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A variety of amines induced a dose-dependent and time-dependent increase in thromboplastin activity of cultured human monocytes. The increase required protein synthesis, and reached a peak after about 18 h. Some inhibitory effects were noted at low concentrations of NH4Cl. It is suggested that the amines act by raising the pH of acidic intracellular compartments.
To evaluate the use of the activated partial thromboplastin time (APTT), as measured by the Coag-A-Mate semi-automatic unit, in lowering the dosage of heparin in stable chronic hemodialysis patients, four protocols for anticoagulation were utilized. Ten patients were dialyzed five times with each protocol. In protocol I, clotting time was performed baseline, 2 and 4 hours and in protocol II, baseline and every 30 minutes, with heparin administered by bolus to keep the clotting time at 2-2 1/2 times normal. In protocols III and IV the APTT was performed every 30 minutes, with heparin given by bolus in protocol III and infusion in protocol IV, to keep the APTT 1 1/2-2 times normal. Protocol I required 6000 +/- 543 U of heparin with the dose decreasing significantly to 3694 +/- 158 U in protocol II, 2634 +/- 139 U in protocol III and 2013 +/- 117 U in protocol IV (P less than 0.05- less than 0.001). Three episodes of clotting occurred, one in protocol III and two in protocol IV. There was no bleeding, and clearances of urea, creatinine, phosphate and uric acid at 1 and 5 hours were similar in all protocols. APTT, as measured by the Coag-A-Mate unit, provides a simple means of lowering heparin requirements in routine dialysis patients.
The international sensitivity index (ISI) of the first working standard of Simplastin HTF, a new human tissue factor thromboplastin derived from cultured human cells, has been assessed in a calibration exercise in two Canadian and five European laboratories. Calibrations against international reference preparations (IRP) were performed for the manual method and six types of automated coagulometers that cover the majority of clotting endpoint principles in routine use. The ISI was method-dependent and varied between 1.03 and 1.29 when calibrated against rTF/95 (human IRP). The ISI was also dependent on the route of calibration. Compared with calibration against rTF/95, the ISIs obtained by calibration against RBT/90 (rabbit IRP) were on average 4.4% higher (P < 0.005). Considering the principle of 'like vs. like', the ISIs obtained by calibration against rTF/95 should be preferred.
Heparin can be quantified with antifactor Xa and IIa tests (aXa, aIIa) but the anticoagulant power of heparin depends upon plasma properties as well as upon heparin concentrations and thus differs between subjects. Measuring the effect, as with the activated partial thromboplastin time (APTT) therefore is clinically more relevant. Here we investigate the use of the endogenous thrombin potential (ETP) for this purpose. In 12 volunteers 9000 IU of four heparins of different mol. wt distributions were injected. Samples were taken at 11 time points between 0 and 24 h. With the exception of the 0 and 24-h time points, heparin could be demonstrated by its aIIa and aXa activity in virtually all samples. The APTT showed the effect of this heparin in 34% of the samples; the ETP in 80%. This is partly due to the wide margins of the normal values, caused by large interindividual variation [coefficient of variation (CV) approximately 12% for the APTT, approximately 17% for the ETP]. The intraindividual variation is much smaller (CV approximately 4% for the APTT, approximately 5% for the ETP). Relative to the baseline value of the individual, the heparin effect was recognized by the APTT in 55% of the cases and by the ETP in 98%. There were no large differences between the different types of heparin.
BACKGROUND: Venous thromboembolism (VTE) is a multi-factorial disease. Extensive thrombophilia screening is costly and often inconclusive. Simple laboratory methods are required to predict the risk of recurrence. OBJECTIVE: To assess if measurement of activated partial thromboplastin time (APTT) allows stratification of patients with VTE into high- and low-risk categories with regard to recurrence. PATIENTS AND METHODS: We prospectively followed 918 patients with a first unprovoked VTE and studied the relationship between recurrence and an APTT after discontinuation of anticoagulation. APTT was expressed as a ratio of test to reference coagulation times. Study endpoint was symptomatic recurrent VTE. RESULTS: Venous thromboembolism recurred in 101 (11%) patients. Patients without recurrence had a greater APTT ratio than those with recurrence (0.97 +/- 0.09 vs. 0.93 +/- 0.09, P = 0.001). After 4 years, probability of recurrent VTE was 8.5% (95% CI: 5.5-11.5%) among patients with a ratio equal to or > 0.95 and 15.6% (95% CI: 11.4-19.9%) among patients with a lower ratio (P = 0.005). Compared with patients with an APTT ratio < 0.95, the relative risk (RR) of recurrence among patients with a ratio equal to or > 0.95 was 0.56 (95% CI: 0.38-0.84, P = 0.005) before and 0.58 (95% CI: 0.39-0.87, P = 0.009) after adjustment for sex, age, factor V Leiden, and factor II G20210A. CONCLUSIONS: Measurement of APTT allows stratification of patients with VTE into high- and low-risk categories with regard to recurrence.
