The effects of aprotinin and tranexamic acid on thrombin generation and fibrinolytic response after cardiac surgery

Background: Thrombin formation during cardiac surgery could result in disordered hemostasis and thrombosis. The aim of the study was to examine the effects of aprotinin and tranexamic acid on thrombin generation and fibrinolytic activity in patients undergoing cardiac surgery. Methods: Data were collected prospectively from 60 patients undergoing coronary artery bypass grafting using cardiopulmonary bypass (CPB). In a randomized sequence, 20 patients received aprotinin, 20 patients received tranexamic acid, and in 20 patients placebo was used. Results: Significant thrombin activity was found in all the studied patients. Thrombin generation was less in the aprotinin group than in the tranexamic acid and the placebo group (thrombin/anti‐thrombin III complexes 33.7 ± 3.6, 53.6 ± 7.0 and 44.2 ± 5.3 µg/l 2 h after CPB and F1 + 2 fragment 1.50 ± 0.10, 2.37 ± 0.37 and 2.04 ± 0.20 nmol/l 6 h after surgery, respectively). The inhibition of fibrinolysis was significant with both anti‐fibrinolytic drugs (d ‐dimers 0.427 ± 0.032, 0.394 ± 0.039 and 2.808 ± 0.037 mg/l 2 h after CPB, respectively). The generation of d ‐dimers was inhibited until 16 h after CPB in the aprotinin group. The plasminogen activation was significantly less in the aprotinin group (plasmin/anti‐plasmin complexes 0.884 ± 0.095, 2.764 ± 0.254 and 1.574 ± 0.185 mg/l 2 h after CPB, respectively). Conclusion: Thrombin formation is inevitable in coronary artery bypass surgery when CPB is used. The suppression of fibrinolytic activity, either with aprotinin or with tranexamic acid interferes with the hemostatic balance as evaluated by biochemical markers. Further investigations are needed to define the role of hemostatic activation in ischemic complications associated with cardiac surgery.     

Use of antifibrinolytics in pediatric cardiac surgery: Where are we now?

Fibrinolytic activation is a major and preventable source of bleeding in neonates and children undergoing cardiac surgery with cardiopulmonary bypass. Based on the existing literature (adult and pediatric; cardiac and noncardiac), prophylactic administration of antifibrinolytic agents can help reduce fibrinolytic activation, and consequently reduces perioperative bleeding and the requirement for blood product transfusion. Due to the increased risk of renal failure and mortality reported in adults undergoing cardiac surgery, aprotinin should not be considered as a safe option in neonates and children. Further well‐designed studies would be required before the prophylactic administration of aprotinin could be considered in pediatric cardiac surgery. The lysine analogs, tranexamic acid and ?‐aminocaproic acid,, should be considered as safe and effective antifibrinolytic agents. Although no major side effects have been reported following the administration of lysine analogs in children undergoing cardiac surgery, high‐dose tranexamic acid should not be recommended in order to avoid the increased risk of clinical seizures. Despite the recent advances made in our understanding of the pharmacokinetics of tranexamic acid and ?‐aminocaproic acid,, the optimal plasmatic concentration to be targeted remains unknown. Further studies are therefore urgently needed to better define the optimal dose regimen to be used in neonates and children. In the meantime, the dose regimen published in the most recent pharmacokinetic studies can be used. Although no studies have assessed the effect of massive bleeding and transfusion on the plasmatic concentrations of the lysine analogs, additional boluses might be considered in the presence of bleeding and/or when signs of fibrinolytic activations are observed on viscoelastic hemostatic assays.     

Impaired fibrinolysis in cyclosporine-treated renal transplant patients. Analysis of the defect and beneficial effect of fish-oil.

