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Patients with a prolonged bleeding time and normal aggregation tests may have storage pool deficiency: studies on one hundred six patients.

One hundred six patients with storage pool deficiency (SPD) were studied with respect to platelet count, bleeding time, total platelet ATP and ADP, platelet serotonin, and in vitro aggregation. The diagnosis of SPD was made on basis of a prolonged bleeding time, a decreased total platelet ADP, and a diminished level of serotonin. Fifty-one patients from 34 unrelated families had congenital SPD, and 55 patients had acquired SPD. Congenital SPD was a common disorder in patients with a lifelong bleeding tendency and a prolonged bleeding time. The frequency in this group of patients was 18%, about one-half the frequency of von Willebrand's disease (vWd). Twenty-three percent of all patients had normal aggregation responses to ADP, epinephrine, and collagen; 33% had aggregation tracings typical for a secretion defect; and 44% had miscellaneous aggregation abnormalities. These findings indicate that SPD is common, heterogeneous, and not necessarily associated with in vitro aggregation abnormalities.

Bleeding Time↗

Correlation between bleeding time and antithrombotic effect of platelet-suppressive agents in rat experimental model.

To examine whether the dosage of a platelet-suppressive agent at which an antithrombotic effect is adequate and bleeding tendency is not increased can be found, the antithrombotic effects, antiplatelet effects and bleeding times of ticlopidine and aspirin were investigated in the rat experimental thrombus formation model. Thrombus formation was determined by measuring the change in wet weight of a silk thread placed in a carotid arteriovenous shunt. Ticlopidine inhibited thrombus formation and platelet aggregation at rather low doses (50-100 mg/kg) without prolonging bleeding time. However, aspirin did not inhibit thrombus formation at even the highest examined dose (200 mg/kg), while bleeding time was prolonged at even the lowest dose (50 mg/kg). These results suggest that a dosage of antithrombotic agent that does not increase bleeding tendency can be easily established using ticlopidine, although it is relatively difficult using aspirin.

Animals↗

Bleeding time in normal children.

PURPOSE: Because there is little information on bleeding times (BTs) in children we initiated the following study. MATERIALS AND METHODS: Normal children undergoing elective surgery and adult volunteers had their bleeding times measured with a disposable device (Simplate) with a vertical incision in the forearm. Results in children (four age groups) and adults, male and female, were compared. RESULTS: The mean time in children was 270 s with a 95th percentile of 420 s compared with a mean time in adults of 320 s and a 95th percentile of 480 s (p = 0.001). Although the values in the various age groups and sexes were different, only sex had a statistically different value in adults. CONCLUSIONS: The following reference values should be used for children: 0-4 years, 4 +/- 1 min; boys > 4 years, 5 +/- 1 min; girls > 4 years, 5.5 +/- 1 min. We conclude that results obtained in children are significantly shorter than those obtained in normal adult subjects.

Adolescent↗

The post-aspirin bleeding time: a screening test for evaluating haemostatic disorders.

To evaluate the usefulness of the template bleeding time post-aspiring ingestion, this test was performed with other tests of haemostasis in 28 controls and 71 patients. The mean bleeding time (B.T.) in 24/28 true controls was 3.5 +/- 1 min (1 SD). Following the ingestion of 600 mg aspirin the B.T. was 6.3 +/- 1.4 min. Four out of 28 false 'controls' with negative bleeding histories were documented to have asymptomatic von Willebrand's disease and abnormal post-aspirin B.T. Of the 71 patients studied, 22 had initial B.T. that were abnormal (16 with classical von Willebrand's disease and six with platelet dysfunction). Of the remaining 49 patients with initially normal B.T., 30 had abnormal post-aspirin B.T. Of these 30 patients 13 had von Willebrand's disease. In eight, initially the abnormal B.T. post-aspirin was the only abnormality demonstrable but later they were shown to have von Willebrand's disease. In four the abnormal post-aspirin B.T. was combined with abnormal Ristocetin aggregations and a positive family history. These patients were presumed to have a variant of von Willebrand's disease. The remaining five had platelet dysfunctional states. Of the 19 patients with normal initial post-aspirin B.T., 16 demonstrated no haemostatic abnormality, and three were proven to have von Willebrand's disease. The aspirin tolerance test raised the sensitivity of the B.T. as a screening test for haemostasis from 40% to 94% in the abnormal patient population.

