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PubMed1999

Iopiperidol: nonionic iodinated contrast medium with promising anticoagulant and antiplatelet properties.

RATIONALE AND OBJECTIVES: The purpose of this study was to determine the anticoagulant and antiplatelet characteristics of iopiperidol, a nonionic, triiodinated contrast agent. MATERIALS AND METHODS: Anticoagulant effects of iopiperidol were assessed both in vitro and in vivo after single or repeated intravenous administrations to rats. To this aim, results of prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests were evaluated. To define better the mechanism of action of iopiperidol and of the contrast media used for comparison, in vitro tests to study the effects on thrombin activity and on thrombin generation were performed. In addition, the effect of iopiperidol was studied on adenosine diphosphate- and collagen-induced platelet aggregation both in vitro and in vivo after single or repeated intravenous administrations in the rat. RESULTS: In vitro, iopiperidol showed anticoagulant properties similar or superior to those of the ionic ioxaglate. Iopiperidol also inhibited collagen-induced platelet aggregation statistically significantly more than iodixanol and ioxaglate (P < .05). In vivo, no significant differences between iopiperidol and ioxaglate were observed after single or repeated administrations. CONCLUSION: The in vitro anticoagulant effect of iopiperidol is similar or even superior to that of ioxaglate; the in vivo effect is similar to that of reference nonionic contrast media.

Animals↗
PubMed1985

Heparin-enhanced inhibitors during reversible disseminated intravascular coagulation.

Intravenous injection of homologous lung or brain tissue thromboplastin in dogs under general anesthesia induced changes of conventional hemostasis variables consistent with acute DIC (prolongation of prothrombin times, thrombin times, APTT, drop of fibrinogen and a transient reduction of the platelet count). The animals reacted with accelerated respiration and pulse rates. After recovery from anesthesia they resumed their normal activity as before. Fibrinogen reached a minimum within 40 min after the DIC trigger dose had been injected. Dependent on the size of the latter up to 80% of clottable fibrinogen was consumed. No consumption of antithrombin III and heparin cofactor II could be demonstrated by functional assays based on thrombin inhibition by diluted plasma in the presence of heparin or dermatan sulfate. Prothrombin measured amidolytically by an Echis Carinatus venom assay remained practically unchanged. These findings are consistent with free thrombin concentrations in the nanomolar range sufficient to clot fibrinogen rapidly without visibly affecting the up to 1,000 fold higher concentrations of inhibitors and prothrombin. Heparin administered before tissue thromboplastin virtually suppressed the evolution of DIC but its protective effect was overcome by higher trigger doses. Heparin injected after the induction of DIC had no protective effect. The reversible DIC model in dogs may be a promising tool to study activated coagulation in vivo at practically constant inhibitor concentrations. One dog can be used for several acute experiments with homologous tissue thromboplastin, thus the number of animals and their costs may remain within reasonable limits.

Animals↗
PubMed1991

Potential thrombogenicity of heat-treated prothrombin complex concentrates in Haemophilia B.

We have studied the potential thrombogenicity of two different heat-treated prothrombin complex concentrates (PCC) in patients with Haemophilia B. Seven patients were studied on nine separate occasions. Four of the patients had chronic hepatitis C (HCV) associated liver disease and three were HIV-antibody positive. The PCCs were Profilnine (Alpha Therapeutics, Thetford, UK) and 9A (Bio-Products Laboratory, Elstree, UK) and the dose administered ranged from 35 to 60 U/kg. Blood samples were taken on ten separate occasions; twice before the infusion and at 15, 40, 60, 75 and 120 min and 4, 8 and 24 h after the infusion of PCC. Investigations included prothrombin time, kaolin cephalin clotting time, thrombin time, fibrin(ogen) degradation products, factor VIII, factor IX, antithrombin III and fibrinopeptide A (FPA). Fibrinopeptide A rises were seen following two of six infusions of 9A and one of three infusions of Profilnine. On all three occasions the rise in FPA was transient, returning to baseline levels within 120 min. Plasma beta-thromboglobulin (BTG) was assayed in three patients and in one patient, the rise in FPA was followed by an increase in BTG. No other changes were observed and there were no clinical features of disseminated intravascular coagulation. Our results indicate that even with normal clinical doses of PCC, intravascular thrombin generation can occur in patients with Haemophilia B. However, this effect is inconsistent both with respect to PCC batch and patient, but may occur in the absence of HIV infection and HCV liver disease.

Blood Coagulation↗
PubMed1998

Study of haemostasis in depressive patients treated with fluoxetine.

