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Effects of intravenous high doses of ketoprofen on blood clotting, bleeding time and platelet aggregation in man.

The effect of ketoprofen (Orudis, Farmitalia) on ADP, epinephrine (EPI) and collagen (COLL) induced platelet aggregation (PlA), simplate bleeding time (SBT), partial thromboplastin time (PTT) and per cent prothrombin activity (PrA) was studied in eleven patients, four males and seven females (median age 59 years) with rheumatoid arthritis (six cases), cancer (four cases) and osteoarthrosis (one case). Tests were performed before and 1, 8 and 24 hours after a single intravenous dose (600 mg) of ketoprofen and on Days 4 and 8 during a 7-day treatment (200 mg i.v. every 8 hours) and 1 day after withdrawal of the drug. PTT and PrA were not affected by the drug. Bleeding time was not significantly modified by the acute treatment, but was prolonged during the subacute course, though it was not different from baseline values at the end of the trial. Significant reduction of platelet aggregation was seen in both acute and subacute conditions with complete or almost complete recovery 36 hours after the last dose. It is concluded that ketoprofen affects platelets with readily reversible inhibition of in vitro aggregation and a slight increase of bleeding time.

Aged↗

Prolonged bleeding times after aspirin ingestion in patients with aspirin idiosyncrasy.

Measurements of the bleeding time after the ingestion of small doses of aspirin in patients with aspirin idiosyncrasy demonstrate a marked prolongation compared with control patients. Confirmation of this finding offers a clue to the pathogenesis of this condition. Despite the prolonged bleeding time, gastrointestinal haemorrhage is an uncommon event in patients with aspirin idiosyncrasy.

Adult↗

Effect of magnesium infusion on bleeding time in healthy male volunteers.

Intravenous magnesium has proved to be valuable in the treatment of cardiac arrhythmias and eclampsia, but the specific mode of action is not established. In this study the effect of magnesium sulphate (MgSO4) infusion on bleeding time and endogenous prostacyclin (PGI2) production in healthy male volunteers was investigated. Thirty-five males (age 18-30 years) randomized in a double-blind, placebo-controlled, cross-over study were investigated. MgSO4 was given as a bolus (8 mmol, 12 min) followed by continuous infusion (8 mmol in 108 ml saline, 120 min). Control was equal volumes of physiological saline. Heart rate, blood pressure and bleeding time (according to Ivy) were recorded as well as blood concentrations of magnesium and creatinine. Urine PGI2 was analysed as the stable metabolite 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha). Treatment with MgSO4 did not affect bleeding time (MgSO4; 8.4+/-3.5 vs. control 8.0+/-2.7 min) nor the production of PGI2 (MgSO4; 1.2 microg 6-keto-PGF1alpha/g creatinine vs. control; 1.1 microg 6-keto-PGF1alpha/g creatinine). Intravenous infusion of MgSO4 does not affect the PGI2/platelet axis in healthy male volunteers. Studies in patients with endothelium dysfunction and/or concomitant drug therapy are required before the anti-thrombogenic effect of MgSO4 in vivo is discarded.

6-Ketoprostaglandin F1 alpha↗

Nonpeptide glycoprotein IIb/IIIa inhibitors. 15. Antithrombotic efficacy of L-738,167, a long-acting GPIIb/IIIa antagonist, correlates with inhibition of adenosine diphosphate-induced platelet aggregation but not with bleeding time prolongation.