Adolescent↗

[Exploring the effect of aspirin on primary hemostasis through bleeding time. Study of 16 volunteers].

Strong anti-binding platelets, aspirin is used in the treatment or the prevention of many thrombotic pathologies. We wanted to study the effect of aspirin over the bleeding time of a group of volunteers. It consisted of 16 volunteers aged from 20 to 25 years and having no haemorrhagic or thrombotic antecedent. For each of them, we have carried out a blood count by means of an automaton Sysmex K800, followed by a measure of the bleeding time (BT). Immediately after, each volunteer has ingested 250 mg of Aspegic; then, the BT has been measured every 24 hours and up to the fifth day. The BT has been carried out by means of IVY technique 3 points, that besides the time, allows to measure the volume of bleeding (microliter). All the check-ups were normal, however, the time and volumes of bleeding were respective by short and weak. After having taken aspirin, the bleeding time has significantly become longer to day 1 and day 2 (respectively 48% and 31.5% with regard to day 0) and the volume has increased to day 1, day 2 and day 3 (respectively 122.6%, 74.7% and 38.1% with regard to day 0).

Adult↗

Antithrombotic effects and bleeding time prolongation with synthetic platelet GPIIb/IIIa inhibitors in animal models of platelet-mediated thrombosis.

Cyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-alpha-aspartyl- cyclic (1-->5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-propyl-L-arginyl-glycyl-L-alpha- aspartyl-[0-methyltyrosyl]-L-arginyl-L-cysteinamide, cyclic 1-->9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor. The relationship between antithrombotic effect, ex vivo platelet aggregation and bleeding time prolongation with both agents was studied in hamsters with a standardized femoral vein endothelial cell injury predisposing to platelet-rich mural thrombosis, and in dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in vivo thrombus formation with a 50% inhibitory bolus dose (ID50) of approximately 20 micrograms/kg, ex vivo ADP-induced platelet aggregation with ID50 of 10 micrograms/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 +/- 9 to 1,100 +/- 330 s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID50 of 30 micrograms/kg, ex vivo platelet aggregation with an ID50 of 50 micrograms/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 micrograms/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induced ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 +/- 0.4 to 12 +/- 2 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

A monoclonal antibody that recognizes the GPIIb/IIIa antagonist DMP 728. Reversal of the effects of DMP 728 on platelet aggregation and bleeding time in the dog.

Since hemorrhagic events represent a major safety concern associated with the use of new antithrombotic therapies such as glycoprotein (GP) IIb/IIIa receptor blockade, we evaluated the ability of a monoclonal antibody recognizing DMP 728 (cyclic [D-2-aminobutyryl-N2-methyl-L-argininyl-glycyl-L-aspartyl-3- aminomethyl-benzoic acid] methanesulfonic acid salt), a potent GPIIb/IIIa receptor antagonist, to reverse the pharmacological actions of DMP 728 in the dog. DC11 was chosen for in vivo evaluation based on its ability to inhibit the binding of [3H]DMP 728 to activated platelets and to attenuate the inhibition of ADP-induced aggregation on platelet-rich plasma ex vivo by DMP 728. After anesthesia mongrel dogs were given DMP 728 (20 micrograms/kg body wt IV) infused into the femoral vein, bleeding times were determined using a Simplate device from incisions on the backside of the tongue, and platelet aggregation was determined ex vivo. Nearly complete inhibition of platelet aggregation was observed for the dogs treated with DMP 728 (20 ug/kg IV) for up to 210 minutes, and bleeding times were prolonged > 15 minutes for 2 hours and remained elevated for more than 4 hours. DC11 (0.2 or 1.0 mg/kg body wt IV) given to dogs 10 minutes after DMP 728 resulted in 50% attenuation of the effect of DMP 728 on aggregation at 3 hours. Approximately 34% inhibition of the DMP 728-mediated bleeding time was achieved at 1 hour with the 0.2 mg/kg dose, whereas approximately 50% inhibition of the bleeding time was observed for the 1 mg/kg dose at 1 hour.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Comparison of the effects of acetylsalicylic acid, ticlopidine and cilostazol on primary hemostasis using a quantitative bleeding time test apparatus.

