Repeated doses of oral and subcutaneous heparins have similar antithrombotic effects in a rat carotid arterial model of thrombosis

Although heparins are usually injected intravenously or subcutaneously, antithrombotic activity is observed in rat models following single oral heparin doses. Since repetitive dosing is usually needed for thromboprophylaxis, study objectives were to determine whether repetitive oral heparin prevented arterial thrombosis and to compare effectiveness to subcutaneous administration. Wistar rats were given subcutaneous or oral unfractionated heparin ([UFH] 1 mg/kg per 48 h), low-molecular-weight heparin ([LMWH] tinzaparin, 0.1 mg/kg per 12 h), or saline for 30 days. On the last day, thrombosis was initiated by placing 30% FeCl(3)-soaked filter paper on the distal carotid. Subsequent flow measurements, for a 60-minute period, included recorded time of initial thrombus formation (time till thrombus begins [TTB]), and time until carotid occlusion (time till occlusion [TTO]). The formed thrombus was dried and weighed. The activated partial thromboplastin time (aPTT), anti-factor Xa, and antithrombin activity were determined from the plasma. Both oral and subcutaneous heparins significantly increased TTB and TTO. Time of initial thrombus formations were 12.6 ± 1.1, 21.2 ± 2.2, 25.3 ± 3.9, 21.7 ± 3.1, and 21.3 ± 1.7 minutes and TTOs were 29.3 ± 3.6, 54.8 ± 4.0, 60.0 ± 0.3, 56.7 ± 3.3, and 58.3 ± 1.7 minutes (mean ± SEM) for control, subcutaneous UFH, oral UFH, subcutaneous LMWH, and oral LMWH, respectively. Thrombus weight was 2.52 ± 0.29 g in control and was reduced to 43%, 23%, 33%, and 28% of control weight for subcutaneous UFH, oral UFH, subcutaneous LMWH, and oral LMWH, respectively. Thrombus weight was significantly less for oral compared to subcutaneous UFH. The aPTT for oral UFH, and anti-factor Xa activity in the LMWH-treated groups were significantly greater than control (two-tailed t tests). These findings confirm that orally administered heparins are absorbed. Repeated treatment with oral heparin showed similar antithrombotic activity compared to subcutaneous heparin. Oral heparin use for arterial thromboprophylaxis should be further investigated.     

A randomized,double‐blind study of certoparin vs. unfractionated heparin to prevent venous thromboembolic events in acutely ill,non‐surgical patients: CERTIFY Study

Summary. Background: In medically ill patients, no contemporary double‐blind head‐to‐head evaluation of low molecular weight heparin vs. unfractionated heparin (UFH) for the prevention of venous thromboembolic events is available. Objectives: To compare the efficacy and safety of certoparin with those of UFH. Patients/Methods: In this double‐blind, randomized, controlled trial, acutely ill, non‐surgical patients aged ≥ 70 years were randomized to certoparin (3000 U of anti‐factor Xa once daily) or to UFH (5000 IU t.i.d.). The primary endpoint was the composite of proximal deep vein thrombosis as assessed by bilateral compression ultrasonography, symptomatic non‐fatal pulmonary embolism and venous thromboembolism‐related death, and was assessed by a blinded central adjudication committee. Non‐inferiority margins were set at 1.8 for the odds ratio (OR) and 3.45% for the absolute difference. Results: Three thousand two hundred and thirty‐nine patients aged 78.8 ± 6.3 years were treated for 9.1 ± 3.4 days. The incidence of the primary endpoint was 3.94% in the certoparin group and 4.52% in the UFH group, with a difference in proportions of ? 0.59% [95% confidence interval (CI) ?2.09 to 0.92; P < 0.0001 for non‐inferiority], and an OR of 0.87 (95% CI 0.60–1.26; P = 0.0001 for non‐inferiority). Major bleeding occurred in 0.43% of certoparin‐treated patients and 0.62% of UFH‐treated patients (OR 0.69; 95% CI 0.26–1.83). Any bleeding occurred at 3.20% in certoparin‐treated patients vs. 4.58% in UFH‐treated patients (OR 0.69; 95% CI 0.48–0.99; P < 0.05), and 5.73% of certoparin‐treated patients and 6.63% of UFH‐treated patients experienced serious adverse events. All‐cause mortality was 1.27% in certoparin‐treated patients and 1.36% in UFH‐treated patients. Conclusions: In acutely ill, non‐surgical elderly patients, thromboprophylaxis with certoparin (3000 U of anti‐FXa once daily) was non‐inferior to 5000 IU of UFH t.i.d., with a favorable safety profile.     

Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients on long-term oral anticoagulants: the REGIMEN registry.

BACKGROUND: Patients who receive long-term oral anticoagulant (OAC) therapy often require interruption of OAC for an elective surgical or an invasive procedure. Heparin bridging therapy has been used in these situations, although the optimal method has not been established. No large prospective studies have compared unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for the perioperative management of patients at risk of thromboembolism requiring temporary interruption of long-term OAC therapy. PATIENTS/METHODS: This multicenter, observational, prospective registry conducted in North America enrolled 901 eligible patients on long-term OAC who required heparin bridging therapy for an elective surgical or invasive procedure. Practice patterns and clinical outcomes were compared between patients who received either UFH alone (n = 180) or LMWH alone (n = 721). RESULTS: Overall, the majority of patients (74.5%) requiring heparin bridging therapy had arterial indications for OAC. LMWH, in mostly twice-daily treatment doses, represented approximately 80% of the study population. LMWH-bridged patients had significantly fewer arterial indications for OAC, a lower mean Charlson comorbidity score, and were less likely to undergo major or cardiothoracic surgery, receive intraprocedural anticoagulants or thrombolytics, or receive general anesthesia than UFH-bridged patients (all P < 0.05). The LMWH group had significantly more bridging therapy completed in an outpatient setting or with a < 24-h hospital stay vs. the UFH group (63.6% vs. 6.1%, P < 0.001). In the LMWH and UFH groups, similar rates of overall adverse events (16.2% vs. 17.1%, respectively, P = 0.81), major composite adverse events (arterial/venous thromboembolism, major bleed, and death; 4.2% vs. 7.9%, respectively, P = 0.07) and major bleeds (3.3% vs. 5.5%, respectively, P = 0.25) were observed. The thromboembolic event rates were 2.4% for UFH and 0.9% for LMWH. Logistic regression analysis revealed that for postoperative heparin use a Charlson comorbidity score > 1 was an independent predictor of a major bleed and that vascular, general, and major surgery were associated with non-significant trends towards an increased risk of major bleed. CONCLUSIONS: Treatment-dose LMWH, mostly in the outpatient setting, is used substantially more often than UFH as bridging therapy in patients with predominately arterial indications for OAC. Overall adverse events, including thromboembolism and bleeding, are similar for patients treated with LMWH or UFH. Postoperative heparin bridging should be used with caution in patients with multiple comorbidities and those undergoing vascular, general, and major surgery. These findings need to be confirmed using large randomized trials for specific patient groups undergoing specific procedures.     

Individual patient data meta‐analysis of enoxaparin vs. unfractionated heparin for venous thromboembolism prevention in medical patients

Summary. Background: Unfractionated heparin (UFH) and low‐molecular‐weight heparin (LMWH) are both recommended for venous thromboembolism (VTE) prophylaxis in hospitalized medical patients. Objective: To perform an individual patient data meta‐analysis to evaluate the relative efficacy and safety of the LMWH enoxaparin and UFH in preventing VTE in hospitalized medical patients. Methods: Randomized clinical trials comparing subcutaneous enoxaparin (4000 IU once‐daily) and UFH (5000 IU subcutaneous two‐ or three‐times daily) for VTE prevention were identified by a systematic search. Individual patient data were obtained from each eligible trial. Results: Overall, four trials were eligible, including 3600 patients randomized to receive enoxaparin (n = 1799) or UFH (n = 1801). Median patient age was 71 years, and 49.3% were female. Compared with UFH, enoxaparin was associated with risk reductions of 37% for total VTE [relative risk (RR) 0.63, 95% confidence interval (CI) 0.51–0.77] and 62% for symptomatic VTE (RR 0.38, 95% CI 0.17–0.85) at day 15. RR for total VTE in stroke and non‐stroke patients was 0.59 (95% CI 0.47–0.74) and 0.87 (95% CI 0.51–1.50), respectively. Major bleeding rates were consistently low and similar between treatment groups at day 15 (RR 1.13, 95% CI 0.53–2.44). There was a trend towards reduced risk for mortality in patients receiving enoxaparin (RR 0.83, 95% CI 0.64–1.08), compared with UFH. Conclusions: Enoxaparin significantly reduces VTE in hospitalized medical patients, compared with UFH, without increasing the risk for major bleeding, and was associated with a trend towards reduced all‐cause mortality.     

