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Impact of Triton X-100 on alpha 2-antiplasmin (SERPINF2) activity in solvent/detergent-treated plasma

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Impact of Triton X-100 on alpha 2-antiplasmin (SERPINF2) activity in solvent/detergent-treated plasma
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  Impact of Triton X-100 on alpha 2-antiplasmin (SERPINF2) activityin solvent/detergent-treated plasma Thierry Burnouf   a, *, Hadi Alphonse Goubran  b , Miryana Radosevich  a ,Makram A. Sayed  c , George Gorgy  d , Magdy El-Ekiaby  d a  Research Department, Human Plasma Product Services, 18 rue Saint Jacques, 59800 Lille, France b  Faculty of Medicine, Cairo University, Cairo, Egypt  c  Fayoum University, Fayoum, Egypt  d Shabrawishi Hospital Blood Bank, Giza, Egypt  Received 15 January 2007; revised 1 March 2007; accepted 6 March 2007 Abstract Large-pool solvent/detergent (SD) plasma for transfusion exhibits reduced alpha 2-antiplasmin ( a 2-AP; SERPINF2) functional activity. Thereason for the loss of   a 2-AP has not been described and could be due to the SD incubation itself and/or to the processing steps implemented toremove the solvent and the detergent. We have studied  a 2-AP activity during six down-scale preparations of plasma virally-inactivated by 1%(v/v) TnBP combined with two different non-ionic detergents, either 1% Triton X-100 or 1% Triton X-45, at 31   C for 4 h. The SD-treatedplasmas were then extracted with 7.5% (v/v) soybean oil, centrifuged at 3800  g  for 30 min, and subjected to hydrophobic interaction chro-matography (HIC) to remove the SD agents. Control runs without TnBP and Triton were performed to evidence possible impacts of each processstep on  a 2-AP activity. TnBP, Triton X-100, and Triton X-45 were measured at all stages of the processes to evaluate potential interferences withthe  a 2-AP assay. Alpha 2-AP activity was about 10% that of starting plasma after 1% TnBP-1% Triton X-100 incubation and about 50% after oilextractions, centrifugation, and HIC. By contrast about 73% of the antiplasmin activity was found after the incubation with 1% TnBP and 1%Triton X-45, 88% after removal of the SD agents by oil extractions, 90% after centrifugation and 92% after HIC. The control runs performedwithout SD agents showed that the process steps did not affect the  a 2-AP activity. In conclusion, the agent altering  a 2-AP activity in SD-plasmais Triton X-100. The choice of detergents for the SD viral inactivation of therapeutic plasma fractions used in patients at risk of fibrinolysisshould consider the impact on  a 2-AP activity.   2007 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved.  Keywords:  Alpha 2-antiplasmin; SERPINF2; Solvent/detergent; Plasma; Virus 1. Introduction Solvent/detergent (SD) is the main viral inactivation treat-ment of many plasma products on the market, includingplasma for transfusion [1,2]. The procedure generally consistsin incubating protein solutions for 1 e 6 h with 0.3 e 1% of anorganic solvent, tri(n-butyl) phosphate (TnBP), and of one orseveral detergents, generally Tween-80, Triton X-100, orsodium deoxycholate [3,4]. The treatment preserves the func-tional activities of a wide range of coagulation factors andother labile plasma proteins with an excellent record of viru-cidal efficiency for the pathogenic lipid-enveloped blood-borne viruses [5]. Still, large-pool SD-treated plasma fortransfusion (LP/SD) subjected to 1%TnBP-1% Triton X-100incubation, oil extraction, clarification, filtration, and hydro-phobic interaction chromatography (HIC) [1,6], has low alpha2-antiplasmin ( a 2-AP or SERPINF2) functional activity [7 e 10]. The loss of   a 2-AP activity may reflect a conversion of  * Corresponding author. Tel.:  þ 33 3 28 38 19 30; fax:  þ 33 3 20 42 19 53.  