A randomized, multicenter trial of weight-adjusted intravenous heparin dose titration and point-of-care coagulation monitoring in hospitalized patients with active thromboembolic disease. Antithrombotic Therapy Consortium Investigators

BACKGROUND: Therapy with intravenous unfractionated heparin improves clinical outcome in patients with active thromboembolic disease, but achieving and maintaining a therapeutic level of anticoagulation remains a major challenge for clinicians. METHODS: A total of 113 patients requiring heparin for at least 48 hours were randomly assigned at 7 medical centers to either weight-adjusted or non-weight-adjusted dose titration. They were separately assigned to either laboratory-based or point-of-care (bedside) coagulation monitoring. RESULTS: Weight-adjusted heparin dosing yielded a higher mean activated partial thromboplastin time (aPTT) value 6 hours after treatment initiation than non-weight-adjusted dosing (99.9 vs 78.8 seconds; P =.002) and reduced the time required to exceed a minimum threshold (aPTT >45 seconds) of anticoagulation (10.5 vs 8.6 hours; P =.002). Point-of-care coagulation monitoring significantly reduced the time from blood sample acquisition to a heparin infusion adjustment (0.4 vs 1.6 hours; P <.0001) and to reach the therapeutic aPTT range (51 to 80 seconds) (16.1 vs 19.4 hours; P =.24) compared with laboratory monitoring. Although a majority of patients participating in the study surpassed the minimum threshold of anticoagulation within the first 12 hours and reached the target aPTT within 24 hours, maintaining the aPTT within the therapeutic range was relatively uncommon (on average 30% of the overall study period) and did not differ between treatment or monitoring strategies. CONCLUSIONS: Weight-adjusted heparin dosing according to a standardized titration nomogram combined with point-of-care coagulation monitoring using the BMC Coaguchek Plus System represents an effective and widely generalizable strategy for managing patients with thromboembolic disease that fosters the rapid achievement of a desired range of anticoagulation. Additional work is needed, however, to improve on existing patient-specific strategies that can more effectively sustain a therapeutic state of anticoagulation.     

Accuracy of coagulation values obtained from a heparinized central venous catheter

PURPOSE/OBJECTIVES: To compare coagulation values of blood samples drawn from heparinized central venous catheters (CVCs) and peripheral veins. DESIGN: Correlational. SETTING: Adult, acute-care hematology/oncology unit in a 1,000-bed teaching hospital. SAMPLE: Twelve adult patients with cancer who had varied diagnoses and patent CVCs. METHODS: Simultaneous blood samples were drawn from the CVC and a peripheral vein and were tested for prothrombin time (PT) and activated partial thromboplastin time (aPTT). MAIN RESEARCH VARIABLES: PT and aPTT values. FINDINGS: PT and aPTT values were significantly prolonged in samples drawn from CVCs when compared to peripherally drawn samples. CONCLUSIONS: Accurate coagulation values cannot be obtained from a heparinized CVC. IMPLICATIONS FOR NURSING PRACTICE: Blood for coagulation values should be obtained from peripheral veni-puncture. Further research should explore the effects of various catheters, heparin dwell time, and systemic anticoagulation on coagulation values.     

Laboratory assessment of antithrombotic therapy: what tests and if so why?

A critical review is given of the tests available for the assessment of the action of anticoagulants, such as heparins, oral anticoagulants and direct thrombin inhibitors, in patients under antithrombotic therapy. The principle of action and the performance of the thromboplastin time (PT), the activated partial thromboplastin time (aPTT), the whole blood clotting time, the thrombin time, the ecarin clotting time and the endogenous thrombin potential (ETP) is discussed, as well as the evidence behind the accepted therapeutic ranges. The two most common tests, PT and aPTT, respond in an essentially different way to clinically effective anticoagulation with heparin and with oral anticoagulants. This means that they covariate with, but do not themselves represent the essential parameter influenced by anticoagulation. The experimental basis for the widely accepted two times prolongation of the aPTT as an indicator for adequate anticoagulation is shown to be meagre in the case of unfractionated heparin and lacking for the other anticoagulants. Common sources for error in the interpretation of anti-factor Xa- and anti-thrombin activity of heparins are indicated. Extensive experience with new tests like the ecarin clotting time and the ETP is still lacking. On the basis of preliminary data and in view of the importance of the enzymatic action of thrombin in the pathogenesis of thrombosis, the ETP is considered a possible candidate for a common parameter to assess different types of anticoagulants.     