Hospital-based costs associated with venous thromboembolism treatment regimens

Summary.  Introduction:  Venous thromboembolism (VTE) poses a significant health and economic burden in US hospitals. Clinical guidelines for acute VTE treatment recommend antithrombotic therapy (at least 5 days) with low molecular weight heparin (LMWH) or unfractionated heparin (UFH). With upcoming US national performance measures requiring successful implementation of evidence-based therapy, cost considerations for anticoagulant choice are of increasing importance to hospitals. Methods:  This retrospective cohort analysis utilizes discharge records from a large real-world US population (January 2002 to December 2006) to provide total, direct, inpatient medical costs associated with LMWH and UFH for acute VTE treatment. Furthermore, for both LMWH and UFH discharges, we compare VTE-related readmission rates at 30 and 90 days after discharge. Results:  In total, 57 131 discharges were identified (57.7% LMWH; 42.3% UFH). After adjustment for covariates, including age, severity of illness, and length of stay, total direct medical costs per hospital discharge for UFH were $3476.22 vs. $3056.42 for LMWH ( P  < 0.0001; difference $420). Costs were significantly higher in the UFH group for most cost categories. Notably, drug acquisition cost was higher for LMWH. LMWH treatment was 12% [odds ratio (OR) 0.876; P  < 0.001] and 10% (OR 0.895; P  = 0.0006) less likely to result in VTE readmission within 30 and 90 days, respectively. Conclusions:  This study provides the first large, real-world analysis of the total direct medical costs of treating VTE in-hospital. It confirms that, despite higher drug acquisition costs, LMWH is cost-saving compared with UFH in the inpatient setting, and is associated with a lower VTE readmission rate at 30 and 90 days than is UFH.     

瑞替普酶并低分子肝素用于急性心肌梗死再灌注治疗的有效性与安全性研究

目的探讨急性心肌梗死(AMI)瑞替普酶静脉溶栓并应用低分子肝素(LMWH)替代普通肝素(UFH)抗凝治疗的安全性与有效性。方法106例AMI患者经瑞替普酶静脉溶栓后,随机分为LMWH组(低分子肝素5000U皮下注射,2次/d)和静脉UFH组(普通肝素静脉泵入24h后改为低分子肝素5000U皮下注射,2次/d),1周后行冠状动脉造影及冠脉介入治疗(PCI)。观察临床再通率、血管开通率、急性期并发症、出血及不良反应的发生率。结果①LMWH组与静脉UFH组相比,临床再通率(82.1%vs78.0%)、血管开通率(78.9%vs75.0%)高,临床再通病例梗死后心绞痛发生率(8.70%vs12.8%)低,但两组之间差异无统计学意义;②LMWH组出血并发症明显低于静脉UFH组(7.14%vs18.0%),差异有统计学意义(P<0.05)。③两组PCI后均予LMWH抗凝治疗,30d内无急性或亚急性支架内血栓形成发生。结论本研究结果提示,瑞替普酶并LMWH用于AMI再灌注治疗是安全、有效、方便的,LMWH用于PCI后抗凝治疗疗效确切。     

An individualized pre-operative blood saving protocol can increase pre-operative haemoglobin levels and reduce the need for transfusion in elective total hip or knee arthroplasty

summary .  We have prospectively evaluated the efficacy of an individualized pre-operative blood saving protocol in elective total hip arthroplasty (THA) or total knee arthroplasty (TKA). The primary aim was to obtain a pre-operative haemoglobin (Hb) level of ≥14 g dL⁻¹. A reduction in requirements for allogeneic transfusion was considered the second aim. Several strategies are available for increasing pre-operative Hb levels and reducing red blood cell (RBC) transfusions following THA or TKA, but the success of these programmes depends on selecting the most appropriate treatment for each patient. Three hundred and five patients with an indication of elective THA or TKA were individually assigned to the following strategies according to Hb and ferritin levels and medical conditions: (a) no pre-operative intervention, (b) oral iron therapy, (c) intravenous (i.v.) iron therapy, (d) recombinant human erythropoietin alpha with i.v. iron and (e) pre-operative autologous donation (PAD) plus oral iron. Eighty-two percent of the patients reached a pre-operative Hb level of ≥14 g dL⁻¹ compared with 62% of patients with Hb levels of ≥14 g dL⁻¹ at the baseline visit. Treatment with PAD showed a significant reduction in the pre-operative Hb levels. The rate of RBC transfusion was 18·8% compared with 31·5% of matched historic group ( P  < 0·001). In conclusion, all patients scheduled to undergo THA or TKA should be candidates for an individualized pre-operative blood salvage programme.     

