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.     

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.     

Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis

BACKGROUND: Randomized trials have demonstrated the importance of achieving adequate heparinization early in the course of therapy. Recently, some authors reported a pooled analysis of selected studies in the literature that suggested that there is no convincing evidence that the risk of recurrent venous thromboembolism is critically dependent on achieving a therapeutic activated partial thromboplastin time result at 24 to 48 hours. METHODS: We provide the analyses of patient groups entered into our series of 3 consecutive double-blind randomized trials evaluating initial heparin therapy for proximal deep venous thrombosis. RESULTS: Logistic regression analysis of the patient groups receiving the less intense initial intravenous heparin dose of 30,000 U/24 h demonstrated that subtherapy for 24 hours predicted the onset of venous thromboembolic events. Failure to achieve a therapeutic activated partial thromboplastin time by 24 hours was associated with a 23.3% frequency of venous thromboembolism vs 4% to 6% for those whose activated partial thromboplastin time exceeded the therapeutic threshold by 24 hours (P=.02). Time-to-event analysis shows the increased frequency of recurrent venous thromboembolic events during the period of study in patients who were subtherapeutic for 24 hours compared with those who were therapeutic (P=.001). CONCLUSIONS: Our findings reaffirm the clinical importance of rapidly achieving therapeutic levels of heparin. Patients who failed to achieve the therapeutic threshold by 24 hours were at an increased risk of subsequent recurrent venous thromboembolism. These findings are independently supported by the results of a randomized trial comparing different intensities of initial heparin treatment by continuous infusion.     

Aging and heparin-related bleeding

BACKGROUND: Many studies have suggested that elderly patients are at increased risk of bleeding during heparin therapy. OBJECTIVE: To establish whether the risk of bleeding in the elderly results from concomitant risk factors or is associated with the aging process itself. METHODS: One hundred ninety-nine patients who presented with proximal deep vein thrombosis were treated with a standard intravenous heparin protocol in a double-blind, randomized, prospective study. Bleeding complications were monitored. Activated partial thromboplastin times and heparin levels were assessed 4 to 6 hours after a standard intravenous heparin bolus and infusion. Heparin doses and heparin levels were also assessed after stable therapeutic heparin infusion rates were established. RESULTS: There was an increase in total and major bleeding complications with aging (P < .05) that was not accounted for by standard risk factors for bleeding. Aging was associated with an increase in heparin levels (r = .239, P = .003) and a tendency for an increase in activated partial thromboplastin time (r = .134, P = .07) after standard heparin doses. Aging was also associated with lower heparin dose requirements (r = .267, P = .003) after therapeutic activated partial thromboplastin times were achieved. CONCLUSION: Aging is a risk for heparin-related bleeding that may be explicable by age-related changes in the pharmacologic characteristics of heparin.     

Intracerebral hemorrhage after carotid endarterectomy: incidence, contribution to neurologic morbidity, and predictive factors

PURPOSE: With a diminishing rate of cardiac and neurologic events after carotid endarterectomy, intracerebral hemorrhage is gaining increasing importance as a cause of perioperative morbidity and mortality. To date, information has been largely anecdotal, and there has been no comparison with a control group of patients. METHODS: The records of all patients experiencing symptomatic intracerebral hemorrhage after carotid endarterectomy were reviewed and compared with data from 50 randomly selected patients who did not experience intracranial bleeding. Univariate analyses were performed, using the Fisher exact test for dichotomous data and the Student t test for continuous data. RESULTS: During a 6-year period, symptomatic intracranial hemorrhage developed in 11 (0.75%) of 1471 patients undergoing carotid endarterectomy, accounting for 35% of the 31 total perioperative neurologic events. Hemorrhage occurred a median of 3 days postoperatively (range, 0 to 18 days). Signs and symptoms included hypertension in all 11 patients, headache in 7 conscious patients (64%), and bradycardia in 6 patients (55%). Massive hemorrhage with herniation and death occurred in 4 patients (36%). Moderate hemorrhage developed in 5 patients (45%); 3 of these patients had partial recovery, and 2 had complete recovery. Petechial hemorrhage occurred in the remaining 2 patients (18%), 1 with partial and 1 with complete recovery. In comparison with the control group, there were no differences in respect to sex, indication for operation, smoking or diabetic history, and antiplatelet therapy or perioperative heparin management. Patients with intracranial hemorrhage were, however, younger, more frequently hypertensive, had a higher degree of ipsilateral and contralateral carotid stenosis, and had a higher rate of contralateral carotid occlusion. CONCLUSION: Intracranial hemorrhage occurs with notable frequency after carotid endarterectomy and accounts for a significant proportion of neurologic morbidity and mortality. Younger patients, hypertensive patients, and patients with severe cerebrovascular occlusive disease appear to be at greatest risk for the complication.     

