Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor.

We evaluated an elderly patient with a lifelong history of se- vere bleeding after surgery or trauma and with evidence of persistent hyperfibrinolysis. Routine coagulation studies were normal. Serum plasminogen (40%, normal 72-128%) and a2- antiplasmin (55%, normal 70-145%) activities were decreased. Euglobulin clot lysis was abnormally shortened (50 min) and normalized in vitro with e-aminocaproic acid (EACA). The pa- tient was treated with EACA with prompt cessation of bleeding. Patient tissue-plasminogen activator (t-PA) levels in serum were normal (4.7 ng/ml, control 3.5-7.2) as detected by a two-site immunoradiometric assay (IRMA). Patient fibrino- lytic inhibitor activities were assessed by incubating 11I-labeled t-PA with either whole blood or serum followed by SDS-PAGE and autoradiography to identify the resultant protease/ protease inhibitor complexes. In comparison to blood samples obtained from normal donors, patient plasma and serum dem- onstrated reduced binding of a fast-acting plasminogen activa- tor inhibitor to '251-labeled t-PA. Immunoprecipitation experi- ments indicated diminished complex formation between type 1 plasminogen activator inhibitor (PAI-1) in patient serum and 1251-labeled t-PA. Low patient PAI-1 activity was confirmed in serum (0.36 U/ml, control 0.87-1.81; n = 3) and in platelet lysates using a functional IRMA to quantitate PAI-1 binding to immobilized t-PA. However, patient serum PAI-1 antigen was within the normal range when analyzed by IRMA (31.8 ng/ml, control 19.642.2); this result was confirmed in both serum and platelets by Western blot (n = 3). Mixing experiments using purified PAI-1 as well as patient and control sera did not show evidence for an inhibitor against PAI-1. We conclude that this patient's bleeding diathesis was due to hyperfibrinolysis and defective PAI-1. This patient provides the first dem- onstration of a link between decreased in vivo PAI-1 activity and disordered hemostasis, and supports a role for PAI-1 in control of in vivo fibrinolysis.