Trends in microvascular research: The microembolism syndrome

Abstract

Our present viewpoints on the pathogenesis of the microembolism syndrome have been arrived at from investigations covering the last 10 years, and comprise parallel clinical, pathologico-anatomical, and experimental studies of this condition. The early microembolism syndrome was studied in 22 patients who underwent a standardized trauma, namely total hip-replacement surgery. In these patients, microembolization to the lungs was studied by means of labelled fibrinogen and platelets and external detection, and the pulmonary arterial blood was examined for fat globules and tissue-thromboplastic activity. The delayed microembolism syndrome was shown to have a very typical clinical, roentgenological, and pathologico-anatomical picture. Our conclusions are based on the findings in 84 patients who died of this syndrome, several of whom were studied clinically. For diagnosis of the syndrome 125I-labeled fibrinogen was used, with measurement of fibrin trapping in the lungs by external detection. The experimental studies were made possible by the development of a new specific, quantitative method for demonstrating microemboli in various organs. The human microembolism syndrome, both the early and the delayed form, could be reproduced in both dogs and rats by intravenous injection of thrombin and a fibrinolysis inhibitor, tranexamic acid (AMCA). In trauma, especially fractures of the pelvis and lower extremities and in major soft tissue injuries, thromboplastic material is released from the damaged area, mainly as a constituent of bone marrow fat or crushed subcutaneous adipose tissue, and enters the venous system. This release takes place partly at the time of trauma and partly post-traumatically, e.g., when fractured bones are moved. On its way to the lungs, the thromboplastin gives rise to the formation of thrombin and fibrin. This fibrin is accumulated almost exclusively in the lungs in the form of microemboli; “disseminated intravascular coagulation” on the arterial side is very rare. In the early microembolism syndrome, the microemboli accumulated in the lungs give rise to transitory pulmonary dysfunction, with a reduction of PaO 2. A strong correlation between the thromboplastic activity in the pulmonary artery as well as the deposition of fibrin in the lungs and the PaO 2 reduction was seen in our patients. Through mechanical obstruction, secondary vasoconstriction, and peripheral airway constriction caused by fibrin degradation products and prostaglandins released from the platelets and the damaged pulmonary tissue, there is a reduction of the ventilation/perfusion ratio; this is due to increased perfusion in nonembolic parts of the lung due to shunting of blood and decreased ventilation in parts with airway constriction. This ventilation/perfusion disturbance results in an increase in total venous admixture, with a decrease in PaO 2. This acute reaction is often of very short duration. The delayed microembolism syndrome is a result of persistent microemboli in the pulmonary circulation. The delayed fibrin elimination is caused mainly by an inhibition of the fibrinolytic system, with impaired lysis of the microemboli, where an increased blood level of plasminogen activation inhibitors plays the most important role. Starting about 12 hr after trauma the synthesis of PAI in the liver is enhanced as a result of an earlier increase in free fatty acids in the blood due to catecholamine stimulation of lipolysis. A PAI from post-traumatic patients has been purified by immunosorbence and affinity chromatography, and has been characterized. It has a molecular weight of about 90,000. This inhibitor binds to the plasminogen, and as a result the plasminogen activators in the blood and tissues are unable to induce plasmin formation and consequent resolution of the fibrin microemboli. A low plasminogen level in the blood can also be a contributory cause of the delayed elimination of fibrin from the lungs in some cases. The persistence of fibrin microemboli in the lungs induces first an interstitial and later an alveolar oedema; the mixed venous blood perfuses these nonventilated alveoli, with a progressive decrease in PaO 2 as a result. The oedema is caused through an increase in vascular permeability; this is induced by an impairment of the endothelial function caused by the fibrin itself and by a permeability increasing factor. The latter may be, as recently has been shown, identical with a fibrin-degradation product (FDP). Neither platelets, leucocytes, red cells, histamine, serotonin, prostaglandins, SRS, bradykinin, nor bronchoconstriction were shown to play a role in the development of the oedema. The only factors which seems to be prerequisites for the induction of the delayed microembolism syndrome seem to be fibrin and FDP.