High-dose Unfractionated Heparin Research Articles

Administration of antithrombin concentrate in infants and children on extracorporeal life support improves anticoagulation efficacy.

Unfractionated heparin (UFH) is required in children on extracorporeal life support (ECLS) to maintain circuit patency. When high-dose UFH is inadequate to maintain an anticoagulant effect, the addition of antithrombin concentrate (ATC) is considered. The objective of this study was to review clinical experience giving 1,000 units (U) of ATC to patients on ECLS and UFH anticoagulation. Specifically, antithrombin (AT) levels pre- and post-administration of high-dose ATC, estimation of the efficacy of high-dose ATC administration as measured by the level of anticoagulation, and the incidence of adverse effects were determined. A retrospective chart review of all infants and children on ECLS who received ATC between June 2008 and May 2011 at Stollery Children's Hospital, Edmonton, Canada, was performed. A total of 78 doses of ATC were administered to 36 patients with a median age of 2.9 months (interquartile range, 0.6-12.6) on ECLS. Mean dose of ATC was 241 U/kg (95% confidence interval, 199-283). Mean AT level pre- and post-administration was 0.40 and 0.93 U/ml, respectively. Mean anti-Xa level pre- and post-AT administration was 0.23 and 0.41 U/ml, respectively. There were no associated acute adverse events. The administration of high-dose ATC decreases UFH dose requirements.

Monitoring of Haemostasis and Anticoagulation in Cardiopulmonary Bypass Patients

Patients undergoing cardiac surgery with cardiopulmonary bypass are at risk of increased blood loss and transfusion requirements. Contact of blood with the surgical wound and the artificial surfaces of the extra-corporeal circuit results in a coagulopathy. Haemodilution during cardiopulmonary bypass also aggravates the reduction of haemostatic factors even further. On the other hand, systemic anticoagulation using high dose unfractionated heparin challenges the adequate anticoagulant monitoring. The most frequently used test to monitor systemic anticoagulation is the whole blood activated clotting time. This has, however, proven not be a reliable test. Other haemostatic assays have their own advantages and disadvantages, but tools to monitor anticoagulation and haemostasis adequately during and after cardiopulmonary bypass are to date lacking and/or show only a weak association with clinical bleeding. Viscoelastic whole blood techniques (TEG/ROTEM) have emerged as alternatives to the routine coagulation tests, and could be more suitable for providing information about the different phases of the blood clotting. Platelet function tests give more information about the presence of platelet dysfunction one, which is a major cause of bleeding after cardiac surgery. Likewise, thrombin generation tests reflect much, if not all, of the overall function of the blood clotting system. Further research of the applicability and added values of the viscoelastic whole blood tests and the thrombin generation tests in the cardiac surgical patient undergoing cardiopulmonary bypass is warranted. Simplicity in performing the test, preferably point-of-care, and rapid availability of the results, should thereby be the primary focus for targeted haemostatic interventions.

