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A reassessment of the bleeding time: association of age, hematocrit, platelet function, von Willebrand factor, and bleeding time thromboxane B2 with the length of the bleeding time.

In order to provide an overview of the relative contribution of platelet, von Willebrand factor, and other abnormalities to patients with clinical bleeding difficulties, we performed a retrospective survey of coagulation studies on 569 individuals referred to the University of Manitoba coagulation laboratory because they, or a closely related family member, showed clinical evidence of a bleeding disorder. There was a highly significant (p less than 0.001) negative correlation between the bleeding time and each of the following parameters: the platelet count; the hematocrit; the percent aggregation to collagen, epinephrine, ADP, and arachidonic acid; and the logarithm of von Willebrand factor antigen and a measure of its activity (ristocetin cofactor). A significant and independent inverse relationship between the length of the bleeding time and the extent of platelet adhesion to glass beads, patient age, and prothrombin consumption were also observed. Multivariate analysis of the ability of all parameters to predict the bleeding time showed an r2 of only 0.33. Bleeding time thromboxane B2, in a second smaller study of 70 patients, showed a negative correlation with the length of the bleeding time (p = 0.0001), and, when used together with the above parameters, significantly enhanced the ability to predict the length of the bleeding time (r2 = 0.55). Defects in platelet function, as measured in vitro, and significant enough to have an effect on the bleeding time, occurred with greater frequency than defects in von Willebrand factor in the Manitoba patients evaluated.

Adolescent

A bleeding risk index for estimating the probability of major bleeding in hospitalized patients starting anticoagulant therapy.

PURPOSE: To construct and test prospectively a bleeding risk index for estimating the probability of major bleeding in hospitalized patients starting long-term anticoagulant therapy. PATIENTS AND METHODS: In an inception cohort of 617 patients starting long-term anticoagulant therapy in one hospital, data were gathered retrospectively and bleeding was classified using reliable explicit criteria. We constructed a bleeding risk index by identifying and weighting independent predictors of major bleeding using a multivariate proportional-hazards model. The bleeding risk index was tested in 394 other patients prospectively identified in a second hospital. The index was compared to physicians' predictions. RESULTS: Major bleeding developed before discharge in 61 of all 1,011 patients (6%). The bleeding risk index included four independent risk factors for major in-hospital bleeding: the number of specific comorbid conditions; heparin use in patients aged 60 years or older; maximal prothrombin or partial thromboplastin time 2.0 or more times control; liver dysfunction worsening during therapy. In the testing group, the index predicted major bleeding, which occurred in 3% of 235 low-risk patients, 16% of 96 middle-risk patients, and 19% of 63 high-risk patients (p less than 0.001). The bleeding risk index performed as well as physicians' predictions, and integration of the bleeding risk index with physicians' predictions led to a classification system that was more sensitive (p = 0.03) than physicians' predictions alone. In 86% of patients with a high risk of major bleeding, we identified specific ways of improving therapy, e.g., avoiding overanticoagulation and nonsteroidal anti-inflammatory agents. CONCLUSION: The bleeding risk index provides valid estimates of the probability of major bleeding in hospitalized patients starting long-term anticoagulant therapy and complements physicians' predictions. The possibility that bleeding can be prevented in high-risk patients warrants prospective evaluation.

Aged

Bleeding time prolongation and bleeding during infusion of recombinant tissue-type plasminogen activator in dogs: potentiation by aspirin and reversal with aprotinin.

