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At least 397 records · Page 22Linked to original sources
PubMed1993

Inhibitory role of capsaicin-sensitive afferent neurons and nitric oxide in hemostasis.

Capsaicin-sensitive afferent neurons control blood flow via release of peptide transmitters and formation of nitric oxide (NO). The present study examined whether capsaicin-sensitive afferent neurons and NO interact in the control of hemostasis. Afferent nerve ablation by pretreating rats with a neurotoxic dose of capsaicin (125 mg/kg) led to a 26% reduction of the time of bleeding from punctured small mesenteric arteries in pentobarbital-anesthetized animals. Blockade of NO formation by NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg) attenuated the bleeding time in capsaicin-pretreated rats but had no effect in vehicle-pretreated rats. Platelet aggregation induced by ADP was significantly augmented by 12% in capsaicin-pretreated rats. L-NAME did not alter platelet aggregation in vehicle-pretreated rats but enhanced it in capsaicin-pretreated animals. The prothrombin and partial thromboplastin time and the plasma levels of fibrinogen and antithrombin III remained unchanged by capsaicin or L-NAME, whereas the thrombin time was reduced in capsaicin-pretreated rats. These data indicate that capsaicin-sensitive afferent neurons play an inhibitory role in platelet aggregation and hemostasis, a function in which they interact with the NO system.

Animals↗
PubMed2000

17beta-estradiol corrects hemostasis in uremic rats by limiting vascular expression of nitric oxide synthases.

Conjugated estrogens shorten the prolonged bleeding time in uremic patients and are similarly effective in a rat model of uremia. We have previously demonstrated that the shortening effect of a conjugated estrogen mixture or 17beta-estradiol on bleeding time was abolished by the nitric oxide (NO) precursor L-arginine, suggesting that the effect of these drugs on hemostasis in uremia might be mediated by changes in the NO synthetic pathway. The present study investigated the biochemical mechanism(s) by which conjugated estrogens limit the excessive formation of NO. 17beta-estradiol (0.6 mg/kg), given to rats made uremic by reduction of renal mass, significantly reduced bleeding time within 24 h and completely normalized plasma concentrations of the NO metabolites, nitrites and nitrates, and of NO synthase (NOS) catalytic activity, determined by NADPH-diaphorase staining in the thoracic aorta. Endothelial NOS (ecNOS) and inducible NOS (iNOS) immunoperoxidase staining in the endothelium of uremic aortas of untreated rats was significantly more intense than in control rats, while in uremic rats receiving 17beta-estradiol staining was comparable to controls. Thus 17beta-estradiol corrected the prolonged bleeding time of uremic rats and fully normalized the formation of NO by reducing the expression of ecNOS and iNOS in vascular endothelium. These results provide a possible biochemical explanation of the well-known effect of estrogens on primary hemostasis in uremia, in experimental animals and humans.

Animals↗
PubMed1998

Effects of Epoetin alfa on hemostasis in chronic renal failure.

Epoetin alfa is the cornerstone of anemia therapy in patients with end-stage renal disease. In addition to stimulating erythropoiesis, Epoetin alfa has been demonstrated to affect hemostasis. Such effects may be important because patients with chronic renal failure have a bleeding diathesis that is multifactorial in origin. Therefore, a computer literature search on the relationship between Epoetin alfa therapy for anemia in patients with end-stage renal disease and platelets, coagulation, coagulation inhibitors, and fibrinolysis was performed. All articles and abstracts reporting original data in the English language on Epoetin alfa and its effect on hemostasis were reviewed. The literature suggests that the effects of Epoetin alfa on the coagulation cascade are of minimal clinical importance. However, Epoetin alfa transiently increases the number of circulating platelets and improves platelet function, and these effects are associated with a return of the bleeding time towards normal.

Anemia↗
PubMedDate not supplied

Endoscopic hemostasis of bleeding peptic ulcers.

Developments in therapeutic endoscopy over the last decade have made it possible to perform endoscopic hemostasis for bleeding peptic ulcers. This review traces the developments in this field in the Department of Surgery of the National University of Singapore. A recently conducted prospective randomized controlled trial using intralesional adrenaline and heater probe demonstrated that initial hemostasis could be achieved in 100% of patients with actively bleeding ulcers or stigmata of recent hemorrhage. The rebleed rate was 6.6% compared with 20.3% in a well-matched control group. The recent advent of laparoscopic vagotomy and laparoscopic Billroth II gastrectomy offers a low-morbidity surgical option to long-term medical treatment for the follow-up management of patients with bleeding ulcers.