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Introduction: Heparin-induced thrombocytopenia (HIT) is a serious adverse effect of heparin treatment characterized by formation of antibodies to heparin–platelet factor 4 (H–PF4) complexes. Clinically, patients with HIT demonstrate a fall in platelet count of more than fifty percent, occurring 5–10 days after the start of heparin treatment; some also develop HIT related thrombosis (HITT). Cardiopulmonary bypass (CPB) is associated with platelet activation, thrombocytopenia and the release into the plasma of large amounts of PF4, as well as exposure to high doses of unfractionated heparin (UFH). Up to 50% of patients develop antibodies to H–PF4 complexes following CPB. However, less than 3% of those patients develop actual HITT, characterized by a second episode of thrombocytopenia 5-10 days after CPB ("P1 pattern" reported by Pouplard et al.). ECMO is a modified CPB circuit that critically ill patients may be exposed to for days and weeks. The incidence of HIT in patients undergoing ECMO is unknown. Furthermore, clinical scores used to diagnose HIT may not be useful in ECMO patients given the high prevalence and persistence of thrombocytopenia caused by artificial circuit and underlying disease. We sought to determine the incidence of HIT/HITT and platelet patterns potentially suggestive of HIT in a cohort of ECMO patients at our institution Methods: After IRB approval, a prospectively collected data set encompassing all ECMO patients from 2009 to 2012 at our institution was reviewed. To compare platelet trends, we only included patients who survived longer than 48 hours after ECMO initiation. Patients were tested for HIT based on presence of thrombocytopenia and clinical suspicion. Institutional criteria defines patients as "HIT positive" if they meet any of the following serological criteria: HIT ELISA Ab(+)/SRA(+); HIT ELISA Ab(-)/SRA(+); HIT ELISA(+) with optical density (OD)>1. "HIT positive" patients with evidence of thrombosis were considered as having HITT. Patients who didn't meet these criteria, or were not tested due to lack of clinical suspicion, were considered "HIT negative". Daily platelet counts were recorded for 10 days inclusive of day of ECMO initiation. Statistical analysis was done using the Wilcoxon rank sum test and Fisher exact test as appropriate for the data sets. Results: 85 patients underwent ECMO from 2009 to 2012. 68 (80%) patients survived longer than 48 hours after ECMO initiation. Of those, 50 patients(73.5%) were tested for HIT ELISA, SRA or both. 4 patients were deemed "HIT positive" and 3 of those patients had documented thrombo-embolic events (HITT) based on predefined criteria (HIT and HITT incidence in the study group of 5.9% and 4.4% respectively). HIT positive patients were significantly younger (53.1 vs. 37.5 years, p=0.048) and had a trend toward higher average HIT ELISA OD (1.246 vs. 0.258, p=0.056). Only significantly different average platelet count between "HIT negative" and "HIT positive group" was at day 10 (163 vs. 53.7, p=0.024).This difference remained significant when we excluded patients from "HIT negative" group who were not tested for HIT ELISA, SRA or both (127.9 vs. 53.7, p=0.033). No other platelet parameter, such as average highest platelet count, platelet nadir, days to nadir and percentage platelet drop, differed significantly between the groups. However, plots of average daily platelet counts suggests a potentially revealing pattern in "HIT positive" group, where a gradual drop to platelet nadir (post ECMO day 5-6) is followed by a period of persistently depressed platelet counts (days 6-10). Conclusions: Incidence of both HIT and HITT is relatively high in patients who survive ECMO for longer than 48 hours at our institution. Traditional clinical scores for diagnosis of HIT such as "4 Ts", or presence of "P 1" platelet pattern (typical of HIT in cardiac surgery patients) are not useful in ECMO patients. Pattern of depressed platelet counts after nadir may be suggestive of HIT in these patients.

Effects of unfractionated heparin on renal osteodystrophy and vascular calcification in chronic kidney disease rats

Unfractionated heparin (UFH) is the most widely used anticoagulant in hemodialysis for chronic kidney disease (CKD) patients. Many studies have verified that UFH can induce bone loss in subjects with normal bone, but few have focused on its effect on renal osteodystrophy. We therefore investigated this issue in adenine-induced CKD rats. As CKD also impairs mineral metabolism systemically, we also studied the impacts of UFH on serum markers of CKD–mineral and bone disorder (CKD–MBD) and vascular calcification. We administered low and high doses of UFH (1U/g and 2U/g body weight, respectively) to CKD rats and compared them with CKD controls. At sacrifice, the serum markers of CKD–MBD did not significantly differ among the two UFH CKD groups and the CKD control group. The mean bone mineral densities (BMDs) of the total femur and a region of interest (ROI) constituted of trabecular and cortical bone were lower in the high-dose UFH (H-UFH) CKD group than in the CKD control group (P<0.05 and P<0.01, respectively). The BMD of the femoral ROI constituted of cortical bone did not differ between the H-UFH CKD group and the CKD control group. Histomorphometrical changes in the CKD rats indicated secondary hyperparathyroidism, and the femoral trabecular bone volume, but not cortical bone volume, significantly decreased with increasing UFH dose. The same decreasing trend was found in osteoblast parameters, and an increasing trend was found in osteoclast parameters; however, most differences were not significant. Moreover, no distinct statistical differences were found in the comparison of vascular calcium or phosphorus content among the CKD control group and the two UFH CKD groups. Therefore, we concluded that UFH could induce bone loss in CKD rats with secondary hyperparathyroidism, mainly by reducing the trabecular volume and had little effect on cortical bone volume. The underlying mechanism might involve inhibition of osteoblast activity and promotion of osteoclast activity by UFH. We did not find any effect of UFH on vascular calcification in CKD rats with secondary hyperparathyroidism.

Incidence of thrombotic and bleeding complications during cardiac catheterization in children: comparison of high‐dose vs. low‐dose heparin protocols