Thrombolytic therapy is associated with a bleeding tendency that may be exacerbated by adjunctive antiplatelet agents. The effect of recombinant tissue-type plasminogen activator (rt-PA) alone or in combination with aspirin on serial measurements of template bleeding time, ex vivo platelet aggregation and coagulation factors and the frequency of bleeding was studied in dogs. During infusion of rt-PA (15, 30 or 60 micrograms/kg per min for 90 min), a dose-related increase in bleeding time was observed. In a randomized blinded study of 25 dogs, the baseline bleeding time (mean +/- SD) was 3.5 +/- 1 min in control animals and 4 +/- 2 min after oral aspirin (15 mg/kg body weight). Infusion of rt-PA (15 micrograms/kg per min for 90 min) prolonged the bleeding time to a maximum of 15 +/- 12 min. In contrast, combined aspirin and rt-PA therapy produced an increase to greater than 30 min during infusion, reverting to 13 +/- 10 min within 2 h after cessation of infusion. Recurrent continuous bleeding from incision sites occurred in one of six dogs given aspirin alone, two of seven given rt-PA alone and all six dogs given both aspirin and rt-PA (p = 0.02). Bleeding time greater than 9 min correlated significantly with bleeding frequency (p less than 0.0001), with a sensitivity of 100% and a specificity of 87%. Intravenous bolus injection of aprotinin (20,000 kallikrein inhibitor units/kg body weight) in six dogs given both rt-PA and aspirin produced a decrease in bleeding time from greater than 30 min to 9.5 +/- 9 min and resulted in cessation of bleeding. Thus, bleeding and bleeding time prolongation in this canine model are potentiated by a marked interactive effect of rt-PA and aspirin that is rapidly reversible. Template bleeding times may provide a useful quantitative index for monitoring the bleeding tendency associated with thrombolytic therapy.

Animals

Correlation between template bleeding times and spontaneous bleeding during treatment of acute myocardial infarction with recombinant tissue-type plasminogen activator.

The purpose of this study was to correlate bleeding complications during and after treatment with recombinant tissue-type plasminogen activator (rt-PA) with serial template bleeding time measurements, with ADP-induced platelet aggregation, with clinical characteristics, and with hemostatic parameters. Fifty-two of 55 consecutive patients with acute myocardial infarction and template bleeding times (Ivy method) of less than 9.5 minutes were treated with rt-PA in a total dose of 55-212 mg (mean, 109 mg) over 90 to 360 minutes (median, 240 minutes) combined with heparin. The mean bleeding time was significantly prolonged at 90 minutes (from 5.0 +/- 1.9 to 8.2 +/- 4.3 minutes, p less than 0.0001) but returned toward baseline after 4 hours (from a median of 8.0 to 7.0 minutes, p less than 0.05). Thirteen patients (25%) suffered relatively minor but spontaneous bleeding that did not correlate with age, hypertension, smoking, partial thromboplastin time, platelet count, ADP-induced platelet aggregation, steady-state rt-PA level, or extent of fibrinogen degradation. In multivariate analysis, only the 90-minute bleeding time correlated with spontaneous bleeding (p = 0.01). Prolongation of the 90-minute bleeding time to greater than or equal to 9 minutes, which occurred in 21 patients, correlated with spontaneous bleeding with a sensitivity of 69% (95% confidence interval, 39-90%) and a specificity of 69% (95% confidence interval, 52-83%). Retrospective analysis revealed that in 14 patients taking aspirin, the bleeding time at 90 minutes was significantly more prolonged (p less than 0.05) and spontaneous bleeding significantly more frequent (p less than 0.01) than in patients not taking aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate

Oral estrogens decrease bleeding time and improve clinical bleeding in patients with renal failure.

PURPOSE: A prolonged bleeding time is associated with platelet dysfunction and clinical bleeding in patients with renal failure. Parenteral estrogens have been shown to shorten the prolonged bleeding time in patients with chronic renal failure, although the mechanism of action is unknown. We conducted a study to evaluate the efficacy of oral conjugated estrogens in this setting. PATIENTS AND METHODS: Four patients with renal failure, prolonged bleeding time, and clinical bleeding were given 50 mg of conjugated estrogen (Premarin) daily. RESULTS: Bleeding time normalized in two cases and was reduced to less than 50% of the pretreatment value in one of the remaining two cases. Bleeding stopped in all patients within two days. Ten dialysis patients with prolonged bleeding time were randomized to a course of 50 mg of Premarin daily or placebo. The bleeding time in all five patients in the Premarin group normalized or decreased to below 50% of the pretreatment value after 7.0 +/- 4.2 days of therapy. The bleeding time did not normalize in the five patients treated with placebo. No side effects attributable to therapy were reported. CONCLUSION: We conclude that orally administered conjugated estrogens effectively improve the bleeding tendency in patients with chronic renal failure.

