thromboplastin and Body-Weight

A total of 1290 patients (Pts) undergoing general surgery were enrolled in a randomized, multicentre double-blind study in order to investigate the efficacy and safety of two different doses of a low molecular weight heparin (LMWH) (Logiparin) for the prevention of deep vein thrombosis. Patients were randomized to either 5,000 IU unfractionated heparin twice daily, 2,500 anti-Xa or 3,500 anti-Xa units of Logiparin once daily. Each treatment was given subcutaneously two hours before surgery and continued for seven to ten days. All coagulation tests were performed blindly in a core laboratory. Blood samples were collected before surgery and then 3 hours after injection on Day 3 and 5 after surgery. Anti-Xa amidolytic activities were significantly higher in the two LMW Heparin groups than in the unfractionated heparin group (mean peak levels +/- s.e.m. on Day 3: 0.097 +/- 0.004; 0.152 +/- 0.004 and 0.034 +/- 0.003 IU respectively). As expected a significant correlation was observed between anti-Xa activity and the dose of LMW Heparin injected. The correlation coefficient was higher when the doses were expressed in anti-Xa units/kg body weight. However, the body weight accounts for only 16% of the interindividual variability of anti-Xa activity. Therefore, there is no clear evidence to suggest that weight-adjusted doses should be recommended when this LMW Heparin is used as prophylactic treatment in general surgery. A weak negative correlation was found between anti-Xa activity and thrombosis as demonstrated by a positive radiolabelled fibrinogen uptake test and confirmed by positive phlebography. No significant correlation was demonstrated between anti-Xa activity and the occurrence of postoperative bleeding.

Topics: Body Weight; Double-Blind Method; Drug Administration Schedule; Factor VII; Factor Xa Inhibitors; Female; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Lipoproteins; Male; Postoperative Period; Thromboplastin; Thrombosis

A prospective open study was performed in a series of 547 patients undergoing gynecologic surgery. A dose of 20 mg of enoxaparin was administered to all patients 2 hours before surgery. Then patients at high risk of thrombosis (mostly oncologic surgery) received 40 mg of enoxaparin daily whereas those at moderate risk received 20 mg of enoxaparin daily. The principal aim of this prospective open study was to monitor amidolytic anti Xa activity and to study the inhibition of intrinsic prothrombinase using prothrombin consumption measurement as a simple and global test. A second aim was to investigate efficacy and tolerance of these regimens. Treatment tolerance was satisfactory with both regimens since the total incidence of bleeding was 1.8%. A single patient developed a clinically significant thrombosis during hospital stay. The results confirm and extend previous reports regarding a dose effect relationship between the dose of Enoxaparin and plasma Anti Xa activity 3 hours after s.c. injection. A significant relationship was found between Anti Xa activity and patients body weight. Interestingly a dose dependent inhibition of intrinsic prothrombinase was observed when using a one stage prothrombin consumption assay in whole blood. This test in whole blood can be considered as closer to physiological conditions than assays performed in citrated platelet rich or platelet poor plasma samples. The mechanism of intrinsic prothrombinase inhibition during prophylactic treatment with enoxaparin requires further investigation.

Topics: Adult; Body Weight; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Genital Diseases, Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Injections, Subcutaneous; Middle Aged; Partial Thromboplastin Time; Postoperative Complications; Prospective Studies; Prothrombin; Risk Factors; Thromboembolism; Thromboplastin

Tissue factor (TF), the trigger protein of the extrinsic blood coagulation cascade, is abundantly expressed in various cancers including gastric cancer. Anti-TF monoclonal antibodies (mAbs) capable of targeting cancers have been successfully applied to armed antibodies such as antibody-drug conjugates (ADCs) and molecular imaging probes. We prepared an anti-TF mAb, clone 1084, labeled with astatine-211 (

Topics: Animals; Antibodies, Monoclonal, Humanized; Ascorbic Acid; Astatine; Blood Coagulation; Body Weight; Cell Line, Tumor; Female; Heterografts; Humans; Immunoconjugates; Linear Energy Transfer; Mice; Mice, Inbred BALB C; Mice, Nude; Protein Denaturation; Radiation-Protective Agents; Radioimmunotherapy; Receptor, ErbB-2; Stomach Neoplasms; Thromboplastin