Cyclosporine treatment has been associated with thrombotic vascular complications. We investigated the activity of the fibrinolytic system and its capacity to respond upon DDAVP stimulation in a group of 20 cyclosporine-treated patients as compared with a group of 9 azathioprine-treated patients. Furthermore, the effect of the administration of fish-oil to these patients on the endogenous fibrinolytic activity was studied in a double-blind randomized, placebo-controlled cross-over study. The cyclosporine-treated patients showed a significantly reduced plasminogen activator activity and plasmin generation response upon the infusion of DDAVP as compared with the azathioprine group. In the cyclosporine group 60% of the patients had an impaired fibrinolytic response, whereas this was found in only 11% of the azathioprine-treated patients (P < 0.05). The impairment of the endogenous fibrinolysis activity could be attributed either to a defective release of plasminogen activator from the vessel wall (67% of patients) or to high plasma levels of plasminogen activator inhibitor 1 (33% of patients). Administration of fish-oil resulted in a significant improvement of the impaired fibrinolysis in the cyclosporine group. Particularly, in patients with a defective release of plasminogen activator from the vessel wall, fish-oil treatment resulted in a normalization of the fibrinolytic activity. These results indicate that cyclosporine treatment induces an impaired fibrinolysis that may contribute to the frequent occurrence of thromboembolic complications and eventually the impairment of renal function in cyclosporine-treated patients. The beneficial effect of the administration of fish-oil on the endogenous fibrinolysis may result in a reduction of the adverse events associated with cyclosporine treatment.     

Effects of minimal dose aprotinin on blood loss and fibrinolytic system-complement activation in coronary artery bypass grafting surgery

BACKGROUND: To determine whether 500,000 KIU aprotinin is effective to reduce blood loss in coronary artery bypass grafting (CABG) and to evaluate the effects of this regimen on hematologic parameters. METHODS: Forty-four patients scheduled for primary CABG were randomly assigned to the aprotinin (n = 24) or control group (n = 20). In aprotinin group, aprotinin was administered in two equal doses (before skin incision and added to the pump prime). Ventilation time, intensive care unit stay, mediastinal tube drainage, hospitalization, transfusion requirements, and postoperative morbidities and mortality were noted. Hematologic markers of fibrinolytic activity and complement activation were also measured pre- and postoperatively. RESULTS: Although less mediastinal drainage occurred in aprotinin group, the difference was not statistically significant. Other postoperative variables like transfusion requirements, morbidities, and mortality were also found to be similar between groups. Among hematologic parameters, only postoperative levels of alpha2-antiplasmin and plasminogen activator inhibitor-1 were significantly higher in aprotinin group. CONCLUSIONS: Although plasmin inhibitors begin to rise at this very low aprotinin dosage, it is not advisable to use this aprotinin regimen in CABG patients.     

Fibrinolytic inhibitors in off-pump coronary surgery: a prospective, randomized, double-blind TAP study (tranexamic acid, aprotinin, placebo).

OBJECTIVE: To evaluate and compare hemostatic effects of tranexamic acid vs. aprotinin vs. placebo in off-pump coronary artery bypass (OPCAB) surgery and, in addition, to assess the safety of fibrinolytic inhibitors therapies. METHODS: In a prospective, randomized, double-blind study finally 91 patients undergoing OPCAB were investigated (group A, n=32, tranexamic acid 1g before skin incision and continuously 200mg/h; group B, n=29, aprotinin 1,000,000IU before skin incision and 250,000IU/h; group C, n=30, placebo). RESULTS: Highly significant inter-group differences were found in cumulative blood loss within 4h (geometric means [95% confidence intervals]-group A: 89.3 [72.7, 109.8] mL, group B: 72.3 [49.2, 106.3] mL and group C: 192.3 [151.8, 243.5] mL) (P<0.001), within 8h (group A: 152.1 [120.7, 191.6] mL, group B: 130.3 [88.1, 192.8] mL and group C: 283.8 [226.0, 356.3] mL) (P=0.001), and within 24h postoperatively (group A: 410.3 [337.6, 498.6] mL, group B: 345.8 [256.0, 398.2] mL and group C: 619.8 [524.3, 732.8] mL) (P<0.001). At all time points, placebo group C was significantly distinct from the groups treated with fibrinolytic inhibitors (groups A and B). However, no differences between groups A and B were found. Both mean hemoglobin and hematocrit values 24h postoperatively were different between the groups (P=0.018 and P=0.077, respectively), acheiving the lowest value in group C. Number of re-transfuzed patients was highest in group C, but without statistical significance (either packed red blood cells, P=0.119 or fresh-frozen plasma, P=0.118). We observed one postoperative myocardial infarction in aprotinin treated group B and one temporary postoperative myocardial ischemia in placebo group C, no cerebrovascular or pulmonary embolism was noticed. Treated groups A and B did not demonstrate postoperative increase in mean levels of myocardial enzymes, compared with group C. Significantly higher mean values of D-dimer were found in group C 24h postoperatively (P<0.001). CONCLUSIONS: Both tranexamic acid and aprotinin seem to be similarly effective in the reduction of postoperative blood loss in OPCAB. Tranexamic acid appears to be cost-effective and safe alternative to aprotinin.     

