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Bleeding Diathesis Due to Decreased Functional Activity of Type 1 Plasminogen Activator Inhibitor

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Bleeding Diathesis Due to Decreased Functional Activity of Type 1 Plasminogen Activator Inhibitor Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor. R R Schleef, … , E Pillemer, L J Levitt J Clin Invest. 1989;83(5):1747-1752. https://doi.org/10.1172/JCI114076. Research Article We evaluated an elderly patient with a lifelong history of severe bleeding after surgery or trauma and with evidence of persistent hyperfibrinolysis. Routine coagulation studies were normal. Serum plasminogen (40%, normal 72-128%) and alpha 2-antiplasmin (55%, normal 70-145%) activities were decreased. Euglobulin clot lysis was abnormally shortened (50 min) and normalized in vitro with epsilon-aminocaproic acid (EACA). The patient 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 fibrinolytic inhibitor activities were assessed by incubating 125I-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 demonstrated reduced binding of a fast-acting plasminogen activator inhibitor to 125I-labeled t-PA. Immunoprecipitation experiments indicated diminished complex formation between type 1 plasminogen activator inhibitor (PAI-1) in patient serum and 125I-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 19.6- 42.2); this result was confirmed in both serum and platelets by Western […] Find the latest version: https://jci.me/114076/pdf Bleeding Diathesis Due to Decreased Functional Activity of Type 1 Plasminogen Activator Inhibitor Raymond R. Schleef,* Deborah L. Higgins,t Eric Pillemer, and Lee J. Levitt Department ofMedicine, Stanford University Medical Center, Stanford, California 94305; *Department ofImmunology, Research Institute ofScripps Clinic, La Jolla, California 92037; tDepartment ofCardiovascular Research, Genentech, Inc., South San Francisco, California 94080 Abstract enzyme plasmin. Plasmin is formed in the circulation from the zymogen plasminogen through the proteolytic action of plas- We evaluated an elderly patient with a lifelong history of se- minogen activators (PAs).' PAs are highly specific serine pro- vere bleeding after surgery or trauma and with evidence of teases found in normal or neoplastic tissues and can be divided persistent hyperfibrinolysis. Routine coagulation studies were into two distinct groups, tissue-type (t-PA) and urokinase-type normal. Serum plasminogen (40%, normal 72-128%) and a2- (u-PA) plasminogen activator (4). The principal physiologic antiplasmin (55%, normal 70-145%) activities were decreased. inhibitor of plasmin is a2-antiplasmin. Inhibitors of plasmino- Euglobulin clot lysis was abnormally shortened (50 min) and gen activation also appear to play an important role in the normalized in vitro with e-aminocaproic acid (EACA). The pa- physiologic control of fibrinolysis (5). At least four immuno- tient was treated with EACA with prompt cessation of bleed- logically distinct molecules with plasminogen activator inhibi- ing. Patient tissue-plasminogen activator (t-PA) levels in tor (PAI) activity have been identified (6). Type 1 PAI (PAI- 1), serum were normal (4.7 ng/ml, control 3.5-7.2) as detected by formerly termed the endothelial cell PA inhibitor, inhibits a two-site immunoradiometric assay (IRMA). Patient fibrino- both t-PA and u-PA by forming 1:1 stoichiometric complexes lytic inhibitor activities were assessed by incubating 11I-la- with them. It has been detected in a large variety of cells cul- beled t-PA with either whole blood or serum followed by SDS- tured in vitro, and is also found in plasma and in the a-gran- PAGE and autoradiography to identify the resultant protease/ ules of blood platelets (5-7). A number of experimental obser- protease inhibitor complexes. In comparison to blood samples vations support the hypothesis that PAI- 1 is the principal phys- obtained from normal donors, patient plasma and serum dem- iologic inhibitor of t-PA and a primary regulator of in vivo onstrated reduced binding of a fast-acting plasminogen activa- fibrinolysis (6-8). In this study we report our investigations of tor inhibitor to '251-labeled t-PA. Immunoprecipitation experi- an elderly man with a lifelong history of postoperative bleeding ments indicated diminished complex formation between type 1 who was found to have sustained hyperfibrinolysis. Our results plasminogen activator inhibitor (PAI-1) in patient serum and suggest that his bleeding diathesis is due to decreased func- 1251-labeled t-PA. Low patient PAI-1 activity was confirmed in tional activity of PAI- . 