During cardiac catheterization (CC) in children, unfractionated heparin (UFH) is used for primary prophylaxis of thrombotic events (TE). However, the optimal UFH dose to minimize TE and bleeding in children has yet to be established. To (i) objectively assess the incidence of TE and bleeding during pediatric CC using clinical assessment and ultrasound; and (ii) compare a high-dose vs. low-dose UFH protocol for thromboprophylaxis. A randomized controlled trial (RCT) comparing high-dose UFH (100 units kg(-1) bolus, followed by 20 units kg h(-1) continuous infusion) vs. low-dose UFH (50 units kg(-1) bolus) during CC. Outcome assessment was by clinical examination and vascular ultrasound, performed by blinded examiners before and within 48 h after CC. Children with no consent for randomization were followed in a cohort receiving standard-of-care UFH (parallel-cohort RCT). A total of 227 children were included; 137 were randomized and 90 followed in the cohort study. The overall incidence of TE was 4.6% and bleeding 6.6%. The RCT was stopped early for futility as there were no differences between the high-dose and the low-dose UFH in TE (5% vs. 3%; risk ratios [RR] 1.5, 95% confidence interval [CI] 0.3; 9) and bleeding (7% vs. 12%, RR 0.6, 95% CI 0.2; 2). There were also no differences when RCT and cohort study populations were combined. The incidences of TE and bleeding during CC in children were low. There were no differences between the high-dose and the low-dose UFH protocols studied. Although Heparin Anticoagulation Randomized Trial in Cardiac Catheterization (HEARTCAT) was not designed as non-inferiority trial, low-dose UFH (50 units kg(-1) bolus) appears sufficient for thromboprophylaxis during CC.

Reversal of Heparin by Novel Synthetic Antagonist PMX-60056 Exhibits a Linear Dose-Response Relationship

AbstractAbstract 3329PMX-60056 is a small-molecule first-in-class new chemical entity designed to bind to the pentasaccharide group in unfractionated heparin (UFH) and low-molecular-weight heparins (LMWH), and reverse their anticoagulation effects. It has been shown to reverse UFH and the LMWH tinzaparin to date, and without rebound anticoagulation.When no UFH or LMWH is present, PMX-60056 dosing has been limited by transient hypotension at doses over 0.4 mg/kg in volunteers, but its use for heparin reversal should eliminate this effect as PMX-60056 preferentially binds to heparin. A study with UFH at 70 U/kg and reversal with 0.3 mg/kg PMX-60056 showed full efficacy, and mild blood-pressure reductions in half the subjects that suggested excess PMX-60056.Therefore, we examined the dose-response, efficacy, and safety at higher doses of UFH as used in cardiac surgery. Hemodynamic effects were recorded with lithium-dilution cardiac output, and blood pressures were continuous intra-arterial measurements. PMX-60056 dose was titrated using activated clotting times (ACTs), and protamine requirements were also estimated by heparin-protamine titrations to determine heparin levels.350 U/kg of heparin was reversed in 6 normal volunteers, after an initial 10-minute infusion of 0.7 mg/kg PMX-60056 and subsequent smaller doses as needed to normalize ACT. Hemodynamics were unaffected until total PMX-60056 dose exceeded 1 mg/kg – the initial dose of 0.7 mg/kg never produced a change. When a hemodynamic effect did occur (in 3 of the 6), it was initiated by a fall in systemic vascular resistance. Only 1 of these 6 subjects had a clinically significant hypotension, which lasted 15 minutes with pressor agents and limb elevation; this subject was subsequently found to have a past history suggestive of vaso-vagal instability. The other 5 subjects had no appreciable change in blood pressure.Per protocol the antagonist doses were in discrete amounts, so some overshoot was inevitable. Therefore, the total dose of PMX-60056 to the point immediately preceding full reversal of ACT was correlated with ACT, with initial protamine requirement according to heparin levels, and with estimated residual heparin (calculated from dose given and time elapsed). These data were highly correlated with a straight line from zero: R-squared was 0.90 with initial ACT, 0.96 with initial protamine requirement according to heparin levels, and 0.97 with estimated residual heparin (calculated).These data suggest that measurements routinely available during cardiac surgery are sufficient for predicting a single reversing dose of PMX-60056 that will safely and effectively neutralize UFH-induced anticoagulation.After reversal, the ability to re-anticoagulate is sometimes important. The same study also established that reversal of anticoagulation with PMX-60056 did not inhibit subsequent repeat anticoagulation with heparin a few minutes later, which was then also reversed with PMX-60056.This study was conducted according to cGCP at Duke University's Anesthesiology Research Unit. More results will be forthcoming as the analysis proceeds. Disclosures:McAllister:PolyMedix, Inc.: Employment.

High-dose unfractionated heparin therapy in a pregnant patient with antiphospholipid syndrome: a case report

A case of a 37-year-old pregnant patient with antiphospholipid syndrome (APS), who has a medical history of both thrombosis and recurrent fetal loss, is presented. She was treated with predonisolone and fixed-dose unfractionated heparin (UFH) infusion, followed by plasmaphereses and fixed-dose low-molecular-weight heparin infusion during her fourth pregnancy. Unfortunately, this treatment did not have beneficial effects, resulting in intrauterine growth restriction and finally neonatal death. Continuous intravenous UFH infusion and low-dose aspirin were administrated under the monitoring of the activated partial thromboplastin time to achieve a target level of 120 s during her fifth pregnancy. A healthy baby weighing 1818 g at birth was delivered by Cesarean section at the 34th week of pregnancy. High-dose UFH infusion may be considered to be one of the preferable options to manage pregnant patients with refractory APS.