The object of this study was to investigate a possible pharmacological effect of fluoxetine on haemostatic function, with special attention on primary haemostasis, in order to explain haemorrhagic complications reported in some treated, depressed patients. The haemostatic function of depressive patients, who required fluoxetine therapy, was studied before and after 1 month of treatment with fluoxetine 20 or 40 mg daily. Exclusion criteria were: pregnancy, initial abnormal haemostatic function, history of coagulation abnormalities, treatment with drugs that interfere with haemostasis, and recent fluoxetine therapy. The following tests were performed: prothrombin time, partial thromboplastin time, thrombin time, plasma fibrinogen, platelet counts, bleeding time, platelet aggregation induced by ADP, epinephrine, ristocetin, collagen, arachidonic acid, and plasma determination of fluoxetine and norfluoxetine levels. Statistical analysis was performed by Wilcoxon paired sample, one-tailed test (alpha=0.05). Among 18 patients included, only eight completed the trial. The single statistically significant difference was a decreased velocity in platelet aggregation induced by epinephrine without increased bleeding time. The results failed to demonstrate any compromised haemostatic function after 20 mg daily fluoxetine therapy in patients with initial haemostatic function. However, the results suggest possible effects of fluoxetine on platelet adrenoreceptors.

Journal Article↗
PubMed1990

Poly(dimethylsiloxane)-poly(ethylene oxide)-heparin block copolymers. II: Surface characterization and in vitro assessments.

Amphiphilic block copolymers containing poly(dimethylsiloxane), poly(ethylene oxide), as well as heparin-coated glass beads and tubes were evaluated for the amounts and activities of surface-immobilized heparin. Because the amphiphilic copolymer system is thermodynamically predicted to demonstrate low-energy phase enrichment on the surfaces of air-cast films, studies were also undertaken to understand the in vitro results. Solvent-cast copolymer films have a heterogeneous microphase-separated structure according to transmission electron micrographs. Wilhelmy plate contact angle analysis indicates significant surface restructuring occurs upon hydration. Attenuated total reflectance infrared spectroscopy studies of the desiccated and hydrated films at two different sampling depths show compositional heterogeneity as a function of depth, as well as near surface restructuring allowing surface enrichment of the high-energy segments following contact with water. Significant concentrations of heparin are detected on the surface of these coatings by toluidine blue assays. In addition, a portion of the surface-bound heparin maintains its original bioactivity as determined by recalcification times, thrombin times, and Factor Xa assays. These substrates were also tested for platelet adhesion and activation reactions in vitro using polymer-coated beads in rabbit platelet-rich plasma. Heparinized polymers promoted low levels of platelet adhesion and serotonin release. Surface concentrations of heparin from bioactivity assays were then correlated with platelet adhesion and the extent of platelet release to assess the efficacy of this heparin-immobilized copolymer as a blood-compatible material or coating.

Animals↗
PubMed1976

Blood coagulation studies during six day heparinless venoarterial bypass in sheep.

Heparinless venoarterial bypass (HL-VAB) was carried out in 16 sheep for 6 days, by means of a closed circuit tubing coated with nonthrombogenic polyurethane-polyvinyl-graphite (PPG) and a roller pump. Nine experiments were completed uneventfully. Seven sheep died during bypass. The causes of death were pneumonia (2), caseous granulomatous lung abscess (3) or abdominal abscess (1), and thromboembolism (1). The last complication was caused by inadverten trauma to the PPG coating at the time of tubing connection. In the animals in which HL-VAB was uneventful, no significant changes were noted in the hematologic studies including white blood counts, platelet counts, hematocrit, plasma fibrinogen levels, prothrombin time, thrombin time, activated partial thromboplastin time, Factors V and VIII, and free plasma hemoglobin levels. Inconsistant changes in the above parmeters were noted in the animals which died of complications. In conclusion, prolonged HL-VAB has no adverse effects on blood coagulation mechanism.

Animals↗
PubMed1981

The influence of haemoperfusion on haemostasis and cellular constituents of the blood in the treatment of intoxications: a comparative study of three types of columns (Haemocol, Amberlite XAD-4, Gambro Adsorba 300 C).

