Oral estrogen improves serum lipids, homocysteine and fibrinolysis in elderly men.

The effects of estrogen on cardiovascular risk factors have been less well defined in men than in women. We measured lipid and lipoprotein concentrations, lipoprotein particle size distributions, lipoprotein (a), homocysteine, and markers of thrombosis and fibrinolysis in 18 [corrected] healthy elderly men (age 74 +/- 3 years, mean +/- S.D.) before and after 9 weeks of treatment with 0.5, 1 or 2 mg/day of oral micronized 17beta-estradiol. LDL-C (-6%), apo B (-9%), triglyceride (-5%), and homocysteine (-11%) concentrations decreased with estradiol, whereas HDL-C (+14%) increased. Intermediate-size VLDL subclass concentrations were lowered and LDL and HDL subclass levels altered in such a way as to cause average LDL and HDL particle size to increase. Lipoprotein (a) did not change. Fibrinogen (-13%) and plasminogen activator inhibitor-1 (PAI-1) concentrations (-26%) decreased, but there were no changes in thrombotic markers including thrombin-antithrombin III complex, prothrombin fragment 1.2, D-dimer, antithrombin activity, protein-C and S and von Willebrand factor antigen. Breast tenderness occurred in four men and heartburn in five but did not require discontinuation of treatment. We conclude that oral estrogen in men reduces homocysteine, fibrinogen, and PAI-1 concentrations and favorably influences VLDL, LDL and HDL subclass levels without increasing markers of thrombotic risk.

Acquired protein S deficiency in children infected with human immunodeficiency virus.

OBJECTIVES: To determine the prevalence of an acquired deficiency of protein S, a coagulation inhibitor, in children infected with the human immunodeficiency virus (HIV) and to identify clinical and laboratory features associated with this coagulation abnormality. METHODS: A convenience sample of HIV-infected children, ages 2 to 18 years, was evaluated for total, free and functional protein S; total and functional protein C; prothrombin and activated partial thromboplastin times; fibrinogen; antithrombin III activity; dilute Russell viper venom time; IgG anticardiolipin antibodies; von Willebrand factor antigen; C4b-binding protein; CD4+ T lymphocyte counts; HIV p24 antigen concentration; and serum beta 2-microglobulin concentrations. RESULTS: Thirty-four subjects were evaluated. Twenty-four subjects were infected perinatally and 10 by transfusion. Nine of the subjects were CDC Class N (asymptomatic), 13 were Class A/B (symptomatic without AIDS-defining condition) and 12 were Class C (AIDS). None had previously documented thrombosis, nephrosis or significant hepatic dysfunction. Twenty-six subjects (76.5%) had decreased free protein S, and 19 (55.9%) had functional protein S < 2 SD below the mean of laboratory controls. Decreased functional protein S was seen in 33.3% of Class N, 53.8% of Class A/B and 75.0% of Class C subjects. The prevalence of decreased total and functional protein S was greater in those with absolute CD4+ T lymphocyte counts < 200/mm3 compared to those with CD4+ counts > or = 200/mm3 (75.0% vs. 38.9%; chi square, 4.48, P = 0.034). A trend toward negative correlation was observed between protein S and duration of HIV infection only for Class N subjects. No linear correlation was seen between protein S and CD4+ T lymphocyte counts; and no significant relationships were observed between protein S values and CMV status, HIV p24 antigen, C4b-binding protein, von Willebrand factor antigen, IgG anti-cardiolipin antibodies or serum beta 2-microglobulin values. CONCLUSIONS: Acquired protein S deficiency is common in HIV-infected children. The high prevalence of this anticoagulant abnormality suggests an increased risk for thrombotic complications in this population.

Direct measurement of unfractionated heparin using a biochemical assay.

