Postoperative Hemostasis and Fibrinolysis in Patients Undergoing Cardiopulmonary Bypass with or without Aprotinin Therapy

1994 ◽  
Vol 72 (03) ◽  
pp. 438-443 ◽  
Author(s):  
He Lu ◽  
Charles Du Buit ◽  
Jeannette Soria ◽  
Bernard Touchot ◽  
Bernard Chollet ◽  
...  

SummaryIntra- and postoperative blood loss during open heart surgery is reduced by approximately 50% when aprotinin, a potent inhibitor for plasmin and kallikrein, is administered during surgery. But whether aprotinin increases the risk of thrombotic complications remains controversial. The aim of this study was to evaluate the effects of aprotinin administration on coagulation and fibrinolysis during and after cardiopulmonary bypass (CPB). Thirty patients undergoing CPB were randomly assigned to two comparable groups for a double-blind study (16 patients receiving high-dose aprotinin, 14 patients receiving placebo). Patients’ plasma levels of ATM (thrombin-induced modified antithrombin III), FbDP (fibrin degradation products, D-Dimers), t-PA (tissue-type plasminogen activator) and PAI-1 (plasminogen activator inhibitor type 1) were measured at regular intervals. In both groups, ATM level increased during surgery (from less than 30 to 90-110 ng/ml) and returned to normal 24 h after surgery and remained unchanged thereafter. Aprotinin reduced this increase in ATM levels (p = 0.02 at 30 min after the start of CPB). The FbDP generated during surgery was greatly reduced in the aprotinin group (945 ng/ml) in comparison with the placebo group (1889 ng/ml, p = 0.004). After surgery, FbDP levels decreased in both groups with nadirs at 2nd day (placebo group: 940 ng/ml and aprotinin group: 865 ng/ml) indicating a hypo-fibrinolytic period. Then, the FbDP level in both groups started to increase up to the 9th day, in an identical manner. This postoperative hypofibrinolysis is related to the changes of t-PA and PAI-1 levels: immediately after surgery there was a 2’fold increase in t-PA level and a 4-5 fold increase in PAI-1 level in the two groups. During the following 24 h, t-PA levels decreased in both groups. In contrast, PAI-1 levels in the placebo group during the same time increased sharply to a maximum level (175.7 ng/ml). This further increase did not occur in the aprotinin group although it remained at a high level (79.2 ng/ml). The difference in the increase of PAI-1 between the 2 groups (value at 24 h minus preoperative value: Dl-Tl) was significantly different (p = 0.04). Then t-PA continued to decrease and PAI-1 began to decrease steadily. Total blood loss was significantly reduced by aprotinin therapy (3.06 ml/kg versus 5.86 ml/kg). The present study confirms the inhibitory effects of aprotinin on both fibrinolytic activity and blood coagulation activation during CPB, and reveals an hypofibrinolytic period that lasts 48 h after surgery in both aprotinin and placebo groups. This inhibition of fibrinolysis is apparently associated with high PAI-1 level. The data of this study also show that 2 days after aprotinin therapy, there is no prolonged effect of aprotinin on fibrinolysis. In addition, the lower level of PAI-1 in the aprotinin group after surgery might result from a protection of endothelial cells by aprotinin, suggesting an unexpected benefit of aprotinin therapy.

2020 ◽  
Author(s):  
Zhen-feng ZHOU ◽  
Wen Zhai ◽  
Li-na YU ◽  
Kai SUN ◽  
Li-hong SUN ◽  
...  