External pneumatic compression and fibrinolysis in abdominal surgery

INTRODUCTION: External pneumatic compression (EPC) devices prevent lower extremity deep venous thrombosis by increasing venous flow and thereby reducing stasis. Early studies suggested that they also enhance systemic fibrinolytic activity and thus prevent thrombus formation; more recent studies have been conflicting. The hypothesis of this study was that EPC devices enhance systemic fibrinolysis or reduce postoperative fibrinolytic impairment in patients undergoing abdominal surgical procedures. METHODS: Each of 48 patients (98% male; mean age, 67 years) undergoing major intra-abdominal surgical procedures (36 bowel procedures, 12 aortic reconstructions) was prospectively randomized to one of three treatments for deep venous thrombosis prophylaxis: subcutaneous heparin injections (HEP group), use of a thigh-length sequential EPC device (EPC group), or both (HEP + EPC group). Antecubital venous samples were collected for measurement of systemic fibrinolytic activity on the day before surgery, after induction of anesthesia but before prophylaxis was initiated, and on postoperative days 1, 3, and 5. Fibrinolysis was assessed through measurement of the activities of the rate limiting fibrinolytic activator, tissue plasminogen activator, and its inhibitor plasminogen activator inhibitor-1 with amidolytic methods. RESULTS: On the day before surgery, plasminogen activator inhibitor-1 activity was elevated in all groups in comparison with that in age-matched and sex-matched controls (20.3 +/- 0.6 AU/mL). In the HEP group, plasminogen activator inhibitor-1 activity was further elevated above the value for the day before surgery on postoperative day 1 (28.5 +/- 4.3 AU/mL; P =.04) and postoperative day 3 (25.1 +/- 1.9 AU/mL; P =.07). No significant decrease in plasminogen activator inhibitor-1 activity occurred in either group treated with EPC devices in comparison with the HEP group at any time. There were no changes in tissue plasminogen activator activity postoperatively in the HEP group and no significant increases in either EPC group at any point. CONCLUSIONS: Reduced systemic fibrinolytic activity ("fibrinolytic shutdown") occurred in these patients after abdominal surgery; it was manifested as increased plasminogen activator inhibitor-1 activity. EPC devices did not enhance systemic fibrinolysis or prevent postoperative shutdown either by decreasing plasminogen activator inhibitor-1 activity or by increasing tissue plasminogen activator activity. These data suggest that EPC devices do not prevent deep venous thrombosis by fibrinolytic enhancement; effective prophylaxis is achieved only when the devices are used in a manner that reduces lower extremity venous stasis.     

Role of fibrinolysis in the formation of postoperative adhesions

It has been hypothesized that peritoneal hypofibrinolysis is of importance in the formation of postoperative adhesions, but results from experiments with fibrinolytic modulators are conflicting. We tested this hypothesis in a controlled prospective study in rabbits, comparing the effects of fibrinolytic inhibition (tranexamic acid) to fibrinolysis enhancement by local instillation of gel containing tissue-type plasminogen activator. Adhesion formation was measured after 1 week in a strictly standardized way and is presented as a percentage of an induced lesion that was covered by adhesions. Fibrinolytic inhibition significantly increased adhesion formation, both to the parietal peritoneum (34.2%+/- 3.2%) compared with untreated control (19.7%+/- 3.3%, p < 0.01) and to the bowel (76.3%+/- 5.8%) compared with untreated control (51.2%+/- 8.7%, p < 0.05). Control gel significantly increased adhesions to the parietal peritoneum (35.6%+/- 4.6%) versus untreated control (19.7%+/- 3.3%, p < 0.05), whereas gel containing tissue-type plasminogen activator significantly reduced the amount of adhesions to the parietal peritoneum (4.9%+/- 1.7%) compared with untreated control (19.7%+/- 3.3%, p < 0.01) and abolished adhesion formation to the injured bowel. The fibrinolytic system thus seems to be intimately involved in the early formation of intraabdominal adhesions.     

