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PubMed1986

The calibration of rabbit tissue thromboplastins: experience of the Dutch Reference Laboratory for anticoagulant control.

A number of commercial rabbit tissue thromboplastins used in oral anticoagulant control have been calibrated against the first International Reference Preparation for thromboplastins. This was done in a three-stage procedure by one laboratory, each stage representing a different level of thromboplastin comparability. The calibration model recently recommended by ICTH and ICSH was tested. This model proved to be suitable, although a statistically significant aberration was observed for some of the thromboplastins. The bias introduced by using the model in these non-ideal cases was small compared to the overall variation of the International Normalized Ratio, being the universal scale for reporting the prothrombin time during oral anticoagulant control. Batch-to-batch calibration using lyophilized pooled plasmas could be reliably performed for several commercial thromboplastins.

Administration, Oral↗
PubMed1997

Alterations in the structure of apolipoprotein B-100 determine the behaviour of LDL towards thromboplastin.

Apolipoprotein B-100 acts as an inhibitor of thromboplastin activity independently of the tissue factor pathway inhibitor (TFPI) associated with plasma lipoproteins. Analysis of the primary structure of Apo B-100 showed a higher than expected occurrence of lysine groups in the receptor-binding region. In order to demonstrate the participation of lysine groups of Apo B-100 in the inhibition of thromboplastin, thromboplastin and Apo B-100 were incubated together in the presence of poly-L-lysine, poly-L-arginine, lysine and arginine monomers. The inhibition of thromboplastin by Apo B-100 was completely suppressed in the presence of poly-L-lysine. Poly-L-arginine was found to be less effective and neither lysine or arginine monomers had any significant effect on the inhibitory effect of Apo B-100. Alterations in the structure of Apo B-100 reconstituted in lipid vesicles resembling LDL, brought about by lipid peroxidation and lipid loading were examined by means of Fourier transform infra-red spectroscopy. It was found that, upon oxidation without the addition of cupric ions, the apolipoprotein attains a more exposed conformation with an increase in alpha-helical structure. This increase occurred at the expense of beta-structure. On lipid loading, an increase in beta-structure at the expense of the alpha-helix, was demonstrated. It is therefore proposed that the variable action of LDL towards thromboplastin derives from alterations in the secondary structure of the Apo B-100, particularly the receptor-binding region.

Apolipoprotein B-100↗
PubMed1996

Comparison of lyophilized plasmas with fresh plasmas for calibration of thromboplastin reagents in oral anticoagulant control.

In a multicentre study of four thromboplastin reference materials (three from rabbit brain and one from bovine brain combined with adsorbed bovine plasma), three types of lyophilized plasmas were included. One was a pooled normal plasma, another was made by pooling plasmas of coumarin-treated patients, and the third was prepared by adsorption of vitamin K dependent clotting factors (artificially depleted). The purpose of this study was to investigate whether these lyophilized plasmas could be used for reliable calibration of the four thromboplastins. Calibration line slopes were calculated for the lyophilized plasmas and compared to the slopes based on fresh plasmas. When a rabbit thromboplastin was calibrated against a similar but not identical reagent (like-to-like comparison), the slopes for lyophilized plasmas and for fresh plasmas were the same. However, significant differences between lyophilized and fresh plasmas were observed in the calibration of unlike thromboplastins. The deviation of the slope with artificially depleted plasma was greater than that with lyophilized coumarin plasma. Indiscriminate use of these lyophilized plasmas for thromboplastin calibration should be avoided.

Administration, Oral↗
PubMed2001

Effects of temperature on partial thromboplastin time in heparinized plasma in vitro.

