Nitrophorins and related antihemostatic lipocalins from Rhodnius prolixus and other blood-sucking arthropods.
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Recent gene sequence and crystal structure determinations of salivary proteins from several blood-sucking arthropods have revealed an unusual evolutionary relationship: many such proteins derive their functions from lipocalin protein folds. Many blood-sucking arthropods have independently evolved the ability to overcome a host organism's means of preventing blood loss (called hemostasis). Most blood feeders have proteins that induce vasodilation, inhibit blood coagulation, and reduce inflammation, but do so by distinctly different mechanisms. Despite this diversity, in many cases the antihemostatic activities in such organisms reside in proteins with lipocalin folds. Thirteen such lipocalins are described in this review, with a particular focus on the heme-containing nitrophorins from Rhodnius prolixus, which transport nitric oxide, sequester histamine, and disrupt blood coagulation. Also described are the antiplatelet compounds RPAI, moubatin, and pallidipin from R. prolixus, Ornithodoros moubata, and Triatoma pallidipennis; the antithrombin protein triabin from T. pallidipennis; and the tick histamine binding proteins from Rhipicephalus appendiculatus. (+info)
Criteria for evaluating evidence that laboratory abnormalities are associated with the development of venous thromboembolism.
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The identification of conditions associated with an increased risk of venous thromboembolism may indicate the need for aggressive prophylaxis during periods of high risk, prolonged anticoagulant therapy after an initial venous thromboembolic episode, the investigation of asymptomatic family members and the avoidance of oral contraceptives. Advances in laboratory medicine have led to the identification and assessment of many proteins responsible for normal hemostasis, and associations between abnormalities in a number of these proteins and venous thromboembolism have been reported. Without the ability to appraise this information critically, physicians may be unable to determine whether or how they should modify their clinical practice. Criteria for determining whether specific laboratory abnormalities have a relationship with venous thromboembolism are proposed here, and one example of the application of these guidelines is provided. (+info)
Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells.
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Detailed studies of tumor cell-associated procoagulants and fibrinolytic factors have implied that local thrombin generation and fibrin deposition and dissolution may be important in tumor growth and dissemination. To directly determine whether fibrin(ogen) or plasmin(ogen) are determinants of the metastatic potential of circulating tumor cells, this study examined the impact of genetic deficits in each of these key hemostatic factors on the hematogenous pulmonary metastasis of 2 established murine tumors, Lewis lung carcinoma and the B16-BL6 melanoma. In both tumor models, fibrinogen deficiency strongly diminished, but did not prevent, the development of lung metastasis. The quantitative reduction in metastasis in fibrinogen-deficient mice was not due to any appreciable difference in tumor stroma formation or tumor growth. Rather, tumor cell fate studies indicated an important role for fibrin(ogen) in sustained adhesion and survival of tumor cells within the lung. The specific thrombin inhibitor, hirudin, further diminished the metastatic potential of circulating tumor cells in fibrinogen-deficient mice, although the inhibitor had no apparent effect on tumor cell proliferation in vitro. The absence of plasminogen and plasmin-mediated fibrinolysis had no significant impact on hematogenous metastasis. The authors concluded that fibrin(ogen) is a critical determinant of the metastatic potential of circulating tumor cells. Furthermore, thrombin appears to facilitate tumor dissemination through at least one fibrin(ogen)-independent mechanism. These findings suggest that therapeutic strategies focusing on multiple distinct hemostatic factors might be beneficial in the containment of tumor metastasis. (+info)
o-raffinose cross-linked hemoglobin improves the hemostatic defect associated with anemia and thrombocytopenia in rabbits.
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Several different preparations of cross-linked hemoglobin (CLHb) are being evaluated for their efficacy and safety as red cell substitutes in a variety of preclinical and clinical settings. Because CLHb is known to sequester nitric oxide (NO) and inhibit NO-mediated processes, we hypothesized that CLHb would have a hemostatic effect by enhancing platelet reactivity, inducing vasoconstriction, or both. Infusion of o-raffinose CLHb shortened the prolonged microvascular bleeding time and decreased blood loss from ear incisions in rabbits rendered anemic and thrombocytopenic. Moreover, this hemostatic effect persisted for at least 24 hours after infusion. Phenylephrine induced a degree of vasoconstriction similar to that induced by CLHb but did not shorten the bleeding time or decrease blood loss, suggesting that vasoconstriction alone cannot account for the hemostatic effect of CLHb. There was no evidence of CLHb-induced activation of coagulation in vivo, since infusion of CLHb did not increase circulating levels of thrombin-antithrombin complex. In vitro, CLHb abolished the inhibitory effect of the NO donor 3-morpholinosydnonimine on platelet aggregation and enhanced the aggregation of stimulated but not resting platelets. This potentiating effect was not attenuated by the addition of superoxide dismutase or catalase. To evaluate the potential arterial thrombogenicity of CLHb, a model of carotid artery thrombosis was developed in rabbits without thrombocytopenia or anemia. Compared with albumin infusion, CLHb infusion shortened the time to complete carotid occlusion. These data suggest that CLHb may shift the thromboregulatory balance toward clot formation, resulting in decreased bleeding in anemic and thrombocytopenic rabbits and possibly increasing arterial thrombogenicity in normal rabbits. (+info)
Effects of hormonal replacement therapy on lipid and haemostatic factors in post-menopausal ESRD patients.
