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356 Reduced fibrinolysis in preeclampsia (PE) with intrauterine gowth retardation (IUGR)
POSTER PRESENTATIONS
P-XV Pathophysiological
Studies
105
354
355
PLASMINOGEN ACTIVATION IN UNSTABLE ANGINA IS ASSOCIATED WITH AN ACUTE PHASE REACTION, BUT DOES NOT CORRELATE WITH OTHER INDEXES OF THROMBOTIC OR FIBRINOLYTIC ACTIVITY.
FLUVASTATIN REDUCES t-PA ANTIGEN AND t-PA/PAI-I COMPLEXES IN CORONARY PATIE/~TS WITH PRIMARY HYPERCHOLESTEROLEMIA AND HIGH LP(a). M. Bevilacqua, E. Santoli*, T. Vago, A. Rogolino, G. Norbiato, M. Milanl**. *Cardiovascular Surgery, Endocrinology Depamnent, "L. Sacco" Hospital, Milan, Italy.**Sandoz Prodotti Fannaceutici S.p.A., Medical Department, Milan, Italy.
G. Quaranta, L. M. Biasucci., G. Liuzzo, G. Caligiuri, C. Monaco, F. Summaria, A. Men, L. Massa, W. van de Greef, A. G. Rebuzzi, *C. Kluft, A. Maseri. Cardiology Institute, UCSC-Rome, Italy. * P G - T N O G a u b i u s Inst. Leiden, NL. In Unstable Angina (UA) an acute phase response and an increase in plasminogen have been reported. To assess whether plasminogen activation is related to the hemostatie or to the inflammatory systems in UA, we measured plasma levels o f Plasmin-c~2-antiplasmin (PAP), C-Reactive protein (CRP) and Thrombin-AntiThrombin 111 ( T A T ) , as markers o f plasminogen activation, inflanunation and thrombin production, respectively. W e also measured plasma levels o f D - D i m e r (DD), a fibrin degradation product, to assess actual lysis o f fibrin. W e studied 47 pts admitted to our C C U for severe U A Blood samples were taken at C C U admission. Results (median and range): Elevated levels were considered a b o v e m e a n +2 SD for PAP (700 ng/ml), D D (30gg/l) and T A T (6 Bg/ml) and levels >3 mg/I for CRP (90 ° percentile o f healthy subjects). Elevated levels o f P A P were observed in 18/47 pts (38%), but elevated levels o f D D and T A T were found only in 9/47 pts (19%). Conversely CRP w a s raised in 28/47 pts ( 6 0 % ) PAP levels (594ng/ml, 234-1899) did not correlate with levels o f DD (12.1gg/l, range 1.9-182; p~ns) or o f T A T (2.1~lg/ml, range 0.8-39, p=ns). Conversely a significant correlation was observed between P A P and CRP (3.7 rag/l, range 0.4-82; r - 0 . 4 5 , p=0.005), as well as between T A T and D D (r=0.3, p=0.047). Conclusions: An increased plasminogen activation is c o m m o n in UA, but is not associated to a similar activation o f the hemostatic system, as detectable by T A T and DD, but correlates with levels o f the acute phase protein CRP, suggesting that in unstable angina a strong endothelial activation m a y have place, as source o f plasminogen production, possibly on an inflammatory basis.
