Stroke is a leading cause of death and disability worldwide, mainly affecting the elderly. To date, tissue plasminogen activator (tPA), the only FDA approved treatment agent, is of limited use in stroke patients mainly due to its narrow therapeutic window and hemorrhage complication. Vepoloxamer is a highly purified proprietary amphipathic copolymer, which has potent anti-thrombotic and rheological properties for treating various thrombotic disorders. In an effort to increase the efficacy and safety of tPA thrombolytic therapy, the present study evaluated the neuroprotective effect of combination treatment with Vepoloxamer and a low dose of tPA in aged rats after embolic middle cerebral artery occlusion (MCAO). Male aged rats (18 month) subjected to MCAO were randomly divided into the following groups (n=10/group): tPA alone (5mg/kg, IV) at 2h; tPA (5mg/kg, IV) at 2h in combination withVepoloxamer (300mg/kg at 2h, IV; followed by a 12h IV infusion of 100 mg/kg/hr starting at 10h); or saline at 2h as control. An array of behavioral tests were performed weekly for 4 weeks. Infarct volume was measured 4 weeks after MCAO. The combination treatment with tPA and Vepoloxamer significantly (p<0.05) reduced infarct volume (20±3%) compared with rats treated with saline (31±2%) or tPA alone (32±2%). In addition, the rats treated with tPA in combination with Vepoloxamer exhibited sustained improvements in neurological function up to 4 weeks starting at 1d after MCAO, when compared with rats treated with saline or tPA monotherapy. However, tPA monotherapy failed to reduce neurological functional deficits compared with the saline control. The combination of tPA and Vepoloxamer did not increase the mortality rate nor the incidence of cerebral hemorrhage compared with saline or tPA monotherapy. In conclusion, our data demonstrated that the adjuvant treatment with Vepoloxamer and tPA amplifies the therapeutic efficacy of low-dose tPA in aged rats after embolic stroke without increasing the incidence of hemorrhagic transformation.

Background and Purpose- Thrombolytic treatment of acute ischemic stroke with tPA (tissue-type plasminogen activator) is hampered by its narrow therapeutic window and potential hemorrhagic complication. Vepoloxamer is a nonionic surfactant that exerts potent hemorheologic and antithrombotic properties in various thrombotic diseases. The current study investigated the effect of vepoloxamer on tPA treatment in a rat model of embolic stroke. Methods- Male Wistar rats subjected to embolic middle cerebral artery occlusion were treated with the combination of vepoloxamer and tPA, vepoloxamer alone, tPA alone, or saline initiated 4 hours after middle cerebral artery occlusion. Results- Monotherapy with tPA did not reduce infarct volume, and adversely potentiated microvascular thrombosis and vascular leakage compared with the saline treatment. Vepoloxamer monotherapy reduced infarct volume by 25% and improved brain perfusion. However, the combination treatment with vepoloxamer and tPA significantly reduced infarct volume by 32% and improved neurological function, without increasing the incidence of gross hemorrhage. Compared with vepoloxamer alone, the combination treatment with vepoloxamer and tPA robustly reduced secondary thrombosis and tPA-augmented microvascular leakage and further improved brain perfusion, which was associated with substantial reductions of serum active PAI-1 (plasminogen activator inhibitor-1) level and tPA-upregulated PAI-1 in the ischemic brain. Mechanistically, exosomes derived from platelets of ischemic rats treated with tPA-augmented cerebral endothelial barrier permeability and elevated protein levels of PAI-1 and TF (tissue factor) in the endothelial cells, whereas exosomes derived from platelets of rats subjected to the combination treatment with vepoloxamer and tPA diminished endothelial permeability augmented by tPA and fibrin and reduced PAI-1 and TF levels in the endothelial cells. Conclusions- The combination treatment with vepoloxamer and tPA exerts potent thrombolytic effects in rats subjected to acute ischemic stroke. Vepoloxamer reduces tPA-aggravated prothrombotic effect of platelet-derived exosomes on cerebral endothelial cells, which may contribute to the therapeutic effect of the combination treatment.