We examined and compared the effects of aspirin (ASA), ticlopidine (TP) and cilostazol (CS) on bleeding time (BT) in 10 healthy adult male subjects using a newly developed quantitative bleeding time (QBT) test apparatus capable of simultaneously measuring total blood loss (Tv), maximum bleeding rate (Rmax), and bleeding pattern in addition to BT. All 3 drugs inhibited platelet aggregation response to ADP, collagen, epinephrine and arachidonic acid (p < 0.05), but not to ristocetin. Following oral administration of ASA (330 mg/day) or TP (300 mg/day) for 3 days, BT was significantly prolonged (mean BT increased from 359.3 to 646.0 s, p < 0.001, and from 323.3 to 528. 7 s, p < 0.01, respectively) and Tv was significantly increased (from 14.5 to 30.2 microl, p < 0.05, and from 12.5 to 19.2 microl, p < 0.01, respectively). Aspirin also increased Rmax (from 0.118 to 0. 159 microl/s, p < 0.05). The prolonged bleeding patterns after administration of ASA and TP were both type III, which has been reported to be less likely to lead to bleeding accidents. In contrast, none of these QBT parameters were altered by CS administration.

Adult↗

Normal and abnormal bleeding times in neonates and young children utilizing a fully standardized template technic.

Prior reports of bleeding times for newborn infants have utilized nonstandardized methods. The standard adult template method was modified for use with infants by decreasing the incision size (5 mm x 0.5 mm) and the sphygmomanometer pressure used to stress local hemostasis. The bleeding time with this technic for healthy term (3.4 min +/- 0.9) and preterm (3.6 min +/- 1.0) newborn infants did not differ from that for healthy young children (3.4 min +/- 1.3). The method is sensitive to the antiplatelet effects of aspirin and indomethacin, decreasing platelet count (r = 0.76), and the platelet dysfunction of von Willebrand's disease and platelet storage pool disease. Platelet dysfunction was documented in association with severe internal bleeding for a group of premature infants who had respiratory distress syndrome. The advantages of this method include full standardization of the incision size, minimal blood loss, and use of equipment readily available to any clinical laboratory.

Adult↗

Quantitative bleeding time (hemorrhagometry). A review.

Accurately determining the amount of blood lost during bleeding time tests has been little exploited. Equipment is now available for measuring both the time and volume automatically--a technique called hemorrhagometry. This quantitative procedure has generated a number of interesting and unsuspected observations. Bleeding times lengthen and blood loss is exaggerated as the skin is cooled. This is particularly true of patients who have hemostatic defects, such as hemophilia A; Not only is the hemophiliac different from normal in this regard but, in Sutor's preliminary observations, the asymptomatic carrier of hemophilia A also seems to be distinguishable from the noncarrier on this basis. The test seems potentially useful in evaluating the effect of drugs on platelet function and in assessing mild bleeding diatheses. Variations induced by either warming or cooling the skin may well have clinical applicability.

Blood↗

Lack of effect of prednisone administration on bleeding time and platelet function of normal subjects.

The effect of 80 mg prednisone given orally for 2 d on normal and post-aspirin bleeding times and platelet function has been studied in a randomized, multiple cross-over, double-blind controlled trial in 12 normal volunteers. Mean template bleeding times were 6.6 min (placebo/placebo), 5.9 min (prednisone/placebo), 10.0 min (placebo/aspirin) and 8.7 min (prednisone/aspirin). The shortening after prednisone administration was not statistically significant. Prednisone had no effect on platelet glass bead retention nor on platelet aggregation by collagen, adrenalin and adenosine diphosphate. Thus conventional clinical doses of prednisone did not impair platelet function and did not enhance primary haemostatis in normal subjects as measured by the bleeding time.