Changes in plasma epinephrine concentration and in heart rate during head-up tilt testing in patients with neurocardiogenic syncope: correlation with successful therapy with beta-receptor antagonists

OBJECTIVE: To develop, implement and evaluate an effective and efficient heparin nomogram. DESIGN: Retrospective and prospective data collection. SETTING: Coronary care unit (CCU) of a university-affiliated hospital. PATIENTS: Patients with acute coronary ischemic syndromes requiring intravenous (i.v.) heparin who were not receiving thrombolytic and/or warfarin therapy. INTERVENTIONS: A retrospective chart review of 52 CCU patients receiving iv heparin provided the historical control group. The effectiveness of a heparin nomogram (5000 U bolus followed by an initial weight-based infusion of 15 U/kg/h with subsequent rate adjustments according to activated partial thromboplastin time [aPTT] results) was then prospectively assessed in a further 56 consecutive patients. MAIN RESULTS: The historical control and nomogram groups did not significantly differ with respect to age, weight, duration of therapy or total number of aPTTs drawn. Approximately 79% and 84% of patients in the control and nomogram groups, respectively, achieved an aPTT within the therapeutic range (60 to 90 s, P > 0.05), whereas 89% and 100% of control and nomogram patients, respectively, surpassed the therapeutic threshold (longer than 60 s) at some point during treatment (P = 0.009). Compared with empiric dose adjustment, the nomogram more effectively avoided periods of inadequate anticoagulation. Similarly, the time to achieve the therapeutic threshold was significantly longer in the control than in the nomogram group (8.2 +/- 5.9 versus 6.7 +/- 3.7 h, P = 0.026). No adverse bleeding events were noted in either group. CONCLUSIONS: Compared with conventional approaches, the heparin nomogram successfully achieved and maintained adequate anticoagulation in a greater proportion of patients with acute cardiovascular diseases without the need for additional aPTT measurements.     

Inability of the activated partial thromboplastin time to predict heparin levels. Time to reassess guidelines for heparin assays

BACKGROUND: In treating venous thromboembolic disorders, patient outcomes appear to correlate with heparin levels. Due to pharmacokinetic and pharmacodynamic variations, a relationship between heparin dose and level cannot be reliably predicted in individual patients. Some patients have low heparin levels despite therapeutic activated partial thromboplastin times (aPTTs), which may increase their risk for recurrent thromboembolism. Patients with high heparin requirements appear to have fewer bleeding episodes with heparin level-guided therapy. The aPTT does not reliably correlate with heparin blood concentrations or antithrombotic effects. Consequently, heparin therapy monitored with heparin levels may be more effective and safer. OBJECTIVES: To prospectively determine whether (1) the aPTT therapeutic range adequately predicts heparin levels in 38 patients used to establish the therapeutic aPTT range as is currently recommended and (2) whether 3 paired sets of aPTT-antifactor Xa levels provide the basis for using aPTTs to predict subsequent heparin levels in individual patients (n = 27) receiving intravenous heparin for coronary artery disease or venous thromboembolic disease. RESULTS: In the therapeutic aPTT range established, the R2 value for the relationship was 0.4. Prediction intervals were wide. For an aPTT of 60 seconds, the 95% prediction interval estimates were heparin levels of 0.05 to 1.0 U/mL. In individual patients, the aPTT-antifactor Xa relationship had an average R2 value of 0.75. There was no consistent relationship between the aPTT and anti-factor Xa level in a significant number of patients. CONCLUSIONS: The aPTT does not appear to be a useful surrogate for heparin levels. These findings suggest that the current recommendations on the use of heparin levels should be expanded.     

Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I trial

BACKGROUND: Although intravenous heparin is commonly used after thrombolytic therapy, few reports have addressed the relationship between the degree of anticoagulation and clinical outcomes. We examined the activated partial thromboplastin time (aPTT) in 29,656 patients in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial and analyzed the relationship between the aPTT and both baseline patient characteristics and clinical outcomes. METHODS AND RESULTS: Intravenous heparin was administered as a 5000-U bolus followed by an initial infusion of 1000 U/h, with dose adjustment to achieve a target aPTT of 60 to 85 seconds. aPTTs were collected 6, 12, and 24 hours after thrombolytic administration. Higher aPTT at 24 hours was strongly related to lower patient weight (P < .00001) as well as older age, female sex, and lack of cigarette smoking (all PT< .0001). At 12 hours, the aPTT associated with the lowest 30-day mortality, stroke, and bleeding rates was 50 to 70 seconds. There was an unexpected direct relationship between the aPTT and the risk of subsequent reinfarction. There was a clustering of reinfarction in the first 10 hours after discontinuation of intravenous heparin. CONCLUSIONS: Although the relationship between aPTT and clinical outcome was confounded to some degree by the influence of baseline prognostic characteristics, aPTTs higher than 70 seconds were found to be associated with higher likelihood of mortality, stroke, bleeding, and reinfarction. These findings suggest that until proven otherwise, we should consider the aPTT range of 50 to 70 seconds as optimal with intravenous heparin after thrombolytic therapy.     

Establishing an institution-specific therapeutic range for heparin

The relationship between heparin concentration and activated partial thromboplastin time (aPTT) in pooled plasma was compared with that in patient samples to assess the feasibility of using heparin-spiked pooled plasma in determining a therapeutic range for aPTT. Blood samples were taken from 32 patients who had been receiving intravenous unfractionated heparin sodium for more than 24 hours. The samples were stored at -70 degrees C until anti-Xa assay within three months of collection. Pooled normal plasma was spiked with unfractionated heparin sodium to produce nominal anti-Xa concentrations of 0, 0.05, 0.1, 0.2, and 0.5 unit/mL. Heparin concentrations and a aPTT values were measured, and the relationship between the two was determined by linear regression. For the ex vivo samples, the range of aPTT values corresponding to therapeutic heparin concentrations of 0.3-0.7 anti-Xa unit/mL was 64-106 seconds, which corresponds to an aPTT range of 2.3-3.9 times the mean of the normal range (compared with the traditionally defined therapeutic range of 1.5-2.5 times the control value). For the in vitro samples, the aPTT range corresponding to heparin concentrations of 0.3-0.7 unit/mL was 121-256 seconds, which corresponds to an aPTT range of 4.4-9.4 times the mean of the normal range. Each institution should establish a therapeutic aPTT range by calibrating aPTT values against heparin concentrations from blood samples of patients receiving intravenous heparin.     

Activated partial thromboplastin time is a predictive parameter for further miscarriages in cases of recurrent fetal loss

OBJECTIVE: To determine whether clinically routine clotting tests such as activated partial thromboplastin time (aPTT), prothrombin time (PT), or fibrinogen can be used to predict further miscarriages. DESIGN: Prospective study. SETTING: Nagoya City University Hospital, Nagoya, Japan. PATIENT(S): A total of 261 patients with a history of two consecutive first-trimester spontaneous abortions who had no antiphospholipid antibodies or other autoimmune diseases and no anatomic anomalies were examined for aPTT, PT, and fibrinogen before becoming pregnant again. INTERVENTION(S): Blood tests were performed before pregnancy. Patients then were followed up during subsequent pregnancy and their outcomes were compared with their previous blood test results. MAIN OUTCOME MEASURE(S): Activated partial thromboplastin time, PT, and fibrinogen were measured by coagulation time methods. RESULT(S): Fifty-eight of 261 patients (22.2%) had a subsequent miscarriage. Mean (+/-SD) values for preconception aPTT in individuals whose subsequent pregnancies ended in success and failure were 88.2%+/-23.4% and 99.3%+/-26.4%, respectively. The difference was statistically significant. Respective values were 106.8%+/-22.8% and 106.3%+/-21.4% for PT and 245+/-61.1 mg/dL and 259.1+/-57 mg/dL for fibrinogen. These findings were not significantly different. CONCLUSION(S): A shortened aPTT before conception is associated with further miscarriages in patients with a history of recurrent spontaneous abortions who have no antiphospholipid antibodies.     

