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PubMed1996

Bleeding time and platelet function in essential thrombocythemia and other myeloproliferative syndromes.

Bleeding time (BT) and platelet function tests have been widely used in patients with essential thrombocythemia (ET), with the aim to support diagnosis and to identify laboratory predictors of haemorrhagic and thrombotic complications. BT is significantly prolonged in 7-19% of ET patients and several functional abnormalities have been observed in platelet structure, biochemistry and survival. However, the attempt to relate these in vivo and in vitro platelet dysfunctions with diagnosis or clinical sequelae has been generally disappointing. Therefore, BT and platelet function tests are currently not recommended in the initial evaluation or during the follow-up of patients with ET, unless in the setting of a clinical or biological study. A noteworthy exception is represented by a subset of patients characterized by very high platelet count (> 1500 x 10(9)/L) and bleeding symptoms, who can have an acquired von Willebrand disease. In these cases, prolonged BT and abnormal multimeric pattern of von Willebrand factor are useful for diagnosing and monitoring this acquired hemorrhagic disease. BT and platelet function tests should be included in the baseline evaluation of ET patients enrolled in prospective clinical trials aiming assess their predictive role on clinical end-points.

Arachidonic Acid↗

PubMed1982

Bleeding time in rats: a comparison of different experimental conditions.

The tail bleeding time (BT) in rats definitely varies according to the method applied. Of the various variables that may influence BT, we have evaluated the position (horizontal or vertical) of the tail, the environment (air or saline), the temperature (4 degrees, 23 degrees or 37 degrees C) and the type of anaesthesia. Transection of the tail tip cannot be used to screen drugs active on platelet function since it is sensitive to coagulation defects. Template BT in contrast is not modified by heparin and is sensitive to defects of platelet number and function ("storage pool disease", dipyridamole-like drugs, exogenous prostacyclin). In contrast the test fails to detect aspirin-induced platelet dysfunction. The evidence reported indicates that thromboxane A2-prostacyclin balance is not a factor regulating BT. Aspirin treatment however may be a precipitating factor when associated with other abnormalities of platelet function. Template BT is a valid screening test for platelet disorders and for antiplatelet drugs.

Anesthetics↗

PubMed2001

Potent dibasic GPIIb/IIIa antagonists with reduced prolongation of bleeding time: synthesis and pharmacological evaluation of 2-oxopiperazine derivatives.

A series of 2-oxopiperazine derivatives, possessing basic moieties at the 3- and the 4-positions, were synthesized and evaluated for their abilities to inhibit platelet aggregation and for their effects on bleeding time. Among the compounds, 2-[(3S)-4-[2-[(4-guanidinobenzoyl)amino]acetyl]-3-[3-[(4-guanidinobenzoyl)amino]propyl]-2-oxopiperazinyl]acetic acid (12c) showed a potent inhibitory effect on platelet aggregation and good dissociation between the efficacy and the bleeding side effect. Intravenous infusion of compound 12c at 1.6 microg/mL/min completely prevented arterial thrombus formation induced by endothelial injury in guinea pigs. The dose of 12c that prolonged the bleeding time to three times the control value was 5.8 microg/mL/min. These results suggest that compound 12c might be useful in the clinical treatment of thrombotic diseases, and we selected 12c (TAK-024) as a candidate for the clinical trials.

Adenosine Diphosphate↗

PubMed1999

Antithrombotic effects and bleeding time of thrombin inhibitors and warfarin in the rat.

Warfarin limits the synthesis of y-glutamyl carboxylated forms of coagulation factors, factor II, factor VII, factor IX, and factor X, protein C, and protein S and as a result impairs the function of these proteins. In contrast, direct inhibitors of thrombin only affect one enzyme in the coagulation cascade. The aim of this study was to investigate the antithrombotic effect and the slope of the dose-response curves of the multifactorial coagulation inhibitor warfarin in comparison with the single factor low-molecular-weight thrombin inhibitors melagatran and inogatran. An arterial thrombosis model in rats was used, and vessel damage was induced by topical application of ferric chloride to the carotid artery. The slopes of the dose-response curves were 3.6, 1.8, 1.1, and 1.2, for warfarin, heparin, inogatran, and melagatran, respectively. For warfarin the antithrombotic effect increased from 23% to 81% when the dose was doubled. In contrast, 10-fold increases in the doses of inogatran and melagatran were necessary to obtain a similar increase in antithrombotic effect. The doses needed to obtain 80% antithrombotic effect for heparin, warfarin, and melagatran were investigated in a tail transection bleeding model. For heparin, this dose significantly prolonged the bleeding time and the blood loss; for warfarin, only the total bleeding time was increased while for melagatran there was no increase in bleeding. We conclude that, thrombin inhibitors affecting only one enzyme in the coagulation cascade seem preferable to inhibitors affecting multiple enzymes, such as warfarin, due to shallower dose-response curves and a wider therapeutic interval.

