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`Transfusion.
`V. 54, no. 6 (June 2014)
`General Collection
`W1 TR228W
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`- 547W.mane 2014
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`Ak.\«_
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`“Wm" MEDICINE
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`IIIIIIJJJIIIIIIIJJIJJJIJIIIIIIIII
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`Page 1 of 14
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`CSL EXHIBIT 1048
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`PROPERTY
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`mNA'l'lORJ/RJE
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`Page 1 of 14
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`CSL EXHIBIT 1048
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`
`
`
`Table of Contents
`
`EDITORIALS
`M47 Transfusion CME hits 50
`A.E Eller and RM. Nuts
`
`”48 'Do you catch my drift?”
`TI Harmon
`
`1450 Can a comparative database study help to develop an effective risk index
`system?
`]. Dalton and E Famg
`
`5. Sapatnelmr and HI. Figueroa
`
`HOWDOI...?
`
`1452 How do we use molecular red blood cell antigen typing to supplement
`pretrnnafuslon testing?
`
`Our cover was penned by Jessica Nagy,
`an artist and writer best known [or her
`mititmmg'fofi?’ Indexeruhttpt/l
`
`TFlANSFUSION MEDICINE ILLUSTRATED
`1459
`Schistocytes
`I. Jz‘ Lesesua, O. Femmlemt. and G. Zinl
`
`
`Disclaimer
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`TRANSFUSION Volume 54. June 2014
`
`This materialwas copied
`attire NLM and maybe
`r..t.t... Irrf--...i-h-l -.. .
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`Page 2 of 14
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`

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`TABLE OF CONTENTS (Continued)
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`BLOOD MANAGEMENT
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`[Culglccal Predictors of postoperative hemoglobin drift
`1460
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`d rGilt, GJ. Whitman, W.]. Sal/age, RM. N055. and SM. Frank
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`$.48 ’Elcztmg blood loss and transfusion requirement in patients undergoing surgery for museuloskeletal tumors
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`ompmn, D. May, RE Choong, M. Tacey, D. Liew, and M.I:‘ Cole-Sinclair
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`69
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`IMMUNOHEMATOLOGY
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`35:35:10.“ Of a single-chain human leukocyte antigen-DRAIDRB3*0 1:01 molecule and differential binding of a monoclonal
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`F E 30 Y 1n the presence of specifically bound human platelet antigen-la peptide
`- Ouwmans, PA. Smetlzurst, Sf: Garner, W.H. Ouwehand, and S.L. Morle
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`A new bead-based
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`human platelet antigen antibodies detection assay versus the monoclonal antibody immobilization of
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`P attlet antigens assay
`L. Porcelijn, E. Huiskes. I. Comijs- van Osselen, A. Chhatta, V. Rathore, M. Meyers, and M. de Haas
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`1486
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`TRANSPLANTATION AND CELLULAR ENGINEERING
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`l 493
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`Sfiperlor'ity of preemptive donor lymphocyte infusion based on minimal residual disease in acute leukemia patients after
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`a Ogeneic hematopoietic stem cell transplantation
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`Y Tan. K. Du, Y. Luv, 1. Ski, L. Can, Y. Zheng. G. Zheng, Y. Zhao, X. Ye, Z. Cai, and [1. Huang
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`EV§lufltion of peripheral blood stem cell quality in products transported by traditional courier or commercial overnight
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`Sh'PPlng services
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`A. Howard, 12 Chitphakdiihai, EK. Waller, w. Harris, H. Rosenthal, w. Nelson, N. Majhailv W NaWWr 5' waldwgel' 1‘ Lisy,
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`1. Uecker, ]. Miller, and SR. Spellman
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`Fryopreserved stem cell products containing dimethyl sulfoxide lead to activation of the coagulation system without any
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`Impact on cngraftment
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`A. HOlbrO, L. Graf, M. Topalidou, C. Hitcher, ].R. Pasxweg, and DA. Tsakiris
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`The natural killcr—activating receptor; NKGZD, on CD3+CD8+ T cells plays a critical role in identifying and killing
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`autologous myeloma cells
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`L. Talebian, D./l. Fischer, 1. Wu, ].Y. Channon, C.L. Sentman, M.S. Ernstoff, and KR. Meehan
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`TRANSFUSION PRACTICE
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`1522
`Continuing Medical Education Program in Ti‘ansfilsion
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`A}? Eder
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`The impact of platelet additive solution apheresis platelets on allergic transfusion reactions and corrected