Breast cancer has the potential to metastasize to bone, causing debilitating symptoms. Although many tumor cells have thrombin-generating systems originating from tissue factor (TF), therapy in terms of the coagulation system is not well established. To elucidate the efficacy of the thrombin inhibitor, argatroban, on bone metastasis, we investigated TF activation and vascular endothelial growth factor (VEGF) secretion on treatment with thrombin and argatroban.. MDA-231 breast cancer cells were treated with thrombin in presence or absence of argatroban, and TF activity was measured in the form of activated factor X. Enzyme-linked immunosorbent assay (ELISA) was used to measure VEGF concentrations in the medium. MDA-231 cells were injected into the left heart ventricle of mice, and then argatroban or saline was administered intraperitoneally for 28 days. After 28 days, incidence of bone metastasis was evaluated in the limbs by radiography.. TF activity and VEGF secretion were upregulated by thrombin. Argatroban inhibited the enhancement of TF activity and VEGF secretion induced by thrombin. In vivo analysis revealed that the number of metastasized limbs in the argatroban group was significantly lower compared with the saline group (P < 0.05).. Thrombin not only enhances VEGF secretion but also has a positive feedback mechanism to reexpress TF. These results indicate that inhibition of thrombin is of great value in suppression of tumor metastasis. Argatroban is a noteworthy and useful thrombin inhibitor because it has already been used in the clinical setting and has antimetastatic effects in vivo.

Topics: Animals; Antithrombins; Arginine; Body Weight; Bone Neoplasms; Breast Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Humans; Mice; Pipecolic Acids; Sulfonamides; Thrombin; Thromboplastin; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Ozone is a well-known oxidant air pollutant, inhalation of which can result in oxidative stress, and lead to pulmonary inflammation. The aim of this study was to evaluate the time-course events after a single ozone exposure in transcription-coupled repair defective Csb and wild type mice. Mice were exposed for 3 h to 2 ppm ozone and biological parameters related to oxidative stress and inflammation were examined in the lungs at 0, 4, 9, 24 and 48 h after exposure. In addition the procoagulant and thrombomodulin activities were explored by a combination of assays for tissue factor and thrombin generation. This study revealed a significant biological response to ozone, for both Csb and wild type mice. The onset of inflammation in Csb mice, as indicated by an increase in interleukin-6, tumor necrosis factor-alpha and total cell influx, occurred earlier compared with those seen in wild type mice. On the other hand, Csb mice showed a delayed antioxidant reaction compared with wild type mice. Both genotypes developed a procoagulant reaction characterized by a stably increased tissue factor activity and a progressive increase in thrombin generation after 2 days. These experiments have shown that ozone, a well-known toxic substance from the environment, induces not only inflammation, but also procoagulant reactions in the lungs of mice. These results have implications for understanding the systemic effects induced by oxidant air pollutants.

Topics: Air Pollutants, Occupational; Animals; Body Weight; Bronchoalveolar Lavage Fluid; Calibration; DNA Repair; Male; Mice; Mice, Inbred C57BL; Organ Size; Oxidants, Photochemical; Oxidative Stress; Ozone; Pneumonia; RNA, Messenger; Thromboplastin; Thrombosis; Time Factors

