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Fish oil diet rich in eicosapentaenoic acid increases bleeding time in the rat by interaction with sympathetic transmitters.

The influence of a diet supplemented with MaxEPA (a fish oil concentrate, rich in eicosapentaenoic acid = EPA) on bleeding time in small mesenteric arteries of the rat and on formation of thromboxane B2 (TXB2) by ADP-stimulated platelets was investigated. Since EPA has been found to antagonize noradrenaline (NA) - induced vasoconstriction, the influences on bleeding time of the alpha-receptor antagonist phentolamine and of the adrenergic neuron blocking agent guanethidine alone as well as during dietary supplementation with MaxEPA were studied. Bleeding time slowly increased during the MaxEPA diet over a period of 12 weeks resulting in a final prolongation of about 75%. Indomethacin which dose-dependently increased bleeding time in control rats, further increased the already prolonged bleeding time in rats on the MaxEPA diet. Guanethidine prolonged bleeding time strongly in control animals but caused no further increase in those on the MaxEPA diet. Indomethacin also further increased the bleeding time prolonged by guanethidine, just as it did in animals on MaxEPA diet. In contrast to guanethidine, phentolamine prolonged bleeding time only slightly. The ability of platelets from rats on the diet to generate TXB2 was reduced to 59.5% but was more drastically reduced (to 26.7%) from rats pretreated with indomethacin. The results indicate that MaxEPA feeding prolongs bleeding time by a mechanism other than that of indomethacin. We speculate that EPA prolongs bleeding time rather by antagonizing the vasoconstrictor effect of sympathetic transmitters at the site of the injured vessel than by a reduced formation of TXA2.

Animals↗

Bleeding time, blood groups and von Willebrand factor.

The bleeding time in healthy volunteers was determined according to both the Ivy and the Simplate II techniques. A significantly longer bleeding time in people with blood group O than in people with non-O blood groups was demonstrated with both techniques. This difference could not be attributed to a difference in sex ratio, platelet count or haematocrit. The mean level of von Willebrand factor in blood group O is lower than in non-O blood groups, but we found no association between the level of von Willebrand factor and the bleeding time, despite the very broad range of von Willebrand factor levels in the subjects examined.

ABO Blood-Group System↗

A randomized and blinded comparison of the sensitivity and the reproducibility of the Ivy and Simplate II bleeding time techniques.

The authors compared the sensitivity and the reproducibility of the bleeding time techniques according to Ivy and Simplate II. The sensitivity was studied in two groups: one group of 64 healthy volunteers and another group of 40 patients with various disorders of hemostasis, including 28 patients with Von Willebrand's disease. Ivy and Simplate II bleeding times were performed on each subject. The reproducibility was studied in 48 patients with mildly or moderately prolonged bleeding times that resulted from various disorders who had a duplicate Ivy or a duplicate Simplate II bleeding time. All subjects were randomized over the technologists and they were blinded for each other's results. By a receiver operating characteristic analysis, the Ivy method appeared to offer greater overall detection efficacy than the Simplate II method. For the Ivy method, the standard deviation of the ratios of the duplicate bleeding times was 0.37 and for the Simplate II method it was 0.33. The authors conclude that the Simplate II method is not superior in sensitivity or reproducibility to the Ivy method, which is cheaper, takes less time, and does not leave scars.

Adult↗

Subcutaneous desmopressin (DDAVP) shortens the prolonged bleeding time in patients with liver cirrhosis.

The intravenous infusion of 1-deamino-8-D-arginine vasopressin (DDAVP) shortens the prolonged bleeding time in patients with congenital or acquired bleeding disorders, including patients with uremia or liver cirrhosis. We carried out a double-blind, placebo-controlled crossover study in ten patients with liver cirrhosis to evaluate whether or not their prolonged bleeding times could be shortened by subcutaneous injections of DDAVP (0.3 microgram/kg), a more practical route of administration than intravenous infusions. One hour after DDAVP injection the bleeding time was significantly shortened (p less than 0.05). After 4 h, however, the bleeding time shortening was no longer statistically significant. There was no bleeding time change after placebo. Plasma levels of von Willebrand factor antigen (vWF:Ag) did not significantly increase after DDAVP or placebo. The study shows that subcutaneous DDAVP is an alternative method for short-term shortening of the bleeding time in liver cirrhosis.

