aPTT Measurements Research Articles

Assessment of activated partial thromboplastin time and factor IX in subjects attending an anticoagulation clinic.

Very low factor IX (FIX) levels in patients during oral anticoagulant (OA) treatment, due to mutations in the FIX gene, with prolonged activated partial thromboplastin time (aPTT) and associated with bleeding complications have recently been described. We measured aPTT in 595 OA patients while being within therapeutic ranges. Patients were divided into increasing international normalized ratio (INR) classes, and FIX determined in those belonging to the first and fifth quintiles of the aPTT distribution in each INR class. Results obtained in patients of all the first aPTT quintiles were compared with those of all the fifth quintiles. While INR was not different (2.79 versus 2.77 INR), aPTT was longer (1.65 versus 1.21 ratio; P < 0.0001) and FIX lower (0.29 versus 0.44 IU/ml; P < 0.0001) in patients of the fifth quintiles. Only one patient had a markedly reduced FIX (0.03 IU/ml). Bleeding rate was 4.8 and 6.2% patient-years (not significant) in patients of the first and fifth quintiles, respectively. We therefore found that FIX levels vary greatly in spite of similar achieved anticoagulation intensity; very low FIX is, however, a rare condition. In conclusion, screening for the recently identified mutations in FIX gene does not seem justified, and identifying patients with disproportionately prolonged aPTT, to detect those with particularly low FIX levels, is difficult because of the effect of the achieved anticoagulation intensity. Therefore, aPTT measurement is indicated only in patients with increased bleeding during OA.

Role of low-molecular-weight heparins in the management of patients with unstable angina pectoris and non–q-wave acute myocardial infarction

The development of effective approaches to the management of the unstable coronary syndromes has resulted from an improved understanding of interactions between the vascular wall, platelets, and coagulation factors, and of their response to pharmacologic and mechanical interventions. Furthermore, the occurrence of frequent adverse events after discharge in patients with unstable coronary artery disease (CAD) treated with these therapies alone would argue that, for many of these patients, such stabilization is not the end of the therapeutic pathway; rather, these therapies are for many a preparation for ultimate revascularization, to preserve myocardium and minimize periprocedural complications. The low-molecular-weight heparins with their unique pharmacology offer a new option in the therapy of patients with unstable CAD. There is now extensive experience in the use of several of the low-molecular-weight heparins, particularly dalteparin and enoxaparin, in the management of patients with unstable angina. Several trials have investigated the questions raised by these observations, taking advantage of the unique pharmacologic properties of the low-molecular-weight heparins for both acute inpatient use and prolonged outpatient administration. Although differences in study design preclude direct comparison between the available low-molecular-weight heparins, in these trials low-molecular-weight heparins have been shown to be effective alternatives to conventional heparin for the management of patients with unstable angina and non–Q-wave infarction. These include several small-scale trials and the larger FRagmin during InStability in Coronary artery disease (FRISC), Fragmin in Unstable Coronary Artery Disease (FRIC), Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-Wave Coronary Events (ESSENCE), FRISC II, and Thrombolysis in Myocardial Infarction (TIMI)–11B trials. Thus, the low-molecular-weight heparins appear to be a superior alternative to traditionally administered intravenous unfractionated heparin. They are more predictable in action, do not require frequent activated partial thromboplastin time (aPTT) measurements and dosage adjustments, are easier to administer, and are potentially more efficacious. With their proven efficacy, predictability of action, and convenience of administration and dosing, there are very good reasons for selecting them as first-line therapies for patients presenting with unstable angina and non–Q-wave myocardial infarction.

Use of bedside activated partial thromboplastin time monitor to adjust heparin dosing after thrombolysis for acute myocardial infarction: Results of GUSTO-I

Background The safety and efficacy of bedside monitors of activated partial thromboplastin time (aPTT) have not been examined in a large population receiving intravenous heparin after thrombolytic treatment for acute myocardial infarction. We compared outcomes among patients monitored with these devices versus standard monitoring methods. Methods and Results Investigators chose the bedside device (n = 1713 patients) or their standard method (n = 26,162) for all aPTT measurements at their sites. Clinical outcomes at 30 days, 1-year mortality rate, and aPTT levels at 6, 12, and 24 hours were compared. Bedside-monitored patients had significantly less moderate/severe bleeding (10% vs 12%, P < .01), fewer transfusions (7% vs 11%, P < .001), and a smaller decrease in hematocrit (5.5% vs 6.7%, P < .001) but significantly more recurrent ischemia (22% vs 20%, P = .01). Fewer bedside-monitored patients had subtherapeutic aPTT levels at 12 and 24 hours. Among patients with subtherapeutic levels at 6 and 12 hours, more bedside-monitored patients had therapeutic levels when next monitored. After adjustment for baseline differences, no significant difference in mortality rate was observed in bedside-monitored patients at 30 days (4.3% vs 4.8%, P = .27) and at 1 year (7.1% vs 7.7%, P = .38). The groups had similar rates of reinfarction, shock, heart failure, and stroke. Conclusions This prospective substudy supports the use of bedside monitoring of heparin anticoagulation after thrombolysis. (Am Heart J 1998;136:868-76.)