The inhibition of blood coagulation by heparins of different molecular weight is caused by a common functional motif—the C-domain

Summary.  Background : Heparins in clinical use differ considerably as to mode of preparation, molecular weight distribution and pharmacodynamic properties. Objectives : Find a common basis for their anticoagulant action. Methods : In 50 fractions of virtually single molecular weight (Mr), prepared from unfractionated heparin (UFH) and four low-molecular-weight heparins (LMWH), we determined: (i) the molar concentration of material (HAM) containing the antithrombin binding pentasaccharide (A-domain); (ii) the specific catalytic activity in thrombin and factor Xa inactivation; (iii) the capacity to inhibit thrombin generation (TG) and prolong the activated partial thromboplastin time (APTT). We also calculated the molar concentration of A-domain with 12 sugar units at its non-reducing end, i.e. the structure that carries antithrombin activity (C-domain). Results : The antithrombin activity and the effects on TG and APTT are primarily determined by the concentration of C-domain and independent of the source material (UFH or LMWH) or Mr. High Mr fractions (>15 000) are less active, probably through interaction with non-antithrombin plasma proteins. Anti-factor Xa activity is proportional to the concentration of A-domain, it is Ca²⁺- and Mr-dependent and does not determine the effect on TG and APTT. Conclusion : For any type of heparin, the capacity to inhibit the coagulation process in plasma is primarily determined by the concentration of C-domain, i.e. the AT-binding pentasaccharide with 12 or more sugar units at its non-reducing end.     

Intravascular release and urinary excretion of tissue factor pathway inhibitor during heparin treatment

Tissue-factor-pathway inhibitor is the principal regulator of tissue factor-induced coagulation. Heparin treatment mobilizes TFPI into the circulation and contributes to the anticoagulant effects of heparins. Previous studies have demonstrated a selective depletion of intravascular TFPI by unfractionated heparin (UFH) but not by low-molecular-weight heparin (LMWH). In this study we sought to investigate the time- and dose-dependent relationships between release of TFPI and lipoprotein lipase (LPL) in respons to UFH and LMWH and to investigate whether the selective depletion of TFPI by UFH but not by LMWH is related to differential urinary excretion of TFPI. Eight healthy males participated in an open crossover study in which participants were assigned to receive (1) continuous infusion of unfractionated heparin (UFH, 450 IU/kg/24 hr); (2) subcutaneous dalteparin, 100 IU/kg given twice at a 12-hr interval; (3) subcutaneous dalteparin, 200 IU/kg given once; or (4) saline-solution infusion. Similar dose-dependent mobilization of TFPI and lipoprotein lipase (LPL), another glucosaminoglycan (GAG)-anchored protein of the endothelial membrane, was observed after both subcutaneous and intravenous administration of heparins. However, UFH induced a more efficient release of both TFPI and LPL into plasma than did LMWH at equivalent anti-Xa levels, indicating molecular-weight dependence of the release reactions. However, LPL reached peak levels faster and was more rapidly cleared from the circulation than was TFPI, regardless of the treatment modality. Only trace amounts of TFPI were detected in the urine in a native form (38 kD). UFH and LMWH treatment reduced renal clearance of TFPI compared with the control regimen. Our findings suggest that displacement of TFPI from the endothelial-surface GAG is the main mechanism for TFPI release during heparin treatment in vivo and that differential urinary excretion of TFPI is not the explanation for selective depletion of TFPI during UFH treatment.     

Cost-minimization analysis of low-molecular-weight heparin (dalteparin) compared to unfractionated heparin for inpatient treatment of cancer patients with deep venous thrombosis

Goals Low-molecular-weight heparin (LMWH) has shown to be as effective as unfractionated heparin (UFH) in the treatment of deep venous thrombosis (DVT). Although the acquisition cost of LMWH is significantly greater than that of UFH, we hypothesized that once-daily dalteparin, a LMWH, could reduce treatment costs of cancer patients with DVT by eliminating anticoagulation monitoring and shortening hospitalization.Patients and methods We developed a cost-minimization model by using outcomes and resource utilization data from two retrospective matched cohorts of cancer patients who, between 1994 and 1999, were hospitalized at our comprehensive cancer center for treatment of DVT with either LMWH (n=21) or UFH (n=168). We assumed all LMWHs and UFH to be equally effective. The total costs for the dalteparin strategy and the UFH strategy were calculated in year 2003 U.S. dollars, from the providers perspective, by multiplying the number of resources used for inpatient treatment of DVT by their unit costs.Results The mean total cost for inpatient care was $3,383 (95% CI= $2,683– $4,083) for dalteparin and $4,952 (95% CI=$4,718–$5,185) for UFH. Substantial savings resulted from shorter hospitalization among the dalteparin-treated patients (mean 3.19 versus 5.22 days). Sensitivity analysis did not change the conclusion that dalteparin is less expensive than UFH.Conclusions Savings realized from less anticoagulant monitoring and shorter hospitalization offset the higher acquisition cost of dalteparin. The dalteparin strategy is less expensive than the UFH strategy for the inpatient treatment of DVT among cancer patients.Presented in part at the 3rd Annual Houston Area Health Services & Outcomes Research Conference, Houston, TX, USA, November 25, 2002     