The nonpeptide platelet glycoprotein IIb/IIIa antagonist, L-738, 167, was characterized in dog and nonhuman primate. In an anesthetized canine model of coronary artery electrolytic lesion, L-738,167 elicited dose-dependent (3, 4, 4.5 and 5 micrograms/kg i.v.) decreases in incidence of occlusion, reductions in thrombus mass and elevations in bleeding time. Antithrombotic efficacy correlated with inhibition of adenosine diphosphate-induced platelet aggregation but was dissociated from marked bleeding time elevation. Similarly, suppression of platelet-dependent cyclic flow reductions with L-738,167 in the canine coronary artery (5 micrograms/kg i.v.) and African green monkey carotid artery (10 micrograms/kg i.v.) correlated with inhibition of adenosine diphosphate-induced platelet aggregation but not with inhibition of thrombin-induced platelet aggregation or significant prolongation of bleeding time. In conscious dogs and sedated chimpanzees, single dose intravenous bolus (5-20 micrograms/kg) and oral (25-200 micrograms/kg) administration of L-738,167 exhibited long duration (> or = 8 hr) inhibition of ex vivo platelet aggregation. Once daily oral administration to conscious dogs (10-30 micrograms/kg/day for 15 days) and rhesus monkeys (200-250 micrograms/kg/day for 11 days) maintained significant but submaximal (50-90% inhibition) trough levels of inhibition of adenosine diphosphate-induced ex vivo platelet aggregation. Platelet sensitivity to adenosine diphosphate after multiple days of oral dosing in dogs was similar to pretreatment sensitivity. L-738,167 showed characteristics suitable for chronic oral therapy with a glycoprotein IIb/IIIa inhibitor.

Adenosine Diphosphate↗

[Effect of Polfos on bleeding time. I. Changes in the formed elements of the blood in rats exposed to Polfos].

The influence of Polfos and its metabolite, 2,4 dichlorophenacyl bromide, on the bleeding time, count of platelets, platelets aggregation, count of erythrocytes, level of haemoglobin and count of leucocytes in rats were studied. The data indicate that Polfos prolonged the bleeding time in the 2nd hour after its administration. A decrease of the platelets count was observed only in the initial phase of the intoxication. In the study the platelets count, red cells count, hematocrit and the level of haemoglobin increased 24 hours after the administration of the pesticide. The results demonstrate that the prolongation of the bleeding time in the rats after the administration of Polfos partly depends on the changing of the platelets count.

Animals↗

The bleeding time is inversely related to megakaryocyte nuclear DNA content and size in man.

The relation between the bleeding time and the megakaryocyte nuclear DNA content and size was evaluated in eleven consecutive patients with normal steady state thrombopoiesis undergoing thoracotomy. A statistically significant inverse correlation was found between the bleeding time and both megakaryocyte DNA content (r = -0.71, p less than 0.05), megakaryocyte total size (r = -0.58, p less than 0.05), megakaryocyte cytoplasmic size (r = -0.64, p less than 0.05) and megakaryocyte nuclear size (r = -0.58, p less than 0.05). The megakaryocyte total size and the megakaryocyte cytoplasmic size were statistically significantly larger in men than women (p less than 0.02 and p less than 0.03 respectively). Changes in the megakaryocytes in the bone marrow are associated with changes in primary haemostasis in normal individuals.

Adult↗

Altered bleeding time associated with ibuprofen and zidovudine use.

The purpose of this article is to describe a patient who was HIV-positive, had a massive venous ulcer, and developed a prolonged bleeding time with marked blood loss from the ulcer. The patient underwent a workup to rule out possible causes for this prolonged bleeding time; all studies were negative. A review of his history identified that he was self-medicating with ibuprofen while taking zidovudine. A potentiated effect of these two medications on the bleeding time has been reported in the literature. This case illustrates the importance of revisiting a patient's history while working up an acute problem as well as clinically monitoring for blood loss if a person takes ibuprofen and zidovudine.

Adult↗

Comparison of thromboelastography to bleeding time and standard coagulation tests in patients after cardiopulmonary bypass.

This prospective study of 36 adult patients undergoing cardiopulmonary bypass (CPB) was conducted to determine the utility of thromboelastography (TEG) versus platelet studies (bleeding time, platelet count, mean platelet volume) and standard coagulation tests (prothrombin time, activated partial thromboplastin time, fibrinogen) to more effectively discriminate patients likely to benefit from platelet or fresh frozen plasma (FFP) transfusion. Although the sensitivities of the bleeding time (71.4%) and platelet count (100%) were similar to the TEG (71.4%), the specificity (89.3%) of the TEG was greater than that of the bleeding time (78.5%) and platelet count (53.6%). Seven patients experienced clinically significant hemorrhage; 5 (71.4%) had an abnormal TEG. Three of 8 (38%) other patients with an abnormal TEG had no abnormal bleeding. Only 2 of 27 (7.4%) patients with a normal TEG had abnormal bleeding requiring platelet or FFP transfusion. Therefore, it is suggested that post-CPB patients with a normal TEG should not receive platelet or FFP transfusions empirically. If excessive bleeding is noted in a patient with a normal TEG, this suggests a surgically correctable etiology. Data from this series suggest that patients displaying an abnormal TEG appear to be at increased risk for hemorrhage; therefore, appropriate blood product support should be initiated at the first sign of accelerated bleeding.

