It is now widely accepted that various low-molecular-weight heparins (LMWHs) exhibit specific molecular and structural attributes that are determined by the type of manufacturing process used. For example, enoxaparin, which is prepared by benzylation followed by alkaline hydrolysis of unfractionated heparin (UFH), exhibits a double bond at the nonreducing end and the presence of a unique bicyclic structure namely 1,6 anhydromanno glucose or mannose, or both, at the reducing end. Similarly, the other LMWHs, such as dalteparin, nadroparin, tinzaparin, and parnaparin, exhibit specific structural characteristics that may contribute to their own unique biochemical and pharmacological profiles. These unique features may not exhibit any major influence on the routinely determined anti-Xa and anti-IIa activities. However, these may have an impact on the pharmacokinetics and other biological actions such as the interactions with growth factors, blood components, and vascular cells. This is the reason for the initial caution for the noninterchangeability of the anti-Xa adjusted dosing of the different LMWHs. Although the nonanticoagulant biological effects of these drugs are poorly understood at this time, they are now recognized as contributing significantly to the overall therapeutic effects of these drugs. Because some of these drugs have proved to be effective in the management of cancer-associated thrombosis and exhibit improvements in mortality outcome, these LMWHs may also produce several other effects by modulating inflammatory processes, apoptosis, and other regulatory functions related to cellular functions at different levels. Thus, the interactions of these LMWHs with antithrombin and heparin cofactor II are not the only determinants of their biological actions. Release of tissue factor pathway inhibitor (TFPI), regulation of cytokines, nitric oxide, and eicosanoids contribute to their individuality. Such properties are not only dependent on the oligosaccharide sequence and consensus sites but also depend mainly on microchemical and structural attributes in these drugs. European Pharmacopoeia (EP) and the World Health Organization (WHO) have developed guidelines to characterize these agents in terms of their molecular and biological profile. Regulatory agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA) consider each of these drugs as distinct pharmacological agents. This has prompted the requirement for product-specific clinical data for the approval of their use in various clinical indications. There is a clear concern regarding the development of potential generic versions of branded products and the submissions by generic manufacturers for the regulatory approval of generic interchangeability that refers to the substitution of an apparent chemically identical and bioequivalent versions of the branded LMWHs. Currently, there are no regulatory guidelines or consensus opinions on the acceptance of generic versions of the branded products. Because the LMWHs represent not only a biological entity but also product-specific molecular and structural attributes, the acceptance of a generic version must be based on clearly defined guidelines stipulating minimal molecular and structural, biological, and clinical validation requirements. It is therefore to be stressed that each of the LMWHs is a distinct drug entity that characteristically exhibits a product-based therapeutic spectrum in different thrombotic and nonthrombotic disorders. Thus, until the establishment of valid regulatory guidelines for the generic interchangeability of the commercially available LMWHs is completed, generic substitutes are not recommended.

BACKGROUND

Over 2 million patients in North America are on warfarin anticoagulation therapy for prevention of thromboembolism. Suspension of warfarin therapy is often required to prepare patients for invasive procedures or surgeries. To protect these patients against thromboembolism while they are off warfarin, shorter-acting parenteral agents such as low-molecular-weight heparins (LMWHs) are often used. We conducted a retrospective observational study of our anticoagulation clinic patients to assess the safety and efficacy of LMWHs using a standardized protocol for periprocedural anticoagulation therapy.

METHODS

We included 69 consecutive patients who required interruption of their long-term warfarin therapy between August 2001 and August 2002, and were deemed by the treating physician to be at high enough risk for perioperative thromboembolism to justify bridging anticoagulation. We used a standard bridging therapy protocol in our anticoagulation clinic. Sixty-six patients received enoxaparin and three patients received tinzaparin for a mean duration of 7.7 days postoperatively. Outcomes were assessed for 30 days post-procedure. Safety outcomes included major bleeding and minor bleeding. Efficacy outcomes included thromboembolic event or death.

RESULTS

There were two major bleeding events, one minor bleeding event, and no cases of thromboembolism. Twelve patients experienced some bruising around the injection site.

CONCLUSIONS

LMWH administration using our standard outpatient bridging protocol for perioperative anticoagulation appears to be relatively safe and efficacious, offering an alternative to inpatient administration of intravenous unfractionated heparin (UFH). Our study provides additional evidence to the limited published observational data regarding the safety and efficacy of LMWH as bridging therapy in the perioperative and periprocedural setting. Large, multicenter, randomized controlled trials are necessary to fully assess the safety and efficacy of LMWH for perioperative anticoagulation.We conducted a retrospective observational study of 69 consecutive anticoagulation clinic patients on warfarin between August 2001 and August 2002, who were undergoing a procedure or surgery. The study was done to assess the safety and efficacy of an outpatient LMWH bridging protocol. Sixty-six patients received enoxaparin and three patients received tinzaparin for a mean duration of 3 days preoperatively and 7.7 days postoperatively. Outcomes were assessed for 30 days post-procedure. Safety outcomes included major bleeding and minor bleeding. Efficacy outcomes included thromboembolic event or death. There were two major bleeding events, one minor bleeding event, and no cases of thromboembolism. Twelve patients experienced some bruising around the injection site.