Administration, Oral

Relationship of first-trimester subchorionic bleeding detected by color Doppler ultrasound to subchorionic fluid, clinical bleeding, and pregnancy outcome.

We analyzed retrospectively the incidence of subchorionic fluid and embryonic death in 2116 consecutive patients evaluated with abdominal ultrasound and 783 patients evaluated with vaginal ultrasound. These women were examined during the first 12 postmenstrual weeks and had conceived as a result of infertility treatment. In addition, we analyzed the relationship of subchorionic bleeding to subchorionic fluid in 230 patients evaluated with color Doppler ultrasound and the relationship of subchorionic bleeding to clinical bleeding, precipitating factors, pregnancy outcome, and the karyotypes of abortuses. In single gestational sac pregnancies, subchorionic fluid was found equally often in women scanned with vaginal or color Doppler ultrasound, and less often with abdominal ultrasound (P less than .0001). Embryonic death was increased only in patients with large amounts of subchorionic fluid observed on abdominal ultrasound. Color Doppler ultrasound revealed subchorionic bleeding in 87 of 235 ultrasound scans (37%) and in 48 of 102 patients (47%) when subchorionic fluid was present. Subchorionic bleeding was associated with moderate or large amounts of subchorionic fluid (P = .041), with precipitating events (P less than .0001), and with clinical bleeding (P = .001). It was occult in ten of 48 patients (21%). Embryonic death occurred equally often in women with no fluid and in those with subchorionic fluid, with and without subchorionic bleeding. Abortuses were karyotypically abnormal in an equal proportion of cases with subchorionic bleeding, subchorionic fluid, and no fluid. These findings indicate that subchorionic fluid and subchorionic bleeding are common findings in early pregnancy and are not associated with embryonic death unless they are accompanied by clinical bleeding.

Female

Non-occlusive bleeding times may improve the value of Ivy bleeding times.

The present studies measured bleeding times, without venous occlusion, in a series of patients, whose bleeding times (+ venostasis) consistently exceeded 20 min. During these tests, the amount of blood loss (expressed as mg/min) was also quantitated. To allow comparison, normal controls were studied before and following aspirin ingestion. In normal controls, the mean standard Ivy bleeding time was 5.0 with a range of 2.5 to 7.5 min. Two hours after aspirin (650 mg), this increased to 7.3 min (range 4.0-12.0). For comparison, the non-occlusive bleeding time averaged 3.8 min (1.0-6.5) and after aspirin 5.3 min (2.5-11.5). The measured amount of blood loss was 5.0 mg/min (0-10.5 mg/min) under all of the above conditions. At the other extreme, patients with severe bone marrow failure had occluded and non-occluded bleeding times in excess of 20 min. Moreover, these were often associated with excess blood loss. By contrast, patients with "Ivy" values greater than 20 min in association with platelet counts greater than 10,000/microliters had unpredictable bleeding parameters. In the latter group, the non-occluded values ranged from 1 to greater than 20 min. Of particular note, the non-occlusive times appeared to correlate with spontaneous bleeding manifestations. Only a rare patient (1/37), whose non-occluded value was less than 20 min, had worrisome bleeding. By contrast, serious bleeding manifestations were observed in 39% whose non-occluded value exceeded 20 min. This was even higher (64%) in those with a non-occluded value greater than 20 min and excess blood loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Arm

The bleeding severity index: validation and comparison to other methods for classifying bleeding complications of medical therapy.

Reports of bleeding complications of medical therapy should be based on valid methods of classification, but the reproducibility of existing methods has not been tested. Therefore, we prospectively studied three methods to classify the severity of bleeding: a purely subjective implicit method, a previously published explicit method using brief criteria, and the bleeding severity index, which is a new explicit method using detailed criteria about the amount, rate, and consequences of bleeding. Three physicians independently reviewed abstracts of 168 patients treated with anticoagulants. The proportion of cases classified as major bleeding varied widely when the implicit method was used (2, 14 and 39%), less when the old explicit method was used (28, 40 and 47%), and not at all when the new bleeding severity index was used (20, 20 and 20%). Intraobserver agreement was excellent for both explicit methods (kappa greater than or equal to 0.95). However, interobserver agreement was better for the bleeding severity index (kappa = 0.87) than for the old explicit method (kappa = 0.69) or the implicit method (kappa = 0.39). We conclude that the classification of bleeding complications of medical therapy depends on the method used. In comparison to older methods, the bleeding severity index is highly reproducible and should be tested more widely to determine whether it can be applied to the burgeoning clinical research in anticoagulation and thrombolysis.