BACKGROUND AND OBJECTIVE: Perioperative hypothermia has been found to impair the coagulation cascade and to increase blood loss and transfusion requirements. The effect of concomitant in vitro heparinization on coagulation during hypo- and hyperthermic conditions has not been well defined. METHODS: In the present study, activated partial thromboplastin time was examined in vitro at 33 degrees C, 35 degrees C, 37 degrees C, 39 degrees C and 41 degrees C in normal human plasma in response to unfractionated heparin. RESULTS: Hypothermia <or= 35 degrees C prolonged activated partial thromboplastin time by 10% compared with test temperatures at 37 degrees C (P < 0.05). Hyperthermia alone had no effect. Unfractionated heparin (0.1-0.4 IU mL(-1)) increased activated partial thromboplastin time in a dose-dependent manner (by 189% at 0.4 IU mL(-1), P < 0.05). Test temperatures of 33 degrees C and 41 degrees C increased heparin-induced prolongation of activated partial thromboplastin time. At a heparin concentration of 0.4 IU mL(-1), hypothermia (33 degrees C) and hyperthermia (41 degrees C) prolonged partial thromboplastin time by 12% and 22%, respectively, compared with normothermic test temperature of 37 degrees C within the heparin group (P < 0.05). CONCLUSIONS: These observations suggest that both hypo- and hyperthermia increase the response to heparin in vitro. Further studies are needed to identify the effect of patient's body temperature on heparin activity and bleeding tendency in vivo.

Adult↗
PubMed1996

Protective effects of DX-9065a, an orally active, novel synthesized and selective inhibitor of factor Xa, against thromboplastin-induced experimental disseminated intravascular coagulation in rats.

We investigated the protective effects of DX-9065a, an orally active, newly synthesized, and specific inhibitor of factor Xa, against experimental disseminated intravascular coagulation (DIC) in rats. Experimental DIC was induced by a 4 hour sustained infusion of thromboplastin at a dose of 2.5 mg/kg. The rats were orally administered DX-9065a at 10, 30, 100 mg/kg 30 minutes before thromboplastin injection. In this DIC model, DX-9065a showed a protective effect against DIC, at all doses and in all parameters, including fibrin(ogen) degradation products, fibrinogen level, thrombin-antithrombin III complex level, prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count, and the number of renal glomeruli with fibrin thrombi. When DX-9065a was orally administered at 100 mg/kg without thromboplastin, no significant changes were seen in hemostatic parameters except PT and APTT, and no fibrin thrombi or abnormal bleeding were seen in renal specimens. These findings suggested that the new oral anti-Xa drug, DX-9065a, has a protective effect against thromboplastin-induced DIC model with little risk of bleeding.

Administration, Oral↗
PubMed1995

Heparin-induced increase in the international normalized ratio. Responses of 10 commercial thromboplastin reagents.

A clinician's concern about an erratic response to oral anticoagulation in a patient treated concurrently with heparin and warfarin led the authors to investigate the effect of heparin on INR values obtained with various commercial thromboplastin reagents. Studies conducted with pooled normal plasma and with pooled plasma from patients treated long-term with oral anticoagulants demonstrated a wide range of sensitivities to heparin of these reagents as characterized by prolongation of INR values. Innovin was unaffected by concentrations of heparin as high as 1 U/mL. In contrast, Ortho thromboplastin showed the greatest increase in INR values over the range of heparin concentrations studied. Three other thromboplastins including Neoplastine CI, Dade thromboplastin, and Simplastin A demonstrated only limited sensitivity to heparin. Prolongation of the INR by heparin was reversed by protamine in a dose-related manner and also by preincubation of the plasma with heparinase. Some patients treated with warfarin while on the authors' institutional protocol for heparin had plasma concentrations greater than 0.8 U/mL. When thromboplastin reagents sensitive to heparin were used with such specimens, the INR values obtained were falsely elevated. The authors suggest that reagents insensitive to heparin be employed to avoid this difficulty.

Blood Coagulation↗
PubMed1998

Highly sensitive thromboplastins do not improve INR precision.

For determination of the international normalized ratio (INR), it has been suggested that "highly sensitive" thromboplastin reagents (International Sensitivity Index [ISI] < or = 1.2) provide the most consistent performance and minimize interlaboratory variability. We compared the INR values obtained from 69 specimens drawn from patients receiving long-term oral anticoagulant therapy, using four thromboplastin preparations (manufacturer-assigned ISI range of 0.96-1.10) and two automated photo-optical analyzers. Multivariate analysis of the INR response matrix (552 INR values) indicated that the eight reagent-coagulometer combinations did not produce equivalent INR values. Similar analysis indicated that INR values were not normalized when uncorrected prothrombin ratios or INR values, calculated after assignment of "local ISI values" to each thromboplastin reagent, were compared. The INR differences also seemed to be clinically significant because 17% to 29% of paired thromboplastin values were discordant when all INR values were assigned to one of four therapeutic categories used in oral anticoagulant therapy (< 2.0; 2.0-3.0; 3.0-4.5; or > 4.5). These differences in INR values obtained with two photo-optical coagulometers and four highly sensitive thromboplastin reagents suggest that the existing INR system has not achieved the goal of standardized prothrombin time values and does not support the recommendation to use only highly sensitive reagents for the regulation of oral anticoagulant therapy.

