Elsa Eriksson

Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1

Recent epidemiologic studies have shown that abdominal obesity, characterized by a high waist to hip circumference ratio (WHR), is associated with increased cardiovascular morbidity and mortality. The present study examines components of the fibrinolytic system in obese and lean middle-aged women with a high and low WHR. Ten women in each group were carefully matched with respect to age, body weight, lean body mass, and body fat. Fibrinogen and endothelial type of plasminogen activator inhibitor -1 (PAI-1) were significantly elevated in the obese women with a high WHR compared with the obese women with a low WHR or with both groups of lean women. In addition, obese women with a high WHR exhibited a greater metabolic risk profile (elevated glucose, insulin, and triglyceride levels). When all subjects were pooled for the analyses, both fibrinogen and PAI-1 levels correlated positively with glucose and insulin levels. PAI-1 was also negatively related to degree of insulin sensitivity measured with the euglycemic clamp technique. In the obese groups, WHR but not body mass index (BMI), correlated with PAI-1 levels. No such correlations were seen in the lean groups. In conclusion, the data show that a high WHR in obese, but not lean middle-aged women, is associated with an impaired fibrinolytic activity. This perturbation becomes enhanced when it is associated with hyperinsulinemia and insulin resistance, which is a typical feature of abdominal obesity.

Hemofiltration modifies complement activation after extracorporeal circulation in infants

Complement and fibrinolytic factors were measured in 9 infants undergoing hemofiltration immediately after cardiopulmonary bypass in an attempt to reduce activation of these systems. Plasma levels of C3a, C5a, and terminal complement complexes increased during bypass by 460%, 85%, and 745%. Plasma levels were reduced after hemofiltration in 8 of the 9 infants, and C3a and C5a fractions were recovered in the ultrafiltrate. The observed activation of the fibrinolytic system seemed to be unaltered by hemofiltration. Fibrinolytic factors were not filtered. Our study shows that increased concentrations of complement factors in the plasma after bypass in infants may be reduced by hemofiltration.

Thrombosis after hip replacement: Relationship to the fibrinolytic system

Twenty-nine patients were operated on with the Charnley hip prosthesis. All the patients were given dextran 70 as thrombosis prophylaxis. Deep vein thrombosis (DVT) was diagnosed in 10 patients with the radioactive fibrinogen uptake test and phlebography. Variables of coagulation and fibrinolysis were studied before and after surgery. Tissue plasminogen activator (t-PA) activity in the plasma without venous occlusion decreased postoperatively, but there was no correlation with DVT. The t-PA activity in venous occlusion plasma was not reduced after surgery. Plasminogen activator inhibitor (PAI-1) levels were raised immediately postoperatively. There was a significant correlation between preoperative PAI-1 activity and development of postoperative DVT (P less than 0.05). Patients developing DVT had higher levels of PAI-1 postoperatively than patients not developing DVT. A defective fibrinolytic system, as defined by high PAI-1 activity, thus predisposed to postoperative DVT.

Impaired fibrinolysis and postoperative thromboembolism in orthopedic patients

The incidence of deep vein thrombosis (DVT) and pulmonary embolism was studied prospectively in patients undergoing elective total hip replacement. 96 patients were randomly allocated to receive either low molecular weight heparin (LMWH) or unfractionated heparin (UFH). All patients had bilateral phlebography and pulmonary perfusion/ventilation scintigraphy 10-12 days after surgery. The following fibrinolytic variables were analysed in plasma and related to thromboembolism: tissue plasminogen activator (t-PA) activity, t-PA antigen (t-PA Ag), plasminogen activator inhibitor (PAI-1) activity and PAI-1 antigen (PAI-1 Ag). No significant difference was found, regarding the fibrinolytic response to surgery, between patients treated with LMWH and UFH. The level of PAI-1 activity was significantly increased before operation in patients developing DVT as compared to non-DVT patients (p less than 0.03). Immediately after surgery and in the morning the first postoperative day the levels of PAI-1 activity, PAI-1 Ag and t-PA Ag were positively correlated to thromboembolism. PAI-1 activity was the only preoperative fibrinolytic variable correlated to thromboembolism.

A sensitive assay for tissue plasminogen activator activity in plasma, using adsorption on lysine-sepharose

Tissue plasminogen activator (t-PA) in plasma was separated from inhibitors by adsorption on lysine-Sepharose. It was then determined indirectly by measuring the plasmin generated from plasminogen with poly-lysine as stimulator, in a chromogenic, parabolic rate assay. The reaction proceeded with tissue plasminogen activator and plasmin(ogen) adsorbed on the gel, and followed the kinetics described for similar parabolic rate assays in soluble systems. The assay was standardized against melanoma plasminogen activator (m-PA) and had the sensitivity range of 0.001-0.020 IU (4-80 pg). Anti-m-PA IgG quenched the activity generated in plasma on venous occlusion and part of the activity in pre-occlusion plasma. The method was sensitive to purified urokinase. The basic plasma values in resting normal individuals were: mean 0.08, range 0.01-0.26 X 10(3) IU/l (n = 19), and after 20 min of venous occlusion: mean 2.48, range 0.24-4.34 X 10(3) IU/l (n = 10). The assay correlates well with a fibrin plate method, r = 0.96.