The influence of haemoperfusion on blood-coagulation and cellular constituents of the blood was studied in three groups of patients. In four patients haemoperfusion was performed using a column containing acrylic-hydrogel coated activated charcoal (Haemocol), in five patients with a column containing uncoated XAD-4 nonionic polystyrene resin (Amberlite) and in five patients with a column containing cellulose coated activated charcoal (Gambro Adsorba 300 C). Perfusion was performed during 4 h with a flow of 300 ml/min. Before the start, 2 h after the start, at the end and 2 h after the end of the perfusion the haemoglobin concentration, haematocrit, leucocyte number, differential white cell count, thrombocyte number and heparin concentration were measured. Before the start and 2 h after the end prothrombin time, thrombin time, partial thromboplastin time, reptilase time, fibrinogen, prothrombin, factors V, VII, X, antithrombin III, bleeding time (Ivy), ethanol gelation test, fibrin split products and plasminogen were measured. The following conclusions can be drawn: haemoperfusion per se causes haemodilution; polystyrene resin causes in some patients a temporary reduction of the leucocyte number during haemoperfusion; polystyrene resin causes a significant reduction of thrombocyte number compared to coated activated charcoal; polystyrene resin and to a lesser extent acrylic-hydrogel-coated activated charcoal causes in some patients a prolongation of bleeding time probably by inducing alteration of thrombocyte function caused by release; polystyrene resin and probably also acrylic-hydrogel-coated activated charcoal causes an increased fibrinolytic activity without signs of disseminated intravascular coagulation.

Adult↗
PubMed1979

Coagulation abnormalities in diabetic coma before and 24 hours after treatment.

A coagulation screen consisting of measurement of the prothrombin time, thrombin time, kaolin caphalin clotting time, platelet count, plasma fibrinogen level, fibrin degradation products and ethanol gelation test was performed on 24 patients with impairment of consciousness due to acute diabetic metabolic decompensation at the start of treatment and 24 hours later. 22 out of 24 patients showed at least one coagulation abnormality on admission of which the commonest were a prolonged prothrombin time, shortened kaolin cephalin clotting.time and raised plasma fibrinogen level. After 24 hours of treatment these values were more normal but 20 out of 22 patients still displayed some abnormality. 15 patients had two or more coagulation abnormalities on admission including 3 patients with haematological abnormalities suggestive of disseminated intravascular coagulation. This group was older and had higher blood ureas than those with fewer abnormalities, but plasma glucose, sodium, potassium and bicarbonate levels were similar in both groups of patients. All 5 patients with hyperosmolar non-ketotic coma and all 3 patients who died without recovering consciousness had two or more coagulation abnormalities on admission.

Adolescent↗
PubMed1986

[Monitoring drug therapy in venous thrombosis].

Minimal prerequisites for the follow-up of thrombolytic therapies are determinations of partial thromboplastin time, thrombin time and fibrinogen concentration. With help of these tests it is possible to lower the risk of rethromboses and haemorrhages. By including additional tests some patients may benefit in respect of safety and better knowledge of the underlying mechanisms. However, until now there exists no laboratory tests that is able to give information about success or failure of the therapy independent of phlebography. For the gentechnological products like tPA and prourokinase final conclusions can be drawn only after having established dose-response curves for patients suffering from thromboses.

Fibrinolytic Agents↗
PubMed1985

Tolerance in patients with terminal renal insufficiency of high doses of cefotaxime.

Eleven patients with terminal renal insufficiency requiring dialysis were treated with 3 X 2 g cefotaxime in an open study lasting five days when the clinical findings strongly indicated a serious bacterial infection. The effect of the administration of the high-dose antibiotic on the coagulation system (Quick test, partial thromboplastin time, thrombin time, antithrombin III and platelets) and on brain function (EEG) was investigated. The serum levels showed that the serum concentrations were not abnormally high in cases of terminal renal insufficiency requiring dialysis. In contrast to previous investigations in other beta-lactam antibiotics, no changes in the coagulation system or EEG occurred. On the basis of these findings, no reduction in the dose appears necessary for cefotaxime, if therapy does not exceed five days.

Adult↗
PubMed1991

Effect of heparin and prostacyclin-heparin infusion on blood coagulation in haemodialysed patients.

In 10 patients (8 men and 2 women) aged 28 to 58 years (mean 44.4 years) treated by repeated haemodialysis due to end-stage renal failure, the bleeding time, whole-blood coagulation time, one-stage prothrombin time, thrombin time of plasma, activated partial thromboplastin time (APTT), fibrinogen level and euglobulin lysis time have been determined (1) during a 4-hour haemodialysis using heparin as an antithrombotic agent, and (2) one week later in the course of another haemodialysis using prostacyclin-heparin. The values for any of the above parameters with both anticoagulant treatment types did not differ. Plasma fibrinogen level after haemodialysis was significantly lower after administration of heparin alone as compared with the group treated by prostacyclin-heparin infusion. During haemodialysis performed with prostacyclin-heparin infusion, activation of the blood fibrinolytic system was manifested by a significant shortening of euglobulin lysis time, observed after 1.5 hours and after the end of haemodialysis. The above phenomenon did not occur when haemodialysis was performed with heparin alone.