Adolescent↗

L-arginine, the precursor of nitric oxide, abolishes the effect of estrogens on bleeding time in experimental uremia.

We have reported previously that conjugated estrogens that are effective in shortening the prolonged bleeding time in uremic patients are also effective on bleeding time in a rat model of uremia. Using such a rat model we have recently demonstrated that nitric oxide (NO), an endothelium-derived vasodilator, is involved in mediating the bleeding tendency of uremia. With the present study we wanted to investigate whether conjugated estrogen mixture or its active component, 17 beta-estradiol, reduce uremic bleeding by interfering with the NO pathway. Our results showed that the shortening effect of conjugated estrogen and 17 beta-estradiol on bleeding time of uremic rats was completely reversed by giving the animals the NO precursor L-arginine, but not D-arginine, which is not a precursor of NO. Dexamethasone which at variance to progesterone inhibits the process of induction of NO-forming enzyme, shortened the prolonged bleeding time of uremic rats within 4 hours from injection. This effect was eliminated by L-arginine but not D-arginine administration. The glucocorticoid receptor antagonist cortexolone prevented the shortening of bleeding time induced by dexamethasone, suggesting that a receptor-mediated mechanism is involved in the hemostatic effect of dexamethasone as previously reported for estrogens. Unlike conjugated estrogens and dexamethasone, progesterone had no effect on bleeding time. All these findings would indicate that the effect of estrogens and dexamethasone on primary hemostasis in uremia might be mediated by changes in NO synthetic pathway.

Animals↗

The effect of smoking on the stressed template bleeding time.

Tobacco cigarette smoking is known to affect platelet function. The purpose of this study was to determine whether cigarette smoking acutely shortens the bleeding time of healthy men. The mean initial stressed template bleeding time of 12 nonsmokers (9.0 minutes) was not significantly different from that of nine habitual smokers (9.2 minutes) who were asked to abstain from smoking for 12 hours before determination of the bleeding time. The mean bleeding time was the same immediately before and after the 21 men smoked two filtered tobacco cigarettes in 20 minutes. Separate analyses showed that the mean bleeding time of neither the nonsmokers nor the habitual smokers changed significantly after experimental smoking. We conclude that smoking two cigarettes has no effect on the stressed template bleeding time of healthy men.

Adult↗

Bleeding times and the antithrombotic effects of high-dose aspirin, hirudin and heparins in the rat.

Bleeding can occur unexpectedly during antithrombotic therapy. Impaired haemostasis is commonly measured by the bleeding time. We measured it by 3 methods in controls and in anticoagulated animals and related it to their antithrombotic status. In 42 control rats template, tail-tip transection and needle occlusion bleeding times correlated poorly (r = 0.05-0.34). The template method had the best range (mean 126.97 +/- SEM secs) and consistency. In 10 control animals it correlated mildly (r = 0.55) with venous thrombus in the same animal. Thrombus was measured by its weight deposited on platinum wires (2 cm long, 0.4 mm diameter) set in vein and in artery for 1 h. In respective groups of 10 rats, a decrease of mean thrombogenesis was obtained using aspirin, heparin and low molecular weight heparin in 2 dosages and hirudin in 1 dosage. The drugs reduced mean venous thrombus by 13-86 per cent of the mean control thrombus, and prolonged the mean template bleeding time by 29-199 per cent. The ranking of the drugs according to their increase of template bleeding time was virtually the same as the ranking given by their reduction of thrombus weight (Spearman rank coefficient 0.81, sig 0.007). The transection test produced a similar ranking and similar correlation with thrombus (0.71, sig 0.049). Low molecular weight heparin induced the greatest thrombus reduction (39 per cent) for least prolongation of bleeding time (24 per cent). Arterial thrombus was more variable. The bleeding times and thrombus weight were measured in each animal of 2 groups given aspirin, the template method correlating mildly with venous thrombus reduction (r = 0.23, 0.58 respectively), the transection method with arterial (0.74, 0.45) and the occlusion test poorly with either (0.13, 0.22). Bleeding time lengthens with increasing antithrombotic effect of drugs, but not in direct proportion, nor similarly with each drug.