E-mail address:  tburnou@attglobal.net (T. Burnouf).1045-1056/07/$32.00    2007 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.biologicals.2007.03.002Biologicals 35 (2007) 349 e 353www.elsevier.com/locate/biologicals  the native conformation of the protein to a latent or polymer-ized inactive form [11]. Recently, we have developed a mini-pool SD-plasma process (MP/SD) that uses 1% TnBP and 1%Triton X-45, followed by oil extractions only. Interestingly,this MP/SD-plasma has normal  a 2-AP activity [12].One should detect the reason why  a 2-AP activity is low inLP/SD-plasma since in some clinical situations, such as occurduring liver transplantation, this serine protease inhibitor (ser-pin) is important to regulate acquired fibrinolytic states associ-ated with  a 2-AP consumption [13]. To investigate the reasonfor the loss of   a 2-AP in LP/SD-plasma, we have designedan experimental down-scale study where batches of the samepools of plasma were subjected in parallel to the LP/SD andMP/SD treatments. Samples were taken at all stages of theprocess to determine the functional activity of   a 2-AP. 2. Materials and methods  2.1. Preparation of plasma Apheresis plasma was collected and processed at the Shab-rawishi Hospital blood bank (Giza, Cairo, Egypt) from regularvolunteer plasma donors. Eligibility of the donor to donatewas determined following local regulations and standardSOPs used at this ISO 9000 certified collection centre. Plasmawas frozen at   20   C or colder within 4 h of collection andstored for less than 3 months prior to processing [12]. Plasmadonations were thawed in their collection bags in a temperaturecontrolled water-bath at 30  1   C. For each experiment, twounits of plasmas were pooled together (500 ml) in a transferbag (JMS Singapore PTE Ltd, Singapore), mixed for 5 min,then split into two equal units that were transferred into indi-vidual polyvinyl chloride JMS transfusion bags.  2.2. Down-scaled SD treatment of plasma 2.2.1. LP/SD process One of the plasma bags from each pool was incubated with1% (v/v) TnBP (Prolabo, VWR, Fontenay-sous-bois, France)and 1% (v/v) Triton X-100 (Merck, Darmstadt, Germany) at31  0.5   C for 4 h, under constant gentle stirring at 150 rpmusing a shaker-incubator (Lab Therm LT-W, Ku¨hner, Switzer-land). The plasma e SD mixture was then transferred into a sec-ondtransfusionbagand7.5%(v/v;finalconcentration)soybeanoil (Sigma-Aldrich Chimie SARL, Lyon, France) was added.After agitation on the shaker incubator (150 rpm) and decanta-tion for 30 min at20 e 25   C,the plasma layer was recovered bygravityintoasecondbagandtheoillayerwasdiscarded.Theoilextraction was repeated a second time to ensure sufficientremoval of TnBP (which is soluble in oil) and avoid or reducepotentialinterferencesonthe a 2-APassay.Plasmawasclarifiedbycentrifugationat3800  g for30 minat4   C(Jouan,St-Her-blain, France). Aliquots (8 ml) of the plasma were then sub- jected to HIC in Poly-Prep chromatography columns (BioRad,Hercules, CA) containing 1.5 g of preparative C18, 125 A˚,55 e 105  m m bulk material (Waters Corp., Milford, MA). Theplasma and the C18 material were mixed on a Baxter (BaxterHealthcare Corp., Deerfield, IL) shaker for 20 min at 20 e 25   C. Plasma was then recovered in the breakthrough fractionfrom the column.  2.2.2. MP/SD process The other plasma bag of each pool was processed in paral-lel and by the same operator. Plasma was treated by 1% TnBPand 1% (v/v) Triton X-45 (Sigma Chemical, St. Louis, MO) at31   C for 4 h. It was then subjected to two soybean extrac-tions, centrifugation and C18-HIC, as described for theLP/SD-plasma.  