Anticoagulants↗
PubMed1990

Spinal cord thromboplastin-induced coagulopathy in a rabbit model.

Coagulopathy results from many diverse events, including several neurogenic causes. Using a rabbit model, we produced coagulopathy by injecting autologous spinal cord and extracted thromboplastin intravenously. Serial coagulation panels were performed to evaluate the activation of the thrombotic and fibrinolytic pathways. Group 1 animals (n = 4) received intravenous injections of homogenized spinal cord tissue. Coagulopathy was not produced with 36 mg of homogenized spinal cord tissue, but 50 mg or more resulted in death. Group 2 animals (n = 12) received intravenous injections of extracted rabbit cord thromboplastin, which contained approximately 60% activity of a commercially purified rabbit brain thromboplastin. Five animals receiving 2.5 to 5.5 mg of thromboplastin per kilogram of body weight survived with evidence of coagulopathy. Seven animals receiving 2.5 to 100 mg of thromboplastin per kilogram of body weight died. Group 3 (4 control animals) received normal saline injections without changes in clinical or laboratory status. The thrombotic pathway was activated in all animals as evidenced by decreased platelet counts and fibrinogen levels. Activation of the fibrinolytic system was demonstrated by increased concentrations of protamine sulfate and abnormal euglobulin clot lysis times. The most sensitive parameters were the platelet count, protamine sulfate concentration, and white cell count (margination), which became abnormal within 15 minutes after the injections and returned to normal within 1 hour.

Animals↗
PubMed1983

Cellular cooperation in endothelial cell thromboplastin synthesis.

Endothelial cells from human umbilical veins produce a procoagulant identified as thromboplastin (tissue factor, factor III) when stimulated with the phorbol ester 12-0-tetradecanoyl-phorbol-13-acetate (TPA), phytohaemagglutinin (PHA) or endotoxin, Inducible thromboplastin synthesis (i.e. synthesis of the protein component of thromboplastin, apoprotein III) was totally inhibited by cycloheximide and actinomycin D, indicating that de novo protein and RNA syntheses are necessary. Serum enhanced the induced apoprotein synthesis. Of the total thromboplastin activity in homogenates of stimulated endothelial cells, about 50--70% was available on the cell surface for interaction with other coagulation factors, inactivation by trypsin and neutralization with antiserum against apoprotein III. Induced synthesis of thromboplastin in endothelial cells was 2--7-fold enhanced by the presence of several other cell types in optimal ratio 4--10 cells per endothelial cell. Some of these cell types were themselves thromboplstin producers (U-937, U-937-4), some were not inducible (lymphocytes, granulocytes and the lymphoblast lines Daudi and Molt 4). This enhancing effect was also seen with cell-free culture supernatants, but these were generally somewhat less effective than the intact cells. Supernatants derived from cells cultured in the presence of TPA, PHA or endotoxin were in most cases more effective than supernatants from unstimulated cells.

Cell-Free System↗
PubMed1984

Production and availability of thromboplastin in endothelial cells: the effects of thrombin, endotoxin and platelets.

Freshly prepared endothelial cells from umbilical cord veins were demonstrated to possess a weak but significant thromboplastin activity. Upon exposure of cultured endothelial cells to catalytically active thrombin (4.5 U/ml) or endotoxin (0.05 microgram/ml), the thromboplastin activity of the cells was increased 10-40-fold during 5 h incubation, and with the additional presence of washed, isolated platelets during the incubation, the activity was enchanced up to 170-fold. Platelets or catalytically inactivated thrombin added alone were largely ineffective as stimulants. 75-80% of the enhanced thromboplastin activity became available on the surface of the cultured cells as demonstrated by utilizing thromboplastin antibodies. Such exposed activity is suggested to be important in thrombotic situations where initial formation of thrombin may significantly accelerate the generation of thrombin by a positive feedback effect upon thromboplastin synthesis in the endothelial cells.

