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PubMed1999

Activated partial thromboplastin time and clinical outcome after thrombin inhibition in unstable coronary artery disease.

UNLABELLED: Aims Direct thrombin inhibitors have failed to prove superiority over unfractionated heparin in several clinical trials of unstable coronary artery disease. We have investigated the relationship between activated partial thromboplastin time levels and adverse clinical events, i.e. death, myocardial (re-)infarction or refractory angina. Methods and Results One thousand two hundred and nine patients with unstable coronary artery disease were randomized to 72 h infusion with inogatran, a low molecular mass direct thrombin inhibitor, or unfractionated heparin. During 30 days follow-up there was no significant difference between inogatran and unfractionated heparin treatment as regards clinical outcome. 11.6% of the 464 inogatran treated patients with activated partial thromboplastin time above the median at 6 h (44 s) had a clinical event in 7 days, and 6.6% of the 423 patients with activated partial thromboplastin time below the median (P=0.01). After 30 days the event rate was still 41% higher in the inogatran patients with activated partial thromboplastin time above the median (P=0.06). Activated partial thromboplastin time in quartiles indicated a direct relationship between higher activated partial thromboplastin time and worse outcome. In contrast, during heparin infusion there was a trend for improved clinical outcome with activated partial thromboplastin time above the median, but this benefit was lost after cessation of treatment. CONCLUSIONS: Higher activated partial thromboplastin time levels during inogatran treatment are related to increased risk of death, myocardial infarction or refractory angina. This might, at least in part, be explained by differences in anticoagulant mechanisms between direct thrombin inhibitors and heparin, and further emphasizes the poorly defined optimal activated partial thromboplastin time range during treatment with direct thrombin inhibitors in unstable coronary artery disease.

Adult↗

PubMed2006

Phospholipid composition controls thromboplastin sensitivity to individual clotting factors.

BACKGROUND: Tissue factor is the active ingredient in thromboplastin reagents used to perform prothrombin time (PT) clotting tests to monitor oral anticoagulant therapy and to screen for clotting factor deficiencies. Thromboplastins are complex mixtures prepared from extracts of brain or placenta, although newer thromboplastins contain recombinant tissue factor incorporated into phospholipid vesicles. Thromboplastins can vary widely in their sensitivity to reductions in the levels of vitamin K-dependent clotting factors. A system to compensate for this, the International Sensitivity Index (ISI) and International Normalized Ratio (INR), has revolutionized the monitoring of oral anticoagulant therapy. The INR system is also sometimes used to monitor coagulopathies in patients with sepsis or liver failure, applications for which it was not originally designed and for which it has not been rigorously validated. OBJECTIVES: To better understand thromboplastin performance, we systematically investigated which properties of recombinant thromboplastins influence their sensitivities to changes in the levels of specific clotting factors. RESULTS: We now report that relative sensitivities to changes in the plasma levels of factors V, VII, X (FV, FVII, FX) and prothrombin are differentially influenced by a recombinant thromboplastin's content of phospholipid and sodium chloride. Furthermore, thromboplastins of similar ISI values may exhibit quite different sensitivities to each of these clotting factors. CONCLUSIONS: Differing sensitivities of thromboplastin reagents to individual clotting factor levels have implications for monitoring of oral anticoagulant therapy and interpreting results of the PT assay.

Adolescent↗

PubMed1982

The production and availability of tissue thromboplastin in cellular populations of whole blood exposed to various concentrations of endotoxin. An assay for detection of endotoxin.

These studies were undertaken to determine the type and availability of the procoagulant activities generated in blood incubated with endotoxin. The shortening of the recalcification time of blood incubated with endotoxin was directly correlated with the increase in synthesis of tissue thromboplastin in the monocytes. The procoagulant activity which resulted in the shortening of the clotting time was shown to be almost totally blocked by tissue thromboplastin antibodies. Thus, no additional procoagulant activity was generated in platelets during the 5 h incubation of blood with endotoxin. However, lysed platelets enhanced the synthesis of tissue thromboplastin in blood monocytes in the presence of endotoxin. Lysed red blood cells or granulocytes had no such effect. In endotoxin stimulated monocytes the main part of the newly synthesized tissue thromboplastin appeared to be exposed on the cellular surface. Thus, only 25% of the tissue thromboplastin activity was recovered when tissue thromboplastin antibodies had been present during the stimulation. Unstimulated monocytes were also found to possess tissue thromboplastin activity, but this low activity was not affected by tissue thromboplastin antibodies unless the monocytes were disrupted by sonication. The high percentage of tissue thromboplastin exposed on the surface of the endotoxin stimulated monocytes in whole blood may contribute significantly to the rapid induction of disseminated intravascular coagulation in gram negative sepsis.