Oral delivery of anticoagulant doses of heparin. A randomized, double-blind, controlled study in humans

BACKGROUND: Parenteral heparin is the anticoagulant of choice in hospitalized patients. Continued anticoagulation is achieved by subcutaneous administration of low-molecular-weight heparin or with an orally active anticoagulant such as warfarin. An oral heparin formulation would avoid the inconvenience of subcutaneous injection and the unfavorable drug interactions and adverse events associated with warfarin. A candidate delivery agent, sodium N-[8(-2-hydroxybenzoyl)amino]caprylate (SNAC), was evaluated with escalating oral heparin doses in a randomized, double-blind, controlled clinical study for safety, tolerability, and effects on indexes of anticoagulation. METHODS AND RESULTS: Increases in activated partial thromboplastin time (aPTT), anti-factors IIa and Xa, and tissue factor pathway inhibitor (TFPI) concentrations were detected when normal volunteers were dosed with 10.5 g SNAC/20000 IU heparin by gavage in some subjects. For the entire group, 30000 IU SNAC and heparin elevated TFPI from 74.9+/-7.6 to 254.2+/-12.3 mg/mL (P<0.001) 1 hour after dosing (P<0.001). Similar changes occurred in anti-factor IIa and anti-factor Xa. aPTT rose from 28+/-0.5 to 42.2+/-6.3 seconds 2 hours after dosing (P<0.01). No significant changes in vital signs, physical examination, ECGs, or clinical laboratory values were observed. Neither 30000 IU heparin alone nor 10.5 g SNAC alone altered the hemostatic parameters. Emesis was associated with 10.5 g SNAC. A taste-masked preparation of SNAC 2.25 g was administered orally with heparin 30000 to 150000 IU. Both aPTT and anti-factor Xa increased with escalating doses of heparin. This preparation was well tolerated. Conclusions-Heparin, administered orally in combination with the delivery agent SNAC, produces significant elevations in 4 indexes of anticoagulant effect in healthy human volunteers. These results establish the feasibility of oral delivery of anticoagulant doses of heparin in humans and may have broader implications for the absorption of macromolecules.     

Automated heparin-delivery system to control activated partial thromboplastin time: evaluation in normal volunteers

BACKGROUND: Unfractionated heparin is used widely; however, control of the level of anticoagulation remains its greatest problem, with fewer than 35% of patients having activated partial thromboplastin times (aPTTs) within a range of 55 to 85 seconds in recent trials. METHODS AND RESULTS: We developed and tested a prototype of an automated heparin control system (AutoHep) in which a computer-based titration algorithm adjusted the heparin infusion to reach a target aPTT. In 1 study, 12 healthy male subjects received an intravenous infusion of heparin with the rate determined by AutoHep and were randomized to receive an initial bolus or no bolus of heparin preceding the infusion. A second study evaluated the automated blood sampling system in 12 subjects. Of the 344 end-point aPTT measurements, 78% were within +/-10 seconds of the target (prespecified primary end point), and 89% were within a +/-15-second range. The time to achieve a target aPTT was 93 minutes without and 150 minutes with an initial heparin bolus. The total percentage of time within the target range +/-15 seconds was 46 of 48 hours (96%). The automatic blood sampling system successfully obtained 96% of all scheduled samples. CONCLUSIONS: These results suggest that the AutoHep system has the potential to significantly improve aPTT control of intravenous heparin compared with current clinical practice.     