A number of investigations have noted that functional biological assays for heparin are not always reliable and may not reflect the actual biochemical level of heparin in patients receiving anticoagulant therapy. This creates the possibility that patients receiving anticoagulant treatment may have an excess or deficiency of circulating levels of heparin. To address this problem, we have developed a direct biochemical measurement of heparin. The heparin assay uses fluorophore-assisted carbohydrate electrophoresis (FACE) to directly measure the predominate disaccharide of unfractionated heparin. In this study, unfractionated heparin was measured in vitro throughout a wide range of heparin concentrations in plasma. Seven in vivo pharmacokinetic studies in five normal subjects given 3,000 USP units of unfractionated heparin intravenously showed a three-phase elimination process with higher peak plasma levels and shorter elimination times than predicted from previous studies. At these doses, heparin is largely eliminated intact through urinary excretion. Body weight has a significant effect on heparin kinetics. When we compared the direct biochemical assay with two biological clotting assays, we found the latter can overestimate biochemical heparin concentrations. The FACE assay, due to its sensitivity, is also able to measure circulating levels of endogenous heparin in plasma and urine. Direct heparin measurement using the FACE technique is practical and useful for studies of the correlation of biochemical and biological activities.

Resistance to activated protein C: a major cause of inherited thrombophilia.

Blood coagulation proteins play a major role in the development of pathological venous and arterial thrombosis. Inherited disorders of thrombosis are due to deficiencies of the anticoagulant proteins antithrombin, protein C, and protein S in 10% to 15% of individuals that present with venous thrombosis. A recently described cause of venous thrombosis is characterized by a poor response to activated protein C. In 90% of cases the activated protein C resistance is attributable to a mutation in the factor V gene (factor V Leiden). Activated protein C resistance is found in up to 7% of the Caucasian population but essentially unseen in other races. Activated protein C resistance is associated with a 5 to 10X increased risk of venous thrombosis in individuals that are heterozygous for the defect and a 50 to 100X increased risk in those individuals that are homozygous for factor V Leiden. Activated protein C resistance can be detected in the laboratory by modifications of the activated partial thromboplastin time assay. This assay is easy to perform and can be automated for a variety of instruments. Confirmation of the mutation of the factor V gene is accomplished through polymerase chain reactions that require DNA extraction from the patient's blood sample. Global assays that reflect the functionality of the protein C pathway have recently been introduced to the marketplace.

Statin therapy and thromboxane generation in patients with coronary artery disease treated with high-dose aspirin.

Aspirin and statin therapy are mainstay treatments in patients with coronary artery disease (CAD). The relation between statin therapy, in vivo thromboxane (Tx) generation; a marker of inflammation, and blood thrombogenicity has never been explored. Urinary 11-dehydro (dh) TxB2 was determined in patients with suspected CAD on 325 mg daily aspirin therapy prior to undergoing cardiac catheterisation (n=281). Thrombogenicity was estimated by thrombelastographic measurement of thrombin-induced platelet-fibrin clot strength (TIP-FCS) and lipids/lipoproteins were determined by vertical density gradient ultracentrifugation/ELISA. The influence of statin therapy and dose was analysed by the atorvastatin equivalent dose (5-10 mg, 20-40 mg, or 80 mg daily). Statin therapy (n=186) was associated with a dose-dependent reduction in urinary 11-dh TxB2 (p=0.046) that was independent of LDL and apo B100 levels but was strongly related to TIP-FCS (p=0.006). By multivariate analysis, no statin therapy (n=95) and female gender were independently associated with high urinary 11-dh TxB2 [OR=2.95 (0.1.57-5.50, p=0.0007); OR=2.25 (1.24-4.05, p=0.007)], respectively. In aspirin-treated patients, statin therapy was independently and inversely associated with inflammation in a dose-dependent manner. Elevated 11-dh TxB2 was associated with a prothrombotic state indicated by high TIP-FCS. Our data suggest that measurement of urinary 11-dTxB2 may be a useful method to optimise statin dosing in order to reduce thrombotic risk.

[Effects of delivery and oophorectomy on urethral collagen: an experimental study]. / Efectos del parto y ooforectomía sobre el colágeno uretral: estudio experimental.