Animals↗

PubMed1986

Thromboplastin content in the vessel walls of different arteries and organs of rabbits.

Homogenized arterial walls of rabbits were shown to possess significant amounts of thromboplastin activity. The specific activity, percent activity per mg tissue, varied in different arteries. Thus the thromboplastin activity of the carotid was found to be about ten-fold higher compared to the femoral. Thromboplastin activity measurements of different organs revealed a very high level of thromboplastin in lung, whereas kidney and spleen had respectively 6 and 25 times less activity than the lung. Induction of generalized Shwartzman reaction by giving two doses of endotoxin 24 hours apart, caused no significant rise in thromboplastin activity of either arteries or organs, but induced a 35-fold increase of thromboplastin activity of circulating monocytes. The very high thromboplastin activity in the lung probably reflects the widespread and dense population of vessel in this particular organ. It is concluded that the amount of thromboplastin present in the vessel wall gives the possibility for a potent activation of the clotting system in normal haemostasis.

Animals↗

PubMed1985

Thromboplastin (tissue factor) in plasma membranes of human monocytes.

The synthesis of thromboplastin, a potent trigger of blood coagulation, can be induced in human peripheral blood monocytes. Indirect evidence suggests that newly synthesized thromboplastin becomes in part available on the cell surface. We have attempted to study the localization and availability of thromboplastin more directly by isolating plasma membranes from isolated human peripheral blood monocytes. The specific activities of the plasma membrane markers increased 16-22-fold in these preparations with a recovery of about 15%. The contamination by mitochondria, lysosomes, nuclei and endoplasmic reticulum was low as estimated by marker enzymes and electron microscopy. In both unstimulated and stimulated monocytes thromboplastin was largely recovered in this plasma membrane fraction, providing direct evidence for its membrane localization. Phospholipase C (E.C. 3.1.4.3) is a potent inactivator of thromboplastin through its hydrolysis of the phospholipids necessary for thromboplastin activity [Otnaess, Prydz, Bjørklid & Berre (1972) Eur. J. Biochem. 27, 238-243]. About 70% of the total membrane thromboplastin activity was inactivated when whole cells were treated with phospholipase C and the membranes subsequently isolated. Following stimulation to induce thromboplastin synthesis, the plasma membranes showed a shift in their relative content of phosphatidylcholine and phosphatidylethanolamine consistent with a transmethylation process.

Cell Membrane↗

PubMed1981

Prospective double-blind clinical trial of bovine, human, and rabbit thromboplastins in monitoring long-term oral anticoagulation.

A prospective double-blind trial was performed to investigate the safety of long-term oral anticoagulant control when dosaged adjustment depends on the prothrombin times assessed with one type of thromboplastin being calculated as if assayed by another type. The three main types of thromboplastin, i.e., bovine (Thrombotest), human (British Comparative Thromboplastin), and rabbit (Simplastin Automated) were tested. Before entering the actual trial, patients had been checked with the bovine type of thromboplastin. During the actual comparison study, prothrombin times obtained with the human and the rabbit types of thromboplastin were translated, using the appropriate calibration data, into terms of the bovine type of thromboplastin, which were used for dosage prescription. After six months, all patients returned to bovine-type thromboplastin control. No substantial difference among the three groups was observed in the prothrombin times, the dosage of the anticoagulant, the bleeding complications, and the dropouts. It was concluded that the safety of monitoring patients receiving long-term oral anticoagulation was independent of the type of thromboplastin used.

Administration, Oral↗

PubMed2006

Traces of factor VIIa modulate thromboplastin sensitivity to factors V, VII, X, and prothrombin.

