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      Prospective Evaluation of the Pre-, Intra-, and Postoperative Kinetics of ADAMTS-13, von Willebrand Factor, and Interleukin-6 in Vascular Surgery

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          Abstract

          Postoperative thrombotic thrombocytopenic purpura (TTP) shows clinical presentation similar to classical TTP, whereas exact pathophysiological contexts remain unexplained. In this study, we investigated intraoperative and postoperative changes in ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13), von Willebrand factor (VWF), large VWF multimers, and interleukin-6 (IL-6) in vascular surgery patients. The objective was to compare the impact of endovascular, peripheral, and aortic surgery on target parameters which are supposed to play a role in surgery-associated TTP. A total of 93 vascular surgery patients were included and divided into 4 groups according to the specific type of intervention they underwent. Blood samples were taken preoperatively, intraoperatively, and postoperatively on days 2 and 4. The ADAMTS-13 activity decreased significantly in 3 of the 4 groups during surgery (from median 81% to 49%, P < .001, in the group undergoing aortoiliacal interventions), whereas the percentage of large VWF multimers increased in all groups of patients. von Willebrand factor antigen increased significantly in all groups on postoperative day 2 and IL-6 increased significantly in the intraoperative and early postoperative period. There was no significant correlation between the intraoperative decrease in ADAMTS-13 and the increase in VWF or IL-6. No patient in this study showed clinical picture of TTP; the precise cause and clinical significance of moderately reduced ADAMTS-13 activity in the perioperative setting have not yet been definitely determined.

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          Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura.

          Thrombotic thrombocytopenic purpura is associated with acquired or congenital deficiency of a plasma von Willebrand factor-cleaving protease (VWFCP). Based on partial amino acid sequence, VWFCP was identified recently as a new member of the ADAMTS family of metalloproteases and designated ADAMTS13. The 4.6-kilobase pair cDNA sequence for VWFCP has now been determined. By Northern blotting, full-length VWFCP mRNA was detected only in liver. VWFCP consists of 1427 amino acid residues and has a signal peptide, a short propeptide terminating in the sequence RQRR, a reprolysin-like metalloprotease domain, a disintegrin-like domain, a thrombospondin-1 repeat, a Cys-rich domain, an ADAMTS spacer, seven additional thrombospondin-1 repeats, and two CUB domains. VWFCP apparently is made as a zymogen that requires proteolytic activation, possibly by furin intracellularly. Sites for Zn(2+) and Ca(2+) ions are conserved in the protease domain. The Cys-rich domain contains an RGDS sequence that could mediate integrin-dependent binding to platelets or other cells. Alternative splicing gives rise to at least seven potential variants that truncate the protein at different positions after the protease domain. Alternative splicing may have functional significance, producing proteins with distinct abilities to interact with cofactors, connective tissue, platelets, and von Willebrand factor.
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            Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura.

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              Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis.

              Proteolytic cleavage of von Willebrand factor (vWF) takes place in the circulating blood of healthy subjects and is increased in some patients with von Willebrand disease type 2A. The hemostatically active large vWF multimers are degraded to smaller less active forms. It has been suggested that the polypeptide subunit of vWF is cleaved at the peptide bond 842Tyr-843Met. We purified (approximately 10,000-fold) from human plasma a vWF-degrading protease, using chelating Sepharose, hydrophobic interaction chromatography, and gel filtration. The enzyme was found to be virtually absent in the platelet lysates obtained by repeated freezing and thawing. The proteolytic activity was associated with a high molecular weight protein (approximately 300 kD) as judged by gel filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. vWF was resistant against the protease in a neutral buffer at physiological ionic strength but became degraded at low salt concentration or in the presence of 1 mol/L urea. No degradation of human fibrinogen, bovine serum albumin, of calf skin collagen by the purified protease was noted under the same experimental conditions. Proteolytic activity showed a pH optimum at 8 to 9 and was strongly inhibited by chelating agents, whereas only slow inhibition was observed with N-ethylmaleimide. There was no inhibition by iodoacetamide, leupeptin, or serine protease inhibitors. The best peptidyl diazomethyl ketone inhibitor was Z-Phe-Phe-CHN2. Activation by divalent metal ions was found to increase in the following order: Zn2+ approximately Cu2+ approximately CD2+ approximately Ni2+ approximately Co2+
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                Author and article information

                Journal
                Clin Appl Thromb Hemost
                Clin Appl Thromb Hemost
                CAT
                spcat
                Clinical and Applied Thrombosis/Hemostasis
                SAGE Publications (Sage CA: Los Angeles, CA )
                1076-0296
                1938-2723
                6 October 2020
                Jan-Dec 2020
                : 26
                : 1076029620930273
                Affiliations
                [1 ]University Hospital Frankfurt, Medical Clinic II, Institute of Transfusion Medicine and Immunohematology, Hemophilia Center, Frankfurt, Germany
                [2 ]Department for Vascular Surgery, University Hospital Mannheim, Mannheim, Germany
                [3 ]Department for Anesthesiology, Intensive Care Medicine and Emergency Medicine, Asklepios Klinik Wandsbek, Hamburg, Germany
                [4 ]German Red Cross Blood Center Frankfurt am Main, Institute of Transfusion Medicine and Immunohematology, Frankfurt, Germany
                Author notes
                [*]Wolfgang Miesbach, Hemophilia Center, University Hospital Frankfurt, Medical Clinic II, Institute of Transfusion Medicine and Immunohematology, 60590 Frankfurt, Germany. Email: wolfgang.miesbach@ 123456kgu.de
                Author information
                https://orcid.org/0000-0003-2712-8277
                https://orcid.org/0000-0002-4506-0061
                Article
                10.1177_1076029620930273
                10.1177/1076029620930273
                7545751
                33023308
                1a3896dc-af5a-4f2f-b600-314a0ce96b17
                © The Author(s) 2020

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                : 11 March 2020
                : 01 May 2020
                : 04 May 2020
                Funding
                Funded by: Shire Deutschland GmbH, Berlin, Germany, a member of the Takeda group of companies;
                Award ID: IIR H14-23621
                Categories
                Original Article
                Custom metadata
                January-December 2020
                ts3

                adamts-13,vascular surgery,von willebrand factor,interleukin-6,thrombotic thrombocytopenic purpura,thrombotic microangiopathy

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