OBJECTIVES: Existing clinical practice guidelines for ordering prothrombin time (PT) and partial thromboplastin time (PTT) tests in the emergency department (ED) include physician expectation of an invasive procedure as a criterion. This study sought to determine whether this criterion accurately identifies patients who undergo an invasive procedure and whether an amalgam of these guidelines identifies patients at low risk of an adverse medical outcome. METHODS: A prospective observational cohort study of adults treated in a university medical center ED between July 1997 and March 1998. Physicians were surveyed at order placement to determine the presence of guideline criteria. Adverse clinical outcomes defined as an International Normalized Ratio [INR] > 1.3 or PTT > 39.9 seconds combined with consequent directed medical therapy were abstracted from ED and the first 24 hours of inpatient medical records. RESULTS: The sensitivity of ED physician expectation of an invasive procedure was 60.0%; therefore, it was excluded from both the PT and PTT guidelines. There were 553 patients with a PT test order; test order indications were absent in 190 (34.4%), of which one (0.5%, 95% CI = 0.1% to 2.9%) had adverse outcomes. There were 547 patients with a PTT test; test order indications were absent in 226 (41.3%), of which three (1.3%, 95% CI = 0.4 to 3.8%) had adverse outcomes. All three were taking warfarin when they presented to the ED. CONCLUSIONS: Emergency department physician expectation of an invasive procedure for patients with PT or PTT test orders is an insensitive predictor of patients who undergo such procedures. Clinical practice guidelines that exclude this criterion identify ED patients at the time of ED presentation at low risk for adverse medical outcomes in the ED or shortly after admission.
The protein and phospholipid components of tissue thromboplastin have been isolated and their interactions with factor VII and factor Xa have been studied by gel filtration, centrifugation and heat inactivation. As expected, the phospholipid fraction bound both factors in the presence of Ca2+. No evidence for an interaction of apoprotein III with factor VII or Xa was obtained.
The Activated Partial Thromboplastin Time (APTT) test, Cephotest, was compared to other APTT methods in current use in 4 specialized coagulation laboratories. In 3 of 4 laboratories, the sensitivity of Cephotest was superior (P less than 0.001) to that of the local APTT method. There was no statistically significant difference between the APTT methods with regard to precision of repetitive testing. In each laboratory, the normal range of Cephotest was estimated on freshly collected plasma samples from healthy subjects. A mean value between 28.8 and 35.8 s, with a standard deviation of 1.1-3.3 s, was obtained. It is concluded that the composition of the APTT method if of importance for the sensitivity of this test, but does not influence the precision of repetitive testing to a significant degree. The use of a standardized reagent facilitates comparison of the results obtained with the APTT method from one laboratory to another.
A study has been carried out in two stages to compare the sensitivity of different Partial Thromboplastin Time (P.T.T.) methods to partial deficiencies of factor VIII. In Stage 1, 63 laboratories throughout the world compared their own methods with a reference method, all using samples of the same three mild haemophilic plasmas. Wide variation was found between laboratories using the same method, especially for those methods which were not well standardised. There was fairly good agreement for the reference method. All methods correctly diagnosed the three mild haemophilic plasmas, but their factor VIII levels were rather low. Stage 2 was restricted to seven laboratories in Great Britain, comparing seven well-standardised commercial methods and the same reference method. A much wider range of abnormal plasmas was tested, and a variety of normal ones. P.T.T.'s for all plasmas (factor VIII levels from 5 to 58 iu/dL) fell outside the normal range by all methods, with a few exceptions. It was not possible to rank the methods in any order.
Collaborative studies to measure the effect of heparin on the activated partial thromboplastin time (APTT) have been conducted by the National (UK) Reference Laboratory for Anticoagulant Reagents and Control (NRLARC) in Great Britain and overseas and by the College of American Pathologists (CAP) in the United States. The value of multicentre trials to assess the various APTT methods, as opposed to single centre investigations, is discussed. Results from the NRLARC studies indicate that APTT methods from commercial manufacturers are relatively insensitive to heparin at low levels, compared with the standardised APTT reagent and technique produced by the NRLARC. The latter shows good sensitivity over a wide range of heparin concentrations. Variables encountered with the different commercial APTT methods are outlined. An APTT reagent should show good sensitivity at low levels and a linear response to a wide range of heparin concentrations. The in vivo response of the NRLARC standardised method in detecting circulating heparin during a clinical study of low-dose heparin prophylaxis during surgery has also been evaluated.