Monitoring the effects of heparin: evaluation of a new portable device

The aim of this study was to measure the effects of heparin therapy in patients undergoing vascular surgery, and to monitor the effectiveness of continuous intravenous heparin therapy in ward-based patients. In addition, we compared results from a new portable device with those from the standard laboratory assay. A prospective comparison of the two methods in patients undergoing peripheral vascular surgery, and in ward-based patients who were receiving intravenous heparin infusions was undertaken. Fifty patients who were undergoing vascular surgery and receiving a bolus dose of intravenous heparin, and 22 patients receiving a continuous heparin infusion, were recruited. Blood samples were taken 10 and 40 min following bolus heparin administration or after >12 h of a continuous heparin infusion. Plasma activated partial thromboplastin times (APTTp) measured by the haematology laboratory were compared with whole blood (APTT B) ascertained with the CoaguChek Plus Device (Boehringer Mannheim UK Diagnostics and Biochemicals Limited) at each time point. The results from the two methods were compared using the method of Bland and Altman ( Lancet, 1986, 307–310). We found a good level of agreement between the two methods (at induction, mean bias was −0.050, limits of agreement −0.46–0.36; heparin infusions, mean bias was −0.283, limits of agreement −1.64–1.07). In addition we discovered that many of our patients appeared to be excessively anticoagulated during surgery (10 min following heparin bolus 47/50 patients had an APTT B >150 s, 45/50 had an APTTp >250 s; at 40 min 45/50 had an APTT B >150 s, 39/50 had an APTTp >250 s). In conclusion, whole blood APTT measurement allows rapid and accurate assessment of the effects of heparin therapy when compared with laboratory APTT measurement and may prevent both excessive and suboptimal anticoagulation.

Unfractionated Heparin Dosing in the FRIC Study

To the Editor: In the recent FRIC study,1 the subheading on page 65 states “Anti–Factor Xa Activity and aPTT Values in the Acute Phase,” but no activated partial thromboplastin time (aPTT) values were provided. Because one of the measures of performance of unfractionated heparin (UFH) dosing is the aPTT achieved, the reader cannot interpret the degree of anticoagulation achieved with UFH if no aPTT values are provided. Because aPTT measurement was mandated per protocol at 6 and 12 hours as well as daily through 48 hours, these median aPTT values should be reported as well as the percentages of patients below and above …

A pump-prime aprotinin dose in cardiac surgery: Appraisal of its effects on the hemostatic system

Objectives: To examine pump-prime aprotinin action on coagulation and fibrinolysis in patients undergoing primary coronary revascularization. Design: A prospective randomized study. Setting: A university hospital. Participants: Forty-three patients were randomly assigned to either group A, 21 patients treated with 2 × 10 6 kallikrein inhibitor units (KIU) of aprotinin in the cardiopulmonary bypass (CPB) prime, or group B, 22 patients, untreated. Interventions: Patients, scheduled for elective coronary surgery, were treated with 2 × 10 6 KIU of aprotinin in the CPB prime. Markers of coagulation and fibrinolysis were evaluated. Measurements and Main Results: Surgical times, number of reopenings, and allogeneic blood requirements were collected for each patient. Blood samples were obtained before and after surgery for assessing coagulation (prothrombin time [PT], activated partial thromboplastin time [aPTT], ethanol test, factor VII, antithrombin III [AT III], thrombinantithrombin III complex [TAT], fragment 1.2 of prothrombin [F1.2]) and fibrinolysis (fibrin degradation products [FDP], plasmin-antiplasmin complexes [PAP], D-dimers) markers variations. In group A surgical times were faster, there were fewer reopenings (0 v 3), and fewer blood transfusions (1 patient v 4 patients). The two groups did not differ for PT, aPTT, and fibrinogen measurements. Postoperative FDP (measurable in more patients of group B at the end of the operation), PAP, and D-dimers postoperatory levels (less increased in aprotinin group) show the antifibrinolytic properties of the drug. Regarding the coagulation markers, factor VII decreased, whereas TAT and F1.2 increased, all to a lesser extent in the aprotinin group compared with the untreated patients, at the end of operation. Conclusion: Pump-prime aprotinin minimized, even if not completely inhibited, the activation of coagulation and fibrinolysis during CPB, possibly ensuring a less complicated and safer postoperative recovery. It seemed to allow the maintenance of a correct balance of hemostatic systems, avoiding the risk of thrombotic phenomena.

