Improving platelet transfusion safety: biomedical and technical considerations.

Platelet concentrates account for near 10% of all labile blood components but are responsible for more than 25% of the reported adverse events. Besides factors related to patients themselves, who may be particularly at risk of side effects because of their underlying illness, there are aspects of platelet collection and storage that predispose to adverse events. Platelets for transfusion are strongly activated by collection through disposal equipment, which can stress the cells, and by preservation at 22 °C with rotation or rocking, which likewise leads to platelet activation, perhaps more so than storage at 4 °C. Lastly, platelets constitutively possess a very large number of bioactive components that may elicit pro-inflammatory reactions when infused into a patient. This review aims to describe approaches that may be crucial to minimising side effects while optimising safety and quality. We suggest that platelet transfusion is complex, in part because of the complexity of the "material" itself: platelets are highly versatile cells and the transfusion process adds a myriad of variables that present many challenges for preserving basal platelet function and preventing dysfunctional activation of the platelets. The review also presents information showing--after years of exhaustive haemovigilance--that whole blood buffy coat pooled platelet components are extremely safe compared to the gold standard (i.e. apheresis platelet components), both in terms of acquired infections and of immunological/inflammatory hazards.

The clinical and biological impact of new pathogen inactivation technologies on platelet concentrates.

Since 1990, several techniques have been developed to photochemically inactivate pathogens in platelet concentrates, potentially leading to safer transfusion therapy. The three most common methods are amotosalen/UVA (INTERCEPT Blood System), riboflavin/UVA-UVB (MIRASOL PRT), and UVC (Theraflex-UV). We review the biology of pathogen inactivation methods, present their efficacy in reducing pathogens, discuss their impact on the functional aspects of treated platelets, and review clinical studies showing the clinical efficiency of the pathogen inactivation methods and their possible toxicity.

Immune-reactive soluble OX40 ligand, soluble CD40 ligand, and interleukin-27 are simultaneously oversecreted in platelet components associated with acute transfusion reactions.

BACKGROUND: Leukoreduction of labile blood components dramatically decreases the frequency of minor, intermediate, and severe adverse events (AEs), referred to as acute transfusion reactions (ATRs), especially after transfusion of platelet components (PCs). The pathophysiology of AEs may result from accumulation of soluble, secreted, platelet (PLT) factors with proinflammatory functions stored in PCs. Thus, several cosynergizing factors associated with PLT accumulation in PCs may contribute to clinically reported ATRs with inflammatory symptoms. STUDY DESIGN AND METHODS: We screened for 65 PLT-associated secretory products in PCs that caused ATRs and identified PLT molecules associated with ATRs and inflammation. A functional in vitro study using PC supernatants assayed on reporting immune cells was performed to indicate relevance. RESULTS: Among 10,600 apheresis PCs, 30 caused inflammatory ATRs and contained significantly elevated levels of soluble CD40 ligand (sCD40L), interleukin (IL)-27, and soluble OX40 ligand (sOX40L). Normal PLTs secreted IL-27 and sOX40L at bioactive concentrations upon thrombin stimulation and were up regulated in association with ATRs, similar to sCD40L. Other secreted products were identified but not investigated further as their positivity was not consistent. CONCLUSIONS: This study demonstrates the putative participation of PLT-derived sOX40L, IL-27, and sCD40L, which accumulate in PC supernatants, with inflammatory-type ATRs. Further studies are required to determine the clinical significance of these findings to forecast preventive measures whenever possible.

An active hemovigilance program characterizing the safety profile of 7483 transfusions with plasma components prepared with amotosalen and UVA photochemical treatment.

BACKGROUND: Photochemical pathogen inactivation treatment (PCT) of plasma components with amotosalen and UVA has been implemented in Europe. To establish a postapproval safety database, an active hemovigilance (HV) program utilizing an electronic data capture system (EDCS) was initiated. STUDY DESIGN AND METHODS: The response to transfusion was documented after each PCT-plasma transfusion. The primary outcome was the incidence of acute transfusion reactions (ATRs) within 24 hours of transfusion. An ATR was defined as an adverse event (AE) possibly related, probably related, or related to the PCT-plasma transfusion. For AEs, the following were collected: time of event after transfusion, clinical description, vital signs, clinical and laboratory test results, severity (Grade 0-4), seriousness, and causal relationship to transfusion of PCT-plasma. RESULTS: To date, 3232 patients (59.1% male) with a primary indication for plasma transfusion due to a hematology disorder (23.1%), surgery (32.4%), or a general medical condition (44.4%) received 7483 PCT-plasma transfusions (composed of 19,069 apheresis plasma components). The mean age of the patient population was 57.3 years (2884 adults, 160 children, and 188 infants). ATRs were reported for 8/7483 transfusions (0.11%; 95% confidence interval [CI], 0.03-0.19) and 8/3232 patients (0.25%; 95% CI, 0.08-0.42%). Five ATRs were of Grade 1 severity. The remaining three ATRs were classified as serious. No deaths or episodes of transfusion-related acute lung injury attributed to a PCT-plasma transfusion were reported. CONCLUSION: PCT-plasma transfusions were well tolerated in routine clinical use. The EDCS HV program facilitated collection and reporting of safety information on a real-time basis from multiple sites.

Low-dose urokinase in massive pulmonary embolism when standard thrombolysis is contraindicated.

