Relative Activities of Heparin Fractions Obtained by Gel Chromatography

Graham, David; Pomeroy, A R

doi:10.1055/s-0038-1657063

Cited by 16 publications

(8 citation statements)

References 3 publications

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“…These molecular components exert specific pharmacologic actions by interacting with various endogenous proteins, thereby collectively producing an antithrombotic effect. 12,15,16,[18][19][20][21]27,36 It has been suggested that the primary antithrombotic actions of heparin are determined by molecular fractions that exhibit strong affinity for antithrombin III and in a complex form with this plasma cofactor produce potent antiprotease actions. 7,8a,10,11,22,35 It has also been proposed that low-affinity heparin fractions produce a modulatory action on the pharmacologic activity of high-affinity fragments.…”

Section: Discussionmentioning

confidence: 99%

“…Utilizing newer separation techniques, heparin can be fractionated into various molecularly defined species possessing specific, individual biochemical and pharmacologic actions. 7,11,12,20,23,26 Furthermore, based on structural information, oligosaccharide fragments with high affinity to antithrombin III can be obtained by various physicochemical methods. 10,11,28,31,37 Moreover, it is now possible to study completely synthetic oligosaccharides, of which pentasaccharide represents the first molecularly defined biologically active fragment of heparin.…”

Section: Discussionmentioning

confidence: 99%

“…The inhibitory action was somewhat stronger in the case of bovine Xa than the human Xa preparations, as observed by other investigators for other heparin products. 1,20,34,39 These actions are dependent on a complex with antithrombin III, since no inhibition was observed in the albumin system. In addition, the plasma system produced a greater inhibitory effect than the pure antithrombin III system, suggesting that another endogenous inhibitor, such as heparin cofactor II, is also responsible for these actions.…”

Section: Discussionmentioning

confidence: 99%

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Preliminary Biochemical and Pharmacologic Studies on a Chemically Synthesized Pentasaccharide

Walenga¹,

Fareed²

1985

Semin Thromb Hemost

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Preliminary Biochemical and Pharmacologic Studies on a Chemically Synthesized Pentasaccharide

Walenga¹,

Fareed²

1985

Semin Thromb Hemost

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“…41,52 Experiments by academic and commercial investigators rapidly exploited this new field, reporting on newer methods of fractionation, relationships between molecular weight and antithrombin activity, and the ratio of factor Xa to IIa activity. [53][54][55] Fractionation methods are listed in Table 1.…”

Section: Era Of Rapid Expansion 1977 To 2003mentioning

confidence: 99%

Heparin to Pentasaccharide and Beyond: The End Is Not in Sight

2004

Semin Thromb Hemost

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The 87-year history of heparin began in 1916 when a 26-year-old medical student named Jay McLean startled his mentor William Howell, Professor of Physiology at Johns Hopkins University, by proclaiming that he had discovered "antithrombin." This discovery was so surprising to Howell because he had expected McLean to isolate thromboplastin, a clot-promoting substance from animal tissue. In 1928, Charles Best, M.D., in Toronto, Canada, organized a team of chemists, physiologists, and surgeons to focus on the development of heparin. This group determined which animal tissues were the best source, had performed purification and identification, and had determined pharmacologic properties in vitro. By 1935, they were ready for human trials. By 1941, the group reported a series of 700 patients treated with the glycosaminoglycan called heparin. Meanwhile a critical cofactor, antithrombin, had been discovered at the University of Iowa (Brinkhous, et al). Introduction of newer tests for laboratory monitoring enabled refinement of dosages during the 1960s and 1970s. Its use permitted the development of hemodialysis and cardiopulmonary bypass surgery, and the prophylaxis of deep vein thrombosis in surgical patients. The concept of low-molecular-weight heparin occurred to Dr. Choay and others in France in the late 1970s. During the 1980s and 1990s, the development of low-molecular-weight heparins evolved for both prophylaxis and therapy. The first synthetic product was called the pentasaccharide, named for the five critical sugar units in heparin that bind to antithrombin (1983). Since then, this drug has been studied extensively to prove its clinical efficacy and safety.

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“…They have varying affinities to antithrombin III (AT III) and exhibit inhibitory effects on serine proteases. 9,14,[16][17][18] Heparin and several heparin fractions have been studied in multiple in vitro and ex vivo test systems to demonstrate the utility of various serine proteases and global coagulant and synthetic substrate-based assays.…”

mentioning

confidence: 99%

Validity of Serine Protease Inhibition Tests in the Evaluation and Monitoring of the Effect of Heparin and Its Fractions

Hoppensteadt¹,

Walenga²,

Fareed³

1985

Semin Thromb Hemost

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The advent of heparin fractions for clinical use has prompted a reevaluation of the available methods for the assaying of heparin activity in blood. Newly developed heparin fractions are routinely evaluated in terms of their anti-Xa and anti-IIa amidolytic USP, APTT, and anti-Xa coagulant actions. A wide variation between these assays exists due to the use of nonstandard reagents and varying assay conditions. Amidolytic assays, although more biochemically defined than coagulant assays, do not use a natural substrate and work in a diluted plasma system. This may account for discrepancies and differing sensitivities between results in the amidolytic and coagulant assays. The APTT, PTT, and TT may not be effected by the LMFs, and these are the tests currently used to monitor patients on heparin therapy. A poor correlation is observed between the global tests with the newly developed anti-Xa and anti-IIa assays. Furthermore, marked differences in the inhibitory responses are observed with heparin and its fractions. The anti-Xa and anti-IIa assays may provide a more sensitive assay than the APTT, but the poor correlation between assays suggests a multiple effect of heparin and its fractions. Which assay or assays are the best measure of the antithrombotic efficacy of this drug remains to be determined. However, a random selection of an assay is surely not a proper means to monitor these drugs, and a battery of current methodology should be considered.(ABSTRACT TRUNCATED AT 250 WORDS)

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Relative Activities of Heparin Fractions Obtained by Gel Chromatography

Cited by 16 publications

References 3 publications

Preliminary Biochemical and Pharmacologic Studies on a Chemically Synthesized Pentasaccharide

Preliminary Biochemical and Pharmacologic Studies on a Chemically Synthesized Pentasaccharide

Heparin to Pentasaccharide and Beyond: The End Is Not in Sight

Validity of Serine Protease Inhibition Tests in the Evaluation and Monitoring of the Effect of Heparin and Its Fractions

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