrinogen source. The majority of these 12 hospitals are non-academic hospitals, suggesting that process change rather than some inherent belief in the superiority of cryoprecipitate is resulting in a delay in transitioning. Change during COVID-19 is not easy. In addition, almost every transfusion laboratory is struggling with staffing due to shortages in medical laboratory technologists. A few of these 12 hospitals also have pediatric patients and are ordering single units suggesting reluctance to extrapolate the data from adult trials to pediatric patients. Fortunately, there have been two randomized trials comparing cryoprecipitate to fibrinogen concentrate in pediatric cardiac surgical patients with similar outcomes for efficacy and safety. ^3,4 One would hope we would prioritize pediatric patients to getting access to a safer fibrinogen replacement, since these patients are most likely to live long enough to be affected by a novel blood borne pathogen. Dr. Steven Kleinman estimated the economic impacts of a novel blood borne pathogen and the estimated number of affected patients in Canada; the estimates are staggering.⁵

In addition, to the paramount safety concern with the use of a non-pathogen reduced product when a safer product is available, cryoprecipitate has other negative characteristics we need to consider. First, Canadian Blood Services must collect B2-pack whole blood for their manufacture. Nancy Heddle has raised the concern in an article in Lancet Haematology in 2016 that the outcome for the recipient of these matching B2 red cells may be inferior. ⁶ Second, when we utilize plasma for the manufacture of cryoprecipitate, the residual plasma cannot be used for either transfusion or for the manufacture of derivatives. Third, the B2 pack production line cannot be used to produce platelet concentrates. Fourth, cryoprecipitate is frozen and therefore cannot be easily redistributed if not used before impending expiration. Fifth, cryoprecipitate must be thawed and pooled before issue (along with a lot of computer clicks) delaying issue to hemorrhaging patients. This is also workload our dwindling supply of technologists must bear. Lastly, we have no idea what the patient safety risk of the impurities in cryoprecipitate may be for our patients (platelet microparticles, factor VIII, von Willebrand factor, etc.). Indeed, concern for an increased risk of thromboembolic complications has been raised by two papers.^7,8

La Dre Judith Pool a inventé le « cryoprécipité de Pool » en 1964 pour traiter le déficit congénital en facteur VIII9. Ce produit a par la suite aussi servi au traitement de l’hypofibrinogénémie acquise10. Son emploi au cours des 60 dernières années en remplacement du fibrinogène a sans doute sauvé bien des vies, même si le produit a aussi été impliqué dans la transmission d’infections, y compris dans un cas notoire [Blood money | Maclean’s | 28 mars 1994 (macleans.ca)]. La plupart des pays d’Europe ont terminé leur transition vers les concentrés de fibrinogène11; il est rassurant de voir que l’Ontario y est presque arrivé.

Figure 1. Unités de cryoprécipité émises mensuellement aux hôpitaux ontariens depuis 3 ans.

Références:

Callum J, Farkouh ME, Scales DC, Heddle NM, Crowther M, Rao V, Hucke HP, Carroll J, Grewal D, Brar S, Bussieres J, Grocott H, Harle C, Pavenski K, Rochon A, Saha T, Shepherd L, Syed S, Tran D, Wong D, Zeller M, Karkouti K, Group FR. Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery: The FIBRES Randomized Clinical Trial. JAMA 2019;322: 1966-76.
Webert KE, Cserti CM, Hannon J, Lin Y, Pavenski K, Pendergrast JM, Blajchman MA. Proceedings of a Consensus Conference: pathogen inactivation-making decisions about new technologies. Transfus Med Rev 2008;22: 1-34.
Galas FR, de Almeida JP, Fukushima JT, Vincent JL, Osawa EA, Zeferino S, Camara L, Guimaraes VA, Jatene MB, Hajjar LA. Hemostatic effects of fibrinogen concentrate compared with cryoprecipitate in children after cardiac surgery: a randomized pilot trial. J Thorac Cardiovasc Surg 2014;148: 1647-55.
Downey LA, Andrews J, Hedlin H, Kamra K, McKenzie ED, Hanley FL, Williams GD, Guzzetta NA. Fibrinogen Concentrate as an Alternative to Cryoprecipitate in a Postcardiopulmonary Transfusion Algorithm in Infants Undergoing Cardiac Surgery: A Prospective Randomized Controlled Trial. Anesth Analg 2020;130: 740-51.
Kleinman S, Cameron C, Custer B, Busch M, Katz L, Kralj B, Matheson I, Murphy K, Preiksaitis J, Devine D. Modeling the risk of an emerging pathogen entering the Canadian blood supply. Transfusion 2010;50: 2592-606.
Heddle NM, Arnold DM, Acker JP, Liu Y, Barty RL, Eikelboom JW, Webert KE, Hsia CC, O’Brien SF, Cook RJ. Red blood cell processing methods and in-hospital mortality: a transfusion registry cohort study. Lancet Haematol 2016;3: e246-54.
Myers SP, Brown JB, Leeper CM, Kutcher ME, Chen X, Wade CE, Holcomb JB, Schreiber MA, Cardenas JC, Rosengart MR, Neal MD, group Ps. Early versus late venous thromboembolism: A secondary analysis of data from the PROPPR trial. Surgery 2019;166: 416-22.
Roy A, Stanford S, Nunn S, Alves S, Sargant N, Rangarajan S, Smith EA, Bell J, Dayal S, Cecil T, Tzivanakis A, Kruzhkova I, Solomon C, Knaub S, Moran B, Mohamed F. Efficacy of fibrinogen concentrate in major abdominal surgery – A prospective, randomized, controlled study in cytoreductive surgery for pseudomyxoma peritonei. J Thromb Haemost 2020;18: 352-63.
Swenson E, Hollenhorst MA. Dr Judith Graham Pool and the development of cryoprecipitate. Transfusion 2021;61: 1676-7.
Callum JL, Karkouti K, Lin Y. Cryoprecipitate: the current state of knowledge. Transfus Med Rev 2009;23: 177-88.
Nascimento B, Goodnough LT, Levy JH. Cryoprecipitate therapy. Br J Anaesth 2014;113: 922-34.

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