Interlaboratory agreement in the monitoring of unfractionated heparin using the anti-factor Xa-correlated activated partial thromboplastin time

Summary.  Background:  In an effort to improve interlaboratory agreement in the monitoring of unfractionated heparin (UFH), the College of American Pathologists (CAP) recommends that the therapeutic range of the activated partial thromboplastin time (APTT) be defined in each laboratory through correlation with a direct measure of heparin activity such as the factor Xa inhibition assay. Whether and to what extent this approach enhances the interlaboratory agreement of UFH monitoring has not been reported. Objectives:  We conducted a cross-validation study among four CAP-accredited coagulation laboratories to compare the interlaboratory agreement of the anti-FXa-correlated APTT with that of the traditional 1.5–2.5 times the midpoint of normal (1.5–2.5:control) method for defining the therapeutic APTT range. Patients and methods:  APTT and FXa inhibition assays were performed in each laboratory on plasma samples from 44 inpatients receiving UFH. Results:  Using the anti-FXa-correlation method, there was agreement among all four laboratories as to whether a sample was subtherapeutic, therapeutic or supratherapeutic in seven (16%) patient samples. In contrast, consensus was achieved in 23 (52%) samples when the 1.5–2.5:control method was employed. Conclusions:  The anti-FXa-correlation method does not appear to enhance interlaboratory agreement in UFH monitoring as compared with the traditional 1.5–2.5:control method. Adoption of the anti-FXa-correlation method produces considerable disparity in UFH dosing decisions among different centers, although the clinical impact of this disparity is not known.     

髋关节置换后利伐沙班与低分子肝素预防下肢深静脉血栓的比较

背景:低分子肝素可显著降低髋关节置换后下肢深静脉血栓的发生率,但其因需皮下注射而存在局限性。目的:比较全髋关节置换后应用利伐沙班与低分子肝素预防下肢深静脉血栓疗效和安全性的差异。方法:58例全髋关节置换患者按随机数字表法分为2组,利伐沙班组28例,低分子肝素组(达肝素)30例。置换后行双下肢彩色多普勒检查评估DVT形成情况,并观察治疗期间出血情况。结果与结论:利伐沙班组与达肝素组患者在预防下肢深静脉血栓疗效上差异无显著性意义(P>0.05)。两组在治疗期间均无严重出血,置换后非严重出血差异也无显著性意义(P>0.05)。提示利伐沙班在预防全髋置换后下肢深静脉血栓的疗效与安全性上与低分子肝素作用相当。     

PROphylaxis for ThromboEmbolism in Critical Care Trial protocol and analysis plan

Background

This article reports the preparatory studies as well as the design, implementation, and a priori analysis plans of PROphylaxis for ThromboEmbolism in Critical Care Trial (PROTECT) before dissemination of results. PROphylaxis for ThromboEmbolism in Critical Care Trial (NCT00182143) is a randomized, stratified, concealed international trial comparing subcutaneous injection of unfractionated heparin (UFH) 5000 IU or the low-molecular weight heparin (LMWH) dalteparin 5000 IU once daily plus once-daily placebo for the duration of the intensive care unit stay.

Methods

The objective of PROTECT is to examine, among medical-surgical critically ill patients, the effect of the LMWH vs heparin on the primary outcome of proximal leg deep vein thrombosis (DVT) and the following secondary outcomes: DVT elsewhere, pulmonary embolism, any venous thromboembolism (DVT or pulmonary embolism), the composite of venous thromboembolism or death, bleeding, and heparin-induced thrombocytopenia. Patients are followed up to death or hospital discharge. Venous thromboembolism events were included after intensive care unit discharge. All patients, families, clinicians, research personnel, and the trial biostatistician are blind to allocation.

Results

We describe the pilot work, large trial methodology, implementation methods, and the analytic plan. Patient recruitment is complete, but 2 patients remain in the hospital. The rigorous design of PROTECT suggests that the risk of systematic error will be low. The sample size suggests that the risk of random error will be low. PROTECT will be the largest investigator-initiated peer-review funded thromboprophylaxis trial in critical care in the world.