Anticoagulant Therapy for Percutaneous Coronary Intervention

Received June 2, 2009; accepted November 16, 2009. Percutaneous coronary intervention (PCI) is the most commonly performed invasive therapeutic cardiac procedure and plays an important role in the treatment of ischemic heart disease. Since the first description of coronary angioplasty in a human by Gruntzig,1 the technique, equipment, and associated pharmacotherapy have undergone substantial evolution, leading to significant improvements in periprocedural complications.2 In particular, procedural anticoagulant therapy has been the focus of numerous clinical trials, and several options are now available and supported by practice guidelines; each agent has both advantages and disadvantages, and procedural pharmacotherapy continues to be a focus of drug development. The purpose of this review is to summarize the goals of anticoagulant therapy during PCI, the pharmacokinetics and pharmacodynamics of available agents, and the clinical data surrounding each agent and to identify new agents in development. The goals of pharmacotherapy during PCI are 2-fold: (1) to mitigate the sequelae of iatrogenic plaque rupture from balloon angioplasty or stenting and (2) to reduce the risk of thrombus formation on intravascular PCI equipment. Central to these thrombotic events is thrombin (factor IIa). Iatrogenic damage to the endothelium during PCI leads to increased expression of tissue factor, activation of the coagulation cascade, and formation of activated factor Xa. This ultimately leads to the generation of thrombin, conversion of fibrinogen to fibrin, and thrombus formation.3 In addition to its effects on fibrin, thrombin also directly activates platelets, enhances platelet aggregation, and is proinflammatory.4 Because of its multiple actions in promoting thrombosis, the focus of most anticoagulant agents is thrombin inhibition. Available agents for use include unfractionated heparin (UFH), low-molecular-weight heparins (LMWH, of which enoxaparin has the largest body of clinical data), the synthetic pentasaccharides (of which fondaparinux has the largest body of clinical data), and the …

Heparinresistenz und Antithrombinmangel*

The phenomenon of heparin resistance (HR) is characterized by high doses of unfractionated heparin (UFH) being required to bring activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) within therapeutically desired ranges, or by the impossibility of reaching these ranges. At UFH dosages > 35,000 IU/d, HR should be considered a factor. The most frequent cause of HR is deficiency of antithrombin (AT), the presence of which is essential for UFH to exert its anticoagulatory effect. AT in concentrate form may be applied to overcome AT-dependent HR. The main clinically relevant situations in which AT-dependent HR occurs, with possible indication of AT substitution, are congenital AT deficiency, asparaginase therapy, disseminated intravascular coagulation (DIC) and administration of high doses of heparin during extracorporeal circulation, where it is significant, due to the need to maintain a very high ACT (> 400 s), that use of heart-lung machines is associated with an HR incidence of approximately 20%. The following procedure is recommended when there is no DIC and when extracorporeal circulation is not used: if HR is suspected and AT activity is < or = 60%, UFH should first be reduced to 500 IU/h (to prevent bleeding complications), before AT is substituted. AT activity should then exceed 80%. Under normalized and stable AT activity, the UFH dose should be adjusted such that aPTT is within a range of 60-100 s. If anticoagulation over a longer term is indicated, then overlapping anticoagulation with a vitamin K antagonist should be started as quickly as possible.

Polymorphisms in TNFA and CTLA-4 Genes and the Risk of Heparin Induced Thrombocytopenia.