2.2.3. Control experiments Experimental controls were performed to evaluate theimpact of the various process steps on  a 2-AP activity. Aplasma pool was divided into two batches. One was incubatedin the presence of TnBP e Triton X-100 at 31   C for 4 h, theother was incubated at 31   C for 4 h without the SD agents.Both were then processed in parallel and by the same operatorand subjected to soybean oil extractions, centrifugation, andC18-HIC, as described above.  2.2.4. Sampling Multiple 1-ml plasma samples were taken at all steps of theprocesses, collected in closed plastic tubes (Becton Dickinson,Franklin Lakes, NJ), kept on the bench at 20 e 25   C andfrozen at   80   C at the end of each run. Prior to functionalassays, plasma samples were subjected to one freeze/thawcycle, since this is done also with the product that is transfusedinto the patient.  2.3. Alpha 2-antiplasmin kinetic amidolytic assay Samples were thawed at 37   C and analyzed within 2 h.The  a 2-AP activity of standard human plasma (Dade-Behring,Newark, NJ), the starting plasma pools, and the SD-plasmafractions was determined by a kinetic amidolytic assay usingBerichrom  a 2 -antiplasmin (Dade-Behring) as described bythe manufacturer. Twenty microliters of various dilutions of plasma were mixed with 1000  m l of plasmin at 0.1 CTAunits/ml (Committee for Thrombolytic Agents) reconstitutedin 100 mmol/L potassium phosphate containing 9 g/L sodiumchloride, and 250 g/L glycerol, pH 7.5. After incubation for1 min at 37   C, 100  m l of the D-Norvalyl-cyclohexylalanyl-lysil-  p -nitroanilide substrate (Dade-Behring) was added andsamples were mixed carefully. The optical density at 405 nmwas measured within 30 s using a Spinlab spectrophotometer(Spinreact S.A., Sant Esteve de Bas, Girona, Spain) and there-after at exact 60 and 120 s intervals at 37   C to calculate the D OD/min and determine the  a 2-AP inhibitory activity.  2.4. TnBP and Triton assays Residual TnBP and Triton X-45 and X-100 were deter-mined from 1 ml plasma aliquots and analyzed by gas chroma-tography and high performance liquid chromatography, asdescribed before [12,14]. 350  T. Burnouf et al. / Biologicals 35 (2007) 349 e  353   2.5. Statistical analysis Statistical comparisons were made with a two-tailed pairedStudent’s  t  -test. A  p  value of less than 0.05 was used to assessthe significance of the differences between the plasmas at dif-ferent steps of the procedure. Values are presented as NS( < 0.05),  < 0.01, or  < 0.001. Precise  p  values are indicatedwhen close to 0.05. 3. Results Fig. 1 shows the  a 2-AP activity at the various stages of thepreparation of 6 plasma batches subjected to the TnBP e TritonX-100 (A) and the TnBP e Triton X-45 (B) processes. After theTnBP e Triton X-100 incubation, the  a 2-AP activity was aboutone tenth (mean ¼ 12%;  p < 0.001) that of the srcinal plasma(mean ¼ 107%). It increased to about 50% that of startingplasma after oil extractions (mean ¼ 51%;  p < 0.001), centri-fugation (mean ¼ 46%;  p < 0.001), and HIC (mean ¼ 52%;  p < 0.001). During the TnBP e Triton X-45 process, mean a 2-AP activity after the viral inactivation step was 78.6%(  p < 0.01), then increased after oil extractions (mean ¼ 95%;  p ¼ 0.041), centrifugation (mean ¼ 97%;  p ¼ 0.044) and HIC(mean ¼ 99%,  p ¼ 0.027), as the SD chemicals were removed.Data of a control experiment are shown in Fig. 2. Whena plasma pool was subjected to 4 h of incubation at 31   Cwith 1% TnBP-1% Triton X-100, then to oil extractions, cen-trifugation and HIC (A), the evolution of   a 2-AP activity dur-ing the various process steps was similar to that observedbefore (Fig. 1). When the same plasma was subjected to incu-bation for 4 h at 31   C (without TnBP nor Triton X-100), fol-lowed by oil extractions, centrifugation, and C18-HIC (B),there was