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`count increment
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`A.A.R. Tobinn, AK. Fuller, K. Uglik, D.I. Tisclz, RD. Barge, R.I. Benjamin, PM. N653, and KB. King
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`Periopcrative and transfusion outcomes in women undergoing cesarean hysterectomy for abnormal placentation
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`K1: Brookfield, L. 1‘ Goodnough, DJ. Lyell, and A]. Bunuick
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`1,113 I{Se of an objective structured clinical examination to assess internal medicine residents’ transfusion knowledge
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`L. Saldenberg and D. Pugh
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`Deferasirox improves hematologic and hepatic function with effective reduction of serum ferritin and liver iron
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`concentration in transfusional iron overload patients with myelodysplastic syndrome or aplastic anemia
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`].-W. Cl'zeong, H.-]. Kim, K.-H. Lee, S. -S. Yuan, ].H. Lee, H.-S. Park, H.Y. Kim, H. Shim, C.-M. Seong, C.S. Kim, J. Chung, M.5. Hyun,
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`D.-Y. Io, C. W. lung, S.K. Solm, H. .1. Ynon, as. Kim, Y.-D. I00, c. -Y. Park, and Y.H. Min for the Korean Society OfHematology Aw“?
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`Myeloid Leukemia/Myeludysplaszic Syndrome Working Party
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`Pharmacokinetics of plasma-derived Cl—esterase inhibitor after subcutaneous versus intravenous administration in
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`subjects with mild or moderate hereditary angioedema: the PASSION study
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`I. Mtlrtinez-Saguer, M. Cictmii, C. Suffritti, E. Rusicke. E. Aygiiren-Piirsiin, H. Stall, 73 Rossmanith, A. Feussnel; U. Kalzncz,
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`and W. Kreuz
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`BLOOD COMPONENTS
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`1562
`In vitro properties of platelets stored in a small container for pediatric transfusion
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`N. ’Iynngzird, M. Trinks, and G. Berlin
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`Isoprostane and isofuran lipid mediators accumulate in stored red blood cells and influence platelet function in vitro
`S.L. Spinelli, KL. Lanmm, AB. Casey, A. Croasdell, TM. Curran, ICE Henrichs, S.I. Pollock, GA. Milne, MA. Refacn, C.W. FlallClS,
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`RP Phipps, and N. Blumberg
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`Comparison of antibody titers in donor specimens and associated AS-l leukoreduced donor units
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`EA. Hill and BJ. Bryant
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`Quality of red blood cells washed using an automated cell processor with and without irradiation
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`AL. Hansen, ’ER. Turner, Q.-L. Yi, and 1.12 Acker
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`The effects of rejuvenation during hypothermic storage on red blood cell membrane remodeling
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`].D.R. Km‘aclz, R. Almizrat], B. Bicalho, ].I?Acicer, and ].L. Holovnti
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`Page 3 of 14
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`This mate-rialwasropied
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`Volume 54, June 2014 TRANSFUSION
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`Page 3 of 14
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`

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`TABLE OF CONTENTS (Continued)
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`1504
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`Leukoreduced whole blood—derived platelets treated with antimicrobial peptides maintain in vitro properties during
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`storage
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`M. Bosch—Marcé, S. Seethuruman, I. Kuitz, K.V.K. Mohan, 8.]. Wagner, and CD. Aireyu
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`1610 Determination of thromboelastographic responsiveness in stored single-donor platelet concentrates
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`1.]. Boniekoe, PE van der Meer, and D. de Korie
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`BLOOD GROUP GENOMICS
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`FINA-3 gene frequencies in Brazilians and a new polymerase chain reaction—restriction fragment length polymorphism
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`method for HNA-3a/3b genotyping
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`LB, Lopes, W Baleotti Jr, RB. Suzuki, A. Fabron Jr, AK. Chiba. 1.133. Vieim-Filho, B. tie Souza Castro, AM. Kunioshi, and
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`1.0. Bordin
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`HEMAPHERESIS
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`1622 Unstimulated Ieukapheresis in patients and donors: comparison of two apheresis systems
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`M. Schulz, H. Bialleck, K. Thorausch, G. Bug, U. Diinzinger, L'. Seifried, and H. Bo‘nig
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`Severe pertussis and hyperleukocytosis: is it time to change for exchange?