Abstract Background: The blood saving efficacy of TXA in cardiac surgery has been proved in several studies, but TXA dosing regimens were varied in those studies. Therefore, we performed this study to investigate if there is a dose dependent in-vivo effect of TXA on fibrinolysis parameters by measurement of fibrinolysis markers in adults undergoing cardiac surgery with CPB, which has not been systematically elucidated.Methods: A double-blind, randomized, controlled prospective trial was conducted from February 11, 2017 to May 05, 2017. Thirty patients undergoing cardiac valve surgery were identified and randomly divided into a placebo group, low-dose group and high-dose group by 1: 1: 1. Fibrinolysis parameters were measured by plasma levels of D-Dimers, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), plasmin-antiplasmin complex (PAP), tissue plasminogen activator (tPA) and thrombomodulin (TM). Those proteins were measured at five different sample times: preoperatively before the TXA injection (T1), 5 min after the TXA bolus (T2), 5 min after the initiation of CPB (T3), 5 min before the end of CPB (T4) and 5 min after the protamine administration (T5). A Thrombelastography (TEG) and standard coagulation test were also performed.Results: Compared with the control group, the level of the D-Dimers decreased in the low-dose and high-dose groups when the patients arrived at the ICU and on the first postoperative morning. Over time, the concentrations of PAI-1, TAFI, and TM, but not PAP and tPA, showed significant differences between the three groups (p <0.05). Compared with the placebo group, the plasma concentrations of PAI-1 and TAFI decreased significantly at the T3 and T4 (p <0.05); TAFI concentrations also decreased at the T5 in low-dose group (p <0.05). Compared with the low-dose group, the concentration of TM increased significantly at the T4 in high-dose group. No significant differences were observed in the levels of the coagulation proteins at any points between the groups.Conclusions: The vivo effect of low dose TXA is equivalent to high dose TXA on fibrinolysis parameters in adults undergoing valvular cardiac surgery with cardiopulmonary bypass, and we recommend a low dose TXA regimen for those patients.Clinical trial number and registry URL: ChiCTR-IPR-17010303; http://www.chictr.org.cn, Principal investigator: Zhen-feng ZHOU, Date of registration: January 1, 2017.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhen-feng Zhou ◽  
Wen Zhai ◽  
Li-na Yu ◽  
Kai Sun ◽  
Li-hong Sun ◽  
...  

Abstract Background The blood saving efficacy of TXA in cardiac surgery has been proved in several studies, but TXA dosing regimens were varied in those studies. Therefore, we performed this study to investigate if there is a dose dependent in-vivo effect of TXA on fibrinolysis parameters by measurement of fibrinolysis markers in adults undergoing cardiac surgery with CPB. Methods A double-blind, randomized, controlled prospective trial was conducted from February 11, 2017 to May 05, 2017. Thirty patients undergoing cardiac valve surgery were identified and randomly divided into a placebo group, low-dose group and high-dose group by 1: 1: 1. Fibrinolysis parameters were measured by plasma levels of D-Dimers, plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), plasmin-antiplasmin complex (PAP), tissue plasminogen activator (tPA) and thrombomodulin (TM). Those proteins were measured at five different sample times: preoperatively before the TXA injection (T1), 5 min after the TXA bolus (T2), 5 min after the initiation of CPB (T3), 5 min before the end of CPB (T4) and 5 min after the protamine administration (T5). A Thrombelastography (TEG) and standard coagulation test were also performed. Results Compared with the control group, the level of the D-Dimers decreased in the low-dose and high-dose groups when the patients arrived at the ICU and on the first postoperative morning. Over time, the concentrations of PAI-1, TAFI, and TM, but not PAP and tPA, showed significant differences between the three groups (P <  0.05). Compared with the placebo group, the plasma concentrations of PAI-1 and TAFI decreased significantly at the T3 and T4 (P <  0.05); TAFI concentrations also decreased at the T5 in low-dose group (P < 0.05). Compared with the low-dose group, the concentration of TM increased significantly at the T4 in high-dose group. Conclusions The in-vivo effect of low dose TXA is equivalent to high dose TXA on fibrinolysis parameters in adults with a low bleeding risk undergoing valvular cardiac surgery with cardiopulmonary bypass, and a low dose TXA regimen might be equivalent to high dose TXA for those patients. Trial registration ChiCTR-IPR-17010303, Principal investigator: Zhen-feng ZHOU, Date of registration: January 1, 2017.


1994 ◽  
Vol 22 (5) ◽  
pp. 529-533 ◽  
Author(s):  
M. J. Swart ◽  
P. C. Gordon ◽  
P. B. Hayse-Gregson ◽  
R. A. Dyer ◽  
A. L. Swanepoel ◽  
...  

Fifty patients undergoing primary coronary artery bypass surgery and 50 patients undergoing valve surgery received either high-dose aprotinin (2 million units loading dose, 2 million units added to the CPB prime, and 500,000 units/hr maintenance infusion) or placebo. Mean postoperative blood loss in the first six hours was reduced from 321 ml in the placebo group to 172 ml in the aprotinin group (95% confidence interval (CI) for difference = 95 to 189 ml). Seven patients in the placebo group and 16 patients in the aprotinin group did not require transfusion with homologous blood. This study adds to the growing body of evidence that the administration of high-dose aprotinin reduces blood loss and blood transfusion requirements associated with primary cardiac surgery.