Effect of Weight, Sex, Age, Clinical Diagnosis, and Thromboplastin Reagent on Steady-state Intravenous Heparin Requirements

There is a significant direct relationship between steady-state intravenous heparin dose requirements and total body weight. Less is known about whether sex, age, clinical diagnosis, and the thromboplastin used to measure the activated partial thromboplastin time (aPTT) affect heparin dose requirements. Four cohorts of patients treated with intravenous heparin were gathered from 3 hospitals: 2 cohorts with deep vein thrombosis (DVT) and 2 cohorts with coronary artery disease (CAD). For each clinical diagnosis, half the patients were monitored using one aPTT reagent and the remainder were monitored using a second reagent. Heparin doses and aPTT measurements were recorded, and the dose necessary to achieve an aPTT ratio of 2.0 was calculated using a computer software program. We analyzed the records of 340 patients: 165 with DVT and 175 with CAD. Using analysis of variance, there was a significant difference in the steady-state heparin requirements among patients with DVT compared with patients with CAD (P < .001). For each clinical diagnosis, the use of a different thromboplastin reagent did not affect heparin dose requirements (P > .42). Linear regression modeling disclosed that the steady-state heparin dose for patients with DVT was a function of weight plus an effect modifier involving weight and age, whereas for patients with CAD there was only a weak relationship with weight. Steady-state heparin dose requirements were significantly different in patients with DVT compared with patients with CAD, suggesting that different dosing nomograms are needed for each condition. For patients with DVT, the accuracy of the initial heparin dose estimate may be improved by considering the patient's age and weight.

Hirudin in Acute Myocardial Infarction

The TIMI 9 trial evaluated whether the direct antithrombin hirudin is more effective than an indirect-acting antithrombin, heparin, as adjunctive therapy for thrombolysis in myocardial infarction. Patients (n = 3002) with acute myocardial infarction were treated with aspirin and either accelerated-dose tissue plasminogen activator (TPA) or streptokinase. They were randomized within 12 hours of symptoms to receive either intravenous heparin (5000 U bolus followed by infusion of 1000 U/h) or hirudin (0.1 mg/kg bolus followed by infusion of 0.1 mg/ kg per hour). The infusions of both antithrombins were titrated to a target activated partial thromboplastin time (aPTT) of 55 to 85 seconds and were administered for 96 hours. Patients randomized to hirudin were significantly more likely to have an aPTT measurement in the target range (P < .0001). The primary end point (death, recurrent nonfatal myocardial infarction, or development of severe congestive heart failure or cardiogenic shock by 30 days) occurred in 11.9% of the 1491 patients in the heparin group and 12.9% of the 1511 patients in the hirudin group (P = NS). Subgroup analyses did not reveal any profile of patients who benefited more from one of the antithrombins. The rate of major hemorrhage was similar in the heparin (5.3%) and hirudin (4.6%) groups; intracranial hemorrhage occurred in 0.9% of the heparin and 0.4% of the hirudin patients. Heparin and hirudin have an equal effect as adjunctive therapy to TPA and streptokinase in preventing unsatisfactory outcome in patients with acute myocardial infarction. Similar rates of major bleeding were observed for patients in the heparin and hirudin groups.

Early aPTT measurements are not a surrogate for in vivo thrombin inhibition among patients receiving thrombolytic therapy and adjunctive anticoagulation

Early aPTT measurements are not a surrogate for in vivo thrombin inhibition among patients receiving thrombolytic therapy and adjunctive anticoagulation

Effect of heparin on whole blood activated partial thromboplastin time using a portable, whole blood coagulation monitor