This study surveyed current practice in adult intensive care units in the United Kingdom in three key areas of renal replacement therapy when used for acute renal failure: type of therapy used, typical treatment dose and anticoagulation. Responses were received from 303 (99%) of the 306 intensive care units. 269 units (89%) provide renal replacement therapy for acute renal failure. Most (65%) use continuous veno-venous haemofiltration as first-line therapy in the majority of patients, though continuous veno-venous haemodiafiltration is used by 31% of units. For haemofiltration, the median typical treatment dose (interquartile range [range]) is 32 ml.kg(-1).h(-1) (28.6-35.7 [14.3-85.7]), with 49% using a treatment dose of 35 ml.kg(-1).h(-1) or greater. For haemodiafiltration, the median typical treatment dose (interquartile range [range]) is 44 ml.kg(-1).h(-1) (28.6-57.1 [21.4-120.7]), with 67% using a treatment dose of 35 ml.kg(-1).h(-1) or greater. The vast majority of intensive care units use intravenous unfractionated heparin (96%) or epoprostenol (88%) for anticoagulation. Dosage and monitoring of these two agents vary markedly between units. No units use citrate anticoagulation. These results reveal a wide variety of practice in the delivery of renal replacement therapy between intensive care units in the United Kingdom.

Extracorporeal life support applications have evolved considerably in recent years. However, the blood-biomaterial interface remains incompletely understood, and management of the acute inflammatory response and coagulation pathways continues to be challenging. At present, the gold standard for anticoagulation is unfractionated heparin. Since the inception of extracorporeal life support, the mainstay for anticoagulation monitoring has been activated clotting time. However, alongside the technological evolution in extracorporeal life support, the methods for monitoring heparin have also become more sophisticated, adding additional layers of complexity to creating an ideal safe protocol for anticoagulation during extracorporeal life support. To address this, the Extracorporeal Life Support Organization has formed an Anticoagulation Task Force to help direct both a consensus statement and potential guidelines within which the multiple monitoring methods can be customized for extracorporeal life support. One key question that remains in the use of these monitoring methods is whether the objective during extracorporeal life support is to anticoagulate the circuit to prevent thrombus formation within the extracorporeal device or whether it is to systemically anticoagulate the patient. This review details all current monitoring methods and highlights how they can be used during pediatric mechanical circulatory support.

BACKGROUND

Although clinical trials have found that enoxaparin clearance is prolonged in renal impairment, only one letter describes experience with adjusting doses. Only pharmacokinetic studies exist to guide dose adjustment in response to anti-Xa levels. Unfractionated heparin has comparable major bleeding in renal impairment compared with unadjusted enoxaparin. This necessitates a pharmacokinetic program to adjust enoxaparin with anti-Xa monitoring.

METHODS

A pharmacokinetic program was created in response to adverse events and physician interest in a service. A program was designed providing all patients a loading dose of 1 mg/kg enoxaparin. Subsequent doses were 0.50 mg/kg per dose subcutaneously (SC) every 12 hours (q12h) for patients with a creatinine clearance (CrCl) < or =30 mL/min (severe group) and 0.75 mg/kg per dose SC q12h for patients with CrCl of 30 to 60 mL/min (moderate group). A 1-year review of 170 hospitalized patients is reported.

RESULTS

The mean +/- SD [95% CI] anti-Xa level 4 hours after the third dose was 0.65 +/- 0.19 [0.59 to 0.70] IU/mL for the severe group and 0.82 +/- 0.18 [0.79 to 0.85] IU/mL for the moderate group (P <.001). Eighty percent of patients with moderate renal failure and 60% of the patients with severe renal failure were in the therapeutic anti-Xa range after the third dose. A dose-adjustment ratio was used to adjust doses in patients whose levels were outside the therapeutic range: New dose = [(Current dose) x (Goal anti-Xa level)]/(Current anti-Xa level). An incidence of bleeding comparable to that found in normal patients was found.

CONCLUSIONS

In high-risk patients, it is reasonable to limit the exposure of patients to low molecular weight heparins by using anti-Xa levels as a marker. The enoxaparin protocol for renally impaired patients successfully placed patients in the therapeutic range established by consensus guidelines. The dose-adjustment ratio adds significant understanding to the pharmacokinetics of dose adjustment.