BACKGROUND: Thromboplastin reagents are used to conduct prothrombin time (PT) clotting tests to monitor oral anticoagulant therapy and screen for clotting factor deficiencies. Thromboplastins made from purified, recombinant tissue factor are generally more sensitive to changes in plasma factor (F) VII levels than are thromboplastins prepared from tissue extracts. This may be problematic as FVII's short plasma half-life can result in day-to-day fluctuation during oral anticoagulant therapy. We hypothesized that trace contamination of tissue-derived thromboplastins with FVII(a) blunts sensitivity to plasma FVII levels. METHODS: Traces of purified FVIIa were added to thromboplastin reagents prepared using recombinant human tissue factor and the effect on sensitivity to individual clotting factors was quantified in PT clotting assays. RESULTS AND CONCLUSIONS: Adding 5-100 pm FVIIa not only decreased thromboplastin sensitivity to plasma FVII, it surprisingly increased sensitivity to plasma levels of FV, FX and prothrombin. In addition, traces of FVIIa interacted with changes in the salt content and phospholipid composition of recombinant thromboplastins to further modulate their sensitivities to individual clotting factors. These results help explain how thromboplastin reagents of differing composition exhibit differing sensitivities to individual clotting factor levels. Implications of our results for monitoring oral anticoagulant therapy and other uses of the PT assay are discussed.

Anticoagulants↗

PubMed1980

Prothrombin times: an evaluation of four thromboplastins and four machines.

The prothrombin times of 63 patients on oral anticoagulant therapy were tested using 4 different thromboplastins; 2 rabbit brains (Simplastin & Ortho), human placenta (Thromborel) and human brain (Australasian Reference Thromboplastin--ART). Four machines measuring the one-stage prothrombin times were compared with the manual method. Each of the machines and thromboplastins showed highly reproducible and predictable results, but there were differences in thromboplastin sensitivities which would pose major therapeutic problems. A system of correcting ratios of different thromboplastins to a reference preparation would overcome these differences in thromboplastin sensitivities. All thromboplastins gave comparable results with the Clotek, MLA 600 and Coag-A-Pet machines and manual method. Cortek gave comparable ratios with the ART but not with any other thromboplastin.

Administration, Oral↗

PubMed1996

Studies of the initial anticoagulant response in tissue-thromboplastin induced intravascular coagulation.

The very early anticoagulant response was analysed in non-pregnant female New Zealand rabbits infused with rabbit brain tissue thromboplastin for a period of 10 min (n = 6), 20 min (n = 6), and 30 min (n = 6). The rabbits infused with thromboplastin responded with a significant drop in mean arterial pressure (P < 0.05), an increase in blood PaO2 (P < 0.05) and a decrease in PaCO2 (P < 0.05), while control animals remained stable with respect to these variables. The thromboplastin-treated animals had an immediate drop in platelet count (P < 0.05), plasma fibrinogen (P < 0.05) and a prolongation in prothrombin time (P < 0.05) and activated partial thromboplastin time (P < 0.05). The concentrations in a number of proteins involved in the anticoagulant response (antithrombin, plasminogen, antiplasmin) as well as global fibrinolytic activity did not change significantly following 10, 20 and 30 min infusion of thromboplastin, while the concentration of protein C decreased continuously during the infusion periods (P < 0.05) to reach the lowest level (approximately 60%) in animals infused with thromboplastin for 30 min. The animals infused with tissue thromboplastin had microthrombi in 1-6% of the renal glomeruli, but the number of microthrombi did not differ significantly between animals infused for 10, 20 and 30 min. It is concluded that the protein C system may play a key role during the initial phase of intravascular coagulation and immediate activation of protein C may protect against excessive deposition of fibrin.

Animals↗

PubMed1995

The effect of lipid peroxidation and lipolysis on the ability of lipoproteins to influence thromboplastin activity.