Medicina ◽  
2012 ◽  
Vol 48 (10) ◽  
pp. 75
Author(s):  
Agnese Ozolina ◽  
Eva Strike ◽  
Inta Jaunalksne ◽  
Jelena Serova ◽  
Tatjana Romanova ◽  
...  

Background and Objective. The plasminogen activator inhibitor type-1 (PAI-1) gene promoter contains 675 (4G/5G) polymorphism. The aim of this study was evaluate the effect of the PAI-1 promoter-675 (4G/5G) polymorphism on the concentrations of PAI-1 and tissue plasminogen activator/PAI-1 (t-PA/PAI-1) complex and bleeding volume after on-pump cardiac surgery.Material and Methods. A total of 90 patients were included in the study at Pauls Stradins Clinical University Hospital. Seven patients were excluded due to surgical bleeding. Eighty-three patients were classified according to the PAI-1 genotype: 21 patients had the 4G/4G genotype; 42, the 4G/5G genotype; and 20, the 5G/5G genotype. The following fibrinolysis parameters were recorded: the PAI-1 level preoperatively, D-dimer level at 0, 6, and 24 hours after surgery, and t-PA/ PAI-1 complex level 24 hours postoperatively. A postoperative bleeding volume was registered in mL 24 hours after surgery.Results. The patients with the 5G/5G genotype had significantly lower preoperative PAI-1 levels (17 [SD, 10.8] vs. 24 ng/mL [SD, 9.6], P=0.04), higher D-dimer levels at 6 hours (371 [SD, 226] vs. 232 ng/mL [SD, 185], P=0.03) and 24 hours (326 [SD, 207] vs. 209 ng/mL [SD, 160], P=0.04), and greater postoperative blood loss (568 [SD, 192] vs. 432 mL [168], P=0.02) compared with the 4G/4G carriers. There were no significant differences in the levels of the t-PA/PAI-1 complex comparing different genotype groups.Conclusions. The carriers of the 5G/5G genotype showed the lower preoperative PAI-1 levels, greater chest tube blood loss, and higher D-dimer levels indicating that the 5G/5G carriers may have enhanced fibrinolysis.


2008 ◽  
Vol 108 (4) ◽  
pp. 596-602 ◽  
Author(s):  
Jose L. Iribarren ◽  
Juan J. Jimenez ◽  
Domingo Hernández ◽  
Maitane Brouard ◽  
Debora Riverol ◽  
...  

Background Plasminogen activator inhibitor 1 (PAI-1) attenuates the conversion of plasminogen to plasmin. Polymorphisms of the PAI-1 gene are associated with varying PAI-1 levels and risk of prothrombotic events in nonsurgical patients. The purpose of this study, a secondary analysis of a clinical trial, was to investigate whether PAI-1 genotype affects the efficacy of tranexamic acid (TA) in reducing postoperative chest tube blood loss of patients undergoing cardiopulmonary bypass. Methods Fifty patients were classified according to PAI-1 genotype (4G/4G, 4G/5G, or 5G/5G). Twenty-four received 2 g TA before and after cardiopulmonary bypass, whereas 26 received placebo. The authors recorded data related to coagulation, fibrinolysis, and bleeding before surgery, at admission to the intensive care unit (0 h), and 4 and 24 h later. Results In patients not receiving TA, those with the 5G/5G genotype had significantly higher chest tube blood loss and transfusion requirements compared with patients with the other genotypes at all time points. Patients with the 5G/5G genotype receiving TA showed significantly lower blood loss compared with the placebo group. There were no significant differences in blood loss or transfusion requirements between patients with the 4G/4G genotype when TA was used. Conclusions Plasminogen activator inhibitor-1 5G/5G homozygotes who did not receive TA showed significantly greater postoperative bleeding than patients with other PAI-1 genotypes. 5G/5G homozygotes who received TA showed the greatest blood-sparing benefit.


