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Biomedical subjects

Walter P Jeske

Publications and source records attributed to Walter P Jeske.

At least 19 recordsLinked to original sources
PubMed2006

Modulatory effects of Escherichia coli capsular-derived sulfaminoheparosans and heparins on tissue factor-mediated activation of platelets: flow cytometric analysis.

Sulfaminoheparosans (alternatively known as bioheparins) represent sulfated derivatives obtained from the K5 capsular polysaccharide of Escherichia coli. Previous studies have shown that these agents are structurally comparable to heparins and capable of exerting anticoagulant and antiprotease effects like heparins. Furthermore they are also able to release tissue factor pathway inhibitor (TFPI). Tissue factor (TF) plays a vital role in the pathogenesis of thrombotic and cardiovascular disorders. Anticoagulants such as heparins and bioheparins inhibit this thrombogenic mediator and thereby downregulate the activation of prothrombin and factor X. This study was carried out to determine the effects of several bioheparin fractions and heparins on TF-mediated platelet activation and their direct effect on platelets using human whole blood flow cytometry. Four different sulfaminoheparosan fractions with mean molecular weights of 20, 9, 7, and 6 kDa were tested for their inhibitory effects on platelet activation at two different concentrations (100 and 10 microg/mL). Unfractionated heparin and a low-molecular-weight heparin, tinzaparin, were also tested under the same experimental conditions for comparative modulatory responses. Fresh whole blood from healthy female and male volunteers (n = 5) was mixed with each of these agents and incubated with TF (diluted thromboplastin C) to activate platelets. Platelets were labeled with the antibodies CD61 FITC (GP IIIa) and CD62 PE (P-selectin). The data were analyzed in terms of percent platelet aggregation and platelet P-selectin expression. At 100 microg/mL, all of these agents strongly and significantly inhibited (approximately 40%) the platelet activation induced by TF in comparison to saline control. The inhibitory effects of each of these agents were slightly weaker (approximately 24% inhibition) at 10 microg/mL. The inhibitory effects of these agents on P-selectin expression correspond to their effects on platelet aggregation. At 100 microg/mL all the agents produced greater than 80% inhibition of P-selectin expression whereas at 10 microg/mL, the inhibition is greater than 70% except for bio-20 kDa, which produced less than 50% of inhibition. No molecular weight dependence was observed with bioheparin fractions in terms of inhibitory effects on platelet aggregation or P-selectin expression. None of the bioheparins and heparins exhibited any direct effects on platelets. These observations suggest that both the bioheparins and heparins are capable of inhibiting TF-mediated activation of platelets. Thus the therapeutic effects of bioheparins in the TF-mediated pathogenesis of platelet activation may be similar to those of heparins.

Anticoagulants↗
PubMed2006

Product individuality of commercially available low-molecular-weight heparins and their generic versions: therapeutic implications.