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BACKGROUND: Hormone replacement therapy (HRT) has been known to have beneficial effects on various atherosclerotic parameters in the general population of post-menopausal women. To evaluate the effects of HRT on those factors in end-stage renal disease (ESRD) patients, we evaluated the changes of lipid profile, coagulation and fibrinolysis markers, and plasma homocysteine levels after treatment. METHODS: Sixty-five post-menopausal women on maintenance haemodialysis were randomly assigned to either an HRT group (n=33) or a control group (n=32). Median age (range) and duration of haemodialysis (range) were 57 years (40-73) and 42 months (6-150) in the HRT group and 61 years (44-78) and 54 months (8-174) in the control group respectively. Oral conjugated oestrogen (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) was given daily for 12 weeks to the HRT group. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), lipoprotein (a) (Lp(a)), fibrinogen, plasminogen activator type 1 antigen (PAI-1), tissue plasminogen antigen (t-PA), von Willebrand factor (vWF), and plasma total homocysteine (tHcy) were measured before and 12 weeks after the start of the study in both groups. RESULTS: There was no difference in baseline values between the control and HRT groups. At 12 weeks, HRT increased HDL-C by 12% (P:<0.01) and TG by 20% (P:<0. 01). HRT decreased LDL-C by 9% (P:<0.01), and Lp(a) by 36% (P:<0.01). PAI-1 and t-PA concentrations were also reduced by 21% (P:<0.01) and 9% (P:<0.05) respectively. The mean values of TC, fibrinogen, vWF, and tHcy levels did not change significantly after HRT. CONCLUSIONS: The above results suggest that HRT has favourable effects on atherosclerosis risk parameters in post-menopausal women with ESRD as in the general population of post-menopausal women. (+info)
Effects of alcohol and the evening meal on shear-induced platelet aggregation and urinary excretion of prostanoids.
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Moderate regular alcohol intake has been found to be associated with a decreased risk for coronary heart disease and stroke. We investigated the effects of acute intake of red wine (60 g ethanol) and a standard dinner under controlled conditions on haemostatic factors. Shear-induced platelet aggregation (SIPA) decreased after the intake of alcohol irrespective of whether the subjects were fasting or not, and also after the intake of food. The intake of alcohol inhibited the postprandial increase of von Willebrand factor multimers. Plasma levels of plasminogen activator inhibitor 1 activity (PAI-1) and serum triglycerides were increased by alcohol. Excretion of the platelet thromboxane A(2) metabolites 11-dehydrothromboxane B(2) and 2,3-dinorthromboxane B(2), as well as the endothelial prostacyclin metabolite 2, 3-dinor-6-ketoprostaglandin F(1)alpha, into urine was not influenced by either alcohol or food. We conclude that eating a dinner together with red wine has no untoward effect on SIPA and that the decrease of SIPA is not specific for alcohol. (+info)
Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera.
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Thrombohemorrhagic complications are a major cause of morbidity and mortality in patients with essential thrombocythemia (ET) and polycythemia vera (PV). The pathogenesis of these complications is not completely clarified. Several studies have described abnormalities of red blood cells and platelets in these patients. However, no studies are available on changes in the polymorphonuclear leukocytes (PMNs), which can play an important role in the activation of the hemostatic system. In patients with ET (n = 37) and PV (n = 34), a series of PMN activation parameters (PMN membrane CD11b and leukocyte alkaline phosphatase [LAP] antigen expression, cellular elastase content, plasma elastase, and myeloperoxidase levels) was evaluated simultaneously with the levels of plasma markers of endothelial damage (thrombomodulin and von Willebrand factor antigen) and hypercoagulation (thrombin-antithrombin complex, prothrombin fragment 1 + 2, and D-dimer). The results show the occurrence of PMN activation in both groups of patients compared with a control group of healthy subjects. An increase in CD11b and LAP expression by PMN membrane was observed, together with a significant increase in cellular elastase content, plasma elastase, and myeloperoxidase levels. In addition, patients had high plasma levels of endothelial and hypercoagulation markers compared with controls. For the first time, these data show that in ET and PV, 2 hematologic conditions that place patients at increased risk for thrombosis, an in vivo leukocyte activation occurs and is associated with laboratory signs of endothelium and coagulation system activation. (Blood. 2000;96:4261-4266) (+info)
Mechanism of action of acetaminophen: is there a cyclooxygenase 3?
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Acetaminophen, also known as paracetamol, is a nonsteroidal anti-inflammatory drug with potent antipyretic and analgesic actions but with very weak anti-inflammatory activity. When administered to humans, it reduces levels of prostaglandin metabolites in urine but does not reduce synthesis of prostaglandins by blood platelets or by the stomach mucosa. Because acetaminophen is a weak inhibitor in vitro of both cyclooxygenase (COX)-1 and COX-2, the possibility exists that it inhibits a so far unidentified form of COX, perhaps COX-3. In animal studies, COX enzymes in homogenates of different tissues vary in sensitivity to the inhibitory action of acetaminophen. This may be evidence that there are >2 isoforms of the enzyme. Recently, a variant of COX-2 induced with high concentrations of nonsteroidal anti-inflammatory drugs was shown to be highly sensitive to inhibition by acetaminophen. Therefore COX-3 may be a product of the same gene that encodes COX-2, but have different molecular characteristics. (+info)