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`A. Kuperman, Y. Hoffmann. D. Glikman, H. Dabbah, and Z. Zonis
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`1652
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`DONOR INFECTIOUS DISEASE TESTING
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`Evaluation of a rapid colorimetric assay for detection of bacterial contamination in apheresis and pooled random dono
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`platelet tmits
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`WA. Heaton. GE. Good, R. Galloway-Hashim, RA. Yomiaviun, and MR. Jacobs
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`A novel approach for rapid detection of bacterially contaminated platelet concentrates via sensitive measurement of
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`microbial DNA polymerase activity
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`D.R. Zweitzig, N.M. Riccardella, ].M. Pester, R. Jeanmonod, MJ. Kopnitsky, and S.M. O'Hara
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`Estimating window period blood donations for human immunodeficiency virus Type 1, hepatitisC virus, and hepatitis B
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`virus by nucleic acid amplification testing in Southern Pakistan
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`B. Moiz, T Manner, U. Shaikh, S. Adil, N. Ali, E Mahar, N. Shamsuddin, and M. Khurshid
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`BLOOD DONORS AND BLOOD COLLECTION
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`1660 Acute hepatitis B in blood donors over a 5-year period in England and North Wales: who is getting infected?
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`GK. Rosenberg. S. Lattimorc, S.R. Bruilsford, P.E. Hewitt, KI. Tettmur, AD. Kitchen, 5. Ijaz, and RS. Tecider
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`TRANSFUSION COMPLICATIONS
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`Incidence of acute transfusion reactions to platelets in hospitalized pediatric patients based on the US hemoyigflance
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`reporting system
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`N. Li, L. Williams, Z. Zhou, and Y.-Y. Wu
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`1666
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`1673 Adoptable strategic approaches to improve outcomes of allo
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`unrelated donors
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`S.K. Sohn und].H. Moon
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`LETTERS TO THE EDITOR
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`Fresh-frozen plasma should not be given to nonbleeding premature infants with “abnormal" coagulation tests
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`AK. Keir and S. Stanworih
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`In reply:
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`C. Dani
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`Parvovirus B19 Genotype 2 in blood donations
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`AM. Eis-Hiihihger, U. Rebel; A. Edelmcmn, U. Kalus, and 1. Hofmarm
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`1685 Does transfusion of salvaged blood products have a significant impact on coagulation?
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`B. Ferro, 1. Frugiuele, C. Faldini, and S. Bonarelli
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`OBITUARY
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`gcncic peripheral blood stem cell transplantations from
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`REVIEW
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`1681
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`1661
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`1682
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`1686 George Garratty, PhD, FIBMS, FRCPath, 1935-2014
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`L.D. Petz
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`ERRATUM
`1688
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`TRANSFUSION Volume 54. June 2014
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`’I‘IIANSFUSION PRACTICE
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`Pharmacokinetics of plasma-derived Cl-esterase inhibitor after
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`subcutaneous versus intravenous administration in subjects with
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`mild or moderate hereditary angioedema: the PASSION study
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`Inmaculada Martinez-Saguer,’ Marco Cicardz'f Chiara Sufirirtifi Eva Rusz’cke,3
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`Emel Aygorerz-Pursiin,3 Hildegard Stall/1 Tanja Rossmanithf Annette Feussner,“ Uwe Kalina,‘i and
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`Wolfluzrt Kreuz’
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`BACKGROUND: Hereditary angloedema (HAE) is a
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`rare disease caused by 01 —esterase inhibitor (Ci—INH)
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`deficiency, characterized by periodic attacks of acute
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`edema affecting subcutaneous (SC) tissues and
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`mucous membranes. Human C1-INH concentrate given
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`intravenously (IV) is effective and safe, but venous
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`access may be difficult. We compared SC and IV
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`administration of human pasteurized C1-lNH concen-
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`trate with respect to pharmacokinetics, pharmacody-
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`namics, and safety.