High, low and very low density lipoproteins and lipoprotein (a) were prepared from porcine serum. The apolipoprotein components of the lipoproteins were then isolated and resuspended in soybean lecithin. Apolipoprotein B was also resuspended in lipids more representative of those found in LDL and VLDL. Lipid peroxidation was induced in samples of all the lipoproteins and reconstituted apolipoproteins by incubation with either Cu2+ ions or hedgehog 15-lipoxygenase. Furthermore, aliquots of the samples were incubated with a mixture of lipases. The effect of native preparations and the treated samples on the procoagulant activity of thromboplastin was examined. Native HDL, apo A-II, native LDL, reconstituted LDL and apo B inhibited thromboplastin activity, whereas native VLDL and reconstituted VLDL enhanced this activity. While the ability of HDL and apolipoprotein A-II to inhibit thromboplastin was unaltered by either Cu2+ oxidation, lipoxygenase oxidation or lipolysis, VLDL and particles resembling VLDL, which acted cooperatively with thromboplastin lost their activating potential. On the other hand, LDL and particles resembling LDL changed from being inhibitory to enhancing the thromboplastin activity following oxidation, but not after lipolysis. Apolipoprotein B fragments obtained by mild digestion of this protein, expressed an inhibitory effect towards thromboplastin, while extensive degradation of the protein reduced its inhibitory potential. It is suggested that modifications of lipoproteins in vivo can lead to a hypercoagulable state by modulation of the cofactor activity of thromboplastin to factor VII.

Animals↗

PubMed1986

Effect of some drugs on thromboplastin activity in mouse trophoblast cells in vitro and in vivo.

Mouse trophoblast cells are constitutive producers of the thromboplastin apoprotein in vitro. The effects on thromboplastin activity of the three transmethylation inhibitors 3-deazaadenosine (DZA), 3-deazaaristeromycin (DZAri) and erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), the four calcium antagonists TMB-8, verapamil, nifedipine and felodipine, the prostaglandin E2 (PGE2), the phosphodiesterase inhibitor 1-methyl 3-isobutylxanthine (MIX) and monensin have been studied. No cytotoxic effects were detected when trypan blue exclusion, release of lactic dehydrogenase, incorporation of 14C-leucine into protein and cell morphology were monitored. TMB-8, felodipine, nifedipine and verapamil all abolished the increase in thromboplastin when added after 68 hr or 90-96 hr in culture. EHNA and DZAri had the same effect (but were only added at 90-96 hr). DZA had a similar effect when added at 68 hr and an even more marked inhibitory effect when added at 90-96 hr. Monensin prevented the increase in thromboplastin activity at 68 hr as well as at 90-96 hr. The combination of DZA and 1-homocysteine thiolactone (Hcy) further increased the inhibition, indicating that in these cases synthesis as well as degradation of thromboplastin were altered. The combination of DZA/Hcy and one of the four calcium antagonists gave no additional inhibitory effect. PGE2 had a biphasic dose-dependent effect. The increased thromboplastin activity at low concentrations of PGE2 (10 ng/ml) was inhibited by addition of one of the compounds verapamil, felodipine, nifedipine or DZA/Hcy. PGE2 at higher levels (10 micrograms/ml) significantly inhibited thromboplastin synthesis. Combination of PGE2 (10 micrograms/ml) and one of the calcium antagonists, DZA/Hcy or MIX gave no significant additive inhibitory effect.

1-Methyl-3-isobutylxanthine↗

PubMed1994

Comparison of a standard and a sensitive thromboplastin in monitoring low intensity oral anticoagulant therapy.

The greater precision in prothrombin time monitoring obtained using thromboplastins with low international sensitivity index (ISI) values are believed to result in improved patient care. The authors conducted a blinded prospective study of 84 random patients on low-intensity warfarin therapy who were monitored with either a sensitive (ISI, 1.3) or standard (ISI, 1.9) thromboplastin. For the patients monitored with standard and sensitive thromboplastins, respectively, no difference was found in the degree of anticoagulation (standard thromboplastin mean INR, 2.4 vs. 2.5, P = .37; sensitive thromboplastin mean INR, 2.6 vs. 2.6, P = .74; mean daily warfarin dose, 5.1 vs. 4.7 mg, P = .28) or efficacy (warfarin dosage adjustments, 117 vs. 116; clinic visits, 362 vs. 378; percentage of therapeutic INR determinations, 47% vs. 48%). In addition, no difference was found in bleeding prevalence or severity (.22 vs. .27 events per person-year observation). The authors concluded that monitoring anticoagulant therapy in the INR range of 2-3 with a standard thromboplastin may be comparable to monitoring with a more sensitive thromboplastin with respect to efficacy, safety, and degree of anticoagulation achieved.