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 Methods immobilized t-PA. However, patient serum PAI-1 antigen was within the normal range when analyzed by IRMA (31.8 ng/ml, Case report control 19.642.2); this result was confirmed in both serum The patient is a 76-yr-old man seen in consultation for persistent and platelets by Western blot (n = 3). Mixing experiments bleeding after transurethral resection of the prostate. He had a long using purified PAI-1 as well as patient and control sera did not history of bleeding after surgery. In 1969 severe postoperative bleeding show evidence for an inhibitor against PAI-1. We conclude occurred after total hip replacement. In 1978 revision of his hip pros- that this patient's bleeding diathesis was due to hyperfibrino- thesis was associated with postoperative bleeding requiring 10 U of provides the first dem- packed red blood cells. From 1978 to 1981, five episodes of upper lysis and defective PAI-1. This patient transfu- link between decreased in vivo PAI-1 activity gastrointestinal bleeding occurred requiring multiple blood onstration of a was identified upper gastroin- a role for PAI-1 in sions. No specific site ofbleeding despite and disordered hemostasis, and supports testinal series and endoscopy. In 1984, the patient fell on his side and control of in vivo fibrinolysis. developed a massive hematoma; the prothrombin time (PT), partial thromboplastin time (PITl), and platelet count were all normal. In Introduction August 1986, he developed obstructive urinary symptoms and under- Regulation of fibrinolysis is critical during hemostasis, wound went a transurethral resection of the prostate. Pathology revealed be- and other biologic processes nign hyperplasia. The postoperative course was complicated by bleed- repair, neoplasia, inflammation, red cells. The PTT, platelet fibrin clots is mediated by the ing requiring 4 U of packed blood PT, (1-3). Proteolytic degradation of count, and bleeding time were all normal. Bleeding resolved but the patient was readmitted 3 d after discharge with persistent gross hema- turia. Cystoscopy was negative and clot was evacuated. The patient This work was presented in part at the annual meeting ofthe American continued to bleed and was treated with 8 U of red blood cells and 8 U Society of Hematology, Washington, DC, December 1987, and has of fresh-frozen plasma without cessation of bleeding. Consultation was been published in abstract form (1987. Blood. 70:378a). requested. Routine coagulation studies were normal including the PT Address reprint requests to Dr. Levitt, Room S- 161, Hematology and P171. There was no evidence of ongoing disseminated intravascu- Division, Stanford, CA 94305-5112. Receivedfor publication 27 June 1988 and in revisedform 28 Oc- tober 1988. 1. Abbreviations used in this paper: EACA, e-aminocaproic acid; IRMA, immunoradiometric assay; PA, plasminogen activator; PAI- 1, J. Clin. Invest. type 1 plasminogen activator inhibitor, p-APMSF, p-amidinophenyl- © The American Society for Clinical Investigation, Inc. methylsulfonyl fluoride; PT, prothrombin time; PTT, partial throm- 0021-9738/89/05/1747/06 $2.00 boplastin time; t-PA, tissue-type plasminogen activator; u-PA, uroki- Volume 83, May 1989, 1747-1752 nase-type plasminogen activator. Hemorrhage and Decreased Functional Plasminogen Activator Inhibitor 1747 lar coagulation with normal fibrinogen (256 mg/dl, normal 160-350), dimensional gel electrophoresis (15). Monoclonal antibody (MAB thrombin and reptilase times and D dimer, and only modestly (20-40, 2D2) directed against human PAI-I was produced according to de- normal < 10) elevated fibrin degradation products. The bleeding time scribed protocols (10). Thrombin was a generous gift from Dr. J. Fen- and von Willebrand factor antigen, ristocetin cofactor, and factor VIII ton (New York State Department of Health, Albany, NY). Pancreatic coagulant activity were normal, suggesting that a diagnosis of von elastase was purchased from Elastin Products Co. (Pacific, MO). Mo- Willebrand's disease was unlikely. Although routine coagulation tests lecular mass markers for SDS-PAGE were purchased from Sigma were normal, there was evidence of ongoing fibrinolysis with a short- Chemical Co. (St. Louis, MO) and included myosin (205,000 D), fl- ened euglobulin clot lysis time (50 min, normal no lysis at 2 h) which galactosidase (116,000 D), BSA (66,000 D), egg albumin (45,000 D), partially corrected in vitro (1 h, 45 min) after the addition of the and carbonic anhydrase (29,000 D). antifibrinolytic agent, E-aminocaproic acid (EACA). Additionally, Blood proteinase inhibitor complex assay. This assay was per- serum plasminogen (40%, normal 72-128%) and a2-antiplasmin (55%, formed to assess the ability of inhibitors in whole blood to form com- normal 70-145%) were persistently decreased. The patient was pre- plexes with 1251-labeled t-PA ('25I-t-PA) (11). Purified recombinant sumed to have a hyperfibrinolytic state of undetermined etiology and t-PA was radiolabeled with Enzymobeads (Bio-Rad Laboratories, was treated empirically with EACA with prompt resolution of his Richmond, CA) as described (1 1).
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