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Irreversible denaturation of tissue thromboplastin from human brain occurred at pH values below 5.0 and above 11.0. Coagulating activity of total phospholipid fraction of thromboplastin was decreased after incubation in acid or alkaline media.
The influence of heparin and thromboplastin on the halflife of 125I-protein C in rat blood was under investigation. It was found that t1/2 of protein C was of 2.3 h. The intravenous administration of heparin resulted in the prolongation of t1/2 to 6.5 h, that could be explained by inhibition of thrombin generation. Upon the 40-min infusion of thromboplastin the rate of 125I-protein C decay in blood enhanced. That could be explained by the generation of the endogenous thrombin and participation of thrombomodulin in the protein C activation as well as in the removal of the endogenous thrombin from blood.
In a collaborative trial of eleven laboratories which was performed mainly within the framework of the European Community Bureau of Reference (BCR), a second reference material for thromboplastin, rabbit, plain, was calibrated against its predecessor RBT/79. This second reference material (coded CRM 149R) has a mean International Sensitivity Index (ISI) of 1.343 with a standard error of the mean of 0.035. The standard error of the ISI was determined by combination of the standard errors of the ISI of RBT/79 and the slope of the calibration line in this trial. The BCR reference material for thromboplastin, human, plain (coded BCT/099) was also included in this trial for assessment of the long-term stability of the relationship with RBT/79. The results indicated that this relationship has not changed over a period of 8 years. The interlaboratory variation of the slope of the relationship between CRM 149R and RBT/79 was significantly lower than the variation of the slope of the relationship between BCT/099 and RBT/79. In addition to the manual technique, a semi-automatic coagulometer according to Schnitger & Gross was used to determine prothrombin times with CRM 149R. The mean ISI of CRM 149R was not affected by replacement of the manual technique by this particular coagulometer. Two lyophilized plasmas were included in this trial. The mean slope of relationship between RBT/79 and CRM 149R based on the two lyophilized plasmas was the same as the corresponding slope based on fresh plasmas. However, the mean slope of relationship between RBT/79 and BCT/099 based on the two lyophilized plasmas was 4.9% higher than the mean slope based on fresh plasmas.(ABSTRACT TRUNCATED AT 250 WORDS)
The binding of 125I-labeled human prothrombin to native and papain-treated tissue thromboplastin in the presence of CaCl2 or EDTA was studied. The Scatchard plots for the protein binding suggest the presence at thromboplastin surface of two types of binding sites, high affinity [Kd(app) = 7.4.10(-8) M] and moderate affinity [Kd(app) = 7.9.10(-5) M]. The removal of Ca2+ did not influence the Kd (values for these) sites but markedly reduced their number. Proteolysis by papain caused a decrease in the affinity of high affinity sites without affecting the Kd values of the moderate affinity sites yet caused a proportional increase in the number of both high and moderate affinity sites in the presence of Ca2+. At low prothrombin concentrations a positive cooperativity of protein binding at high affinity sites in the presence of Ca2+ was observed.
The i.v. administration of 1.5 ml of the heparin complexes with plasma proteins prior to the injection of tissue thromboplastin induced a stronger neutralization of formed thrombin in the blood and higher anticoagulating and fibrinolytic activities in albino rats as compared to the injection of tissue thromboplastin alone.
The molecular structure of the human brain tissue thromboplastin was studied by the method of NMR-31P and 1H using the shifting reagent. Molecular model of the tissue thromboplastin is suggested. According to the model only 10-20% of polar phosphate-containing heads are exposed outside. Phospholipids located deeper form hexagonal (HII) cylinders which may consist only of lipids or of complexes with proteins.