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.     

Randomised comparison of subcutaneous heparin, intravenous heparin, and aspirin in unstable angina. Studio Epoorine Sottocutanea nell'Angina Instobile (SESAIR) Refrattorie Group

Intravenous heparin has been used in the control of myocardial ischaemia in patients with unstable angina. We set out to assess the efficacy of subcutaneous heparin in reducing myocardial ischaemia in patients with unstable angina. 343 of 399 patients with unstable angina were monitored for 24 h and 108 were refractory to conventional antianginal treatment and were entered into a randomised multicentre trial. 37 patients were assigned to heparin infusion (partial thromboplastin time 1.5-2 times baseline), 35 to subcutaneous heparin (adjusted dose with partial thromboplastin time 1.5-2 times baseline), and 36 to aspirin (325 mg daily). All had additional conventional antianginal therapy. After the run-in patients were monitored for 3 days. The primary endpoint was reduced myocardial ischaemia assessed by the number of anginal attacks, silent ischaemic episodes, and duration of ischaemia per day. At 1 week and 1 month we accounted for anginal attacks and other clinical events (myocardial infarction, revascularisation procedures, and death). Aspirin did not significantly affect the incidence of myocardial ischaemia. On the first 3 days, infused and subcutaneous heparin significantly decreased the frequency of angina (on average by 91% and 86%, respectively), episodes of silent ischaemia (by 56% and 46%), and the overall duration of ischaemia (66% and 61%) versus run-in day and aspirin (p < 0.001 for all variables). The favourable effects of heparin therapy remained evident during follow-up. Only minor bleeding complications occurred. Subcutaneous heparin is effective in the control of myocardial ischaemia in patients with unstable angina.     

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.     

Differential expression of rat brain bcl-2 family proteins in development and aging

1. The effects of YM-60828, a newly synthesized factor Xa inhibitor, were investigated to analyse the relationship between its antithrombotic effects and its prolongation of template bleeding time in rats. YM-60828 was compared with argatroban, heparin and dalteparin. All agents were intravenously administered as a bolus. 2. In ex vivo studies, YM-60828 and argatroban prolonged both prothrombin time and activated partial thromboplastin time in a dose-dependent manner, while heparin and dalteparin prolonged only activated partial thromboplastin time. 3. In a venous thrombosis model, all agents exerted antithrombotic effects in a dose-dependent manner. The ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.0081 mg kg(-1), 0.011 mg kg(-1), 6.3 iu kg(-1) and 4.7 iu kg(-1), respectively. 4. In an arterio-venous shunt model, all agents exerted antithrombotic effects in a dose-dependent manner. The ID50 values of YM-60828, argatroban, heparin and dalteparin were 0.010 mg kg(-1), 0.011 mg kg(-1), 10 iu kg(-1) and 4.2 iu kg(-1), respectively. 5. In bleeding time studies, all agents prolonged template bleeding time in a dose-dependent manner. ED2 values, the doses causing a 2 fold prolongation of bleeding time in the saline group, of YM-60828, argatroban, heparin and dalteparin were 0.76 mg kg(-1), 0.081 mg kg(-1), 18 iu kg(-1) and 25 iu kg(-1), respectively. 6. The ratio (ED2/ID50) of YM-60828 was more than 30 fold greater than that of heparin and more than 10 fold greater than those of argatroban and dalteparin. 7. These data show that YM-60828 can exert its antithrombotic effects with little prolongation of bleeding time compared with the other currently used anticoagulant agents.     

TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators

BACKGROUND: Bolus thrombolytic therapy is a simplified means of administering thrombolysis that facilitates rapid time to treatment. TNK-tissue plasminogen activator (TNK-tPA) is a highly fibrin-specific single-bolus thrombolytic agent. METHODS AND RESULTS: In TIMI 10B, 886 patients with acute ST-elevation myocardial infarction presenting within 12 hours were randomized to receive either a single bolus of 30 or 50 mg TNK-tPA or front-loaded tPA and underwent immediate coronary angiography. The 50-mg dose was discontinued early because of increased intracranial hemorrhage and was replaced by a 40-mg dose, and heparin doses were decreased. TNK-tPA 40 mg and tPA produced similar rates of TIMI grade 3 flow at 90 minutes (62.8% versus 62.7%, respectively, P=NS); the rate for the 30-mg dose was significantly lower (54.3%, P=0.035) and was 65. 8% for the 50-mg dose (P=NS). A prespecified analysis of weight-based TNK-tPA dosing using median TIMI frame count demonstrated a dose response (P=0.001). Similar dose responses were observed for serious bleeding and intracranial hemorrhage, but significantly lower rates were observed for both TNK-tPA and tPA after the heparin doses were lowered and titration of the heparin was started at 6 hours. CONCLUSIONS: TNK-tPA, given as a single 40-mg bolus, achieved rates of TIMI grade 3 flow similar to those of the 90-minute bolus and infusion of tPA. Weight-adjusting TNK-tPA appears to be important in achieving optimal reperfusion; reduced heparin dosing appears to improve safety for both agents. Together with the safety results from the parallel Assessment of the Safety of a New Thrombolytic: TNK-tPA (ASSENT I) trial, an appropriate dose of this single-bolus thrombolytic agent has been identified for phase III testing.     

Effect of warfarin on activated partial thromboplastin time in patients receiving heparin

BACKGROUND: The activated partial thromboplastin time (APTT) is used to adjust heparin sodium dosage. However, warfarin sodium is often administered concomitantly with heparin and may also affect the APTT and, therefore, heparin dose. We performed a prospective cohort study to quantify the effect of warfarin on the APTT in patients who are being treated with heparin. METHODS: Serial assays of APTT, international normalized ratio, heparin levels, and functional levels of prothrombin (factor II) and factors VII and X were performed in 24 patients with acute venous thromboembolism who were treated with concomitant continuous intravenous heparin and warfarin. The effects of warfarin, as expressed by international normalized ratio and coagulation factor levels, on APTT were determined. RESULTS: Warfarin markedly affected APTT; for each increase of 1.0 in the international normalized ratio, the APTT increased 16 seconds (95% confidence interval, 10-22 seconds). The effects of warfarin and heparin on APTT were additive. Consequently, warfarin markedly altered the relationship between APTT and heparin levels; of the 29 blood samples with supratherapeutic APTT, 13 had a therapeutic heparin level and 10 had a subtherapeutic heparin level. CONCLUSIONS: In patients receiving concomitant heparin and warfarin therapy, APTT reflects the combined effects of both drugs. Because of the marked effect of warfarin on the APTT, decreasing heparin dose in response to a high APTT frequently results in subtherapeutic heparin levels.     

Comparison of the antithrombotic effects of low molecular weight heparinoid KB-101 and heparin in a rat experimental model

1. We compared the low molecular weight heparinoid KB-101 and heparin with regard to suppression of experimental thrombus formation and effects on bleeding time, prothrombin time (PT), and activated partial thromboplastin time (APTT) in rats. 2. KB-101 exerted a similar antithrombotic activity as that of heparin. 3. Heparin prolonged bleeding time, PT, and APTT more than KB-101 did. 4. These results suggested that KB-101 is superior to heparin as an anticoagulant.     

