Minoru Kusagawa

Alterations in coagulation and fibrinolysis associated with cardiopulmonary bypass during open heart surgery

The effect of heparin as an anticoagulant was examined and the extent of fibrinolytic activity during cardiopulmonary bypass (CPB) was measured. Twenty patients undergoing valve replacement or aortocoronary bypass surgery were studied. Fibrinopeptide A (FPA) levels gradually became elevated as CPB proceeded, and antithrombin III (AT III) decreased during CPB. This indicates that despite the use of heparin, the coagulation system was activated, leading to fibrin formation in the microcirculation. On the other hand, fibrinopeptide B (FPB beta 15-42) also increased to four times the preoperative value at two hours on CPB. Intrinsic fibrinolytic activity, as determined by the activity of kaolin-activated euglobulin, was transiently increased only at the beginning of CPB. The C1 inactivator-resistant fibrinolytic activity and tissue plasminogen activator antigen (t-PA;Ag) increased sharply during CPB and reached maximum levels one hour after the start of CPB, indicating that enhanced fibrinolytic activity during CPB is predominantly of extrinsic origin as the result of t-PA release from the vascular walls. It is concluded from the above findings that thrombin activity continues during CPB. Enhanced fibrinolytic activity during CPB appears to be important because t-PA activates plasminogen predominantly where fibrin is formed, leading to dissolution of the microthrombi formed during CPB.

Ca2+-Calmodulin-dependent protein kinase II phosphorylates various types of non-epithelial intermediate filament proteins

We have investigated the actions of Ca2(+)-calmodulin (CaM)-dependent protein kinase II on various types of non-epithelial intermediate filament proteins, vimentin, desmin, glial fibrillary acidic protein (GFAP) and neurofilament triplet proteins. Most of these filament proteins could serve as substrates. The effects of phosphorylation on the filamentous structure of vimentin were investigated in sedimentation experiments and by using electron microscopy. The amount of unassembled vimentin increased linearly with increased phosphorylation. However, the extent of the effect of phosphorylation on the potential to polymerize was also affected by the MgCl2 concentration, under conditions for reassembly. The actions of Ca2(+)-CaM-dependent protein kinase II on non-epithelial intermediate filaments under physiological conditions are given attention.

Platelet dysfunction during cardiopulmonary bypass surgery : with special reference to platelet membrane glycoproteins

Changes in platelet membrane glycoproteins (GPIb, GPIIb/IIIa, and GMP-140) were evaluated using flow cytometry after binding with monoclonal antibodies in 22 adult patients undergoing cardiopulmonary bypass (CPB) surgery. The amount of GPIb on platelets decreased significantly during CPB, reaching a minimum level of 64 +/- 26% of the pre CPB value at 120 min of CPB. There was no significant change in the amount of GPIIb/IIIa on platelets. In accordance with these changes, ristocetin induced agglutination decreased to 56.7 +/- 16.2% of the pre CPB value during CPB. However, there were no significant changes in ADP and collagen induced aggregation throughout the procedure. The number of the activated platelets expressing GMP-140 on their surfaces increased significantly during CPB. There was an upper limit to the amount of GMP-140 expression on each platelet in the circulating blood, suggesting that excessively activated platelets are removed from the circulation. The authors conclude that CPB reduces the amount of GPIb on platelets, which results in platelet dysfunction. In addition, removal of excessively activated platelets from the circulation may lead to thrombocytopenia after CPB.

Rupture of a benign mediastinal teratoma into the right pleural cavity

A 27-year-old woman with a ruptured mediastinal cystic teratoma had high levels of amylase and carcinoembryonic antigen in cystic fluid. The activity of the amylase is thought to be the most likely cause of the rupture. High levels of carcinoembryonic antigen in pleural fluid are not necessarily indicative of a malignant lesion but may suggest the presence of a ruptured teratoma in patients with mediastinal tumors.

The role of the protein C-thrombomodulin system in physiologic anticoagulation during cardiopulmonary bypass.

Changes in the protein C-thrombomodulin (PC-TM) system in relation to other coagulofibrinolytic parameters were examined in 25 patients undergoing open heart surgery. Although all patients were given heparin, a decrease in antithrombin III (ATIII) and progressive increase in thrombin-ATIII complex (TAT) and fibrinopeptide A (FPA) levels were noted during cardiopulmonary bypass, which indicated that heparinization did not completely inhibit the formation of thrombin and its function. C1-inactivator (INA) resistant fibrinolytic activity increased markedly during CPB, in parallel with the change of tissue plasminogen activator antigen (t-PA;Ag), which indicates that fibrinolytic activity during CPB is mainly of extrinsic origin caused by t-PA. Protein C antigen (PC;Ag), protein S antigen (PS;Ag), and thrombomodulin antigen (TM;Ag) were all decreased significantly during CPB. This is considered to reflect the activation and consumption of the PC-TM system in response to generated thrombin. Furthermore, enhancement of the extrinsic fibrinolytic system is easily explained by the action of activated PC, which counteracts plasminogen activator inhibitor (PAI-1), to cause enhancement of t-PA activity.