Regional fibrinolysis following total hip replacement

The local effect of operative trauma on the fibrinolytic system was studied in ten patients undergoing total hip replacement. Catheters were inserted in the femoral veins on both sides and blood was sampled from these catheters perioperatively. The following fibrinolytic variables were analysed in plasma and related to the different steps of surgery: tissue plasminogen activator (t-PA) activity, t-PA antigen and plasminogen activator inhibitor (PAI-1) activity. During surgery PAI-1 activity and t-PA antigen in the operated limb were significantly increased compared with preoperative values. There was a significant difference in PAI-1 activity and t-PA antigen between the operated and the non-operated limbs during surgery and within one hour postoperatively. During fixation of the femoral implant there was a significant difference between the operated and the non-operated limbs in t-PA activity. Thus the regional fibrinolytic response to trauma was dissociated from the response in the non-operated limb. The clinical relevance of the observed alterations in regional fibrinolysis, as related to thrombogenic mechanisms after hip surgery, remains to be elucidated.

Disseminated intravascular coagulation

This review encompasses a description of the main pathophysiological events leading to disseminated intravascular coagulation (DIC). Emphasis has been put on microcirculatory disturbances and endothelial dysfunction. The normal hemostatic functions of the vascular endothelium are described. The close connection between endothelium and superimposed immuno‐modulators is stressed as is the interrelation between the proteolytic cascade systems in the blood. The importance of differentiating local and systemic events is discussed. Organ dysfunction in multiple organ failure (MOF) is exemplified by pulmonary insufficiency in the adult respiratory distress syndrome (ARDS). Essential laboratory tests of DIC are described as are the cornerstones of treatment.

Reactive oxygen intermediates and ischemia-reperfusion injury release tissue plasminogen activator from isolated rat hearts

Tissue plasminogen activator (t-PA) is a marker of endothelial cell injury or activation. The release of t-PA from isolated rat hearts (Langendorff model) subjected to ischemia-reperfusion or reactive oxygen intermediates (ROI) generated by H2O2 was investigated. H2O2 (200 microM) increased t-PA activity in the coronary effluent to 305 +/- 84% of initial value (mean +/- SEM, p < 0.04 vs controls) at the end of a 10 min intervention. The hydroxyl radical scavenger thiourea (10 mM) only partially inhibited the increase (175 +/- 27%, p < 0.01 compared to controls). 20 min normothermic ischemia increased t-PA activity to 416 +/- 108% (p < 0.005 compared to controls) at the start of reperfusion. In conclusion, cardiac injury by ischemia-reperfusion or ROI increases release of t-PA.

Disturbances of blood-flow velocity in the dorsal veins of the hand after vein cannulation and cannula fixation in the anaesthetised patient

Modifications of the mean blood‐flow velocity in the dorsal veins of the hand were assessed semi‐quantitatively with continuous wave (CW) Doppler equipment in 32 anaesthetised patients (17 men and 15 women), 23–78 (median= 56) years of age, before and after venous catheterisation with cannula fixation to the skin. Cannulation of the vein caused a 48% reduction in the mean blood‐flow velocity and made it impossible to detect any flow with the equipment used in 22% of the patients. A 10% further reduction in the mean blood‐flow velocity and in the number of subjects with undetectable blood flow was observed after fixation of the cannulae. Age, small vein diameter, and hyperventilation (end‐tidal carbon dioxide 7l & ht3.5 volume %) appeared to be significant factors reducing blood‐flow velocities in the cannulated veins. It is concluded that venous catheterisation and fixation of the cannula induce a significant reduction in the blood‐flow velocity.

Release of markers of myocardial and endothelial injury following cold cardioplegic arrest in pigs

Cold cardioplegic arrest causes reperfusion injury to both endothelium and myocardium. We investigated release of troponin-T (TnT), tissue plasminogen activator activity (t-PA) and histamine (HA) from the heart before and after 2h of cold crystalloid cardioplegia in eight Swedish landrace pigs. Coronary sinus blood flow was measured in an external shunt between the coronary sinus and the right atrium. TnT, t-PA and HA were measured concomitantly in arterial and coronary sinus plasma, and the cardiac release was calculated. Cardiac release of TnT increased from 18 (15-25) micrograms/min (median (central 90% percentile)) before cold cardioplegia to maximum 281 (132-510) micrograms/min 30 min after aortic declamping (p < 0.02 vs initial value). t-PA rose from -4 (-52-34) to maximum 249 (75-691) IU/min 2 min after declamping (p < 0.01) and thereafter returned to baseline levels. The net cardiac release of HA was 72 (-80-1321) nmol/min before cardioplegia, rising to 234 (-188-524) after 2 min of reperfusion (p < 0.02) and returning to baseline after 30 minutes. We conclude that the porcine heart releases t-PA, Tn-T and HA during postcardioplegic reperfusion. The differing kinetics of their release may indicate different affection of the myocardium and the endothelium. Tn-T, t-PA and HA are potential markers of myocardial and endothelial injury in the porcine heart.