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`STUDY DESIGN AND METHODS: This was a prospec—
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`tive, randomized, open-label, crossover study. Twenty-
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`four subjects with mild or moderate HAE were randomly
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`assigned during an attack-free interval to receive 1000
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`units of human pasteurized CI-INH concentrate IV or
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`SC. Plasma levels of C1-INH activity and antigen, C4
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`antigen, cleaved high-molecular-weight kininogen
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`(clHK), and Ct-INH antibodies were measured.
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`RESULTS: The mean relative bioavailability of func-
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`tional C1—lNH after SC administration was 39.7%.
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`Maximum C1-lNH activity alter SC administration
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`occurred within 48 hours and persisted longer than after
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`IV administration. C4 antigen levels increased and clHK
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`levels decreased after IV and SC administration, indi-
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`cating the pharmacodynamic action of C1—INH. The
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`mean half-life of functional Ct-INH was 62 hours after
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`IV administration and 120 hours after SC administration
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`(p : 0.0595). Ci-INH concentrate was safe and well
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`tolerated when administered via both routes. As
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`expected, SC administration resulted in a higher inci-
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`dence of injection site reactions, all of which were mild.
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`CONCLUSION: With a relative bioavailability of 39.7%,
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`SC administration of human pasteurized C1-INH yields
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`potentially clinically relevant and sustained plasma
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`levels of Ct-INH and is safe and well tolerated.
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`ABBREVIATIONS: Allts) : adverse eventts); AUC : area under
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`the curve; Cl~INH : Cl-esterase inhibitor; CL : total Clearance;
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`clI-IK = cleaved high-molecular-weight kininogen;
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`Cm, = maximum concentration; HAE : hereditary angioedcrna;
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`HK = high-molecular-weight kininogen; MRT = mean residence
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`time; SC = subcutaneous; t, ,2 : terminal elimination half—life;
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`TmX : time of maximum concentration; V2 = volume of
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`distribution at the terminal phase.a
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`From the lHemophilia Center Rhine Main GmbII,
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`Morfelden-Walldorf, Germany; the 2Department of Clinical
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`Science “Luigi Sacco," University of Milan, Milan, Italy;
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`the 3Department of Pediatric Hematology, Oncology,
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`Hemostaseology and Cardiology, University Hospital Frankfurt,
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`Frankfurt am Main, Germany; the ‘Technical Solutions Center,
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`Siemens Healthcare Diagnostics GmbH. Eschborn, Germany;
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`the 5Clinical 1er Center Rhine-Main [KSRM], University
`Hospital Frankfurt, Frankfurt am Main, Germany; and GCSL
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`Behring GmbIrI, Marburg, Germany.
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`Address reprint requests to: Inmaculada Martinez-Saguer,
`Hemophilia Center Ithine Main GmbH, Hessenring 1321, 64546
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`Morfelden-Walldorf, Germany; e—mail:
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`Inmaculada.Martinez@hzrm.de.
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`This study was supported financially by CSL Behring
`GmbH, Marburg, Germany.
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`ClinicalTrials.gov Identifier: NCT00748202.
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`Received for publication lune 7, 2013; revision received
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`October 23, 2013, and accepted October 23, 2013.
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`doi: 10.1111/trf.12501
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`© 2013 The Authors. Transfusion published by Wiley
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`Periodicals, Inc. on behalf of AABB.
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`This is an open access article under the terms of the
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`Creative Commons Attributi0n-NonCommcrcial-NoI)erivs
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`License, which permits use and distribution in any medium,
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`provided the original work is properly cited, the use is
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`non-commercial and no modifications or adaptations are
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`made.
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`TRANSFUSION 2014;511:1552-1561.
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`1552 TRANSFUSION Volume 54, June 2014
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`Page 5 of 14
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`Page 5 of 14
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`SUBCUTANEOUS PHARMACOKINETICS 0F C1-INH CDNCENTRATE
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`eredirary angioedema {HAEL caused by func—
`tional deficiency of C1~esterase inhibitorl
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`[Cl-INI-I), is a rare disease characterized by
`recurrent. spontaneous. nonaliergic edema
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`in subcutaneous (SC) tissues and mucous membranes. In
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`case of laryngeal edema. HAE is associated with high mor-
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`tality rates when there is a delay in treating the attacks.“
`I-IAE is a debilitating disease that can have a severe effect
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`on quality oflife.