Animals↗

PubMed2000

In vitro bleeding time test can diagnose thrombotic thrombocytopenia purpura and can possibly monitor therapeutic plasma apheresis.

Thrombotic thrombocytopenia purpura (TTP) is perplexing, mainly because of its difficult diagnosis and dramatic clinical presentations, high mortality rates, and the effectiveness of empirical plasma infusions and plasma exchanges. Scientific evidence supports the hypothesis that TTP results from platelet hyperagglutination. To support this, a new in vitro bleeding time (Platelet-Stattrade mark) test was used. Eleven patients had a mean in vitro bleeding time of 7.3 +/- 2.1 seconds prior to plasma exchange and eight patients had a mean of 13.6 +/- 4.7 seconds after the plasma exchange procedure. Normal controls were 14 +/- 2 seconds. The test was used to monitor plasma exchanges in two patients. At the time the platelet count and LDH returned to normal, the Platelet-Stattrade mark remained shortened. The two patients relapsed and required continued plasma exchanges until Platelet-Stattrade mark corrected to normal. These results suggest that plasma exchanges may be effectively monitored by Platelet-Stattrade mark rather than the traditional parameters, i.e., LDH. Therefore, the Platelet-Stattrade mark test may be a useful test to diagnose TTP and monitor therapy in this disease.

Bleeding Time↗

PubMed1987

Bleeding time and PAF-acether-induced platelet aggregation in atopy.

In a double-blind cross-over study 20 mg of aspirin or placebo were administered to 18 patients with respiratory atopy without eczema and to 12 healthy controls. Mean bleeding time before administration of either aspirin or placebo was on average about 1 min. longer in atopics than in the controls, and this difference was significant (p 0.05). Atopics' platelets also aggregated less well in response to arachidonic acid in comparison to controls. On the contrary, no difference in platelet aggregability was detected in response to either PAF-acether alone or to combination of subthreshold, synergistic concentrations of PAF-acether and collagen. Aspirin at a dose used did not affect either bleeding time or platelet aggregability. Thus, in respiratory atopy there exists a moderate hemostatic imbalance, the reason of which remains to be established.

Adult↗

PubMed1989

Studies on the prolonged bleeding time in von Willebrand's disease.

Ten studies of the effect of cryoprecipitate infusion in four patients with von Willebrand's Disease (vWD) are reported. The doses studied (4, 8 and in one case 10 bags of cryoprecipitate) were based on previous reports of correction of the bleeding time (BT) with such doses. A modest shortening of the BT was observed in only 2 studies and complete correction of the BT at 1 and 4 hours was observed in only one study. This latter result could not be reproduced in a subsequent study of the same patient. In all cases, the von Willebrand factor antigen (vWF:Ag) multimer patterns were normal in the infused cryoprecipitate and in the recipients' plasma post infusion with the presence of high molecular weight multimers demonstrated in all samples. These results contradict earlier reports of the effect on the BT of similar doses of cryoprecipitate and suggest that the presence of the high molecular weight forms of vWF:Ag does not necessarily correlate with the presence of the factor which corrects the bleeding time.

Adult↗

PubMed1984

Alteration and recovery of bleeding times, platelet aggregation and fatty acid composition of individual phospholipids in platelets of human subjects receiving a supplement of cod-liver oil.

