Fibrinolysis in critically ill patients

Impaired fibrinolysis may contribute to development of adult respiratory distress syndrome (ARDS). Pathologic increases in endogenous plasminogen activator inhibitor (PAI-1) may blunt normal fibrinolysis and unmask alternate fibrinolytic mechanisms, such as elastase-induced fibrin degradation. We measured PAI-1 and elastase-induced fibrin(ogen) degradation products in 69 critically ill patients in our medical intensive care unit (MICU) and in nine healthy volunteers. Factor VIII-related antigen protein (VIII:Ag), a reported marker of acute lung injury, and alpha-1-protease inhibitor (alpha-1-PI), an acute phase reactant, were also measured. MICU patients included 24 control patients with no known risk of ARDS, 35 patients with risk factors for ARDS including sepsis, pneumonia, aspiration, and shock, and 12 patients with ARDS including two patients from at-risk groups who developed ARDS. Plasma PAI-1 was determined by chromogenic assay, elastase-induced peptides by a new radioimmunoassay, VIII:Ag by immunoelectrophoresis, and alpha-1-PI by immunodiffusion. When compared to normal volunteers, MICU control patients had elevated PAI-1, VIII:Ag, elastase-induced peptides, and alpha-1-PI. Patients with ARDS had significantly higher PAI-1 and VIII:Ag than did MICU control patients; elastase-induced peptides and alpha-1-PI were not higher. However, at-risk patients who did not develop ARDS also had high PAI-1 or VIII:Ag. Although these data cannot refute the possible role of these compounds in the pathogenesis of ARDS, they demonstrate that PAI-1 and VIII:Ag may be elevated in many critically ill patients but may not be useful markers for the subsequent development of ARDS.     

EPA and DHA attenuate ox-LDL-induced expression of adhesion molecules in human coronary artery endothelial cells via protein kinase B pathway

Uptake of oxidized low-density lipoprotein (ox-LDL) by endothelial cells is a critical step for the initiation and development of atherosclerosis. Adhesion molecules are inflammatory makers, which are upregulated by ox-LDL and play a pivotal role in atherogenesis. A number of studies suggest that fish and its constituents can reduce inflammation and decrease atherosclerosis. We hypothesized that fish oil constituents namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) may reduce expression of adhesion molecules induced by ox-LDL. Cultured human coronary artery endothelial cells (HCAECs) were incubated with ox-LDL for 24 h. Parallel groups of cells were pretreated with DHA or EPA (10 or 50 microM) overnight before incubation with ox-LDL. Ox-LDL markedly increased the expression of P-selectin and intracellular adhesion molecule-1 (ICAM-1) (both protein and mRNA) in HCAECs, and enhanced the adhesion of monocytes to the cultured HCAECs. Both EPA and DHA decreased ox-LDL-induced upregulation of expression of P-selectin and ICAM-1, and the enhanced adhesion of monocytes to HCAECs. To determine the role of protein kinase B (PKB) as an intracellular-signaling pathway, HCAECs were treated with the PKB upstream inhibitor wortmannin (100 nM) or transfected with plasmids encoding dominant-negative mutants of PKB (PKB-DN) before treatment with DHA. Ox-LDL alone downregulated the activity of PKB; DHA attenuated this effect of ox-LDL, and both wortmannin and PKB-DN blocked the effect of DHA. The present study in human coronary endothelial cells suggests that both EPA and DHA attenuate ox-LDL-induced expression of adhesion molecules, and the adhesion of monocytes to HCAECs by modulation of PKB activation. These effects may be important mechanisms of anti-atherosclerotic effects of fish and fish oils.     