Adult↗

Comparison of enteric-coated aspirin and uncoated aspirin effect on bleeding time.

Aspirin therapy is an essential part of the drug regimen for patients with acute myocardial infarction (MI), unstable angina, or after coronary angioplasty and coronary stenting. Recognizing this importance, this study sought to compare the bleeding time in two groups of 10 normal volunteers 4 hr after ingestion of either an enteric-coated aspirin or an uncoated aspirin, assuming that a difference between the two groups could be clinically significant. Defining < or = 8 min as normal, 80% of the uncoated group developed abnormal bleeding times, compared to 10% of the enteric-coated group (P < 0.01). The study demonstrates a significant difference between the two types of aspirin preparations on bleeding times in normal individuals. This strongly suggests that some enteric-coated aspirin preparations may not be as effective as uncoated aspirin in acutely decreasing platelet aggregation. Therefore, uncoated aspirin is recommended in the setting of acute MI, unstable angina, or after percutaneous transluminal coronary angioplasty.

Aspirin↗

The effects of different doses of some acetylsalicylic acid formulations on platelet function and bleeding times in healthy subjects.

In an attempt to find the most appropriate dose and formulation(s) of acetylsalicylic acid (ASA) for thrombosis prophylaxis, healthy volunteers were given doses of ASA for 1 wk daily ranging from 50 to 3900 mg as either Aspro-Clear (soluble), Astrix (enteric coated pellets) or Ecotrin (enteric coated tablets). Platelet function and bleeding times were monitored. All doses of ASA significantly inhibited platelet function (p less than 0.05) and increased bleeding times (p less than 0.05) relative to control values. Irrespective of the formulation, maximum increases in bleeding time and platelet dysfunction were obtained with daily doses of about 100 mg, and no further changes were observed with higher doses.

Adult↗

The Hermansky-Pudlak syndrome. Variable reaction to 1-desamino-8D-arginine vasopressin for correction of the bleeding time.

The effect of the synthetic vasopressin derivative 1-desamino-8D-arginine vasopressin (DDAVP = Minrin) on bleeding time was studied in nine patients with Hermansky-Pudlak syndrome; four of them were Dutch, five were Belgian. Shortening of bleeding time was observed in four of the patients with this type of storage pool disease; in one patient the response was equivocal, in two patients the response was not dramatic and in two there was no response at all. DDAVP may be useful in managing the bleeding disorder in some patients with Hermansky-Pudlak syndrome. Therefore, every patient with this syndrome should be tested with DDAVP as a preventive measure.

Adolescent↗

Thromboxane A2 and prostacyclin release in bleeding time blood during primary haemostasis in healthy individuals.

It is generally believed that prostacyclin (PGI2) generation is greatly stimulated when blood vessels are injured, even by minor trauma, such as venepuncture. The Simplate technique for measuring skin bleeding time was adapted to quantify by radioimmunoassay PGI2 and thromboxane A2 (TXA2) in the emerging blood, as the stable degradation products 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TXB2), both of which were measured in venous plasma as well as in serum (clotted at 37 degrees C for 1 h). During bleeding, when platelets aggregate to occlude the injured vessels, the median TXB2 level in the emerging bleeding time blood was 1.7 ng/ml. The median TXB2 level in plasma was less than 1 ng/ml and in serum 275 ng/ml. The levels of immunoreactive 6-keto-PGF1 alpha were always below determination limit in bleeding time blood (0.2 ng/ml) and in plasma (0.1 ng/ml), whereas in serum the levels ranged between 0.26 and 0.47 ng/ml. The fact that enhanced PGI2 production in primary haemostasis in skin incisions could not be demonstrated calls for further investigations of possible PGI2 production with more sensitive assays or in injured large vessels.