Pharmacological treatment of deep vein thrombosis (DVT) in the future may target inhibitors of specific procoagulant proteins. This study used a non-human primate model to test the effect of PHA-798, a specific inhibitor of the tissue factor/Factor VIIa complex (TF/VIIa), on venous thrombus formation.. PHA inhibits the TF/VIIa complex with an IC(50) of 13.5 nM (K(i) 9 nM) and is more than 2000-fold selective for the TF/VIIa complex with respect to IC(50)s for factor Xa and thrombin. In the model, a thrombogenic surface was introduced into the vena cava of a primate, and the amount of thrombus accumulated after 30 min was determined.. PHA-798 reduced thrombus formation on the thrombogenic surface in a dose-dependent manner (56+/-1.9% and 85+/-0.3% inhibition with 100 and 200 microg/kg/min PHA-798, respectively) indicating that the model is sensitive to TF/VIIa inhibition. Treatment with 1 mg/kg intravenous (IV) acetyl salicylic acid (ASA) resulted in only a slight (4-12%), non-significant inhibition of thrombus formation. However, the combination of 100 microg/kg/min PHA-798 and 1 mg/kg ASA resulted in an 89% inhibition of thrombus formation. Additionally, while ASA alone increased bleeding time (BT) from 3.3 min at baseline to 4.6 min following treatment, addition of PHA-798 (100 microg/kg/min) to ASA did not significantly increase the BT further (4.7 min).. The results of this study indicate that inhibition of TF/VIIa may be safe and effective for the prevention of the proprogation of venous thrombosis and that the combination of ASA and PHA may provide increased efficacy with little change in safety.

Topics: Animals; Aspirin; Bleeding Time; Body Weight; Disease Models, Animal; Factor VIIa; Macaca fascicularis; Male; Platelet Aggregation Inhibitors; Thromboplastin; Thrombosis

The rat model of chronic intoxication by N(G) -nitro-L-arginine methyl ester (L-NAME) induces severe systemic arterial hypertension and progressive ischemic lesions in the central nervous system and kidneys. We investigated the possible molecular basis of these thrombotic events.. Administration of L-NAME increased plasma markers of thrombin generation, thrombin-antithrombin complexes, and soluble glycoprotein V, measured by specific ELISA. Thrombin generation in vivo was associated with ex vivo platelet desensitization to adenosine 5'-diphosphate and collagen-induced aggregation. In the aortic layers and renal arterioles, tissue factor mRNA (semi-quantitative RT-PCR) and activity (coagulation assay) were increased. In contrast, tissue factor activity was not modified in glomeruli. In parallel, an impairment of the fibrinolytic system was demonstrated by an increase in plasma levels and arterial secretion of plasminogen activator inhibitor-1. In the arterial wall, plasminogen activator inhibtor-1 mRNA was significantly increased. Moreover, antifibrinolytic activity, studied by fibrin reverse zymography, was increased whereas all tissue-plasminogen activator activity secreted by the hypertensive arterial wall was detected as complexes with its specific inhibitor. In animals treated with the angiotensin-converting enzyme (ACE) inhibitor Zofenil, all of these parameters remained at control levels.. These results indicate that chronic blockade of nitric oxide production in rats results in enhancement of blood markers of thrombin generation associated with tissue factor induction and impairment of fibrinolysis in the vascular wall, which may contribute to the thrombotic complications associated with hypertension.

Topics: Animals; Anticoagulants; Arteries; Blood Platelets; Blood Pressure; Body Weight; Enzyme Inhibitors; Fibrinolytic Agents; Heart; Hemostasis; Hypertension; Kidney Glomerulus; Lipoproteins; Male; NG-Nitroarginine Methyl Ester; Organ Size; Plasminogen Activator Inhibitor 1; Platelet Activation; Random Allocation; Rats; Rats, Wistar; Thrombin; Thromboplastin; Tissue Plasminogen Activator

Obesity and insulin resistance are associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathic phenomena, and increased concentrations and activity in blood of plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of fibrinolysis.. To determine whether hypofibrinolysis in blood and tissues and its potential sequelae could be attenuated pharmacologically, we studied genetically modified obese mice. By 10 weeks of age, obese mice exhibited increases in left ventricular weight and glucose and immunoreactive insulin in blood. PAI-1 activity in blood measured spectrophotometrically was significantly elevated as well. The difference compared with values in lean controls widened by 20 weeks of age. Perivascular fibrosis in coronary arterioles and small coronary arteries was evident in obese mice 10 and 20 weeks of age, paralleling increases in PAI-1 and tissue factor expression evident by immunohistochemical image analysis, in situ hybridization, and reverse transcription-polymerase chain reaction. Inhibition of ACE activity initiated in obese mice 10 weeks of age and continued for 20 weeks arrested the increase in PAI-1 activity in blood and in cardiac PAI-1 and tissue factor mRNA as well as coronary perivascular fibrosis.. Thus, inhibition of proteo(fibrino)lysis and augmented tissue factor expression in the heart precede and may contribute to the coronary perivascular fibrosis seen with obesity and insulin resistance. Furthermore, inhibition of ACE activity can attenuate all 3 phenomena.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Body Weight; Coronary Vessels; Diabetes Mellitus; Fibrinolysis; Fibrosis; Heart Ventricles; Immunohistochemistry; In Situ Hybridization; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Myocardium; Obesity; Organ Size; Peptidyl-Dipeptidase A; Plasminogen Activator Inhibitor 1; RNA, Messenger; Thiazepines; Thromboplastin