Young rats (weight 190-200 g) were subjected to splenectomy or sham laparotomy and gram-negative bacteraemia was induced by caecal perforation or by injection of viable Escherichia coli intraperitoneally (10(9) bacteria) or intravenously (2 X 10(8]. Clearance of bacteria was significantly less in the splenectomized than in the sham-laparotomized rats, irrespective of the mode of microbial inoculation. Monocyte thromboplastin activity, shown to be a sensitive indicator of gram-negative bacterial presence, was heightened in the asplenic rats. When the infectious challenge was made 15 weeks postoperatively, however, no significant difference in bacterial clearance or in monocyte thromboplastin values was found between splenectomized rats and controls. Nor was increased susceptibility to gram-negative bacteria found in asplenic rats when both operation (splenectomy vs. sham laparotomy) and bacterial challenge were performed at a late age (weight 530-580 g). The postsplenectomy clearance of gram-negative bacteria thus seemed to be age-dependent.
Reversible acute disseminated intravascular coagulation (DIC) has been induced in dogs by intravenous injection of homologous tissue thromboplastin. There was no measurable consumption of antithrombin III and heparin cofactor II even if fibrinogen was reduced during DIC by more than 80% of its baseline. The prothrombin level remained practically constant. These data correspond to the generation of a few nanomoles of thrombin in vivo with subsequent pseudo-first order inactivation by the major thrombin inhibitors. An ex vivo measure of the pseudo-first order rate constant (dynamic thrombin inhibitory capacity, DTIC) was a sensitive probe of circulating heparin. There was no change of DTIC during DIC in the absence of exogenous heparin suggesting that heparin-like endogenous glycosaminoglycans were not released in substantial amounts. Pretreatment with heparin efficiently inhibited the development of tissue thromboplastin induced DIC. This animal model may serve as a tool for the study of glycosaminoglycan anticoagulants in vivo.
A breach in the inactivation of thrombin activity by antithrombin III following numerous repeated intravenous injections of tissue thromboplastin to albino rats was established. Seven injections of tissue thromboplastin to animals (at 30-40 min-interval) caused functional exhaustion of anticoagulation system and increased thrombin blood circulation level.
To determine the clinical usefulness of the activated partial thromboplastin time in screening patients before surgery, we related preoperative test results to the occurrence of hemorrhagic complications, studying all adult inpatients undergoing invasive diagnostic or therapeutic procedures at a large university hospital during a one-year period. Using clinical characteristics to divide the population into two groups according to a priori risk of hemorrhagic complications, we found that the activated partial thromboplastin time had no ability to predict the occurrence or absence of hemorrhage in the low-risk group, but that it was a predictor of modest strength in the high-risk group. Our data justify limiting preoperative coagulation screening to patients with active bleeding, known or clinically suspected bleeding disorders (including use of anticoagulants), liver disease, malabsorption, malnutrition, or other conditions associated with acquired coagulopathies and patients whose procedures may interfere with normal coagulation.
Trophoblasts from murine placenta synthesize thromboplastin in the absence of inducing agents and a functional complement system, nor is the rate or level of synthesis enhanced by inducers. A serum factor which is destroyed/removed by addition of oxalate and subsequent dialysis appears to enhance the ability of trophoblasts to synthesize thromboplastin.
The International Reference Preparation of human brain thromboplastin coded 67/40 has been thought to show evidence of instability. The evidence is discussed and is not thought to be strong; but it is suggested that it would be wise to replace 67/40 with a new preparation of human brain, both for this reason and because 67/40 is in a form (like Thrombotest) in which few workers seem to use human brain. A 'plain' preparation would be more appropriate; and a freeze-dried sample of BCT is recommended as the successor preparation. The opportunity should be taken also to replace the corresponding ox and rabbit preparations. In the collaborative study which would be required it would then be desirable to test in parallel line the three old and the three new preparations. The relative sensitivities of the old preparations could be compared with those found in earlier studies to obtain further evidence on the stability of 67/40; if stability were confirmed, the new preparations should be calibrated against it, but if not, the new human material should receive a calibration constant of 1.0 and the new ox and rabbit materials calibrated against that. The types of evidence available for monitoring the long-term stability of a thromboplastin are discussed.
In this study we have looked for differences in coagulation parameters before and after surgical removal of benign or malignant tumours. A striking increase in thromboplastin activity of the blood monocytes was seen 1 d after surgery. This paralleled a fall in factor VII activity. At the same time, the sensitivity of the blood monocytes to stimulation by endotoxin increased significantly. We propose from this study that monocyte thromboplastin may be a postoperative thrombogenic factor. Increased levels of factor VIII and fibrinogen 2-3 d postoperatively were found, probably caused by inflammation reactions induced by the surgery. No difference in coagulation parameters could be demonstrated between patients with benign, noninvasive lesions and patients with invasive, carcinomatous lesions.
