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Utility of activated partial thromboplastin time waveform analysis for identification of sepsis and overt disseminated intravascular coagulation in patients admitted to a surgical intensive care unit.

OBJECTIVE: An abnormality of the optical transmission waveform obtained during measurement of the activated partial thromboplastin time (aPTT) has been described in association with overt disseminated intravascular coagulation. This abnormality, a biphasic waveform, is caused by the in vitro formation of Ca2+-induced complexes between very low density lipoprotein and C-reactive protein. We have evaluated the diagnostic utility of aPTT waveform analysis for identifying patients with overt disseminated intravascular coagulation and sepsis. DESIGN: Observational study investigating the predictive value of biphasic waveform for the diagnosis of sepsis and overt disseminated intravascular coagulation. SETTING: Surgical intensive care unit of a university hospital. SUBJECTS: We studied 331 consecutive patients admitted to the intensive care unit during a period of 6 months. INTERVENTIONS: Laboratory analyses, including prothrombin time, aPTT, aPTT waveform analysis, fibrinogen, D-dimer antigen, and platelet count. MEASUREMENTS AND MAIN RESULTS: At the most sensitive threshold value of the waveform variable for detection of the biphasic waveform (slope_1 = -0.05 %T/sec), this abnormality was detected in 54 of 331 patients (16.3%) at admission and 95 of 331 patients (28.7%) during the entire course of intensive care unit treatment. At this threshold, 59.3% of patients with a biphasic waveform on admission and 45.3% with a biphasic waveform during the total intensive care unit course were diagnosed with sepsis. Depending on the threshold value of slope_1, the sensitivity of aPTT waveform analysis for detection of sepsis varied between 22% and 55% at admission and between 48% and 74% during the entire intensive care unit stay. The specificity for sepsis varied between 92% and 98% and between 81% and 94%, for admission and total intensive care unit course, respectively. Biphasic waveform showed a comparable specificity for the diagnosis of overt disseminated intravascular coagulation, albeit at a lower sensitivity. CONCLUSIONS: As an adjunct to routine coagulation testing in intensive care unit patients, aPTT waveform analysis is an elegant means for the rapid and highly specific identification of patients with sepsis.

Adolescent↗

Activated partial thromboplastin time waveform analysis: a new tool to detect infection?

OBJECTIVE: An abnormality of the optical transmission waveform obtained during measurement of the activated partial thromboplastin time (aPTT) has been described to identify a high-risk intensive care unit population consisting of patients with sepsis or with higher mortality rates than patients with normal aPTT waveforms. We investigated the abnormal aPTT biphasic waveform as a diagnostic and prognostic marker of infection. DESIGN: Prospective, observational study investigating the predictive value of aPTT waveform analysis for the diagnosis and prognosis of sepsis. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: We studied 187 consecutive patients who fulfilled at least two or more criteria of the systemic inflammatory response syndrome at admission or during intensive care stay and classified as having systemic inflammatory response syndrome, sepsis, severe sepsis, or septic shock during an 8-month period. INTERVENTIONS: Laboratory analyses including aPTT waveform analysis and procalcitonin and C-reactive protein concentrations were measured at days 1-3. MEASUREMENTS AND MAIN RESULTS: The final diagnoses were systemic inflammatory response syndrome in 49%, sepsis in 16%, severe sepsis in 12%, and septic shock in 23% of patients. On day 1, the biphasic waveform was significantly more abnormal in patients with severe sepsis or septic shock than in patients with systemic inflammatory response syndrome or sepsis. The biphasic waveform was more accurate than procalcitonin and C-reactive protein for differentiating patients with severe sepsis and septic shock, with 90% sensitivity and 92% negative predictive value. Biphasic waveform values were significantly more abnormal during days 1-3 in septic nonsurvivors than in survivors and nonseptic nonsurvivors. The biphasic waveform exhibited the best specificity (91%) and negative predictive value (98%) for the prognosis of sepsis-related mortality on day 3. CONCLUSIONS: In intensive care units, when the analyzer is available, aPTT waveform analysis is an inexpensive, rapid, effective, and readily available tool providing information for the diagnosis of severe sepsis and the prognosis of septic patients.