BACKGROUND:Use of the plasticiser di(2-ethylhexyl) phthalate (DEHP) in polyvinyl chloride (PVC) blood bags poses a potential dilemma. The presence of DEHP in blood bags has been shown to be beneficial to red blood cells during storage by diminishing haemolysis. However, DEHP use in PVC may be carcinogenic or estrogenising. Vepoloxamer is a poloxamer with rheological and cytoprotective rheological properties and a favourable toxicity profile in clinical trials. We hypothesised that vepoloxamer may be sufficient to replace the plasticiser DEHP to prevent elevated haemolysis while conserving the biochemical and redox potential++ in RBCs stored for up to 42 days.MATERIALS AND METHODS:Paired analyses of aliquots from pooled RBC suspensions of ABO identical donors were aseptically split into test storage containers (DEHP/PVC or DEHP-free/ethylene vinyl acetate [EVA]) supplemented with or without vepoloxamer (at concentrations of 0.1, 1, 5 or 7.89 mg/mL) and cold stored for up to 42 days.RESULTS:Vepoloxamer significantly prevented the increased haemolysis induced by the absence of DEHP in EVA bags in a dose-dependent manner by days 28 and 42 of storage (approx. 50% reduction of the maximum concentration of vepoloxamer; p<0.001). There was an inverse correlation between the concentration of vepoloxamer used and the haemolysis rate (r2=0.27, p<0.001) and a direct correlation between haemolysis and phosphatidylserine (PS) exposure (r2=0.42; p<0.01). Increased osmotic fragility and shear induced deformability of 42-day stored RBC in EVA bags was significantly corrected by the addition of vepoloxamer.DISCUSSION:Vepoloxamer, in a concentration-dependent fashion, is able to partly rescue the increased haemolysis and PS exposure induced by the absence of the commonly used plasticiser DEHP. These results provide initial but strong evidence to support vepoloxamer use to replace DEHP in long-term storage of RBC.

Vepoloxamer is an amphipathic polymer that has shown potent hemorrheologic, cytoprotective, and anti-inflammatory effects in both pre-clinical and clinical studies. This study was designed to investigate the therapeutic effects of vepoloxamer on sensorimotor and cognitive functional recovery in rats after traumatic brain injury (TBI) induced by controlled cortical impact. Young adult male Wistar rats were randomly divided into the following groups: 1) sham; 2) saline; or 3) vepoloxamer. Vepoloxamer (300 mg/kg) or saline was administered over 60 min via intravenous infusion into tail veins starting at 2 h post-injury. Sensorimotor function and spatial learning were assessed using a modified neurological severity score and foot fault test, and Morris water maze test, respectively. The animals were sacrificed 35 days after injury and their brains were processed for measurement of lesion volume and neuroinflammation. Compared with the saline treatment, vepoloxamer initiated 2 h post-injury significantly improved sensorimotor functional recovery (Days 1-35; p < 0.0001) and spatial learning (Days 32-35; p < 0.0001), reduced cortical lesion volume by 20%, and reduced activation of microglia/macrophages and astrogliosis in many brain regions including injured cortex, corpus callosum, and hippocampus, as well as normalized the bleeding time and reduced brain hemorrhage and microthrombosis formation. In summary, vepoloxamer treatment initiated 2 h post-injury provides neuroprotection and anti-inflammation in rats after TBI and improves functional outcome, indicating that vepoloxamer treatment may have potential value for treatment of TBI. Further investigation of the optimal dose and therapeutic window of vepoloxamer treatment for TBI and the mechanisms underlying beneficial effects are warranted.

Sickle Cell Disease (SCD) is an autosomal recessive disorder caused by a single amino acid substitution in the Hemoglobin (Hb) β chain which causes it to polymerize in the deoxy state.Acute Chest Syndrome (ACS) with hypoxemic respiratory failure is a common cause of death in adult SCD subjects.Recent research has revealed how multiple disease processes including inappropriate cellular adhesion, hemolysis, dysfunctional coagulation, inflammation, and ischemia and tissue injury are involved in ACS pathophysiology.In this review article, we discuss how the activity of the highly purified non-ionic amphiphilic triblock copolymer vepoloxamer in the repair of damaged membranes and hindrance of inappropriate adhesive interactions and activation events potentially has utility in ACS, by virtue of its capacity for affecting multiple aspects of the pathophysiology.

