Heparin Loading Research Articles

Optimal Anticoagulation during Off Pump Coronary Artery Bypass in Patients Recently Exposed to Clopidogrel

PurposeThe aim of this study was to find an optimal range of activated clotting time (ACT) during off-pump coronary artery bypass surgery (OPCAB) yielding ischemic protection without the risk of hemorrhagic complications in patients with recent exposure to dual antiplatelet therapy.Materials and MethodsThree hundred and five patients who received aspirin and clopidogrel within 7 days of isolated multi-vessel OPCAB were retrospectively studied. Combined hemorrhagic and ischemic outcome was defined as the occurrence of 1 of the following: significant perioperative bleeding (>30% of estimated blood volume), transfusion of packed red blood cell (pRBC) ≥2 U, or myocardial infarction (MI). This was compared in relation to the tertile distribution of the time-weighted average ACT-212-291 sec (first tertile), 292-334 sec (second tertile), 335-485 sec (third tertile).ResultsThe amount of perioperative blood loss was 937±313 mL, 1014±340 mL, and 1076±383 mL, respectively (p=0.022). Significantly more patients in the third tertile developed MI (4%, 4%, and 12%, respectively, p=0.034). The incidence of significant perioperative blood loss and transfusion of pRBC ≥2 U were lower in the first tertile than those of other tertiles without statistical significance. In the multivariate analysis, the first tertile was associated with a 52% risk reduction of combined hemorrhagic and ischemic outcomes (95% confidence interval: 0.25-0.92, p=0.027).ConclusionA lower degree of anticoagulation with a reduced initial heparin loading dose should be carefully considered for patients undergoing OPCAB who have recently been exposed to clopidogrel.

Variations in the Circulating Heparin Levels During Maintenance Hemodialysis in End Stage Renal Disease Patients

Abstract 3412 Introduction:Unfractionated heparin has remained the anticoagulant of choice for hemodialysis patients. The anticoagulation facilitates blood flow through the dialysis circuit and assures the patency of the dialysis membrane. Wide variations in the heparinization responses have been observed in patients undergoing this procedure. The purpose of this investigation was to measure circulating heparin levels in patients prior to and after hemodialysis. Methods:This study included 119 ESRD patients undergoing maintenance hemodialysis after appropriate IRB approval and patient consent. For the 3–4 hour hemodialysis duration, a heparin loading dose of 1000 Units followed by two additional dosages of 500 Units/hour were administered. Citrated blood samples were collected prior to and immediately after the dialysis session. The blood samples were centrifuged for 15 minutes at 3000 g at 4°C and platelet poor plasma (PPP) was extracted.Citrated plasma was frozen at −70°C and analyzed utilizing such clot based methods as Activated Partial Thromboplastin Time (APTT), Heptest and Prothrombinase Induced Clotting Time (PiCT). Circulating Anti-Xa levels were measured using a chromogenic substrate method. Thromboplastin induced thrombin generation was also measured using a fluorogenic substrate method, Thrombin Generation Assay (TGA). The Antithrombin (AT) levels in each of these patients were also measured using a functional assay. The circulating levels of heparin were determined using a calibration curve constructed from the heparin used in the dialysis unit. Results were computed for the individual tests and heparin concentrations were obtained using the assay based calibration procedures. Results:In the clot based assays such as APTT and Heptest, no significant differences between pre and post plasma samples were noted. The circulating levels of heparin were from 0 to 1.08 U/ml with a mean of 0.07 ± 0.11 for the APTT and a range of 0 to 1.98 for the Heptest with a mean of 0.09 ± 0.26 U/ml. In the PiCT test the range was from 14.0 to 300 seconds for the pre dialysis samples with a mean of 32.0 ± 38.2, whereas for the post samples the range was from 15.2 to 110 with a mean of 29.6 ± 14.0. For the Anti-Xa levels the % inhibition for the two groups was similar. The circulating Anti-Xa levels in the pre dialysis samples ranged from 0 to 0.77 with a mean of 0.10 ± 0.14, whereas the post level ranged from 0 to 0.51 with a mean of 0.13 ± 0.11. For the thrombin generation, the % inhibition levels ranged from 0 to 100% pre dialysis with a mean of 34.2 ± 34% and ranged 0 to 100% post dialysis with a mean of 44.5 ± 34.4%. The Antithrombin levels ranged from 28 to 130% with a mean of 86.6 ± 19.5% in the pre dialysis samples.There was no significant difference between pre and post dialysis samples using APTT, Heptest and PiCT, whereas the Thrombin generation and Anti-Xa resulted in a statistically significant p value < 0.05 when comparing the two groups. Conclusion:Wide variations in circulating heparin levels are noted in maintenance hemodialysis patients at pre dialysis and post dialysis time periods. Some patients exhibit higher levels of heparin due to a vascular access flush. These results also suggest that the use of heparin in maintenance hemodialysis patients in repeated regimen results in a steady state hypocoagulation as evidenced by the inhibition of thrombin generation, circulating Anti-Xa level and the prolongation of various clotting times. Disclosures:No relevant conflicts of interest to declare.