Inhibition of smooth muscle cell proliferation and neointimal growth by low-anticoagulant heparin

Low-anticoagulant heparin (LA-heparin) obtained by affinity chromatography on antithrombin III Sepharose inhibits the proliferation of cultured arterial smooth muscle cells in an in vitro bioassay system as effectively as standard heparin. A growth inhibition of smooth muscle cells of about 60% is achieved when LA-heparin or heparin is added to the culture medium to a concentration of 50 micrograms/ml. In normolipemic rats LA-heparin suppresses the formation of neointimal thickenings and stenosis after balloon catheter-induced deendothelialization of the carotid artery. In terms of mass a dose of 5 mg/kg body weight/d given subcutaneously twice daily one week before and 2 weeks after balloon injury the cross sectional area of the neointima is reduced to 36% as compared with the nontreated control group (100%). This 64% reduction is statistically highly significant (p < 0.001). After treatment with 0.5 mg LA-heparin/kg/d the reduction of the neointima was 11% (p < 0.05). At a dose of 5 mg/kg body weight single or repeated administrations of LA-heparin caused only a small and transient increase in activated partial thromboplastin time values. The results show that subcutaneous administration of LA-heparin very effectively prevents smooth muscle cell proliferation and balloon catheter-induced neointimal growth. The well tolerated systemic application of this chemically non-modified LA-heparin might justify clinical trials for prevention of restenosis after percutaneous transluminal coronary angioplasty or other invasive cardiovascular interventions without complications of bleeding.     

Low-dose heparin thromboembolism prophylaxis

OBJECTIVE: To determine a rational approach to heparin dosing for thromboembolism prophylaxis. DESIGN: Literature review. RESULTS: Three commonly used heparin dosing regimens were identified: (1) standard low-dose heparin (5000 U administered subcutaneously 2-3 times per day); (2) adjusted-dose heparin (adequate to elevate the activated partial thromboplastin time to 5 seconds above the upper limit of normal); and (3) low-molecular-weight heparin (30 mg subcutaneously twice daily without monitoring). CONCLUSIONS: Adjusted-dose heparin thromboembolism prophylaxis is both the safest and most reliable method currently available.     

A new route of heparin administration--the lung

Instillation of a single dose of heparin into the lungs of the dog resulted in a steady prolonged hypocoagulability as measured by the Lee and White clotting time, partial thromboplastin and activated partial thromboplastin times. 15 mg of heparin/kg increased clotting time three to five times control values. The anticoagulant effect occurred within one hour and lasted 48 h or more, in contrast to the short effect of intravenous heparin. For doses of 8, 10, 12, 15 and 20 mg/kg, there was a corresponding increase in the area under the response curve. The very prolonged moderate anticoagulant state with intrapulmonary heparin did not show the wide fluctuations in coagulation test values which occur with intravenous heparin.     

The effects of heparin on recovery from ischemic brain injuries in cats

Since ischemic anoxia in experimental animals has been reported to produce areas of cerebral postocclusive nonperfusion, the authors studied the effect of heparin on recovery from tourniquet-produced cerebrovascular injury in 41 barbiturate-anesthetized, ventilated cats (PaCO2 30 +/- 2.5 torr). Twenty-four control animals were subjected to 2-to-12-minute ischemic injuries without further treatment. Seven experimental animals were given heparin (1000 u/kg) 1 minute before 4-to-7-minute ischemic injuries, while 10 animals received heparin (1000 u/kg) immediately after 4-to-7-minute injuries. All animals were monitored with continuous arterial and intracranial pressure (ICP) recordings, EEG, and evoked cortical responses. Ischemia and evoked-response recovery times were linearly related in all groups (r = 0.998 control, r = 0.936 heparin preinjury, r = 0.951 heparin postinjury). Regression-line slope comparison indicated shorter evoked response and EEG recovery times in the heparin-treated groups than in the control group. Heparin administration did not effect elevations of ICP seen 6 and 12 hours postinjury in control versus experimental groups. In cats with injuries lasting 5 minutes or more, all control animals were decerebrate and apneic, while 5/12 heparin-treated animals had lesser neurologic deficits.     

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.     

