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Human <X2-Macroblobulin and Plasmin. (459) Antithrombin III

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Human <X2-Macroblobulin and Plasmin. (459) Antithrombin III 924 Abstracts added before the incubation of CPA positive plasma at 0° C for 20 hours. Addition of CIINH after CPA generation did not affect the shortened Thrombotest Time (TT). Synthetic amidino compounds (diOHstilbamidine, dibromopropamidine}, which have b een cla imed as sp ecific inhibitors of CI est e rase, were al so effective inhib i tors of CPA in final concentrations of l0- 4 - lO- • M . Alike to CliNH t h ey h ad no effect on a TT shortened by previous gen eration of CPA. In 8 subjects with CIINH d eficiency the shortening of t.he TT of plasma incubated at 0° C for 20 hours exeeeded that in a control group of 48 men and women not us ing oestrogenic drugs (p 0.05). CIINH activity proved to be consumed during CPA probably by binding of kallikrein, since purified CPA-kallikrein blocked purified CIINH activity. The antigen level of CIINH was n ot affected by CPA. This finding h as diagnostic importa nce since fal se low levels of CfiNH activity may b e detected in serum samples exp osed to CPA favouring conditions. In fact t his proved to be the case in a l arge proport ion of subjects t h ou ght to be suffering from so-called acquir ed angioneurotic oed em a (Quincke's oedema urticaria) on ground of low CfiNH activity determined in a frozen and thawed serum sample. C1INH activity proved to b e completely normal in fresh samples. P . Lambin, J. ll!J.. Fine, R. Audran and M. Steinbuch (Centro N ational de Transfusion Sanguine, 6 rue Alexandre-Cabanel, Paris XVe): The Interaction Mecl1anism between Human <X 2-Macroblobulin and Plasmin. (459) When purified homogen ous <X 2M is submitted to SDS polyacrylamide el ectrophoresis splitting in half molecules of MW of 380.000 is observed. If increasing amounts of plasmin are added to a given amount of <X 2M, a n ew component of M'V 450,000 incr eases whereas as the MvV 380,000 component d ecreases. This n ew component consists of one ha lf molecule of <X 2M arid one plasmin molecule. In the presence of re ducing agents and SDS the half molecules of <X 2M a r e further cleaved sh owing that t h e molecule is composed of 4 ch a ins having a MW of 180,000. If <X 2M/plasmin complexes are submitted to the same t r eatm e nt, a major component MW of 95,000 appears p roportionally to the amount of added plasmin. As al ready shown by Harpel this component is a split product to the proteolytic action of plasmin. Other components of m a jor interest correspond to the heavy c hain of plasmin MW 50,000 and a component of MW 120,000 which r e presents the association of the MvV 95,000 frag me nt of <X 2M a nd t h e ligh t chain of plasmin (25,000). This assumption is materialized by t h e u se of 1'31-labeled plasmin. Both t h e 450,000 component and the 120,000 component are r evaled by a uto-radiography. Thus a stable, eventually covale nt linkage between :z 2M and pl asmin can be assumed. H . C. Godal, K. Gmvem, K. Laake and M . Rygh (Hem. Res. Lab., Dept. IX, U llevaJ Hospital, University Clinic, Oslo, Norway): Inactivation of Factor VII by Heparin an1l Antithrombin III. ( 460) In the presence of heparin and antithrombin III, activated factor VII was progressively inactivated . Inactivation occurred in plasma as well as in preparations of h ighly purified factor VII an d a ntithrombin III. The inactivation process was slow, and could only be demonstrated at t e mper atures b el ow 37° C. N eu t ra lisation of h e parin with polyb ren e (after incubation) did not lead to r egain of factor VII activ ity, su ggesting t h at inactivation This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. is irreversible. Whether al so non-activated factor VII is affected by h ep arin and anti- t hrombin III, re mains to be settled . S. Chandra and N. U. Bang (Lilly L aboratory for Clinical R esearch and Indiana University School of M edicine, Indianapolis, Indiana 46202 U .S.A.): The Biophysical and Functional Properties of Antithrombin III (A'r III) in Vitro and in Vivo. (4.61) Human and rabbit AT III were purified by a two-step procedure of h e parin-agarose affinity ch romatograph y and Sephadex G150 gel filtration. The