The effect of cyanosis on active clotting time during diagnostic catheterization.

Cardiac catheterization is a common procedure which needs a careful coagulation monitoring. In our study, we aimed to find factors influencing active clotting time (ACT) following heparin therapy. ACT of 71 patients who were scheduled to undergo transcutaneous diagnostic catheterization and angiography were measured at baseline, 2 and 60 minutes after 50 IU/kg heparin loading. ACT in two groups of patients (cyanotic and non-cyanotic) was compared. All data were analyzed with Wilcoxon, Mann-Whitney test and Pearson in SPSS 16, P value less than 0.05 was considered significant. ACT following heparin at 2nd and 60th minutes was not significantly different in cyanotic and non-cyanotic groups. At 60th minute following heparin administration, ACT decreased more dramatically in older children. Cyanosis does not affect ACT measures following heparin treatment. Moreover, after 60 minutes, heparin efficacy (ACT values) decreased more with increase in patients' age.

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心サルコイドーシスの活動性評価ならびに治療効果判定にヘパリン負荷FDG-PETが有効であった2 症例

Functionalization of chitosan/poly(lactic acid‐glycolic acid) sintered microsphere scaffolds via surface heparinization for bone tissue engineering

Scaffolds exhibiting biological recognition and specificity play an important role in tissue engineering and regenerative medicine. The bioactivity of scaffolds in turn influences, directs, or manipulates cellular responses. In this study, chitosan/poly(lactic acid-co-glycolic acid) (chitosan/PLAGA) sintered microsphere scaffolds were functionalized via heparin immobilization. Heparin was successfully immobilized on chitosan/PLAGA scaffolds with controllable loading efficiency. Mechanical testing showed that heparinization of chitosan/PLAGA scaffolds did not significantly alter the mechanical properties and porous structures. In addition, the heparinized chitosan/PLAGA scaffolds possessed a compressive modulus of 403.98 +/- 19.53 MPa and a compressive strength of 9.83 +/- 0.94 MPa, which are in the range of human trabecular bone. Furthermore, the heparinized chitosan/PLAGA scaffolds had an interconnected porous structure with a total pore volume of 30.93 +/- 0.90% and a median pore size of 172.33 +/- 5.89 mum. The effect of immobilized heparin on osteoblast-like MC3T3-E1 cell growth was investigated. MC3T3-E1 cells proliferated three dimensionally throughout the porous structure of the scaffolds. Heparinized chitosan/PLAGA scaffolds with low heparin loading (1.7 microg/scaffold) were shown to be capable of stimulating MC3T3-E1 cell proliferation by MTS assay and cell differentiation as evidenced by elevated osteocalcin expression when compared with nonheparinized chitosan/PLAGA scaffold and chitosan/PLAGA scaffold with high heparin loading (14.1 microg/scaffold). This study demonstrated the potential of functionalizing chitosan/PLAGA scaffolds via heparinization with improved cell functions for bone tissue engineering applications.