Diminished anticoagulant and fibrinolytic activity following liver transplantation.

This study analyzed the coagulation changes in twenty patients after orthotopic liver transplantation. The procoagulant, anticoagulant, and fibrinolytic systems were studied during the first two postoperative weeks. Within the first postoperative day all extrinsic and intrinsic pathway factors became normal except factors IX, VII, and X, which recovered within the next 24 hr. Of interest are the changes in factor VIII, which reached a high concentration with an increase in its antigenic fraction during the study. However, coagulation inhibitors showed a different pattern. In fact, antithrombin III (AT-III) and protein C (PC) needed from 7 to 14 days to reach normal values. Total protein S (TPS) and free protein S (FPS) did not recover until day 7, whereas heparin cofactor II (HC-II) remained at subnormal levels throughout the study. Thrombin-antithrombin III complex (TAT) values were strikingly elevated in the immediate postoperative period. Fibrinolysis parameters showed plasminogen (PL) levels in the normal range until day 4. Antiplasmin (AP) followed a curve parallel to that of plasminogen but its levels were higher during this observation period. Similarly the initial elevation in plasminogen activator inhibitor 1 endothelial type (PAI-1) levels remained high until days 4 and 7. In summary, it can be concluded that during the postoperative phase after OLT a hypercoagulable state is developed as a result of diminished anticoagulant and fibrinolytic activity. This coagulation might be a nontechnical factor contributing to the thrombotic vascular complications of some liver recipients.     

Local Coagulofibrinolysis in the Postsurgical Recovery of Patients with Chronic Subdural Haematoma

Summary  Postoperative recovery of patients with chronic subdural haematoma (CSH) was investigated by comparing pre- and postoperative coagulant and fibrinolytic activity in the haematoma contents of 15 patients with SCH. Patients in this study were treated draining the haematoma cavity without irrigation, a procedure dubbed the closed drainage. Haematomas were collected during, and 24 hrs after, surgery. Postoperative fibrinolytic activity was lower than that observed pre-operatively. In particular, levels of tissue plasminogen activator activity (TPA), and fibrin and fibrinogen degradation products (FDP) all decreased. In contrast, coagulant activity increased postoperatively.  This paper will discuss the role of local coagulofibrinolysis in the postoperative recovery of CSH patients.     

Comparative evaluation of the effects of tranexamic acid and low-dose aprotinin on post-valvular heart surgery bleeding and allogenic transfusion

Bleeding diathesis and allogenic transfusion after complex heart surgery, such as heart valve surgery, may result in complications such as transfusion reaction, viral infection, postoperative infection, haemodynamic disturbance, prolonged stay in the intensive care unit and hospital, renal and respiratory failure and mortality. In this prospective, double-blind, randomized, placebo-controlled clinical trial, 90 patients were randomly divided into three groups: aprotinin, tranexamic acid and control. Chest-tube drainage, transfusion requirements and renal and neurological complications were evaluated. We found that chest-tube drainage during the first (P < 0.0001) and second 24 h (P = 0.001) after admission to the intensive care unit were significantly lower in the aprotinin group. The amounts of transfused packed red blood cells (P < 0.0001) and platelets (P = 0.02) were significantly lower in the aprotinin and tranexamic acid groups. The quantity of transfused fresh frozen plasma (P = 0.034) was significantly lower in the aprotinin group only. We did not find any neurological complications or renal failure in the three groups. Our data suggest that in valvular heart surgery, low-dose aprotinin is significantly better than tranexamic acid or a placebo for reduction of postoperative bleeding and allogenic transfusion, without increasing adverse outcomes.     