An inappropriate blood-to-anticoagulant ratio can cause an artifactual prolongation of the activated partial thromboplastin time (APTT) and prothrombin time (PT). In a drug safety study in dogs, we observed a 4- to 5-second increase in the APTT from baseline coincident with increased hematocrit values (56% to 65%) secondary to drug-induced vomiting and diarrhea. The PT and platelet counts were unchanged, and there was no clinical evidence of bleeding associated with venipuncture. Although we were unable to sample the same dogs to investigate the possible effect of hemoconcentration on the prolonged APTT, the question was addressed by an in vitro study. The hematocrit value for citrated blood samples collected from healthy beagle dogs was increased by the addition of aliquots of red blood cell/plasma mixtures in vitro while maintaining a 9:1 blood-to-anticoagulant ratio. There was a 2- to 4-second prolongation of the APTT associated with hematocrit values of 55% to 61%, but the PT was not prolonged. Adjustment of the blood-to-anticoagulant ratio corrected the prolongation. This study emphasizes the important relationship of the blood-to-anticoagulant ratio when measuring coagulation tests in hemoconcentrated samples.
Intravenous injection of autologous lipoprotein (thromboplastin) or thrombin produced a lethal, hemorrhagic syndrome in chicken embryos. The embryos could be protected from this fatal result by injection of antithrombin III, an alpha(2)-globulin (molecular weight 60,000 to 80,000) purified from human, bovine, and guinea pig blood. Heparin also protected the embryos, but other inhibitors were less protective.
Peroxidase-conjugated antibodies were used to determine the histologic and cytologic localization of bovine and human tissue factor (thromboplastin). Tissue factor antigen was found in highest concentration in the intima of blood vessels, particularly in the plasma membranes of endothelial cells and in human atheromatous plaques. Tissue factor was also found limited to the plasma membranes of many cell types. The presence of tissue factor in the plasma membranes of endothelial cells and atheromata suggests that it may play a significant role in hemostasis and thrombosis.
The British comparative thromboplastin (BCT) was used to monitor the effectiveness of oral anticoagulants in preventing deep vein thrombosis (DVT) in patients undergoing major gynaecological surgery. All patients were screened for DVT with the use of the (125)I-fibrinogen scan.One hundred and forty-five patients aged 40 years or more were randomised into three groups. Group 1 received oral anticoagulant (nicoumalone) treatment, stabilised over five days before surgery and continuing into the second postoperative week. The other patients served as two contrast groups and were managed on a double-blind basis. Group 2 received a subcutaneous low-dose regimen of heparin calcium. Group 3 received subcutaneous saline. Eleven of 48 patients in the saline group, three of 49 patients in the heparin group, and three of 48 patients in the oral anticoagulant group developed DVT as judged by (125)I-fibrinogen scanning. The incidences in groups 1 and 2 were significantly lower than in the saline group. The falls in haemoglobin concentration and incidence of haemorrhage were similar in all three groups.The study showed that oral anticoagulant prophylaxis stabilised preoperatively and low-dose heparin were equally effective in preventing deep vein thrombosis in a moderate-risk group. Immediate preoperative prothrombin ratios of 2.0-2.5 and postoperative ratios of 2.0-4.0 with the BCT gave adequate protection without increased haemorrhagic risk.
Activated partial thromboplastin times (APTT) for monitoring heparin therapy for venous thromboembolism tended to be inappropriately short if blood was collected in commercially available evacuated glass tubes. Five types of evacuated tubes marketed under the trade names Vacutainer and Venoject were examined. The APTT of heparinized blood collected in these tubes correlated poorly (r = 0.04 to 4 = 0.25) with that of blood samples from the same patients collected in plastic tubes. Most of the evacuated tube APTT were shorter than that of blood collected in plastic or siliconised glass tubes, but the results were unpredictable and varied from tube to tube and from batch to batch. This effect on heparin is apparently due to an unidentified substances which is eluted from the rubber stoppers of the tubes. Heparin control according to the APTT blood collected in these evacuated tubes is hazardous.
