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Being a putative predictor of ischemic heart disease, the measurement of factor VII (FVII) coagulant activity will be presumably requested to clinical laboratories with increasing frequency. To assess the influence on FVII assays of different thromboplastins and FVII-deficient plasmas we compared performances of all possible combinations of 5 thromboplastins and 6 deficient plasmas. The reproducibility of the clotting times of the dose-response curves for human and rabbit thromboplastins were acceptable (CV lower than 7%), whereas bovine thromboplastin had a higher CV. Reproducibility was very similar for all deficient plasmas when they were used in combination with a given thromboplastin. Responsiveness of the dose-response curve did not depend on the deficient plasma but rather on the thromboplastin: one rabbit thromboplastin was the least responsive, the bovine thromboplastin the most responsive, the human and the remaining two rabbit thromboplastins had intermediate responsiveness. Assay sensitivity to cold-activated FVII varied according to the thromboplastin: the bovine thromboplastin was the most sensitive, the human thromboplastin the least sensitive, of the three rabbit thromboplastins two were relatively sensitive, one was almost insensitive. In conclusion, our results indicate that thromboplastin rather than deficient plasma is the crucial factor in the standardization of FVII assay.
Lipoprotein-associated coagulation inhibitor produces feed-back inhibition of tissue factor (tissue thromboplastin)-induced coagulation in the presence of factor Xa Recombinant lipoprotein-associated coagulation inhibitor (rLACI) was tested for its ability to modify thromboplastin-induced intravascular coagulation in a rabbit model that allows monitoring of iodine-125 fibrin accumulation/disappearance in the lung and sampling of blood for the measurement of coagulation parameters. Infusion of thromboplastin into the rabbit caused a rapid increase of radioactivity over the lungs, possibly due to the accumulation of 125I fibrin in the lungs, followed by a rapid decline of radioactivity, suggestive of removal of fibrin from the lungs. Thromboplastin also caused a rapid decrease of systemic fibrinogen that was accompanied by a lengthening of the activated partial thromboplastin time and prothrombin time. The effect of coinfusion of rLACI with thromboplastin or bolus injection of rLACI before thromboplastin infusion was studied. At a high dose of rLACI (800 micrograms/kg body weight), the thromboplastin-induced radioactivity increase in the lungs and the systemic fibrinogen decrease were completely suppressed. The activated partial thromboplastin time and prothrombin time of the plasma samples lengthened, possibly due to the presence of thromboplastin in circulation. The thromboplastin-induced radioactivity increase over the lungs was not completely suppressed by lower doses of rLACI (135 to 270 micrograms/kg body weight), but these doses of rLACI prevented systemic fibrinogen decrease. At a bolus dose of 23 micrograms/kg body weight, rLACI provided 50% protection of the fibrinogen consumption (fibrinogen decreased to 82% compared with 65% in rabbits treated with thromboplastin alone). These results show that rLACI is effective in the inhibition of thromboplastin-induced coagulation in vivo.
Twelve thromboplastins were tested against a secondary reference thromboplastin (human brain CRM BCR No. 147) or a tertiary house standard (human brain thromboplastin) with plasmas from normal healthy individuals and patients on oral anticoagulant therapy. The relationship between the prothrombin ratios of the thromboplastins tested versus the reference reagent was either a straight or curved line. The International Sensitivity Index (ISI) was estimated for each of the test thromboplastins and these ranged from 0.98 to 2.24. Some ISIs stated by manufacturers were different from our results. Thromboplastins with a high ISI showed a loss of sensitivity in assessing the level of anticoagulation at the upper end of the therapeutic range. In addition, the 95% Confidence Interval (CI) of the ISI estimations were widest for thromboplastins with the highest ISIs. Conversion of the prothrombin ratio to International Normalized Ratio (INR) was most accurate with the Australasian Reference Thromboplastin (ART) and least accurate with reagents having an ISI of 2.00 and over. Thromboplastins with an ISI between 1.10 and 1.50 may be adequate for the control of oral anticoagulant therapy, but were less accurate than a thromboplastin with an ISI approximating 1.00. Factors other than ISI should be considered in the choice of a thromboplastin, in particular a measurement of the accuracy of the ISI estimation such as the 95% confidence interval estimation used here.
High-sensitivity thromboplastin reagents suitable for use in the prothrombin time (PT) assay are typically prepared from human brain and placenta, tissues that are in limited supply and subject to viral contamination. Cloning and expression of recombinant human tissue factor (TF) has enabled production of a new generation of thromboplastin reagents whose performance and utility are under active investigation. The purpose of this study was to determine the feasibility of producing a sensitive human thromboplastin reagent from a non-recombinant source: cultured human cells. Several human cell lines with apparently high constitutive TF synthesis were identified, and a viable thromboplastin reagent (Humaplastin) was produced from a human lung cell line via a non-conventional process that did not require reconstitution or rehydration of TF in cell membranes. When calibrated against BCT/253, a human brain international reference thromboplastin, Humaplastin exhibited a mean normal prothrombin time of 12.6 +/- 0.7 s (mean +/- SD: n = 20) and an International Sensitivity Index of 1.09 +/- 0.019. The performance of this reagent was well correlated (r = 0.983) with Thromborel S, a commercially available human placental thromboplastin reagent. Orthogonal least squares regression of the log PT values from the placental thromboplastin reagent versus Humaplastin and two recombinant TF-based thromboplastin reagents suggested that the latter three reagents are somewhat more sensitive than the placental thromboplastin reagent, although such differences should not be expected to have a significant impact on clinical utility. It is concluded that cultured human lung cells represent a suitable source of tissue thromboplastin for production of a high-sensitivity non-recombinant thromboplastin reagent.