Poloxamer 188 (P-188; Mast Therapeutics, San Diego, Calif) is a synthetic, organic compound that acts as a surfactant by binding hydrophobic pockets in the circulation. P-188 has been shown to have anti-adhesive properties within the circulation and is currently being tested in patients with microcirculatory insufficiency such as in sickle cell disease. The aim of this study was to investigate drug interactions between P-188 and heparin and tissue plasminogen activator (tPA). Bleeding Time (BT): Under general anesthesia, saline or P-188 (25 mg/kg) was administered to Sprague-Dawley Rats via tail vein. After 5 minutes, the rats were treated with either saline, low-dose (LD) heparin (125 ug/mg), or high-dose (HD) heparin (250 ug/kg; n = 6 each group). After 5 minutes, distal 2 mm of the tail was cut and BT measured. Statistical analysis was performed using a t-test. Clot Lysis (CL): Mosquito forceps were used to induce thrombosis in the internal jugular vein (IJV) via intermittent jugular clamping. Once thrombosis was confirmed by continuous wave Doppler, either saline or P-188 (25 mg/kg) was administered via tail vein. After 5 minutes, the rats were treated with saline, LD tPA (500 ug/mg), or HD tPA (1 mg/kg; n = 6 each group). CL was defined as detection of flow in the IJV by Doppler. Time to CL was recorded. No flow up to 15 minutes was recorded as no lysis. Statistical analysis was performed using Fischer exact test. P-188 increased the tail BT by itself and with LD heparin (Table I). With HD heparin, P-188 had no additive effects. P-188 alone did not influence CL (Table II). However, with LD tPA, it tended to facilitate CL (P = .06). With HD tPA, P-188 had no effects on CL. P-188 potentiates the action of heparin and tPA at low doses. P-188 has potential as an anti-thrombotic and thrombolytic adjunct. As an adjunct, P-188 may improve drug efficacy and may decrease adverse effects and cost. More studies need to be done in order to fully elucidate this drug interaction between P-188 and both heparin and tPA.Table IBleeding time (BT)TreatmentSalineHeparin (125 ug/mg)Heparin (250 ug/mg)Saline7.1 ± 1.06.2 ± 1.217.0 ± 1.4P-18810.3 ± 1.614.2 ± 2.917.5 ± 3.1P.001<.001NSNS, Not significant. Open table in a new tab Table IIPercent of rats with thrombolysisTreatmentSalinetPA (0.5 mg/kg)tPA (1 mg/kg)Saline005 (83%)P-18804 (67%)4 (67%)P.06NSNSNS, Not significant. Open table in a new tab

Introduction: Poloxamer-188 (P188) is an amphiphilic, non-ionic, tri-block copolymer surfactant. It has been shown to be effective in the repair/recovery of damaged cell membranes. It enhances the survival of red blood cells by increasing the stability of the membrane and decreasing the fragility profile. P188 is an attractive and promising agent for enhancing the blood cell viability and functions during prolonged storage in blood banking. Platelets gradually lose their functionality during storage. The aim of the study is to test the protective effect of P188 on platelet function.Material and Methods: Blood samples were collected in 3.2% sodium citrate from 20 heathy volunteers. To investigate the effect of P188 on platelet function two experimental methods were used. In the first approach, P188 was added to citrated whole blood (wb) in a 1:10 ratio at a final concentration of 10 mg/mL. For control studies, saline was used in the same manner. Saline and P188 containing tubes were centrifuged to collect Platelet Rich Plasma (PRP) and platelet poor plasma (PPP). These were referred to 'saline-wb-preparation (saline-WBP)' and 'P188-wb-preparation (P188-WBP)'. In second procedure, citrated wb was centrifuged to obtain PRP and PPP. P188 was added to PRP at a concentration of 10 mg/mL. For control purposes, saline was used in the same manner. These were referred to saline-PRP-preparation (saline-PRPP) and 'P188-PRP-preparation (P188-PRPP). Similar procedures were repeated at a lower concentration of 2mg/mL. Agonist induced aggregation (AIA) studies were performed at 30 minutes (min), 180 min and >300minutes at all different concentrations utilizing at PAP-8 aggregometer (Biodata Corporation). Such agonists as ADP, Arachiconic Acid (AA), Collagen and Epinephrine were used.Results: In the saline supplemented systems all the agonists showed a time dependent decrease in platelet aggregation induced by different agonists. In the P188 supplemented systems there was no protective effect of P188 on AA and Epinephrine induced aggregation. However, there was a protective effect on ADP and Collagen induced aggregation except at 10 mg-WBP. After 300 min, the observed protective effect of on ADP induced aggregation was found to be 50.2% higher in comparison to saline control in 2mg-WBP. This protective effect was found to be 43.13 % at 10mg-PRPP and 10.4% at 2mg-PRPP. After 300 min, protective effect on Collagen induced aggregation was 65.9% compared to saline control in 2mg-WBP. This protective effect was 42.74 % at 10mg-PRPP and 11.42% at 2mg-PRPP. The aggregation values were lower in platelets recovered from P188-WBP in comparison to P188-PRPP with the exception of epinephrine induced aggregation.Discussion: Platelets are known to lose their functionality upon storage. Several approaches to restore platelet functionality upon storage have been attempted. In this study, protective effects of P188 were observed on ADP and collagen induced aggregation while a decrease aggregation response was noted with AA and Epinephrine aggregation. This suggests that P188 modulates specific receptors on platelet surface. Since ADP and Collagen receptors have a major role in aggregation, the protective effects of P188 on these receptors may be contributed to the restoration of platelet functionality upon storage. Thus P188 supplementation to storage platelets may be useful in prolonging the functionality of platelets used for therapeutic purposes.Disclosures Emanuele: Mast Therapeutics: Employment.