Relationship between the antithrombotic effect of YM-75466, a novel factor Xa inhibitor, and coagulation parameters in rats

The relationship between the antithrombotic effects of intravenous infusions of YM-75466 [N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naph thyl)methyl] sulfamoyl]acetic acid monomethanesulfonate), a novel factor Xa (FXa) inhibitor, and various coagulation parameters (prothrombin time, activated partial thromboplastin time, thrombin-antithrombin III complex (TAT), anti-FXa activity and anti-thrombin activity) in rats was studied and compared with results for heparin. In the arterio-venous shunt model, both agents exerted antithrombotic effects in a dose-dependent manner. Coagulation parameters were studied simultaneously with antithrombotic effects. YM-75466 did not prolong coagulation time even at the dose which exerted significant antithrombotic effects, while it decreased TAT level in plasma in a dose-dependent manner. YM-75466 exerted anti-FXa activity but not anti-thrombin activity. In contrast, heparin prolonged activated partial thromboplastin time in a dose-dependent manner and decreased TAT level in plasma with increasing inhibition of thrombus formation. Heparin exerted both anti-FXa and anti-thrombin activity in a dose-dependent manner. These results suggest that TAT is a suitable parameter for monitoring the antithrombotic effect of YM-75466 in the arterio-venous shunt model in rats and that YM-75466, unlike heparin, exerts its antithrombotic effect through specific inhibition of FXa without any effect on thrombin.     

Pharmacokinetics of heparin and its pharmacodynamic effect on plasma lipoprotein lipase activity and coagulation in healthy horses

We evaluated the pharmacokinetics of IV administered sodium heparin and the pharmacodynamic effect of heparin on lipoprotein lipase (LPL) activity. Horses were allotted to 3 groups. Plasma samples were obtained from each horse before and at various times for 6 hours after heparin administration for determination of heparin concentration, LPL activity, and activated partial thromboplastin time (APTT). The disposition of heparin was dose dependent. The area under the plasma heparin concentration vs time curve (AUC) increased more than proportionally with dose, indicating that heparin elimination was nonlinear. Total clearance of heparin was similar after the 40 and 80 IU/kg of body weight dosages, averaging 0.45 and 0.36 IU/kg/min, respectively. However, after administration of the 120 IU/kg dose, clearance was significantly less than that after the 40 IU/kg dose. The half-life of heparin averaged 53, 70, and 136 minutes after 40, 80, and 120 IU/kg, respectively, with significant differences observed between the low and high doses. In contrast to heparin, the area under the plasma concentration vs time curve for LPL activity increased less than proportionally with dose. Maximal LPL activity observed was independent of dose, averaging 4.8 mumol of free fatty acids/ml/h. The APTT was significantly prolonged for 120 minutes after administration of the 40 IU/kg dose. Correlation coefficients for LPL activity vs either plasma heparin concentration or APTT were less than 0.7, indicating that neither laboratory measure can be used to accurately predict plasma LPL activity.     

Anticoagulation in hemodialysis with a single dose of low molecular weight heparin

The aim of this work was to compare the benefits and problems of low molecular weight heparin use in chronic hemodialysis, compared to conventional heparin. We studied 35 patients that received low molecular weight heparin (Enoxaparine, molecular weight 4000) during 115 consecutive hemodialysis procedures and conventional heparin during the subsequent 35 procedures. We assess the heparin dose, partial thromboplastin time before dialysis and at 3 and 120 min during the procedure, arterio-venous fistula compression time, clot formation in the circuit and residual volume of filters. Median total dose of conventional heparin was 6289 U (range 3000-10000) compared to 5555 U (range 2000-8000) of low molecular weight heparin. When the dose was calculated per kg of body weight, it was lower for low molecular weight heparin than for conventional heparin (87.8 U (range 33-100) vs 100 U (range 50-176)). Partial thromboplastin time achieved was lower with low molecular weight heparin, compared with conventional heparin, at 3 (64.26 vs 125.2 sec) and 120 min (39.1 vs 84.45 sec). Clot formation, arteriovenous fistula compression time and residual volume of filters were similar for both types of heparin. It is concluded that a single dose of low molecular weight heparin simplifies anticoagulation during hemodialysis, modifies less the partial thromboplastin time and does not alter filter re-utilization.