The approach taken to reducing the risk of transfusion related acute lung injury in Canada.

Transfusion related acute lung injury (TRALI) has become a major reported cause of severe transfusion reactions and mortality. Over the past four years significant changes have been taken in Canada in order both to improve the recognition of the risk and to decrease its incidence. An international meeting was held in April of 2004 entitled "Towards an Understanding of TRALI". As a result of the analysis and recommendations from this meeting, the Canadian Blood Services established an ongoing review committee and established a laboratory diagnostic facility to identify at risk donors and recipients. A system has been developed to identify implicated donors and exclude them from the blood donor pool. Other steps have been taken to exclude potentially high risk donors, such as previously pregnant females, from the plasma and platelet donor pool. A considerable amount of education also has been offered to clinical services in the country. This paper summarizes the definitions, categorizations of implicated donors, and the ongoing precautionary activities related to plasma products. Noted within the article are the methods used for locating and selecting data. These were primarily based on the international TRALI conference in 2004, and from ongoing discussions and information provided by the Canadian Blood Services TRALI Review Committee. No ethics referral or approval was requested, and a summary is included in the article.

Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A.

To determine whether the factor V Leiden mutation is associated with decreased bleeding in individuals with severe hemophilia A, factor concentrate utilization, maximum annual number of bleeding episodes, and the prevalence of hemophilic arthropathy between carriers and non-carriers of the factor V Leiden mutation were compared. Heterozygosity for the factor V Leiden mutation was found in 6 of 137 subjects (4.4%). Carriers of the factor V Leiden mutation utilized less factor concentrate (geometric mean: 310 vs. 1185 units/kg/year) and had fewer bleeding episodes than non-carriers (proportion with 10 or fewer bleeding episodes in their worst year: 50 vs. 11%). However, the factor V Leiden mutation was not associated with the absence of arthropathy. The intron 22 inversion mutation of the factor VIII gene was tested for in a subgroup of 80 subjects, but it was not found to be a significant variable for any of the bleeding endpoints. The results of this small study are consistent with the hypothesis that the factor V Leiden mutation imparts a protective effect; however, a larger confirmatory study in which the factor VIII molecular defects can be controlled for is needed. Furthermore, most severe hemophiliacs who used fewer than 200 units/kg/year of factor concentrate or who had experienced 10 or fewer bleeding episodes per year did not carry the factor V Leiden mutation, suggesting that the proportion of severe hemophiliacs whose mild clinical course can be attributed to the factor V Leiden mutation is small.

The development of indications for the preoperative use of recombinant erythropoietin.

OBJECTIVE: To develop indications for the preoperative use of recombinant erythropoietin (rHuEPO) alone and in conjunction with preoperative autologous donation (PAD). DESIGN: A 2-round modified Delphi-consensus process. PARTICIPANTS: Nine physicians representing multiple clinical specialties, practice environments and geographic locations. METHOD: From evidence tables and a literature summary (MEDLINE database from January 1985 to August 1996) provided and using the RAND-UCLA appropriateness method, the physicians developed 264 indications for the preoperative use of rHuEPO by permuting 7 clinical factors (age, history of transfusion or antibody incompatibility, hemoglobin level, anemia of chronic disease, expected blood loss, presence of cardiovascular or cardiopulmonary disease and patient anxiety). These indications were rated on a 9-point appropriateness scale. Median scores and measures of agreement were determined. OUTCOME MEASURES: The significance of cost constraints or cost and blood supply constraints and the impact of each clinical factor on the ratings as judged by statistical analysis. RESULTS: Of the 264 indications, 54% were rated appropriate, 18% uncertain and 28% inappropriate. Expected blood loss had the greatest impact on the ratings (high expected blood loss had a 5.9 point more appropriate rating on the 9-point scale than low expected blood loss [p < 0.0001]). Preoperative hemoglobin level also significantly influenced the ratings (p < 0.0001). Compared with the clinical context, the ratings under the cost constraint were 1.0 less appropriate (p < 0.0001) for rHuEPO alone and 1.2 less appropriate for rHuEPO and PAD (p < 0.0001). The ratings for patients with moderate expected blood loss were significantly influenced by the cost constraint (less appropriate). CONCLUSIONS: Expected blood loss and preoperative hemoglobin level were the best indicators of rHuEPO appropriateness. Different contexts modify the appropriateness ratings of an expensive drug like rHuEPO.

Effect of splenectomy on slowing human immunodeficiency virus disease progression.