Background and Purpose: The utilization of tissue plasminogen activator (tPA) for stroke treatment is hampered by its narrow therapeutic window and hemorrhagic complication. MST-188 (Vepoloxamer) is a proprietary tri-block copolymer with rheological and membrane-protective properties. The current study investigated whether MST-188 enhances the therapeutic effect of tPA on ischemic damage in a rat model of embolic focal cerebral ischemia. Methods: Male Wistar rats (n=10) subjected to embolic middle cerebral artery occlusion (MCAO) were treated post stroke with the combination of MST-188 (300 mg/kg at 3.5h, IV; followed by a second dose of 2,000 mg/kg at 9.5h, IP) and tPA (10 mg/kg at 4h, IV). Ischemic rats treated with tPA (10 mg/kg at 4h, IV) alone, or saline were used as control groups (n=10/group). An array of behavioral tests were performed at 1 and 7 days after MCAO. Ischemic lesion volume was measured 7 days after MCAO. Results: All rats exhibited neurological deficits measured by the Longa scale 30 min after MCAO. Treatment with tPA alone failed to reduce infarct volume and neurological functional deficits compared with saline treated rats. However, MST-188 in combination with tPA significantly (p<0.05) reduced neurological functional deficits measured by the adhesive removal test (90±29 at 1d and 63±39 seconds at 7d) and modified neurological severity score (mNSS, 9±2 at 1d and 6±3at 7d) compared with rats treated with tPA alone (116±9 at 1d and 96±17 seconds at 7d by adhesive removal test, 11±1 at 1d and 9±1 at 7d by mNSS) and saline (113±12 at 1d and 95±16 seconds at 7d by adhesive removal test, 11±1 at 1d and 8±1 at 7d by mNSS). Histopathological analysis showed that the combination of MST-188 with tPA treatment significantly reduced lesion volume (21±10%, p<0.05) compared with rats treated with tPA alone (35±12%) and saline (34±11%). No significant differences of the incidence of gross hemorrhage were detected among groups. Conclusions: MST-188 enhances the therapeutic effect of tPA without increasing the incidence of hemorrhagic transformation when tPA is administered 4h after embolic MCAO.

Background: Sickle erythrocyte adhesion and membrane fragility contribute to vaso-occlusion and downstream tissue and organ ischemia in sickle cell disease (SCD). Vepoloxamer is an amphipathic triblock copolymer with multi-mechanistic properties believed to improve these pathophysiologic consequences, by sealing damaged cell membranes and inhibiting hydrophobic cellular adhesive interactions. Vepoloxamer reduced both acute vaso-occlusive crisis duration and total opioid analgesic requirements in previous clinical studies. A phase 3 clinical trial of vepoloxamer in acute vaso-occlusive crises is ongoing. Currently, there are no standardized clinical assays to assess membrane properties such as adhesion and fragility that vepoloxamer is believed to target. We evaluated if and to what extent vepoloxamer affected adhesion, thrombosis, and membrane fragility in individual patient samples in our standardized microfluidic flow-based whole blood assays.

Poloxamer 188 (P188) is a non-ionic amphiphilic copolymer with hemorheologic, antithrombotic, anti-inflammatory, and cytoprotective properties. It potentially has clinical utility in diverse diseases, such as acute myocardial infarction, acute limb ischemia, shock, acute stroke, heart failure, and sickle cell crisis. P188 is available as an excipient-grade product, manufactured to National Formulary specifications, which we refer to as P188-NF. During synthesis of P188-NF, polymerization of its polyoxyethylene and polyoxypropylene components generates undesirable low molecular weight (LMW) substances, such as truncated polymers and glycols. In early clinical studies, P188-NF yielded unexpected renal dysfunction. Here, we explore the nature of the renal dysfunction associated with P188-NF and use a purified (more homogenous) form of P188-NF (P188-P) to show that removal of LMW substances is associated with substantially less renal dysfunction. In both a remnant-kidney animal model and in clinical studies, P188-P demonstrates a substantially improved renal safety profile.