Anticoagulants

Histometric analysis of epithelial alterations in bleeding and non-bleeding gingivae after probing and their corresponding stereomicroscopic findings of vasculature.

The present study was carried out to investigate and compare the thickness and number of rete pegs of the sulcular epithelium histometrically in bleeding and non-bleeding gingivae with special reference to comparisons of their relationship with corresponding stereomicroscopic findings. A total of 78 biopsies (40 bleeding and 38 non-bleeding gingival specimens) was obtained from 33 patients. Tissue sections with H&E stains were performed. Each gingival section was divided into three portions (coronal, middle and apical) along the gingival sulcular epithelium horizontally. The rete pegs were counted and the thickest and thinnest parts of the epithelium in three individual portions were also measured histometrically. The results show that the epithelial thickness of bleeding gingiva at the coronal and middle portions was significantly thinner than that of non-bleeding gingiva. There were also greater numbers of rete pegs of the sulcular epithelium in bleeding gingiva than of those in non-bleeding gingiva. However, there was no specific relationship between epithelial alterations of gingiva and the visibility of vasculature by stereomicroscopy. It is suggested that epithelial alterations of gingiva to some extent might be responsible for the gingival bleeding on probing clinically and highly associated with the volumetric density of underlying infiltrated connective tissue, but might not be related to the visibility of vasculature by stereomicroscopy.

Epithelium

Synergistic shortening of the bleeding time by desmopressin and ethamsylate in patients with various constitutional bleeding disorders.

Desmopressin and ethamsylate were evaluated for possible synergistic effects on the bleeding time. The drugs were administered individually and together to 12 patients with markedly prolonged bleeding times known to be relatively or absolutely unresponsive to desmopressin alone. The bleeding disorders studied included Glanzmann's thrombasthenia (one), other disorders of platelet function (four), pseudo-von Willebrand disease (one), and von Willebrand disease type I (three), type II (two), and type III (one). Desmopressin alone shortened the bleeding time from 23.9 +/- 1.5 to 19.5 +/- 2.3 min (p = 0.03). Ethamsylate alone was without effect. Desmopressin and ethamsylate together shortened the bleeding time to 11.2 +/- 1.4 min (p less than 0.01 compared to baseline, p = 0.02 compared to desmopressin alone). The combination was ineffective in three patients, with Glanzmann's thrombasthenia (one), and von Willebrand disease type I (one) and type III (one). Toxic effects of the drugs were not observed. Five patients received desmopressin and ethamsylate prior to dental work with mandibular block (one), heart surgery requiring cardiopulmonary bypass (two), and adenotonsillectomy surgery (two). Normal hemostasis was achieved in each case. A synergistic shortening of the bleeding time was observed with the combination of desmopressin and ethamsylate in a wide range of bleeding disorders.

Adolescent

Histometric analysis of infiltrated connective tissue in bleeding and non-bleeding gingivae after probing.

The present study was carried out to evaluate and compare the volumetric densities of subepithelial infiltrated connective tissue (ICT) geographically in bleeding and non-bleeding gingivae with special reference to comparisons of the relationships with their corresponding stereomicroscopic findings. A total of 51 biopsies (25 bleeding and 26 non-bleeding gingival specimens) was obtained from 33 patients. After stereomicroscopic examinations, tissue sections were obtained with H&E stain. On each section, the density of ICT was calculated by volumetric analysis. The results showed that the volume of ICT in bleeding-gingiva was significantly greater than that in non-bleeding gingiva. However, there was no specific relationship between the ICT of gingiva and the visibility of vasculature by stereomicroscopy. These results suggest that increased infiltrated inflammatory volumes of gingiva may play a role in the presenting of bleeding on clinical probing, but appear not to be related to the visibility of vasculature by stereomicroscopy.