Duodenal Ulcer↗
PubMed1991

Effects of epsilon aminocaproic acid on primary hemostasis.

These studies examined the effect of an oral dose of epsilon-aminocaproic acid (EACA) on primary hemostasis. Bleeding time tests (with and without the use of a blood pressure cuff) were measured before and 2 h following EACA in 56 patients with mild bleeding disorders and/or thrombocytopenia. Preliminary studies evaluated the reproducibility of these tests in 13 patients who had bleeding times (cuff) ranging from 8.0 to greater than 20 min. Their replicate bleeding time values with cuff agreed within 2.5 min and those without cuff within 3 min. Therefore, the 56 study patients were considered to have had no change in their bleeding times after EACA, if their bleeding time with cuff was +/- 2.5 min and/or their nonoccluded value was +/- 3 min of their baseline values, respectively. An isolated increase in bleeding times was observed in 6 of 56 (11%) patients. All 6 had myelodysplasia associated with long bleeding times; their nonoccluded values increased by 5-14 min. Of the 56 study patients, 54% showed a decrease in their bleeding times following EACA. The changes were evident with venostasis in 18 of 30 (60%) and without venostasis in 12 (40%) patients. These studies suggest that EACA may improve primary hemostasis in some patients with prolonged bleeding times.

Administration, Oral↗
PubMed1996

Cellular interactions in hemostasis.

Coagulation reactions normally occur on cell membranes in vivo. Using a cell-based in vitro model system, we have shown that where a factor is located, not simply how much is activated, is critically important in determining its role in hemostasis. Factor Xa activated on a tissue factor (TF)-bearing cell is not equivalent to factor Xa activated on a platelet surface. Factor IX and factor VIII are required for hemostasis because they combine to generate factor Xa on the platelet surface. Factor X activation by factor VIIa/TF does not compensate for a lack of factor IX or VIII because the factor Xa activated by VIIa/TF is located on the wrong surface for efficient thrombin generation.

Blood Coagulation↗
PubMedDate not supplied

Prediction of the transfusion effect of platelet concentrates as measured by a model of primary hemostasis ex vivo.

A method to determine primary hemostasis ex vivo (Thrombostat) was modified to monitor the transfusion effect of platelet concentrates (PC) in 12 patients with thrombocytopenia following bone marrow transplantation. It was possible to measure platelet function in patients with a platelet count lower than 2 x 10(10)/l. In addition, the platelet aggregometer (Born) was adapted to determine cell function in PC anticoagulated with acid citrate dextrose of citrate phosphate dextrose. It was possible to make a prediction (r = 0.89) of the effect of a given PC on a patient's ex vivo primary hemostasis parameters. Platelet aggregation following addition of 20 muM ADP to PC, obtained from 12 single donors, resulted in an average maximal light transmission (light transmission/age of concentrate in days) of 61%/1 day and 37%/5 days, respectively. The same experiment gave only 39%/1 day and 13%/4 days for pooled platelets. To avoid possible immunization and bleeding complications, a reliable monitoring of platelet transfusion seems highly desirable.

Bone Marrow Transplantation↗
PubMed1977

The importance of continuous pump suction in TUR hydraulic hemostasis.

An intravesicoprostatic hydrostatic pressure below 10 mm Hg maintains normal anatomy and physiology of the muscular and vascular prostatic structures by continuous pump suction. An increase of the hydrostatic intravesicoprostatic pressure above 10 mm Hg produces a distortion in the musculature of the prostate, especially at the true capsule, opening the cut vessels, making possible the absorption of the irrigant free of electrolytes (TUR syndrome). A low hydrostatic intravesicoprostatic pressure permits the compression of cut vessels by the inflow hydraulic pressure of 90 cm H2O achieving hydraulic hemostasis during TURP reducing the bleeding and operative time by more than 50% and making hemostasis easier. In our last 400 TURs, blood transfusions have been unnecessary. Less electrocoagulation is required, resulting in a more rapid recovery.

Endoscopy↗
PubMed2004

Role of tissue factor in hemostasis, thrombosis, and vascular development.

Tissue factor (TF) is best known as the primary cellular initiator of blood coagulation. After vessel injury, the TF:FVIIa complex activates the coagulation protease cascade, which leads to fibrin deposition and activation of platelets. TF deficiency causes embryonic lethality in the mouse and there have been no reports of TF deficiency in humans. These results indicate that TF is essential for life, most likely because of its central role in hemostasis. In addition, aberrant TF expression within the vasculature initiates life-threatening thrombosis in various diseases, such as sepsis, atherosclerosis, and cancer. Finally, recent studies have revealed a nonhemostatic role of TF in the generation of coagulation proteases and subsequent activation of protease activated receptors (PARs) on vascular cells. This TF-dependent signaling contributes to a variety of biological processes, including inflammation, angiogenesis, metastasis, and cell migration. This review focuses on the roles of TF in hemostasis, thrombosis, and vascular development.

