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Reduction of Contact Activation Related Fibrinolytic Activity in Factor XII Deficient Patients

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Reduction of Contact Activation Related Fibrinolytic Activity in Factor XII Deficient Patients Reduction of contact activation related fibrinolytic activity in factor XII deficient patients. Further evidence for the role of the contact system in fibrinolysis in vivo. M Levi, … , H R Büller, J W ten Cate J Clin Invest. 1991;88(4):1155-1160. https://doi.org/10.1172/JCI115416. Research Article In this study the contribution of activation of the contact system to activation of the fibrinolytic system in vivo was investigated in healthy volunteers and in factor XII deficient patients. The plasminogen activating activity in plasma from healthy volunteers after infusion of desamino D-arginine vasopressin (DDAVP) was only partially blocked (for 77%) with specific antibodies to tissue-type plasminogen activator and urokinase type plasminogen activator. The residual activity could be quenched by a monoclonal antibody that inhibits factor XII activity and was not present in patients with a factor XII deficiency. The formation of plasmin upon the DDAVP stimulus as reflected by circulating plasmin-alpha 2-antiplasmin complexes was lower in factor XII deficient patients than in healthy volunteers. Activation of the contact system occurred after DDAVP infusion in healthy volunteers and was absent in factor XII deficient patients. These results indicate that DDAVP induces a plasminogen activating activity that is partially dependent on activation of the contact system and that contributes to the overall fibrinolytic activity as indicated by the formation of plasmin-alpha 2-antiplasmin complexes. This fibrinolytic activity is impaired in factor XII deficient patients which may explain the occurrence of thromboembolic complications in these patients. Find the latest version: https://jci.me/115416/pdf Reduction of Contact Activation Related Fibrinolytic Activity in Factor Xll Deficient Patients Further Evidence for the Role of the Contact System in Fibrinolysis In Vivo Marcel Levi,* C. Enk Hack,* Jan Paul de Boer,* Does P. M. Brandjes,* Harry R. B olhr,* and Jan Wouter ton Cate* *Centerfor Hemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, Academic Medical Center, University ofAmsterdam, 1105 AZ Amsterdam, The Netherlands; and tDepartment ofAutoimmune Diseases, Central Laboratory ofthe Netherlands Red Cross Blood Transfusion Service and Laboratoryfor Clinical and Experimental Immunology, 1066 CX, Amsterdam, The Netherlands Abstract several pathways (1, 2). The two most extensively studied are the tissue-type plasminogen activator (t-PA)1 and urokinase- In this study the contribution of activation of the contact system type plasminogen activator (u-PA) dependent pathways. The to activation of the fibrinolytic system in vivo was investigated exact contribution of both pathways to the development of in healthy volunteers and in factor XII deficient patients. endogenous fibrinolytic activation under basal and activated The plasminogen activating activity in plasma from healthy conditions has not been precisely determined. volunteers after infusion of desamino D-arginine vasopressin Activation ofplasminogen in vivo can reproducibly be stud- (DDAVP) was only partially blocked (for 77%) with specific ied by a short lasting infusion ofdesamino D-arginine vasopres- antibodies to tissue-type plasminogen activator and urokinase- sin (DDAVP). This substance induces increases in plasma lev- type plasminogen activator. The residual activity could be els of plasminogen activator activity and of both t-PA and u- quenched by a monoclonal antibody that inhibits factor XII PA antigen (3-5). In addition, it induces activation of activity and was not present in patients with a factor XII defi- plasminogen in vivo as reflected by increasing levels of plas- ciency. The formation of plasmin upon the DDAVP stimulus as min-a2-antiplasmin (PAP) complex levels (Levi, M., et al., reflected by circulating plasmin-a2-antiplasmin complexes was manuscript submitted for publication). Previous experiments lower in factor XII deficient patients than in healthy volunteers. have shown that quenching of both t-PA and u-PA by specific Activation of the contact system occurred after DDAVP infu- antibodies in plasma obtained from healthy volunteers shortly sion in healthy volunteers and was absent in factor XII deficient after infusion of DDAVP, does not completely abolish plas- patients. minogen activator activity (5), indicating the existence of a These results indicate that DDAVP induces a plasminogen third pathway of plasminogen activation. This third pathway activating activity that is partially dependent on activation of of plasminogen activation has been claimed to be dependent the contact system and that contributes to the overall fibrino- on activation of the contact system of blood coagulation (6). lytic activity as indicated by the formation of plasmin-a2-anti- Involvement of the contact system (for reviews see Colman et plasmin complexes. This fibrinolytic activity is impaired in fac- al. [71 and Kaplan et al. [8]) in fibrinolysis is supported by tor XII deficient patients which may explain the occurrence of several lines of evidence. First, patients with severe factor XII thromboembolic complications in these patients. (J. Clin. In- deficiency have a higher incidence of thromboembolic events, vest. 1991. 