Adult

Bleeding time in uremia: a useful test to assess clinical bleeding.

Modified Ivy bleeding time (template) and platelet aggregation to ADP, epinephrine, and collagen were studied in 26 uremic patients who had not recently ingested anti-platelet drugs. Regardless of the aggregating agent used, the abnormalities in platelet aggregation were often mild, even with advanced uremia, and frequently less severe than the effects of common anti-platelet drugs. The inhibition of collagen-induced aggregation was significantly correlated with both increased bleeding time and blood urea nitrogen. Platelet aggregation was not discriminative between clinically bleeding and non-bleeding groups of patients, but the bleeding time was helpful in this regard. In certain cases, the aggregometric patterns differed between drug-induced and uremic thrombocytopathies. Platelet aggregometry appears to be of little help clinically in assessing the severity of the uremic bleeding diathesis.

Adenosine Diphosphate

Usefulness of the bleeding time to predict the risk of clinical bleeding in patients with uraemia.

In a prospective study of haemostatic status of 15 uraemic Nigerians a highly significant prolongation of bleeding time (p less than 0.001) and significantly lower haematocrit levels (p less than 0.001) were detected in comparison to healthy controls. A highly significant positive correlation (r = +0.778) between prolongation of bleeding time and blood urea was present. Six patients had overt clinical bleeding with significantly prolonged bleeding time (p less than 0.01) compared to uraemics without overt bleeding. Blood urea was significantly different in both groups (p greater than 0.1). Platelet count, prothrombin time, partial thromboplastin time and Hess tourniquet test did not differ between the uraemic patients and controls. Haemostatic dysfunction has been noted in Nigerian uraemics we studied. Bleeding time is a useful but simple means of assessing such dysfunction.

Adolescent

Effects of acute exercise on bleeding time, bleeding amount and blood cell counts: a comparative study.

Twenty-five men and 26 women were studied to investigate the effects of acute strenuous exercise on hemostasis after obtaining their informed consent. After familiarization, they performed exercise on a bicycle ergometer at 75% of their predetermined maximal workload until exhaustion. Bleeding time, measured by the Simplate method, and venous blood cell counts of platelets (Plt), erythrocytes (RBC), leukocytes (WBC) were determined at rest and immediately after exercise. We found that bleeding time of Chinese in our study was longer than those of the westerners in other studies and that bleeding time was significantly shortened after exercise from 8.3 +/- .7 to 6.5 +/- .5 min in men and from 11.4 +/- .9 to 8.6 +/- .8 min in women (p less than 0.001). In men, but not in women, acute exercise also augmented the initial bleeding rate and bleeding amount from standard incisions. We also observed that RBC, WBC and Plt counts were greatly increased. The increased percentages for RBC, WBC and Plt in men were 7 +/- 1%, 59 +/- 7%, 16 +/- 3%, and those in women were 5 +/- 1%, 42 +/- 6% and 17 +/- 2% respectively.

Adult

Studies in patients with bleeding disorders show that platelet-vessel interaction is important for thromboxane formation in bleeding time wounds.

The production of thomboxane B2, the primary metabolite of thromboxane A2, and 6-keto prostaglandin F1 alpha, the primary metabolite of prostacyclin, were measured in response to a standardized vascular injury, the bleeding time, in patients with von Willebrand's disease and in patients with platelet function defects. Compared to controls, thromboxane B2 levels in bleeding time blood were significantly lower in subjects with von Willebrand's disease. In patients with platelet function defects associated with a deficient response to thromboxane A2, thromboxane B2 production in bleeding time blood was similar to controls. In subjects with other platelet function defects, thromboxane production was significantly lower than normal. 6-keto PGF1 alpha production in bleeding time blood was not significantly different in patients compared to controls. The results suggest that bleeding time thromboxane production is influenced by the extent of platelet-vessel interaction.

