Prolonged thromboprophylaxis with oral anticoagulants after total hip arthroplasty: a prospective controlled randomized study

BACKGROUND: The optimal duration of thromboprophylaxis after major orthopedic surgery is controversial. Although oral anticoagulants are still widely used for the prevention of venous thromboembolism after hip replacement, to our knowledge no study has assessed the benefit of prolonging anticoagulation beyond the hospital stay. METHODS: Consecutive patients who had received warfarin sodium prophylaxis after total hip arthroplasty were randomized to stop taking the drug at the time of hospital discharge or to continue taking it for 4 more weeks. The rate of symptomatic and asymptomatic venous thromboembolic events (as shown by compression ultrasonography of the proximal-vein system) occurring during the study period was compared between the 2 groups. The study was prematurely terminated after the inclusion of the first 360 patients because a statistically significant and clinically relevant superiority of extended over short-term thromboprophylaxis was observed. RESULTS: Objectively confirmed venous thromboembolic complications were recorded in 10 patients: 9 (5.1%) in the group of 176 control patients, and 1 (0.5%) in the group of 184 patients who continued the warfarin treatment. The absolute difference in the incidence of events was 4.57% (95% confidence interval [CI], 1.15-7.99). The relative risk of venous thromboembolism developing in control patients compared with patients assigned to extended thromboprophylaxis was 9.4 (95% CI, 1.2-73.5). The number needed to treat was 22. Major bleeding developed in 1 patient who was randomized to the extended prophylaxis group (0.5%; 95% CI, 0.02-3.0) compared with none in the control group. CONCLUSION: Extending prophylaxis with warfarin for a few more weeks beyond the hospital stay has the potential to considerably improve the outcome of patients who undergo hip arthroplasty.     

Plasminogen activator inhibitor type 1 is increased in the arterial wall of type II diabetic subjects

Plasma plasminogen activator inhibitor type 1 (PAI-1) increases in diabetes, and this might contribute to decreased fibrinolysis and accelerated atherosclerosis. Increased PAI-1 levels in the vessel wall could decrease local fibrinolysis and elevate thrombus formation and the unfavorable evolution of atherosclerotic plaques. High glucose increases PAI-1 synthesis in arterial wall cells in culture, and aortic wall PAI-1 levels have been found to be elevated in diabetic animals. However, arterial wall PAI-1 levels have not been investigated in diabetic subjects. Therefore, the aim of this study was to determine the effect of diabetes on PAI-1 levels in the arterial wall. Blood samples and small tissue specimens from the mammary artery were obtained from 11 diabetic and 10 nondiabetic subjects who underwent coronary artery bypass graft surgery. PAI-1 antigen localization in the arterial wall was obtained by immunohistochemistry and was read by laser scanning confocal microscopy; plasma fibrinolytic activity was measured by lysis of fibrin plates; and PAI-1 activity was assessed by a chromogenic method. PAI-1-related immunofluorescence was increased in the arterial wall of diabetic patients, whereas plasma fibrinolysis was reduced. These data provide evidence that diabetes is associated with increased PAI-1 in the arterial wall. This might be an important factor for increased cardiovascular risk and unfavorable plaque evolution in diabetes.     

Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia

Although hyponatremia is known to be associated with osteoporosis and a high fracture risk, the mechanism through which bone loss ensues has remained unclear. As hyponatremic patients have elevated circulating arginine-vasopressin (AVP) levels, we examined whether AVP can affect the skeleton directly as yet another component of the pituitary-bone axis. Here, we report that the two Avp receptors, Avpr1α and Avpr2, coupled to Erk activation, are expressed in osteoblasts and osteoclasts. AVP injected into wild-type mice enhanced and reduced, respectively, the formation of bone-resorbing osteoclasts and bone-forming osteoblasts. Conversely, the exposure of osteoblast precursors to Avpr1α or Avpr2 antagonists, namely SR49059 or ADAM, increased osteoblastogenesis, as did the genetic deletion of Avpr1α. In contrast, osteoclast formation and bone resorption were both reduced in Avpr1α^−/− cultures. This process increased bone formation and reduced resorption resulted in a profound enhancement of bone mass in Avpr1α^−/− mice and in wild-type mice injected with SR49059. Collectively, the data not only establish a primary role for Avp signaling in bone mass regulation, but also call for further studies on the skeletal actions of Avpr inhibitors used commonly in hyponatremic patients.Over the past decade, studies by others and us have documented direct effects of pituitary hormones on the skeleton. We have identified functional receptors for thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), adrenocorticotropic hormone (ACTH), and oxytocin (OT) on murine and human bone cells, namely bone-forming osteoblasts and bone-resorbing osteoclasts (1–4). The genetic deletion of either the receptor or the ligand itself, as in the case of FSH and OT, results in overt skeletal abnormalities. Specifically, deleting OT or its receptor, the Oxtr, causes profound osteopenia, which primarily arises from a dramatic reduction in bone formation by the osteoblast (4). Such studies have helped establish a pituitary-bone axis, in which pituitary hormones bypass their known targets, such as the thyroid, ovaries, adrenal, and breast, to regulate bone directly (5).This growing body of data not only informs us of novel functions of pituitary hormones, but also explains the hitherto poorly understood mechanisms of certain forms of osteoporosis, which have traditionally been attributed solely to changes in distal hormones. For example, we find that low TSH signaling contributes to the bone loss in hyperthyroidism, which was thought solely to be a result of elevated thyroid hormones (6). We have also speculated that the rapid bone loss that occurs during late perimenopause, at a time when estradiol levels are relatively normal, could—at least in part—be caused by elevated serum FSH levels. Thus, an antibody to FSH reduces bone loss in ovariectomized mice by stimulating bone formation and inhibiting bone resorption (7). Similarly, through its skeletal anabolic actions, elevated OT levels during pregnancy and lactation could play a major role in enabling fetal skeletal mineralization and allowing the mother to recover from the osteoporosis caused by the intergenerational transfer of calcium (8).Here, we report studies on arginine-vasopressin (AVP), another posterior pituitary hormone, which differs from OT only by two amino acids (9). The direct skeletal actions of AVP have never been explored, despite multiple and recurring observations that hyponatremia, which is invariably accompanied by elevated plasma AVP levels, is associated with bone loss and a high fracture risk (10–16). It has been thought that, as bone is a large reservoir for sodium ions, hyponatremia will trigger sodium release from the skeleton by increasing bone resorption (17, 18). However, the molecular basis of any such effect remains unknown. Interestingly, a recent study has described a male patient with syndrome of inappropriate secretion of antidiuretic hormone- (SIADH) induced hyponatremia, who had severe osteoporosis, despite having no identifiable risk factors (19). Plasma AVP was elevated by ∼30-fold, raising the possibility that high circulating AVP levels may cause the profound bone loss.We show that AVP is a key regulator of bone resorption and formation, the two principal components of bone remodeling. Both Avp receptors, Avpr1α and Avpr2, are expressed on osteoclasts and osteoblasts, and their stimulation triggers extracellular signal regulated kinase (Erk) activation, which in turn suppresses bone formation and stimulates bone resorption. This decoupling would favor bone loss, as noted in hyponatremic states. However, we also find that the genetic deletion of Avpr1 or the pharmacologic inhibition of Avpr1 or Avpr2 increases bone mass not only by stimulating osteoblastogenesis and new bone synthesis, but also by simultaneously inhibiting osteoclast formation and bone resorption. We speculate, therefore, that the targeted therapy of hyponatremia with aquaretics (or AVPR inhibitors) could result in overall bone gain. Purposefully designed clinical studies in populations in whom hyponatremia is a significant clinical problem (20), and whom are otherwise also at a high risk for fracture (21), should shed further light on the proposed osteoprotective action of AVPR antagonists in people.     

Beta 3 subunit of vitronectin receptor is present in osteoclast adhesion structures and not in other monocyte-macrophage derived cells

The distribution of extracellular matrix receptors in human osteoclasts has been studied; a beta 3 integrin is colocalized with vinculin and talin in the podosomes of osteoclastoma giant cells and not in macrophages from the same source.     

White sponge naevus with minimal clinical and histological changes: report of three cases

White sponge naevus (WSN) is a rare autosomal dominant disorder that predominantly affects non-cornified stratified squamous epithelia: oral mucosa, oesophagus, anogenital area. It has been shown to be related to keratin defects, because of mutations in the genes encoding mucosal-specific keratins K4 and K13. We illustrate three cases diagnosed as WSN, following the clinical and histological criteria, with unusual appearance. They presented with minimal clinical and histological changes that could be misleading in the diagnosis. The patients showed diffuse irregular plaques with a range of presentations from white to rose coloured mucosae involving the entire oral cavity. In one case the lesion was also present in the vaginal area. The histological findings included epithelial thickening, parakeratosis and extensive vacuolization of the suprabasal keratinocytes, confirming WSN diagnosis. Clinical presentation and histopathology of WSN are discussed in relation to the differential diagnosis of other oral leukokeratoses.