Adult↗

Heparin solution locked in acute hemodialysis catheters: impact on activated partial thromboplastin time.

Fifteen patients on hemodialysis, wearing acute dual lumen hemodialysis catheters (DLHCs) locked with a 4 ml heparin solution (HS) containing 7,500 IU of conventional heparin (3,750 IU/lumen), were studied. After the preexisting HS was aspirated and discarded, 10 ml of blood was withdrawn from each lumen in a syringe. Then, two 3 ml blood samples (A and B) were withdrawn in a row from the venous lumen; a third blood sample (C) was withdrawn from a peripheral vein, and the 20 ml of blood in the syringe was returned to the patient. Patient to control ratios of activated partial thromboplastin time (aPTT) in samples A, B, and C were 2.87 +/- 1.04, 2.02 +/- 0.85, and 1.06 +/- 0.14, respectively (p < 0.002 comparing A to B and B to C). In these patients, we also studied the effect of the same HS on the aPTT, 10 minutes after the filling of the DLHCs postdialysis. A blood sample (H1) was withdrawn at the end of the session; 10 minutes after injecting each lumen of the DLHC with a 2 ml HS containing 3,750 IU of heparin, a second blood sample (H2) was drawn from a peripheral vein. The aPTT ratios in samples H1 and H2 were 1.15 +/- 0.13 and 3.58 +/- 0.61 respectively (p < 0.0001). We concluded that even after the aspiration of 15 ml from the venous lumen of a DLHC filled with a 2 ml HS containing 3,750 IU of heparin, the next blood sample remains contaminated by heparin. Filling each lumen of a DLHC with the same HS results in a significant increment of the aPTT 10 minutes later.

Adolescent↗

Effect of argatroban on the activated partial thromboplastin time: a comparison of 21 commercial reagents.

Argatroban is a direct thrombin inhibitor used for the treatment of heparin-induced thrombocytopenia. The drug is administered by continuous infusion, at a recommended initial dose of 2 microg/kg per min, to achieve activated partial thromboplastin times (aPTTs) 1.5-3.0 times baseline. We evaluated the effect of argatroban, at clinically relevant concentrations, on aPTTs using 21 commercially available reagents. The aPTTs of plasma containing argatroban at 0.125-8.0 microg/ml (final concentration) were assessed using each reagent and an ACL 3000+ coagulation analyzer. Argatroban increased aPTTs (and aPTT ratios relative to control) in a broadly comparable fashion among reagents. Concentration-aPTT ratio profiles linearized well using logarithmic-logarithmic transformation (r > 0.98), with the regression slope taken as the reagent's sensitivity to argatroban. Sensitivity ranged from 0.304 +/- 0.006 to 0.364 +/- 0.007. Only the least and two most sensitive reagents (all now unavailable in the United States) differed significantly in sensitivity from the other reagents (P < 0.05). aPTT ratios of 2.25 occurred for all reagents at 0.41-0.92 mug/ml argatroban, and for 14 (67%) reagents at 0.53-0.67 microg/ml. This corresponds to a approximately 0.5 microg/kg per min dose difference in healthy subjects. We conclude that most aPTT reagents are similarly sensitive to argatroban, and reagent choice is unlikely to significantly affect argatroban monitoring in patients with heparin-induced thrombocytopenia.

Arginine↗

Effects of melagatran on activated partial thromboplastin time and on ecarin clotting time in cord versus adult plasma.