Introduction: MST-188 (purified poloxamer 188) is a tri-block co-polymer with high affinity to hydrophobic cellular surfaces that inhibits hydrophobic adhesive interactions in the circulation. It also facilitates blood flow by reducing blood viscosity and reportedly exhibits anti-adhesion and anti-inflammatory properties. Currently, this agent is under study in with patients experiencingsickle cell crisis and in patients with acute limb ischemia. Since MST-188 may be administered with other anti-coagulant agents such as heparin its potential interaction to modulate the anti-coagulant effects of this drug require experimental validation. These studies are designed to investigate the potential interactions between heparin and MST-188 in a rat model of tail transection bleeding and jugular vein clamping induced thrombosis model. Materials and Methods: The in vitro interactions between MST-188 were investigated by supplementing this agent to normal rat plasma (NRP) and heparinized rat plasma at a fixed concentrations of 1.25 and 2.50 mg/mL. The concentration of heparin was kept at 1.25 and 2.50 μg/mL. In the in vivo studies individual groups of rats (n=6-8) were administered with saline as a control, heparin in the dosage range of 125-500 ug/kg intravenously and MST-188 at 25 mg/kg IV followed by heparin at the 125-500 ug/kg dosages. Rat tail resection time was measured 5 minutes after administration of heparin and clot occlusion index was measured as number of jugular vein clamping required to occlude the blood vessel. After the completion of the procedure blood samples were obtained through cardiac puncture and used for ex vivo analysis of PT, aPTT, heptest and thrombin time. Results: In the in vitro studies heparin produced a concentration dependent prolongation of the aPTT, heptest and thrombin time. MST-188 did not produce any effects on the aPTT and heptest time, however it decreased the thrombin time. MST-188 at a higher concentration of 2.5 and 5.0 mg/ml produced a shorting of heparins anticoagulant responses, as measured by aPTT and thrombin time. Heparin produced a dose dependent increase in both the bleeding time (p<0.0001) and number of jugular vein clamps to occlude the blood vessel (p<0.0001). MST-188 at dosages of 25 mg/kg produced a significant increase on both bleeding time (p <0.05) and number of clampings required to occlude the blood vessel (p<0.0001). When MST-188 was administered simultaneously with heparin it augmented the bleeding time (p < 0.05) and increased the number of jugular vein clamps required to occlude the blood vessel (p < 0.05). The ex vivo analysis of blood samples collected from rats treated in different regimens did not exhibit any anti-coagulant effects as measured by PT, aPTT, heptest and thrombin time. Conclusion: These studies suggest a differential response of MST-188. While in vitro it exhibits a prohemostatic response as evident by shortening of thrombin time, in the in vivo setting it enhances the anticoagulant effects of heparin as evident by increased bleeding time and increased number of jugular vein clamps required to occlude the vessel. Thus, both of these mechanisms are involved in the mediation of the beneficial effects observed with this agent in vaso-occlusive and thrombotic processes. Disclosures Emanuele: Mast Therapeutics: Employment.