BACKGROUND

Anti-Xa activity is used as a clinical guide to anticoagulation with heparin, but heparin dosing regimens for hemodialysis were established before anti-Xa assays were developed; thus, the optimal regimen for heparin dosing was not determined. The aim is to confirm the interesting characteristics of unfractionated heparin pharmacokinetics for hemodialysis anticoagulation, provide insight into the hemorrhagic risk of hemodialysis patients, and determine the dose of unfractionated heparin and its adequate mode of administration.

METHODS

Cross-sectional study of the pharmacokinetics of unfractionated heparin performed during and after a 4-hour midweek hemodialysis session.

METHODS

35 long-term hemodialysis patients at the Sainte-Marguerite Unit of the Marseille University Hospital, Marseille, France.

METHODS

Hemodialysis anticoagulation with continuous unfractionated heparin infusion at a dose of 50 IU/kg/session (25 IU/kg/h during the first hour, 12.5 IU/kg during the second and third hours, and stop during the last hour).

METHODS

Anti-Xa activity was monitored during the 10 hours after the beginning of the hemodialysis session. Levels of 0.3 to 0.7 IU/mL are considered sufficient for anticoagulation. Pharmacokinetics was determined by using a population approach (nonlinear mixed-effects modeling). The final model and corresponding parameter values (including interindividual and residual variability) were used to simulate 1,000 replicates.

RESULTS

No case of clotting was recorded. A pharmacokinetic model with 1 compartment and first-order elimination best fitted the data. Terminal half-life was 54 minutes. Median anti-Xa activities were 0.55 IU/mL at peak, 0.25 IU/mL at end of the 4-hour session, and less than 0.1 IU/mL at 90 minutes after the session. We simulated a continuous infusion of the dose of 50 IU/kg for 1, 2, 3, and 4 hours. Peak values were 1.1, 0.8, 0.6, and 0.5 IU/mL, respectively. Values at the end of the session were 0.12, 0.18, 0.3, and 0.5 IU/mL, respectively. Values became less than 0.1 IU/mL at 15, 60, 105, and 120 minutes after the session, respectively.

CONCLUSIONS

Interindividual variability in unfractionated heparin pharmacokinetics.

CONCLUSIONS

Unfractionated heparin administered by means of a 3-hour continuous infusion for hemodialysis anticoagulation provided an efficient and safe effect that quickly disappeared after the end of the session.

Anticoagulation is essential to hemodialysis, and unfractionated heparin (UFH) is the most commonly used anticoagulant in the United States. However, there is no universally accepted standard for its administration in long-term hemodialysis. Dosage schedules vary and include weight-based protocols and low-dose protocols for those at high risk of bleeding, as well as regional anticoagulation with heparin and heparin-coated dialyzers. Adjustments are based largely on clinical signs of under- and overanticoagulation. Risks of UFH use include bleeding, heparin-induced thrombocytopenia, hypertriglyceridemia, anaphylaxis, and possibly bone mineral disease, hyperkalemia, and catheter-associated sepsis. Alternative anticoagulants include low-molecular-weight heparin, direct thrombin inhibitors, heparinoids, and citrate. Anticoagulant-free hemodialysis and peritoneal dialysis also are potential substitutes. However, some of these alternative treatments are not as available as or are more costly than UFH, are dependent on country and health care system, and present dosing challenges. When properly monitored, UFH is a relatively safe and economical choice for anticoagulation in long-term hemodialysis for most patients.

Work with low-molecular-weight heparins (LMWHs) continues to provide suggestions for survival advantages among patients with cancer diagnoses. Momentum is building in support of this theory through reports, the vast majority of which are derived from secondary analyses of clinical trials on the treatment of thromboembolism. The data retrieved from such studies that compare unfractionated heparin (UFH) with LMWH indicate that LMWH is equally beneficial if not more beneficial to cancer patients in terms of survival. In retrospective analysis, this improved life expectancy is not considered a result of reduced complications from thromboembolism. Thus, theories of antitumor effects of LMWH have developed, supported by evidence that most of the survival benefits are during long-term comparisons. Reports describing the effects of heparin in the setting of cancer have existed for over a half-century, although specific mechanisms for the marginal results seen thus far have yet to surface. Proposals for the most likely targets of the effective heparins include enzyme interaction, cellular growth modifications, and antiangiogenesis.

Heparins represent the first choice for prevention and treatment of venous thromboembolism. In particular, low molecular weight heparins (LMWHs) provide pharmacokinetic advantages compared to unfractionated heparin (UFH): longer half-life, better bioavailability, and lower binding to plasma proteins. In the last years results of preclinical and clinical studies have suggested that LMWH may be able to inhibit cell growth, cell invasion, and angiogenesis, which are key mechanisms involved in tumor progression, possibly influencing favorable clinical outcome in at least a proportion of cancer patients. In this work we investigated the effect of LMWH (enoxaparin) on cell growth and cell invasion in primary cell cultures obtained from high-grade glioma specimens: 5 anaplastic astrocytoma (AA) and 13 glioblastoma multiforme (GBM). Apoptosis and expression of the thrombin receptor PAR1 were also assessed. A significant decrease in tumor cell growth was observed after treatment with 10 U/ml (-21%; p = 0.001) and 100 U/ml (-26%; p < 0.001); tumor cells from AA (grade III; WHO) were more affected by LMWH treatment compared to cell lines from GBM (grade IV; WHO). The antiproliferative effect was more pronounced in cell cultures displaying higher expression of PAR1. Glioma cell cultures were able to invade a model of basement membrane (Matrigel matrix) in standard culture conditions, but migration was not modulated significantly by LMWH treatment at any of the concentrations tested (1, 10, 100 U/ml). In conclusion, our results confirm the antineoplastic effect of LMWH, suggesting a potential direct role on tumor cell growth in high grade gliomas.

