Factor XIIa is a kinetically favorable plasminogen activator.

Initiation of the plasma contact system has been shown to play a significant role in the fibrinolysis, activating both pro-urokinase and plasminogen. The aim of the present study was to further evaluate the functional role of the factor XIIa catalyzed activation of plasminogen. Activation of plasminogen by factor XIIa followed the Michaelis-Menten rate equation. In a continuous assay system the Km was 0.27 microM; the kcat 0.078 min(-1) and the kcat/Km 0.31x10(6) M(-1) x min(-1). In an end-point assay system the Km was 0.58 microM; the kcat 0.096 min(-1) and the kcat/Km 0.16x10(6) M(-1) x min(-1). The discrepancy between the kcat in the two assays is not significant. Theoretically the higher Km in the end-point assay system may be due to the presence or generation of an unidentified competitive inhibitor in this assay system. Comparing the catalytic constants of factor XIIa with those of urokinase activation of plasminogen, the specificity constant, kcat/Km, of factor XIIa activation of plasminogen was 20-fold lower. However, taking the low physiological concentration of urokinase into account, the efficiency of activated factor XII is equivalent to that of urokinase. When monitoring factor XIIa activation of plasminogen in a clot lysis assay, the clot lysis time was 2- to 4-fold as long as that accommodated by urokinase at factor XIIa concentrations equivalent with 5-20% of the zymogen concentration in plasma. The factor XIIa mediated clot lysis was prevented completely by the presence of a polyclonal antibody to factor XII.

Comparison of two protocols for heparin neutralization by protamine after cardiopulmonary bypass.

Twenty patients undergoing cardiac operations were randomly assigned to two protocols for heparin neutralization by protamine after cardiopulmonary bypass. In all patients protamine chloride was given at a ratio of 1 unit of protamine to 1 unit of injected heparin. In Group I (10 patients) all protamine was infused within 10 minutes after termination of cardiopulmonary bypass. Group II (10 patients) received 75% of the calculated protamine dose within 10 minutes after termination of bypass and the remainder after transfusion of all blood in the heart-lung machine. Plasma heparin levels were significantly lower in Group II 5 minutes after transfusion of all blood in the heart-lung machine and were 0.13 units/ml (standard deviation 0.04) in Group I and 0.06 units/ml (standard deviation 0.05) in Group II (p less than 0.001) 60 minutes after bypass. Activated partial thromboplastin time mirrored the changes in plasma heparin, whereas activated clotting time (Hemochron) was too insensitive to detect these low plasma heparin levels. We conclude that the two-dose protocol resulted in more complete heparin neutralization than the one-dose protocol.

Somatosensory evoked potentials and cerebral metabolism during cardiopulmonary bypass with special reference to hypotension induced by prostacyclin infusion.

Somatosensory evoked potentials and cerebral metabolism were studied during cardiopulmonary bypass in 41 patients undergoing coronary bypass. Twenty-two patients received prostacyclin 50 ng/kg/min during cardiopulmonary bypass for platelet protection and 19 patients served as controls. Mean arterial blood pressure in the prostacyclin group was below 30 mm Hg during the first 30 minutes of bypass, but it remained above 50 mm Hg in the control group. Central conduction time, a measure of the electrical conduction time in the central nervous system, was prolonged in both groups during bypass up to 30 minutes of rewarming. The prolongation was greater in the control group early during bypass. At 20 minutes of cardiopulmonary bypass, central conduction time was increased by 81% (standard deviation 38) of the prebypass value in the control group and by 44% (standard deviation 17) in the prostacyclin group (p less than 0.001). Arteriovenous oxygen difference across the brain was greater in the prostacyclin group early during bypass. It was 36 ml/L (standard deviation 9) in the control group and 60 ml/L (standard deviation 18) in the prostacyclin group (p less than 0.001) at 10 minutes of bypass. There was no difference between the groups in regard to glucose and lactate. We conclude that cardiopulmonary bypass with hypothermia prolongs central conduction time. The hypotension induced by prostacyclin (50 ng/kg/min) did not further impair conduction in the central nervous system.

Effects of prostacyclin infusion on platelet activation and postoperative blood loss in coronary bypass.

