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CARDIOVASCULAR, PHARMACOLOGY and CHEMISTRY Activated: 10/15/63 C010ITTEE: 633 TIIIItD AVE.UE - NEW YORK. N. Y. idoi~ Renewed t 10/15/64 Dr. Cattell, Chm. Renewed: 10/15/65 Tiar,, CoU;r•CiL FOR To13Acco Frf:SL11RCH - U.S.A. Cf. #3 - Activated: 10.15 No. 56 -R1 Dr. Jacobson Dr. Bing :. ~`.. Application For Renewal of Research Grant First (5 1. Name of Investigator(s): (include title and degrees Second 0; Kenneth M. Moser, M.D. Associate Professor of Medic' .2. tnstitutiond~ Georgetown University Medical School, Washi Address: 3. ShortT,tleofProject: Smoker- Non-Smoker Differences in Activation of Fibrinolytic-Coagulation Systems. d. Proposed Renewal Starting Date:(Anniversory or other) E November, 1967. 5. Discuss any Important Changes or Additions to Objectives or Specific Aims: No ma jor changes have occurred in objectives or specific aims from those stated in the 1966 application. The goal is still to ~ define smoker-non-smoker differences in coagulation-fibrinolytic behavior which might bear upon the statistic relationsh,ip•6etween heart disease (especially coronary thrombosis) and cigarette smoking. • 6. Give a Brief Statement of your Working Hypothesis if altered or modified: The basi c hypothesi s remai ns unaltered; namely, that smoking may enhance thromboatherogenesis via the coagulation-fibrinolytic system.

I 2. =.::..7. Changes or Additions to Experimental Design and Procedures: (Attach Separate Pages) At present there have , , ~, been no majo, changes in experimental design. However, if current trends in data are substantiated ::. three additiot,s to the protocol may be instituted: 1) studyof the changes in "platelefi adhesiveness" associated with smoking (in smokers) or h erventilation (non-smokers), 2) limited studies f yp ; o • fibrinogen turnover rates in age-sex matched smokers and non-smokers; 3) addition of an exercise ~~ test to the nicotinicacid stimulus; i.e., to determine whether exercise produces the some type of k- k d'ff s e d t' ' erences rxc mo r non smo er t as oes ntco iaci . :_~"~;..,,,~ The rationale for these otenfial additio s lies i the data e ded (Tabfe f-'A W7~ n n n s .,.:.: p app , e ave recenfily subjected a considerable amount of our data in this study to computer statistical analysis 'mean; standard deviation, standard error, correlation and "t" tests) . This analysis has revealed, '~ry :`several instructive smoker-non-smoker differences. In basel:fne-only studies (Table I) smokers have a statistically significant (P <•05) higher level of plasminogen. While other differences exist , they are not statistically significant. However, in this analysis there is a significant positive : eorrelation. between! age and fibrinogen concentration in non-smokers - not in smokers. Thus ;•smokers do not apper to have the expected age-related' rise in fibrinogen, although the mean :: fibrinogen is higher in smokers. (Continued - pages 2-A thru 2-E) 8. Additional Requirements: • We currently have no major additional requirements. 9. Changes in Personnel with. Biographical Sketches of new Personnel (append)' Dr. Paul G: Harsanyi joined our research staff this year. (see attached bibliographic sketch,.page 2-F) • •io. Publications or Papers in Press resulting from the Projecl or closely related work is currently being prepared for publication. The datQ presented i n Ta6f es 1-3