Cancer and its treatments are well-recognized risk factors for venous thromboembolism (VTE). Although the incidence of VTE in cancer patients is not well documented, there is evidence that the absolute risk depends on the tumor type, the stage or extent of the cancer, and treatment with antineoplastic agents. The most common cancer types seen in patients with thrombosis are breast, colorectal and lung, reflecting the prevalence of these malignancies in the general population. When the underlying prevalence is taken into account, cancers of the pancreas, ovary and brain are the most strongly associated with thrombotic complications. Although idiopathic thrombosis can be the first manifestation of an occult malignancy, extensive screening for cancer in these patients has not been shown to improve survival and is not warranted. Prophylaxis in patients undergoing major surgery for cancer with either unfractionated or low-molecular-weight heparin (LMWH) is strongly recommended, but prophylaxis in ambulatory medical oncology patients is not routinely indicated. Anticoagulant therapy remains the mainstay treatment of VTE in cancer patients and recent evidence shows that LMWH is effective and well tolerated for both initial therapy and secondary prophylaxis. Despite treatment, cancer patients with thrombosis have a poor prognosis. This is likely due to premature deaths from recurrent VTE and to the aggressive nature of the underlying cancer. Whether LMWH is capable of modifying tumour biology remains unanswered. Further research is needed to address the many clinical questions in the management of thrombosis in patients with cancer.

BACKGROUND

Unfractionated heparin therapy is care intensive because of dose-response variability, and because of the necessity of constant intravenous infusion and frequent monitoring. We sought to assess the real-world course of transition from heparin to warfarin in hospitalized patients undergoing anticoagulation therapy for acute venous or arterial thrombosis at our medical center.

METHODS

Patients were retrospectively identified from July 1998 to December 1998. Data collected included initiation and maintenance doses of heparin, frequency of monitoring and dose adjustments, time to the therapeutic range, complications and interruptions of therapy, and characteristics of heparin-to-warfarin transition.

RESULTS

Of the 311 patients who met the study criteria during the 6-month period, 134 had venous thromboembolism, 122 had cerebral arterial thrombosis, and 55 had peripheral arterial thrombosis. Groups differed in use and magnitude of initial heparin bolus, frequency of monitoring, and time to the therapeutic range. Dose response to intravenous heparin was highly variable. Even when the activated partial thromboplastin time reached the therapeutic range of 55 to 85 seconds, the next 2 consecutive measurements remained in this range in only 29% of the patients. Patients received an average of 4 different heparin doses over the first 3 days of treatment, and the therapeutic range was maintained on each of 4 sequential days in only 7% of them. During the course of therapy, 54% of the patients had at least 1 prolonged interruption in heparin infusion, and 4.8% sustained a major hemorrhage. Overall, 20% of the patients met the currently recommended treatment guideline of 4 days or more of heparin and warfarin overlap, until the international normalized ratio is greater than 2.0 for 2 consecutive days.

CONCLUSIONS

Multiple challenges to effective anticoagulation treatment with unfractionated heparin exist in the hospital setting. Strategies are needed to improve the overall quality of anticoagulant care, including the substitution of low-molecular-weight heparin for unfractionated heparin, where appropriate.

Previous studies have shown that high-affinity (HA) heparin oligosaccharides, with molecular weights of 3,000-5,000, were less effective than unfractionated heparin in preventing serum-induced venous thrombosis in rabbits, using a Wessler stasis model. In the present study, a larger high-affinity fragment (M.Wt. 6,000-6,500) was also found to be less effective than unfractionated heparin as an antithrombotic agent. However, addition of 80 micrograms/kg low affinity (LA) heparin to 80 micrograms/kg of this HA fragment significantly potentiated its antithrombotic activity, and the antithrombotic action of the mixture was equivalent to that of unfractionated heparin. Significant potentiation of antithrombotic activity was also observed on the addition of LA heparin to a HA decasaccharide (M.Wt. 3,000-3,500) with anticoagulant activity only against Factor Xa. The LA heparin content of low molecular weight heparin fractions appears to be an important determinant of their antithrombotic activity.