Backgroud and objectives: The formation of antibodies (Abs) to heparin platelet factor 4 complexes (H/PF4) associated with heparin-induced thrombocytopenia (HIT) is a T-helper cell dependent event that involves antigen presenting cells (APC) and B-lymphocytes. Polymorphisms of the CTLA-4 (cytotoxic T lymphocyte antigen 4) gene have been described as a risk factor in several autoimmune diseases. In addition, TNFα is a major inflammatory cytokine with potent regulatory functions and polymorphisms in TNFA have also been associated with autoimmune antibody-mediated diseases. We therefore evaluated the possibility that an association between polymorphisms in CTLA-4 (−318 C/T and +49 A/G) or TNFA (−308 G/A) and the development of Abs to H/PF4 and HIT might exist.Methods: Eighty-three patients identified as having developed definite HIT with significant levels of Abs to PVS/PF4 in ELISA (HAT 45, GTI, Brookfield, WI, USA) and positive serotonin release assay were studied (HIT group). Two control groups were studied: the Abneg group consisted of 83 patients who had undergone heart surgery with high doses of unfractionated heparin administered during cardiopulmonary bypass (CPB), and who were tested negative for Abs to PVS/PF4 at the 8th post operative day. The Abpos group consisted of 58 patients who had also undergone CPB but had developed high levels of Abs to PVS/PF4 without significant change in the platelet count post-operatively. Three single nucleotide polymorphisms (SNPs), one in TNFA (−308G/A) and two in CTLA-4 (−318 C/T and +49A/G) were studied by conventional RFLP analysis as described (Astermark et al, Blood 2006 and Astermark et al, Thromb Haemost 2007).Results: The CTLA-4 +49 A/G and −318 C/T genotypes and allele distributions were similar in the 3 groups of patients (Table). In contrast, the frequency of TNFA –308 G/G homozygotes was higher in the HIT group compared to patients without HIT whether they had developed PF4-specific Abs or not (p=0.035). Therefore, the A allele was less frequent in HIT patients (p=0.026, OR 0.49; CI95% 0.26–0.93) but there was no significant difference when comparing patients with and without PF4-dependent antibodies.Genotype Allele frequencyAbneg (n = 82)Abpos (n = 58)HIT (n = 82)CTLA-4(+49)A/A31 (38%)24 (41%)35 (43%)A/G40 (49%)26 (45%)41 (50%)G/G11 (13%)8 (14%)6 (7%)CTLA-4(−318)C/C63 (77%)49 (84%)67 (82%)C/T19 (23%)9 (16%)17 (21%)T/T000 (0%)TNFα(−308)G/G59 (72%)41 (71%)68 (84%)G/A20 (24%)15 (26%)12 (15%)A/A3 (4%)2 (3%)1 (1%)A Allele0.1600.1600.09G Allele0.8400.8400.910Conclusion: The TNFA –308 A allele appears to be protective regarding the risk of heparin-induced thrombocytopenia in patients having developed PF4-specific antibodies. A similar effect has been suggested in immune thrombocytopenic purpura (Foster et al, Brit J Haematol 2001) despite individuals with this allele have been identified as high TNFα producers. Therefore, the mechanisms involved for explaining this apparent protective effect of the TNFA −308A allele in patients at risk for HIT have to be identified.

Hemorrhagic Complications of Anticoagulant and Thrombolytic Treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

This article about hemorrhagic complications of anticoagulant and thrombolytic treatment is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Bleeding is the major complication of anticoagulant and fibrinolytic therapy. The criteria for defining the severity of bleeding vary considerably between studies, accounting in part for the variation in the rates of bleeding reported. The major determinants of vitamin K antagonist (VKA)-induced bleeding are the intensity of the anticoagulant effect, underlying patient characteristics, and the length of therapy. There is good evidence that VKA therapy, targeted international normalized ratio (INR) of 2.5 (range, 2.0-3.0), is associated with a lower risk of bleeding than therapy targeted at an INR > 3.0. The risk of bleeding associated with IV unfractionated heparin (UFH) in patients with acute venous thromboembolism is < 3% in recent trials. This bleeding risk may increase with increasing heparin dosages and age (> 70 years). Low-molecular-weight heparin (LMWH) is associated with less major bleeding compared with UFH in acute venous thromboembolism. Higher doses of UFH and LMWH are associated with important increases in major bleeding in ischemic stroke. In ST-segment elevation myocardial infarction, addition of LMWH, hirudin, or its derivatives to thrombolytic therapy is associated with a small increase in the risk of major bleeding, whereas treatment with fondaparinux or UFH is associated with a lower risk of bleeding. Thrombolytic therapy increases the risk of major bleeding 1.5-fold to threefold in patients with acute venous thromboembolism, ischemic stroke, or ST-elevation myocardial infarction.

Monitoring Unfractionated Heparin (UFH) therapy: Which Anti Factor Xa assay is appropriate?

Introduction Anti-Factor Xa (Anti-Xa) assays specifically determine the anticoagulant activity of UFH by measuring the ability of heparin-bound Antithrombin (AT) to inhibit a single enzyme, Factor Xa (FXa). Recent improvements in the automation, cost-effectiveness and accessibility of the assay to clinicians, have resulted in the Anti-Xa assay becoming a part of daily clinical practice in many institutions. Objectives We hypothesized that different Anti-Xa assays have different applicability for use in clinical settings, depending on the amount of UFH administered. This was investigated in a tertiary paediatric institution. Materials and methods Samples were collected from children receiving Low-dose of UFH of at least 10 IU/kg/h, with or without a previous bolus of up to 25 IU/kg/h, within the previous 6 h in the PICU and HDU. High-dose UFH population consisted of children undergoing Cardiac Catheterization (CC), who received a bolus of UFH of 100 IU/kg body weight, 30 min prior to sampling. Results and conclusions The Anti-Xa activity for a given dose of UFH was found to vary significantly based on the Anti-Xa assay and the population being monitored. Our study suggests that the MODIFIED COMATIC Anti-Xa assay provides the best physiological measure of the UFH effect in children, as it does not introduce sources of error, such as exogenous AT, which may increase the measured ant Factor Xa activity, nor Dextran Sulphate which can displace plasma protein bound heparin and once again leading to falsely elevated assay results. Further studies that include assessment of clinical outcomes are required to confirm the applicability of use of this particular assay in monitoring UFH therapy.