To evaluate the responsiveness of whole blood activated partial thromboplastin time (aPTT) to varying heparin doses in vitro and to examine the ex vivo relationship of whole blood aPTT to plasma heparin concentration. Prospective, controlled laboratory study. Surgical suites and laboratory at a tertiary center. Surgical patients and volunteers at a tertiary center were eligible for inclusion in this study. In vitro evaluation was performed using specimens obtained from each of five, healthy volunteers. Ex vivo evaluation was performed using specimens obtained from 30 cardiac surgical patients before and after systemic administration of heparin for extracorporeal circulation. Blood specimens were obtained from volunteers and added to syringes containing varying amounts of unfractionated porcine heparin for in vitro evaluation. For ex vivo evaluation, blood specimens were obtained from patients before and after systemic administration of 20 U/kg of heparin. For the in vitro evaluation, specimens were divided into two aliquots after mixing with varying amounts of unfractionated porcine heparin. One aliquot was used to measure whole blood aPTT using a whole blood coagulation monitor immediately after blood collection and 3 mins later, and a second aliquot was used to determine plasma aPTT with a conventional, laboratory-based assay. Linear regression analysis demonstrated a high correlation (r = .94; r2 = .88) between aPTT assay systems and bias analysis demonstrated a mean aPTT measurement difference of 1.6 secs with +/- 2 SD limits of -15 to +18.2 secs. As indicated by comparable regression slopes, the in vitro aPTT responsiveness to increasing heparin concentration was similar with the two assay systems among individual subjects. Whole blood aPTT measurements after 3 mins of blood specimen storage were similar to immediate measurements. For ex vivo evaluation, blood specimens obtained from patients before and after systemic administration of heparin were divided into two aliquots. One aliquot was used to measure whole blood aPTT in duplicate and a second aliquot was used to measure plasma heparin concentration with an antifactor X active chromogenic assay. A high correlation (r = .89; r2 = .79) between whole blood aPTT and plasma heparin concentration was observed. Heparin responsiveness of whole blood aPTT, measured with a portable whole blood coagulation monitor, is similar to that of conventional laboratory aPTT over a clinically relevant range of heparin concentrations in vitro and ex vivo. On-site whole blood aPTT measurements should be useful in clinical situations requiring rapid aPTT results.

Transepithelial transport properties of peptidomimetic thrombin inhibitors in monolayers of a human intestinal cell line (Caco-2) and their correlation to in vivo data.

Peptidomimetic thrombin inhibitors (TI), derived from L-Asp-D-Phe were examined in confluent monolayers of a human colon carcinoma cell line (Caco-2) to elucidate their transepithelial transport properties. Effect availabilities, based on activated partial thromboplastin time (aPTT) measurements in rats, after peroral administration of five TI correlated reasonably well with permeability coefficients obtained from in vitro transport studies in Caco-2 monolayers, whereas physicochemical properties, such as molecular mass, solubilities, pKa and octanol-buffer partition coefficients failed to yield meaningful relationships. Substitution of the beta-carboxylic group of L-Asp leads to analogues which are mainly transported by passive diffusion, while an unsubstituted carboxylic group favours carrier-mediated active transport. The effects of concentration, temperature, competitive inhibitors and direction dependence on in vitro transport were investigated. The results obtained are compatible with a saturable carrier-mediated transport, operating parallel to a passive paracellular route. The Michaelis-Menten parameters for the active transport component (Km = 1.67 mM, Vmax = 26.5 pmol min-1 mg protein-1) indicate an involvement of the intestinal di/tripeptide transport system for one of the TI. The Caco-2 transport model may be helpful for the design of perorally active peptidomimetics.

New polyurethane compositions able to bond high amounts of both albumin and heparin

In order to prepare polymers provided with better haemocompatibility with respect both to the coagulative cascade and to platelet aggregation and activation, we have synthesized new polyurethanes containing in the chain extender [di-(2-hydroxyethyl) hexa-decylamine (DHHA)] both a long chain alkyl group (able to bond albumin) and a tertiary ammonium group able, after suitable quaternization reaction, to bind ionically significant amounts of heparin. The amounts of heparin and albumin bonded to the polymer films were determined spectrophotometrically. A biological in vitro evaluation of the heparinized and albuminized films was also carried out, with respect to the blood coagulation factors (by APTT measurements) and to platelet adhesion. For the sake of comparison, polyurethanes containing as chain extenders two different monomers (containing, respectively, the long alkyl and the quaternary ammonium group), and polymer blends consisting of these copolymers, were also prepared and evaluated as above. It was seen that the type of the adsorption sequence for albumin and heparin, respectively, onto films of the various homopolymers, copolymers and blends, plays an important role in their biological properties.

Diurnal changes in heparin effect during continuous constant-rate infusion. A study in nine patients with venous thromboembolism.