Adult↗
PubMed1997

[Surgery in patients treated with anticoagulation during emergency and elective interventions].

Patients under oral anticoagulation with coumarin derivatives have a variable perioperative thromboembolic risk which necessitates continuation of their thromboembolic prophylaxis during elective and emergency surgery. Because of their better handling unfractionated heparin and low-molecular-weight heparins are used most often for this purpose. The overlapping effect of coumarin and heparin therapy requires a close daily monitoring of the clotting inhibition (partial thromboplastin time, thromboplastin time, thrombin time). In elective surgery coumarin therapy is interrupted 2-3 days preoperatively; in emergency cases vitamin K or fresh frozen plasma have to be substituted. Patients under heparin therapy or prophylaxis are easier to handle, because the effect of heparin disappears in a few hours after stopping the treatment. In the immediate postoperative phase the heparin application is interrupted for 6 h because of increased bleeding risk. It is important to take into account additional risk factors like the underlying disease, disturbances of platelet function, liver diseases and renal insufficiency.

Anticoagulants↗
PubMed1977

Progestational agents and blood coagulation. VIII. Effect of low-dose, alternate-day, estrogen-progestin combinations on blood coagulation factors in man, with a special note on the effect of freezing of blood samples.

Changes in the blood coagulation system were studied in three groups of 20 patients each. The first group received 0.5 mg. of norethindrone daily, plus 0.06 mg. of ethinyl estradiol on alternate days from cycle Day 5 through 25. The second group, all of whom had been fitted with an intrauterine contraceptive device (IUD), received no hormonal treatment and served as a control group. The third group received 0.5 mg. of norethindrone daily, combined with 0.045 mg. of ethinyl estradiol given on alternate days from cycle Day 5 through 25. Blood samples were drawn prior to the initiation of the study and after three months of treatment. Tests of the following parameters of the blood coagulation system were performed: direct platelet count; platelet adhesiveness; prothrombin time; thrombin time; fibrinogen; factor II assay; activity of factors V, VII, VIII, IX, and X; antithrombin III; and fibrin/fibrinogen degradation products. For a number of these factors, both fresh and frozen blood samples were examined. It was concluded that the two treatment regimens, with the use of alternate-day estrogen administration over a three-month period, had no clinically significant effect on the blood coagulation system.

Adolescent↗
PubMed1994

Predictive value of blood clotting tests in cardiac surgical patients.

This study prospectively evaluated numerous tests of clotting function in 897 consecutive adult cardiac surgical patients over 18 months. This included coronary operation, valve replacement, and reoperative patients. The tests included activated clotting time, activated partial thromboplastin time, prothrombin time, thrombin time, fibrinogen, fibrin/fibrinogen degradation products, platelet count, and Duke's earlobe bleeding time. Other variables such as age, sex, and cardiopulmonary bypass duration were included in the multivariate analysis. Statistically significant correlations were found between 16-hour mediastinal drainage and activated partial thromboplastin time, fibrinogen, activated clotting time, fibrin/fibrinogen degradation products, platelet count, and prothrombin time. Scatter plots indicate that these relationships, although statistically significant, had little predictive value and were largely significant as a result of the large number of patients in each group, which permitted weak correlations to reach statistical significance. The best multivariate model constructed could explain only 12% of the observed variation in postoperative blood loss. Because the predictive values of the tests are so low, it does not appear sensible to screen patients routinely using these clotting tests shortly after cardiopulmonary bypass.

Adult↗
PubMed1984

Effect of levonorgestrel contraceptive implants, Norplant, on blood coagulation.

A longitudinal study of coagulation parameters was carried out on 47 women using the levonorgestrel subdermal implants, NORPLANT. The study comprised measurement of platelet count, prothrombin time, thrombin time, partial thromboplastin time with kaolin, clotting factors I, II, V and VI through XIII, plasminogen, antithrombin III (AT III), alpha 1 antitrypsin, alpha 2 macroglobulin and fibrinogen degradation products. The tests were done at admission and after one, three and six months of NORPLANT use. Parallel and similar studies were done on two groups of oral contraceptive users; the first group used a pill containing 1 mg norethisterone and 50 micrograms mestranol, and the second a pill consisting of 150 micrograms levonorgestrel and 30 micrograms ethinylestradiol. Results from this ongoing study have indicated that women using NORPLANT implants evidenced lack of effects on most of the parameters tested except for factor VII activity which was increased and AT III concentration which was decreased after six months of use. The combined pill users evidenced marked changes in the platelet count, the screening tests and in most of the coagulation-promoting factors; the changes were apparent after three months of use and became more pronounced after six months. The results demonstrate, with marked contrast, that the implants had less pronounced effects on the blood coagulation system than did the combined pills used in this study.