META-ANALYSIS: THREE TIMES DAILY SUBCUTANEOUS HEPARIN IS NOT SUPERIOR TO TWICE DAILY THERAPY IN THE PREVENTION OF VENOUS THROMBOEMBOLISM IN MODERATE TO HIGH RISK MEDICAL INPATIENTS

PURPOSE: The majority of symptomatic and fatal venous thromboembolic (VTE) events in hospitalized patients occur in the medical population. It has been shown that therapy with both low dose unfractionated heparin (LDUH; defined as 5000 units subcutaneously BID) and low molecular weight heparin (LMWH) reduce this risk by at least 50%, and that LMWH may be more effective in the highest risk subgroups. Despite the lack of any comparative trials, many practitioners have extrapolated this data to suggest that high dose unfractionated heparin (HDUH; defined as 5000 units subcutaneoulsy TID) is superior to LDUH in moderate to high risk medical patients.

Anticoagulant Use in Patients with Chronic Renal Impairment

Patients with renal failure have an increased risk of both thrombotic and bleeding complications. A number of antithrombotic drugs undergo renal clearance. Therefore, estimation of renal function is necessary when prescribing these drugs to patients with renal dysfunction. Pharmacokinetic and clinical data in patients with chronic renal impairment are limited for several anticoagulants, and adequate administration information is often absent. Dose adjustment of anticoagulants may be indicated when the creatinine clearance falls below 30 mL/min. Unfractionated heparin, argatroban, and vitamin K antagonists generally do not require dose adjustment with renal dysfunction. However, smaller doses of warfarin may be required to achieve a particular target international normalized ratio. Close monitoring of anticoagulation is recommended when argatroban or high doses of unfractionated heparin are administered in patients with severe chronic renal impairment. Low-molecular weight heparins, danaparoid sodium, hirudins, and bivalirudin all undergo renal clearance. Lower doses and closer anticoagulation monitoring may be advisable when these agents are used in patients with chronic renal failure. We recommend that fondaparinux sodium and ximelagatran (not yet licensed) be avoided in the presence of severe renal impairment and be used with caution in patients with moderate renal dysfunction. While acknowledging the lack of pharmacokinetic data, this review provides specific recommendations for the use of anticoagulants in patients with chronic renal impairment.

Extremely High Levels of Microvesicle-Associated Tissue Factor in a Patient with Cancer-Related Thrombosis.

Trousseau's syndrome is a prothrombotic state associated with malignancy. Although well-established as a clinical entity, its pathophysiology is poorly understood. Here we report the case of a patient with giant-cell lung carcinoma who developed a severe form of Trousseau's syndrome, which eventually led to his death. The patient was a 55-year-old white male who presented initially with left upper extremity deep vein thrombosis. His clinical course was dominated by extreme hypercoagulability characterized by multiple venous thromboembolic events, three myocardial infarctions, two ischemic cerebrovascular events, splenic and right renal infarcts, popliteal artery thrombosis, and a mitral valve thrombus. All of these events developed in the face of potent anti-thrombotic therapies, such as unfractionated heparin, low molecular-weight heparin, lepirudin, warfarin, aspirin, and clopidogrel. In order to gain insight into this patient's relentless thrombosis, we analyzed his blood for the presence of tissue factor (TF), the major initiator of blood coagulation. Using ELISA, we measured TF levels in the patient's cell-free plasma and in 16 age- and sex-matched controls. The mean TF plasma concentration in the controls was 22.7 ± 15.5 pg/mL. In marked contrast, the patient's TF levels were 941 pg/mL, 41-fold higher than in controls. In cell-free plasma, tissue factor is either associated with cell-derived membrane microvesicles, or exists as the free, soluble form, derived by alternative mRNA splicing. In this patient, the vast majority of the TF was associated with microvesicles, separable from the plasma by centrifugation at 200,000 g for 5 hr. The TF concentration was 888 pg/mL in the microvesicle pellet and 28.5 pg/mL in the supernatant. Similar results were obtained by flow cytometry, where the number of annexin V-(FITC)-positive particles was much greater in the patient's cell-free plasma than in controls (17,235 Vs. 5835 events in 150 sec). The TF-VIIa activity in the patient's plasma was 7-fold greater than the average control value, as measured by a chromogenic assay employing a Factor Xa-specific substrate. The specificity of the assay was confirmed with a blocking TF monoclonal antibody. Because the patient was receiving high-dose unfractionated heparin at the time his blood was drawn, and the TF-VIIa activity assay is based on Xa generation/activity, these values are likely to grossly underestimate the true activity. Interestingly, TF-bearing microvesicles in the patient's plasma exhibited very low quantities of TFPI as determined by western blots of microvesicles captured with anti-TF-coated beads. By immunohistochemistry, we found intense staining for TF in tumor cells from a lymph node containing metastatic tumor. Further, the blood vessels infiltrating the tumor also contained cell-free material that stained intensely for TF. These studies strongly suggest that the release of microvesicle-associated TF into the patient's blood, at least partially originating from the cancer, was largely responsible for his marked hypercoagulable state. We propose that such a mechanism may account for many cases of cancer-associated thrombosis, the severity being dependent on the TF level and it degree of encryption.