Initiation of a fibrinolytic system in hepatic resection: The roles of tissue-type plasminogen activator and plasminogen activator inhibitor-1

The factors related to the initiation of fibrinolysis, especially with regard to the tissue-type plasminogen activator (tPA) and the plasminogen activator inhibitor-1 (PAI-1), were investigated in 15 patients who underwent hepatic resection, and the findings were compared between those with normal livers and those with diseased livers. It was found that tPA increased before hepatic division, whereas PAI-1 increased after hepatic division and reached a peak immediately following the operation. Plasminogen decreased during hepatectomy, reaching its lowest point on postoperative day 1, and increasing later. Decreased levels of both plasminogen and the ₂-plasmin inhibitor were considered to be partly due to plasmin formation in the blood. Patients with a diseased liver tended to have higher intraoperative values of euglobulin lysis activity and higher postoperative values of plasminogen activator, but significantly lower postoperative values of ₂-plasmin inhibitor than those with a normal liver. The results of this study suggest that activation of the fibrinolytic system occurs both during hepatectomy and in the early postoperative period, and that patients with a diseased liver are prone to develop hyperfibrinolysis during hepatectomy. Moreover, the increased levels of both tPA and PAI-1 can serve as one of the most sensitive markers for the vital reaction against surgical stress.     

Immunohistochemical analysis of vascular prostheses implanted with the left ventricular assist system.

BACKGROUND: Dacron vascular prostheses are associated with thromboembolic complications and inflammatory responses; impregnation with bovine collagen reportedly stimulates additional inflammatory/immunologic complications. The Novacor (Baxter Healthcare Corp., Oakland, CA, USA) left ventricular assist system uses Dacron inflow and collagen-impregnated Dacron outflow prostheses. METHODS: Explanted inflow and outflow prostheses were evaluated for inflammatory/immunologic, hemostatic, anticoagulant, and fibrinolytic pathways. Non-implanted prostheses immersed in whole blood or plasma were used as controls. RESULTS: Immunoglobulins and complement components were observed in all prostheses with activated macrophages being present only in implanted prostheses. Antithrombin III was observed in all prostheses whereas fibrin, tissue plasminogen activator, and alpha-2 plasmin inhibitor were present only in implanted prostheses. Endothelial and smooth muscle cells associated with vascular structures containing collagen type IV and laminin were observed solely in implanted prostheses. CONCLUSION: An inflammatory response occurs and key components of hemostatic, anticoagulant, and fibrinolytic pathways are present within implanted prostheses. These processes are accompanied by endothelial and smooth muscle cell infiltration which appear to lay the foundation for neovessel development.     

High accumulation of plasminogen and tissue plasminogen activator at the flow surface of mural fibrin in the human arterial system

PURPOSE: We assessed the fibrinolytic activity of the organized mural thrombus lining of aneurysms and prosthetic grafts. METHODS: Between May 1995 and April 1998, the full-thickness mural thrombi of aneurysms and the pseudointima lining of vascular grafts were obtained from 12 patients, ranging from 55 to 78 years in age, who underwent elective surgery. These included five aortic arch aneurysms, four abdominal aortic aneurysms, and three patent synthetic vascular grafts. The specimens were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)/immunoblot and immunohistochemistry for human plasmin/plasminogen, tissue plasminogen activator (tPA), and fibrin degradation product (D-dimer). RESULTS: In the SDS-PAGE/immunoblot, 25- and 27-kd bands appeared specifically in experimental fibrin plates after limited digestion by plasmin and were also recognized in the mural thrombi. The presence of bands at 25 and 27 kd, which were most prominent in sections near the flow surface layer, was consistent with the hypothesis that the mural fibrin was digested by the endogenous plasmin. Apparent immunoreactivity was found at the flow surface of the masses at a thickness of 10 to 400 micrometer suggesting the presence of a plasminogen and tPA-rich layer, with D-dimer as a consequential product of fibrinolysis. CONCLUSION: The hypothesis that fibrin surfaces in the arterial system acquire fibrinolytic activity because of digestion by circulating endogenous plasmin was confirmed; this may contribute to the antithrombogenicity of these flow surfaces.     

Effect of low dose aprotinin on reduction of blood loss after extracorpreal circulation

Aprotinin administration during open heart surgery has been reported to reduce blood loss after extracorporeal circulation (ECC). We administered aprotinin to 12 patients undergoing CABG or prosthetic valve replacement. We examined the blood loss, the coagulation, and the fibrinolytic system in comparison with that in non-aprotinin group of 12 patients. In the aprotinin group, 1,000,000 units of aprotinin was infused intravenously before initiation of ECC and mixed with priming volume of ECC. After ECC, 250,000 units/hr was continuously infused until 1 hour after operation. The aprotinin group showed a significantly enhanced level of alpha 2 plasmin inhibitor and a significantly reduced level of plasmin-alpha 2 plasmin inhibitor complex and D-dimer. Post operative blood loss was not different between two groups. Operation time and closure time after heparinneutralization was shorter and postoperative blood use was lower in the aprotinin group. In conclusion, The administration of low dosed of aprotinin suppresses the fibrinolytic system resulting in the reduction of operation and closure time.     