Unfractionated heparin given during cardiopulmonary bypass is remarkably immunogenic, as 25% to 50% of postcardiac surgery patients develop heparin-dependent antibodies during the next 5 to 10 days. Sometimes, these antibodies strongly activate platelets and coagulation, thereby causing the prothrombotic disorder, heparin-induced thrombocytopenia. The risk of heparin-induced thrombocytopenia is 1% to 3% if unfractionated heparin is continued throughout the postoperative period. When cardiac surgery is urgently needed for a patient with acute or subacute heparin-induced thrombocytopenia, options include an alternative anticoagulant (bivalirudin, lepirudin, or danaparoid) or combining unfractionated heparin with a platelet antagonist (epoprostenol or tirofiban). As heparin-induced thrombocytopenia antibodies are transient, unfractionated heparin alone is appropriate in a patient with previous heparin-induced thrombocytopenia whose antibodies have disappeared.

BACKGROUND

Low-molecular-weight heparins and heparinoids are anticoagulants that may be associated with lower risks of haemorrhage and more powerful antithrombotic effects than standard unfractionated heparin. This is an updated version of the original Cochrane review first published in Issue 1, 1995 and previously updated in Issue 2, 2005.

OBJECTIVE

To compare the effects of low-molecular-weight heparins or heparinoids with those of unfractionated heparin in people with acute, confirmed or presumed, ischaemic stroke.

METHODS

We searched the Cochrane Stroke Group Trials Register (last searched June 2007). In addition we searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2007), MEDLINE (1966 to June 2007) and EMBASE (1980 to June 2007). For previous versions of this review we searched MedStrategy (1995) and also contacted pharmaceutical companies.

METHODS

Randomised trials comparing heparinoids or low-molecular-weight heparins with standard unfractionated heparin in people with acute ischaemic stroke. We only included trials where treatment was started within 14 days of stroke onset.

METHODS

Two review authors independently selected studies for inclusion, assessed trial quality and extracted the data.

RESULTS

Nine trials involving 3137 people were included. Four trials compared a heparinoid (danaparoid), four trials compared low-molecular-weight heparin (enoxaparin or certoparin), and one trial compared an unspecified low-molecular-weight heparin with standard unfractionated heparin. Allocation to low-molecular-weight heparin or heparinoid was associated with a significant reduction in the odds of deep vein thrombosis compared with standard unfractionated heparin (odds ratio (OR) 0.55, 95% confidence interval (CI) 0.44 to 0.70). However, the number of more major events (pulmonary embolism, death, intracranial or extracranial haemorrhage) was too small to provide a reliable estimate of the benefits and risks of low-molecular-weight heparins or heparinoids compared with standard unfractionated heparin for these, arguably more important, outcomes. Insufficient information was available to assess effects on recurrent stroke or functional outcome.

CONCLUSIONS

Since the last version of this review none of the three new relevant studies with 2397 participants have provided additional information to change the conclusions. Treatment with a low-molecular-weight heparin or heparinoid after acute ischaemic stroke appears to decrease the occurrence of deep vein thrombosis compared with standard unfractionated heparin, but there are too few data to provide reliable information on their effects on other important outcomes, including death and intracranial haemorrhage.

BACKGROUND

Abnormalities in alveolar coagulation occur in idiopathic pulmonary fibrosis (IPF). Anticoagulants attenuate bleomycin-induced lung fibrosis in animals. In this study, we first examined the pharmacokinetics of inhaled heparin in healthy subjects. Second, we investigated the safety and tolerability of heparin inhalation in IPF patients.

METHODS

Coagulation assays were performed in blood and bronchoalveolar lavage fluid samples from 19 healthy volunteers after inhalation of increasing amounts of unfractionated heparin. The acute effects of heparin inhalation on lung function and exercise capacity and the safety and tolerability of chronic heparin inhalation for 28 days were assessed in 20 IPF patients in an open-label exploratory pilot study.

RESULTS

In healthy subjects, inhalation of 150,000 IU heparin ("filled dose") significantly increased the partial thromboplastin time and anti-factor Xa activity in blood samples indicating the threshold dose. The local alveolar anticoagulant effect was detectable up to 72 h, and the alveolar half-life was estimated at 28 h. In IPF-patients, no acute deleterious effects on pulmonary function, gas exchange, or exercise capacity were noted after inhalation of the threshold dose. During chronic treatment, where one-fourth of the threshold dose was inhaled every 12 h for 28 days to obtain a steady-state anticoagulant activity in the alveolar space approximating the anticoagulant activity observed after threshold dose inhalation, no heparin-related side effects, such as hemoptysis or heparin-induced antibodies and thrombocytopenia, were detected in any patient, and median lung function values, exercise capacity, and quality of life scores appeared largely unaltered. Three adverse and one serious adverse events were noted; however, the relation of these events to the heparin inhalation was assessed as "unlikely" or "no relation" in each case.