essentially no loss of   a 2-AP activity.In the TnBP e Triton X-100 process, residual TnBP inplasma was between 20 and 70 ppm after 2 oil extractionsand centrifugation, and less than 10 ppm after C18-HIC, andTriton X-100 was still high (400 e 600 ppm) after two oil ex-tractions and centrifugation, and decreased (5 e 15 ppm) afterthe C18-HIC (not shown). In the TnBP e Triton X-45 process,residual TnBP and Triton X-45 content of plasma was 50 e 100 ppm after two oil extractions and centrifugation, and < 10 ppm after C18-HIC (not shown). These values are consis-tent with the observation that both TnBP and Triton X-45 areremoved by oil [12], whereas Triton X-100, which is poorlysoluble in oil, must be removed by HIC [1]. 4. Discussion The present data confirm that  a 2-AP activity is well pre-served in plasma incubated with the TnBP e Triton X-45combination, as observed during the development of the MP/ SD-plasma process that comprises SD treatment and threeoil extractions [12]. By contrast, the  a 2-AP activity at theend of the TnBP e Triton X-100 process was only 50% (0.4 e 0.6 IU/ml) of the starting plasma. This is consistent with ca.50 e 70% lower levels reported on commercial LP/SD-plasmasmanufactured in the USA and Europe [7,9,15 e 19]. Mast et al.[11], using like in our experiments an antiplasmin kinetic as-say, reported a total lack of antiplasmin activity in commercialSD-plasma batches manufactured in the USA. These authorsobserved that the TnBP e Triton X-100 treatment leads  a 2-AP to adopt a latent or polymerized conformation. They alsoobserved that the antiplasmin activity in about 10% of theSD-plasma aliquots subjected to a freeze e thaw process pre-cipitated completely out of solutions as small aggregates.These aggregates were thought to be removed by the sterile fil-tration process during the manufacture of LP/SD-plasma and,according to Mast et al. [11], to possibly contribute to lowantiplasmin activity. Therefore, the low, but slightly higherantiplasmin activity we found in our final LP/SD-plasma 020406080100120Start SD Oil Centrifugation HIC AB    I  n   h   i   b   i   t  o  r  y  a  c   t   i  v   i   t  y ,   % Fig. 1. Alpha 2-antiplasmin activity (%) in 6 series of experiments where thestarting plasmas were treated in parallel by the 1% tri(n-butyl) phosphate-1%Triton X-100 (A) or by the 1% tri(n-butyl) phosphate-1% Triton X-45 viralinactivation processes (B). Activity was measured in the starting plasma; afterSDtreatment;afteroilextractions;aftercentrifugation;andafterC18hydropho-bicinteractionchromatography. HIC,hydrophobic interaction chromatography. 020406080100120Start Incubation Oil Centrifugation HIC AB    I  n   h   i   b   i   t  o  r  y  a  c   t   i  v   i   t  y   %  Fig. 2. Alpha 2-antiplasmin activity (%) in one batch of plasma incubated with1% tri(n-butyl) phosphati-1% Triton X-100 at 31   C for 4 h, then subjected tooil extractions, centrifugation, and C18 hydrophobic interaction chromatogra-phy (A). The same plasma (control) was subjected to the same process stepapart that tri(n-butyl) phosphate and Triton X-100 were not added for the31   C incubation (B). Activity was measured in the starting plasma; after31   C incubation; after oil extractions; after centrifugation; and after C18hydrophobic interaction chromatography. HIC, hydrophobic interactionchromatography.351 T. Burnouf et al. / Biologicals 35 (2007) 349 e  353  may be due to the fact that our down-scale process did not in-clude steps like sterile filtration, nor exposed the protein solu-tions to long incubation and operational times which maycontribute to additional loss of antiplasmin activity at indus-trial scale. Another difference in our antiplasmin assay is theabsence of pre-treatment of the plasma samples