Administration, Oral↗

PubMed1983

Thromboplastin as a marker for monocyte differentiation.

The thromboplastin synthesis of the human monocytoid cell line U-937 and its two subclones designated U-937-3 and U-937-4 has been studied. U-937-4 seems by several functional criteria to represent a more advanced stage of monocyte differentiation than the original U-937. U-937-3 appears to be arrested at an even more immature stage than the original population. The basal thromboplastin activity was higher in U-937-4 than in U-937-3 or U-937 cells (7.0 +/- 1.9 (SEM), 1.0 +/- 0.2 and 1.6 +/- 0.6 units/mg protein, respectively) although not as high as in human normal monocytes (14.1 +/- 2.4). The thromboplastic expression of the two clones was maximal when cells were in logarithmic growth. Both clones responded with a weak to moderate thromboplastin synthesis upon addition of stimulants like phytohaemagglutinin (PHA), immune complexes or endotoxin. Thromboplastin production was also potentiated in the presence of lymphocytes. The supporting effect of lymphocytes was strong in the case of U-937-3 as well as in U-937 cells, but less pronounced in U-937-4 cells as it also is in human monocytes. The thromboplastin response after PHA stimulation was more rapid in U-937-4 cells (maximal after 4-8 h) than in U-937 or U-937-3 cells (12-16 h). Human monocytes also responds quickly to PHA (maximally 4 h). Total phospholipid content and the relative distribution of individual phospholipids were essentially similar in U-937-3, U-937-4 and U-937. With regard to thromboplastin production, U-937-4 cells seem to be more monocyte-like than the more immature cells U-937-3 and U-937. It is concluded that thromboplastin seems to be a useful marker for monocyte differentiation.

Antigen-Antibody Complex↗

PubMed2004

Activated partial thromboplastin time abnormality in patients with cholangiocarcinoma.

Cholangiocarcinoma can be detected worldwide, but is most common in tropical areas where crowded living conditions and poor sanitation exist. This infection can demonstrate a wide spectrum of clinical presentations from no complaints to arrest. Similar to the other liver diseases, the activated partial thromboplastin time abnormality can be seen in the patients with cholangiocarcinoma. The activated partial thromboplastin times among 33 Thai hospitalized patients with cholangiocarcinoma are studied. The correlation between the activated partial thromboplastin time and the other characteristics of the patients is studied. Most characteristics of the patients show no significant correlation with activated partial thromboplastin time (p > 0.05). The only two parameters that showed significant correlation are alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (p < 0.05). Because the activated partial thromboplastin times shows significant relation to AST and ALT but not to serum bilirubin and alkaline phosphatase, this might mention that the prolonged activated partial thromboplastin time seems to relate with the process of hepatic parenchyma damage than the biliary tract obstruction. Hence, as a hypothesis, the prolonged activated partial thromboplastin time might be a useful indication for excessive parenchymal involvement in cholangiocarcinoma. However, because the total number of cases in this study is rather small, a larger study to answer this question is necessary. In addition, the more systematic evaluations are required to answer the raised hypothesis.

Adult↗

PubMed1975

A simplified thromboplastin calibration procedure for standardization of anticoagulant control.

In thromboplastin calibration, the possibility of replacing fresh individual plasmas by pooled fresh plasmas (used immediately after preparation or after storage at -25 degrees C) or by pooled lyophilized plasmas has been investigated. It was found that the thromboplastin sensitivity ratios (TSR's) assessed with pooled fresh plasmas show no divergence from those obtained with the original Biggs/Denson calibration procedure. With pooled lyophilized plasmas a small divergence can be found in particular with so-called PIVKA-insensitive rabbit-tissue thromboplastins. Since, in contrast to the original procedure, only a limited number of determinations with pooled fresh or lyophilized plasmas are needed to obtain an accurate TSR value, the modification substantially simplifies thromboplastin calibration. Moreover, the technique using lyophilized plasmas can be applied in laboratories where an insufficient number of patients are available or none at all. However, as long as pooled lyophilized plasmas display a more or less pronounced activation, it might be preferable to restrict calibration to qualified expert laboratories, i.e. national reference laboratories. The merits of pooled lyophilized plasma are those of good stability even under the condition of accelerated degradation. They might be just as useful as thromboplastins for use as (long-term) reference material in the standardization and quality control program of manufacturers of thromboplastins, and for laboratorians preparing their own thromboplastin for the anticoagulant control. Conditions for the preparation and use of lyophilized reference plasmas have been worked out and are presented.