The effect of inhibition of thromboxane synthesis in experimental thrombosis and hemostasis

The effect of a selective inhibitor of thromboxane synthesis (dazoxiben) was evaluated in different acute models for thrombosis and hemostasis. Dazoxiben significantly reduced the thrombogenicity of the modified human umbilical vein (Dardik Biograft) inserted in the carotid artery position in sheep. The effect was evident concerning patency, thrombus weight and platelet accumulation at the distal anastomosis. This paralleled a decreased production of thromboxane in both anastomoses and the midgraft region. Dazoxiben did not reduce either the frequency of jugular vein thrombosis (induced by a combination of endothelial damage and flow restriction) or arteriolar microembolism after laser injury in rabbits. Neither did it influence initial hemostasis as evaluated by measuring the hemostatic plug formation in the rabbit mesenteric microcirculation. It is concluded that thromboxane synthesis inhibition may be of value when attempting to improve the performance of small diameter vascular prostheses, the data obtained indicating a low risk for hemorrhagic complications.     

Pulmonary Microembolism During Intramedullary Orthopaedic Trauma

Patienten, die für prothetische Hüftoperationen nach der Methode nach Charnley vorgesehen waren, erhielten am Tag vor dem Eingriff ⁵¹Cr-markierte Thrombozyten und ¹²⁵I-markiertes Fibrinogen. Wahrend des chirurgischen Eingriffes wurden beide Arten der Radioaktivät über der rechten Lunge extern registriert. Eine vorübergehende Anhäufung der ⁵¹Cr-Aktivität über der Lunge wurde während des Ausraumens des Knochenmarks aus dem Femur und nach dem Einsetzen der Femurstammprothese beo-bachtet. Wahrend dieser zweiten Phase wurde auch eine vorubergehende Haufung der ¹²⁵I-Radio-aktivitat registriert. Nach dem Einsetzen der Femurprothese fiel die arterielle Sauerstoffspannung (Pa_O2) significant ab. Der Korrelationskoeffizient war—0,97 zwischen dem vermehrten Auftreten der ¹²⁵I-Radioaktivität in der Lunge und der nach dem Einsetzen der Femurprothese auftretenden Pa_O2-Reduktion. Diese Resultate könnten als Anzeichen von Mikroembolis-ationen in die Lunge in diesem Operationsstadium interpretiert werden bei gleichzeitiger pulmonaler Dysfunktion.     

Effect of hydrocortisone on the elimination of fibrin from the pulmonary vessels in the rat

Administration of hydrocortisone resulted in delayed fibrin elimination from the lungs in rats with thrombin induced intravascular coagulation. The fibrinolytic system was inhibited, with increased fibrinolysis inhibition activity and decreased fibrinolytic activity in the blood, and decreased fibrinolytic activity in the pulmonary vessels. This inhibition of the fibrinolytic system might explain the delayed fibrin elimination from the lungs.     

Deposition and clearance of fibrin in the rat lung following acute haemorrhage

The effect of acute haemorrhage on the deposition and clearance of fibrin in the rat lung after thrombin-induced intravascular coagulation was investigated. Haemorrhage was followed by less embolization of fibrin to the lungs and delayed elimination from the lungs. As lung tissue fibrinolysis was not diminished, the peripheral and pulmonary circulatory disturbance was probably in itself responsible for the observed effects.     

Structural,functional and circulatory placental changes associated with impaired glucose metabolism

OBJECTIVE: To investigate associations between structural, functional and circulatory placental changes in pregnancies complicated by impaired glucose metabolism. DESIGN: Umbilical artery (UA) blood flow resistance was measured by Doppler velocimetry in 21 gravidae with diabetes/impaired glucose tolerance (IGT) and 10 healthy gravidae. Umbilical and placental vessel segments were incubated for determination of prostacyclin and thromboxane synthesis, and tissues histologically examined. Non-parametric statistical tests at a two-tailed P<0.05 were used. RESULTS: Placental lesions were more common in diabetes/IGT and, although not being an uniform finding, in general associated with a higher vascular synthesis of thromboxane and/or lower prostacyclin/thromboxane synthesis ratio. As an exception, ischemic villitis was associated with a higher ratio and higher UA flow resistance. CONCLUSIONS: Placental lesions are associated with an altered vascular prostanoid synthesis in diabetes/IGT, but not until structural signs of ischemia develop is a rise of UA blood flow resistance detected.