To evaluate the importance of diurnal variations in the effect of a continuous infusion of unfractionated heparin. Twenty-four-hour follow-up. Tertiary referral centre. Patients (five male, four female) with acute venous thromboembolic diseases. Two-hourly measurement of anti-IIa activity, anti-Xa activity, APTT (Cephotest and automated APTT), antithrombin III and cortisol for 24 h. The maximum anticoagulant effect was found at 04.00-06.00 hours, and the minimum effect at 12.00 hours. The difference was 0.40 U ml-1 for anti-IIa activity (95% confidence interval (CI) 0.03-0.78; P < 0.05), 0.36 U ml-1 for anti-Xa activity (95% CI-0.05-0.72; not significant [NS]), 15.1 s for Cephotest APTT (95% CI 3.3-26.9; P < 0.03), and 112.9 s for automated APTT (95% CI 7.8-218.0; P < 0.05). Antithrombin III decreased from 97.9% at the start to 82.6% 24 h later (P = 0.001). Cortisol showed a typical diurnal rhythm. Expressed as a percentage of the individual 24-h mean, a maximum was found at 04.00 hours (anti-IIa activity), 06.00 hours (both APTTs), and 08.00 hours (anti-Xa activity) and a minimum at 12.00 hours (all variables). The difference was 26% for anti-IIa activity (P < 0.05) and anti-Xa activity (NS), 22% for APTT (Cephotest; P < 0.03), and 44% for APTT (automated APTT; P < 0.05). A continuous intravenous infusion of unfractionated heparin has a maximum anticoagulant effect between 04.00 and 8.00 hours and a minimum effect at noon. For individual patients the moment of minimum and maximum effect varies widely. Because the most impressive changes occur between 06.00 and 08.00 hours, laboratory control can best be performed at fixed times, e.g. at 10.00 and at 22.00 hours.

On-site Prothrombin Time, Activated Partial Thromboplastin Time, and Platelet Count A Comparison between Whole Blood and Laboratory Assays with Coagulation Factor Analysis in Patients Presenting for Cardiac Surgery

Although available hemostasis assays from institutional laboratories permit an analytical approach to diagnosis and treatment of coagulation disorders following cardiopulmonary bypass, their clinical utility has been limited by delays in obtaining results. The development of instrumentation for on-site testing allows rapid return of results. This study was designed to compare whole blood (WB) results obtained from on-site coagulation assays with values provided by our institutional laboratory (LAB). After Institutional Human Studies Committee approval, 362 patients presenting for cardiac surgery requiring cardiopulmonary bypass were enrolled in this study. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet count (PLT) assays were performed in both WB and LAB systems. PT, aPTT, and PLT measurements were compared between WB and LAB assays using blood specimens obtained from at least two time points for each patient. Normal range values for both PT and aPTT methods were determined by using measurements from a normal reference population. Coagulation factor levels were measured in a subset of patients to characterize the response of PT and aPTT assays to individual and multiple factor levels. To employ Bayes' theorem and calculate predictive indexes (e.g., sensitivity, specificity), the disease or factor deficiency was determined using factor levels. Predictive indexes were used to evaluate the ability of PT and aPTT assays to identify factor deficiency. PLT counts were similar between systems. Linear regression and bias analysis demonstrated similar results for WB and LAB PT and discordant results for aPTT measurements. Both PT assays had a similar normal range, whereas a wider distribution of results was evident for the WB aPTT normal range. Although statistically greater slopes for factor:aPTT regressions were observed for the WB system, WB aPTT correlated better with factor V and with factor V, VIII, and XII levels (multivariate linear regression). Diagnostic performance for factor levels less than 0.3 and 0.4 U/ml was similar for both WB and laboratory PT and aPTT assays. WB and LAB PT and aPTT assays performed similarly in detecting factor deficiency in the period after cardiopulmonary bypass. WB PT and PLT values correlate well with those obtained from the LAB. The discrepancy between measurement systems in aPTT values is probably a reflection of both different normal ranges and responsiveness to factor deficiency. These WB assays provide coagulation results that can accurately identify patients with quantitative deficiencies in platelets and coagulation factors.

Dihydroergotamine-Heparin Prophylaxis of Postoperative Deep Vein Thrombosis-Reply

In Reply.— We appreciate Dr Hattersley's interesting and informed comments concerning the utility of an adjusted-dose heparin regimen and the relationship between heavier weight and DVT. In our trial of patients undergoing elective general surgery, we did not include serial APTT measurements and therefore cannot corroborate the findings of Leyvraz et al, who found that adjusting heparin dosage provided a more effective prophylactic regimen. However, we believe that if appropriate prophylactic measures are to be encouraged, the recommended regimens ought to be simple to administer. Adding APTT measurements to adjust heparin prophylaxis dosage merely serves to complicate the regimen, which will only discourage the use of prophylactic measures in the United States. In response to one of the other questions, we found that the percentage of patients with DVT who were above average weight (76.8 kg [170 lb] for men, 70.5 kg [156 lb] for women) was as follows: dihydroergotamine/