ADMINISTRATION OF GAMMA-INTERFERON IN HUMAN-SUBJECTS DECREASES PLASMINOGEN ACTIVATION AND FIBRINOLYSIS WITHOUT INFLUENCING C1 INHIBITOR

Recombinant gamma interferon (rHuIFN-gamma) has been recognized to inc rease mRNA and protein levels of C? inhibitor (CI INH) in various huma n cells. Further, when administered to patients with colon cancer, it increased plasma CI INH levels. A prospective trial was initiated to d etermine whether rHuIFN-gamma could elevate plasma CI INH levels in si x normal volunteers and two patients with type I angioedema. After I m onth of observation of plasma CI INH levels, rHuIFN-gamma was administ ered subcutaneously at 25 mu g/M(2) daily for 4 consecutive days. All healthy volunteers and patients experienced local erythema, headache, myalgias, and chills during the administration of rHuIFN-gamma. CI INH , prekallikrein, high-molecular-weight kininogen, and factor XII level s in plasma were not influenced by the rHuIFN-gamma administration. On e patient with hereditary angioedema (HAE) had an attack of angioedema 3 days after completion of rHuIFN-gamma therapy. During the attack, c irculating cleaved high-molecular-weight kininogen, kallikrein-alpha(2 )-macroglobulin complexes, and an altered 50 kd form of kallikrein wer e detected in the patient's plasma. Additional studies showed that rHu IFN-gamma treatment resulted in decreased total fibrinolytic activity. It was found that immediately after rHuIFN-gamma treatment, tissue pl asminogen activator activity and antigen levels were not significantly decreased in volunteers. Plasminogen activator inhibitor levels rose significantly, but this activity was not due to plasminogen activator inhibitor-1 antigen, whose value significantly fell. These data sugges t that rHuIFN-gamma may stimulate the expression of another plasminoge n activator inhibitor. Because reduced fibrinolytic activity should re sult in prevention of acute attacks of angioedema, rHuIFN-gamma may al so induce angioedema independent of activation of contact and fibrinol ytic proteins.