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`Cl-lNI—I is a serine protease inhibitor that controls
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`vascular permeability by acting on the initial activation
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`phase ofthe complement, coagulation. contact, and fibri-
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`nolytic systems. The functional deficiency of Cl-INH
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`leads to increased activation'of plasma kallikrein and
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`Factor (FIXIia with a subsequent release of bradykinin,
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`which is a key mediator of vascular permeability." Addi-
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`tionally. Cl-INi-I is the main inhibitor of FXIa. which plays
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`an important role in the generation of thrombin, a positive
`modulator of vasopermeabilitys'”
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`HAE Typel results from a quantitative deficiency
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`in functional Cl-INI-i. whereas the less common I-IAE
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`Type II, affecting 15% of patients. results from a dysfunc-
`tional form of Cl-lNI—I circulating at normal or elevated
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`plasma concentrations." Both defects are inherited as an
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`autosomal dominant trait. ['LALE Type III is extremely rare.
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`with mainly women being clinically affected; it is not asso-
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`ciated with CI-INH deficiency and its pathoplrysiology
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`is uncertain.“ Gammon anti-inflammatory treatments.
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`such as corticosteroids. antihistamines. or epinephrine.
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`are usually inappropriate for treating acute attacks caused
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`by HAE. 1" Clinical studies,‘ "'3 as well as rrrore than 30yea1‘s
`of clinical use.”-'5 have shown that
`intravenous (IV)
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`Cl-INH replacement therapy with human Cl-INH con-
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`centrate is an effective and safe treatment for acute
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`edema attacks in patients with HAE. Therefore, Cl-INH
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`concentrate is recommended as first-line therapy in this
`indication.“
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`of Cl-INH activity. In addition to assessing the safety
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`and toierability ofC I -IN H concentrate when administered
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`via both these routes. we also assessed plasma levels
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`of Cl-INH antigen and cleaved high-molecular-weighr
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`kininogen (clHK). serum levels of C4 antigen. and the
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`presence of Cl-INH antibodies after treatment. These
`additional endpoints were assessed to provide insight into
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`the pharmacokinetic and pharmacodynatnic effects of
`the Cl-INH concentrate administered.
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`MATERlALS AND METHODS
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`Study design and treatment
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`This was a single-center, prospective. randomized. open-
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`label, crossover study in adults with mild or moderate
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`HAE Type I or Type II. The study was conducted between
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`September 22. 2008 (first subject first visit). and November
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`1. 2010 (last subject last visit]. Subjects enrolled into the
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`study had to present during an attack-free interval. In
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`total, 24 subjects were each randomly assigned to one of
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`two treatment sequences. AB or BA (A = N; B = SC). at a
`ratio of 1:1. Blinded randomization envelopes were used.
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`Blinding procedures were otherwise not needed because
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`the study involved treatment with only one study drug.
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`The sample size was calculated in accordance with the
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`guideline on clitrical
`investigation of recombinant or
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`human plasma-derived F IX products
`(EMAICHMP!
`BPWPI 144552l2009).
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`According to the randomization sequence. human
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`pasteurized Cl-INH concentrate (Berinert. CSL Behring]
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`was administered during an attack—free interval as either
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`an IV infusion or an SC infusion, in each case as a single
`dose of 1000 U in 20 mL ofsolution. with a washout period
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`of at least 7 days before study enrollment and between the
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`two treatments. The IV infusion was administered over a
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`time period of 3 minutes. The SC infusion was adminis-
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`tered over a 15-minute period using two medical infusion
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`pumps for continuous.
`simultaneous administration
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`(MEDIS Infusa Tl portable syringe driver. OMT. Minder].
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`Germany] of two doses OFSUU U each at two different loca-
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`tions in the abdomen. A follow-up visit was performed
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`3 months after the second administration of Cl-INI-I
`concentrate.
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`Plasma sanrples for pharmacokinetic and pharmaco-
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`dynamic analyses were collected at t), 0.25, 0.5. 0.75. 1. 2. 4.
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`6. 8. 12. 16, 20. 24, 36, 4t}. 60, 72, 120. and 168 hours after
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`each treatment. In addition. after amending the protocol
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`during the study. additional sampling times [at 336 i
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`48 and 504 i 48 hr after treatment] were introduced for
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`the analysis of Cl-INH activity and antigen levels, and C4
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`antigen levels. to investigate pharmacokinetic and phar-
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`macodynarnic trends over a longer period in six subjects.