Glucosamine

We have taken a stepwise approach to improving the dosing of continuous intravenous heparin in patients with acute coronary syndromes. Our primary objective was to use computer modeling to develop a nomogram for managing heparin therapy and to put in place a continuous quality monitoring system to evaluate the nomogram's effectiveness. We prospectively collected data on 41 patients with unstable angina or myocardial infarction who were treated with heparin. Their response to heparin was computer modeled and the dose to achieve an activated partial thromboplastin time (aPTT) ratio of 2.0 was established. This dose was regressed against all demographic characteristics to establish predictors of heparin dose (phase I). The regression formula was used prospectively in 110 patients to initiate the infusion rate of heparin and a bolus dose to achieve an aPTT ratio of 2.5. Subsequent dosage adjustments were achieved by computer modeling the patient's aPTT response (phase II). A nomogram was developed that simulated the decisions achieved using computer-assisted methods. This was retrospectively tested and then prospectively tested in 50 patients using nursing staff (phase IV). The nomogram was then made generally available (phase IV) and has been tested in an additional 310 patients. Phase I: Of the original 41 patients, 32% of the aPTT ratios were in the therapeutic range, 36% were supratherapeutic, and 32% were subtherapeutic after the first 24 hours. Phases II and III resulted in 85% of the aPTT ratios between 1.5 and 2.5 at 24 hours. Phase 4 had similar results in 310 patients. The use of computer-assisted or a computer-generated nomogram to adjust heparin therapy results in better control of heparin therapy than using standard methods.     

Weight-based heparin dosing: clinical response and resource utilization

The objective of this study was to assess a weight-based heparin (WBH) nomogram (80-U/kg bolus, 18-U/kg-per-hour initial infusion) and determine its clinical performance and impact on resource utilization. All patients treated with heparin for venous thromboembolism or unstable angina during a 15-week study period were included in this retrospective, chart-review study. Three groups were identified: patients treated with WBH, patients whose regimen deviated from the weight-based nomogram (DEV), and matched historical controls (HCs). In patients receiving heparin for more than 24 hours, those treated with WBH achieved threshold activated partial thromboplastin time (aPTT) levels significantly faster than did HC or DEV patients. However, 42% of WBH-treated patients were found to have initial supratherapeutic responses. Logistic regression analysis identified age > or =67 years, prior warfarin therapy within 7 days of heparin, and high initial infusion rate as predictive of a supratherapeutic aPTT response; smoking was predictive of a subtherapeutic response. Bleeding events were not significantly different between groups. An infusion rate of 15 U/kg per hour was found to closely approximate our population's actual heparin infusion requirement. Resource utilization was significantly different between the WBH and HC groups in terms of nursing interventions at 48 to 72 hours. We concluded that WBH rapidly drives patients' aPTT response above the therapeutic threshold for heparin; however, prudent adjustment of the initial infusion rate is necessary to avoid a supratherapeutic aPTT response. Our data support a nomogram with an initial infusion rate of 15 U/kg per hour.     

Risks of anticoagulation therapy after experimental corticectomy in the rat

To determine the optimal postoperative interval after which heparin therapy can be safely initiated, a rat model for experimental craniotomy and corticectomy was developed. In 50 rats (100 lesions), heparin therapy was initiated 1, 2, 3, 5, or 7 days after standardized bilateral frontal corticectomy and was continued for 7 days. Intraperitoneally administered heparin, 75 to 100 U/kg.h, was continuously given to maintain the activated partial thromboplastin time in one of two ranges: therapeutic (1.5-3 times control) or supratherapeutic (> 3 times control). The size of intracranial hemorrhage was determined from coronal brain sections by automated image analysis. No significant hemorrhage was observed in control (saline infusion) animals or in rats receiving therapeutic doses of heparin beginning more than 24 hours after surgery. Small (10-50 mm3) and large (> 50 mm3) hemorrhages were frequent at all intervals up to 5 days in animals with supratherapeutic activated partial thromboplastin time (P < 0.01). Judicious heparin therapy may be safely initiated at 48 hours after craniotomy and corticectomy in rats, whereas supratherapeutic anticoagulation is associated with intracranial hemorrhage at intervals of up to 5 days.     