The effect of supplementation with cod-liver oil containing eicosapentaenoic acid (EPA), 20:5 omega 3, on bleeding times, thrombin-induced platelet aggregation, platelet protein, platelet cholesterol, and the level and fatty acid composition of individual phospholipids in the platelets of human subjects was determined. Measurement of these parameters was conducted before the subjects received the supplement (day 0), after they received the supplement for 14 days (day 14), and 14 days after the supplement was terminated (day 28) so as to monitor recovery. The mean bleeding times exhibited a marked increase (by 81%) with supplementation and returned to near basal (day 0) values within 14 days after the supplement was terminated. Cod-liver oil supplementation significantly reduced thrombin-induced platelet aggregation with a partial recovery being exhibited by day 28. The content of phospholipid, cholesterol and protein (microgram/10(9) platelets) was not significantly different (P greater than 0.05) when isolated from the subjects at day 0, 14 and 28, as neither were the composition of individual phospholipids [phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI) and sphingomyelin (SPH)] given as % of total phospholipid. However, the fatty acid compositions of all platelet phospholipids were altered significantly by the fish oil supplement. In PC, EPA rose from 0.3 to 2.9% of total fatty acids and docosahexaenoate from 0.7 to 1.8% concomitant with a drop in arachidonate (from 14.1 to 9.6%) and linoleate (from 10.2 to 7.9%); these levels approached basal levels 14 days after supplementation was terminated.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1976

[A comparison of different methods of measuring bleeding time (author's transl)].

Two methods of determining bleeding time (Ivy's and Duke's) were compared using a standardized method. Skin cuts were made with either a disposable scalpel or a precision plunger. Ivy's method gave results which were markedly superior to those with Duke's. It was, furthermore, shown that reproducibility of two successive determinations in the same person largely depended on the experience of the investigator. Best results were obtained using the precision plunger and automatic collection of blood. But even when these were used, there were frequent deviations of more than 20% in duplicate samples.

Blood Coagulation Tests↗

PubMedDate not supplied

Extracorporeal circulation in sheep with normal bleeding time using a surface heparinized circuit.

Bleeding due to systemic heparinization represents the major side effect of extracorporeal respiratory support. In the present animal study, a surface heparinized system (Carmeda Biological Active Surface) was applied to assess the feasibility of prolonged perfusion at low circulating heparin levels. Eight sheep divided into two groups: group A (5 animals) and group B (3 animals) underwent venovenous bypass using a heparin coated surface circuit. The following protocol was used: a) 24 hours at high heparin dose (30 to 100 U/kg/hr with an ACT [activated coagulation time] three to four times normal); b) 24 hours at low heparin dose (3 to 8 U/kg/hr with an ACT within the normal range); c) 24 hours at high heparin dose. Group B animals also received fresh frozen sheep plasma (14 ml/kg/day). During Period b, the clotting times were within baseline range. The bleeding time showed a dramatic decrease after change from a to b (27.9 +/- 3 minutes vs. 10.2 +/- 5.6 minutes). There was a negative relationship between antithrombin III (AT III) and thrombin coagulase time (TC); the latter is considered to be an aspecific indicator of circulating fibrin(ogen) degradation products. Maintaining AT III over 70%, TC changes were only minor. The use of the bioactive heparin surface allowed the performance of a 24 hour bypass, with normal coagulation times, at low circulating heparin levels.

Animals↗

PubMed1987

Effects of low doses of aspirin, 10 mg and 30 mg daily, on bleeding time, thromboxane production and 6-keto-PGF1 alpha excretion in healthy subjects.

To compare the long term effects of two low doses of aspirin taken daily, we performed a placebo-controlled cross-over study in 19 normal subjects. Aspirin 10 mg daily for 3 weeks caused a significant inhibition by 61 +/- 12 percent of platelet thromboxane B2 generation but had no effect on the Simplate bleeding time. Aspirin 30 mg daily for 3 weeks reduced thromboxane B2 production by 94 +/- 5 percent and caused a significant prolongation of the bleeding time, 1.6 times the control value. No cumulative inhibitory effects were observed after the first week of treatment. Both doses did not effect the urinary excretion of 6-keto-PGF1 alpha.

6-Ketoprostaglandin F1 alpha↗

PubMed1988

Plasma collagen cofactor correlates with von Willebrand factor antigen and ristocetin cofactor but not with bleeding time.