Adolescent↗

Anemia-induced increase in the bleeding time: implications for treatment of nonsurgical blood loss.

BACKGROUND: Preoperative bleeding time (BT) does not correlate with postoperative bleeding in patients subjected to surgical procedures. A significant positive correlation has been reported between the BT 2 hours after cardiopulmonary bypass surgery and the nonsurgical blood loss during the first 4 hours after bypass surgery. This study was done to investigate the effect of Hct and platelet count on the BT measurement in normal, healthy men and women. STUDY DESIGN AND METHODS: To assess the relative effect of RBCs and platelets on the BT, 22 healthy male and 7 healthy female volunteers were subjected to the removal of 2 units of RBCs (360 mL), followed by the return of the platelet-rich plasma (PRP) from both units and the infusion of 1000 mL of 0.9-percent NaCl. Four of the men and all seven women received their RBCs 1 hour after their removal. Shed blood levels of thromboxane B(2) (TXB(2)), 6-keto prostaglandin F(1 alpha), and peripheral venous Hct were measured. BTs were measured in 15 men and 13 women before and after a plateletpheresis procedure to collect 3.6 x 10(11) platelets per unit. RESULTS: The 2-unit RBC apheresis procedure produced a 60-percent increase in the BT associated with a 15-percent reduction in the peripheral venous Hct and a 9-percent reduction in the platelet count. The plateletpheresis procedure produced a 32-percent decrease in the platelet count, no change in peripheral venous Hct, and no change in the BT. After the removal of 2 units of RBCs, the shed blood TXB(2) level decreased significantly. Reinfusion of 2 units of RBCs restored the BT and restored the TXB(2) level to the baseline levels. CONCLUSION: The acute reduction in Hct produced a reversible platelet dysfunction manifested by an increase in BT and a decrease in the shed blood TXB(2) level at the template BT site. Return of the RBCs restored both the BT and the shed blood TXB(2) level to normal. The platelet dysfunction observed with the reduction in Hct was due in part to a reduction in shed blood TXB(2) and other, unknown mechanisms.

Adult↗

A randomized and blinded comparison of three bleeding time techniques: the Ivy method, and the Simplate II method in two directions.

We compared the Ivy bleeding time method and two alternatives of the Simplate II method (incisions in horizontal and vertical direction) with each other, with regard to the sensitivity, the specificity, the costs and the burden for the patient. In the aspirin study an aspirin-induced bleeding defect was used. Seventy-two healthy volunteers were randomized to receive either 500 mg acetylsalicylic acid (ASA) or a placebo. Double blinding was maintained throughout the study. In the anticoagulation study 62 patients participated, who received oral anticoagulants (OAC) for various reasons. All participants received two bleeding time methods. The burden for the participants of each method was screened by a small standard questionnaire. The differences in sensitivity and specificity between the three methods proved minimal. The Ivy method was more often preferred by the participants than the Simplate methods. Since a choice on the basis of sensitivity and specificity appears not possible, we prefer the Ivy method because of lower costs and less burden.

Adult↗

Pharmacological characterization of N-tert-butyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea (BM-573), a novel thromboxane A2 receptor antagonist and thromboxane synthase inhibitor in a rat model of arterial thrombosis and its effects on bleeding time.