Purpose: we assessedthe effectsof 20-weektreatmentwith fluvastatin,the first fully synlethic HMGCoA reductaseinhibitor, on lipidprofilesand fibrinolyticparameters in coronaryheart diseasepatients with prima~ hypercholesterolemiaand high levels of Lp(a). Patients and Methods: in a randomized, double-blind, parallelgroups,placebocontrolledstudy, 50 patients(35 males,mean age 62 years)with clinic coronaryheart diseases, primaryhypercholesterolemia(total cholesterol >200 <300 mg/dL)and high Lp(a) levels(>30 mg/dL)were er~olled and randomlygiven fluvastatin(F) 40 mg once daily at bed-timeor the correspondingplacebo(P) for 20 weeks. At baseline(after a 4-weekof a controlleddiet single-blindplacebo run-in period), at week 8 and at week 20 total cholesterol(TC) HDL cholesterol (HDL-C), calculatedLDL choleaerol (LDL-C)triglycerides(TG), Apo-B, Lp(a), tissue-plasminogen activator(t-PA)antigen and t-PA/PAI-1complexeswere assessed. TC, HDL-C,TG were assessedby eilzymaticmethods.LDL-Cwas calculatedaccordingto Friedewald's fon,ula. Apo B was measuredby radial inmmnodiffusion.Lp(a), t-PA antigen and t-PA/PAI-1 complexeswere evaluated by means of ELISAinethods (Biopool). Duringthe entire study, all patients underwentdietary counseling. Results: 48 patients concluded the study. Two patients withdrawn because of side effects (F~ diffuse skin reaction; P- worseningin angina). At baseline, the two groups were well matched regarding all parametersevaluated:mean(SD)TC:F 246(42);P-251(58);LDL-C: F= 174(36);P- 175(51);HDLC: F- 48(14); P- 44(13); TG: F- 117(43); P- 134(63); Lp(a): F- 57(14); P- 54(16)(mg/dL).t-PA antigen and t-PA/pAI-Icomplexes,at baseline, were: 7.0(1) ng/mL and 8.2(3) ng/mL in F group and 6.3(2) ng/mL and 10.5(3)ng/mLin P grouprespectively.At week8, as comparedto baseline, F reduced significantly (T-test; p 0.004) TC and LDL-Cby 16% and 25% respectively.These positive effects were maintainedat week20. At week20, as comparedto randomizedplacebo,fluvastatinsignificantly (ANOVAtest; p< 0.03) reducedTC and LDL-Cby 23% and 30% respectively,and induceda significant increase(8%) in HDL-C(p 0.05). Aim B levelsdecreasedsignificantly(p- 0.03), since week S, in F group only,by 15% as compared1o baseline. No modificationsin Lp(a) levelswereobservedin the two groups duringthe study. Treatmentwith F was no characterizedby an increasein Lp(a) levels.At week 20, t-PA antigen levelsdecreasedsignificantly(T-test;p- 0.03), as comparedto baseline, in F group (from7 to 4 nghnL)but not in P group,t-PA antigenreductionwas not correlatedwith TC and LDL-C decrease.At week20 t-PA/pAI-Icomplexesin F groupweresignificantlyloweras comparedto P group (p<0.05; ANOVAtest) Conclusions: in high risk coronarypatients, tluvastatintreatment significantly reduces athcrogeniclipid fractions with a concomitantpositive effects on HDL-C and on circulathlg markersof endothelialinjuriesan&'oractivationsuch as t-PAandgenand t-PA/PAI-1 complexes.
356
357
REDUCED FIBRINOLYSIS IN PREECLAMPSIA (PE) WITH INTRAUTERINE GOWTH RETARDATION (IUGR) He.S1, Bremme K2 and Blombtick K 1 Dept. of Laboratory Medicine 1 and Dept. of Woman and Child Health 2, Karolinska Hospital, S-17176 Stockholm, Sweden Fibrin D-dimer is an end product in plasmin digestion of crosslinked fibrin. Its raised levels indicate increased fibrin formation and fibrinolysis. To study whether a more hypercoagulable state exists in PE with IUGR than in those without, we investigated plasma levels of fibrinogen, thrombin-antithrombin complex (TAT), D-dimers and plasminogen activators 1 and 2 (PAl-1 and PAl-P) in 14 normal pregnant (NP) and 33 PE women (NP and PE groups) during gestational weeks 30-35. The PE group consisted of 24 patients with IUGR and 9 without (IUGR and nonIUGR groups). Placental infarctions were present in 12 IUGR but not in the other 12 IUGR pregnancies (infarction and noninfarction groups) and the non-lUGR group. In PE group, levels of fibrinogen, TAT, D-dimer and PAl-1 were increased (p0.05), but the levels of D-dimer and PAl-2 were lower (p0.05). The rises in levels of fibrinogen, TAT and D-dimer comfirmed enhanced fibrin generation in PE, compared to NP. The lower D-dimer level in the IUGR group than in the non-lUGR implied that the fibrinolytic activity is suppressed in IUGR gestations whereas no significantly different levels of fibrinogen and TAT were found. The findings may explain a thrombotic state in the placenta. In the IUGR group, the PAl-2 level was decreased and the PAl-1 level was similar to that in the non-lUGR group, therefore the reduction in the fibrinolysis should not be related to these two inhibitors.