Conclusions

If PROTECT shows that LMWH is more effective than UFH, this trial will change practice in that LMWH may be the anticoagulant thromboprophylaxis of choice for this population. If the results show that UFH is as effective or more effective than LMWH, intensivists in many parts of the world may continue to use UFH, whereas those currently using LMWH may reconsider and change to use UFH. Unfavorable consequences such as major bleeding, ease of use, and the costs of complications will also factor into such decisions.     

Studies on the effects of heparin products on pregnancy-associated plasma protein A

BackgroundIntravenous low molecular weight (LMWH) and unfractionated heparin (UFH) increase the circulating concentrations of pregnancy-associated plasma protein A (PAPP-A), a novel cardiac risk marker, in haemodialysis and coronary angiography patients.MethodsTo further investigate the mechanisms of heparin effects, free PAPP-A was analysed in serial serum samples collected during haemodialysis (intravenous LMWH), carotid endarterectomy or abdominal aortic aneurysm surgery (intravenous UFH), treatment at intensive care unit (subcutaneous LMWH), and coronary angiography (intravenous bivalirudin). PAPP-A was extracted from plaque tissue samples of endarterectomy and aneurysm patients. The interaction between heparin products and free PAPP-A was studied with gel filtration.ResultsAfter intravenous UFH and LMWH free PAPP-A increased significantly but bivalirudin had no effect. After LMWH bolus in haemodialysis patients 85% of free PAPP-A was cleared with a half-life of 13.1 min and the rest with a half-life of 96.6 min. Subcutaneous LMWH led to lower and slower free PAPP-A elevation. PAPP-A extracted from plaque tissues was in free form and extraction was strongly enhanced by LMWH. Heparin products increased the molecular size of free PAPP-A.ConclusionsThe heparin-induced PAPP-A elevation is seen in various patients and should be taken into account when PAPP-A is studied as a biomarker.     

Unfractionated heparin dosing in young infants: clinical outcomes in a cohort monitored with anti‐factor Xa levels

Summary. Background: Unfractionated heparin (UFH) is a widely used anticoagulant. Current American College of Chest Physicians guidelines for infants extrapolated from adults recommend 28 U kg^?1 h^?1 of UFH to achieve an anti‐factor Xa level of 0.35–0.7 IU mL^?1. Objective: To assess the profile of anti‐FXa‐based UFH dosing guidelines in infants. Patients/Methods: We included all infants aged < 6 months treated with per‐protocol intravenous UFH at the Hospital for Sick Children, Toronto, over a 3.5‐year period. Results: Of 100 infants, 11% achieved sustained therapeutic anti‐FXa levels with current dose recommendations. Only 15% achieved target anti‐FXa levels within 24 h with per‐protocol dose escalations. Seventeen per cent of patients never achieved therapeutic anti‐FXa levels, despite up to 60 days of therapy and triple the recommended dose. The median dose needed to achieve therapeutic anti‐FXa levels in the remaining 83 infants was 33 U kg^?1 h^?1 (interquartile range, 30–36). Two in three infants had decreased thrombus size at completion of therapy and no thrombus progression/recurrence, and 11/100 infants suffered major bleeding. Without exclusion of extracorporeal membrane oxygenation patients, an activated partial thromboplastin time (APTT) of > 180 s was detected as a risk factor for major bleeding. Conclusions: UFH monitoring is challenging in infants. Despite their delay in reaching therapeutic anti‐FXa levels, infants monitored with the adult‐based anti‐FXa range have a high thrombus resolution rate, no thrombus progression, but a relatively high bleeding rate. Extreme APTT elevation may contribute to this bleeding risk, particularly in critically ill patients. Current UFH guidelines for young infants may still be inadequate, and laboratory methods with age‐appropriate ranges may be required to further improve clinical outcomes within this population.     

Heparin‐associated thrombocytopenia in 24 401 patients with venous thromboembolism: findings from the RIETE Registry1

Summary. Background: Whether the treatment of venous thromboembolism (VTE) with unfractionated heparin (UFH) confers a higher risk of thrombocytopenia than does treatment with low molecular weight heparin (LMWH) remains controversial, and very few data are available from routine clinical practice. Objectives: We assessed the incidence, risk factors and prognosis of heparin‐associated thrombocytopenia (HAT) according to the type of heparin therapy, UFH or LMWH. Patients/Methods: Data were obtained from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE), which included 25 369 patients with confirmed VTE until February 2009. Among them, 24 401 patients were treated either with UFH or with LMWH, and had available information about the 6‐month occurrence of confirmed thrombocytopenia, defined as a platelet count ≤ 150 000 mm^–3. Results: One hundred and forty‐one patients receiving UFH and/or LMWH developed thrombocytopenia within a 6‐month period. The incidence of HAT was significantly higher in the UFH group (1.36%, 95% confidence interval [CI] 0.79–2.17) than in the LMWH group (0.54%, 95% CI 0.44–0.64). As compared with LMWH, UFH significantly increased the risk of HAT in female patients (adjusted hazard ratio [HR] 4.90%, 95% CI 2.58–9.31, P = 0.001) but not in male patients (adjusted HR 1.60%, 95% CI 0.64–3.97, P = 0.31); P = 0.027 for comparison. In each gender, the UFH‐associated excess risk was confined to patients with VTE unrelated to cancer. The poor prognosis of patients with thrombocytopenia was not influenced by the type of heparin therapy. Conclusions: In routine clinical practice, treatment of VTE with UFH seems to confer a higher risk of thrombocytopenia than does treatment with LMWH, especially in women and non‐cancerous patients.     