with methyl-amine, a compound that quenches the activity of alpha 2-mac-roglobulin ( a 2-MG) activity [20], another plasmin inhibitor[11]. Although the incubation time of the plasma samplesand plasmin was short (1 min) and although we did not usean end-point assay to limit interferences with slower actingplasmin inhibitors, one cannot exclude that alpha 2-macro-globulin, alpha 1-antitrypsin ( a 1-AT), C1-inhibitor (C1-Inh),or inter-alpha-trypsin-inhibitor may thus contribute for the re-sidual antiplasmin activity measured in our LP/SD-plasma[11].Mast et al. already suspected a role of detergents in the in-hibition of   a 2-AP in SD-plasma produced in the USA [11].Previous analyses have shown that  a 2-AP activity is unalteredin plasma virally-inactivated by 2% TnBP alone [12]. Our datanow provide evidence that the ca. 50% alteration of the anti-plasmin activity in our experimental LP/SD-plasma is linkedto the use of Triton X-100 during the SD treatment. Our exper-iments excluded a possible interference of Triton X-100 withthe functional  a 2-AP assay performed on the final SD plasmasamples since the C18 step was found to remove efficientlythis detergent down to trace levels, as already established[1]. By contrast, the even lower antiplasmin activity (10 e 20% of the starting plasma) found in assessing the samplestaken right after SD incubation may be due to an interferencecaused by having the SD reagents present during the assayprocedure. For instance, we have already observed a partial in-hibition of in vitro global plasma coagulation test, such as PTand aPTT, when assessing plasma samples containing SD re-agents [12]. Alternatively, we cannot exclude that the increasein antiplasmin activity observed after oil extraction may reflecta partial reversal of   a 2-AP, or the slower acting antiplasminproteins, to an active conformation. We also verified that thevarious process steps, in particular the C18 chromatography,do not affect  a 2-AP activity, since essentially full activitywas preserved during the control runs performed without SDaddition. Our experiments cannot exclude the possibility thatTnBP may contribute to enhance the inactivation effect of  a 2-AP by Triton X-100.Tritons X-45 and X-100 are octylphenoxy polyoxyethyleneethers which differ only in the number of the ethylene oxidegroups and thus in their average molecular mass. Triton X-45, with five ethylene oxide groups, has a total chain lengthof 18 carbon atoms, whereas Triton X-100 with nine to tenethylene oxide groups has a chain length of 26 e 28 carbonatoms. The influence of Triton X-100, but not Triton X-45,on  a 2-AP activity is intriguing, and suggests a differentialimpact of the two non-ionic detergents on the conformationof this serpin. Plasma inhibitory serpins of known clinicalrelevance include also  a 1-AT (SERPINA1), antithrombin(AT; SERPINC1), heparin cofactor II (SERPIND1), plasmino-gen activator inhibitor (PAI-1; SERPINE1), and C1-Inh(SERPING1) [21]. Inhibitory serpins are known to behave as’’suicide’’ inhibitors that go through a unique and extensiveconformational change to inactivate proteases [22 e 25]. Onehallmark of inhibitory serpins structure is the reactive centreloop (RCL), a protein motif with a scissile bond between res-idues P1 and P1 0 which is cleaved by target proteases. In theactive conformation, a large part of the RCL is exposed tothe ambient medium, facilitating the binding to the target pro-tease. By contrast, in the latent inactive conformation, or aftercleavage by protease, the RCL undergoes partial or completeinsertion into ‘‘A’’  b -sheet of the molecule. Serpins can alsopolymerize through insertion of the RCL of one moleculeinto the ‘‘A’’  b -sheet of another, leading to the formation of inactive stable