The effects of heparin releasing hydrogels on vascular smooth muscle cell phenotype

Poly(ethylene glycol) diacrylate (PEGDA) hydrogel scaffolds were engineered to promote contractile smooth muscle cell (SMC) phenotype via controlled release of heparin. The scaffold design was evaluated by quantifying the effects of free heparin on SMC phenotype, engineering hydrogels to provide controlled release of heparin, and synthesizing cell-adhesive, heparin releasing hydrogels to promote contractile SMC phenotype. Heparin inhibited SMC proliferation and up-regulated expression of contractile SMC phenotype markers, including smooth muscle α-actin, calponin, and SM-22α, in a dose-dependent fashion (6 μg/ml to 3.2 mg/ml). Heparin release from PEGDA hydrogels was controlled by altering PEGDA molecular weight (MW 1000–6000) and concentration at polymerization (10–30% w/w), yielding release profiles ranging from hours to weeks in duration. Heparin released from PEGDA gels, formulated for optimized heparin loading and release kinetics (30% w/w PEGDA, MW 3000), stimulated SMCs to up-regulate contractile marker mRNA. A cell-instructive scaffold construct was prepared by polymerizing a thin hydrogel film, with pendant RGD peptides for cell attachment, over the optimized hydrogel depots. SMCs seeded on these constructs had elevated levels of contractile marker mRNA after 3 d of culture compared with SMCs on control constructs. These results indicate that RGD-modified, heparin releasing PEGDA gels can act as cell-instructive scaffolds that promote contractile SMC phenotype.

Loading efficiency and surface conductance of heparin-modified poly(lactide- co-glycolide) nanoparticles

Poly(lactide- co-glycolide) (PLGA) nanoparticles (NPs) with surface modification of heparin were fabricated by microemulsion–diffusion method. These novel colloidal particles were stabilized by lecithin and Tween 80. The effects of lecithin on the loading of heparin onto PLGA NPs and on the surface conductance were analyzed. The electronic micrographs revealed that spherical colloids were prepared and the incorporation of heparin caused a slight coalescence of the particles. In addition, the average diameter of heparin-modified PLGA NPs was between 70 and 220 nm. An increase in the weight percentage of lecithin or in the concentration of heparin enlarged the average diameter. Based on constant amount of surfactants, the loading efficiency of heparin on the particle surfaces reached a maximum when the weight percentage of lecithin was 50%. Moreover, the surface conductance of heparin-modified PLGA NPs was improved by an increased weight percentage of lecithin. A high concentration of heparin in microemulsion also promoted the loading efficiency and surface conductance of heparin-modified PLGA NPs.

Inter‐Regional Collaboration for Errors and Near Misses with Unfractionated Heparin

ABSTRACTBackgroundUnfractionated heparin is a high‐risk medication, as serious adverse events may result from errors of use. Different practices and protocols for unfractionated heparin are used at the three district health boards in Auckland. Concern about the inadequacies of heparin use prompted a collaborative evaluation of adherence to unfractionated heparin protocols and to aid the formulation of solutions for process improvement.AimTo evaluate the three district health boards' compliance with unfractionated heparin protocols, and to identify issues with prescribing and administration and the occurrence of adverse events.MethodA retrospective audit of all patients started on unfractionated heparin at the three district health boards was undertaken from March to June 2005. An audit tool was developed to evaluate compliance with 6 criteria of prescribing and administration common to each hospital protocol and data were collected on indication and occurrence of adverse events.Results61 patients were audited. 51% had a baseline activated partial thromboplastin time (aPTT) measured, 39% had an aPTT measured at 6 hours, 80% received a heparin loading dose (90% as per protocol), 85% received maintenance infusion dose and rate as per protocol and 35% had failed to reach target aPTT at 72 hours. None of the 6 criteria achieved 100% compliance.ConclusionCompliance with the specified protocols was low. Systems changes have been identified that can improve the safety and effectiveness of unfractionated heparin use.