CONCLUSIONS

Inhaled heparin appears to be safe and well tolerated in IPF patients. Future clinical trials are required to demonstrate the long-term safety and efficacy of inhaled heparin in IPF.

In addition to their anticoagulant activity, unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) have important immunomodulatory properties. However, different studies have reported conflicting pro- and anti-inflammatory effects in association with heparin. Moreover, the molecular basis for these heparin effects on inflammation remains unclear. It was the objective of this study to determine how UFH and LMWH regulate lipopolysaccharide (LPS)-induced activation of human mononuclear cells in whole blood, and define the role of lipopolysaccharide-binding protein (LBP) in mediating this effect. Whole blood was pre-treated with UFH or LMWH (0.1-200 IU/ml), prior to stimulation with LPS (10 ng/ml). After six hours, monocyte pro-inflammatory cytokine (interleukin (IL)-1beta, IL-6, IL-8, and TNF-alpha) secretion was determined by plasma ELISA. Parallel experiments using THP-1 cell line and primary monocytes were performed under serum-free conditions, in the presence or absence of LBP (50-100 nM). Under serum-free conditions, heparin demonstrated dose-dependent anti-inflammatory effects, significantly reducing secretion of pro-inflammatory cytokines (IL-1beta, IL-6, IL-8, and TNF-alpha) in response to LPS-stimulation of THP-1 cells and primary monocytes. In contrast, in the presence of LBP, both UFH and LMWH demonstrated dose-dependent pro-inflammatory effects at all heparin concentrations. In ex-vivo whole blood experiments, pro-inflammatory effects (increased IL-1beta and IL-8 following LPS-stimulation) of heparin were also observed, but only at supra-therapeutic doses (10-200 IU/ml). Our data demonstrate that in the absence of LBP, the direct effect of heparin on LPS-stimulated monocytes is anti-inflammatory. However in whole blood, the immunomodulatory effects of heparin are significantly more complex, with either pro- or anti-inflammatory effects dependent upon heparin concentration.

Because many biological actions of heparin including the antiallergic activity are molecular weight dependent, we hypothesized that low-molecular-weight heparin (LMWH) may have greater potency in attenuating exercise-induced bronchoconstriction (EIB). Therefore, in the present investigation we studied the effects of inhaled LMWH, enoxaparin, and unfractionated heparin on EIB in subjects with asthma. Thirteen asthmatic subjects performed a standardized exercise challenge on a treadmill to document the presence of EIB. The workload was increased until 85% of predicted maximal heart rate was achieved, and the exercise was sustained at that workload for 10 min. EIB was assessed by measuring FEV(1) before and immediately after the exercise. On five different experiment days the subjects were pretreated with 4 ml of aerosolized heparin (80,000 units = 7.5 mg/kg), placebo, or 3 different doses of enoxaparin (0.5 mg/kg, 1 mg/kg, 2 mg/kg) in a double-blind, randomized, crossover design, and exercise challenge was performed 45 min later. Bronchial provocation with methacholine was also performed in five subjects on two additional days after pretreatment with either placebo or inhaled enoxaparin (2 mg/kg), and venous blood was obtained for analysis of plasma antifactor Xa. Postexercise, the maximal decreases in FEV(1) (mean +/- SE) were 30 +/- 4% and 29 +/- 5% on control and placebo days. The exercise-induced decreases in FEV(1) were inhibited by 31% with heparin (DeltaFEV(1) = 20 +/- 4%); and by 28%, 38%, and 48% by enoxaparin at doses of 0.5 mg/kg (DeltaFEV(1) = 21 +/- 5%), 1 mg/kg (DeltaFEV(1) = 18 +/- 5%), and 2 mg/kg (DeltaFEV(1) = 15 +/- 3%), respectively (p < 0.05). The inhibitory effect of 0.5 mg/kg dose of enoxaparin was comparable to heparin (7.5 mg/kg), whereas 2 mg/ kg dose of enoxaparin was the most potent. Inhaled enoxaparin failed to modify the bronchoconstrictor response to methacholine, and did not change the plasma antifactor Xa activity. These data demonstrate that inhaled enoxaparin prevents EIB in a dose-dependent manner; and its antiasthmatic activity is independent of its effect on plasma antifactor Xa activity.