Anticoagulants↗

PubMed1965

Studies on tissue thromboplastin. II. Species specificity.

Purified brain tissue thromboplastins of human, bovine and chicken origin have been tested on homologous and heterologous plasmas. Purified brain tissue thromboplastin is species specific. Lipid extracts from purified brain tissue thromboplastin prepared with pyridin show a negligable residual species specificity, probably caused by a slight contamination with brain tissue thromboplastin. The activity curves of our lipid extracts differ from typical curves expected for lipid activators by a less distinct inhibition in high concentrations probably caused by a different composition of petrol-ether and pyridin extracts. The protein part of tissue thromboplastin does not activate prothrombin in any system. The protein part of tissue thromboplastin of one species could be combined with the lipid part of another species to form an active tissue thromboplastin. The species specificity of these combinations was determined by the source of protein used.

Animals↗

PubMedDate not supplied

[Obtaining a reference pattern of rabbit brain thromboplastin].

Thromboplastin is a tissue extract used in the prothrombin time test (PT) necessary for oral anticoagulant control. The interlaboratory variability of the results of the PT test with thromboplastins of different tissue types, besides differences due to reporting PT in seconds or percentage, indicate the need for a standardized reference thromboplastin in order to express PT results on a common scale. The aim of the present work is to encourage the laboratory hospital either singly or in regional groups, to produce a standardized thromboplastin for their own use, to insure the control of oral anticoagulant therapy. Rabbit brain thromboplastin was prepared by Quick's technique. The reagent was calibrated against the international reference thromboplastin RBT/079, following the recommendations of the World Health Organization (WHO). Statistical analyses of the data were performed using an orthogonal regression. We obtained an international sensitivity index (ISI) of 2.177, a standard error of 0.0454 and a coefficient of variation of 2.09%. An international normalized ratio (INR) was also obtained for the conversion of measured PT to a common scale. The INNSZ thromboplastin is the first national reference preparation. With this reagent the introduction of an international scale for the control of oral anticoagulant therapy has become feasible in our country.

Animals↗

PubMed1983

Is lymphocyte co-operation necessary for thromboplastin synthesis by human monocytes?

Human monocytes synthesize the protein component of thromboplastin and express increased procoagulant activity when appropriately stimulated in vitro. The activity reached maximum between 2 and 20 h depending on the stimulant used. The presence of lymphocytes (lymphocyte: monocyte ratio 4:1) enhanced this activity only very slightly (up to 1.3-fold) at the time of maximal monocyte thromboplastin expression. Lymphocytes had a marked potentiating effect on PHA stimulation that became clearly evident after 12 h, at which time the thromboplastin response of monocytes alone to PHA had subsided. The thromboplastin activity of monocytes remained at a high level for 24-40 h in the presence of PHA or endotoxin and lymphocytes, but lymphocytes did not influence the early (4-8 h) thromboplastin response. Neither did lymphocytes alter the magnitude or the time course of the response when monocytes were stimulated with PPD, TPA or immune complexes. The lymphoblastoid cell line Molt 4 (T cell like) was as effective as lymphocytes, Daudi cells (B cell like) were slightly less effective. The enhancement of thromboplastin activity in PHA-stimulated monocytes could be induced also by conditioned medium from PHA stimulated lymphocytes. We conclude that freshly isolated monocytes synthesize thromboplastin directly upon interaction with a stimulant, and are not dependent on a helper effect of lymphocytes or lymphocyte products. Such help, however, will prolong the ability of the monocytes to respond.

Antigen-Antibody Complex↗