OBJECTIVE: Stereological evaluation of the concentration of type I and III collagen fibers in the urethral tissue of rats subjected to simulated labor and oophorectomy. To compare the concentrations of collagen between oophorectomized and non-oophorectomized rats. MATERIAL AND METHOD: Sixty adult Wistar rats were divided into six groups. A group made up of virgin rats was used as control group and another group was made up of oophorectomized rats. Two groups underwent vaginal distention for 30 and 120 minutes, respectively. The two other groups were subjected to the same distension periods, followed by oophorectomy. Sixty days later, euthanasia and removal of urethral tissue was carried out for stereological analysis of type I and III collagen after staining with hematoxylin and eosin and picrosirius red. RESULTS: A decrease in estrogen levels was observed in the oophorectomized rats. There was a reduction of type III collagen in the oophorectomized control group compared to the control group when analyzed independently. No significant differences were observed among the other groups. Type I collagen decreased in all groups compared to the control group. However, in the prolonged vaginal distension and oophorectomy group, these fibers increased. CONCLUSION: In normal rats, simulation of labor does not alter the collagen III levels. In hypoestrogenic rats, the concentration of collagen type I and III decreased, except in those undergoing prolonged labor simulation in which collagen I increased.

[Biomechanical effects of the inclusion of holes to facilitate the integration in monofilament polypropylene meshes: an experimental study]. / Efectos biomecánicos de la inclusión de orificios facilitadores de la integración en mallas de polipropileno monofilamento: estudio experimental.

OBJECTIVE: To evaluate the biomechanical properties of a type of monofilament polypropylene mesh used to repair vaginal prolapse, as well as the effects of the inclusion of standard size orifices, called "helper orifices," on the interface resistance in the receiving area. MATERIAL AND METHODS: Forty female Wistar rats, 3 month-old, received an implant of monofilament polypropylene mesh, measuring 24 x 11 mm with no orifices, on left side of the abdominal wall (block 1). On the right side, a similar mesh with two circular orifices (6 mm diameter) was implanted (block 2). The rats were euthanized 90 days later and their abdominal walls were removed and divided into two blocks. The biomechanical study used a precision tensiometer in which the mesh was uniaxially tensioned until it was loosened from the tissue interface. In order to determine the tissue adherence and elasticity in each group, the following variables were analyzed: maximum load; deflection at maximum load; work to maximum load; stiffness as well as load, deflection and work at detachment the mesh. RESULTS: With the exception of stiffness, all the other variables showed statistical differences between the groups, considering that they were increased in meshes with orifices (p<0.001). The inclusion of standard size orifices reduced 30% of the mesh weigth. CONCLUSION: Besides reducing the weight and amount of material, the inclusion of standard size orifices in the monofilament macroporous polypropylene mesh improved the elasticity and adherence to the tissues when implanted in the interface of the abdominal wall in adult female rats.

Hypercoagulability following multiple trauma.

We sought evidence of hypercoagulability in 59 seriously injured trauma patients. An extended coagulation profile (consisting of tissue plasminogen activator antigen concentration, plasminogen activator inhibitor, serum antithrombin III, protein C antigen, functional protein C, protein S antigen, D-dimer, and prothrombin fragment 1.2) was compared to control values. Laboratory evidence of hypercoagulability was seen in 85% (n = 50) of the patients. Patients with an Injury Severity Score (ISS) > or = 16 (n = 36) had significantly elevated levels of D-dimer and decreased levels of functional protein C compared to patients with an ISS < or = 15 (n = 23). Functional protein C had a negative correlation (r = -0.44; p < 0.001) with the ISS. A hypercoagulable state exists immediately following severe trauma. Greater injury severity may increase this hypercoagulable state. Decreased levels of functional protein C best correlated with increased injury severity.

Toward an optimal "antiplatelet" dose of aspirin: Preliminary observations.

It remains unclear which dose of aspirin (ASA) confers the optimal antiplatelet effect. This study focuses on long-term responses to different ASA doses by selected normal subjects. Their baseline platelet aggregabilities exemplified both the average values and the extremes of hyper-and hypoaggregability. Only 41 mg ASA daily stopped all arachidonic acid aggregations and maximally spared endogenous nucleotides. When 2.8 and 9 µM adenosine diphosphate were used as the aggregants, it became evident that higher ASA doses yielded still further grades of change both in aggregation and disaggregation. Disaggregations proved of special interest: distinctive for each subject, they clearly improved more on 325 mg ASA daily than on 41 mg or 81 mg. "Low-dose" ASA, at longer dose intervals of 48 or 72 h, may not be optimal to sustain an adequate antiplatelet effect. More individualized ASA doses, based on selected in vitro measurements of platelet function, might prove useful both in reducing the size and number of cerebral ischemic infarcts and in avoiding hemorrhagic complications in certain patients.