6-Ketoprostaglandin F1 alpha

Upper gastrointestinal bleeding in relation to previous use of analgesics and non-steroidal anti-inflammatory drugs. Catalan Countries Study on Upper Gastrointestinal Bleeding.

To assess the risk of upper gastrointestinal bleeding associated with the use of individual non-narcotic analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), a multicentre study of 875 cases of upper gastrointestinal bleeding and 2682 hospital controls was done. With control for confounding factors, the overall odds ratio estimate for aspirin taken at least once during the week before the first symptom was 7.2 (95% confidence interval 5.4-9.6). Non-aspirin NSAIDs associated with upper gastrointestinal bleeding were diclofenac (7.9 [4.3-14.6]), indomethacin (4.9 [2.0-12.2]), naproxen (6.5 [2.2-19.6]), and piroxicam (19.1 [8.2-44.3]). Paracetamol, propyphenazone, and dipyrone did not increase the risk. A previous history of gastrointestinal bleeding or peptic ulcer did not greatly affect odds ratio estimates, which differed according to sex and were higher for younger than for older patients. However, the incidence of upper gastrointestinal bleeding was higher among the elderly.

Adult

Propranolol for prophylaxis of bleeding in cirrhotic patients with large varices: a multicenter, randomized clinical trial. The Italian Multicenter Project for Propranolol in Prevention of Bleeding.

To assess if propranolol prevents the first bleeding in cirrhosis, we randomly assigned 174 patients with large varices to either propranolol in doses reducing the resting heart rate by 25% (85 patients) or to a placebo (oral vitamin K, 89 patients). Sixty-nine patients had alcoholic cirrhosis, 24 posthepatitis cirrhosis and 81 cryptogenic cirrhosis. At the time of inclusion, 75 patients (43%) had ascites and according to the Child-Pugh classification, 103 (59%) had Class A disease, 60 (34%) Class B and 11 (7%) Class C. We report here an interim analysis of the study when all patients had been followed for at least 1 year (mean follow-up = 22 months). At this time, the cumulative proportion of patients free of bleeding was 74% (both differences not significant), respectively. A retrospective analysis showed that the cumulative percentage of patients free of bleeding was significantly higher in the propranolol- than in the control-group in the subsets of patients without ascites or in Child-Pugh Class A: respectively, 87 vs. 64% (p = 0.023) and 88 vs. 64% (p = 0.01). No differences in bleeding incidence were found in patients with ascites or in Child-Pugh Class B or C. Propranolol treatment did not affect survival in any subgroup. Twenty-five patients had to be withdrawn from propranolol because of side effects (n = 23) or low compliance (n = 2). If confirmed on a longer follow-up, these results suggest that propranolol could prevent the first bleeding in patients with well-compensated cirrhosis.

Clinical Trials as Topic

Epidemiology of AIDS in females with hemophilia and other chronic bleeding disorders in the United States: comparisons with males with chronic bleeding disorders and AIDS and with nonhemophilic female blood-transfusion recipients with AIDS.

From January 1, 1981 through June 30, 1990, 32 females with chronic bleeding disorders were diagnosed with acquired immunodeficiency syndrome (AIDS) in the United States. Most (81.3%) were white and greater than or equal to 30 years of age, with a median age of 37.5 years. Eighteen (56.3%) had von Willebrand's disease. Pneumocystis carinii pneumonia was reported for 16 (50%). None had Kaposi sarcoma. The median survival time was 10.8 months, with a cumulative probability of survival at 1 year of 47.3% and at 2 years of 27.6%. We compared the demographic data and survival times of these females with those of males with a chronic bleeding disorder and AIDS, and with those of nonhemophilic females with AIDS whose exposure to the human immunodeficiency virus (HIV) was through receipt of blood transfusions, blood components, or tissue. The principal demographic difference was age distribution. The females with chronic bleeding disorders tended to be younger than the transfused, nonhemophilic females, but older than the males. The survival time from AIDS diagnosis to death for the females with chronic bleeding disorders did not differ statistically from that of the other two groups, although older nonhemophilic females whose exposure was transfusion may progress more rapidly to AIDS.

Acquired Immunodeficiency Syndrome