-Page2-A 7. Changes or Additions, cont. On the acute smoking (or hyperventilation) studies, other interesting data appear. (Table 2) . Again, there is a positive age-fibrinogen correlation in non-smokers only, with fibrinogen levels again higher (but not quite significant at P < .05) in smokers. The plasminogen levels are again significantly higher in the smokers. In both broups, there is a higFitiy significant rise in plasminogen (P < .001) with smoking (or hyperventilation).. Partial tiiromboplastin time behavior is also interesting. In this study,hasdine PTT was longer in smokers (not significantl.y) but fell, with smoking and after smoking. In non-smokers, PTT increased slightly with and following hyperventilation. , In the nicotinicacid study (Table 3) to date, instructive data have been generated. The most striking is the fact that nicotiryc acid provokes a much greater (and apparently more sustained) enhancement of activator activity in the non-smokers than in the smokers. Significant differences (as measured by both ELT and A-P plates) exist, between smokers and non-smokers at all intervals. Thus, the non-smoker seems to release activator more readily than the smoker. If this is true under all circumstances, itwould; suggest thrombolysis may be impaired in smokers in terms of its response to a-given stress. f As fihe data are exteded fthtlill bidt (A ; •n,urer compuer anayses we carre ou. program h b dld fh) aseeneveopeor tis specific purpose . Analysis of smoker-non-smoker differences between different age and sex-matched groups are contemplated. These may reveal differences obscured by combining all data, as has been done in the analysis reported in Tables 1-3. I ~ N I ~ , ~ . . O O W i ~ ~ ~ ~ ~ ;

Page 2-B Smokers (60) Non-Smokers (50) Pack-Years 18.0 f 15.4 Pro. T. (Sec) 17.9 ~ 3.1 P.T.T. (Sec) 89.3 ~' 30.7 ELT (Min) 234.0 t 74.0 Fibrinogen (mgm%) 451.0 ± 147.0 A-P (mm2) . 192.0 f 121.0 P`gen (mm2) . 329.0 ± 70.0 C. P'gen (CRU) 5.6 ± 4.5 3.7 ± 3.3 Table One: Smokers versus non-smokers. Fasting morning values. .. u _ _ . n~.. ..., . ~ .~. . . .. r...al+. .. - . ...a.. ....J .a<. +.+

Pack-Years .. . 19.8 P.T. 17.2 } 2.8 17.2 ± P.T.T. ELT A-P P'gen C. P'gen N'on-Smokers (40) Age 41.5 f 21.2 6.0 P. T. 16.6 ~ 2.1 17.0 ± 2.4 16.9 } 2.3 s...., . 2.8 17.2 ~'. 33.8 85.9 f 75.0 242.0 ± 151.0 443.0 ~' 123.0 191.0 ~' 81.0 307.0 ~ 5.4 7.5 ± Pack-Years 0 -- -- 96.3 38.1 88.8 t 241.0 ~ 76.0 229.0 t 451.0 t 156.0 451.0 ± 196.0 ~ 126.0 206.0 t 307.0 t 73.0 314.0 ± 5.5 t 5.0 13.4 ± 82.9 t 21.7 92.6 ± 46.7 85.7 f 49.9 243.0 ± 64.0 250.0 t 60.0 240.0 ± 69.0 411.0 ~' 140.0 404.0 ~" 139.0 402.0 ~ 149.0 A-P 172.0 } 74.0 183.0 f 88.0 196.0 f 85..0 h-h . O P'gen 288.0 ± 60.0 285.0 ± 69.0 290.0 ± 60.0 W Table Two: Smokers and non-smokers studied before, at completion and 60 minutes (O after completion of a 30 minute smoking or mild hyperventilation period. C. P'gen 3.8 ~ 3.9 11.9 +' 3.4 4.6 t. 3.6 ~ ~ VI