Novel chitosan microsphere-templated microcapsules suitable for spontaneous loading of heparin

This report aimed to describe a novel type of core–shell-structured microcapsules suitable for spontaneous loading of anticoagulant heparin. Chitosan (CS) microspheres were fabricated by a sodium sulfate-based precipitation process. The microspheres were approximately 1 μm in size and applied as templates for microcapsules prepared by the layer-by-layer (LbL) self-assembly technique. Polyelectrolytes including polyanion poly(styrene sulfonate) and polycation CS were alternately deposited on CS microsphere templates, monitored by flow cytometry and zeta potential analysis. Scanning electron microscopy, confocal laser scanning microscopy, fluorescence microscopy, flow cytometry and laser particle size analysis were used to characterize the microcapsules. The resulted microcapsules were about 1 μm in average diameter, and allowed spontaneous loading of heparin through electrostatic interaction, with the encapsulation efficiency and loading capacity of 74.4% and 10.0%, respectively. Moreover, heparin could be released from the microcapsules in phosphate buffered saline at pH 7.4. It is suggested that the type of microcapsules may provide a new and effective system of heparin delivery for pharmaceutical use.

Sustained release and activation of the growth factor basic fibroblast growth factor from loaded scaffolds in heart valve tissue engineering

Objectives. Loading of biological matrices offers an opportunity to induce specific cell behaviour. We previously reported the use of growth factors to promote cell invasion and proliferation in tissue valve engineering.We investigated biological matrices preloaded with heparin as an ionically attractive template for the binding, activation and sustained release of basic fibroblast growth factor (bFGF).Methods. Heparin loading concentrations were evaluated and different incubation times were tested. Heparin and heparin-bound bFGF uptake and release were evaluated by 123I radio-labelling. Biological activity of bFGF was evaluated in vitro.Results. Maximum heparin uptake was observed for 2000 μg/ml at 2 h and stabilized thereafter. bFGF-loaded matrices showed an initial burst release of 15% within 4 h and thereafter sustained release reaching 21% at 24 h. Released bFGF was bioactive.Conclusions. This model would be useful in tissue engineering using porcine aortic matrices and could be applied using other growth factors or combinations.

Evidence-Based Algorithm for Heparin Dosing Before Cardiopulmonary Bypass. Part 1: Development of the Algorithm

The incidence of heparin resistance during adult cardiac surgery with cardiopulmonary bypass has been reported at 15%–20%. The consistent use of a clinical decision-making algorithm may increase the consistency of patient care and likely reduce the total required heparin dose and other problems associated with heparin dosing. After a directed survey of practicing perfusionists regarding treatment of heparin resistance and a literature search for high-level evidence regarding the diagnosis and treatment of heparin resistance, an evidence-based decision-making algorithm was constructed. The face validity of the algorithm decisive steps and logic was confirmed by a second survey of practicing perfusionists. The algorithm begins with review of the patient history to identify predictors for heparin resistance. The definition for heparin resistance contained in the algorithm is an activated clotting time &lt;450 seconds with &gt;450 IU/kg heparin loading dose. Based on the literature, the treatment for heparin resistance used in the algorithm is anti-thrombin III supplement. The algorithm seems to be valid and is supported by high-level evidence and clinician opinion. The next step is a human randomized clinical trial to test the clinical procedure guideline algorithm vs. current standard clinical practice.

One-Step Surface Modification of Poly(lactide-co-glycolide) Microparticles with Heparin