88:1155-1160.) Key words: plasminogen activator. which might be attributed to an impaired fibrinolytic activity plasminogen * plasmin * hemostasis * thrombosis (9, 10). Second, recent observations in patients with hereditary angioedema, which is caused by a deficiency ofthe major inhib- Introduction itor of the contact system, Cl-inhibitor, have shown that in- creased activity of the contact system is associated with an en- The conversion of the fibrinolytic proenzyme plasminogen hanced plasmin generation (1 1). Finally, factor XII structurally into the proteolytic enzyme plasmin may occur in vivo via resembles t-PA and plasminogen (12). To determine the role of contact activation in fibrinolysis This study was presented in part at the combined 23rd Congress of the we investigated the effect of intravenous administration of International Society of Hematology and the 32nd Annual Meeting of DDAVP on the activation ofthe contact system and the fibrino- the American Society of Hematology, 28 November-4 December lytic system in healthy subjects and individuals with mild or 1990, Boston, MA. severe factor XII deficiency. In addition, we studied the contri- Address correspondence to Dr. Marcel Levi, Center for Hemosta- bution of factor XII to the plasminogen activator activity in- sis, Thrombosis, Atherosclerosis, and Inflammation Research, F4 duced in plasma by DDAVP in these subjects. Our results show Room 237, Academic Medical Center, Meibergdreef 9, 1105 AZ Am- that DDAVP in vivo induces activation of the contact system sterdam, The Netherlands. and the generation of plasminogen activator activity and plas- Receivedfor publication 14 March 1991 and in revisedform 3 June min generation which is dependent in part on factor XII. This 1991. response was impaired in factor XII deficient patients. 1. Abbreviations used in this paper: ANOVA, analysis of variance; DDAVP, desamino -arginine vasopressin; PAP, plasmin-a2-antiplas- Methods min; t-PA, tissue-type plasminogen activator; u-PA, urokinase-type plasminogen activator. Study subjects and DDA VP test. Six healthy volunteers (aged 21-33 yr) and in addition six subjects with a known deficiency of coagulation J. Clin. Invest. factor XII were studied. Of the deficient subjects, three patients (aged © The American Society for Clinical Investigation, Inc. 21-28 yr) had factor XII activity levels below 1% (severe factor XII 0021-9738/91/10/1155/06 $2.00 deficiency) while three other patients (aged 18-44 yr) had factor XII Volume 88, October 1991, 1155-1160 activity levels ranging from 20% to 35% (mild factor XII deficiency). Contact System and Fibrinolysis 1155 All study subjects received DDAVP (Desmopressin, MINRIN4, prekallikrein in this plasma. These antigen assays measure factor XII or Ferring AB Pharmaceuticals, Malm6, Sweden), at a concentration of prekallikrein irrespective of its molecular forms, i.e., native protein or 0.4 Ag/kg body weight in 50 ml of saline over 15 min intravenously. activated protein in complex with Cl-inhibitor. They were seated 10 min before and during the entire experiment, Factor XIIa-CI-inhibitor complexes and kallikrein-CI-inhibitor fasted overnight, and abstained from smoking for 12 h before the ex- complexes were assayed by RIA as described previously (17). Briefly, a periment. The DDAVP infusion started at 9:00 a.m. The study was monoclonal antibody that specifically binds complexed Cl-inhibitor approved by the Institutional Review Board. (KOK-12) was coupled to Sepharose and incubated with plasma sam- Collection ofblood. Blood was collected by separate venipunctures ples. Bound factor XII- or kallikrein-Cl-inhibitor complexes were before and at 15, 30, and 60 min after the start of the DDAVP infusion. quantitated by subsequent incubation with either '251-labeled polyclo- If post-DDAVP plasma is mentioned further, the sample taken 15 min nal anti-factor XII or '25M-labeled anti-kallikrein antibodies, respec- after the start of the infusion is referred to. tively. Results obtained with tested plasma samples were expressed in Blood (9 vol) for the measurement of plasminogen activator activ- milliunits, as calculated by reference to a standard curve that consisted ity, t-PA antigen, u-PA antigen, factor XII activity, factor XII antigen, of dextran sulphate-activated pooled
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