The present study was undertaken to characterize the antiplatelet and antithrombotic effects of BM-573 [N-tert-butyl-N'-[2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl]urea], an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor in rats, and to determine its effects on mice bleeding time. Intraperitoneal injection of a single dose of 5 mg/kg BM-573 to rats inhibited U-46619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F(2))-induced washed platelet aggregation 30 min and 1, 2, and 4 h after drug administration with a maximum antiplatelet effect observed after 1 and 2 h. In a rat model of thrombosis induced by ferric chloride application on the abdominal aorta, BM-573 significantly reduced the thrombus weight by 92.53, 80.20, 64.75, and 18.21% at doses of 5, 2, 0.5, and 0.2 mg/kg, respectively. Time to occlusion of abdominal aorta in the BM-573-treated group (41.50 +/- 5.21 min) was significantly prolonged compared with the vehicle-treated rats (16.16 +/- 0.79 min). Like furegrelate, seratrodast, and acetylsalicylic acid, BM-573 did not affect the tail bleeding time induced by tail transection in mice compared with vehicle-treated mice. Moreover, BM-573, a close derivative of the loop diuretic torasemide, failed to induce a significant increase in diuresis in rat and did not produce a decrease in blood glucose concentration as observed with the sulfonylurea glibenclamide. In conclusion, we have demonstrated that the nitrobenzenic sulfonylurea BM-573, an original combined thromboxane receptor antagonist and thromboxane synthase inhibitor, is a potent antithrombotic agent that does not affect bleeding time. Moreover, BM-573 lost the diuretic property of torasemide and has no impact on glycemia.

Animals↗

Shortening of bleeding time by 1-deamino-8-arginine vasopressin (DDAVP) in the absence of platelet von Willebrand factor in Gray platelet syndrome.

The Gray platelet syndrome is a rare disorder characterised by the absence of platelet alpha-granules and their contents. We describe a new patient and the effects of infusions of 1-deamino-8-arginine vasopressin (DDAVP). The patient had a prolonged skin bleeding time and his platelets had reduced numbers of alpha-granules, increased vacuolation and reduced retention on glass beads. Platelet von Willebrand factor antigen (vWf:Ag) was undetectable and levels of platelet fibrinogen, beta-thromboglobulin, platelet factor 4 and thrombospondin were reduced. All tests of plasma coagulation factors were normal, including Factor VIII (F.VIII:C), vWf:Ag, ristocetin cofactor (R:CoF) and botrocetin cofactor. Platelet ATP, ADP, platelet albumin, surface membrane glycoproteins and 14C-serotonin uptake were also normal. Infusions of DDAVP increased plasma F.VIII:C, vWf:Ag and R:CoF and shortened the bleeding time on two occasions. This suggests that DDAVP shortens the bleeding time by releasing vWf:Ag and/or other proteins from cellular storage sites other than the platelet.

Adult↗

Prolonged bleeding time and increased vascular prostacyclin in rats with chronic renal failure: effects of conjugated estrogens.

The aim of our study was to assess whether the development of chronic uremia in rats with extensive renal mass ablation was associated with an impairment of primary hemostasis as occurs in humans with terminal uremia. We also wanted to assess whether uremic rats had an increased generation of vascular prostacyclin (PGI2) and whether conjugated estrogens could influence such an abnormality. Our results showed that the development of chronic renal failure in rats was associated with a significant prolongation of bleeding time as reported in humans. Thoracic aorta and inferior vena cava specimens from uremic rats produced significantly more 6-keto-prostaglandin F1 alpha (the stable breakdown product of PGI2) than did specimens from the corresponding controls. Conjugated estrogens significantly shortened the bleeding time of uremic rats. The effect on bleeding time was detectable in the majority of animals within 4 hours from conjugated estrogen injection, reached its maximum at 24 hours, and returned to preinjection values within 72 hours from conjugated estrogen injection. Estrogen administration did not influence the generation of vascular PGI2. It is concluded that the model of extensive renal ablation in the rat is a suitable one to study changes in primary hemostasis in chronic renal failure and that the effect of estrogens on primary hemostasis in uremia is not mediated by changes in vascular PGI2.

Animals↗

Prolonged bleeding time with defective platelet filopodia formation in the Wistar Furth rat.