1995 ◽  
Vol 73 (05) ◽  
pp. 825-828 ◽  
Author(s):  
M Spannagl ◽  
G Dooijewaard ◽  
W Dietrich ◽  
C Kluft

SummaryIntraoperative high-dose aprotinin administration has been shown to reduce the intra-and postoperative blood loss in cardiac surgery. The haemostatic effect has been attributed to platelet preserving properties and to inhibition of contact activation reducing thrombotic and fibrinolytic activity during and after cardiopulmonary bypass (CPB).Here we report on the effects of aprotinin on urokinase-type plasminogen activator, especially on the protection of the zymogen singlechain urokinase-type plasminogen activator (scu-PA). scu-PA occurs cell associated as well as free in the circulation (concentration 50 pM, half-life 5 min), and is potentially activated by kallikrein and plasmin, both potent targets for aprotinin. The generated active two-chain u-PA (tcu-PA) is a powerful activator of fibrinolysis.Sixteen male patients undergoing myocardial revascularization were randomly assigned to aprotinin treatment (A) or control group (C).Plasma concentration of total u-PA antigen and of the specific forms scu-PA(zymogen) and tcu-PA(active enzyme) were measured at different stages intraoperatively and two hours postoperatively. After an initial drop due to haemodilution at the onset of CPB, the concentrations of circulating u-PA forms restored intraoperatively in A, but remained subnormal in C until the end of the observation period. The concentration of total u-PA antigen of shed mediastinal blood was both in A and C two-fold higher than in the circulation, but the antigen was preserved as the zymogen scu-PA in A and largely converted to an inactive, non activatable form in C. Intra- and postoperative blood losses were less than half the amount in A as compared to C.It is concluded that without aprotinin administration activation of circulatory scu-PA occurs, accompanied by stimulation of fibrinolysis and bleeding, finally resulting in elimination of tcu-PA complexed with endogenous inhibitors. Furthermore, cellular release of scu-PA occurs at or near the bleeding sites, as evidenced by the two-fold higher u-PA antigen concentration in the shed mediastinal blood. The released scu-PA is also activated and subsequently converted to an inactive form unless aprotinin is administered. High-dose aprotinin application during CPB effectively protects circulating and released scu-PA from activation and attenuates bleeding consequences.


1993 ◽  
Vol 70 (03) ◽  
pp. 486-490 ◽  
Author(s):  
Mojca Stegnar ◽  
Andrej Zore ◽  
Živa Novak-Antolič ◽  
Neva Vovk ◽  
Egbert K O Kruithof

SummaryPregnancy is associated with depressed fibrinolysis as judged from the decreased fibrinolytic response to venous occlusion. In order to elucidate if this decreased response is due to an increase in plasminogen activator inhibitors 1 and 2 (PAI-1, PAI-2), and/or to decreased release of tissue-type plasminogen activator (t-PA) antigen during venous occlusion, 36 women (18 women with normal pregnancy and 18 with gestational hypertension without proteinuria) were followed during pregnancy and puerperium. In each woman a 20 min venous occlusion was performed in the second and in the third trimester of pregnancy and 3 days after delivery. The increase in t-PA antigen after venous occlusion relative to basal value was in the second trimester of pregnancy on average 3.7 fold, in the third trimester 4.4 fold, and so not reduced compared to non-pregnant women (3.7 fold increase). After delivery the increase in t-PA antigen was significantly enhanced (8.5 fold, p <0.005). The fibrinolytic response to venous occlusion measured by euglobulin and t-PA activity was significantly decreased in the third trimester compared to non-pregnant values (both p <0.005) and returned to somewhat higher (euglobulin clot lysis) or significantly higher (t-PA activity, p <0.01) values 3 days after delivery. Decreased euglobulin and t-PA activity after venous occlusion in the third trimester coincided with significant increases in basal PAI activity, PAI-1 antigen and PAI-2 antigen (2.9, 2.5 and >30 fold increase relative to non-pregnant values, respectively, all p <0.001). No significant differences in fibrinolytic variables were observed between nor-motensive and hypertensive pregnant women. It was concluded that t-PA antigen release during venous occlusion is not decreased during pregnancy and puerperium, and that decreased fibrinolytic response measured by global methods should be attributed to increased t-PA inhibitors. Gestational hypertension without proteinuria is not characterized by changes in fibrinolytic responses different from those observed in normal pregnancy.


1993 ◽  
Vol 70 (03) ◽  
pp. 469-474 ◽  
Author(s):  
Johann Wojta ◽  
Marisa Gallicchio ◽  
Hans Zoellner ◽  
Peter Hufnagl ◽  
Karena Last ◽  
...  