Melagatran is the active form of the oral direct thrombin inhibitor ximelagatran. Melagatran does not require antithrombin as a cofactor. Its administration is therefore of special interest in neonatal patients, whose plasma is relatively deficient in antithrombin. We investigated the effects of increasing amounts of melagatran (0.05-1 micromol/l) on the activated partial thromboplastin time (APTT) and ecarin clotting time (ECT) in cord versus adult plasma. Both the APTT and ECT were dose-dependently prolonged in the presence of increasing amounts of melagatran. Furthermore, the ECT revealed a higher susceptibility of cord plasma to addition of melagatran than adult plasma. Whereas similar amounts of melagatran were required in cord and adult plasma samples to double the APTT (IC(50), 0.47 vs 0.46 micromol/l), significantly less melagatran was required in cord versus adult plasma to double the ECT (IC(50), 0.26 vs 0.56 micromol/l). Based on APTT measurements, similar plasma levels of melagatran might be required in neonates and in adults to treat thromboembolic complications. The APTT, however, is relatively insensitive to plasma melagatran concentrations. When the sensitive indicator ECT is used, results suggest that lower amounts of melagatran might be required in neonates than in adults. This has to be scrutinized in future clinical studies.

Adult↗

Calibration of thromboplastins.

Anticoagulant therapy with coumarin drugs requires tests on the patient's blood to determine the dose rate for the drug. The tests involve measuring the effect of a preparation of a certain reagent, thromboplastin, in accelerating the clotting of the patient's blood. Features of the World Health Organization's recommendation on the appropriate laboratory procedure for a calibration assay and evaluation of results call for comment. The standard method involves estimation of a linear structural relation, a statistical technique long known but seldom finding practical application. This paper reviews its history, as a prelude to discussing strange mistakes in earlier publications; it also examines assessment of the precision of estimation and other aspects of the statistical method.

Humans↗

Heparin and partial thromboplastin time: an international survey.

The reliability of routine partial thromboplastin time (PTT) methods in the measurement of the anticoagulant effect of heparin has been assessed in a study involving over 300 hospitals in the U.S. and overseas. Commercial PTT methods were relatively insensitive to heparin, added in vitro, compared with the standardized PTT method tested by the same laboratories. Non-commercial, locally-prepared reagents compared well with the standardized method particularly in the detection of a low concentration of heparin. The value of a sensitive reference preparation for the calibration of routine PTT reagents used in heparin control is demonstrated.

Blood Coagulation↗

Stability of international reference thromboplastins.

Long-term stability of the WHO International Reference Preparation (IRP) of thromboplastin 67/40 and of two secondary preparations, WHO IRP 68/434 and the Dutch RP 73/528 was assessed by two criteria on the basis of the basis of data obtained in the period 1969-79. The clotting times of normal plasmas determined with these preparations over this 10 year period did not show changes which were of practical importance. Moreover, the slopes of the lines relating clotting-time ratios of 67/40 to ratios obtained with 68/434 or 73/528 did not give any firm reasons to assume a systematic change of these slopes with time. These lines were determined by linear regression analysis of individual patient ratios. Corrections were applied to the original data for modifications of the assay technique made during the past 10 years.

Blood Coagulation Tests↗

Falsely prolonged prothrombin time due to an inhibitor to human thromboplastin.

A patient with nephrotic syndrome of unknown aetiology was found to have a grossly prolonged prothrombin time in the absence of any other coagulation abnormality and with no clinical bleeding problem. Subsequent investigations showed his plasma contained an inhibitor-like substance, directed against human but not animal thromboplastin.

Humans↗

Abnormally short activated partial thromboplastin time values are associated with increased risk of recurrence of venous thromboembolism after oral anticoagulation withdrawal.