Background Poloxamer 188 (P188; Mast Therapeutics, Inc.) is a surface-active, non-ionic block copolymer which binds to hydrophobic surfaces on damaged cells improving membrane hydration and lowering adhesion and viscosity.  It is known to improve microvascular function in various pathologic states.  Currently, this agent is under investigation in a phase 3 clinical trial for treatment of sickle cell disease patients experiencing acute vaso-occlusive crisis.  The effect of P188 on blood coagulation and platelet function has been evaluated in several clinical trials where no clinically significant effect has been observed.   In these trials, coagulation studies were based on standard clot based methods (e.g., PT and aPTT) and did not include viscoelastic measurements such as thromboelastography (TEG).   Given P188 alters viscosity, we compared the effect of this agent using various clotbased, chromogenic and viscoelastic measurements of blood coagulation. Materials and Methods Whole blood activated clotting time studies were carried out in groups of healthy individuals (n=10) at a concentration range of 1.872-15.0mg/mL. TEG analysis on native and citratedwhole blood was carried out on TEG 5000 (Haemoscope Corp, Niles, IL) at concentrations of 0-0.45 mg/mL. The effect of P188 on normal plasma clotting parameters, such as PT and aPTT, was measured at a concentration range of 0-10 mg/mL. The effect of P188 on thrombin-induced clot formation was investigated using a fibrinokinetic method. The effect of P188 on thrombin generation was measured using the fluormetric method (Technoclone, Vienna, Austria). The anti-protease effects of P188 were studied using chromogenic substrate methods using isolated biochemical systems. Results At concentrations up to 10 mg/mL, P188 did not produce any modification of Celiteactivated clotting time (Celite-ACT).  At all concentrations the Celite-ACT values remained comparable to saline (138-140 sec for P188 vs. 140 sec for saline).  In the TEG analysis, P188 produced a concentrationdependent hypocoagulant effect in both native and citratedblood as evidenced by increased angle and shortening of maximum amplitude (MA).   In standard PT and aPTT tests, P188 did not produce any effect on the clotting profile at concentrations up to 20 mg/mL.  In fibrinokinetic studies, P188 produced an increase in the fibrin clot density and rate of fibrin polymerization. Discussion These studies demonstrate that even at very high concentrations, P188 does not produce an effect on whole blood clotting as measured by the Celite-ACT assay;   this result was confirmed in other standard assays.  Fibrinokinetic studies revealed an increase in the rate of fibrin formation and clot density.   However, at relatively low concentrations, P188 exhibited a hypocoagulant profile in TEG analysis.  The marked discordance between TEG and other coagulation tests suggest that P188’s effect on viscosity and adhesive interactions result in an artifact in TEG analysis and an incorrect indication of a hypocoagulant effect.  This effect may be due to the viscoelastic endpoint in the TEG assay. Further studies are needed to confirm this hypothesis. Disclosures: Fareed: Mast Therapeutics: Research Funding. Emanuele: Mast Therapeutics: Employment.

Introduction Purified poloxamer188 (P188) (Mast Therapeutics) is a non-ionic, linear block copolymer composed of a central chain of hydrophobic polyoxypropylene and two flanking chains of hydrophylic polyoxyethylene (MW 8.5 kDa). This agent has hemorheologic properties which result in improved microvascular blood flow. P188 has been investigated in a number of indications and is currently under study in an international phase 3 clinical trial in sickle cell patients with vaso-occlusive crisis. Dextrans represent branched polysaccharides of 10-70 kDa that have been used as antithrombotic agents and plasma expanders. Sickle cell disease (SCD) represents a complex hemorheologic condition due to RBC aggregation and cell-fibrin/fibrinogen interactions. The erythrocyte sedimentation rate (ESR) is reflective of RBC and plasma interactions. This study was designed to compare the effect of P188 and dextrans on ESR’s in blood obtained from healthy subjects and patients with sickle cell disease who were seen at Loyola University Medical Center clinics. Material and Methods Whole EDTA blood collected from normal individuals (n=8) and sickle cell patients confirmed by electrophoresis (n=11) were supplemented with P188 or dextran 10K, 18K , 40K and 70K at various concentrations (or saline control). ESR was measured using standard laboratory technique. Results The ESR’s for sickle cell patients (26.4 ± 7.1 mm/hr) were significantly higher in comparison to the ESR’s for healthy subjects (14.6 ± 2.1 mm/hr). Supplementation of P188 decreased ESR’s in both populations. Normal blood ESR’s decreased to 9.1 ± 1.3 mm/hr (38%), whereas the sickle cell patient values decreased to 14.1 ± 4.6 mm/hr (47%). At comparable concentrations, none of the dextrans changed ESR’s in healthy subjects or patients with sickle cell disease. Discussion These results demonstrate that ESR in SCD patients are elevated compared to healthy subjects. P188 supplementation decreased (up to 50%) ESR’s in both the healthy subjects and sickle cell patients. This may be due to the inhibition of rouleaux formation resulting from P188 effects on RBC membranes or cell-protein interactions. None of the dextrans produced a similar decrease, suggesting that the observed lowering of ESR by P188 is unlikely to be due to a non-specific effect related to polymer molecular weight. Clinical Implications P188 is a potential therapeutic agent which may facilitate blood flow and reduce cell-fibrin/fibrinogen interactions in a variety of hemorrheologic disorders. The observed decrease in ESR both in normal and sickle cell blood samples by P188 may primarily be due to increased membrane hydration, fibrinogen dispersion and anti-adhesive effects of this agent. Disclosures: Emanuele: Mast Therapeutics: Employment. Fareed:Mast Therapeutics: Research Funding.