A multi-center study of the three W.H.O. international reference preparations (IRP) for thromboplastin has been performed. The main purpose of the study was the determination of the mean international sensitivity index (ISI) of a proposed replacement IRP for thromboplastin, rabbit, plain. Twenty laboratories in Europe, North America, and Australasia participated in the study. All clotting times were determined with the manual technique. The inter-laboratory variation of the ISI was considered as the relevant parameter for assessment of ISI precision. Low interlaboratory variation was observed in the calibration of rabbit thromboplastin against rabbit thromboplastin (2.9-3.0% coefficient of variation of calibration line slope). Relatively high interlaboratory variation was observed in the calibration of rabbit against human thromboplastin (3.7-7.2 CV). Intermediary interlaboratory variation was obtained in the comparison of rabbit or human plain thromboplastin with bovine combined thromboplastin (3.5-4.0% CV). These findings confirm the principle of like-to-like calibration in biological standardization. The mean ISI values based on the IRP for rabbit thromboplastin (RBT/79) are in excellent agreement with those obtained with the IRP for bovine thromboplastin (OBT/79). In contrast, the mean ISI values determined with the IRP for human thromboplastin (BCT/253) were 6% lower than those with RBT/79. This bias may be caused by a difference in design of the two historical calibration studies. The mean ISI of the proposed replacement IRP for thromboplastin, rabbit, plain obtained by calibration against RBT/79 was 1.035 (standard error: 0.027). It is recommended to round the mean ISI off to 1.0. Opportunity was also taken to compare a lyophilized normal pooled plasma with fresh individual normal plasmas.(ABSTRACT TRUNCATED AT 250 WORDS)
This study was conducted in order to examine possible anticoagulant properties of the lungs during tissue thromboplastin-induced intravascular coagulation. Rabbit brain tissue thromboplastin (n = 17) or saline (n = 6 + 3) was infused above the right atrium (n = 11 + 3) of the heart or in the arcus aorta (n = 6) for a period of 120 min in non-pregnant New Zealand rabbits. Rabbits infused with tissue thromboplastin responded with significantly (p < 0.05) more excessive changes in a number of haemodynamic variables (heart rate, PaO2,PaCO2, blood pH etc.) compared with rabbits infused with saline. Similarly, the prothrombin time (p < 0.05) and the activated partial thromboplastin time (p < 0.05) were significantly more prolonged in rabbits receiving tissue thromboplastin compared with control animals. Also the concentration of blood platelets (p < 0.05), plasma fibrinogen (p < 0.05), antithrombin (p < 0.05), and protein C (p < 0.05) decreased significantly in thromboplastin-treated animals compared with control animals. In all these haemostatic variables there was a common trend that animals infused with tissue thromboplastin in the arcus aorta responded more excessively than animals infused in the right atrium of the heart, and these deviations were statistically significant for fibrinogen (p < 0.05) and prothrombin time (p < 0.05). Similarly, animals infused with tissue thromboplastin in the arcus aorta had an increased number of microthrombi in the lungs and kidneys compared with animals receiving tissue thromboplastin above the right atrium. As the lungs are the first pass organ when you infuse above the right atrium the results from this study suggest that the lungs play a key role in protecting the organism against excessive tissue thromboplastin-induced activation of coagulation.
Factor VII levels as measured in one stage clotting assays are dependent on the degree of activation of factor VII and on the type of thromboplastin used. Bovine thromboplastin (BT) is known to be more sensitive to factor VIIa than human brain thromboplastin and the different sensitivities of these reagents to VIIa have formed the basis of a method for determining VIIa in plasma (16). Since human thromboplastin is no longer widely available, we have re-evaluated this method using bovine and two rabbit thromboplastins (Manchester Reagent, RT MR and Diagen activated, RT Diagen). Activated factor VII was generated in normal plasma by cold activation for 24 hours. During this period, factor VII assays using bovine thromboplastin increased markedly with time whereas the assays using rabbit thromboplastins showed considerably less change. The ratio of factor VII (bovine thromboplastin)/factor VII (rabbit thromboplastin) is a sensitive index of activated factor VII in plasma. The mean ratio in normal plasmas (using BT and RT MR) was found to be 1.02 (+/- s.d., range 0.80-1.24). The ratio was measured in 29 samples from patients with disseminated intravascular coagulation (D.I.C.) and was found to be increased in 24 (mean 1.71, range 0.93-3.38).