The currently available brand-name low-molecular-weight heparins (LMWHs) in the United States include dalteparin (Pfizer), enoxaparin (Aventis), and tinzaparin (Pharmion). Other products available, in Europe, include certoparin (Novartis), reviparin (Abbott), nadroparin (GlaxoSmithkline), and parnaparin (Alpha-Wasserman). Each of these LMWHs has a characteristic molecular weight profile and biological activity in terms of an anti-FXa and anti-FIIa potency. The mean molecular weight of these drugs ranges from 4.0 kDa to 7.0 kDa and the anti-FXa:anti-FIIa ratio ranges from 1.5 to 3.5. These agents may also be characterized by the presence of specific chemical end groups such as 2-O-sulfo-4-enepyranosuronic acid at the nonreducing terminus (enoxaparin) or 2,5-anhydro-D-mannose at the reducing terminus (dalteparin). Further, the component oligosaccharide chains exhibit product-specific distribution profiles. It is now widely accepted that individual LMWHs are chemically unique agents and cannot be interchanged therapeutically. Each commercial LMWH has been individually developed for specific clinical indications, which are dose and product dependent. Recently, several generic LMWHs have become available in India (Cutenox and Markaparin) and South America (dilutol, clenox, dripanina), and three companies have filed for regulatory approval of a generic version of enoxaparin in the United States. As the primary aim of a generic drug is to reduce cost without compromising patient care, a generic drug is required to be chemically and biologically equivalent to the pioneer drug. Because LMWHs represent complex natural mucopolysaccharide drugs that have undergone chemical and enzymatic modifications, physicochemical and biological information in addition to molecular weight and anti-FXa:anti-FIIa ratio should be used to determine generic equivalency to the branded drug. We have utilized a previously reported approach to systematically compare three generic versions of enoxaparin obtained from India and Brazil with the branded enoxaparin (Lovenox) available in the United States. Testing included molecular and structural profiling, evaluation in clot-based and amidolytic anti-FXa and anti-FIIa assays, and heparinase-I digestion profiles. While the molecular profiles (4.8 +/- 1.8 kD) and anticoagulant potencies as determined by activated partial thromboplastin time (APTT) were comparable for all four agents, the generic products showed variations in the thrombin time (TT) and Heptest assays. Two generic and the branded enoxaparin were readily digested by heparinase-I, losing most of their anticoagulant activity, but one generic product resisted digestion. This may have been due to a unique structural feature in this product. These studies show that, while generic LMWHs may exhibit acceptable molecular weight and anti-FXa profiles, they can exhibit assay-based differences and digestion profiles. Testing in animal models to determine safety, efficacy, and pharmacodynamic parameters may be important to verify equivalence. In order to assure that the generic LMWHs are equivalent to branded LMWHs such that equivalent clinical results are obtained, there is a need to develop clear stepwise guidelines that will establish equivalency in terms of physical, chemical, biochemical, pharmacokinetic, and pharmacodynamic properties for these anticoagulant drugs.

Blood Coagulation Tests↗
PubMed2005

Antiplatelet agents: current drugs and future trends.

Antiplatelet drugs in clinical use are discussed in terms of their mechanisms of action and the relevancy of that to the physiology of platelets and the pathophysiology of arterial thrombosis. Current clinical usage is outlined in detail for each drug. Experimental antiplatelet drugs also are discussed.

Blood Platelets↗
PubMed2005

Development of generic low molecular weight heparins: a perspective.

It is clear that the introduction of generic versions of low molecular weight heparins (LMWHs) is inevitable; however, it is important that the generic products are manufactured in strict compliance with the manufacturing specification of the branded product. Furthermore, regulatory agencies should require additional data on the chemical biologic, pharmacologic/toxicologic, and dose-response relationship in specific settings. Although there is strong opposition to stop the introduction of these drugs, their development will reduce cost and permit availability to all patients who need them. Some objective guidelines for the proper development of these drugs are needed. Only expert groups and advisory panels to the regulatory bodies can develop these guidelines.

Drug Approval↗
PubMed2005

Unfractionated heparin compared with low-molecular-weight heparin as related to heparin-induced thrombocytopenia.

PURPOSE OF REVIEW: Heparin-induced thrombocytopenia is a severe side effect of treatment with unfractionated heparin. The relation of low-molecular-weight heparin to heparin-induced thrombocytopenia is less well understood. This review will summarize what is known about the similarities and differences between thrombocytopenia induced by low-molecular-weight heparin and that induced by unfractionated heparin. RECENT FINDINGS: The pathophysiology of unfractionated heparin-induced thrombocytopenia, caused by the development of antibodies to heparin/platelet factor 4 complexes, holds true for low-molecular-weight heparin because the molecules of the latter are of the same saccharidic structure as those of unfractionated heparin. Owing to their smaller size, however, low-molecular-weight heparin does not interact with platelet factor 4 and platelets as efficiently as does unfractionated heparin. This translates to a two- to threefold lower risk of immune sensitization (antibody generation and occurrence of clinical heparin-induced thrombocytopenia). Low-molecular-weight heparin-induced thrombocytopenia antibodies are more often immunoglobulin A and immunoglobulin M, in contrast to the immunoglobulin G antibodies generated with unfractionated heparin-induced thrombocytopenia, which tend to be more often associated with clinical heparin-induced thrombocytopenia. The clinical expression of low-molecular-weight heparin-induced thrombocytopenia is generally similar to that of unfractionated heparin-induced thrombocytopenia but can have a slower onset, more severe thrombocytopenia, and slower platelet count recovery. Given that low-molecular-weight heparin, of itself, is linked with heparin-induced thrombocytopenia pathophysiology and it can interact with most preexisting heparin-induced thrombocytopenia antibodies generated after exposure to unfractionated heparin, treatment of heparin-induced thrombocytopenia patients with low-molecular-weight heparin is contraindicated. SUMMARY: The risk of the development of heparin-induced thrombocytopenia with low-molecular-weight heparin treatment is reduced relative to the frequency of unfractionated heparin-induced thrombocytopenia, but it is not eliminated, and platelet counts should be monitored with treatment.