6-Ketoprostaglandin F1 alpha↗

No alteration in the PFA-100 in vitro bleeding time induced by the Ginkgo biloba special extract, EGb 761, in elderly patients with mild cognitive impairment.

EGb 761 is widely used in the management of mild cognitive impairment in the elderly population. Elucidation of the effects of EGb 761 on primary haemostasis via PFA-100 could represent an important step for better understanding of the haemostatic safety of EGb 761. The purpose of this prospective study is to assess the effects of Ginkgo biloba special extract, EGb 761, on PFA-100 in vitro bleeding time in elderly patients with mild cognitive impairment. A total of 40 elderly patients aged 65-79 years who were referred for geriatric assessment and who were diagnosed as having mild cognitive impairment were included. Patients were started on 80 mg EGb-761 three times daily. The complete set of PFA-100 in vitro bleeding time and coagulation parameters including prothrombin time, activated partial thromboplastin time and International Normalized Ratio were assessed before and on the seventh day of treatment with EGb 761. There was no statistically significant prolongation in PFA-100 in vitro bleeding time or coagulation parameters in patients receiving EGb 761 after 7 days. The data about the safety of EGb 761 from the point of primary haemostasis in our elderly patient population with mild cognitive impairment casts hope for the future management of this 'difficult-to-treat' population with the promising Ginkgo extracts.

Aged↗

Antithrombotic activity of AT-1015, a potent 5-HT(2A) receptor antagonist, in rat arterial thrombosis model and its effect on bleeding time.

The antithrombotic activity of N-[2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino)ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate (AT-1015; a 5-HT(2A) receptor antagonist) was studied in a photochemically induced arterial thrombosis (PIT) model in the rat femoral artery, and in the tail transection bleeding time test. Ticlopidine (an antiplatelet agent) and sarpogrelate (a selective 5-HT(2A) receptor antagonist) were studied as reference compounds. Pretreatment with AT-1015 (1 mg/kg, p.o.) significantly prolonged the time required to occlusion of the artery with thrombus, and the effect (3 mg/kg, p.o.) persisted for 24 h with significant inhibition of 5-HT-induced vascular contraction. Ticlopidine and sarpogrelate also significantly prolonged the time to occlusion at 100 mg/kg, p.o. Sarpogrelate (300 mg/kg, p.o.) showed the similar antithrombotic efficacy to AT-1015 (3 mg/kg, p.o.), while the effect disappeared within 6 h. No significant bleeding time prolongation was observed at 10 mg/kg of AT-1015, which is 10 times higher than the antithrombotic effective dose; whereas ticlopidine significantly prolonged bleeding time at the same dose as the antithrombotic effective dose. These results suggested that AT-1015 is a potent and long-acting oral antithrombotic agent in this model, which may be elucidated by its potent and long-acting inhibition of vasoconstriction through 5-HT(2A) receptor.

Animals↗

DDAVP infusion in five patients with type Ia glycogen storage disease and associated correction of prolonged bleeding times.

Five patients with glycogen storage disease type I (GSD-I) were evaluated for a bleeding diathesis and subsequently were given an infusion of 1-deamino-8-D-arginine vasopressin (DDAVP). Although platelet counts were normal or slightly elevated, the baseline template bleeding times were prolonged in four of the patients. Prothrombin times and activated partial thromboplastin times were normal, while ADP- and epinephrine-induced platelet aggregations were absent in the three patients tested. Ristocetin- and collagen-induced platelet aggregations were abnormal. Laurell and immunoradiometric determinations of the factor VIII-related antigen (vWf antigen) were decreased. Glyoxyl agarose gel electrophoresis of the patients' plasma revealed abnormal multimer patterns in four of the five patients. After the DDAVP infusion the platelet aggregation abnormalities persisted; however, the bleeding time and the von Willebrand antigen and activity corrected. We conclude that GSD-Ia patients may have a metabolically acquired form of von Willebrand's syndrome as well as an acquired intrinsic platelet defect, and that DDAVP may be useful in the management of bleeding in these patients.

Adult↗