Effect of tissue plasminogen activator on vascular smooth muscle cells

OBJECTIVE: Engineered overexpression of tissue plasminogen activator (tPA) in vascular cells has been proposed as a means to decrease intravascular thrombosis; however, tPA gene transfer has augmented intimal hyperplasia in vivo in some studies. The purpose of this study was to define in vitro the effect of tPA gene transfer on smooth muscle cells (SMCs). METHODS: Human SMCs were retrovirally transduced with the tPA gene (SMCs/tPA). RESULTS: In the absence of plasminogen, no statistical differences in proliferation, migration, and morphology were observed between SMCs/tPA and SMCs. In the presence of plasminogen, many differences became apparent. Matrix metalloproteinase-2 (MMP-2) activation was 10-fold higher in SMCs/tPA than in SMCs. This activation was inhibited by aprotinin, a plasmin inhibitor. Collagen degradation increased sevenfold in SMCs/tPA. SMCs/tPA contracted dramatically in the presence of plasminogen. This cell contraction, indicative of extracellular matrix degradation, was blocked by aprotinin and partially inhibited by MMP inhibitors. SMC/tPA-conditioned medium induced significantly more SMC proliferation. The migration of SMCs/tPA through a porous membrane significantly exceeded untransduced SMCs. CONCLUSIONS: Over-expression of tPA in SMCs results in increased extracellular matrix degradation and can promote cell proliferation and migration. This effect is mediated via plasmin, which further activates MMP-2. CLINICAL RELEVANCE: TPA has been clinically used as a thrombolytic agent in the treatment of acute thrombotic disorders. Transferring the tPA gene into vascular cells as a strategy of gene therapy has been proposed to enhance fibrinolytic capability and therefore inhibit thrombosis and restenosis after vascular interventions. The mechanism(s) by which tPA affects SMC proliferation and vascular remodeling has not been thoroughly characterized. This study unveils the relationship between thrombolytic activity and intimal hyperplasia by showing how the elevated expression of tPA affects the vascular remodeling. This study underscores that the overexpression of an enzyme thought beneficial to blood flow can potentially compromise blood flow by altering the biology of the cell engineered to express it. The results are important to the rational engineering of bioactive grafts with better patency. A new strategy to enhance the thrombolytic ability of a vascular surface without inducing excessive neointimal hyperplasia is proposed.     

Local and systemic hemostasis in surgery]

Surgery inevitably leads to bleeding, and hemostasis aims at reducing the amount of blood loss and the need for transfusion as well as preventing rebleeding, hematoma formation, and the need for repeat surgery. Various locally applicable agents are in use including bone wax, gelatin, collagen, oxidized regenerated cellulose, fibrin sealant glues, and synthetic glues. Some evidence from randomized controlled trials (RCT) exists regarding the use of fibrin sealants on their own or combined with collagen fleece. Systemic hemostasis may be achieved with lysine analogs such as epsilon-aminocaproic acid or tranexamic acid and aprotinin, which are inhibitors of fibrinolysis. There is much albeit sometimes conflicting evidence from RCT regarding the use of these substances in surgery. The role of recombinant activated factor VII in achieving systemic hemostasis is being investigated.     

Möglichkeiten der lokalen und systemischen Blutstillung bei chirurgischen Eingriffen

Surgery inevitably leads to bleeding, and hemostasis aims at reducing the amount of blood loss and the need for transfusion as well as preventing rebleeding, hematoma formation, and the need for repeat surgery. Various locally applicable agents are in use including bone wax, gelatin, collagen, oxidized regenerated cellulose, fibrin sealant glues, and synthetic glues. Some evidence from randomized controlled trials (RCT) exists regarding the use of fibrin sealants on their own or combined with collagen fleece. Systemic hemostasis may be achieved with lysine analogs such as epsilon-aminocaproic acid or tranexamic acid and aprotinin, which are inhibitors of fibrinolysis. There is much albeit sometimes conflicting evidence from RCT regarding the use of these substances in surgery. The role of recombinant activated factor VII in achieving systemic hemostasis is being investigated.     