Recombinant human factor VIIa and a factor VIIa-analogue reduces heparin and low molecular weight heparin (LMWH)-induced bleeding in rats

Summary.  Background:  Heparin and low molecular weight heparin (LMWH) are widely used for prevention and treatment of thromboemobolic events, but may occasionally cause uncontrollable bleeding. Heparin can readily be antagonized with protamine, but this is less effective against LMWH. Objectives:  To test the effects of rFVIIa or an analogue of rFVIIa, NN1731, on heparin- and LMWH-induced bleeding in rats. Methods:  Initially the doses of heparin and tinzaparin (a LMWH) were determined by dose-titration. Following pretreatment with heparin or tinzaparin in rats, tail-transection was performed, and the effect of rFVIIa and NN1731 on the bleeding was observed. Results:  rFVIIa (5, 10 and 20 mg kg⁻¹) reduced bleeding time and blood loss caused by heparin- and tinzaparin-induced bleeding, using doses of 200 IU kg⁻¹ ( n  = 8) and 500 IU kg⁻¹ ( n  = 9), respectively. Similarly, 10 mg kg⁻¹ NN1731 significantly reduced both heparin- and tinzaparin-induced bleeding to the normal level. Following severe anticoagulation with 1800 IU kg⁻¹ tinzaparin, 10 mg kg⁻¹ NN1731 reduced and normalized the bleeding, while the effect of 20 mg kg⁻¹ rFVIIa failed to reach statistical significance. These data are consistent with the hypothesis that rFVIIa/NN1731 are capable of generating sufficient thrombin locally on the surface of activated platelets to induce hemostasis in the presence of heparin/LMWH. Conclusions:  This study suggests that rFVIIa and NN1731 may have the potential to control bleedings caused by heparin or LMWH.     

Heparin-induced hyponatremia

OBJECTIVE: To report a case of hyponatremia in a patient receiving systemic unfractionated heparin (UFH) therapy and parenteral nutrition. CASE SUMMARY: A 70-year-old African American woman was started on parenteral nutrition for postoperative ileus following an elective surgical procedure. Three days later, she was diagnosed with a pulmonary embolism and intravenous UFH therapy was initiated. During the 7-day course of UFH therapy, the patient's serum sodium concentration steadily declined and urine sodium concentration progressively increased. Physical examination revealed no signs or symptoms of hypo- or hypervolemia. The patient's serum potassium concentration increased modestly, although significant hyperkalemia was not observed. After discontinuation of UFH, serum concentrations of both sodium and potassium returned to baseline levels. DISCUSSION: Although heparin-induced hyperkalemia is well documented, cases associated with substantial hyponatremia have been reported less frequently. An objective causality assessment revealed that the adverse drug reaction was probable in this case. Hyponatremia and hyperkalemia result from the antagonism of aldosterone by UFH within the zona glomerulosa of the adrenal glands. CONCLUSIONS: The use of UFH may result in significant hyponatremia as well as hyperkalemia. Reversal of these electrolyte disturbances occurs after discontinuation of heparin.     

Effect of Body Mass Index on Bleeding Frequency and Activated Partial Thromboplastin Time in Weight-Based Dosing of Unfractionated Heparin: A Retrospective Cohort Study