Hereditary macrothrombocytopenia is a hallmark of Wistar Furth (WF) rats. In addition, a platelet/megakaryocyte alpha granule defect, similar to that of patients with gray platelet syndrome, is present. Several observations indicate cytoskeletal abnormalities in WF platelets and megakaryocytes, suggesting the potential for functional defects in hemostatic processes requiring cytoskeletal reorganization, such as platelet adhesion and spreading. However, no bleeding abnormality has been noted. Here, we report a prolonged bleeding time (>30 minutes in 10 of 11 rats tested) with defective clot formation in the WF strain. Prolonged bleeding time can result from defects in platelet adhesion, aggregation, or the release reaction. Because aggregation to collagen and adenosine diphosphate were reported to be normal, we determined whether WF rat platelets are defective in their ability to adhere to substrates. Platelet adherence and spreading was evaluated from 30 seconds to 30 minutes on Formvar-coated, carbon-stabilized grids or poly-L-lysine-coated glass coverslips by transmission electron microscopy or immunofluorescence, respectively, and scanning electron microscopy. We classified the adhered platelets according to their pattern of spreading, ie, rounded, rounded or spreading with short filopodia, spindle-shaped, spreading with long filopodia, spreading with lamellipodia, and fully spread. Adherent normal rat platelets displayed all stages of spreading within 30 seconds to 2 minutes, including many spindle-shaped forms, and forms with multiple, long filopodia. In contrast, adhered WF platelets at these early time points rarely developed long filopodia or were spindle shaped. The majority of adherent WF platelets at these early time points were either round, spread with a few short filopodia, or extensively spread with wide lamellipodial skirts. By 15 to 30 minutes, most platelets in both Wistar and WF samples were fully spread. These data show abnormal WF platelet spreading. The paucity of spindle-shaped forms and forms with long filopodia may reflect an inability of WF platelets to undergo the early stages of spreading, or, alternatively, their more rapid than normal progression through these stages. We hypothesize that this failure to spread normally may relate to prolonged bleeding times in vivo and defective clot formation in WF rats.

Animals↗

Filter bleeding time: a new in vitro test of hemostasis. I. Evaluation in normal and thrombocytopenic subjects.

Disadvantages of current bleeding time methods include poor reproducibility, limited repeatability, and at times scar formation. We report a new, in vitro technique which circumvents these problems. Venous blood is collected in sodium citrate, stored capped in a siliconized tube at 37 degrees C until use, and made to flow under constant pressure through a filter of Woven Dacron. Flow rate progressively falls as platelet aggregates occlude the filter, as verified by scanning electron microscopy and 111Indium-labeled platelet radioactivity of the filter. Filter bleeding time (FBT) was 4.33 +/- 1.79 (means x +/- SD) min in 23 healthy human volunteers and 3.08 +/- 1.08 min in 14 normal dogs. Bleeding volume (BV) (number of drops) was 29 +/- 12 in the humans and 16 +/- 6 in the dogs. Initial bleeding rate (IBR) (number of drops during first minute) was 14 +/- 3 in citrated blood and 25 +/- 5 drops/min in EDTA blood of the humans (P = 9 X 10(-10)), 8 +/- 2 in citrated blood and 14 +/- 6 drops/min in EDTA blood of the dogs (P = .0004). Percent platelet reduction during passage of blood through the filter (PCR) was 27.5 +/- 7.2 in citrated blood and 4.9 +/- 2.6 in EDTA blood of the humans (P = 2 X 10(-12)), while in dogs it was 25.7 +/- 8.3 in citrated blood and 5.3 +/- 4.2 in EDTA blood (P = 8 X 10(-7)). The results of these parameters using human platelet rich plasmas (PRPs) were similar to those with human whole blood, but significant decrease of drop rate was not observed in canine PRPs during passage of PRP through the filter. FBT, BV, and IBR were correlated (r = -0.91, -0.84 and -0.62 respectively) with platelet count in 12 specimens obtained from 4 dogs in which thrombocytopenia (107 to 4 X 10(3) platelets/microliter) was induced by estradiol. This new test is unaffected by specimen transport by pneumatic tube, is sensitive to platelets, and should be useful for analysis of both quantitative and qualitative platelet abnormalities in man.