Effect of combined infusion of nitroglycerin and nicardipine on femoral-to-radial arterial pressure gradient after cardiopulmonary bypass

Nitrates and calcium channel blockers are frequently administered during cardiac surgery. We simultaneously measured femoral arterial pressure and radial arterial pressure to investigate whether nitrates, in conjunction with calcium channel blockers, would influence the central-to-peripheral arterial pressure gradient. Combined nitroglycerin and nicardipine infusion during cardiac surgery involving coronary artery bypass grafting or valve replacement resulted in a significant increase above baseline levels in the femoral-to-radial arterial pressure gradient at 60 min after Cardiopulmonary bypass. In control patients there was no significant increase in the femoral-to-radial arterial pressure gradient at 60 min after completion of Cardiopulmonary bypass. A subsequent study in patients given nitroglycerin and nicardipine identified that the difference in the systolic arterial pressure between femoral and radial arteries was observed 15, 60, and 120 min after completion of cardio-pulmonary bypass. However, there was no difference in the mean arterial pressure between femoral and radial arteries throughout the same period. We conclude that combined infusion of nitroglycerin and nicardipine, a new calcium channel blocker, intensifies the magnitude and duration of the femoral-to-radial arterial pressure gradient after cardio-pulmonary bypass.

Effects of inhaled nitric oxide in rats with chemically induced pulmonary hypertension.

To determine the model animal with pulmonary hypertension in which nitric oxide (NO) inhalation reduces pulmonary arterial pressure (PAP), we examined the inhalation of 20-100 ppm NO gas on normal rats and rats with monocrotaline induced pulmonary hypertension. In the control group, mean PAP showed no change after spontaneous breathing of NO at the concentration of 20 to 100 ppm for 5 min. On the contrary, in both the severe (mean PAP > 40 mmHg) and moderate (mean PAP < 40 mmHg) pulmonary hypertensive groups, NO inhalation produced a prompt reduction of the mean PAP which had been elevated by monocrotaline. 20 ppm NO inhalation reduced mean PAP from 64.4 +/- 3.7 mmHg to 56.2 +/- 4.4 mmHg (mean +/- SEM, P < 0.01) in the severe pulmonary hypertensive group, from 31.0 +/- 2.0 mmHg to 24.2 +/- 0.9 mmHg in the moderate pulmonary hypertensive group (mean +/- SEM, P < 0.05). The onset of the reduction of mean PAP occurred within 30 sec after the start of NO inhalation and maximum reduction occurred within 4 min. 20 ppm NO inhalation significantly reduced mean PAP, and mean PAP was reduced dose-dependently at the concentration of 20 to 60 ppm and reaction to NO was almost constant at the concentrations of over 60 ppm.

Effects of nafamostat mesilate on platelets and coagulofibrinolysis during cardiopulmonary bypass surgery.

The effect of nafamostat mesilate (FUT-175) on platelet membrane glycoproteins and the coagulofibrinolytic system were analyzed. Twenty-five patients undergoing aorto-coronary bypass surgery were randomly distributed into an FUT treated group and a control group. In the control group, anticoagulation was achieved with sodium heparin (3 mg/kg) immediately before cardiopulmonary bypass (CPB). In the FUT treated group, in addition to the usual treatment with heparin, FUT-175 was infused continuously at a rate of 2 mg/kg/hr. In the control group, alpha 2 plasmin inhibitor/plasmin complex (PIC) and fibrinogen/fibrin degradation products (FDP) D-dimer increased significantly during CPB, reaching 6.1 +/- 5.1 micrograms/ml and 576 +/- 200 ng/ml, respectively, at 60 min of CPB. PIC and FDP D-dimer remained significantly lower in the FUT treated group than in the control group. GPIb on platelets decreased significantly in both groups, but remained higher in the FUT treated group (81 +/- 5% vs. 56 +/- 21% at 60 min of CPB, P < 0.01). There were no significant changes in GPIIb/IIIa on platelets throughout the procedure in either group. Blood loss after CPB was significantly lower in the FUT treated group than in the control group (778 +/- 277 ml vs. 1,342 +/- 426 ml, P < 0.01). The authors conclude that FUT-175 improves hemostasis after CPB, not only by inhibiting fibrinolysis, but also by preserving platelet GPIb during CPB.

The role of surgical resection and the effects of neo-adjuvant therapy in the management of small cell lung cancer

A study was conducted on 58 patients who underwent surgery for small cell lung cancer (SCLC) as resection or exploratory thoracotomy, and 43 patients encountered during the same period who received no surgical treatment. The following conclusions were drawn from our analysis: At stage I, an operation is desirable, regardless of the subtype of SCLC, but chemotherapy should be given first; at stages II and III, by the addition of surgery after neo-adjuvant chemotherapy, “state-of-the-art” results for limited SCLC can be surpassed; in patients with stage II disease on whom curative resection has been performed, particular attention must be paid to the possibility of metastasis to the brain; and finally, exploratory thoractomy did not bring about the early death of patients or reduce the quality of life, but only delayed chemotherapy for about one week, while enabling the staging and histological subtype of SCLC to be clarified.

Surgical treatment of infantile lobar emphysema in cardiovascular disease with left-to-right shunts

Serious symptoms associated with the lobar emphysema in congenital heart diseases with left-to-right shunt disappeared after radical operation for cardiac lesion. The study of seven autopsied cases revealed that the lobar emphysema resulted from check valve mechanism created by compression of the bronchi by distended pulmonary artery. Eight cases of our experience of lobar emphysema disappeared shortly after the operation forccongenital heart disease with left-to-right shunt seems to indicate infantile lobar emphysema in congenital heart diseases with left-to-right shunt should not be treated by resection but rather by radical operation for cardiac lesion as soon as possible even in infancy.