Does a prethrombotic Robert D Rosenberg The last and decade state Kenneth witnessed exist? vided below briefly by basic significant of the functioning mans. For major advances of the blood-coagulation latter, a quiet peptides; transitions these ofspecific to thrombin, as well (release for the conversion The activation-peptide pathways have taught active, albeit assays, converted normal level. circulating to thrombin, tralized by natural wall, such as the low and the resulting systems (5). assays ( 1-4). fined systemically Prethrombotic as occurring by radioimmunoassays augmentation various to thrombin sufficient free thrombin must increase of fibrinopeptide is that in vivo conditions can subsequent platelet surface, events governing the In addition, centration a more peptides. eration possible Indeed, of fivefold above pro- The concen- (over of the generated it may be instrumental for hours or translocation careful of activation of factor cascade days process comparisons peptides in converting pro- (6). The are completely un- systemic con- at various levels Thus, the ceptualized events -mii that (‘/in blood-coagulation as a set are individually Nuir mechanism of tightly 1992:56:787S-8S. controlled regulated Printed should zymogen by normal factor in USA. to the VII normal to pathway XI). of factor to production is IX with mmXII-factor concentrations to convert of of factor factor IXa Xa by X to factor Thus, the intrinsic pathway is to thrombin generation, which complete absence of circulating factor that action the is responsible of the of existing intrinsic factor for generating arterial IXa on cascade-amplification sufficient or venous factor X. event It is outlined thrombin to cause thrombus. normal aging of humans predictably alters coagulation(9). Below age 40 y very few individuals exhibit concentrations of activation peptides. However, from function numbers of humans who are otherwise X activation peptides peptides. are due These altered to increased activaIX and concentrations production rather of than decreased clearance of the markers, as shown by direct investigation of radiolabeled peptides (9). A remarkable correlation coag- ‘From the Department of Biology, Massachusetts Institute of Technology. Cambridge, and Beth Israel Hospital, Boston. 2 Address reprint requests to RD Rosenberg, Department of Biology, be conconversion inhibitory by the activation ulation cascade in health and disease reveal that this series of linked zymogen transitions is a tightly controlled mechanism with little overall step-to-step amplification in enzyme generation. phase under normal exhibit elevated concentrations of prothrombin tion peptide as well as elevated concentrations of factor molecular of the to be due factor-factor are unable recombinant prothrombin (factor conditions. with regard 45 to 70 y, increasing in minutes) to the of the elevated Xa under enzyme VII) with with convert the contact high of patients monitored functions and offactor equivalent factor-factor formation before systemic event from been of the with for the activation relatively also function VIlla. It is surmised that the increased production offree thrombin via the tissue factor-factor VII-factor X extrinsic pathway is probably required to convert small amounts offactor VIII to factor VIlla, with the resultant amplification of thrombin gen- modest of conversion generation be a transitory to thrombin known. excessive translocation where appears A. interesting thrombin A, show by about contribution Xa under ambient normally dormant de- as quantitated to elevate tissue tissue activation-peptide offibrin extent is generated Also with the the is then are operationally in activation that Furthermore, (roughly transitions the thrombin. and the actual in vivo steps studies have demonstrated VII pathway Xa generation thrombotic normalized factor responsible thresholds investigations who have been while factor-factor is continuously neu- the elevations elevations cell surfaces. cascade have to the overall to generate the conversion as well are elevated by which example, deficiencies assays Surprisingly, blood-vessel III and protein regard thrombotic small These inhibitory taught us much about cascade (7, 8). These the tissue imal it appears or overtly certain conditions also mainly acute the generation to fourfold suggest thrombin trations ofthe for fibrinopeptide oftwostudies de- is normally enzyme with states, before to During events, the rates ofprothrombin-to-thrombin as other zymogen-to-serine protease as measured fibrinogen proteins have the coagulation consumption, prothrombin with the activation-peptide etc) example, rearranged mechanism. For various zymogen that anticoagulant mechanisms heparan sulfate-antithrombin C-thrombomodulin 10-fold For to exceed somewhat IXa, mechanism reactions devel- on the biochemically the blood-coagulation of prethrombotic in hu- (prothrombin or substrate the occurrence then to be sequestered on specialized The actual steps in the coagulation to monitor IX to factor substrate based generation at an extremely 0. 