Anticoagulants↗
PubMed2005

Short- and long-acting synthetic pentasaccharides as antithrombotic agents.

Fondaparinux sodium (Arixtra; GlaxoSmithKline) is the first of a new class of antithrombotic agents. It is a chemically synthesised pentasaccharide mimicking the site of heparin that binds to antithrombin. It is purely a factor Xa inhibitor and an inhibitor of thrombin generation that requires binding to antithrombin. Fondaparinux sodium differs from heparin, low-molecular-weight heparin and heparinoids, and cannot be used interchangeably. It has been approved in the US and Europe for the prophylaxis of venous thrombosis after orthopaedic surgery by a fixed dose of 2.5 mg/day without monitoring. Using this pentasaccharide as a backbone, other structures have been synthesised. Idraparinux sodium (Sanofi-Aventis) differs structurally from fondaparinux sodium as it has additional methyl groups, a long half-life, and once-weekly administration. Both drugs are being developed as antithrombotics for venous and arterial thrombosis, acute coronary syndrome, stroke and as adjuncts to thrombolytic therapy.

Animals↗
PubMed2004

Small-molecule direct antithrombins: argatroban.

Argatroban represents the first antithrombin agent that was approved for clinical use. It belongs to the peptidomimetic (arginomimetic) group of drugs with multiple pharmacological properties. Unlike the other antithrombin drugs, such as hirudins and hirulogs, argatroban is a reversible antithrombin agent and therefore exhibits a considerably different pharmacological profile. Although argatroban is considered to be a member of the antithrombin family, its mechanisms of action include several other processes that have not been explored fully to date. These include the inhibition of non-thrombin serine proteases, a direct effect on endothelial cells and the vasculature (generation of nitric oxide), and downregulation of various inflammatory and thrombotic cytokines. Due to its lower molecular weight, argatroban is capable of passing through endovascular and cellular barriers and may, therefore, be more effective than heparins and hirudins in the antithrombotic management of microvascular disorders. Argatroban is an effective anticoagulant agent that produces a stronger anticoagulant effect than heparins and hirudins at equivalent anticoagulant levels, as measured by the activated clotting time (ACT) and activated partial thromboplastin time (APTT). At comparable ACT (300 seconds) and APTT (75-90 seconds), argatroban produces stronger inhibition of thrombin generation, as measured by in-vitro assays. Argatroban does not generate any neutralizing or non-neutralizing antibodies, and has predictable antithrombotic effects in different patients. In addition to the inhibition of thrombogenesis, argatroban also facilitates blood flow, inhibition of platelet activation and endothelial cell stimulation, mechanisms that are not necessarily related to thrombin inhibition. Despite these pharmacological advantages, additional clinical investigations are needed to validate the use of argatroban in clinical indications other than those for which it is currently approved, namely, heparin-induced thrombocytopenia and support of percutaneous coronary angioplasty.