A P R O T I N I N M O D U L A T I O N OF P L A T E L E T A C T I V A T I O N IN C A R D I O P U L M O N A R Y B Y P A S S (CPB) P A T I E N T S Fareed J, Walen~,a JM. Koza M. Primack C. Shankev TV. Sullivan H. Montoya A. Pifarre R Loyola University Medical Center, Maywood, IL USA. Aprotinin (Ap), a proteinase inhibitor, reduces post-operative blood loss in CPB patients. To study the cyto-protective effect o f Ap on platelets, blood samples were collected from CPB patients, with Ap ( n - 7 ) or without (n=10), after anesthesia, 30 rain into CPB, after CPB/protamine, and 90 rain after CPB. Whole blood was incubated with saline (control) or agonists (ADP; ristocetin) at 37°C for 2.5 or 5.0 rain. Fixed samples were centrifuged (600g, 10 rain), the s u p e m a t a n t removed, and resuspended in Tyrode's buffer and anti-CD-6 I - F I T C (anti-GP-Illa) and anti-CD-62-PE (anti-GMP-140). Flow eytometric analysis (Coulter Epics-XL) demonstrated that most activated platelets (at any time point) are bound to other cells (rbds and wbc's). Analyzing this region, platelet activation (% GMP- 140 expression) by ADP decreased in both A p (p<0.001 vs. patients pre-op level) and untreated groups (p=0.037) over time on CPB, and a v e n d toward pre-operative activation levels was observed 90 min after. A trend o f increased ristocetin stimulated platelet activation was observed from on CPB to 90 min after CPB with Ap (11.9 :k 5.1% to 33.1 4- 8.6%) but not without Ap (17.5 ± 0.1% to 17.9 :k 2.3%). Platelet autoactivation increased more with time on CPB in the untreated group (ns). This study suggests that Ap keeps platelets quiet during CPB decreasing their ADP activatibility but preserving their von Willebrand ( G P - l b ; ristocetin activation) adhesion capacity after CPB. Since this flow cytometric analysis demonstrates for the first time that platelet-celhilar interacftions show more activity than platelet-platelet interactions, our future studies will focus on this to identify the principle mechanism(s) o f Ap.
P-XV Pathophysiological
Studies
105
354
355
PLASMINOGEN ACTIVATION IN UNSTABLE ANGINA IS ASSOCIATED WITH AN ACUTE PHASE REACTION, BUT DOES NOT CORRELATE WITH OTHER INDEXES OF THROMBOTIC OR FIBRINOLYTIC ACTIVITY.
FLUVASTATIN REDUCES t-PA ANTIGEN AND t-PA/PAI-I COMPLEXES IN CORONARY PATIE/~TS WITH PRIMARY HYPERCHOLESTEROLEMIA AND HIGH LP(a). M. Bevilacqua, E. Santoli*, T. Vago, A. Rogolino, G. Norbiato, M. Milanl**. *Cardiovascular Surgery, Endocrinology Depamnent, "L. Sacco" Hospital, Milan, Italy.**Sandoz Prodotti Fannaceutici S.p.A., Medical Department, Milan, Italy.