Enoxaparin for unstable angina and ancrod for cardiac surgery following heparin allergy

OBJECTIVE: To describe a patient who presented with heparin allergy and required alternate anticoagulation for unstable angina and coronary artery bypass surgery. To review therapeutic alternatives to porcine heparin for patients with hypersensitivity or intolerance to standard heparin anticoagulation. CASE SUMMARY: A 74-year-old man with a 15-year-old coronary artery bypass graft presented to the emergency room with unstable angina and was scheduled for urgent coronary artery revascularization. A bolus dose of porcine heparin was administered followed by a continuous infusion. Shortly afterward the patient developed a type I allergic reaction to the porcine heparin that was confirmed by rechallenge. Three alternatives to porcine heparin were tried, including bovine lung heparin, low-molecular-weight heparin (enoxaparin), and ancrod. The patient was found to be cross-sensitive to bovine lung heparin, but tolerated enoxaparin for unstable angina without cross-sensitivity. Anticoagulation for cardiopulmonary bypass was achieved with an infusion of ancrod that was later reversed with cryoprecipitate. The patient was discharged postoperatively on day 5 without the complication of excessive bleeding. DISCUSSION: Type I allergic reaction to unfractionated heparin is a rare occurrence and could be the result of a variety of factors. Possible causes for the reaction include a porcine protein, a preservative contained in the heparin solution, or a hapten formed between heparin and a plasma protein. We considered four alternatives to heparin anticoagulation: rush desensitization, bovine lung heparin, low-molecular-weight heparin, and ancrod. The patient was cross-sensitive to bovine lung heparin, but was able to tolerate low-molecular-weight heparin (enoxaparin). This was unexpected because enoxaparin is derived from unfractionated porcine heparin. Testing for cross-sensitivity had no value in this case, as two negative subcutaneous test doses were followed by dramatic reactions when the drugs were given intravenously. Although enoxaparin has been used for anticoagulation during bypass surgery, there is more experience with ancrod as an alternative to heparin. Repeat bypass surgery, which normally results in above-average blood loss, was successfully performed with a very low fibrinogen concentration (< 0.15 g/L) during ancrod anticoagulation. CONCLUSIONS: We conclude that ancrod was a safe and effective alternative to heparin for coronary artery bypass surgery in this patient in whom a heparin product had caused a hypersensitivity reaction. We discovered on two occasions that a negative subcutaneous test dose for heparin allergy did not predict a severe type I allergic reaction when the heparin was later administered intravenously. Furthermore, we found that a low-molecular-weight heparin administered subcutaneously for a short period of time did not cause cross-sensitivity in a patient with a type I allergy to unfractionated heparin.     

Guidelines for management of left-sided prosthetic valve thrombosis: a role for thrombolytic therapy. Consensus Conference on Prosthetic Valve Thrombosis

OBJECTIVES: We sought to form a consensus recommendation for management of prosthetic valve thrombosis (PVT) from previous case and uncontrolled reports from a consensus of international specialists. BACKGROUND: PVT and thromboembolism relate to inadequate anticoagulation and valve type and location. PVT is suspected by history (dyspnea) and auscultation (muffled valve sounds or new murmurs) and confirmed by Doppler echocardiography showing a marked valve gradient. METHODS: A consensus conference was held to recommend management of left-sided PVT. RESULTS: Transesophageal Doppler echocardiography is used to visualize abnormal leaflet motion and the size, location and mobility of thrombus. Thrombolysis is used for high risk surgical candidates with left-sided PVT (New York Heart Association functional class III or IV) because cerebral thromboembolism may occur in 12% of patients. Duration of thrombolysis depends on resolution of pressure gradients and valve areas to near normal by Doppler echocardiography performed every few hours. Lysis is stopped after 72 or 24 h if there is no hemodynamic improvement (operation indicated). Heparin infusion with frequent measurement of activated partial thromboplastin time (aPTT) begins when aPTT is more than twice control levels and can be converted to warfarin (international normalized ratio [INR] 2.5 to 3.5) plus aspirin (81 to 100 mg/day). Patients in functional class I or II have lower surgical mortality, and those with large immobile thrombi on the prosthetic valve or left atrium have responded to endogenous lysis with combined subcutaneous heparin every 12 h (aPTT 55 to 80 s) plus warfarin (INR 2.5 to 3.5) for 1 to 6 months. Operation is advised for nonresponders or patients with mobile thrombi. CONCLUSIONS: Thrombolysis, followed by heparin, warfarin and aspirin, is advised for high risk surgical candidates with left-sided PVT.     