Monocytes are potent regulators of blood coagulation through the expression of tissue factor (TF) on stimulation and of tissue factor pathway inhibitor (TFPI), a selective inhibitor of TF pathway. As hyperlipidemia can modify some monocyte functions, we compared the TF and TFPI expression by circulating monocytes and the plasma TFPI levels between 65 healthy normolipemic controls and 38 nontreated hyperlipemic patients. TF and TFPI relationships with plasma lipoproteins are also examined. TF and TFPI expression were evaluated in peripheral mononuclear cells after isolation from blood by density gradient centrifugation and after short culture with or without lipopolysaccharide (LPS). TF and TFPI activity and antigen were measured in mononuclear cell lysates using amidolytic assay and enzyme-linked immunosorbent assay, respectively. TFPI activity and antigen were measured in plasma using the same methods. Plasma factor VII (FVII) activity and antigen were also determined. LPS-stimulated monocyte TF activity and antigen were lower in hyperlipidemic patients than in controls (0.0001

Topics: Adult; Age Factors; Antigens; Body Mass Index; Body Weight; Chemokine CCL2; Factor VII; Female; Humans; Hyperlipidemias; Lipids; Lipopolysaccharides; Lipoproteins; Male; Middle Aged; Monocytes; Thromboplastin

Tissue factor (TF), a principal initiator of the vertebrate coagulation cascade, is expressed in organ tissues, cells and blood. TF is known to be induced in endothelial cells, monocytes and macrophages by inflammatory stimuli and in many pathologic conditions. By using the modified method for in vivo TF activity assay, we found that turpentine oil injection as an inflammatory stimulus also induced the TF activity in lung and brain tissues of rats. And the age-related increase in TF activity was observed in healthy rat brain tissue.

Topics: Aging; Animals; Body Weight; Brain Chemistry; Calibration; Inflammation; Irritants; Lung; Male; Rats; Rats, Sprague-Dawley; Thromboplastin; Turpentine

There is a significant direct relationship between steady-state intravenous heparin dose requirements and total body weight. Less is known about whether sex, age, clinical diagnosis, and the thromboplastin used to measure the activated partial thromboplastin time (aPTT) affect heparin dose requirements.. Four cohorts of patients treated with intravenous heparin were gathered from 3 hospitals: 2 cohorts with deep vein thrombosis (DVT) and 2 cohorts with coronary artery disease (CAD). For each clinical diagnosis, half the patients were monitored using one aPTT reagent and the remainder were monitored using a second reagent. Heparin doses and aPTT measurements were recorded, and the dose necessary to achieve an aPTT ratio of 2.0 was calculated using a computer software program.. We analyzed the records of 340 patients: 165 with DVT and 175 with CAD. Using analysis of variance, there was a significant difference in the steady-state heparin requirements among patients with DVT compared with patients with CAD (P < .001). For each clinical diagnosis, the use of a different thromboplastin reagent did not affect heparin dose requirements (P > .42). Linear regression modeling disclosed that the steady-state heparin dose for patients with DVT was a function of weight plus an effect modifier involving weight and age, whereas for patients with CAD there was only a weak relationship with weight.. Steady-state heparin dose requirements were significantly different in patients with DVT compared with patients with CAD, suggesting that different dosing nomograms are needed for each condition. For patients with DVT, the accuracy of the initial heparin dose estimate may be improved by considering the patient's age and weight.