Blood Platelets↗
PubMed1989

The reappraisal of dilute tissue thromboplastin inhibition test in the diagnosis of lupus anticoagulant.

The dilute tissue thromboplastin inhibition (DTTI) test (Schleider et al, 1976) is a sensitive but non-specific test for lupus anticoagulant (LA). False positive results are seen in patients with clotting factor deficiency involving the extrinsic pathway and also in some patients with specific factor inhibitors (Triplett et al, 1983; Rosove et al, 1986). Since the effect of LA is phospholipid dependent but those of factor deficiency and specific inhibitors are not, we analyse the test results by comparing the degree of inhibition using different dilutions of tissue thromboplastin and express it as the DTTI index. This is defined as the clotting time ratio with 0.2% tissue thromboplastin divided by the clotting time ratio with 2% tissue thromboplastin. We also perform a dilute tissue thromboplastin time with platelet substitution to see if this could neutralize the inhibition caused by LA. Both of these modifications can reliably distinguish LA from other conditions associated with prolonged APTT better than the original DTTI test.

Adolescent↗
PubMed1979

Enhancement of generation of monocyte tissue thromboplastin by bacterial phagocytosis: possible pathway for fibrin formation on infected vegetations in bacterial endocarditis.

The deposition of fibrin on infected vegetations and the presence of mononuclear phagocytes that have phagocytized bacteria are remarkabe features in experimental bacterial endocarditis. In a study in vitro, we show that phagocytosis of bacteria by human monocytes enhances thromboplastin generation by these cells. Maximal enhancement of the generation of thromboplastin by monocytes was about six times compared with that in the control experiment without bacteria, and it was obtained by preincubation of the monocytes with 5 to 10 bacteria per monocyte. No quantitative difference was observed between Staphylococcus epidermidis and Streptococcus sanguis as to the enhancement of the monocyte thromboplastin generation. An enhancement of the procoagulant activity generation was also observed after addition of bacteria to human or rabbit whole blood. Probably, this generation was also due to synthesis of thromboplastin by monocytes. It is conceivable that fibrin deposition on infected vegetations during bacterial endocarditis is mediated by thromboplastin synthesis by monocytes.

Animals↗
PubMed1989

Effect of international sensitivity index (ISI) of thromboplastins on precision of international normalised ratios (INR)

The contribution of the thromboplastin international sensitivity index (ISI) to the interlaboratory coefficient of variation (CV) of the international normalised ratio (INR) with individual reagents was assessed. In theory the precision of the INR should increase with lower ISI values. An empirical relation has been established between the ISI, the INR, and its CV for two rabbit thromboplastins used in sufficient numbers for analysis in the United Kingdom. This was based on the cumulative data from the United Kingdom National External Quality Assessment Scheme (NEQAS) surveys over two years beginning in 1986. The actual precision achieved in NEQAS for the two reagents depends on the ISI value of the thromboplastin and it agreed closely with the figure predicted by the empirical model. The findings show that the ISI value of a thromboplastin strongly influences the interlaboratory variability of the INR obtained with it. The CV of the INR approximates to the CV of the prothrombin ratio multiplied by the ISI. Manufacturers of thromboplastin should therefore be encouraged to produce reagents showing good precision of results reported as simple prothrombin ratios and a low ISI value to avoid impairment in precision when ratio results are transformed to INR.

Animals↗
PubMed1977

Determination of tissue thromboplastin activity.

The one-stage prothrombin time test for tissue thromboplastin activity was evaluated using the correction method. A strong influence of the intrinsic system was seen depending on the clotting time and the type of tubes. This test was unsuitable for quantitative comparison of thromboplastin activity of different preparations. Subsequently a two-stage assay for human thromboplastin is described using purified human factor VII, artifically prepared factor VII reagent, and a phospholipid suspension. The correction method, applicated to this two-stage assay, resulted in a rectilinear dose-response curve when the clotting times of a thromboplastin dilution series were plotted against the reciprocal of the concentrations. Using this test system it could be shown that thromboplastin from porcine tissue can activate human factor VII quite well, while that from bovine tissue cannot.

Animals↗
PubMed1977

Partial purification of the protein moiety of porcine tissue thromboplastin.