Animals↗
PubMed2005

Tissue-specific hemostasis in mice.

Blood coagulation is essential to maintain hemostasis in organisms with a vascular network. Formation of a fibrin-rich clot at a site of vessel injury is a highly complex process that is orchestrated by the coagulation protease cascade. This cascade is regulated by 3 major anticoagulant pathways. Removal of a clot is mediated by the fibrinolytic system. Defects in the regulation of clot formation lead to either hemorrhage or thrombosis. Tissue factor, the primary cellular initiator of blood coagulation, is a transmembrane receptor that is expressed in a tissue-specific manner. The 3 major anticoagulants are tissue factor pathway inhibitor, antithrombin, and protein C, the latter requiring a transmembrane receptor called thrombomodulin for its activation. Tissue factor pathway inhibitor and thrombomodulin are expressed by endothelial cells in a tissue-specific manner, whereas antithrombin and protein C circulate in the plasma. Fibrinolysis requires the activation of plasminogen to plasmin, which is mediated by tissue-type plasminogen activator and urokinase-type plasminogen activator. Interestingly, tissue-type plasminogen activator is expressed by a subset of endothelial cells of discrete size and location. These observations, together with the phenotypes of mice that have defects in the procoagulant, anticoagulant, and fibrinolytic pathways, indicate that hemostasis is regulated in a tissue-specific manner.

Animals↗
PubMed2002

Prourokinase mutant that induces highly effective clot lysis without interfering with hemostasis.

Prourokinase (proUK) is a zymogenic plasminogen activator that at pharmacological doses is prone to nonspecific activation to urokinase. This has handicapped therapeutic exploitation of its fibrin-specific physiological properties. To attenuate this susceptibility without compromising specific activation of proUK on a fibrin clot, a Lys300-->His mutation (M5) was developed. M5 had a lower intrinsic activity and, therefore, remained stable in plasma at a 4-fold higher concentration than did proUK. M5 had a higher 2-chain activity and induced more rapid plasminogen activation and fibrin-specific clot lysis in vitro. Sixteen dogs embolized with radiolabeled clots were infused with saline, proUK, tissue plasminogen activator, or M5. The lower intrinsic activity allowed a higher infusion rate with M5, which induced the most rapid and efficient clot lysis (50% clot lysis by approximately 600 microg/kg M5 versus approximately 1200 microg/kg proUK). In association with this, M5 caused neither a significant increase in the primary bleeding time nor secondary bleeding (total blood loss). By contrast, these measurements increased 4-fold and 5-fold, respectively, with proUK and >5-fold and 8-fold, respectively, with tissue plasminogen activator. Clot lysis by M5 and hemostasis were further evaluated in 6 rhesus monkeys. M5 again induced rapid clot lysis without a significant increase in the primary bleeding time, and secondary bleeding did not occur. In conclusion, a site-directed mutation designed to improve the stability of proUK in blood at therapeutic concentrations induced superior clot lysis in vitro and in vivo without causing significant interference with hemostasis.

Amino Acid Substitution↗
PubMed1987

Role of proaggregatory and antiaggregatory prostaglandins in hemostasis. Studies with combined thromboxane synthase inhibition and thromboxane receptor antagonism.

Thromboxane synthase inhibition can lead to two opposing effects: accumulation of proaggregatory cyclic endoperoxides and increased formation of antiaggregatory PGI2 and PGD2. The elimination of the effects of the cyclic endoperoxides by an endoperoxide-thromboxane A2 receptor antagonist should enhance the inhibition of hemostasis by thromboxane synthase blockers. We have carried out a series of double-blind, placebo-controlled, crossover studies in healthy volunteers to check if this hypothesis may be operative in vivo in man. In a first study, in 10 healthy male volunteers, the combined administration of the thromboxane receptor antagonist BM 13.177 and the thromboxane synthase inhibitor dazoxiben gave stronger inhibition of platelet aggregation and prolonged the bleeding time more than either drug alone. In a second study, in 10 different healthy male volunteers, complete inhibition of cyclooxygenase with indomethacin reduced the prolongation of the bleeding time by the combination BM 13.177 plus dazoxiben. In a third study, in five volunteers, selective cumulative inhibition of platelet TXA2 synthesis by low-dose aspirin inhibited platelet aggregation and prolonged the bleeding time less than the combination BM 13.177 plus dazoxiben. In vitro, in human platelet-rich plasma stimulated with arachidonic acid, the combination of BM 13.177 and dazoxiben increased intraplatelet cAMP while the single drugs did not affect it. Our results indicate that prostaglandin endoperoxides can partly substitute for the activity of TXA2 in vivo in man and that an increased formation of endogenous antiaggregatory and vasodilatory prostaglandins, as obtained with selective thromboxane synthase inhibitors, may contribute to the impairment of hemostasis.

