Plasminogen activator inhibitor‐1 inhibits factor VIIa bound to tissue factor

Summary. Background and objective: A growing body of experimental evidence supports broad inhibitory and regulatory activity of plasminogen activator inhibitor 1 (PAI‐1). The present study was designed to investigate whether PAI‐1 inhibits factor (F) VIIa complexed with tissue factor (TF), a well‐known procoagulant risk factor. Methods and results: The ability of PAI‐1 to inhibit FVIIa‐TF activity was evaluated in both clotting and factor X (FX) activation assays. PAI‐1 and its complex with vitronectin inhibit: (i) clotting activity of FVIIa‐TF (PAI‐1_IC50, 817 and 125 nm , respectively); (ii) FVIIa‐TF‐mediated FX activation (PAI‐1_IC50, 260 and 50 nm , respectively); and (iii) FVIIa bound to TF expressed on the surface of stimulated endothelial cells (PAI‐1_IC50, 260 and 120 nm , respectively). The association rate constant (k_a) for PAI‐1 inhibition of FVIIa‐TF was determined using a chromogenic assay. K_a for PAI‐1 inhibition of FVIIa bound to relipidated TF is 3.3‐fold higher than that for FVIIa bound to soluble TF (k_a = 0.09 ± 0.01 and 0.027 ± 0.03 μm ^?1 min^?1, respectively). Vitronectin increases k_a for both soluble and relipidated TF by 3.5‐ and 30‐fold, respectively (to 0.094 ± 0.020 and 2.7 ± 0.2 μm ^?1 min^?1). However, only a 3.5‐ to 5.0‐fold increase in the acylated FVIIa was observed on SDS PAGE in the presence of vitronectin for both relipidated and soluble TF, indicating fast formation of PAI‐1/vitronectin/FVIIa/relipidated TF non‐covalent complex. Conclusions: Our results demonstrate potential anticoagulant activity of PAI‐1 in the presence of vitronectin, which could contribute to regulation of hemostasis under pathological conditions such as severe sepsis, acute lung injury and pleural injury, where PAI‐1 and TF are overexpressed.     

HYSTEROSCOPY IN POSTMENOPAUSAL BLEEDING

The purpose of the present study was to evaluate the utility of hysteroscopy as a diagnostic tool in cases of postmenopausal bleeding. The study includes 42 cases presenting with postmenopausal bleeding on which hysterscopy was performed using rigid hysteroscope (CIRCON) with glycine 1.5% as the distension medium. In 17 of the 42 cases positive hysteroscopic findings were noted which included 2 cases of endometrial carcinoma, 2 cases of postmenopausal endometritis, 4 cases of endometrial polyp, 5 cases of endometrial hyperplasia, 1 case of submucous myoma and 3 cases of endocervical polyp whereas normal postmenopausal endometrium was noticed in rest of the 25 cases. Endometrial biopsy was done in all these cases so that the hysteroscopic findings could be corroborated with tissue diagnosis. Hysteroscopy along with directed endometrial biopsy proved to be a useful diagnostic aid in cases of postmenopausal bleeding.KEY WORDS: Hysteroscopy, Postmenopausal bleeding     

Inhibition of tissue factor pathway inhibitor by the aptamer BAX499 improves clotting of hemophilic blood and plasma

Summary. Background: Tissue factor pathway inhibitor (TFPI) is the major inhibitor of tissue factor‐initiated coagulation, making it an interesting and novel therapeutic target in hemophilia treatment. The aptamer BAX499 (formerly ARC19499) is designed to improve hemostasis by specifically inhibiting TFPI. Objectives: The aim of the study was to examine the concentration‐dependent augmentation of clotting by BAX499. Methods: Whole blood clot formation was quantified by rotational thromboelastometry and thromboelastography, and thrombin generation in platelet‐poor plasma was assessed with the calibrated automated thrombogram, in samples from patients with congenital hemophilia A (N = 55) and B (N = 11), patients with acquired hemophilia A (N = 1), and healthy controls (N = 37). Results: BAX499 significantly improved clotting of samples from hemophilic patients in a concentration‐dependent manner, resulting in clotting profiles in samples from patients with severe hemophilia that were similar to those of healthy controls. Conclusion: BAX499 improved ex vivo clotting parameters in blood and plasma from patients with hemophilia A and B with different severity of disease, and also in a patient with acquired hemophilia. These results further support the contention that anti TFPI strategies may be an effective treatment for hemophilic patients.     

A Two-Generation Reproduction Study with Monochlorobenzene Vapor in Rats

Groups of 30 male and 30 female Sprague–Dawley CD rats,designated as the F₀ generation, were exposed to vapor of monochlorobenzene(MCB) at target concentrations of 0, 50, 150, or 450 ppm for10 weeks prior to mating and during mating, gestation, and lactation.The progeny of the F₀ generation was designated as the F₁ generationand groups of 30 male and 30 female F₁ animals were exposedto the same concentrations of MCB as the F₀ parents. Exposureof F₁ animals was initiated 1 week postweaning and lasted 11weeks pnor to mating and through mating, gestation, and lactation.All F₂ pups were observed through weaning at which time theywere killed. Observations made during the study included bodyweights, food consumption, mating and fertility indices, pupand litter survival indices, and histopathology of selectedtissues. No mortality was observed during the course of thisstudy. Body weights and food consumption for all treated groupswere comparable to controls during the growth period. Maternalbody weight data during gestation and lactation were also comparablebetween the control and treated groups. Mating and fertilityindices for males and females for both generations appearedunaffected by treatment. Pup and litter survival indices forall treated groups were comparable to those of controls. Hepatocellularhypertrophy and renal changes (tubular dilation with eosinophilicmaterial, interstitial nephritis, and foci of regenerative epithelium)were observed among F₀ and F₁ male rats exposed to 150 and 450ppm MCB. The incidence of bilateral degeneration of the testiculargerminal epithelium was increased among F₀ adults in the high-concentrationgroup and this lesion was observed only unilaterally in themid- and high-concentration group F₁ adults. The relationshipof these testicular changes to exposure to MCB is unclear becausethere did not appear to be any increase in intensity and/ orincidence of testicular lesions among F₁ adults that had longerexposure. In addition, overall mean mating and fertility indicesfor all groups were comparable for both generations. In summary,exposure of rats to MCB at levels of 50, 150, or 450 ppm didnot have any adverse effects on reproductive performance orfertility of male and female rats.     

Itraconazole therapy for disseminated candidiasis in a very low birthweight neonate

The management of a preterm neonate with systemic candidiasis using oral itraconazole is described. Oral itraconazole was well tolerated and effected a clinical and mycological cure.