OBJECTIVE: To assess bleeding and activated partial thromboplastin time (APTT) in relation to body mass index (BMI) in patients prescribed weight-based dosing of intravenous unfractionated heparin (UFH) for cardiac indications without a maximum (dose-capped) initial bolus or capped initial infusion rate.PATIENTS AND METHODS: Consecutive patients admitted to an academic medical center from February 1, 2002, through November 31, 2003, who were treated with a UFH nomogram consisting of a 60-U/kg intravenous bolus plus an initial continuous intravenous infusion of 12 U/kg hourly and titrated to a goal APTT range corresponding to thromboplastin-adjusted target heparin levels of 0.3 to 0.7 U/mL by anti-Xa assay were evaluated for this retrospective cohort study. Patients were excluded if they concomitantly received a fibrinolytic, glycoprotein IIb/IIIa inhibitor, or any other antithrombotic agent (except warfarin). Study patients were divided into quartiles by BMI.RESULTS: Of the 1054 patients included in the study, 807 (76.6%) had an initial bolus dose higher than 4000 U, and 477 (45.3%) had an initial infusion rate higher than 1000 U/h. Despite a significant difference among BMI quartiles in proportion of supratherapeutic first APTT values (P<.001), no statistically significant difference was found in bleeding frequency (P=.26) or frequency of first APTT within the goal range (P=.27). Logistic regression analyses revealed that BMI was not a significant predictor of bleeding or first APTT within the goal range.CONCLUSION: We did not find any difference in the proportion of first APTT values in the goal range or an increased risk of bleeding in obese patients treated with UFH without a capped initial dose. Our data demonstrate the safe use of weight-based UFH without a capped initial bolus dose or capped initial infusion rate in patients with medical cardiac conditions.APTT = activated partial thromboplastin time; BMI = body mass index; CI = confidence interval; IV = intravenous; OR = odds ratio; PCI = percutaneous coronary intervention; UFH = unfractionated heparinUnfractionated heparin (UFH) is useful for prevention of clot formation or progression of both arterial and venous thromboembolic disorders. A weight-based regimen for determining the dose of UFH has been used for more than 15 years¹; however, the effect of this dosing regimen on obese patients is still poorly understood. The volume of distribution of heparin approximates that of the blood volume (40-70 mL/kg),² with obese patients intuitively requiring larger doses of heparin.³ In contrast, the blood volume of adipose tissue is less than that of lean tissue,² and thus maximum (dose-capped) initial bolus and initial infusion rates for UFH have been suggested. Although guidelines from the American College of Cardiology and American Heart Association for ST-segment elevation myocardial infarction⁴ and non—ST-segment elevation myocardial infarction or unstable angina⁵ advocate institution of UFH with an initial intravenous (IV) bolus dose of 60 U/kg (with a capped initial bolus of 4000 U) and initial IV infusion rate of 12 U/kg hourly (capped initial infusion rate of 1000 U/h), neither guideline contains explicit rationale for the recommended capped initial bolus or capped initial infusion rate. Previous studies^3,6 have attempted to clarify the confusion regarding the effect of obesity on activated partial thromboplastin time (APTT) values. These studies recommended actual body weight for calculation of initial heparin doses; however, they were relatively small and did not evaluate the effect of obesity on bleeding outcomes. We designed the current study to evaluate APTT results and bleeding outcomes in patients in whom UFH was prescribed for medical cardiac indications without a capped initial bolus or capped initial infusion rate regardless of weight.     

Prevalence and risk factors of non-fatal venous thromboembolism in the active population of the VITA Project

Summary.  Cost-effective strategies for the identification of subjects at risk of venous thromboembolism (VTE) in the active population are still lacking. Our objectives were to identify risk factors for venous thromboembolism in active subjects. We analyzed data from a population-based sample of 15 055 Caucasians aged 18–65 years randomly selected from the census list of the township of Vicenza, Italy. A validated methodology was used to retrospectively identify subjects with previous VTE. Body mass index (BMI), smoking, oral contraceptive use, previous superficial vein thrombophlebitis (SVT) and familial history of VTE, all at the age of first thrombosis, were ascertained by direct interview and by review of available medical records. Ninety-two deep vein thromboses [prevalence: 61.1/10 000, 95% confidence interval (CI) 49.2–74.9], three upper deep vein thrombosis (prevalence: 1.9/10 000, 95% CI 0.4–5.8) and 21 pulmonary embolism (prevalence: 13.9/10 000, 95% CI 8.6–21.3) were identified. After age and sex adjustment, clinically identifiable risk factors were: history of SVT [odds ratio (OR) = 6.8], oral contraceptive use (OR = 4.7), family history of VTE (OR = 4.5), smoking (OR = 1.7) and BMI above the third tertile (OR vs. mid-tertile 2.9). While previous SVT and BMI were associated with VTE in all circumstantial situations (surgery/trauma, pregnancy or idiopathic VTE), for oral contraceptive use, positive family history and smoking the degree of association varied significantly depending on the situation. Non-fatal VTE affects 0.7% of the subjects belonging to an active population, 56% of cases being potentially preventable. In 30% of VTE cases, at least two easily recognizable risk factors are present. Clinical assessment of risk factors remains the mainstay of VTE prevention.