Combined treatment of coenzyme Q10 and aprotinin with intraaortic balloon pumping following aorto-coronary bypass surgery

The effect of combined treatment of coenzyme Q₁₀ (CoQ₁₀) and aprotinin with intra-aortic balloon pumping (IABP) was evaluated in patients who underwent aorto-coronary bypass surgery. Forty-one patients were divided into two groups. Group A (27) were treated by IABP only and Group B (14) were treated by the concomitant use of CoQ₁₀ and aprotinin with IABP. Both groups were subdivided into two groups with regard to the ability to be weaned from IABP (Group A-I, Group B-I) or the inability (Group A-II, Group B-II). CoQ₁₀ was administrated intravenously at doses of 5–10 mg/kg/day and aprotinin was infused at doses 5,000–10,000 KU/kg/day. The percentile incidence of ability to be weaned from IABP was 93 per cent (13/14) in Group B was higher than that of 74 per cent (20/27) in Group A. There were no significant differences among Group A-I, Group A-II, and Group B-I with regard to preoperative and intraoperative factors. Serum GOT and CPK levels on the first postoperative day were significantly higher in Group A-II and Group B-I than those in Group A-I but there was no significant difference between GOT or CPK levels in Group A-II and Group B-I. These results suggest that concomitant treatment of CoQ₁₀ and aprotinin with IABP leads to an improvement in postoperative low cardiac output syndrome.     

Plasma proteolytic activity in liver transplant rejection

In this study, we evaluated the role of proteolytic enzymes belonging to the coagulation, fibrinolytic, and plasma contact systems in the early postoperative phase after orthotopic liver transplantation (OLT). Twenty-nine patients were studied at the time of OLT and during the first 2 postoperative weeks. Blood samples were collected daily after OLT and analyzed for kallikrein-like activity (KK), functional kallikrein inhibition (KKI), plasmin-like activity (PL), and α₂-antiplasmin (AP). In addition, prekallikrein (PKK), prothrombin (PTH), antithrombin III (AT III), plasminogen (PLG), prothrombin/antithrombin III complexes (TAT), prothrombin fragment 1 + 2 (F 1 + 2), and plasmin/α₂-antiplasmin complexes (PAP) were measured. Nineteen patients experienced biopsy-verified acute rejections (AR) and ten patients had uneventful courses and served as controls. Plasma analyses showed that the contact, coagulation, and fibrinolytic systems were activated during OLT. Following OLT, continuous thrombin and plasmin generation was observed, and these effects were more pronounced in the group having an uneventful course than in patients with AR. Factors that could possibly affect plasma proteolytic activity, such as blood product usage during and after OLT and cold ischemia time of the liver graft, did not differ between the groups, nor did the routine liver function tests, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Received: 20 January 1998 Received after revision: 11 September 1998 Accepted: 12 October 1998     

Influence of aprotinin, a protease inhibitor, on porcine E. coli shock. Studies on coagulation, fibrinolytic and hemodynamic response

The effect of a protease inhibitor, aprotinin, on hemostasis (a2M, a2AP, AT III, prothrombin-convertin activity, fibrinogen, fibrinogen monomers and fibrinolytic activity on fibrin plates) was investigated in pigs with septic shock. Anesthetized pigs were given live Escherichia coli i.v. (n = 7), or aprotinin (1,000,000 KIE i.v.) 15 min before live E. coli (n = 6), or Ringer's solution only (sham controls, n = 8). Septic shock developed in all E. coli-infused pigs. Pulmonary vascular resistance increased, platelet and leukocyte counts fell and signs of systemic activation of the coagulation and fibrinolytic systems appeared in the E. coli groups, but aprotinin attenuated the effects on these systems and also on the pulmonary circulation. Five of the six aprotinin-pretreated pigs survived, but none of the seven with septic shock and no pretreatment. Thus the shock induced by infusion of live E. coli and the resultant changes in the coagulation and fibrinolytic systems and in cardiopulmonary hemodynamics were diminished by aprotinin pretreatment.