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`The analysis of clHK levels was also added. for which
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`blood samples were collected at 0. 12. 35. 60. 168. and 504
`hours after treatment in these six subjects.
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`In patients with HAE requiring frequent IV treatment
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`with Cl-INH concentrate.either for acute edernaattacks or
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`for prophylaxis. venous access may become difficult over
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`time. The SC administration of CI-INII concentrate
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`is therefore being investigated as a potential alternative
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`therapeutic approach. specifically for the prophylactic
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`treatment ofHAE. in support ofthis approach. a preclinical
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`study with CSL Behring‘s human pasteurized Ct-INH
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`concentrate (Bennett. CSL Behring. Marburg. Germany)
`revealed a relative bioavailability of approximately 70%
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`after SC administration in rabbits, compared with IV
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`administration (Ingo Pragst. CSL Behring, May 2013).
`Building on this preclinical experience, the primary objec-
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`tive of our study was to cotnpare the pharmacokinetics of
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`the same preparation of Cl-INI-i concentrate after N and
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`5C administration in subjects with mild or moderate HAE
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`during an attack-free interval. evaluating the relative
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`bioavailability ofSC administration based on plasma levels
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`Page 6 of 14
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`This material was copied
`s-bOi-takll I! and maul-r:
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`Volum954, June 2014 TRANSFUSIDN 1553
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`MARTINEZ-SAGUEH ET AL.
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`Study population
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`the University Hospital
`The study was conducted at
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`Frankfurt (Frankfurt am Main, Germany), after receiving
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`approval from the applicable ethics committee. All poten-
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`tial study participants provided written informed consent
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`before being screened for eligibility. Men and women
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`could only be enrolled if they were at least 18 years of age
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`and presented with mild or moderate HAE Type I (Cl-INII
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`activity < 50% and Cl-INH antigen < 15.4 mg/dL) or Type
`II (CI-INH activity < 50% and Cl-lNH antigen in normal
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`or elevated concentrations) during an attack-free interval.
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`All but two of the enrolled subjects had mild HAE. Subjects
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`were excluded from the study if HAE was not diagnosed or
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`if their last treatment with Cl—INH concentrate (i.e., their
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`last attack) had occurred within 7 days before enrollment.
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`Subjects with acquired angioedema and all other types of
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`angioedema not associated with Cl-INH deficiency were
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`also excluded. Additionally, subjects who had received any
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`investigational drug (excluding drugs appropriate for
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`treating acute angioedema) during the 30 days before
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`treatment in the current study, subjects who had received
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`any other drug appropriate for the treatment of acute
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`angioedema within 7 days before each administra-
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`tion of study drug in the current study, and subjects
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`undergoing prophylaxis with danazol, antifibrinolytics,
`c-aminocaproic acid, or
`tranexamic acid were also
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`excluded. Further exclusion criteria included known
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`hypersensitivity to the study drug, pregnancy (a rapid
`pregnancy test was required for women of childbearing
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`potential), breast-feeding, malignant disease, immunode-
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`ficiency, and concurrent serious or acute illness or
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`infection.
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`Pharmacokinetic and pharmacodynamic
`assessments
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`The primary endpoint was the bioavailability of functional
`Cl—INH after SC administration relative to IV administra-
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`tion of human pasteurized Cl-INH concentrate, calcu-
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`lated on the basis of plasma Cl-INH activity Secondary
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`endpoints were analyses of plasma Cl—lNH activity and
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`antigen levels, serum C4 antigen levels, and plasma clHK
`levels.
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`Cl-INH activity was determined using the functional
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`chromogenic assay (Berichrom Cl-lNH, commercially
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`available from Siemens Healthcare Diagnostics, Eschborn,
`Germany). Standard human plasma served as the calibra-
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`tor; the results are expressed as percentage of normal
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`values. The assay was performed according to the manu-
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`facturer’s instructions. The citrated plasma samples were
`analyzed undiluted.
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`Both Cl-INH and C4 antigen levels were analyzed
`using nephelometric technology from Beckman Coulter
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`(Brea, CA). The reagents for Cl-INH antigen were
`obtained from Siemens Healthcare D