The effects of infusion of prostacyclin were studied in 41 patients undergoing aortocoronary bypass. Twenty-three patients received heparin (2 mg per kilogram of body weight) and prostacyclin (50 ng per kilogram per minute) during cardiopulmonary bypass (CPB). Eighteen patients received heparin (3 mg per kilogram). One hour after CPB, the platelet count was 98 +/- 16% of the value obtained before CPB in the prostacyclin group and 73 +/- 18% in the control group (p less than 0.001). The plasma level of platelet factor 4 rose only initially during CPB in the prostacyclin group, but increased continuously in the control group; at 90 minutes of CPB it was 92 +/- 35 ng per milliliter and 376 +/- 119 ng per milliliter, respectively (p less than 0.001). Beta-thromboglobulin showed a similar pattern. Postoperative chest drainage was 386 +/- 87 ml in the prostacyclin group and 596 +/- 342 ml in the control group (p less than 0.05). Blood transfused during and five days after operation was 1,359 +/- 751 ml in the prostacyclin group and 2,047 +/- 915 ml in the control group (p less than 0.05).

Cerebral blood flow and metabolism during cardiopulmonary bypass with special reference to effects of hypotension induced by prostacyclin.

Cerebral blood flow and metabolism of oxygen, glucose, and lactate were studied in 43 patients undergoing aortocoronary bypass. Twenty-five patients received prostacyclin infusion, 50 ng per kilogram of body weight per minute, during cardiopulmonary bypass (CPB), and 18 patients served as a control group. Regional cerebral blood flow (CBF) was studied by intraarterially injected xenon 133 and a single scintillation detector. Oxygen tension, carbon dioxide tension, oxygen saturation, glucose, and lactate were measured in arterial and cerebral venous blood. Mean arterial blood pressure decreased during hypothermia and prostacyclin infusion to less than 30 mm Hg. The regional CBF was, on average, 22 (standard deviation [SD] 4) ml/100 gm/min before CPB. It increased in the control group during hypothermia to 34 (SD 12) ml/100 gm/min, but decreased in the prostacyclin group to 15 (SD 5) ml/100 gm/min. It increased during rewarming in the prostacyclin group. After CPB, regional CBF was about 40 ml/100 gm/min in both groups. The cerebral arteriovenous oxygen pressure difference decreased more in the control group than in the prostacyclin group during hypothermia. The cerebral metabolic rate of oxygen decreased in both groups from approximately 2 ml/100 gm/min to about 1 ml/100 gm/min during hypothermia, increased again during rewarming, and after CPB was at the levels measured before bypass in both groups. There was no difference between the groups in regard to glucose and lactate metabolism.

Effects of prostacyclin infusion on renal function during cardiopulmonary bypass.

Infusion of prostacyclin inhibits platelet activation during cardiopulmonary bypass (CPB) but also results in systemic arterial hypotension. Therefore, the effects of CPB and prostacyclin on renal function were studied in 36 male patients undergoing aortocoronary bypass. Nineteen patients (Group 1) received prostacyclin, 50 ng per kilogram of body weight per minute, during CPB, and 17 patients (Group 2) served as controls. There was pronounced hypotension in Group 1 only. Urine production during CPB averaged 88 +/- 140 ml and 2,306 +/- 1,112 ml in Groups 1 and 2, respectively. No patient had renal failure. Glomerular filtration rate (GFR), as measured by clearance of chromium 51-labeled ethylenediaminetetraacetic acid, was increased in Group 1 from 86 +/- 14 to 99 +/- 22 ml/1.73 m2/min (p less than 0.05) the day after operation, but remained unchanged in Group 2 (81 +/- 15 to 82 +/- 21 ml/1.73 m2/min). The increased GFR in Group 1 can be regarded as an expected adaptation to the change in body fluids after CPB. Therefore, the unchanged GFR in Group 2 must be regarded as caused by insufficient adaptation or impaired renal function. Proximal tubular function was evaluated by determination of beta 2-microglobulin in urine. In both groups, urinary beta 2-microglobulin and the ratio of urinary beta 2-microglobulin to urinary creatinine were increased the day after operation. The hypotension in Group 1 did not exacerbate the damage to tubular function.

[Heart surgery in private practice]. / Hjertekirurgi i privat regi.

During the period May 1993-August 1994, 100 patients were operated upon with heart surgery at the Private Hospital Hamlet (Copenhagen). Preoperative risk factors such as age > 70 years, female gender, ejection fraction (EF) < 40%, diabetes mellitus, adipositas > 20% above normal weight, were associatet with an increased mortality rate among those cases (5.4%). Overall mortality was 4%. The results are fully comparable with international reports.