Animals↗

Effects of omega-3 and omega-6 fatty acid-rich oils on the cardiovascular system of thermally injured rabbits: changes in plasma triglycerides, plasma cholesterol, relative blood viscosity, platelet count, and bleeding time.

New Zealand white male rabbits were studied to determine how supplements of soybean oil, soybean + MaxEPA oil, or MaxEPA oil affected their cardiovascular status when they were burned. Plasma triglyceride concentrations increased at 2 hours after burn injury (28 days after supplement administration) and declined by the end of the study in all three experimental groups of rabbits. These same animals showed no noticeable differences in the plasma concentrations of total cholesterol or in the high-density lipoprotein cholesterol subfractions. Plasma low-density/very-low-density lipoprotein cholesterol levels remained unchanged at 2 hours after burn injury/sham treatment but increased by the end of the study in all three experimental groups of rabbits. The mean platelet number was significantly higher in burned/sham treated rabbits given soybean oil supplement as compared with numbers in those given either soybean oil + MaxEPA oil or MaxEPA oil supplement. Plasma relative viscosity was highest in the soybean oil-supplemented rabbits, decreased in animals fed soybean oil + MaxEPA, and lowest in MaxEPA oil-supplemented rabbits. Mean bleeding time was lowest in soybean oil-fed rabbits. The bleeding time was higher in rabbits fed soybean oil+MaxEPA oil and highest in MaxEPA oil-supplemented animals. Platelet number and plasma viscosity were highest in the soybean oil-supplemented rabbits and lowest in the MaxEPA oil-supplemented group. The reverse pattern occurred when bleeding time was established. Overall results obtained suggest that supplementation with oils rich in omega-3 and omega-6 fatty acids may have significant effects on the cardiovascular health of burned male New Zealand white rabbits.

Animals↗

Evidence for tissue factor-dependent activation of the classic extrinsic coagulation mechanism in blood obtained from bleeding time wounds.

The activation of platelets and the coagulation mechanism was studied by collecting blood from a standard bleeding time incision at 30-second intervals and measuring the plasma concentrations of fibrinopeptide A (FPA), platelet factor 4 (PF4), and thromboxane B2 (TxB2). FPA was observed in the first samples (30 to 60 seconds) obtained, increased progressively until cessation of bleeding, and was markedly diminished after heparin administration, thus indicating that thrombin formation occurs early in incisional blood. PF4 increased monotonically throughout blood sampling, whereas the major increase in TxB2 appeared near the cessation of bleeding. The initial increase in FPA content occurred normally in patients with deficiencies of either factor IX or VIII, was markedly diminished in patients with factor X or V deficiency, and was delayed in patients with factor VII deficiency. These studies suggest that tissue factor activation of the classic (activation of factor X) extrinsic coagulation mechanism occurs as an early event during the arrest of bleeding from bleeding time incisions. The relation of the aforementioned to platelet activation is less clear because there was no consistent correlation between decreased FPA formation and impaired PF4 secretion or TxB2 production. In fact, the latter were normal in some subjects with the most impaired FPA formation, which suggests that both collagen and thrombin, perhaps synergistically, may contribute to platelet activation during the primary arrest of bleeding.

Biomechanical Phenomena↗

DDAVP-induced correction of prolonged bleeding time in patients with congenital platelet function defects.

In 37 patients with prolonged bleeding time, where thrombocytopenia, von Willebrand's disease or deficiency of other coagulation factors could be excluded, we have evaluated the effect of a DDAVP-infusion (0.2 ug/kg) together with tranexamic acid (10 mg/kg). Patients with acquired impairment of primary hemostasis were not included, except two cases where this could have been a contributing factor. The bleeding time was completely normalized in 27 cases and partially corrected in three more patients. The predominant feature among those, who did not respond, was a pattern compatible with thrombasthenia or cyclooxygenase deficiency, as assessed by platelet aggregation studies. Among the patients, in whom DDAVP was effective, this drug was thereafter successfully used as an alternative to blood products in 8 cases during and after surgery or delivery.

Adolescent↗