SummaryThe effect of thrombin on the fibrinolytic potential of human vascular smooth muscle cells (SMC) in culture was studied. SMC of different origin responded to thrombin treatment with a dose and time dependent increase in tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) levels in both cell lysates and conditioned media with maximum effects achieved at 10-20 IU/ml thrombin. PAI-1 antigen levels also increased in the extracellular matrix of thrombin treated SMC. PAI-2 levels in cell lysates of such SMC were not affected by thrombin. The effect was restricted to active thrombin, since DFP-thrombin and thrombin treated with hirudin showed no increasing effect on t-PA and PAI-1 levels in SMC.Enzymatically active thrombin also caused a four-fold increase in specific PAI-1 mRNA and a three-fold increase in t-PA mRNA.Furthermore we demonstrated the presence of high and low affinity binding sites for thrombin on the surface of SMC with a K D = 4.3 × 10−10 M and 9.0 × 104 sites per cell and a KD = 0.6 × 10−8 M and 5.8 × 105 sites per cell respectively.Thrombin could come in contact with SMC in case of vascular injury or following gap formation between endothelial cells. Our data support the idea that besides its known proliferative effect for SMC, thrombin could also modulate their fibrinolytic system.


1987 ◽  
Author(s):  
R R Schleef ◽  
M P Bevilacqua ◽  
M Sawdey ◽  
M A Gimbrone ◽  
D J Loskutoff

The regulation of the fibrinolytic system of cultured human umbilical vein endothelial cells (ECs) by two distinct monokines (IL-1 and TNF) was investigated. Conditioned media (CM) was collected from ECs cultured for 24 h in the presence of the monokines and analyzed in quantitative immunological assays for PAI-1 activity and tPA antigen. Both monokines induced a dose-dependent increase in extracellular PAI-1 activity, with a concomitant decrease in tPA antigen. Maximal effects were achieved with either 10 U/ml IL-1 or 200 U/ml of TNF, and resulted in a 4 fold increase in PAI-1 and a 50% decrease in tPA. The kinetics of the effects of both monokines on EC PAI-1 and tPA were similar, with maximal response detected at 24 h. Cell-associated PAI-1 also increased in response to these monokines. For example, a 24 h exposure of EC to TNF (250 U/ml) or IL-1 (5 U/ml) caused a 5-fold increase in cell-associated PAI-1. Northern blot analysis using a PAI-1 cDNA probe indicated that the monokines increased the levels of two RNA species, corresponding to PAI mRNAs of approximately 3.0 and 2.2 kb in length. To determine if the increase in cel 1-associated PAI-1 reflects a storage pool of rapidly releasable PAI-1, ECs were pretreated with IL-1 for 24 h, washed and the PAI-1 activity in CM measured after 5, 15 and 60 min treatment with known secretagogues (i.e., phorbol myristate acetate, calcium ionophore A23187). Although IL-1 treated ECs released PAI-1 at a rate which was 5-fold higher than controls, this rate was not increased further by treatment with phorbol myristate acetate or ionophore. The fact that both monokines act in a similar manner strengthens the hypothesis that the local development of immune and inflammatory processes could reduce endothelial fibrinolytic activity, thus leading to the pathologic formation of intravascular thrombi.


Perfusion ◽  
1992 ◽  
Vol 7 (3) ◽  
pp. 195-199 ◽  
Author(s):  
Carlo Dellora ◽  
Paola Minola ◽  
Filippo Parodi

This study was designed to evaluate the effects of C1-esterase inhibitor (C1-INH) on haemostasis and blood loss in routine cardiopulmonary bypass (CPB). To determine whether or not C1-INH reduces blood loss or transfusion requirements after routine CPB, we randomized 20 patients to receive double-blind either C1-INH (15 IU/kg over 10 minutes intravenously) or placebo following heparin administration. The two groups were similar in age, sex, prior salicylate use and time on CPB. At 30 minutes from the beginning of CPB and postprotamine, factor XII, factor XI, C1-INH and prekallikrein activity were significantly higher ( p < 0.05) than in the placebo group. No manifestations of hypercoagulability were seen in either group. Despite this haemostatic effect, patients treated with C1-INH had similar postoperative blood loss to the placebo group and similar blood transfusion requirements. We conclude that routine use of C1-INH in CPB is unwarranted.


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