This study prospectively evaluated the relationship between activated partial thromboplastin time (aPTT) and risk of venous thromboembolism (VTE) recurrence after oral anticoagulant (OA) withdrawal in patients with a previous unprovoked VTE event. Six hundred twenty-eight patients (331 males; median age: 67 years) were followed after OA interruption (mean follow-up = 22 months). Three to four weeks from OA discontinuation patients were given a complete thrombophilic work-out, including aPTT (automated aPTT). Recurrent symptomatic VTE events (objectively documented) occurred in 71/628 (11.3%, 6.8/100 person-years) patients. The VTE recurrence rate was 17.5% and 7.5% in patients with aPTT in the lower (ratio < or =0.90) and in the upper (ratio >1.05) quartiles. The recurrence risk was more than twofold higher in patients with ratio < or =0.90 versus those of the reference category [Relative risk (RR): 2.38 (95% confidence interval (CI): 1.18-4.78)]. As expected, the increase in recurrence risk disappeared after adjustment for factor VIII, IX and XI levels [RR: 1.74 (95%CI: 0.43-2.76)]. In contrast, the risk was persistently increased in patients with a ratio < or =0.90 [RR: 2.07 (95%CI: 1.02-4.18)] after adjustment for age, gender and d-dimer level. The aPTT predictive value was independent of the presence of inherited thrombophilic alterations. In conclusion, abnormally short aPTT values are associated with a significantly increased risk of VTE recurrence.

Adult↗

Sensitivity of the thrombin clotting time and activated partial thromboplastin time to low level of antithrombin III during heparin therapy.

The thrombin clotting time (TCT) has been used at our institution, along with the activated partial thromboplastin time (aPTT), for monitoring heparin therapy. We have observed that, in some patients, a discrepancy develops between the heparin levels predicted by the TCT and the aPTT with the TCT consistently predicting a lower heparin level than the aPTT. An inverse relationship was noted between the functional antithrombin III (AT-III) level and the magnitude of this discrepancy.

Antithrombin III↗

Usefulness of synthetic phospholipid in measurement of activated partial thromboplastin time: a new preparation procedure to reduce batch difference.

Commercial activated partial thromboplastin time (APTT) reagents prepared with phospholipid extracted from animal or plant sources often differ in their response to heparin and coagulation factors and in their reference values. It is also known that there are variations in phospholipid composition and preparation procedure. The present study attempted to demonstrate that an APTT reagent based on synthetic phospholipids (phosphatidylethanolamine, phosphatidylcholine and phosphatidylserine), which are substances of high purity and homogeneity, reduces batch-to-batch difference when compared with two traditional APTT reagents derived from rabbit brain and soybean. Three types of APTT reagent (SYN-APTT, RBT-APTT, SOY-APTT), prepared respectively from synthetic phospholipid, rabbit brain, and soybean, were tested. The total batch-to-batch difference was coefficient of variation (CV) 0.7-2.4% in the five reagents prepared from synthetic phospholipid (SYN-APTT), but CV 1.5-10.3% in the two traditional reagents (RBT-APTT and SOY-APTT). Additionally, high-performance liquid chromatography (HPLC) analysis showed clear variation in the phospholipid composition of the RBT-APTT and SOY-APTT reagents. In conclusion, the SYN-APTT reagent derived from synthetic phospholipid was shown to reduce batch-to-batch difference, and we therefore suggest that synthetic phospholipid is a substance useful in the preparation of APTT reagent and could contribute to stability of supply and uniform diagnosis.

Animals↗

Thromboplastin (factor III) activity in human monocytes induced by immune complexes.

Immune complexes induced the synthesis of apoprotein III, the protein component of tissue thromboplastin (tissue factor), in human monocytes cultured in vitro. The response was maximal (11.1 +/- 1.7 fold increase (mean +/- SEM) when immune complexes were formed at antigen/antibody equivalence. Immune complexes formed with the antigen-binding fragments (F(ab')2) of immunoglobulins induced a 4.7 +/- 1.4 fold activity increase, suggesting that another signal mechanism in addition to the Fc-receptor may be involved.

Animals↗

Changes of activated partial thromboplastin time during constant intravenous and fixed intermittent subcutaneous administration of heparin.

Marked circadian variations in the activated partial thromboplastin time (APTt) during continuous heparin infusions for thromboembolic episodes have been reported in a French study. The aim of the present study was to test if these variations could be reproduced in a Swedish population. The frequency spectrum variations in APTt values were analysed with the Prony and the statistical Pearson product momentum correlation coefficient methods. In seven patients with pulmonary embolism, APTt was checked every fourth hour during 48 h of continuous, constant heparin treatment. In only one patient was a distinct circadian variation of APTt values seen. In six patients with venous leg thromboses, treated with s.c. heparin, marked variations in APTt were noticed over periods of 12 h. These variations paralleled the regular s.c. injections of heparin every twelfth hour. The results of the present study could not confirm the marked circadian variations in APTt reported in an earlier French study during continuous heparin infusions, except in one patient.