The tissue thromboplastin activity of porcine lung was separated from an aqueous tissue extract by differential centrifugation. Repeated suspension and sedimentation yielded a thromboplastin preparation free of soluble protein. The most effective delipidation of the lyophilized preparation with minimum denaturation of the protein moiety of thromboplastin was achieved using n-heptane/n-butanol extraction. A detergent was required to solubilize the thromboplastin protein moiety from the delipidated preparation. Gel filtration in the presence of detergent permitted further delipidation of the protein moiety and yielded a purified protein moiety. Apparent homogeneity was observed for the purified protein with several fractionation techniques. This apparently homogeneous protein dissociates into the constituent proteins in the presence of dodecyl sulphate. The aggregation of proteins is ascribed to their hydrophobic nature. Gel filtration on Bio-Gel A-1.5 m was found to be useful in the separation of the dodecyl sulphate-protein complexes on a preparative scale. Following the removal of the dodecyl sulphate, the renaturation of the thromboplastin protein moiety was unsuccessful. The purified protein moiety with its low lipid content (1%) is suitable for lipid requirement studies.

Animals↗
PubMed1984

Thromboplastin synthesis in endothelial cells.

Endothelial cells (EC) in culture produce a procoagulant identified as thromboplastin when stimulated with 12-O-tetradecanoyl-phorbol-13-acetate, phytohemagglutinin, endotoxin, thrombin, histamine or epinephrine. Inducible thromboplastin generation most likely depends on de novo synthesis of RNA and the protein component of thromboplastin, apoprotein III. It is further probably regulated by intracellular mechanisms involving cAMP, transmethylation and calcium ions. The EC thromboplastin response is enhanced in lymphocyte-EC and platelet-EC cocultures and thromboplastin becomes partly available on the cell surface. Levels of procoagulant activity are reached which clearly may be of clinical importance if similar levels appear in vivo.

Blood Coagulation Tests↗
PubMed1990

Evaluation of international normalized ratios by a controlled field survey with 4 different thromboplastin reagents.

A nationwide survey has been performed in Japan involving 75 laboratories to assess the relative reliability of different methods of reporting prothrombin time results in anticoagulant control. The interchangeability of results using prothrombin time, prothrombin activity percentage, prothrombin ratio and international normalized ratios (INR) were compared with four different thromboplastin reagents and a range of coagulometers. A secondary batch of reference thromboplastin of human brain origin (BCT/454) was used to calibrate the local thromboplastins and for comparison of methods of reporting. The study revealed the closest agreement of the results between BCT and the other reagents, and the regression lines of these reagents were almost identical, when the results were reported as INR. Box-Whisker plot analysis showed that the distribution of the results was large with the more deficient plasmas with all methods of reporting. It was found by this analysis that the interchangeability of the results was greatest when the results were expressed by INR, because the mean values obtained of each plasma using different thromboplastin reagents gave the lowest CV and the frequency of the far-out data was least, compared with the other methods of expression. On the other hand, the type of coagulometer had almost as much effect as the thromboplastin reagent on the prothrombin time, even if INR was used. Interchangeability of INR would be further improved by providing ISI values for each reagent/instrument combination.

Humans↗
PubMed1990

Detection of lupus-like anticoagulants by an enzyme-linked immunosorbent assay using a partial thromboplastin as antigen; a comparative study.

Clotting assays allow qualitative rather than quantitative detection of the lupus anticoagulant. We have therefore studied the usefulness of an ELISA using a commercial partial thromboplastin, Throombofax, as antigen; the results obtained on 146 selected patient plasmas were compared to the results of coagulation tests (kaolin clotting time, tissue thromboplastin inhibition test, activated partial thromboplastin time) and of ELISAs using cardiolipin or phosphatidylserine as antigen. While satisfactory agreement was found within the group of coagulation tests or that of ELISAs, only a moderate agreement was obtained between clotting tests and ELISAs, the best being with the partial thromboplastin ELISA using low plasma dilutions. The study further indicates that ELISA techniques cannot entirely replace coagulation tests for the detection of a lupus anticoagulant, even when a partial thromboplastin is used as antigen. On the other hand, coagulation tests are less sensitive than ELISAs for the detection of antiphospholipid antibodies.

Antigens↗