G. Quaranta, L. M. Biasucci., G. Liuzzo, G. Caligiuri, C. Monaco, F. Summaria, A. Men, L. Massa, W. van de Greef, A. G. Rebuzzi, *C. Kluft, A. Maseri. Cardiology Institute, UCSC-Rome, Italy. * P G - T N O G a u b i u s Inst. Leiden, NL. In Unstable Angina (UA) an acute phase response and an increase in plasminogen have been reported. To assess whether plasminogen activation is related to the hemostatie or to the inflammatory systems in UA, we measured plasma levels o f Plasmin-c~2-antiplasmin (PAP), C-Reactive protein (CRP) and Thrombin-AntiThrombin 111 ( T A T ) , as markers o f plasminogen activation, inflanunation and thrombin production, respectively. W e also measured plasma levels o f D - D i m e r (DD), a fibrin degradation product, to assess actual lysis o f fibrin. W e studied 47 pts admitted to our C C U for severe U A Blood samples were taken at C C U admission. Results (median and range): Elevated levels were considered a b o v e m e a n +2 SD for PAP (700 ng/ml), D D (30gg/l) and T A T (6 Bg/ml) and levels >3 mg/I for CRP (90 ° percentile o f healthy subjects). Elevated levels o f P A P were observed in 18/47 pts (38%), but elevated levels o f D D and T A T were found only in 9/47 pts (19%). Conversely CRP w a s raised in 28/47 pts ( 6 0 % ) PAP levels (594ng/ml, 234-1899) did not correlate with levels o f DD (12.1gg/l, range 1.9-182; p~ns) or o f T A T (2.1~lg/ml, range 0.8-39, p=ns). Conversely a significant correlation was observed between P A P and CRP (3.7 rag/l, range 0.4-82; r - 0 . 4 5 , p=0.005), as well as between T A T and D D (r=0.3, p=0.047). Conclusions: An increased plasminogen activation is c o m m o n in UA, but is not associated to a similar activation o f the hemostatic system, as detectable by T A T and DD, but correlates with levels o f the acute phase protein CRP, suggesting that in unstable angina a strong endothelial activation m a y have place, as source o f plasminogen production, possibly on an inflammatory basis.
Purpose: we assessedthe effectsof 20-weektreatmentwith fluvastatin,the first fully synlethic HMGCoA reductaseinhibitor, on lipidprofilesand fibrinolyticparameters in coronaryheart diseasepatients with prima~ hypercholesterolemiaand high levels of Lp(a). Patients and Methods: in a randomized, double-blind, parallelgroups,placebocontrolledstudy, 50 patients(35 males,mean age 62 years)with clinic coronaryheart diseases, primaryhypercholesterolemia(total cholesterol >200 <300 mg/dL)and high Lp(a) levels(>30 mg/dL)were er~olled and randomlygiven fluvastatin(F) 40 mg once daily at bed-timeor the correspondingplacebo(P) for 20 weeks. At baseline(after a 4-weekof a controlleddiet single-blindplacebo run-in period), at week 8 and at week 20 total cholesterol(TC) HDL cholesterol (HDL-C), calculatedLDL choleaerol (LDL-C)triglycerides(TG), Apo-B, Lp(a), tissue-plasminogen activator(t-PA)antigen and t-PA/PAI-1complexeswere assessed. TC, HDL-C,TG were assessedby eilzymaticmethods.LDL-Cwas calculatedaccordingto Friedewald's fon,ula. Apo B was measuredby radial inmmnodiffusion.Lp(a), t-PA antigen and t-PA/PAI-1 complexeswere evaluated by means of ELISAinethods (Biopool). Duringthe entire study, all patients underwentdietary counseling. Results: 48 patients concluded the study. Two patients withdrawn because of side effects (F~ diffuse skin reaction; P- worseningin angina). At baseline, the two groups were well matched regarding all parametersevaluated:mean(SD)TC:F 246(42);P-251(58);LDL-C: F= 174(36);P- 175(51);HDLC: F- 48(14); P- 44(13); TG: F- 117(43); P- 134(63); Lp(a): F- 57(14); P- 54(16)(mg/dL).t-PA antigen and t-PA/pAI-Icomplexes,at baseline, were: 7.0(1) ng/mL and 8.2(3) ng/mL in F group and 6.3(2) ng/mL and 10.5(3)ng/mLin P grouprespectively.At week8, as comparedto baseline, F reduced significantly (T-test; p 0.004) TC and LDL-Cby 16% and 25% respectively.These positive effects were maintainedat week20. At week20, as comparedto randomizedplacebo,fluvastatinsignificantly (ANOVAtest; p< 0.03) reducedTC and LDL-Cby 23% and 30% respectively,and induceda significant increase(8%) in HDL-C(p 0.05). Aim B levelsdecreasedsignificantly(p- 0.03), since week S, in F group only,by 15% as compared1o baseline. No modificationsin Lp(a) levelswereobservedin the two groups duringthe study. Treatmentwith F was no characterizedby an increasein Lp(a) levels.At week 20, t-PA antigen levelsdecreasedsignificantly(T-test;p- 0.03), as comparedto baseline, in F group (from7 to 4 nghnL)but not in P group,t-PA antigenreductionwas not correlatedwith TC and LDL-C decrease.At week20 t-PA/pAI-Icomplexesin F groupweresignificantlyloweras comparedto P group (p<0.05; ANOVAtest) Conclusions: in high risk coronarypatients, tluvastatintreatment significantly reduces athcrogeniclipid fractions with a concomitantpositive effects on HDL-C and on circulathlg markersof endothelialinjuriesan&'oractivationsuch as t-PAandgenand t-PA/PAI-1 complexes.