BACKGROUND: Lymphoreticular tissue is the most important site for human immunodeficiency virus (HIV) replication in HIV-infected individuals. OBJECTIVE: To compare the long-term effect of splenectomy on survival and time to development of acquired immunodeficiency syndrome in subjects who had undergone splenectomy with subjects who had not undergone splenectomy. DESIGN: A cohort study with a follow-up of up to 13.4 years. SETTING: Subjects were recruited from a hospital outpatient clinic population and a multicenter study of patients with hemophilia. PARTICIPANTS: Forty-five HIV-infected individuals were observed prospectively for up to 13.4 years (17 had undergone splenectomy and 28 had not undergone splenectomy). Five subjects underwent splenectomy before acquiring HIV infection and 12 underwent splenectomy during the asymptomatic phase of HIV infection. The group who did not undergo splenectomy consisted of HIV-infected individuals who were asymptomatic at study enrollment. MAIN OUTCOME MEASURES: A Cox proportional hazards model was used to test the effects of splenectomy on survival and time to development of acquired immunodeficiency syndrome when adjusting for potential confounders (age, initial CD4+ cell count, and treatment with antiretroviral drugs). Splenectomy was treated as a time-dependent covariate to account for the variation in its timing. RESULTS: During the average follow-up of 8.6 years, 9 (53%) of the 17 subjects who underwent splenectomy and 23 (82%) of the 28 subjects who did not undergo splenectomy died; acquired immunodeficiency syndrome developed in 6 (35%) of the subjects who underwent splenectomy and 23 (82%) of the subjects who did not undergo splenectomy. Splenectomy was associated with a significant reduction of risk of developing acquired immunodeficiency syndrome (adjusted relative risk [RR] <0.4, P<.05), whereas the effect on risk of mortality approached, although it did not reach, significance (adjusted RR approximately 0.5, P approximately .10). CONCLUSION: The absence of a spleen during the asymptomatic phase of HIV infection seems to have a beneficial effect on HIV disease progression.

The introduction of high-purity products in Canada.

In October 1993, the Canadian Blood Agency, the agent for the provinces/territories in Canada, agreed to the introduction of high-purity coagulation products, either recombinant or highly purified factor concentrates, for the management of coagulation deficiencies. This represented a cost increase of approximately $30 million (40%) for the national coagulation product inventory. Representatives of the relevant recipients of the products, some of the treaters, the distributor and the funders met on a regular basis in order to monitor the impact of these new products. The Association of Hemophilia Clinic Directors of Canada also agreed to include some specific outcome studies over a longer period of time to include evaluation of inhibitor formation, prophylaxis regimens, immune status and the incidence of thrombosis. The 'Hemophilia and Von Willebrand's Disease' clinical practice guidelines were also developed under their auspices. A usage monitoring system has been implemented and has been continuously managed by the Canadian Blood Agency. This resulted in trends of practice and rationales for unexpected use being identified early for planning and funding purposes. The Working Group set up under the auspices of the Canadian Blood Agency was an effective vehicle to evaluate the conversion and the impact of these new products in the country and can serve as a model for future endeavours.

Recombinant blood components: clinical administration today and tomorrow.

Improvements in the technology of whole blood fractionation have resulted in the development of many subfractions that allow more specific management of clotting deficiencies, such as the hemophilias. Infective disasters have occurred in recent years, which has led to concern regarding the use of human blood components. There has been great interest in the search for alternatives, such as synthetic volume expanders, antifibrinolytic drugs, and hormones to stimulate bone marrow production. Recombinant technology has developed rapidly over the past 15 years, and several products are now available for use, including recombinant factor VIII and recombinant factor VIIa for the treatment of hemophilia and recombinant erythropoietin to stimulate red blood cell production. As these recombinant proteins are complex, they require mammalian cell lines as their substrate. Recombinant processes have the potential to produce sufficient quantities of these products for the treatment of patients around the world independent of a human plasma source. The introduction of all of the new recombinant products has been done in an orderly fashion through clinical trials. Erythropoietin was extensively reviewed initially for its effect in chronic renal failure patients and appears to have other applications. Recombinant factor VIII has now become a mainstay of treatment for many patients with hemophilia A, and recombinant factor VIIa has a major role to play in the management of patients with inhibitors to factors VIII and IX. We anticipate the availability of other recombinant blood proteins soon.

The Canadian Hemophilia Registry as the basis for a national system for monitoring the use of factor concentrates.

BACKGROUND: Canada's publicly funded blood system has recently introduced high-purity concentrates as the standard treatment for individuals with hemophilia. The added cost and the need to document patient outcomes have prompted the consideration of a national blood product monitoring system. STUDY DESIGN AND METHODS: This study investigates the suitability of the Canadian Hemophilia Registry (CHR) as the basis of such a monitoring system by assessing the degree to which it represents users of factor concentrates. RESULTS: Currently, there are 1978 individuals registered with the CHR, of whom 1594 (81%) have hemophilia A and 384 (19%) have hemophilia B. The total prevalence is 7.2 per 10(5) population, with the prevalence of severe cases being 2.3 per 10(5). This overall prevalence is similar to that seen in other countries with national registries. The CHR national prevalence also compares favorably with that in the province of Quebec, where registration of users of blood products is compulsory. The CHR figures indicate that the number of persons currently infected with human immunodeficiency virus, both alive and dead, is 652, which is similar to the number of applicants (658) to the federal government's assistance program. The registry is stable, and the number of persons with severe cases, other than young children, newly registered or lost to follow-up during the last 2 years is very small. CONCLUSION: The CHR includes the vast majority of factor concentrate users and is therefore ideal as the basis for a national monitoring system.