Adult↗

Effects of dietary supplementation with cod liver oil on monocyte thromboplastin synthesis, coagulation and fibrinolysis.

In a controlled trial 40 healthy persons (20 men and 20 women) were tested before and after a daily supplement with 25 ml cod liver oil for 8 weeks. The diet increased the eicosapentaenoic acid (20:5 n-3) content in serum and monocytes four- to five-fold whereas the arachidonic acid (20:4 n-6) content decreased 10-20% in both serum and monocytes. Stimulation of blood with a low concentration of lipopolysaccharides (LPS) revealed a 40% suppression of LPS-induced thromboplastin synthesis in the monocytes after 8 weeks of CLO intake. In the same LPS stimulation system, men were found to generate significantly more thromboxane B2 than women (4.9 ng ml-1 versus 3.4 ng ml-1). After the CLO supplementation for 8 weeks the thromboxane B2 was reduced by a mean of 70% in women and 60% in men. Factor VII and fibrinogen appeared to be unaltered by CLO intake. Determination of whole blood clot lysis time and tissue plasminogen activator (t-PA) did not indicate any significant influence of n-3 fatty acids on fibrinolysis.

Adult↗

Macrophage heterogeneity in thromboplastin response.

The procoagulant activities of non-elicited mouse monocytes/macrophages from four anatomical localizations were compared. These cell populations were further examined for their ability to increase their procoagulant activity on exposure to endotoxin or phytohaemagglutinin (PHA). Peritoneal macrophages exhibited the highest basal procoagulant activity. Their activity was further enhanced by stimulation with endotoxin and PHA, but marked strain differences were noted. This procoagulant has been identified as tissue thromboplastin. Isolated adherent spleen cells, peripheral blood monocytes or lung alveolar macrophages had a low basal procoagulant activity that did not increase on exposure to PHA or endotoxin. The identity of the weak procoagulant in these cells is uncertain. The presence of lymphocytes in the macrophage cultures (4:1 ratio) enhanced slightly (1.3 to 1.5-fold) the response of peritoneal macrophages to endotoxin or PHA but did not significantly influence the procoagulant activity of the other macrophage subpopulations under the conditions tested. These results demonstrate heterogeneity among different macrophage subpopulations with regard to cellular procoagulant expression.

Animals↗

Intraoperative measurement of activated partial thromboplastin time and prothrombin time with a new compact monitor.

A prospective study was conducted to evaluate a new compact portable coagulation monitor (Ciba-Corning Biotrack 512 Monitor), which enables the clinician to perform instantaneous activated partial thromboplastin time (APTT) and prothrombin time (PT). 126 patients scheduled for heparinized and nonheparinized vascular surgery, and gynaecological surgery, were included. A drop of capillary or venous whole blood was applied in disposable cartridges to successively perform APTT and PT, and the results of the tests were compared with conventional laboratory methods, performed in two different laboratories (Lab. A and B). Comparisons between Lab. A. and Lab. B. enables determination of the bias, precision, and percent of outliers (patients whose values differed more than 20%) in conventional methods. The reference value was defined as the mean of Lab. A. and Lab. B. values. For PT, there were no statistical differences between the capillary and venous samples performed with the portable monitor, and the reference value, for the bias, the precision and the proportion of outliers. For APTT, there were no statistical differences between the capillary and venous samples performed with the portable monitor, and the reference value, for the bias and the precision. The percent of outliers, however, was significantly greater with the venous sample of the compact monitor than with the reference (48 versus 22%), and even if it did not reach the statistical significance (P = 0.07) it was also higher with the capillary sample performed with the Ciba Monitor than with the reference (33%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