Animals↗
PubMed2004

Newer insights on the mechanism of heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) type II is a complex clinical syndrome. It is an immune reaction to heparin in which the formation of antibodies targeted against the heparin-platelet factor 4 complex results in platelet activation. Platelet activation plays a central role in HIT; however, platelet activation does not occur as an isolated physiologic response. To elucidate further the mechanism of thrombogenesis in HIT, we undertook studies to determine the effect of heparin antibodies on endothelial cells, leukocytes, and the inflammatory state. We summarize our previous and new findings. For endothelial cells: Antiheparin antibodies bind to and directly activate microvascular endothelial cells, whereas binding to and activating macrovascular endothelial cells requires preactivation by platelets or tumor necrosis factor alpha (TNFalpha). Increased circulating levels of hemostatic activation factors as observed with thrombosis, particularly soluble P-selectin, plasminogen activator inhibitor type 1 (PAI-1), tissue factor, and thrombomodulin, were associated with endothelial cell activation and were also found in the blood circulation of patients with HIT. For the inflammatory state: Neutrophils and monocytes (but not lymphocytes) bind to and form complexes with platelets in the presence of HIT antibodies. Activated monocytes bind to endothelial cells and produce a procoagulant state. Patients with HIT have an increased level of cytokines in their blood circulation. For HIT antibodies: Only heparin fractions larger than 5 kd interacted with HIT antibodies, explaining why low-molecular-weight heparin (LMWH) usually does not generate antibodies. HIT antibodies are heterogeneous in structure, affinity, and specificity. These data suggest that, in addition to the platelet component, several other mechanisms are associated with the pathophysiology of HIT. These include an inflammatory state, endothelial cell remodeling, and the known procoagulant state. Differences between patients in the levels of the inflammatory markers may relate to various stages of the inflammatory/procoagulant state that exists in patients with HIT. The variations within the HIT antibodies may influence their ability to activate platelets, endothelial cells, and leukocytes, and thus contribute further to the variations in the pathogenicity of HIT.

Autoantibodies↗
PubMed2004

Decreased prevalence of heparin-induced thrombocytopenia with low-molecular-weight heparin and related drugs.

Heparin-induced thrombocytopenia (HIT) Type II represents a disease spectrum associated with a high risk of thrombosis leading to limb loss and death. The pathophysiology of HIT is based on the development of antibodies to the heparin-platelet factor 4 (PF4) complex. Unfractionated heparin (UFH) is heterogeneous in molecular chain length and degree of sulfation accounting in part, for, the heterogeneity of HIT antibodies. Because of its smaller size, low-molecular-weight heparin (LMWH) does not interact with PF4 and platelets as efficiently as does UFH. This translates into a lower risk of immune sensitization with LMWH than with UFH treatment. LMWH is less likely than UFH to cause antibody generation and thus patients do not develop clinical HIT at the same frequency with LMWH as with UFH treatment. The antibodies generated by LMWH treatment are more often immunoglobulin A (IgA) and IgM as opposed to IgG antibodies, which are associated with symptomatic clinical HIT generated by exposure to UFH. However, platelet activation/aggregation can occur from LMWHs in the presence of most pre-existing HIT antibodies that had been generated from UFH exposure, although the response is less than that caused by UFH plus HIT antibody. With the expanded use of LMWH, the frequency of clinical HIT may naturally decline, given that LMWHs are less likely to generate HIT antibody.

Heparin↗
PubMed2004

Generic low-molecular-weight heparins: some practical considerations.

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.

Anticoagulants↗
PubMed2003

Factor Xa inhibitors: today and beyond.

Serine proteases play an important role in thrombogenesis, the process that leads to blood clotting and conditions such as heart attack, stroke and other cardiovascular disorders. In the coagulation network, the activation of various serine proteases facilitates the formation of the serine protease Factor Xa, which plays a central role in the process of coagulation and platelet activation. Factor Xa is an essential component of the prothrombinase complex, from which thrombin is formed, which then directly leads to fibrin clot formation. Thus, the inhibition of Factor Xa and its generation is an important strategy in the development of new antithrombotic drugs.

Anticoagulants↗
PubMed2002

Differential effects of clivarin and heparin in patients undergoing hip and knee surgery for the generation of anti-heparin-platelet factor 4 antibodies.