resulting p r eparation purified approximately 900 fold over plasma was h omogen eou s by SDS gel electrophoresis Abstracts 925 (SDSE), immunoelectrophoresis and gel exclusion chromatography (GEC). Both human and rabbit AT III possessed mol wt's of approximately 68,000 daltons. As previously observed (Rosenberg and Damus: J. Biol. Chern., 248, 6490, 1973), we noted that human as well as rabbit AT III form firm stoichiometric complexes with thrombin demonstrable by SDSE and GEC. 125I labeled rabbit AT III possessing biophysical and biological prop- erties identical t:> the unlabeled product was injected into rabbits. Radi0labeled AT III displayed complex multiphasic disappearance curves with a half-life of the major component of 36 hours. The apparent mol wt of AT III in vivo was reduced to approximately 30,000 daltons within minutes after its administration into rabbits as evidenced by GEC and SDSE. The 30,000 dalton AT III was as capable as the 68,000 dalton AT III to form firm stoichiometric complexes with thrombin. Thus, AT III may exist in different molecular forms possessing similar biological activities. J. Edy, D. Collen and JJ!l. Verstraete (Laboratory of Blood Coagulation, Department of Medical Research, University of Leuven, Belgium): Evidence for a Functionally Important Plasmin Inhibitor in Human Plasma, Different from Ot 2-Macroblobulin, Ot 1-Antitrypsin and Antithrombin III. ( 462) Gel filtration on Sephadex G- 200 of urokinase-activated fresh human plasma containing a trace amount of radiolabeled plasminogen and of serial plasma samples obtained during streptokinase therapy in patients following injection of labelEd plasminogen has been performed. A parallel disappearance of radioactivity and enzymatic activity eluted in the plasminogen position was observed concomitant with the appearance of two radioactive peaks, eluted at the void volume (P-Ot 2M) and just before the globulin peak (P-AP) (D. Collen, Plasminogen and prothrombin metabolism in man, Aggregaatsthesis, Leuven, 1974). The relative distribution of radioactivity over the P-Ot 2M and P-AP peaks depends on the rate of plasminogen activation and may vary from 3 to 1 to 1 to 3, slow activation favoring P - AP formation. The purified P-Ot 2M complex has been identified as plasmin-Ot 2 -macroglobulin complex. The purified P-AP complex, obtained in high yield, does not cross-react with antisera against Ot 1 -antitrypsin or antithrombin III, has a mol wt of about 130,000 by SDS. polyacrylamide gel electrophoresis and upon reduction displays a broad band with a molecular weight of about 70,000. Recently Mullertz (Biochem . J., 143, 273, 1974) has probably identified the same P-AP complex which in addition did not react with antisera against inter-Ot-trypsin inhibitor and C,-esterase inhibitor. All these data suggsst that human plasma contains a functionally important, plasmin inhibitor which is different from the five main protease inhibitors in plasma. We have provisionally named this inhibitor Ot 1 -antiplasmin, in accordance with the nomenclature of Norman (J. Exp. Med .. 108, 639, 1958). 1Vf. Verstraete (Academisch Ziekenhuis, B-3000 Leuven, Belgium): Current Major Trials with Antithrombotic Agents. ( 464) Numerous clinical trials have been recently carried out or are being planned with antithrombotic agents. What is the current knowledge on agents affecting the platelet function : are they clinically useful ? The clinical validity of anti-aggregating agents is to be demonstrated in controlled clinical trials having a vascular occlusion as the end point This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. to judge the drug effect. A survey will be presented on the results available with one of tho three agents currently available, acetylsalicylic acid, dipyridamole and sulfinpyrazone. Following clinical conditions are to b e discussed separately: peripheral arterial disease, coronary artery disease, patients with prosthetic heart valves, certain renal disease, ITP, haemolytic uraemic syndrome and conditions often complicated with deep venous thrombosis. To what extent and subcutaneous heparin used in low-dosage ca.n decrease the incidence of post-operative deep-vein thrombosis and outweight its possible disavantages is another item to be reviewed. .
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