Relationship between activated clotting time and ischemic or hemorrhagic complications: analysis of 4 recent randomized clinical trials of percutaneous coronary intervention.

Unfractionated heparin (UFH) is the most widely used antithrombin during percutaneous coronary intervention (PCI). Despite significant pharmacological and mechanical advancements in PCI, uncertainty remains about the optimal activated clotting time (ACT) for prevention of ischemic or hemorrhagic complications. We analyzed the outcome of all UFH-treated patients enrolled in 4 large, contemporary PCI trials with independent adjudication of ischemic and bleeding events. Of 9974 eligible patients, maximum ACT was available in 8369 (84%). The median ACT was 297 seconds (interquartile range 256 to 348 seconds). The incidence of death, myocardial infarction, or revascularization at 48 hours, by ACT quartile, was 6.2%, 6.8%, 6.0%, and 5.7%, respectively (P=0.40 for trend). Covariate-adjusted rate of ischemic complications was not correlated with maximal procedural ACT (continuous value, P=0.29). Higher doses of UFH (>5000 U, or up to 90 U/kg) were independently associated with higher rates of events. The incidence of major or minor bleeding at 48 hours, by ACT quartile, was 2.9%, 3.5%, 3.8%, and 4.0%, respectively (P=0.04 for trend). In a multivariable logistic model with a spline transformation for ACT, there was a linear increase in risk of bleeding as the ACT approached 365 seconds (P=0.01), which leveled off beyond that value. Increasing UFH weight-indexed dose was independently associated with higher bleeding rates (OR 1.04 [1.02 to 1.07] for each 10 U/kg, P=0.001). In patients undergoing PCI with frequent stent and potent platelet inhibition use, ACT does not correlate with ischemic complications and has a modest association with bleeding complications, driven mainly by minor bleeding. Lower values do not appear to compromise efficacy while increasing safety.

Steady plasma concentration of unfractionated heparin reduces infarct volume and prevents inflammatory damage after transient focal cerebral ischemia in the rat.

Unfractionated heparin (UH) decreases the extent of infarction after transient focal brain ischemia in the rat and abridges neuroinflammatory damage in patients with acute stroke. This study was aimed at assessing whether controlled and steady heparinemia in plasma can reduce infarct volume and exert neuroprotective effects after ischemia. Infarct volume was measured at 24 and 7 days following a 1-hr intraluminal middle cerebral artery (MCA) occlusion in rats treated with UH or with vehicle. After testing several UH administration protocols, we choose to give a bolus of 200 U/kg, which was started 3 hr after the occlusion, followed by a 24-hr intraperitoneal perfusion of 70 U/kg/hr, which maintained a 24-hr steady plasma heparinemia (0.3-0.6 U/ml) and caused no CNS or systemic bleeding. In addition, plasma IL-10 concentration was measured by ELISA, endothelial VCAM-1 expression was evaluated by i.v. injection of a (125)I-labeled monoclonal antibody against VCAM-1, and brain hemeoxygenase-1 (HO-1) expression was determined by Western blot. UH-treated rats showed smaller infarctions than rats treated with vehicle, as well as higher IL-10 plasma levels and HO-1 brain expression and lower endothelial VCAM-1 induction. The study shows that a stable plasma concentration of UH given at nonhemorrhagic doses reduces infarct volume after ischemia-reperfusion in the rat. It also shows that UH prevented the induction of cell adhesion molecules in the cerebral vasculature and increased the expression of molecules with antiinflammatory and prosurvival properties. These findings support further testing of the clinical value of parenteral, adjusted, high-dose UH in patients with acute stroke.