Age • w . ~.~ Pack-Years P. T. P.T.T. ELT Fibrinogen A-P P'gen C. P'gen ~A) nicotinic acid given intravenously. Pagei (Page 1. of Table Three Smokers 0 10 20 40 60 37.8 * 12.8 . . : ' . , 16.3 t 9.8 _ -- ° -" _ 16.0 + 1.9 16.4 t 2.4 16.4 1- 2.2 16.3 t 1.8 16.1 ± 1.8 . 90.3 * 35.7 97.8 t 42.7 102.0 t 45.0 ~98.9 ± 44.0 86.1. '~ 55.9 . 0 t 60.0 263 151.0 ± 112.0 147.0 f 111.0 178.0 ± 96.0 ` 199.0 ± 90.0 ~ • . . . ~ 419.0 t 126.0 408.0 t 156.0 272.0 f 77.0 419.0 ± 138.0 ~ 439.0 f 145.0 ' 135.0 ± 142.0 345.0 ± 277.0 354.0 ± 279.0 271.0 ± 220.0 233.0 ~ ,180:0 262.0 ± 79.0 266.0 t 77.0 265.0 * 73.0 • 274.0 ± 61.0 . 275.0 f '75.0 3.8 ± 2.4 4.4 ± 2.6 ' 4.4 ± 2.8 4.2 ± 6.6 • 3.9 ± 2.2 Table Three: Smokers (38) and non-smokers (30) studied before and at 10, 20, 40, and 60 minutes after 100 mgm 0449MOOZ

Age Pack-Years P. T. P.T.T. ELT Fibrinogen A-P P'gen ;: C. P'gen 16.4 87.6 223.0 355.0 167.0 280.0 1.9 74.0 •` 1 85.0 274.0 - * , 159.0 508.0 ± 288.0 264.0 f 78.0 4.2 ~ ~ 2.6 ± 85.2 . ~ . _ . . ~ - - i 124.0 ~' 120.0 102.0 94.0 .: ; .; ~"143.0 316.0 f T 98.0 314.0 153.0 '~. ;' ', 360.0 , 265.0 * 3.3 f 2.3 73.0:~ Smokers (38) and rion-smokers (30) studied before and at 10, 20; 40, and 60 minutes after 100 mgm nicotinic acid given intravenously. 2.0 + + t 73.0 * 126.0 f 109.0 83.0

R: REDACTED MATERIAL 2- F Budapest, Hungary Page 2, Item 9: Personnel with Biographical S::etches: Dr. Paul G. Harsanyi. • Date of birth: Place of birth: Marital status: M.D.: . P_ University of Budapest, 1962. Internship: ',: 'University of Budapest Medical Center, 1962-62. Residency: °..'University of Pecs Medical Center, 1963-66. _ ;• Visiting Research „ i - Scientist: • University of Vienna: Medical School, I966. Research Associate: Georgetown University Medical School, 1966 to present. (NOTE: Dr. Harsanyi; who joined our Program in 1966, has made a considerable contribution to our. research efforts. His departure from. Hungary interrupted a promising research career there. We are del-ighted he has been able to resume it with us.) . 0 r

R: REDACTED MATERIAL A. Salaries (Personnel by names orcategory) : Professionaf - Kenneth M. Moser, M. D. George C. Hojjar, M,. D, Paul G. Harsanyi, M. D. : Tedin'icol _Charles Brunswick, B.S. _ :: Dorothy Brown, lohnnie Burbank "' :Fringe Benefits (7,12?k) : L ConsumableSupplies (list by categories) Reagents, solutions .. Glassware, needles, miscellaneous tl7s understood that'theappl7cant and institutionol'officen in applying fona grant Hare read and found acceptable the Counc+!'s "Statement of Policy Containing Conditions and Terms Under Which Project Grants Are Made." otca, or a. tew~w .. `1= C. Other Expenses Gtemi:e) Equipment maintenance and repair Preparation of slides, graphs Data analysis (computer time) Phyments to volunteers 1...... ~ . .. .. ~ .. - O. Permanent Equipment (itemize) " Double Vortex Mixer Hand Calculator 500.00 600.00 sub-Total. -_ I,200.00 • 20b-.00 200.00 I 400.00 / 2,032.00 Total 15,980.00 a;r.ww af.Mai.ct Signature J_~'

i 11 Lisl Hnandotsupport fa ra+orch from all aource., lncludinp own InilituFlon, forthG ond%r reloted r.s.arch prol.eh. ~ r CurreM Title of pralect ' Role of Fibrlnolysis In Pulmonary Embolism t Pending Control Mechanisms oF the Fibrinolytic System In Man ~~~9~SEOOti