Diathesis in a Dutch Family: An Inherited Deficiency of a2-Antiplasmin

This study concerns a case of congenital homozygous deficiency in a2-antiplasmin associated with a severe hemorrhagic diathesis. Heterozygous family members also show a mild bleeding tendency. The propositus is a 17yr-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 cx2-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 a2-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 Ill. a2-macroglobulin, factor XIII, and inter-a-trypsin inhibitor were noted. After the T HE PLASMA PROTEINASE inhibitor ct2-antiplasmin is an a2-glycoprotein with an estimated molecular weight of 65,000-70,000 daltons and a plasma concentration established at around I jzM.’4 Its physiologic function is most likely the strong inhibition of plasmin, the ultimate enzyme of the fibrinolytic system. In recent years, the mechanism ofaction of the inhibitor has been further elucidated and conclusive evidence for its specificity for fibninolysis has been provided.4 6 A recently discovered aspect of the mechanism of action of a2-antiplasmin, which is also determinative for its specificity for fibrinolysis, is its covalent binding to fibnin mediated by coagulation factor XIIIa.7 a2Antiplasmin bound to the fibnin clot reduces its breakdown.7 The physiologic importance of a2-antiplasmin was made apparent by the discovery of congenital deficiencies. Theoretically, the lack of a2-antiplasmin leads to unrestrained fibninolysis. Its actual consequence was fully realized only with the discovery ofa person with a homozygous deficiency in the inhibitor who showed a severe hemorrhagic diathesis.8’9 This report concerns a family showing congenital a2-antiplasmin deficiency and including a homozygous case with a severe hemorrhagic diathesis, emphasizing the relation between the symptoms and the deficiency. In addition, a mild hemorrhagic diathesis is reported in six of the heterozygotes, extending the incidence of 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 1 6 individuals (including the father and mother of the propositus) with approximately one-half normal plasma levels of a2antiplasmin 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 a1-antitrypsin (142% ± 39%; p< 0.01 ), indicating systemic consequences of the deficiency and reduced binding ( ± 50%) of a2-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 a2-antiplasmin levels and functions. It is concluded that not only the absence of a2-antiplasmin but also a reduction in its plasma level to ± 60% of normal