When acute massive pulmonary embolism is life threatening, thrombolysis could be a therapeutic option. However, lysis may be contraindicated once the risk of bleeding is high. We report on two patients who have massive pulmonary emboli complicated by severe hypotension, justifying thrombolytic treatment. Nevertheless, recent surgery in the first patient and a fresh hemorrhagic duodenal ulcer in the second patient precluded thrombolytic treatment at the usual dosage. Therefore, prolonged lysis with low-dose urokinase (1,000 units/kg/h) was initiated. After a few hours, the patients became hemodynamically stable and inotrope/vasopressor doses could be reduced and stopped. No major bleeding was observed. Consequently, prolonged thrombolysis with low-dose urokinase could be an alternative approach to therapy in patients with massive pulmonary emboli when recommended thrombolytic dosages are contraindicated.

Universal adoption of pathogen inactivation of platelet components: impact on platelet and red blood cell component use.

BACKGROUND: Pathogen inactivation of platelet (PLT) components (INTERCEPT Blood System, Cerus Europe) was implemented into routine practice at a blood center supporting a tertiary care hospital. Utilization of platelet components (PCs) and red blood cell (RBC) components was analyzed for 3 years before and 3 years after introduction of pathogen inactivation to assess the impact of pathogen inactivation on component use. STUDY DESIGN AND METHODS: This was a retrospective analysis of prospectively collected data. An electronic database used in routine blood bank hemovigilance to monitor production and use of blood components was analyzed to assess clinical outcomes. RESULTS: Transfusion records were analyzed for 688 patients supported with conventional PCs and 795 patients supported with pathogen inactivation PCs. Additional analyses were conducted for intensively transfused hematology patients. Patient demographics (age category, sex, and diagnostic category) were not different in the two observation periods. For all patients, mean numbers of PC per patient were not different for conventional PCs and pathogen inactivation PCs (9.9 +/- 19.5 vs. 10.1 +/- 20.9, p = 0.88). Data for hematology patients (272 conventional PCs and 276 pathogen inactivation PCs) confirmed that days of PLT support were not different (31.6 +/- 42.6 vs. 33.1 +/- 47.9, p = 0.70) nor was total PLT dose (10(11)) per patient (87.3 +/- 115.4 vs. 88.1 +/- 111.6, p = 0.93). RBC use, for all patients and hematology patients, was not different in the two observation periods, either during periods of PLT support or outside periods of PLT transfusion support. CONCLUSION: Pathogen inactivation of PCs had no adverse impact on component use during a 3-year observation period of routine practice.

Release of immune modulation factors from platelet concentrates during storage after photochemical pathogen inactivation treatment.

BACKGROUND: Blood platelets (PLTs) are critical for hemostasis, and they contain biologically active constituents with the potential to modulate inflammatory responses. This study examined the effects of photochemical pathogen inactivation treatment (PCT) on the release of cytokines and/or chemokines from PLT components. STUDY DESIGN AND METHODS: Double-dose apheresis PLT components were suspended in plasma-PLT additive solution mixtures and divided into paired therapeutic units. One unit served as an untreated control and the other unit was treated with PCT. PLT concentrations, pH, and levels of cytokines and/or chemokines (CD62p, platelet-derived growth factor-AB, interleukin [IL]-8, soluble CD40 ligand [sCD40L], IL-1beta, and tumor necrosis factor alpha) were measured during 7 days of storage in PLT component supernatants and PLT lysates. RESULTS: PLT content, pH, and cytokine and/or chemokine content and release from PLT component prepared with PCT were not different (p > 0.05) from paired control components during storage. Levels of sCD40L, however, increased significantly during storage while decreasing in parallel within PLT lysates, although no differences were detected between paired PCT and control PLT component. CONCLUSION: PCT did not increase the release or secretion of PLT chemokines and/or cytokines over a 7-day period compared to conventional PLT component.

Coagulation function in fresh-frozen plasma prepared with two photochemical treatment methods: methylene blue and amotosalen.

BACKGROUND: Pathogen inactivation of plasma intended for transfusion is now the standard of care in Belgium. Two methods for treatment of single plasma units are available: amotosalen plus ultraviolet A light and methylene blue plus visible light. This study compared the quality and stability of plasma treated with these two methods. STUDY DESIGN AND METHODS: Plasma units made from a pool of two ABO-matched fresh apheresis units were photochemically treated with either amotosalen (PCT-FFP) or methylene blue (MB-FFP). A total of 12 paired samples were evaluated. Plasma coagulation function was assessed at three time points: immediately after treatment, after 30 days of frozen storage, and an additional 24 hours at 4 degrees C after thawing. Comparison between PCT-FFP and MB-FFP was assessed with the paired t test and a p value of less than 0.05 indicated statistical significance. RESULTS: Based on statistical analysis, mean levels of factor (F)II, FXII, FXIII, von Willebrand antigen, ADAMTS-13, D-dimers, and protein C were equivalent between PCT-FFP and MB-FFP for all three time points. PCT-FFP exhibited shorter mean prothrombin time, activated partial thromboplastin time (two time points), and thrombin time and higher mean levels of fibrinogen, FXI, and protein S than MB-FFP. Retention of FV, FVII, FVIII, FX, or von Willebrand factor:ristocetin cofactor in PCT-FFP was either equivalent to or higher than MB-FFP. MB-FFP contained higher mean levels of plasminogen, antithrombin, and plasmin inhibitor than PCT-FFP. Retention of F IX in MB-FFP was higher than PCT-FFP only after the 4 degrees C storage after thawing. CONCLUSION: There is adequate preservation of therapeutic coagulation factor activities in both PCT-FFP and MB-FFP. The overall coagulation factor levels and stability of PCT-FFP were better preserved than MB-FFP.