Topics: Aged; Aged, 80 and over; Aging; Anticoagulants; Body Weight; Coronary Disease; Female; Heparin; Humans; Infusions, Intravenous; Linear Models; Male; Middle Aged; Partial Thromboplastin Time; Sex Factors; Thromboplastin; Thrombosis

Two methods of calculating heparin infusion rates for patients with venous thrombotic disease were compared; one method was based on a one-compartment pharmacokinetic model, the other on patient weight. Sixty-eight patients with presumed thromboembolic disease were started on continuous i.v. heparin sodium (porcine) using an infusion pump. Patients were divided into two groups--the infusion rate of Group I was based on patient weight (77 units/kg/4 hrs) and the infusion rate of Group 2 was determined by a pharmacokinetic equation based on a one-compartment heparin model. Heparin effect was measured by an activated partial thromboplastin time (APTT). The initial heparin infusion rate for Group 1 (4,784 +/- 672 units/4 hrs) was significantly greater (p less than 0.039, two-sample t-test) than that for Group 2 (4,413 +/- 779 units/4 hrs), but the variances of the rates were not significantly different (p = 0.40, ratio of variance F-test). Both methods for estimating initial heparin infusion rates gave mean APTT values in the center of the therapeutic range, but the variance in the APTTs of Group 2 patients was significantly smaller (p = 0.004) than that of Group 1. The pharmacokinetic model was more precise and reliable. This model should be valuable for insuring heparin's therapeutic effect without exposing patients to the potential risk of hemorrhage.

Topics: Adult; Aged; Blood Coagulation; Body Weight; Drug Administration Schedule; Female; Heparin; Humans; Infusions, Parenteral; Kinetics; Male; Methods; Middle Aged; Models, Biological; Thromboplastin

The consistency of the anticoagulant effect of intravenously administered heparin was studied. The activated partial thromboplastin time (APTT) was measured for six patients hourly during three consecutive hemodialysis sessions each. Cephaloplastin was the plasma-activating agent. The time required to form a clot was measured by a light-sensitive electronic timer and confirmed within +/- 5% by the tilt tube method. Results are reported in second relative to units of heparin given to patients per kilogram body weight. The range of APTT's measured 55 minutes after each heparin dose greatly exceeded the range of technical variability of the assay method. The probably mechanisms and consequences for this variability after a constant heparin dose are discussed. The anticoagulation effect of heparin during hemodialysis in an otherwise stable clinical situation is not constant. The risks of having too much or too little anticoagulation are not eliminated by having determined a therapeutic heparin dose during one dialysis rung.

Topics: Blood Coagulation Tests; Body Weight; Female; Heparin; Humans; Kidney Failure, Chronic; Male; Renal Dialysis; Thromboplastin

Topics: Animals; Antithrombins; Blood Coagulation; Blood Coagulation Factors; Body Weight; Castration; Disease Models, Animal; Dose-Response Relationship, Drug; Ethinyl Estradiol; Female; Fibrinogen; Fibrinolysis; Hysterectomy; Organ Size; Rats; Thromboplastin; Uterus

Topics: Blood Coagulation; Blood Glucose; Blood Pressure; Body Constitution; Body Weight; Cholesterol; Factor VII; Factor VIII; Factor X; Fibrinogen; Fibrinolysis; Humans; Male; Middle Aged; Myocardial Infarction; Obesity; Plasminogen; Prothrombin; Sampling Studies; Skinfold Thickness; Smoking; Spirometry; Thromboplastin; Triglycerides; Vital Capacity

Topics: Aflatoxins; Alkaline Phosphatase; Animals; Bile Ducts, Intrahepatic; Blood Cell Count; Blood Proteins; Body Weight; Dogs; Feeding and Eating Disorders; Female; Hematocrit; Hemoglobins; Humans; Jaundice; Kidney; Liver; Male; Prothrombin; Thromboplastin; Urine

Topics: Aminocaproates; Animals; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Blood Coagulation Tests; Body Weight; In Vitro Techniques; Prothrombin Time; Rats; Thromboplastin