Venous thrombo-embolism and raised alpha-1-antitrypsin levels. A possible causal relationship between excessive neutral protease inhibition and defective granulocyte-induced fibrinolysis.

The finding of 4 cases of venous thrombosis in patients with raised serum alpha 1-antitrypsin (AAT) levels has focused attention on the role of the inhibitors of leucocyte protease or granulocyte-induced fibrinolysis. A composite fibrin plate assay was devised to determine the fibrinolytic and fibrinolytic-inhibitor potential of viable circulating granulocytes, mononuclear cells and platelet-free plasma. A plasmin-dependent and a plasmin-independent pathway were identified in circulating granulocytes, a biological function which appeared to be completely absent from the mononuclear fraction. In order to explore the effect of AAT on the cellular fibrinolytic pathway, viable granulocyte and plasma fractions were exposed to the inhibitor in a purified system as well as to several aliquots of plasma containing an excess of AAT obtained from a patient with venous thrombo-embolic disease. The unequivocal inhibition of granulocyte fibrinolytic activity by pure AAT solutions as well as by plasma with a raised AAT level would seem to provide further evidence that by counteracting protease liberated by cellular elements, notably the granulocyte, the patient is deprived of a vital component of the fibrinolytic defence mechanism.