Animals↗

Micromethod for bleeding time in the newborn.

A new method of measuring bleeding time using an Autolet device is described. Normal ranges of bleeding time and volume of blood used in the test have been defined in a population including preterm babies. Abnormal values have been shown in newborns with a variety of problems, and an abnormality of bleeding time has been found to precede intraventricular haemorrhage.

Bleeding Time↗

Oral zeranol shortens the prolonged bleeding time of uremic rats.

Intravenous conjugated estrogens reduce the prolonged bleeding time in uremic patients and in a rat model of uremia. However, estrogens have major side effects related to their hormonal activity. We investigated whether a beta-resorcylic acid lactone, zeranol (a compound with close spatial similarity to estrogens but with a weak estrogenic activity), improves primary hemostasis in uremic rats and whether the effect is mediated by estrogen receptors. The results showed that single oral administration of zeranol significantly (P less than 0.01) shortened the bleeding time of uremic rats, 20 mg/kg being the minimum effective dose. This effect was long-lasting (72 hours). The dose of 30 mg/kg zeranol reproduced the pattern observed after 20 mg/kg but bleeding time values were still significantly (P less than 0.01) shortened 96 hours after the administration. No changes in hematocrit, platelet and leukocyte count, and serum creatinine were detected after zeranol administration. When uremic rats were pre-treated orally with two estrogen receptor antagonists, tamoxifen and clomiphene (3 mg/kg), zeranol did not shorten the bleeding time, thus suggesting that the hemostatic effect of zeranol was due to an estrogen receptor-mediated mechanisms. These results might have important future implications for the management of uremic bleeding in humans.

Administration, Oral↗

Hematologic changes during and after cardiopulmonary bypass and their relationship to the bleeding time and nonsurgical blood loss.

The hemostatic dysfunction induced by cardiopulmonary bypass is due, in part, to a platelet dysfunction evidenced by a postoperative extension of the bleeding time; it leads to increased postoperative blood loss and morbidity. This study, which was conducted in 85 patients undergoing cardiopulmonary bypass, was designed to characterize the hematologic changes during and after cardiopulmonary bypass and to elucidate the relationships between these changes, the extension of the bleeding time, and the magnitude of the postoperative nonsurgical blood loss. Variables were measured before, during, and 2, 24, 48, and 72 hours after cardiopulmonary bypass. Univariate and multivariate analyses were performed with either the 2-hour postbypass bleeding time or the 4-hour postbypass blood loss as the dependent variables. The reversal of the extension of the bleeding time in the postoperative period was accompanied by a significant increase in the mean platelet volume and by a significant increase in the level of thromboxane B2 measured in the blood shed from the site of the bleeding time determination. The postoperative bleeding time correlated with the postoperative blood loss, and both parameters were dependent on the duration of cardiopulmonary bypass. In addition, the postoperative bleeding time correlated with the skin temperature and the plasma level of D-dimer, while the postoperative blood loss also correlated with temperature and the plasma levels of C3. These data establish a direct relationship between the postoperative bleeding time, the postoperative blood loss, and temperature. They indicate that the reversal of the postoperative extension of the bleeding time is due in part to rewarming and to the release of larger platelets into the circulation, and they suggest that hyperfibrinolysis and complement activation may play an important role in the cardiopulmonary bypass-induced platelet dysfunction.

Bleeding Time↗

Shortening of the bleeding time in thrombocytopenic rabbits after exposure of jugular vein to high aspirin concentration.

Aspirin, in doses which inhibit platelet thromboxane A2 production, prolongs the bleeding time but this effect on the bleeding time is lost when doses of aspirin which also inhibit vessel wall prostaglandin I2 (PGI2) production are used. PGI2 is both a potent inhibitor of platelet aggregation and a powerful vasodilator. We have investigated the contribution of the vascular effect of PGI2 on hemostasis by studying the effect of high concentrations of aspirin on the jugular vein bleeding time in severely thrombocytopenic rabbits and on the loss of non-platelet-containing fluid from standard puncture wounds in aspirin-treated veins perfused under constant pressure. After aspirin treatment, the bleeding time was significantly shortened in both normal and thrombocytopenic rabbits. This effect was associated with a decreased production of PGI2-like material by the vessel wall and a reduction in the volume of fluid lost from the standard puncture wound in the jugular vein. The effect of aspirin on the bleeding time and on PGI2 production was relatively short-lived and the bleeding time returned to normal within 2-3 hours. These observations indicate that PGI2 can influence hemostasis by mechanisms independent of platelet aggregation.