The aim of this study was to modify the surface of poly(lactide-co-glycolide) (PLGA) microparticles with heparin. The heparin-coated PLGA may enhance blood and tissue compatibility of PLGA devices and provide a novel approach to deliver growth factors. A one-step method using heparin to replace traditional emulsifiers (e.g., PVA) during emulsion-solvent evaporation process was employed to surface-entrap heparin in PLGA microspheres. The emulsifying activity of heparin was modified via varying counter ion form, including univalent (Na(+), K(+), Li(+), and [Formula: see text]) and divalent (Ca(2+), Mg(2+), Ba(2+), and Zn(2+)) cations, and complexation with amino acids (Arg, Lys, Leu, Val, Gly and Glu). Surface accessible and total heparin loading were determined by a modified toluidine blue assay and elemental analysis, respectively. Heparin bound with univalent counter ions and amino acids exhibited emulsifying activity to varying degrees, whereas divalent heparin salts tended to cause complete aggregation of the PLGA o/w emulsion. Increasing pH (>or=7.4) of hardening medium enhanced heparin adsorption and significantly stabilized the PLGA o/w emulsion. The initial surface density of heparin on the PLGA microspheres prepared using univalent heparin salts was around 8-33 mg/m(2). Surface associated heparin desorbed quickly; potassium heparin showed the best retention, with approximately 0.2 and 0.1 mg/m(2) detected on PLGA microsphere surface following 1- and 14-day incubation in PBST at 37 degrees C, respectively. PLGA microparticles were successfully surface-modified with heparin. Univalent salts and amino acid complexes of heparin, as effective emulsifiers, can become surface-immobilized in PLGA microspheres.

Dynamics of controlled release of heparin from swellable crosslinked starch microspheres

The microspheres of crosslinked starch have been prepared and characterized by IR spectral analysis and SEM technique. The prepared microspheres were loaded with an anticoagulant drug 'heparin' and the kinetics of in-vitro release of heparin was investigated spectrophotometrically at physiological pH (7.4) and body temperature (37 degrees C). The influence of percent loading of heparin, chemical architecture of the microspheres and pH of the release medium were examined on the release profiles of the drug. The chemical stability of heparin was tested in phosphate buffer saline (pH 7.4) and the release was also studied in various simulated biological fluids.

In vitro study of drug loading on polymer‐free oxide films of metallic implants

Traditionally, a drug that is loaded onto a metallic surface has to use various polymer bondings as its platform. Unfortunately, polymer coatings on a metallic surface cause numerous problems after implantation, such as late thrombosis, inflammation, and restenosis. This research was conducted to investigate whether an oxide layer can be used as a polymer-free platform for drug loading, especially for cardiovascular stents. The interaction and loading of heparin onto different oxide films on 316LVM stainless steel wire was confirmed in vitro by experimental studies using linear voltammetry, electrochemical impedance spectroscopy, and electron spectroscopy for chemical analysis. The eluting of heparin from heparinized surface was studied by using high-performance liquid chromatography, and activated clotting time in addition to linear voltammetry and electron spectroscopy for chemical analysis analyses. Experimental results show that amorphous oxide could be a potential substitute for the polymer coating of drug-loaded stents for minimizing metallic corrosion, inflammation, late thrombosis, and restenosis.

Heparin-loaded zein microsphere film and hemocompatibility

Zein was studied as a drug-eluting coating film composed of zein microspheres for cardiovascular devices (e.g. stent). In vitro 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) analysis showed that both zein film and its degraded product had better biocompatibility compared with Corning culture plate on the growth of human umbilical veins endothelial cells (HUVECs, p < 0.05, n = 6), and the effect of zein degraded product on HUVECs was dose-dependent. The best result was obtained at 0.3 mg/ml of the addition. The encapsulation efficiency of heparin and heparin loading varied with the amount of both zein and heparin, and the highest encapsulation efficiency (heparin 1.33 mg/ml and zein 16 mg/ml) was 22.77 ± 1.33% ( n = 3). Scanning electron microscope (SEM) observation indicated that the zein film was made of microspheres in diameter from nano- to micrometer, which could be controlled. Sizes of heparin-loaded zein microspheres changed before and after release of heparin because of conglutination among zein microspheres. Release rate of heparin from microsphere film reached to 33.5 ± 1.2% within 12 h, and began to get into subsequent “slow release” phase; about 55% of the entrapped heparin was released after 20 days. Both zein film and heparin-loaded zein microsphere film were effective in suppressing platelet adhesion, and the heparin-loaded film showed a better anticoagulation as determined with thrombin time (TT) assay. These results suggest that zein film could be used directly as a new type of coating material for its better biocompatibility with HUVECs. Moreover, the heparin-loaded zein microsphere film can significantly improve the hemocompatibility.

