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The aim of the study was to evaluate any correlation between the circulating oestrogenic hormone 17beta-oestradiol and haemostatic factors in healthy postmenopausal women. In keeping with this objective, the correlations were evaluated irrespective of whether the source of the hormone was purely endogenous or exogenous as well. Accordingly, a univariate correlation adjusted for age, body mass index, and duration of menopause was determined in 42 healthy postmenopausal women aged 47-78 years, 19 of whom were self-reported users of hormone replacement therapy. The rest were self- reported never users. Serum 17beta-oestradiol exhibited a direct correlation with endogenous thrombin potential extrinsic pathway (R = 0.42, p = 0.01) and prothrombin fragments 1 and 2 (R = 0.37, p = 0.03) and an inverse correlation with antithrombin III (R = -0.36, p = 0.03) and alpha(2)-antiplasmin (R = -0.45, p = 0.005). The observations suggest an association of this hormone with net thrombin generation on the one hand and improved fibrinolysis on the other., (Copyright 2000 S. Karger AG, Basel)

Congenital plasminogen activator inhibitor-1 (PAI-1) deficiency is an extremely rare disorder characterized by a bleeding diathesis that begins in childhood due to hyperfibrinolysis as a result of decreased PAI-1 activity. We now present 4 unrelated pediatric cases of congenital PAI-1 deficiency. All 4 patients had a history of recurrent episodes of subcutaneous bleeding beginning in early childhood. These episodes were characterized by abnormal prolonged bleeding after trauma, tooth extraction, and surgical procedures, as well as by rebleeding following initial hemostasis. The 2 female patients both had symptoms compatible with hypermenorrhea. The family history was positive in 2 of the 4 patients. Hemostatic screening studies in all 4 patients revealed no abnormalities. Testing for factor XIII antigen, von Willebrand factor antigen, ristocetin cofactor activity, alpha(2)-plasmin inhibitor (alpha2PI) activity, and plasminogen activity was normal. The euglobulin lysis times were shortened in all cases as compared with those in normal control subjects. None of the patients had elevated tissue plasminogen activator (tPA) antigen levels, but PAI activity was markedly decreased in all cases. Three of the patients also had reduced levels of PAI-1 antigen. There tended to be a reduction in tPA-PAI-1 complex in all cases. In addition, 2 patients had elevated PIC (plasmin-alpha2PI complex). Tourniquet tests were performed in 2 patients, with no appreciable rise in PAI-1 activity or PAI-1 antigen levels. The administration of tranexamic acid clearly improved hemorrhagic symptoms in these patients. We considered PAI-1 deficiency to be the likely etiology of the congenital bleeding diatheses in these 4 cases., (Copyright 2000 S. Karger AG, Basel)

The ability of human peripheral blood monocytes to secrete plasma serine protease inhibitors was studied. Monocytes from blood obtained from healthy young adult volunteers were cultured for up to 36 h with and without lipopolysaccharide from Escherichia coli. The concentrations of plasma serine protease inhibitors in monocyte culture supernatants were measured by using rocket immunoelectrophoresis. The study showed that human monocytes stimulated with lipopolysaccharide in vitro release antithrombin III, C1 esterase inhibitor, alpha 2-antiplasmin, and alpha 2-macroglobulin.

Ten patients with atherosclerosis obliterans of the lower limbs (Fontaine stage IV) were studied under basal conditions during and after short-term administration of defibrotide (800 mg/day intravenously from day 1 to 10 and then 400 mg/day intramuscularly from day 11 to 30). The clinical effectiveness of defibrotide was evaluated not only clinically (subjective and objective symptomatology) but also by Doppler velocimetry (Windsor's Index (WI] and primary antiplasmin activity. Seven patients (70%) showed improvement in subjective and objective symptomatology. There were increases in WI at the end of intravenous treatment in 6 patients (60%). In the remaining 40%, WI did not change from basal values. All patients showed normalization of primary antiplasmin activity versus basal values (55.62%, 17.75 SD) at the end of both intravenous and intramuscular treatment (101.37%, 15.71 SD and 102.5%, 13.86 SD, respectively). Therefore, we think that defibrotide may be useful for therapy of atherosclerosis obliterans of the lower limbs.

