This study concerns a case of congenital homozygous deficiency in ??2-antiplasmin associated with a severe hemorrhagic diathesis. Heterozygous family members also show a mild bleeding tendency. The propositus is a 17-yr-old male born of white parents and showing a severe hemorrhagic diathesis characterized by spontaneous bleeding in the joints since his early childhood. He was originally suspected of having factor XIII deficiency but was found to have normal functions of the coagulation system and the platelets. Except for ??2-antiplasmin, all protease inhibitors showed normal plasma values. With the immediate plasmin inhibition test (synthetic substrate), only 2% of normal functional inhibition was detected, while no reaction with monospecific antisera for ??2-antiplasmin was observed. Inhibition of activator-induced fibrinolysis in vitro was reduced. No enhanced spontaneous in vitro fibrinolysis was detected nor were there signs of increased in vivo fibrinolysis during an asymptomatic period. During recovery from a hemorrhagic episode, signs of previous consumption of antithrombin III, ??2-macroglobulin, factor XIII, and inter-??-trypsin inhibitor were noted. After the diagnosis was made, treatment with tranexamic acid (4 daily doses of 1 g) was effective for about 2 yr. among the 37 family members studied, a separate group of 16 individuals (including the father and mother of the propositus) with approximately one-half normal plasma levels of ??2-antiplasmin both functionally (59% ?? 6%) and immunologically (48% ?? 8%) was discovered. The defect appeared to be inherited as an autosomal recessive gene; no ancestral consanguinity could be shown. The group of apparent heterozygotes as a whole showed increased levels of ??1-antitrypsin (142% ?? 39%; p < 0.01), indicating systemic consequences of the deficiency and reduced binding (?? 50%) of ??2-antiplasmin to fibrin. Six exhibited a mild hemorrhagic diathesis for which no explanation was provided by routine screening of coagulation and platelet functions; also, within the group of heterozygotes, the occurrence of the bleeding tendency did not correlate with differences in residual ??2-antiplasmin levels and functions. It is concluded that not only the absence of ??2-antiplasmin but also a reduction in its plasma level to ??60% of normal may predispose to a hemorrhagic diathesis. Chemicals/CAS: antithrombin, 9000-94-6; blood clotting factor 13, 9013-56-3; tranexamic acid, 1197-18-8, 701-54-2; alpha-Macroglobulins; Antiplasmin; Factor XIII, 9013-56-3; Plasminogen, 9001-91-6