Amorphous oxide—a platform for drug delivery

Usually, a drug is loaded onto the metallic surface of a medical device by applying a polymer layer containing the drug. Unfortunately, polymer coatings on the metallic surface may exhibit numerous problems after implantation, such as late thrombosis, inflammation, and restenosis. Current research was conducted to investigate whether a suitable oxide layer can be used as a polymer-free platform for drug loading, especially for cardiovascular stents. The loading of heparin onto, as well as eluting of heparin from, the amorphous oxide film on the 316LVM stainless steel wire was confirmed by experimental studies using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), electron spectroscopy for chemical analysis (ESCA), high-performance liquid chromatography (HPLC), and activated clotting time (ACT). Evidence shows that amorphous oxide can be an ideal substitute for the polymer coating of drug-loaded stents to minimize metallic corrosion, inflammation, late-thrombosis, and restenosis.

Continuous Renal Replacement Therapy in the Initial Management of Neonatal Hyperammonemia Due to Urea Cycle Defects

After completing this article, readers should be able to: 1. Describe the metabolic acidosis that may be seen in urea cycle defects. 2. Delineate the most important factor in determining neurologic outcome in urea cycle defects. 3. Explain the factors that affect the blood ammonia concentration in continuous renal replacement therapy (CRRT). 4. Delineate the most difficult issue in pursuing CRRT in neonates. 5. Describe the morbidities associated with CRRT. MP was born at 39 weeks' estimated gestational age by vaginal delivery to a 35-year-old gravida 3 para 2 woman who had an uncomplicated pregnancy. The 3- and 6-year-old female siblings of the patient were healthy. Apgar scores were 8 at 1 minute and 9 at 5 minutes. The newborn was discharged to home after a 2-day stay in the well baby nursery during which time she appeared to be alert and was breastfeeding appropriately. She presented to the emergency department less than 1 day later after her parents noted increasing lethargy and very poor feeding at home. She was admitted to the neonatal intensive care unit (NICU). Results of a complete blood count with differential count and C-reactive protein evaluation were unremarkable, but the patient progressed to worsening lethargy, respiratory failure, and abdominal distension requiring intubation within hours of admission. The anterior fontanelle was soft on admission physical examination. Further testing revealed a base deficit of 6.1 on arterial blood gas, serum ammonia level of 810 mcmol/L (1,134 mcg/dL), serum lactate level of 5.6 mmol/L (5.6 mEq/L), and serum pyruvate level of 0.06 mmol/L. Results of liver function tests were abnormal, and the infant had a prothrombin time of 35.9 seconds, a partial thromboplastin time of 54.3 seconds, and a fibrinogen concentration of 1.75 g/L (175 mg/dL). Genetic and nephrology consultations were requested immediately. Additional metabolic studies were obtained, including measurement of plasma amino …

Heparin Use in Pediatric Bypass—Empirical Regimen (ACT) vs. Heparin Concentration: A Multicenter Trial

There are two common approaches to heparin administration for pediatric bypass: one involves the empirical dosing of heparin based on the activated clotting time (ACT), and the other on heparin concentration. It has been observed that heparin requirements are substantially greater when maintaining a concentration as opposed to an ACT. This study gathered heparin administration data from five pediatric centers, two using an empirical regimen and ACT technique and three using heparin concentration as measured by the Heparin Management System (HMS). All patients less than or equal to 20 kg were evaluated and grouped by technique. There were 49 patients in the HMS group and 46 in the ACT group. There was no significant difference between groups for patient weight, bypass time, postheparin ACT, bypass ACT, protamine dose, or 24-h blood loss (mL/kg/24). There was a significant difference (p &lt; .01) for prime heparin (4.7 ± 1.3 units/cc HMS vs. 1.9 ± 0.4 units/cc ACT), heparin loading dose (476.5 ± 175.3 units/kg HMS vs. 384.6 ± 54.3 units/kg ACT), and total heparin (16.6 ± 6.7 units/kg/min HMS vs. 9.5 ± 5.9 units/kg/min ACT). The use of the HMS for heparin management in pediatric bypass required more heparin but no difference in protamine use or 24-h blood loss.