Collagen cofactor (CCo), an activity of von Willebrand factor (vWF) which increases the rate of adhesion of human fixed washed platelets (FWP) to collagen, was measured in plasma from normal individuals and individuals with von Willebrand's disease (vWD). CCo in vWD plasma was compared to vWF antigen (vWF:Ag), ristocetin cofactor (RCo), factor VIII (VIII) coagulant activity (VIII:C) and the quantitative bleeding time. There was close correlation between CCo and VIII:C (r = 0.909), vWF:Ag (r = 0.975), and RCo (r = 0.936). However, there was no correlation between CCo and the quantitative bleeding time. Plasma CCo in type IIA vWD was markedly lower than vWF:Ag and the ratio of CCo/vWF:Ag was 0.08, which was less than a mean value of 0.92 in type I vWD. CCo activity in normal plasma was completely inhibited by monoclonal antibody CLB-RAg 201, an antibody that inhibits the binding of vWF to collagen, suggesting that the binding of vWF to collagen is required for the expression of CCo. Furthermore, the partial inhibition of CCo by monoclonal antibody CLB-RAg 35 that inhibits the binding of vWF to platelet in the presence of ristocetin, suggests that CCo is partly mediated through platelet membrane glycoprotein Ib. Large multimers of vWF:Ag in normal plasma were preferentially absorbed by collagen. These studies demonstrate that CCo is another functional activity of vWF and the measurement of CCo may be useful for the detection of new variant forms of vWD.

Antibodies, Monoclonal↗

PubMed1984

The long-term effect of dietary supplementation with fish lipid concentrate on serum lipids, bleeding time, platelets and angina.

The effect of a fish lipid concentrate rich in eicosapentaenoic acid was studied in 107 subjects for periods up to 2 years. Ninety-two had heart disease or hyper-lipidaemia and 15 had no history of heart disease. Serum triglyceride levels were rapidly reduced, cholesterol fell more slowly but high density lipoprotein (HDL) cholesterol was increased. Bleeding time increased significantly and the consumption of glyceryl trinitrate (GTN) tablets decreased together with a reduction in anginal attacks. The data are consistent with a reduction in hepatic triglyceride synthesis rather than an increased rate of triglyceride clearance. Total and HDL cholesterol changes are suggestive of an enhanced removal of cholesterol from the tissues. Increased bleeding time and changes in GTN consumption are consistent with decreased platelet aggregation.

Adult↗

PubMed1995

Ehlers-Danlos syndrome, type VIII presenting with periodontitis and prolonged bleeding time.

We report on a case of Ehlers-Danlos syndrome, probable type VIII (EDS VIII) in a 6-year-old girl with severe periodontitis, extensive bruising of the shins, abnormal bleeding time, and thin body habitus. The structure and biosynthesis of types I and III colagen were normal. Desmopressin (DDAVP) was found to correct the bleeding time, and the patient underwent an uneventful dental procedure after DDAVP therapy. The finding of childhood or juvenile periodontitis should prompt consideration of a diagnosis of EDS, particularly type VIII, and alert the clinician to the possibility of a treatable bleeding abnormality.

Blood Coagulation Disorders↗

PubMed1996

Vascular thromboxane formation in hemostasis mechanism: correlation between bleeding time and vascular TXB2 in a patient with congenital platelet cyclo-oxygenase deficiency.

We encountered a patient with congenital platelet cyclo-oxygenase deficiency with normal ability to synthesize vascular prostaglandin I2 (PGI2) and thromboxane A2 (TXA2). The patient's peripheral blood monocytes did not show cyclo-oxygenase (COX) activity, but cultured bone marrow fibroblasts showed COX activity. To determine the mechanism of primary hemostasis in this patient, we examined the effect of oral administration of aspirin (1 g) on bleeding time and thromboxane B2 (TXB2), 6-keto prostaglandin F1 alpha (6-keto-PGF1 alpha) production in the blood emerging from the incision in this patient. The bleeding time was markedly prolonged by the administration of aspirin, and this prolongation was associated with the inhibition of TXB2 in the effluent blood, which seemed to be derived from the vessel wall. These findings suggest that vascular TXA2 production plays an important role in the maintenance of hemostasis.

6-Ketoprostaglandin F1 alpha↗

PubMed1996

Effect of ketorolac on bleeding time and postoperative pain in children: a double-blind, placebo-controlled comparison with meperidine.