Adult↗
PubMed1993

Astrocytes are the primary source of tissue factor in the murine central nervous system. A role for astrocytes in cerebral hemostasis.

Hemostasis in the brain is of paramount importance because bleeding into the neural parenchyma can result in paralysis, coma, and death. Consistent with this sensitivity to hemorrhage, the brain contains large amounts of tissue factor (TF), the major cellular initiator of the coagulation protease cascades. However, to date, the cellular source for TF in the central nervous system has not been identified. In this study, analysis of murine brain sections by in situ hybridization demonstrated high levels of TF mRNA in cells that expressed glial fibrillary acidic protein, a specific marker for astrocytes. Furthermore, primary mouse astrocyte cultures and astrocyte cell lines from mouse, rat, and human constitutively expressed TF mRNA and functional protein. These data indicated that astrocytes are the primary source of TF in the central nervous system. We propose that astrocytes forming the glia limitans around the neural vasculature and deep to the meninges are intimately involved in controlling hemorrhage in the brain. Finally, we observed an increase in TF mRNA expression in the brains of scrapie-infected mice. This modulation of TF expression in the absence of hemorrhage suggested that TF may function in processes other than hemostasis by altering protease generation in normal and diseased brain.

Animals↗
PubMed1993

Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis.

The effects of plasminogen activator inhibitor-1 (PAI-1) gene inactivation on hemostasis, thrombosis and thrombolysis were studied in homozygous PAI-1-deficient (PAI-1-/-) mice, generated by homologous recombination in D3 embryonic stem cells. Diluted (10-fold) whole blood clots from PAI-1-/- and from PAI-1 wild type (PAI-1+/+) mice underwent limited but significantly different (P < 0.001) spontaneous lysis within 3 h (6 +/- 1 vs 3 +/- 1%, respectively). A 25-microliters 125I-fibrin-labeled normal murine plasma clot, injected into a jugular vein, was lysed for 47 +/- 5, 66 +/- 3, and 87 +/- 7% within 8 h in PAI-1+/+, heterozygous PAI-1-deficient (PAI-1+/-), and PAI-1-/- mice, respectively (P = 0.002 for PAI-1+/+ vs PAI-1-/- mice). Corresponding values after pretreatment with 0.5 mg/kg endotoxin in PAI-1+/+ and PAI-1-/- mice, were 35 +/- 5 and 91 +/- 3% within 4 h, respectively (P < 0.001). 11 out of 26 PAI-1+/+ but only 1 out of 25 PAI-1-/- mice developed venous thrombosis (P = 0.004) within 6 d after injection of 10 or 50 micrograms endotoxin in the footpad. Spontaneous bleeding or delayed rebleeding could not be documented in PAI-1-/- mice after partial amputation of the tail or of the caecum. Thus, disruption of the PAI-1 gene in mice appears to induce a mild hyperfibrinolytic state and a greater resistance to venous thrombosis but not to impair hemostasis.

Analysis of Variance↗
PubMed2004

A balance between tissue factor and tissue factor pathway inhibitor is required for embryonic development and hemostasis in adult mice.

Inactivation of the murine tissue factor (TF) gene or tissue factor pathway inhibitor 1 (TFPI) gene results in embryonic lethality, indicating that both are required for embryonic development. We have shown that expression of low levels of TF from a transgene (hTF) rescues TF-null embryos. However, low-TF mice (mTF(-/-)/hTF+) have hemostatic defects in the uterus, placenta, heart, and lung. In this study, we hypothesized that the death of TFPI-/- embryos was due to unregulated TF/FVIIa activity and that the hemostatic defects in low-TF mice were due to insufficient TF expression. Therefore, we attempted to rescue TFPI-/- embryos by reducing TF expression, and to restore hemostasis in low-TF mice by abolishing TFPI expression. Intercrossing TFPI(+/-)/mTF(+/-)/hTF+/- mice generated close to the expected number of TFPI(-/-)/low-TF mice at weaning age from 128 offspring, indicating rescue of TFPI-/- embryos from embryonic lethality. Conversely, a decrease in TFPI levels dose-dependently prolonged the survival of low-TF mice and rescued the hemorrhagic defects in the lung and placenta but not in the heart or uterus. These results indicate that the correct balance between TF and TFPI in different organs is required to maintain hemostasis during embryonic development and in adult mice.