Abstract Thrombosis is an underlying cause of many cardiovascular disorders, and generation of thrombi in the arterial circulation can lead to unstable angina, myocardial infarction, or ischemic stroke. Antithrombotic therapy is widely used, with proven benefit to prevent ischemic stroke and thromboembolic events in patients with atrial fibrillation (AF) or to prevent further ischemic complications in patients with acute coronary syndrome (ACS). Traditional anticoagulants (including unfractionated heparin, low-molecular-weight heparin, and warfarin) and antiplatelet agents (including aspirin, clopidogrel, and prasugrel) are typically used for these indications. Limitations to their use include variable pharmacokinetic and pharmacodynamic profiles, inability to inhibit fibrin-bound thrombin, risk of heparin-induced thrombocytopenia, delayed onset of action, numerous drug interactions, need for substantial laboratory monitoring and dosage titrations, hyporesponsiveness or resistance, hypersensitivity, adverse events, and bleeding. To overcome some of the limitations of traditional agents, new antithrombotic agents under development are highly selective for specific coagulation factors blocking the synthesis of thrombin. Clinicians must have an understanding of the new anticoagulants to aid in the selection of appropriate therapies for patients. We describe the most relevant phases II and III clinical trials that evaluated several recent emerging anticoagulant drugs for use in patients with AF or ACS. The advantages of many new agents include predictable pharmaco-dynamic response and pharmacokinetic parameters, allowing for fixed oral dosing with no need for laboratory monitoring. For patients with AF, dabigatran is already approved for the prevention of stroke and systemic embolism, rivaroxaban appears to be an effective alternative to warfarin in high-risk patients, and apixaban may also be an effective alternative to aspirin in patients unable to take warfarin. Otamixaban shows promise as an intravenous alternative for patients with ACS in the acute care setting. Likewise, rivaroxaban, dabigatran, and darexaban with or without dual antiplatelet therapy may be beneficial for secondary prevention of ischemic events in patients with ACS.

Anticoagulants are the cornerstone of current acute coronary syndrome (ACS) therapy; however, anticoagulation regimens that aggressively reduce ischemic events are almost uniformly associated with more bleeding. REG1, an anticoagulation system, consists of RB006 (pegnivacogin), an RNA oligonucleotide factor IXa inhibitor, and RB007 (anivamersen), its complementary controlling agent. Phase I and IIa studies defined predictable relationships between doses of RB006, RB007, and degree of antifactor IX activity. The efficacy and safety of REG1 for the treatment of patients with ACS managed invasively and the safety of reversing RB006 with RB007 after cardiac catheterization are unknown. Randomized, partially-blinded, multicenter, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system compared to unfractionated heparin or low molecular heparin in subjects with acute coronary syndrome (RADAR) is designed to assess both the efficacy of the anticoagulant RB006 and the safety of a range of levels of RB006 reversal with RB007. The objectives of RADAR are (1) to determine the safety of a range of levels of RB006 reversal with RB007 after catheterization, (2) to confirm whether a dose of 1 mg/kg RB006 results in near-complete inhibition of factor IXa in patients with ACS, and (3) to assess the efficacy of RB006 as an anticoagulant in patients with ACS undergoing percutaneous coronary intervention.

Venous thromboembolism (VTE) events are frequent in neurooncological patients in perioperative period thus increasing mortality and morbidity. The role of prophylaxis has not yet been established with certainty, and in various neurosurgery and intensive care units the practice is inconsistent. A better definition of the risk/cost/benefit ratio of the various methods, both mechanical (intermittent pneumatic compression-IPC, graduated compression stockings-GCS) and pharmacological (unfractionated heparin-UFH or low molecular weight heparin-LMWH), is warranted. We aim to define the optimal prophylactic treatment in the perioperative period in neurooncological patients. A systematic review of the literature was performed in Medline, Embase and Cochrane Library. Thirteen randomized controlled trials (RCTs) were identified, in which physical methods (IPC or GCS) and/or drugs (UFH or LMWHs) were evaluated in perioperative prophylaxis of neurological patients, mostly with brain cancer not treated with anticoagulants for other diseases. The analysis was conducted on a total of 1,932 randomized patients of whom 1,558 had brain tumours. Overall data show a trend of reduction of VTE in patients treated with mechanical methods (IPC or GCS) that should be initiated preoperatively and continued until discharge or longer in case of persistence of risk factors. The addition of enoxaparin starting the day after surgery, significantly reduces clinically manifest VTE, despite an increase in major bleeding events. Further studies are needed to delineate the types of patients with an increase of VTE risk and risk/benefits ratio of physical and pharmacological treatments in the perioperative period.

Venous thromboembolism (VTE) is a common complication after acute ischemic stroke. When screened by 125I fibrinogen scanning or venography, the incidence of deep-vein thrombosis (DVT) in stroke patients is comparable with that seen in patients undergoing hip or knee replacement. Most stroke patients have multiple risk factors for VTE, like advanced age, low Barthel Index severity score or hemiplegia. As pulmonary embolism is a major cause of death after acute stroke, the prevention of this complication is of crucial importance. Prospective trials have shown that both unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are effective in reducing DVT and pulmonary embolism in stroke patients. Current guidelines recommend the use of these agents in stroke patients with risk factors for VTE. Some clinicians are concerned that the rate of intracranial bleeding associated with thromboprophylaxis may outweigh the benefit of prevention of VTE. Low-dose LMWH and UFH seem, however, safe in stroke patients. Higher doses clearly increase the risk of cerebral bleeding and should be avoided for prophylactic use. Both aspirin and mechanical prophylaxis are suboptimal to prevent VTE. Graduated compression stockings should be reserved to patients with a clear contraindication to antithrombotic agents.