356
357
REDUCED FIBRINOLYSIS IN PREECLAMPSIA (PE) WITH INTRAUTERINE GOWTH RETARDATION (IUGR) He.S1, Bremme K2 and Blombtick K 1 Dept. of Laboratory Medicine 1 and Dept. of Woman and Child Health 2, Karolinska Hospital, S-17176 Stockholm, Sweden Fibrin D-dimer is an end product in plasmin digestion of crosslinked fibrin. Its raised levels indicate increased fibrin formation and fibrinolysis. To study whether a more hypercoagulable state exists in PE with IUGR than in those without, we investigated plasma levels of fibrinogen, thrombin-antithrombin complex (TAT), D-dimers and plasminogen activators 1 and 2 (PAl-1 and PAl-P) in 14 normal pregnant (NP) and 33 PE women (NP and PE groups) during gestational weeks 30-35. The PE group consisted of 24 patients with IUGR and 9 without (IUGR and nonIUGR groups). Placental infarctions were present in 12 IUGR but not in the other 12 IUGR pregnancies (infarction and noninfarction groups) and the non-lUGR group. In PE group, levels of fibrinogen, TAT, D-dimer and PAl-1 were increased (p
A P R O T I N I N M O D U L A T I O N OF P L A T E L E T A C T I V A T I O N IN C A R D I O P U L M O N A R Y B Y P A S S (CPB) P A T I E N T S Fareed J, Walen~,a JM. Koza M. Primack C. Shankev TV. Sullivan H. Montoya A. Pifarre R Loyola University Medical Center, Maywood, IL USA. Aprotinin (Ap), a proteinase inhibitor, reduces post-operative blood loss in CPB patients. To study the cyto-protective effect o f Ap on platelets, blood samples were collected from CPB patients, with Ap ( n - 7 ) or without (n=10), after anesthesia, 30 rain into CPB, after CPB/protamine, and 90 rain after CPB. Whole blood was incubated with saline (control) or agonists (ADP; ristocetin) at 37°C for 2.5 or 5.0 rain. Fixed samples were centrifuged (600g, 10 rain), the s u p e m a t a n t removed, and resuspended in Tyrode's buffer and anti-CD-6 I - F I T C (anti-GP-Illa) and anti-CD-62-PE (anti-GMP-140). Flow eytometric analysis (Coulter Epics-XL) demonstrated that most activated platelets (at any time point) are bound to other cells (rbds and wbc's). Analyzing this region, platelet activation (% GMP- 140 expression) by ADP decreased in both A p (p<0.001 vs. patients pre-op level) and untreated groups (p=0.037) over time on CPB, and a v e n d toward pre-operative activation levels was observed 90 min after. A trend o f increased ristocetin stimulated platelet activation was observed from on CPB to 90 min after CPB with Ap (11.9 :k 5.1% to 33.1 4- 8.6%) but not without Ap (17.5 ± 0.1% to 17.9 :k 2.3%). Platelet autoactivation increased more with time on CPB in the untreated group (ns). This study suggests that Ap keeps platelets quiet during CPB decreasing their ADP activatibility but preserving their von Willebrand ( G P - l b ; ristocetin activation) adhesion capacity after CPB. Since this flow cytometric analysis demonstrates for the first time that platelet-celhilar interacftions show more activity than platelet-platelet interactions, our future studies will focus on this to identify the principle mechanism(s) o f Ap.