Physician-guided treatment compared with a heparin protocol for deep vein thrombosis

BACKGROUND: Effective heparin therapy, defined by therapeutic prolongation of the activated partial thromboplastin time (APTT), decreases the risk of recurrent venous thromboembolism. Achieving therapeutic prolongation of the APTT within 24 hours of the start of heparin therapy has proved difficult. We hypothesized that a protocol that delivered high initial heparin infusions to patients without identifiable risk for bleeding complications would decrease the time to achieve a therapeutic anticoagulant effect without increasing the incidence of major bleeding complications. METHODS: To test this hypothesis, we studied concurrent patient cohorts. We defined a therapeutic anticoagulant effect (APTT > 55 seconds) to be an APTT more than 1.5 times the upper limit of normal. Twenty patients with acute symptomatic deep vein thrombosis received a 5000-U heparin bolus, followed by 1680 U/h (low risk to bleed) or 1240 U/h (high risk to bleed), adjusted by protocol-directed response to APTT results. Forty-eight patients with deep vein thrombosis were treated by their physicians. The Kaplan-Meier method was used to examine the proportion of patients who achieved an APTT greater than 55 seconds as a function of time. RESULTS: The two study cohorts did not differ with respect to age, weight, or risk factors for venous thromboembolism. Analysis of Kaplan-Meier curves showed that the heparin protocol decreased the time to achieve a therapeutic anticoagulant effect (P = .025). Ten (91%) of 11 patients (95% confidence interval, 59% to 100%) without risks to bleed who were treated by the heparin protocol and 29 (60%) of 48 patients (95% confidence interval, 45% to 74%) not treated by the protocol had an initial therapeutic APTT (P = .006). CONCLUSION: A protocol that delivers higher initial heparin infusions to patients without identifiable risks for bleeding decreases the time needed to achieve therapeutic prolongation of APTT, when compared with nonprotocol physician management.     

The use of activated clotting time (ACT) to optimize heparinization during coronary angioplasty. The nursing personnel of the Hemodynamics Laboratory

BACKGROUND: Suboptimal anticoagulation during coronary angioplasty is reported to be a major risk factor for occlusive complications. AIM: To define an appropriate timing for activated clotting time (ACT) tests in order to optimize anticoagulation with heparin during coronary angioplasty. METHODS: In 50 consecutive procedures of elective angioplasty ACT was measured at baseline, at 30, 60 and 120 min after heparin 10,000 U iv. In a subgroup of 25 patients (SG1) no additional heparin was given until the ACT test at 60 min. In a second subgroup of 25 patients (SG2) heparin 5,000 U was administered 30-45 min after the initial bolus if the ACT at 30 min was < 300 sec. ACT values were analyzed, and the correlation with the biological variables of patients was tested. RESULTS: In 20 patients out of 50 (40%) ACT values at 30 min were < 275 min. Heparin response was correlated with the body surface area but nor with age, neither with baseline ACT. Values at 60 min showed an adequate anticoagulation in only 6 patients (24%) in SG1 vs 21 (84%) in SG2. There were not complications. CONCLUSIONS: ACT testing 30 min after heparin 10,000 U during coronary angioplasty identifies most patients requiring early supplemental heparin. This yields an adequate anticoagulation at 60 min in most patients.     