Adult↗
PubMed1979

Early increase of a new platelet coagulant activity in rats fed a thrombogenic diet.

A recently described platelet coagulant activity (factor X activating activity), whose pathophysiological significance is as yet unknown, was studied in rats fed a fat-rich (thrombogenic) diet for 1, 2 and 7 weeks and compared to rats fed normal laboratory chow. Whatever the duration of the special feeding period, a highly significant shortening of the clotting time, used for measuring this activity, was observed. When the platelet coagulant activity of individual "fat-fed"rats was quantitated by reference to that of individual control animals, we found a mean increase of 350% (n = 9) after one week and 267% (n = 3) after two weeks of dietary treatment. Partial thromboplastin time, thrombin time and soluble fibrin monomer complexes did not differ in control and treated animals. It seems that platelet coagulant activity, as measured in our test system, is one of the first laboratory parameters to be modified by fat-rich diets. These findings may be relevant to an understanding of the role of platelet coagulant activities other than platelet factor 3 in thrombotic phenomena.

Animals↗
PubMed1988

Bolus dose response characteristics of single chain urokinase plasminogen activator and tissue plasminogen activator in a dog model of arterial thrombosis.

Tissue plasminogen activator (t-PA) and single chain urokinase-plasminogen activator (scu-PA) are relatively "fibrin-specific" thrombolytic drugs with short plasma half lives of 6-8 minutes. Most treatment regimens with these agents utilize a bolus injection followed by continuous drug infusion, usually combined with anticoagulant therapy. The purpose of this study was to establish the dose-response characteristics for scu-PA and t-PA, when given as a single intravenous bolus injection, in a dog model of arterial thrombosis. Eight groups of 6 dogs each were given one of the following doses of scu-PA (mg/kg): 0.20, 0.50, 1.00, 2.00; or t-PA: 0.05, 0.10, 0.20; or an equivalent amount of saline (control group). All doses were given as a single bolus injection 60 minutes after formation of a totally occlusive femoral artery thrombus. Thrombolysis was measured by monitoring the continuous decrement of 125I activity from a radiolabelled thrombus. Ninety minutes after drug injection, all scu-PA treated dogs showed greater thrombolysis (30%, 45%, 56%, and 67%, respectively) than the control group (15%, p less than 0.01). The 0.10 and 0.20 mg/kg t-PA treated dogs showed greater thrombolysis (35% and 49%, respectively) than the control group (15%, p less than 0.01). Both scu-PA and t-PA caused a partial and dose-dependent decrease in alpha 2-antiplasmin activity but scu-PA caused a greater depletion (72% vs. 18%, respectively, p less than 0.05) at 60 minutes after the highest dose of drug administration. Both drugs showed a longer than expected thrombolytic effect based upon the known half lives. Neither drug caused significant changes in the prothrombin time, activated partial thromboplastin time, thrombin time, hematocrit, platelet count, or fibrin degradation product concentration. Single bolus injections of scu-PA and t-PA produce safe and effective thrombolysis in this dog model of arterial thrombosis.

Animals↗
PubMed1987

Untreated prostatic carcinoma is not associated with frequent thrombohemorrhagic disorders.

We conducted an evaluation of the hemostatic integrity of patients with untreated cancer of the prostate. Of 60 patients analyzed retrospectively, only 1 had a mild case of disseminated intravascular coagulation, possibly associated with concomitant estrogen therapy, and in 1 patient mild deep vein thrombosis developed preoperatively, also possibly associated with multiple medications for concurrent disorders. Of 16 other patients prospectively evaluated on admission, only 1 had frankly abnormal levels of fibrinopeptide A unaccompanied by other coagulation abnormalities. Occasional individuals had minimal, negligible deviations of partial thromboplastin times, thrombin time, or antithrombin III values. In none of these patients did hemostatic complications develop during their hospital stay. These results demonstrate that although an occasional coagulation abnormality may occur in patients with cancer of the prostate (albeit with a lower incidence than in other neoplasms), this malignancy does not require increased precautions with respect to those given to the patient population at large.

Adult↗