STUDY OBJECTIVE: To determine whether ketorolac 0.75 mg/kg would provide a comparable degree of analgesia to that of meperidine 1 mg/kg in terms of postoperative opioid requirements and pain scores in children undergoing surgeries associated with mild to moderate postsurgical discomfort. DESIGN: Randomized, prospective, placebo-controlled, double-blinded study of the initial 6 postsurgical hours. SETTING: University affiliated teaching hospital. PATIENTS: 90 healthy ASA status I and II children scheduled for elective general, orthopedic, or genitourinary procedures associated with mild to moderate postsurgical pain. Extensive surgical procedures associated with a significant risk of bleeding were excluded. INTERVENTIONS: Ketorolac 0.75 mg/kg, meperidine 1 mg/kg, or placebo (normal saline) was administered intramuscularly (IM) at the beginning of surgery. MEASUREMENTS AND MAIN RESULTS: Bleeding times were measured prior to and 180 minutes after study drug administration. Time to first rescue medication, total opioid requirement, pain scores, incidence of vomiting and length of stay were evaluated. Placebo-treated patients were rescued earlier (p < 0.0001) and required twice the rescue dosage (p = 0.013) when compared with either the ketorolac or meperidine groups. The ketorolac and meperidine groups did not differ with regard to time until first rescue, cumulative proportion requiring rescue, or the number of rescue doses required. A single dose of IM ketorolac prolonged bleeding time by 53 +/- 75 seconds (p = 0.006). CONCLUSIONS: Ketorolac provided analgesia comparable to that of meperidine and significantly reduced opioid requirements. Since ketorolac was not associated with a reduction in postoperative vomiting or length of stay, and in view of the uncertain risk of bleeding, it offers no advantage over meperidine in the management of mild to moderate acute postsurgical pain.

Analgesics, Non-Narcotic↗

PubMed1989

The effect of continuous intravenous indomethacin infusion on bleeding time and postoperative pain in patients undergoing emergency surgery of the lower extremities.

Fifty-four orthopaedic patients were given either indomethacin (25-50 mg bolus plus infusion, 5-7.5 mg h-1) or only lactated Ringer solution intravenously over 20 h in a randomized and double-blind fashion. The study was started at the casualty department as soon as possible after the decision to operate was made. The patients were given a spinal block with bupivacaine, and the evaluation included postoperative analgesia and IVY bleeding times. Indomethacin plasma concentrations were measured and found to be at a therapeutic level throughout the study. The oxycodone dose (mean +/- s.d.) during the postoperative observation was lower in the indomethacin group (17.4 +/- 13.7 mg) than in the control group (25.6 +/- 15.6 mg) (P = 0.05). Fewer patients in the indomethacin group needed oxycodone more than once during the follow-up period (P less than 0.001). The mean IVY bleeding time was prolonged in the indomethacin group after 20 h of infusion (P less than 0.05). No abnormal bleeding was observed immediately postoperatively. However, at the end of the infusion there were more patients who bled through their bandages and casts in the indomethacin group (4/28 vs. 1/26).

Adult↗

PubMed1998

The bleeding time in pediatrics.

When performed with standardized methods and techniques, the bleeding time (BT) depends on variables that physiologically alter primary hemostasis. These variables include number of platelets and platelet function, white and red blood cell counts, vascular factors, hormones, and temperature. Variations within normal limits reflect the in vivo situation and are of no clinical relevance. If the BT is prolonged far above the upper normal limit, however, defects of primary hemostasis have to be anticipated. These include thrombocytopenia or thrombocytopathy, anemia, leukopenia, and deficiencies of plasmatic factors such as von Willebrand factor (vWF), fibrinogen, the lupus anticoagulant, and factor V. The BT can be used as screening test for patients with bleeding symptoms. As a single test, the BT gives the best information in pediatrics, in which defects of primary hemostasis are more common than coagulopathies. In addition, BT can guide the therapy of these patients, because it reflects clinical improvement. When used as a preoperative screening test, BT should be combined with the activated partial thromboplastin time (aPTT) because BT usually does not recognize patients with coagulopathies. With standardized techniques and the knowledge of its merits and limitations, BT is a useful test for diagnosing hemostatic disorders, guiding their therapy, and warning of unexpected bleeding complications during surgery. The BT is especially suited for use in pediatrics for the following reasons: (1) It does not require a venipuncture and is similar to capillary blood sampling if performed with standardized devices adapted for pediatric use; (2) it is an in vivo test informing mostly on defects of primary hemostasis, which are the most common bleeding diatheses in childhood; (3) the results are immediately available; (4) it requires only minimal amounts of blood; and (5) it does not require unphysiological reagents and preparation of the sample. The test requires a highly motivated and experienced operator who knows of the many variables influencing the BT. The interpretation cannot be done without knowledge of the history and physical status of the patient and of the limitations of the BT.

Bleeding Time↗