Aprotinin reduces the need for blood products during liver transplantation.

BACKGROUND: Bleeding complications and blood product consumption have been a major concern during liver transplantation. Prevention of plasminogen activation and fibrinolysis by aprotinin administration has been shown to reduce perioperative bleeding during operations associated with high blood-product consumption. PATIENTS AND METHODS: Use of blood-products (packed red cells, frozen plasma, platelets, and cryoprecipitate) was analyzed both during the three stages of orthotopic liver transplantation and during total hospitalization of the 26 patients transplanted without aprotinin and the subsequent 40 patients with aprotinin. A similar analysis was performed for 15 patients immediately before and after the introduction of aprotinin to eliminate the "learning curve" effect for liver transplantation. The effect of epsilon-amino-caproic acid was analyzed as 13 patients received neither epsilon-aminocaproic acid nor aprotinin and 13 patients received epsilon-aminocaproic acid but not aprotinin. RESULTS: There was a significant reduction in total hospital use of cryoprecipitate, frozen plasma, platelets, and red cells in the aprotinin-treated patients. This reduction was seen during the anhepatic and reperfusion stages of liver transplantation. There was no difference in blood product consumption between the groups who were or were not treated with epsilon-aminocaproic acid. CONCLUSION: Aprotinin significantly reduces the need for red cell, frozen plasma, platelet, and cryoprecipitate transfusion use during orthotopic liver transplantation, and appears to be more efficacious than epsilon-aminocaproic acid.

Blood product utilization and management in Canada.

The utilization of blood for transfusion in Canada has remained at 900,000-950,000 units p.a. for the past six years. Donation has decreased slightly from a peak of 1,200,000 units p.a. in 1989. The use of fresh plasma and cryo-precipitate has decreased while the use of platelets has doubled in the past six years. The increased use of albumen cannot be explained. In Vancouver, all anaesthesia residents take a compulsory transfusion medicine rotation which appears to be successful in rationalizing transfusion practice.

HIV transmission to patients with hemophilia by heat-treated, donor-screened factor concentrate.

Six hemophilia patients previously seronegative for human immunodeficiency virus (HIV) seroconverted between September 1986 and September 1987. None had risk factors for HIV infection other than hemophilia. We compared the factor concentrates received by these patients with the concentrates received by 10 seronegative hemophilia patients. A statistically significant association was observed between seropositivity and the receipt of two lots of Factor VIII produced from the same plasma pool (odds ratio 77, p = 0.0014); five of the six case subjects but none of the control subjects had received concentrate from one of the two lots. Available evidence suggests that the sixth case subject had also received concentrate from an implicated lot. Symptoms including rash and fever were reported in five cases within 6 weeks after the implicated concentrate had been given. The implicated lots were produced from plasma from paid donors that had been screened and then heated at 60 degrees C for 30 hours in the lyophilized state. Subsequent to our investigation all concentrate produced by this process was removed from distribution.

A trial of desmopressin (1-desamino-8-D-arginine vasopressin) to reduce blood loss in uncomplicated cardiac surgery.

Previous studies have suggested that desmopressin may reduce the bleeding diathesis that often complicates open-heart surgery. To pursue this question further, we performed a double-blind, randomized, placebo-controlled trial to determine whether the previously reported beneficial effect of desmopressin on hemostasis during complex cardiac surgery was applicable to all elective cardiac surgical procedures involving cardiopulmonary bypass. In 150 consecutive patients, most of whom underwent primary coronary-artery bypass grafting, we compared the effects of intravenous desmopressin (0.3 microgram per kilogram of body weight) with those of saline placebo on postoperative blood loss and the need to replace blood products. The median amount of blood lost within the first 24 hours after operation was similar in the desmopressin and placebo groups (865 vs. 738 ml; P = 0.26). The postoperative use of blood replacement products did not differ significantly between the groups (1025 ml [95 percent confidence interval, 300 to 4140 ml] in the desmopressin group and 860 ml [247 to 5346 ml] in the placebo group). Desmopressin is believed to exert its hemostatic effect by releasing von Willebrand factor. The level of ristocetin cofactor, a functional index of the level of von Willebrand factor, was increased approximately twofold from base line in both treatment groups 90 minutes and 24 hours after the administration of medication. Similarly, the levels of von Willebrand factor multimers increased uniformly in both groups. These findings may be consistent with a normal stress response of von Willebrand factor to major surgery and could explain our failure to detect a therapeutic effect of desmopressin. We conclude that the majority of patients who undergo elective cardiac surgery receive no hemostatic benefit from the use of desmopressin.