The pathophysiology of heparin-induced thrombocytopenia (HIT) syndrome is mediated via a heterogeneous group of heparin(s)-platelet factor 4 (H-PF4) complexes bound to their antibodies. These anti-H-PF4 (AHPF4) antibodies that are capable of binding to the FcgammaRIIA receptor [cluster of differentiation (CD) 32] on platelets, resulting in platelet activation, widely vary in their specific activities as platelet activation (functionality). Predisposing factors related to specific pathologic conditions may also contribute to the generation of these antibodies and their relative functionality during HIT syndrome. To understand this phenomenon, a sub-study was carried out in patients undergoing elective total hip and knee replacement surgery (ECHOS Study) and who were treated with unfractionated heparin (UFH) and a low-molecular-weight heparin (LMWH; Clivarin). Approximately 600 patients per arm [UFH=7,500 anti-Xa U twice a day (b.i.d.) subcutaneous (s.c.) and clivarin=4200 U once daily (o.d.) s.c.], age >40 years, received prophylactic treatment for a minimum of 11-14 days. Plasma samples were collected at pre-dose, days 2-4, days 11-14 and at follow-up 6-8 weeks after discharge and were analyzed for AHPF4 antibody titers. Functionality of the enzyme-linked immunosorbant assay (ELISA)-positive AHPF4 antibodies to cause platelet activation was tested by 14C-serotonin release assay (SRA). Both UFH and clivarin treatments in orthopedic surgical patients resulted in a progressive generation of AHPF4 antibodies. The relative prevalence/functionality of AHPF4 antibodies in clivarin arm was markedly lower (two- to threefold, p<0.001) as compared to UFH at each time point. Most of the samples in clivarin group were found to be SRA negative, suggesting the presence of AHPF4 antibodies that did not activate platelets (nonfunctional). Within the UFH arm, the relative prevalence/functionality of AHPF4 antibodies was much higher (p<0.002) in knee group compared to the corresponding hip group. This study, for the first time, reports on the elevated levels of AHPF4 antibodies generated by heparin associated with the pathogenesis of knee surgery. Clinical significance of the differential generation of HIT-associated antibodies remains unexplored at this time.

Adult↗
PubMed2002

Prevalence, isotype, and functionality of antiheparin-platelet factor 4 antibodies in patients treated with heparin and clinically suspected for heparin-induced thrombocytopenia. The pathogenic role of IgG.

Antibodies to heparin-platelet factor 4 (PF4) complexes have been observed in patient with heparin-induced thrombocytopenia (HIT) syndrome. These antibodies may be of various isotypes and differ with respect to their ability to activate platelets/endothelial cells. This study determined the isotypes and functionality of antiheparin-platelet factor 4 (AHPF4) antibodies in 111 patients treated with heparin and clinically suspected for HIT. In this patient population, 50% had detectable AHPF4 cumulative IgA, IgG, and IgM (determined by enzyme-linked immunosorbent assay, ELISA), but only 35% was positive when tested with the (14)C-serotonin release assay (SRA). Using antihuman Ig specific for different isotypes, we found that 50% of the 111 samples was positive for IgG, 45% for IgM, and 37% for IgA. In 50 normal human serum (NHS) samples, only two were positive for IgG, but 33 were positive for IgM, indicating a potential humoral response to the heparin-PF4 complex prior to heparin administration. Patients that were ELISA(+) for AHPF4 antibody titer were subdivided into SRA-positive (+) and SRA-negative (-) groups. The SRA(+) group had a mean ELISA optical density (OD) for AHPF4 IgA/IgG/IgM of 2.1, while the SRA(-) group had a mean OD of 0.8 (P<.001). The SRA(+) group had greater mean OD values for all three individual isotypes. Using flow cytometry, we determined the ability of different patient samples to activate platelets. Samples that contained IgG and were SRA(+) activated platelets (as measured by microparticle generation and P-selectin expression) in the presence of therapeutic concentrations of heparin. NHS and samples containing IgA and/or IgM that were SRA(-) were not able to produce microparticles nor were they able to increase expression of P-selectin. Together, these data indicate that IgG is the principal mediator of platelet activation in patients with HIT, with IgA and IgM playing a less significant role in the pathophysiology of this syndrome.

Antigen-Antibody Reactions↗