Age Factors↗
PubMed2002

Platelet function test HemoSTATUS 2: tool or toy for an optimized management of hemostasis?

BACKGROUND: Bleeding after open heart surgery is a common but unintended problem, which is unequivocally related to platelet function. The target of our study was to correlate platelet activation levels and postoperative blood loss as well as the predictive power of measurements focusing on postoperative hemostasis. MATERIALS AND METHODS: The prospective trial comprised 100 patients (mean age: 64.3 years, 68% male) undergoing cardiac surgery. Platelet activation was measured by the new and modified HemoSTATUS test. Blood samples were drawn pre-, intra- and postoperatively. Standard hemostasis tests, including activated clotting time (ACT), partial thromboplastin time (PTT), hemoglobin, platelet count, antithrombin III (AT III) and fibrinogen, were measured according to the clinical routine. Blood loss and consumed blood products were documented up to the 24th hour after the operation. RESULTS: Platelet activation showed a typical change, with lowest levels after the end of extracorporeal circulation and a restitution to preoperative levels after 24 h. Mean blood loss was 461 ml. Statistical analysis showed neither a correlation to the platelet activation measurements nor to low pre-, intra- or postoperative levels. CONCLUSION: The HemoSTATUS platelet function test is not suitable for a reliable monitoring of platelet pathophysiology and patient outcome after extracorporeal circulation. Furthermore, no correlation of preoperative platelet activation and blood loss could be shown.

Aged↗
PubMed2006

Gelatin and hydroxyethyl starch, but not albumin, impair hemostasis after cardiac surgery.

We investigated the effect of postoperative administration of colloids on hemostasis in 45 patients after cardiac surgery. Patients were randomized to receive 15 mL kg(-1) of either 4% albumin, 4% succinylated gelatin, or 6% hydroxyethyl starch (molecular weight of 200 kDa/degree of substitution 0.5) as a short-term infusion. There was a comparable decrease in maximum clot firmness of thromboelastometry tracings in gelatin and hydroxyethyl starch groups immediately after completion of the infusion, whereas these values remained unchanged in the albumin group. The impairment in clot strength persisted up to 2 h, although the values partly recovered. Postoperative bleeding correlated inversely with the clot strength in pooled data of the artificial colloids. Fibrin formation (clot formation time, alpha-angle) and fibrinogen-dependent clot strength (maximum clot firmness and shear elastic modulus) were more disturbed in the hydroxyethyl starch group than in the gelatin group. We conclude that after cardiopulmonary bypass surgery, both gelatin and hydroxyethyl starch impair clot strength and fibrin buildup, which may predispose patients to increased blood loss. The greatest impairment in hemostasis was seen after hydroxyethyl starch administration, whereas albumin appeared to have the least effect on hemostatic variables.

Adult↗
PubMed1994

Serial changes in hemostasis after intracranial surgery.

We performed hemostatic studies on eight patients undergoing clipping of unruptured cerebral aneurysms to assess the influence of intracranial surgery itself on hemostasis. Blood samples were collected from each patient 10 times: before and after the induction of anesthesia and 6, 12, and 24 hours and 2, 3, 5, and 7 days immediately after surgery. The changes and our interpretation of them include the following: 1) the elevation of thrombin antithrombin III complex levels (activation of blood coagulation) was transient and monophasic; 2) the elevation of plasmin alpha 2-antiplasmin complex and D-dimer levels (activation of fibrinolysis) was biphasic, despite the monophasic elevation of tissue plasminogen activator or plasminogen activator inhibitor-1 levels; 3) the elevation of beta-thromboglobulin and platelet-factor-4 levels (activation of platelet) was also biphasic; 4) fibrinogen level and alpha 2-antiplasmin activity increased in the acute phase of the postoperative course (acute phase reaction); 5) the changes in hematocrit appeared to parallel those in various other parameters, especially platelet count, antithrombin III, and plasminogen levels for 1 or 2 days after surgery; 6) fibronectin appeared to be consumed in the acute phase of postoperative course; and 7) general anesthesia did not significantly affect hemostasis. These serial changes seem to be related to the activation of hemostatic systems after intracranial surgery and the subsequent acute phase reaction.

Acute-Phase Reaction↗