Animals↗

The impact of bleeding times on major complication rates after percutaneous real-time ultrasound-guided renal biopsies.

BACKGROUND: Previous studies have shown that bleeding times have positive predictive values of only 5% for perioperative bleeding in unselected populations. Nevertheless, performing bleeding times prior to all renal biopsies is common in nephrology practice. METHODS: We report complications of 112 renal biopsies done at Walter Reed Army Medical Center (WRAMC) from 1996-99 performed without preceding bleeding times. Renal biopsies were done only on normotensive (<140/90) patients who had not recently been taking aspirin or non-steroidal anti-inflammatory agents, under real-time ultrasound guidance with automated 16 g (WRAMC) spring-loaded guns. High-risk patients (with serum creatinine > or = 3 mg/dl or creatinine clearance < or =30 cc/min by Cockroft-Gault formula, N=18, 16%) at WRAMC were treated with pre-renal biopsy estrogens or DDAVP. Factors were tested for their association with complications after renal biopsy using Chi Square testing for categorical variables and student's t-test for continuous variables. A stepwise logistic regression model was used to test for independent significance of factors. RESULTS: There were two cases each of gross hematuria and inadequate tissue (1.8% each). There were no transfusions or deaths. In univariate analysis, male gender and lower serum creatinine level at time of biopsy were significantly associated with increased risk of complications after biopsy. However, these factors were not significant in logistic regression analysis. CONCLUSION: This study suggests that the use of bleeding times does not significantly alter the major complication rates associated with percutaneous real-time ultrasound guided renal biopsy.

Adolescent↗

Prolonged bleeding time in preterm infants receiving indomethacin for patent ductus arteriosus.

Sequential bleeding times were performed on 25 preterm infants receiving intravenous indomethacin for closure of the patent ductus arteriosus. Prolongation of bleeding time was observed after the initial dose of indomethacin, with an increase from a pretreatment mean of 3.6 minutes to 8.7 minutes. The bleeding time was not further prolonged at the end of the three-dose course of indomethacin, but was still elevated 48 hours after the completion of therapy. Clinical bleeding developed in six of the patients, but was generally limited to occult hematuria. Serial echoencephalography during indomethacin therapy showed progression from mild periventricular-intraventricular hemorrhage to moderate or severe grades in five of 21 infants at risk for this complication. However, no clear temporal relationship between indomethacin administration and intraventricular hemorrhage extension was observed, and no difference in the degree of bleeding time prolongation was noted between infants with and without hemorrhage extension. Other factors, including surfactant deficiency, amount of volume expansion used, and lowest PO2 in the first day of life, did distinguish those with hemorrhage extension. The results suggest that indomethacin-induced platelet dysfunction is not associated with major hemorrhagic complications in the majority of preterm infants with patent ductus arteriosus.

Bleeding Time↗

Bleeding time prolongation with streptokinase and its reduction with 1-desamino-8-D-arginine vasopressin.