In order to investigate whether alpha 2-antiplasmin (alpha 2-AP) levels may be related to thrombin activity, we measured alpha 2-AP and fibrinopeptide A (FPA) in 51 patients with clinical conditions frequently associated with increased thrombin activity. The diagnoses were: atherosclerotic disease, chronic inflammatory disease and hematological neoplastic disease. A significant negative correlation was found between alpha 2-AP and FPA (p less than 0.01). When patients were divided into three subgroups on the basis of their FPA levels, a significant reduction in alpha 2-AP was found in patients with the highest FPA concentration (greater than 9 ng/ml). Accordingly, a significant negative relationship between alpha 2-AP and FPA was found only in this subgroup (p less than 0.01). Our data suggest that the partial consumption of alpha 2-AP in patients with elevated FPA levels may reflect a subclinical fibrinolysis activation secondary to increased thrombin activity.

The variations of different antiplasmins were studied in a group of patients suffering from thromboembolic conditions and receiving three different regimens of thrombolytic treatment with streptokinase and urokinase. The evaluation of the antiproteases was carried out by chromogenic substrate and radial immunodiffusion. The different administration patterns of the fibrinolytic agents were followed by a clear drop in fast antiplasmin and alpha 2-macroglobulin, while alpha 1-antitrypsin was increased. Antithrombin-III activity was reduced while its protein rose in the intermittent treatment with streptokinase. In the conventional treatment with streptokinase, both the activity and the protein of antithrombin-III increased. With urokinase both the protein and the activity of antithrombin-III were slightly reduced. Plasminogen and fibrinogen decreased in the different regimens of thrombolytic treatment, being more evident in continuous administration of streptokinase.

The fibrinolytic and fibrinogenolytic properties of kidney cell pro-urokinase (PUK) were compared with those of natural urinary urokinase in human volunteers. Comparable degrees of fibrinolysis were obtained at a concentration of 500,000 U UK and a concentration of 500,000 IU natural urokinase. Natural urokinase showed a strong activation of the fibrinolytic system in plasma, evidenced by plasminogen activation, alpha 2-antiplasmin consumption, and the rise in fibrinogen-fibrin degradation products. In contrast to UK, there was no fall in plasminogen, no consumption of alpha 2-antiplasmin, and only a slight amount of fibrinogen-fibrin degradation products produced with PUK. These findings with PUK reveal a high affinity for fibrin and may result in better clot selectivity.

Intravenous and subcutaneous administration of PK 10169 in healthy human volunteers were studied utilizing numerous old and new laboratory methods for the monitoring of the effects of this agent. In the intravenous studies, individual groups of 10 healthy volunteers were administered with 2,500-12,500 anti-Xa units (25-125 mg) PK 10169 as a single bolus, and blood samples were drawn at 30 min, 1, 4 and 24 h after the administration of the drug. In the subcutaneous studies, 4,000 anti-Xa units (40 mg) b.i.d. of PK 10169 were administered to a group of 10 healthy individuals for 7 consecutive days, and blood samples were drawn 6 h after each dose. Citrated blood samples collected from both studies were centrifuged, plasma was frozen at -70 degrees C in aliquots, and various laboratory parameters were determined in batches. In the intravenous studies, the global clotting assays (activated partial thromboplastin time and thrombin time) were only prolonged at initial stages of treatment, whereas a marked increase in the antiprotease and antifibrinopeptide A generation activity titer was observed for periods of up to 24 h. In the subcutaneous studies, no significant prolongation of the global clotting assays was noted; however, the anti-Xa levels were significantly increased throughout the study period (7 days). Only a trace of anti-IIa activity was observed. In contrast, a strong antifibrinopeptide A generation activity was observed in all samples which persisted after the discontinuation of PK 10169. These studies suggest that PK 10169 may exert its clinical effects by multiple mechanisms which are only partially assessable by routine laboratory methods.