A functional flow cytometric assay (FCA) for the immediate diagnosis of heparin-induced thrombocytopenia (HIT), with simultaneous compatibility testing for alternative anticoagulant therapies, has been developed to provide rapid and reliable results which effectively support patient management. The assay provides results within 1-2 h, uses readily available non-radioactive reagents, and employs standard equipment. Using the highly sensitive annexin V protein probe, the method detects activated platelets induced by heparin immune-complexes, with 300-fold increased binding to activated platelets. Twenty-five samples from patients clinically-suspected of having HIT (131 tests) and 10 normal control (NG) samples (36 tests) were simultaneously tested with unfractionated heparin (UH) and low-molecular-weight heparin (LMWH), and by the radioactive serotonin-release assay (SRA) (62 and 16 tests respectively). The FCA highly correlated with the SRA, showing 100% specificity and 95% sensitivity. Moreover, the FCA exhibited higher resolution between positive and negative samples (an average value of 8.6-fold the NC versus 4.0-fold the NC by SRA). The LMWH showed concordant results with UH (r = 0.95). We conclude that the functional FCA for HIT is practical, specific and sensitive, thereby permitting the rapid diagnosis of HIT and the suitability of alternative therapies.

BACKGROUND

Low-molecular-weight heparin (LMWH) appears to be safe and effective for treating pulmonary embolism (PE), but its cost-effectiveness has not been assessed.

METHODS

We built a Markov state-transition model to evaluate the medical and economic outcomes of a 6-day course with fixed-dose LMWH or adjusted-dose unfractionated heparin (UFH) in a hypothetical cohort of 60-year-old patients with acute submassive PE. Probabilities for clinical outcomes were obtained from a meta-analysis of clinical trials. Cost estimates were derived from Medicare reimbursement data and other sources. The base-case analysis used an inpatient setting, whereas secondary analyses examined early discharge and outpatient treatment with LMWH. Using a societal perspective, strategies were compared based on lifetime costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio.

RESULTS

Inpatient treatment costs were higher for LMWH treatment than for UFH (dollar 13,001 vs dollar 12,780), but LMWH yielded a greater number of QALYs than did UFH (7.677 QALYs vs 7.493 QALYs). The incremental costs of dollar 221 and the corresponding incremental effectiveness of 0.184 QALYs resulted in an incremental cost-effectiveness ratio of dollar 1,209/QALY. Our results were highly robust in sensitivity analyses. LMWH became cost-saving if the daily pharmacy costs for LMWH were < dollar 51, if>> or = 8% of patients were eligible for early discharge, or if>> or = 5% of patients could be treated entirely as outpatients.

CONCLUSIONS

For inpatient treatment of PE, the use of LMWH is cost-effective compared to UFH. Early discharge or outpatient treatment in suitable patients with PE would lead to substantial cost savings.

Patients with severe traumatic brain injury (sTBI) are at high risk for developing venous thromboembolism (VTE). Nonetheless, pharmacologic VTE prophylaxis is often delayed out of concern for precipitating extension of intracranial hemorrhage (ICH). The purpose of this study was to compare the effectiveness of early vs late VTE prophylaxis in patients with sTBI, and to characterize the risk of subsequent ICH-related complication.

Adults with isolated sTBI (head Abbreviated Injury Scale score ≥3 and total Glasgow Coma Scale score ≤8) who received VTE prophylaxis with low-molecular-weight or unfractionated heparin were derived from the American College of Surgeons Trauma Quality Improvement Program (2012 to 2014). Patients were divided into EP (<72 hours) or LP (≥72 hours) groups. Propensity score matching was used to minimize selection bias. The primary end point was VTE (pulmonary embolism or deep vein thrombosis). Secondary outcomes were defined as late neurosurgical intervention (≥72 hours) or death.

We identified 3,634 patients with sTBI. Early prophylaxis was given in 43% of patients. Higher head injury severity, presence of ICH, and early neurosurgery were associated with late prophylaxis. Propensity score matching yielded a well-balanced cohort of 2,468 patients. Early prophylaxis was associated with lower rates of both pulmonary embolism (odds ratio = 0.48; 95% CI, 0.25-0.91) and deep vein thrombosis (odds ratio = 0.51; 95% CI, 0.36-0.72), but no increase in risk of late neurosurgical intervention or death.

In this observational study of patients with sTBI, early initiation of VTE prophylaxis was associated with decreased risk of pulmonary embolism and deep vein thrombosis, but no increase in risk of late neurosurgical intervention or death. Early prophylaxis may be safe and should be the goal for each patient in the context of appropriate risk stratification.