Quantitative Evaluation of Heparin-Coated versus Non–Heparin-Coated Bypass Circuits During Cardiopulmonary Bypass

The extracorporealization of blood activates various elements of the fibrinolytic, coagulation, and complement systems. It is theorized that advancements in biocompatibility ameliorate many of the changes leading to improved patient management. The purpose of this study was to determine if heparin-coated circuit (HCC) utilization during cardiopulmonary bypass enhances patient outcomes in a cost-effective manner. A search of the English medical literature was completed to identify all clinical, prospective, randomized trials comparing HCC and non-HCC in patients undergoing coronary artery bypass grafting or valvular surgery. Twenty-six papers consisting of a sample size of 1515 patients were identified and included in the study parameters. The study distinguished between Duraflo II and Carmeda coating techniques and matched papers with different heparin loading doses, as well as use of a heparin-coated cardiotomy. Study parameters were matched for all papers and analyzed according to the availability of data. Statistically significant benefits of HCC were found in postoperative blood loss, time in the ICU, end bypass C3a, time to extubation, end bypass lactoferrin, and end platelet count, but not with respect to postoperative chest tube drainage, red blood cell transfusions, and end bypass TAT complex, D-dimers, and BTG. Data comparing the use of coated or uncoated cardiotomy utilization failed to demonstrate a benefit to heparin coating. Several immunological variables were ameliorated when Carmeda HCC was utilized, although data were insufficient to establish a cost–benefit analysis. In conclusion, heparin-coated circuitry provided statistically better results when compared to noncoated circuitry.

Sustained release of heparin from polymeric particles for inhibition of human vascular smooth muscle cell proliferation

Vascular smooth muscle cell (SMC) growth plays an important role in atherosclerosis, restenosis and venous bypass graft disease. With systemic drug administration no effective therapy for restenosis and venous bypass graft disease is available. This could be due to low local concentrations of the drugs at the target site. A directed delivery of drugs to tissues with a sustained release system during percutaneous transluminal coronary angioplasty (PTCA) or during bypass surgery could provide high concentrations of drugs at the target site and avoid systemic side effects. In the present study heparin was encapsulated by spray-drying into biodegradable poly(d,l-lactic-co-glycolic acid) (PLGA) to obtain a system for prolonged drug release. SMC were cultured from saphenous vein explants obtained from patients undergoing coronary bypass surgery. Cell proliferation was measured by [3H]thymidine incorporation. Heparin release from PLGA 50:50 microspheres in an isoosmolar PBS buffer (pH=7.4) showed a triphasic profile with an initial burst (completed after 24 h), a dormant period and a final stage with increased release rate, which lasted about 10–14 days. Cell proliferation as measured by [3H]thymidine incorporation was markedly stimulated by platelet-derived growth factor-BB (PDGF-BB) (5 ng/ml) or serum (5%). Proliferation of SMC was equally reduced (50%; P<0.05; n=9–11) by native heparin or heparin released from PLGA microspheres, while PLGA microspheres without heparin loading had no effect on [3H]thymidine incorporation in human SMC. Similar results were also obtained when SMC were stimulated with 5% serum instead of PDGF-BB (50%; P<0.05; n=6). Thus, heparin encapsulated into PLGA microspheres was released over a prolonged period of time and thereby effectively reduced human SMC proliferation stimulated either with PDGF or serum. Biodegradable PLGA microspheres may also be used to encapsulate other antiproliferative agents and provide a new approach for local drug delivery after PTCA. This may help to prevent restenosis after PTCA or to reduce graft disease after coronary bypass graft surgery.