1% of the allow A or B) (1-4). ofenzyme us that proteases ofthe gen- protein are able factor probably takes place because of rather extent of systemic enzyme generation. in the blood-coagulation Xa, The events in the were mechanism to serine X to factor cesses. its repro- as by studies occurred radioimmunoassays of fibrinopeptide fined which as well revolution zymogens factor as evaluate fibrin advances, investigations of radioimmunoassays activation that these biochemical in our and sections Massachusetts Institute of Technology. enue, Cambridge. MA 02139. pro- © 1992 American Society for Clinical Nutrition E25-229, 77 Massachusetts Av- 787S Downloaded from ajcn.nutrition.org by guest on September 30, 2014 opment the summarize is it?”2 A Bauer understanding of the blood-coagulation mechanism lationship to arterial and venous thrombosis. The erated If so, what ROSENBERG 788S exists between the concentrations of factor IX and factor tivation peptides in any given individual, with a somewhat correlation between these markers and the concentrations AND X acpoorer of 2. prothrombin activation peptide. These observations are interpreted to mean that certain individuals as they age exhibit increased function of the tissue factor-factor VII pathway with augmented activation of factor IX and factor X, which are variably manifest as more extensive conversion of prothrombin to thrombin with minimal elevation in the generation of fibrin 3. from fibrinogen. The critical unanswered question these biochemically hypercoagulable individuals are more likely to have hypersensitive responses to environmental stimuli, with the production of small amounts of extrinsic-pathway-generated free thrombin because their blood-coagulation mechanisms are closer to the threshold of the inhibitory processes. The generated enzyme could then be used to mobilize their dormant intrinsic cascades, which tions of factor are potentially hyperactive (elevated 4. is whether 5. 6. concentra7. 8. References 9. I. Lau H. Rosenberg iS, Beeler DL, Rosenberg RD. The isolation and characterization of a specific antibody population directed against the prothrombin activation fragments F2 and Fl +2. J Biol Chem 1979;254:875 1-6 1. Teitel JM, Bauer KA, Lau HK, Rosenberg RD. Studies ofthe prothrombin activation pathway utilizing radioimmunoassays for the F2/F1 +2 fragment and thrombin-antithrombin complex. Blood l982;59: 1086-97. Bauer KA, Kass BL, ten Cate H, Bednarek MA, Hawiger JJ, Rosenberg RD. Detection of factor X activation in humans. Blood 1989;74:2007-l 5. Bauer KA, Kass BL, ten Cate H, Hawiger ii, Rosenberg RD. Factor IX is activated in vivo by the tissue factor mechanism. Blood 1990;76: 731-6. Meade TW, Miller GJ, Rosenberg RD. Characteristics associated with the risk of arterial thrombosis and the prethrombotic state. In: Fuster V. Verstraete M, eds. Thrombosis in cardiovascular disorders. Philadelphia: WB Saunders 1992;79-97. van der Poll T, Buller HR, ten Cate H, et al. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N EnglJ Med 1990:322:1622-7. Mannucci PM, Bauer KA, Gringeri A, et al. Thrombin generation is not increased in the blood of hemophilia B patients after the infusion of a purified factor XI concentrate. Blood l990;76: 2540-5. Bauer KA, Mannucci PM, Gringeri A, et al. Factor IXa-factor Vilacell surface complex does not contribute to the basal activation of the coagulation mechanism in vivo. Blood 1982:79:2039-47. Bauer KA, Weiss LM, Sparrow D, Vokonas PS, Rosenberg RD. Aging associated changes in indices of thrombin generation and protein C activation in humans. J Clin Invest 1987:80:1527-34. Downloaded from ajcn.nutrition.org by guest on September 30, 2014 IX activation peptide): to explosively generate large amounts of free thrombin: and to develop an arterialor venous thrombus. 13 BAUER