Effects of argatroban and heparin on thrombus formation and tissue plasminogen activator-induced thrombolysis in a microvascular thrombosis model

Effects of (2 R,4 R)-4-methyl-1-[ N 2-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)- l-arginyl]-2-piperidine-carboxylic acid monohydrate (argatroban) and unfractionated heparin (UFH) were compared with respect to thrombus formation and tissue-type plasminogen activator (t-PA)-induced thrombolysis in a microvasculature thrombosis model. The antithrombotic activities of anticoagulants were evaluated with respect to the time required for the initiation of thrombus formation ( T i) and the time required for the thrombus to stop blood flow ( T s). The effects of anticoagulants administered with t-PA were evaluated by percent stenosis of the vessel and percent area of the thrombus. Argatroban (1–3 mg/kg/bolus) significantly prolonged T i and T s in a dose-dependent fashion compared to control. Argatroban (3 mg/kg/bolus) significantly prolonged both the T i and T s more effectively than UFH (100 anti-XaU (a-XaU)/kg/bolus), despite equivalent prolongation of the activated partial thromboplastin time (aPTT). Higher doses of UFH (300–500 a-XaU/kg) were required to significantly prolong T i and T s, but at these doses, UFH caused over-prolongation of aPTT (>180 s), which might consequently cause bleeding complications. Argatroban (0.1–0.3 mg/kg/h) significantly accelerated thrombolysis by t-PA in both a dose- and time-dependent fashion. Although argatroban (0.1–0.2 mg/kg/h) did not significantly prolong the aPTT and bleeding time (BT) as compared with control, it significantly accelerated thrombolysis by t-PA at these doses of lower bleeding risk. Argatroban (0.3 mg/kg/h) significantly enhanced thrombolysis by t-PA, while UFH (12.5 anti-XaU/kg/h) attenuated it again, despite equivalent prolongation of the aPTT and BT. We conclude that argatroban seems to be a more efficient and safer anticoagulant than UFH for the prevention of thrombus formation and acceleration of t-PA-induced thrombolysis.

Unfractionated heparin is associated with a lower rise of serum vascular cell adhesion molecule-1 in acute ischemic stroke patients

We sought to assess the anti-inflammatory properties of unfractionated heparin (UFH) in patients with ischemic stroke treated within 24 h from the onset of symptoms. We studied prospectively 167 patients that received 1000 IU/h intravenous UFH ( n=70) or 300 mg oral aspirin ( n=97) at a mean treatment delay of 6.7 h. Repeated plasma levels of interleukin (IL)-6, IL-10, IL-4, tumor necrosis factor (TNF)-α, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were compared in both groups using multivariate analyses. Whereas TNF-α and sICAM-1 decreased at 48 h, IL-6, IL-4, and sVCAM-1 increased compared with baseline values ( P<0.01). The rise of sVCAM-1 levels at 48 h was significantly lower in patients treated with UFH ( P=0.017) and a two-fold increase of baseline sVCAM-1 was an independent predictor of poor outcome (odds ratio, 2.19, 1.1–4.39). These results suggest that adjusted high-dose UFH has anti-inflammatory effects which might improve recovery if administered early after stroke onset.

Anticoagulant effects of repeated subcutaneous injections of high doses of unfractionated heparin in healthy dogs.

To evaluate s.c. administration of unfractionated heparin (UFH) in accordance with a dosing regimen for high-dose treatment in dogs. 10 healthy adult Beagles. Two groups of dogs (5 dogs/group) were given 6 injections of heparin (500 units of UFH/kg of body weight, s.c.) at intervals of 8 (experiment 1) and 12 (experiment 2) hours. Blood samples were collected before and 4 hours after heparin injections to determine amidolytic heparin activity, activated partial thromboplastin time (APTT), thrombin time, antithrombin activity, platelet count, and Hct. For experiments 1 and 2, mean +/- SD heparin activities before (experiment 1, 1.32 +/- 0.20 U/ml; experiment 2, 0.69 +/- 0.174 U/ml) and 4 hours after the last heparin injection (experiment 1, 1.71 +/- 0.30 U/ml; experiment 2, 1.10 +/- 0.30 U/ml) were higher than values calculated for the regimen used in experiment 1. Results of the investigated thrombin time test system with low thrombin activity were frequently beyond the measurement range, even with UFH activities > or = 0.6 U/ml. Moreover, a severe decrease of antithrombin activity became evident during both experiments (eg, in experiment 2 from 95.6 +/- 4.8 to 59.2 +/- 6.6%). In each treatment group, 2 dogs developed hematomas. Calculations of the course of heparin activity after a single injection do not result in a reliable dosing regimen for high-dose heparin treatment in dogs. High-dose treatment must be monitored for each dog. Thrombin time measured with low thrombin activity is unsuitable for this purpose.