The mechanism by which treatment with thrombolytic agents causes bleeding is not known. Recently, frequency of bleeding events has been shown to correlate with bleeding time, particularly in individuals treated with aspirin. We examined the effects of streptokinase (20,000-60,000 IU/kg) on bleeding time in 40 rabbits pretreated with aspirin, a model for fibrinolytic therapy. We then tested the effects of 1-desamino-8-D-arginine vasopressin (DDAVP) (0.3 microgram/kg), an agent known to reduce bleeding time in a variety of bleeding disorders, in 20 rabbits and compared the results with those of a control group of rabbits receiving normal saline placebo. Aspirin increased the bleeding time from a baseline mean +/- SEM value of 119 +/- 15 to 191 +/- 34 seconds in the control group and from 114 +/- 6 to 188 +/- 18 seconds in the experimental group. The addition of streptokinase increased the bleeding time to 592 +/- 119 seconds in the control group and 810 +/- 114 seconds in the experimental group (p = NS). Subsequent infusion of DDAVP decreased the bleeding time in the experimental group to 302 +/- 29 seconds (p less than 0.01 versus streptokinase) compared with 572 +/- 79 seconds (p = NS versus streptokinase) in the control animals given saline placebo. In a subset of rabbits receiving aspirin and streptokinase (40,000-60,000 IU/kg), samples were obtained for platelet aggregation (n = 16), von Willebrand factor antigen concentration (n = 17), and von Willebrand factor multimer distribution (n = 14). Maximal rates of ADP-induced platelet aggregation were not affected by DDAVP infusion, nor was the plasma concentration of von Willebrand factor antigen, quantified by an immunoradiometric assay, significantly affected by DDAVP infusion. Furthermore, the von Willebrand factor multimer ratio decreased with DDAVP administration. These findings indicate that aspirin and streptokinase combined result in a marked increase in bleeding time that can be reduced by DDAVP. This effect of DDAVP is not accompanied by an increase in platelet aggregation response, plasma von Willebrand factor antigen concentration, or von Willebrand factor multimer ratio.

Animals↗

Bleeding time and platelet volume in acute myocardial infarction--a 2 year follow-up study.

The bleeding time is shortened and the mean platelet volume is increased in the acute phase of myocardial infarction. In this follow-up study we repeated the measurement of the bleeding time, the platelet count and the platelet volume distribution in 18 patients who had suffered from a definite acute myocardial infarction two years before and in 16 control patients who had been admitted with chest pain but no definite myocardial infarction at that time. At the time of follow-up the bleeding time was significantly lengthened in the myocardial infarction group (median values = 169 s and 209 s respectively), whereas it had shortened in the control group (median values = 258 s and 228 s respectively). Comparison of the platelet volume distribution curves of the myocardial infarction patients at time of infarction and 2 years later revealed a significantly higher percentage of small platelets and significantly lower percentages of both medium-sized and large platelets at the time of infarction. These changes in the platelet volume distribution could indicate consumption of medium-sized and large platelets at the time of myocardial infarction. None of the measured variables predicted which of the patients with acute myocardial infarction would subsequently re-infarct or die. In the patients studied with definite ischaemic heart disease (n = 26) a significant negative correlation between bleeding time and mean platelet volume was found. The shortened bleeding time in myocardial infarction is related to the acute event itself or proceeds it, but is reversed two years later.

Bleeding Time↗

Quantification of blood from skin bleeding time determinations: effects of fish diet or acetylsalicylic acid.

The Simplate II technique for measuring bleeding time was adapted to quantify the volume of blood as a function of time and for determining how this parameter was affected by either acetylsalicylic acid (ASA) or a dietary supplement of fish. Both increased the bleeding time significantly. Irrespective of the final bleeding time, the rate of blood loss increased for about the first 2 min and then decreased almost linearly until bleeding stopped. This time course was not affected by either ASA or the fish diet. The lack of effect by ASA suggests that the initial increase in bleeding time, presumably due to reversal of vasoconstriction, does not involve prostaglandin derivatives. After ASA the rate of blood loss was significantly greater throughout, probably caused by deceleration of platelet aggregation. During the fish diet, when bleeding time was increased, there was no change in the rate of blood loss until the last 2-3 min during which bleeding continued at a very low rate. The results support the conclusion that the delay in primary haemostasis produced by a fish diet is due to a different mechanism than that produced by ASA.

Adult↗

Bleeding time. A guide to its diagnostic and clinical utility.

Although the bleeding time is the most widely used clinical test employed to assess platelet function, its indications are poorly defined. The test is commonly used as a preoperative screen to predict hemorrhage, but the data supporting this indication are contradictory at best. In this review we highlight the physiologic basis for the bleeding time and survey the literature for data supporting the valid indications for its use. The bleeding time is a useful test for assessing platelet function in patients with hemorrhagic disorders. Its utility in providing helpful clinical information in patients who do not have a known bleeding diathesis by history is minimal. Specific recommendations regarding the rational use of the bleeding time for the preoperative evaluation of patients are presented.

Bleeding Time↗