A 42-yr-old woman with systemic lupus erythematosus without bleeding diathesis developed a prolonged activated partial thromboplastin time that was not corrected by normal plasma. An inhibitor that acted rapidly and inactivated 0.5 U/ml plasma thromboplastin antecedent (PTA, factor XI) at a 1:200 plasma dilution was demonstrated. In addition to a low titer of PTA (less than 0.01 U/ml), plasma assayed at 20-fold dilution also showed low titers of Hageman (factor XII, 0.02 U/ml), Fletcher (plasma prekallikrein, 0.02 U/ml), and Fitzgerald (high molecular weight kininogen, less than 0.01 U/ml) factors. The titer of these factors, except PTA, returned to normal upon further plasma dilution or upon removal of the inhibitor by protein A adsorption. Thus, the inhibitor appeared to interfere with these clotting factor assays, possibly by inactivating PTA in the substrate plasmas in the test system. Its specificity was further confirmed. The inhibitor did not interfere with surface-induced proteolytic cleavage of Hageman factor. Surface-induced generation of plasma kallikrein activity (amidolysis of H-D-pro-phe-arg-pNa and cold-promoted factor VII activity enhancement) requires only Hageman, Fletcher, and Fitzgerald factors and was normal. Reactions requiring all 4 contact phase factors, including PTA, such as surface-induced generation of plasmin activity (amidolysis of H-D-val-leu-lys-pNa) and activated Christmas factor (factor IXa) activity, were defective. Furthermore, the inhibitor bound to agarose-protein A inactivated and removed PTA selectively from normal plasma. The inhibitor was an IgG-lambda autoantibody that precipitated PTA. The inactivated activated PTA (factor XIa) without the requirement for an additional cofactor. Furthermore, it inhibited surface-induced activation of PTA by interfering with its proteolytic cleavage upon glass surface exposure and with its binding onto the reactive surfaces.
The role of protein moiety of tissue thromboplastin during its specific enzymatic modification by papain was studied. Treatment with papain was followed by a decrease of the number of binding sites for factor X on the surface of factor III. The ability of the remaining sites to bind factor X and to form prothrombinase complexes did not change thereby. The specific interaction of thromboplastin with the factors coupled with the external blood coagulation system are based on asymmetric distribution of phospholipids and apoprotein in the cell membrane.
In a collaborative study of ten laboratories performed mainly within the framework of the BCR (the European Community Bureau of Reference), five thromboplastins were calibrated against the WHO (World Health Organisation) primary international reference preparation 67/40. Of these five thromboplastins, three were BCR reference materials (BCT/099, OBT/79 and RBT/79) and two were WHO secondary international reference preparations (68/434 and 70/178). Human brain tissue type is represented by 67/40 and BCT/099; bovine type by 68/434 and OBT/79, and rabbit type by 70/178 and RBT/79. The calibration relations are expressed in terms of a linear relationship between the logarithms of the prothrombin times, measured in seconds.
In 16 patients, 13 with meningococcal infection and 3 suspected to have this infection, 8 patients were found to possess significant higher level of tissue thromboplastin activity of their monocytes isolated from the blood at the admission to the hospital than normal. Five of those 8 patients had an extremely high concentration, greater than 60-300 fold increase, and all these patients died. The exposed tissue thromboplastin activity on the surface of the endotoxin stimulated monocytes is probably the direct inducer of disseminated intravascular coagulation (DIC) in meningococcal infection.
Certain agents that induce spreading of or increased content or release of lysosomal enzymes from human monocytes also induce a dramatic increase in tissue thromboplastin content of the cells. The increase is inhibited by cycloheximide and actinomycin D and does not appear in granulocyte, lymphocyte or platelet populations treated in the same way. The effect of several other substances on the development of monocyte tissue thromboplastin activity is reported.