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SummaryDiscontinuation of thromboprophylaxis a few days after surgery may unmask delayed hypercoagulability and contribute to late formation of deep venous thrombosis (DVT). To investigate whether thromboprophylaxis should be prolonged beyond the hospital stay, a prospective, double-blind randomised study was conducted in 308 patients. All patients received initial thromboprophylaxis with dalteparin, dextran and graded elastic stockings. On day 7, patients were randomised to receive dalteparin (Fragmin®) 5000IU once daily, or placebo, for 4 weeks. All patients were subjected to bilateral venography, perfusion ventilation scintigraphy and chest X-ray on days 7 and 35. Patients with venographically verified proximal DVT on day 7 were withdrawn from the randomised study to receive anticoagulant treatment. The overall prevalence of DVT on day 7 was 15.9%. On day 35, the prevalence of DVT was 31.7% in placebo-treated patients compared with 19.3% in dalteparin-treated patients (p = 0.034). The incidence of DVT from day 7 to day 35 was 25.8% in the placebo-treated group versus 11.8% in the dalteparin-treated group (p = 0.017). The incidence of symptomatic pulmonary embolism (PE) from day 7 to day 35 was 2.8% in the placebo-treated group compared with zero in the dalteparin-treated group. This included one patient who died from PE. No patients experienced serious complications related to the injections of dalteparin or placebo. This study shows that prolonged thromboprophylaxis with dalteparin, 5000 IU, once daily for 35 days significantly reduces the frequency of DVT and should be recommended for 5 weeks after hip replacement surgery.

The bisdichloroacetyldiamine WIN 18,446 reversibly inhibits spermatogenesis in many species, including humans; however, the mechanism by which WIN 18,446 functions is unknown. As retinoic acid is essential for spermatogenesis, we hypothesized that WIN 18,446 might inhibit retinoic acid biosynthesis from retinol (vitamin A) within the testes by inhibiting the enzyme aldehyde dehydrogenase 1a2 (ALDH1a2). We studied the effect of WIN 18,446 on ALDH1a2 enzyme activity in vitro, and on spermatogenesis and fertility in vivo, in mature male rabbits for 16 weeks. WIN 18,446 markedly inhibited ALDH1a2 enzyme activity in vitro with an IC50 of 0.3 μM. In vivo, the oral administration of 200 mg/kg WIN 18,446 to male rabbits for 16 weeks significantly reduced intratesticular concentrations of retinoic acid, severely impaired spermatogenesis, and caused infertility. Reduced concentrations of intratesticular retinoic acid were apparent after only 4 weeks of treatment and preceded the decrease in sperm counts and the loss of mature germ cells in tissue samples. Sperm counts and fertility recovered after treatment was discontinued. These findings demonstrate that bisdichloroacetyldiamines such as WIN 18,446 reversibly suppress spermatogenesis via inhibition of testicular retinoic acid biosynthesis by ALDH1a2. These findings suggest that ALDH1a2 is a promising target for the development of a reversible, nonhormonal male contraceptive.

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