Mutation analysis of CYP2D6 locus in the Korean population: identification of rare poor metabolizer alleles at the nucleotide level

We conducted studies to determine at what time point an add-on prothrombin time (PT) or activated partial thromboplastin time (APTT) test can be honored on specimens that have been received in the laboratory hours earlier without yielding results with clinically significant differences from those if the test had been performed on the original unstored plasma. PT and APTT tests were performed on blood samples from 20 healthy subjects, 30 patients receiving warfarin, and 30 patients receiving heparin anticoagulation therapy. The tests were performed on plasma prepared initially after the samples were obtained. The same tests were assayed on plasma that had been left on spun-down blood cells at room temperature for 2, 4, and 8 hours. We found that the PT of the majority of plasma samples from healthy subjects and from patients receiving oral anticoagulant therapy tended to become shorter on storage. However, the difference in PT values was small and had no clinical significance. In most cases, the APTT values for the stored plasma from healthy subjects tended to increase with time. Except in one specimen in which the 8-hour add-on APTT was 1.2 seconds longer than the APTT result for the original sample, all others had APTT results less than 1.2 seconds longer than the original values. In patients receiving heparin, the differences in APTT values between the initial and add-on tests were larger than those observed for healthy subjects. However, those differences are not beyond what we would accept for duplicate checks for heparinized samples with high APTT values. Unlike samples from healthy subjects, there was no obvious trend of time-related prolongation of the APTT in heparinized plasma. These results led us to believe that within an 8-hour period and with plasma on spun-down cells at room temperature, add-on tests for PT and APTT could be performed with results similar to what would be obtained from testing unstored samples.     

Effect of intravenous heparin infusion on thrombin-antithrombin complex and fibrinopeptide A in unstable angina

BACKGROUND: In unstable angina, the clinical efficacy of heparin is limited in time, and recurrence of adverse events has been reported after discontinuation of the anticoagulant. METHODS: In 21 episodes of unstable angina, we used the plasma level of fibrinopeptide A (FPA) and of thrombin-antithrombin complex (TAT) to evaluate the pattern of thrombin inhibition by heparin and the effect of stopping heparin and initiating aspirin. RESULTS: At admission, the plasma level of FPA was increased: median value 3.7 ng/mL compared with 5.5 ng/mL in a control group of 20 patients with early myocardial infarction (not significant). The following findings were observed during a 4-day course of intravenous heparin infusion: (1) FPA decreased significantly 6 hours after the start of therapy; (2) FPA was lower when activated partial thromboplastic time (aPTT) was >1.5 times baseline; (3) there was a significant negative correlation between aPTT and FPA. Twenty-four hours after heparin was discontinued and aspirin initiated, a significant increase in TAT and FPA in plasma was observed. CONCLUSIONS: The results confirm ongoing fibrin formation in the active phase of unstable angina, indicate incomplete and variable inhibition of thrombin by heparin during continuous infusion, and suggest a risk of re-emergence of thrombosis (in spite of initiating aspirin) 24 hours after withdrawal of heparin. Data demonstrate a better control of thrombin activity when heparin is infused at rates that maintain aPTT at >1.5 times baseline, as currently recommended in unstable angina.     

D-dimer, thrombin-antithrombin III-complex (TAT) and prothrombin fragment 1+2 (PTF). Parameters for monitoring therapy with low molecular-weight heparin in coagulation disorders

Two groups of 15 patients each with disseminated intravascular coagulation in association with septic disease were treated with low-molecular-weight heparin (lmw-heparin) in different dosages (group I: 1.5-5 IE/kg body weight (BW) per hour; group II: 8-15 IE/kg BW). We studied the levels of D-dimer, thrombin-antithrombin III complex (TAT), prothrombin fragments 1 and 2 (PTF), and global tests of coagulation like prothrombin time (PT), activated partial thromboplastin time (PTT), thrombin time (TT) and platelet count, plasminogen activation (PA) and fibrinogen concentration to estimate the success of heparin therapy in the two groups. TT and fibrinogen concentration were not suitable to follow the course of the coagulation disorder, PT, PTT, platelet count progressively PA, D-dimer, TAT, and PTF normalised progressively after heparinisation. However, only the last three parameters were sensitive enough to show different effects of variable dosages of lmw-heparin. D-dimer, TAT, and PTF levels declined in proportion with heparin concentrations, and thus appear to be the most useful parameters for monitoring the therapeutic effect of heparin in septic coagulopathies.