Effects of prostacyclin infusion on platelets and hemodynamics in coronary bypass surgery.

Twenty patients undergoing aorto-coronary bypass were randomly assigned to a prostacyclin treatment group or control group. Eight patients received 2 mg/kg heparin and 10 ng/kg/min prostacyclin before cardiopulmonary bypass (CPB) and 50 ng/kg/min during CPB. Twelve patients, serving as controls, received 3 mg/kg heparin. Heparinization resulted in a slight but significant increase of plasma beta-thromboglobulin in the control group but not in the prostacyclin group, and of plasma platelet factor 4 (PF-4) in both groups. After 90 minutes of CPB, beta-thromboglobulin was 408 (SD 128) ng/ml in the control group and 111 (SD 50) ng/ml (p less than 0.001) in the prostacyclin group. Platelet count, corrected for hemodilution, was 92% (SD 10) of the pre-CPB value after 10 minutes of CPB and 89% (SD 7) one hour after CPB in the control group, as compared to 113% (SD 10) and 145% (SD 18), respectively, in the prostacyclin group. Prostacyclin infusion before CPB reduced systemic vascular resistance to half of that of the control group, lowered mean arterial blood pressure, and increased cardiac index by 60% to 80%. An infusion of prostacyclin before CPB does not add to the already excellent platelet protective effect of 50 ng/kg/min prostacyclin during CPB, but may be used for vasodilation.

Aortic cross-clamping for more than 2 hours in open-heart surgery. Early results in 87 patients.

Myocardial protection with cold cardioplegia has made it possible to prolong the time of aortic cross-clamping during open-heart surgery. Myocardial ischemia for up to 120 minutes is considered acceptable under these conditions. Eighty-seven patients operated upon for various heart lesions with cardiopulmonary bypass and aortic cross-clamping for more than 2 hours (mean time 146 minutes) were reviewed. Myocardial protection was achieved with cold cardioplegia, in some cases with additional topical cooling of the heart. Ten patients died and 77 were discharged from the hospital. Perioperative and early postoperative deaths could not be correlated to aortic cross-clamping time or the method of myocardial protection. Aortic cross-clamping can be safely performed for a period far longer than 2 hours with myocardial preservation by cold cardioplegia.

Effects of cardiopulmonary bypass and prostacyclin on plasma catecholamines, angiotensin II and arginine-vasopressin.

Infusion of prostacyclin during cardiopulmonary bypass (CPB) reduces platelet activation, diminishes postoperative blood loss and decreases arterial blood pressure. In spite of continuous prostacyclin infusion, there is a delayed gradual rise in arterial pressure and resistance from low initial levels. We measured epinephrine (E), norepinephrine (NE), serotonin (5-HT), angiotensin II (ATII) and arginine-vasopressin (AVP) in plasma and carried out hemodynamic studies in 19 patients operated for coronary vascular disease. Eight patients served as a control group and were subjected to routine CPB. Eleven patients received prostacyclin 50 ng/kg/min during CPB. E and NE increased four- to sixfold during CPB from about 0.5 ng/ml (P less than 0.001). There was no difference between the groups. During CPB AVP increased sixfold from about 20 pg/ml in both groups (P less than 0.001), decreased early after CPB and increased again to high levels 3 h after CPB. The combined action of E, NE and AVP is of likely importance for the rise in systemic vascular resistance and/or need of vasodilation during CPB in the control group. ATII did not increase in the control group, but increased fourfold to about 20 pg/ml (P less than 0.01) during CPB in the prostacyclin group. The addition of AT II to E, NE and AVP seems responsible for the gradual return of arterial pressure and resistance during prostacyclin infusion. Postoperative hypertension and/or need of vasodilation 3 h after CPB was associated with high AVP levels in both groups. Hypotension caused by prostacyclin infusion did not increase E, NE or AVP above levels produced by CPB and moderate hypotension alone.

Insulin sensitivity and glucose uptake in the course of surgical treatment for valvular aortic stenosis.

The dose-response relationship between plasma insulin and systemic glucose uptake was studied before, one hour after and 6 months after valvular surgery in 11 patients with valvular aortic stenosis. The immediate effect of valvular surgery was a dramatic rightward shift of the dose-response curve and a decrease in glucose uptake at peak insulin activity. From a comparison between the preoperative and the 6-month postoperative dose-response curves it is concluded that the patients had adapted metabolically to the preoperative haemodynamic situation with increased insulin sensitivity.