loop-sheet polymers that do not readily convertback to the active conformation [26]. There is now increasingevidence that some detergents may induce changes in the con-formation of purified serpins to a latent or polymerized form,leading to a loss of their inhibitory activity. For instance, PAI-1 converts from the active to the latent conformation when in-cubated with 0.01% or 0.2% Triton-X-100 or sodium dodecylsulfate [27], and its inhibitory activity is reduced over 20-foldat 0   C, but less than 2-fold at 37   C, by Triton X-100 [28].The PAI-1 activity decreases also in the presence of TritonN-101, 0.004% Triton X-15, and 0.6 e 0.8% 2-phenoxyethanol,but not of 1% PEG-400 and PEG-600 or 1% Tween-80 at37   C [29]. Heat-induced polymerization of   a 1-AT is en-hanced by 0.025% Nonidet P-40 [26], and polymerization of AT increases in the presence of 0.6% deoxycholate [30].Therefore, Triton X-100 appears to be the major contributorof the decrease of   a 2-AP activity during SD treatment of plasma. The impact of this detergent on other plasma serpinsof therapeutic value may vary. The anti-elastase activity of  a 1-AT has been found to decrease by 50% in TnBP e TritonX-100 treated plasma manufactured in the USA [11,19], andby about 25% in another SD-plasma produced in Europe[18,19,31 e 33]. The impact of Triton X-45 on anti-elastaseactivity of   a 1-AT is not known yet. Alpha 1-AT concentrates,recently developed for augmentation therapy in deficientpatients with lung emphysema, are virally-inactivated usingTnBP combined with Tween-80 [34,35] or sodium cholate[36], suggesting that these two detergents do not alter itsanti-elastase function. ATand C1-Inh activity is within normalvalues in plasmas treated by both TnBP e Triton X-100 [11] orTnBP e Triton X-45 [12]. In conclusion, SD treatment is a viralinactivation treatment with well established efficacy and safetyand remains a backbone of the viral safety of biologicals.However, detergents used for the SD viral inactivation of  a 2-AP-containing-therapeutic fractions which may be infusedin patients with fibrinolytic risks [13,15] should be selectedcarefully. Acknowledgments Thanks are expressed to Dr. Amr Shabrawishi (Dr. Shabra-wishi Hospital, Cairo, Egypt) for providing the necessary as-sistance from the blood center, including manpower and 352  T. Burnouf et al. / Biologicals 35 (2007) 349 e  353  laboratory space. The dedicated technical assistance from Ms.Nermin Nabil and Mr. Khaled Fathi is acknowledged. 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Transfusion 2003;43:1176 e 8 [author reply 78].[33] Salge-Bartels U, Breitner-Ruddock S, Hunfeld A, Seitz R, Heiden M.Are quality differences responsible for different adverse reactionsreported for SD-plasma from USA and Europe? Transfus Med 2006;16:266 e 75.[34] Kolarich D, Turecek PL, Weber A, Mitterer A, Graninger M,Matthiessen P, et al. Biochemical, molecular characterization, and glyco-proteomic analyses of alpha(1)-proteinase inhibitor products used forreplacement therapy. Transfusion 2006;46:1959 e 77.[35] Doyle JW, Johnson GL, Eshhar N, Hammond D. The use of rabbit poly-clonal antibodies to assess neoantigenicity following viral reduction of analpha-1-proteinase inhibitor preparation. Biologicals 2006;34:199 e 207.[36] Chen SX, Hammond DJ, Lang JM, Lebing WR. Purification of alpha 1proteinase inhibitor from human plasma fraction IV-1 by ion exchangechromatography. Vox Sang 1998;74:232 e 41.353 T. Burnouf et al. / Biologicals 35 (2007) 349 e  353
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SAVE OUR EARTH

We need your sign to support Project to invent "SMART AND CONTROLLABLE REFLECTIVE BALLOONS" to cover the Sun and Save Our Earth.

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