AIMS: To compare the International Normalised Ratio (INR) obtained directly with the two types of WHO plain International Reference Preparation for thromboplastin in patients treated with coumarin. METHODS: Prothrombin times were performed in parallel at four centres using WHO human plain IRP (BCT/253) and rabbit plain IRP (RBT/79). Sixty patients and 20 normal controls were tested at each centre. Differences in INR among the centres were assessed by one factor, analysis of variance. The bias for each centre was assessed by the t test. RESULTS: At all four centres higher INRs were consistently found with the rabbit plain reagent. Two of the centres showed significantly greater bias. CONCLUSIONS: There was a small but significant difference in INR results obtained directly with these two reference reagents at all four centres (mean 7.35%). This in part may result from the different responsiveness of the two IRP to the coumarin defect or to imprecision of the original ISI calibrations of the two plain WHO IRP. The findings support the adoption of a single master IRP, in accord with WHO recommendations, which would resolve the present anomalous situation.
There is evidence that intravenous nitrates which are frequently used in acute coronary syndromes may interfere with the anticoagulant effect of heparin. We compared the effect of two different nitrate preparations on the activated partial thromboplastin time (APTT), anti-thrombin III activity (AT III) and plasma heparin levels in patients (n = 50) undergoing routine percutaneous transluminal coronary angioplasty (PTCA) for stable angina. Patients were randomized to either: (1) intravenous heparin and nitroglycerin (GTN); or (2) intravenous heparin and isosorbide dinitrate. The APTT, plasma heparin concentration and AT III activity were measured before PTCA and at 2 and 4 hours after commencement of infusions. Both groups received identical doses of heparin. Group 1 patients received a constant dose of 16.6 micrograms/minute of GTN, and group 2 patients received 33.3 micrograms/minute of isosorbide dinitrate. At 4 hours the median APTT ratio was significantly lower in group 1 compared with group 2 (2.6 versus 4.5) (P < 0.05) as was the plasma heparin concentration (0.18 U/ml versus 0.32 U/ml (P < 0.05). However, no significant difference in APTT ratios or plasma heparin concentrations were noted at any of the other sample times. AT III activity was not significantly different between the groups at any sample time. Within-group analysis showed significantly lower APTT ratio and heparin concentrations at 4 hours compared with the respective 2 hour values. These results would suggest that there is a potential impairment of anticoagulation with low-dose intravenous nitroglycerin and to a lesser extent with low-dose isosorbide dinitrate. Early and frequent monitoring may therefore be appropriate when intravenous nitrates and heparin are used in combination.
Properties of the protein moieties of canine tissue thromboplastins (TTP's) from brain (BTTP), lung (LTTP), arteries (ATTP), AND VEINS (VTTP) were determined. The maximum specific activity of each protein moiety after its relipidation was obtained when the phospholipid-delipidated TTP ratio was 0.32 and was 1,395 U/mg BTTP, 1,130 U/mg LTTP, 630 U/mg VTTP, and 435 U/mg ATTP. The amino acid contents of the protein moieties of LTTP, ATTP, and VTTP were closely similar, but that of BTTP was significantly different. The Ouchterlony analysis showed that BTTP did not react at all with the antibody against VTTP, but that three other TTP's did and showed the reaction of complete identity. Then, the reactivity of 125-I-labeled TTP's with the anti-VTTP antibody was studied. The results showed that 0.79 +/- 0.01 (SD) % of [125I]BTTP, 10.24 +/- 0.5 (SD) % of [125I]LTTP, 19.4 +/- 0.2 (SD) % of [125I]VTTP, and 5.88 +/- 0.4 (SD) % of [125I]ATTP added were bound to the antibody in 2 h. Next, the molecular weight of each was determined by Sephadex G-200 filtration, which averaged 80,000 +/- 4,000 (SD) ([125I]BTTP), 113,000 +/- 5,000 (SD) ([125I]LTTP), 62,000 +/- 3,000 (SD) ([125I]ATTP), and 47,000 +/- 2,000 (SD) ([125I]VTTP). Finally, the plasma behavior of each was studied in four dogs. The plasma half-life averaged 8.1 +/- 0.24 (SD) h ([125I]BTTP), 14.6 +/- 0.5 (SD) h ([125I]LTTP), 7.38 +/- 0.48 (SD) h ([1252]ATTP), and 24.3 +/- 0.9 (SD) h ([125I]VTTP). These results indicate that the protein moieties of canine TTP's from brain, lung, arteries, and veins are closely similar in some aspects but dissimilar in others and are definitely not identical.