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    The Heparins: Basic and Clinical Aspects
    The Heparins: Basic and Clinical Aspects
    The Heparins: Basic and Clinical Aspects
    Ebook414 pages4 hours

    The Heparins: Basic and Clinical Aspects

    By David Green

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    About this ebook

    The Heparins: Properties and Clinical Applications brings the latest information on heparin, one of the world's most widely used drugs. The book describes the fascinating history of the discovery of this biological agent, how it was isolated and characterized, and its use for the treatment of thrombotic disorders. The structures of various heparins are illustrated, with their function as anticoagulants delineated. This comprehensive resource arms researchers and clinicians with a concise and practical source that will assist in biomedical research, medical practice, and in improving patient outcomes.

    • Describes new pharmaceuticals derived from heparin that are devoid of anticoagulant activity, but still retain anti-inflammatory and anti-proliferative properties
    • Discusses the development of non-anticoagulant heparins for the treatment of diseases, including asthma and cancer
    • Presents the history of the discovery of this biological agent, how it was isolated and characterized, and its use for the treatment of thrombotic disorders
    LanguageEnglish
    PublisherAcademic Press
    Release dateJan 13, 2020
    ISBN9780128190692
    The Heparins: Basic and Clinical Aspects
    Author

    David Green

    David Green is the founder and CEO of Hobby Lobby, the largest privately owned arts and crafts retailer in the world. Hobby Lobby employs over 33,000 people, operates 800 stores in forty-seven states, and grosses more than $5 billion dollars a year. Currently David serves on the Board of Reference for Oral Roberts University in Tulsa, Oklahoma. In 2013, he was honored by receiving the World Changer award and is also a past Ernst & Young national retail/consumer Entrepreneur of the Year Award recipient. In 2017, the Green family opened the Museum of the Bible in Washington, DC.

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      Book preview

      The Heparins - David Green

      pp.

      Part I

      Historical Development and Properties

      Outline

      Chapter 1 Anticoagulant heparins

      Chapter 2 Non-anticoagulant heparins

      Chapter 1

      Anticoagulant heparins

      Abstract

      Anticoagulant activity (heparin) was identified in liver extracts by a medical student, Jay McLean, in 1916 while working in Howell’s laboratory at Johns Hopkins. Subsequent investigators found that a specific pentasaccharide with ≥12 saccharide units at its non-reducing end binds antithrombin, enhancing its inactivation of thrombin; the pentasaccharide alone is sufficient for inactivation of factor Xa. Clinical trials reported that unfractionated heparin prevents thrombus formation after surgery and recurrences after deep vein thrombosis/pulmonary embolism, but it has been replaced by low molecular weight heparin (LMWH) and fondaparinux because they provide more reproducible anticoagulation and are simpler to manage. Unfractionated heparin is used for preventing clots in extracorporeal circuits, and during coronary bypass/valve replacement, renal hemodialysis, and extracorporeal membrane oxygenation. The anticoagulant activity of unfractionated heparin, and to a lesser extent, LMWH, can be reversed by protamine, but there is no specific reversal agent for fondaparinux. Several heparin analogs are under development.

      Keywords

      Unfractionated heparin; Low molecular weight heparin; Fondaparinux; Pentasaccharide; Antithrombin; Factor Xa; Glycosaminoglycans; Heparin analogs

      Discovery

      Anticoagulant activity was detected by Jay McLean incidentally while he was attempting to purify cephalin from canine liver. McLean (1890–1957) had enrolled at Johns Hopkins School of Medicine as a second year medical student in 1915 and shortly thereafter began working in the laboratory of William Henry Howell (1860–1945), who assigned him the cephalin project. In the publication he prepared describing his results, he stated that the phospholipid he extracted from liver has no thromboplastin action and in fact shows a marked power to inhibit the coagulation. [1] Later in 1916, McLean joined the Department of Research Medicine at the University of Pennsylvania, but Howell continued to study this anticoagulant activity, to which he and Emmett Holt gave the name, heparin, because of its origin from the liver [2]. They observed that heparin was water-soluble when separated from cephalin, and a 0.1% solution prevented the clotting of shed blood.

      As early as 1905, Morawitz [3] had proposed that blood coagulation was a two-step process: first, injured tissues released a factor, termed thromboplastin, which converted prothrombin to thrombin, and second, thrombin converted fibrinogen to fibrin. He also recognized that calcium was required for thromboplastin to be active. While this scheme could account for the clotting of shed blood, it did not explain why circulating blood remained fluid. In response, the studies of Howell and Holt [2] suggested that heparin and pro-anti-thrombin…together fulfill the function of safeguarding the fluidity of the blood. They noted that the conversion of pro-antithrombin to antithrombin might protect against small amounts of thrombin, and that heparin functioned as a specific activator of pro-antithrombin and prevented the conversion of prothrombin to thrombin. Howell continued his anticoagulant studies, and in 1925 reported the isolation of a more reliable heparin that was water-soluble, free of protein, and prevented the clotting of 5 mL of blood in concentrations of 1 mg or less [4].

      In 1928, Charles H. Best organized a group to examine the chemistry and physiology of heparin [5]. Their chemical studies were conducted at the Connaught Laboratories of the University of Toronto, the site where they produced insulin in the early 1920s. Best recruited David Scott and Arthur Charles, who reported that heparin could be isolated from beef lung, a much more accessible tissue, and following trypsin digestion could be crystallized as the barium salt [6]. This material had a potency of 100 arbitrary units/mg and they examined its effect on thrombi induced in canine veins. Removal of these veins several days after the injection of heparin showed complete resolution of thrombi and intimal healing.

      Structure

      Although producing heparin from animal tissues was not difficult, defining its chemical structure was challenging. This task was undertaken by J. Erik Jorpes at the Karolinska Institute in Stockholm, Sweden. Jorpes (1894–1973) received his medical degree from the University of Helsinki in 1925 and joined the Department of Chemistry and Pharmacology at the Karolinska; he rose through the academic ranks to become Professor of Medical Chemistry in 1946 [7]. In 1928–29, he visited the laboratories of Howell and Best, and on his return to Sweden, he organized the production of insulin and heparin [8]. In 1935, Jorpes showed that the main carbohydrate constituents of heparin were uronic acid and hexosamine, present in a 1:1 ratio [9]. Subsequently, Jorpes and Bergstrom [10] reported that the anticoagulant activity of heparin could be enhanced by increasing the extent of sulfation. However, a member of Best’s group, Louis Jaques, observed that heparins derived from different species varied in anticoagulant potency despite having similar sulfur content, suggesting that species-specific factors contributed to the anticoagulant activity [11]. Jaques noted that the heparin polymer consisted of alternating sulfoglucosamine and hexuronic acid moieties joined by glycosidic linkages, and that these were present in amounts specific for each species [12]. Active chains generally had molecular weights in the 12,000–20,000 dalton range. He concluded that heparins are mixtures of individual highly negatively charged chains that show a wide spectrum of specific reactions with biologically active proteins. The hexuronic acid was identified as L-iduronic acid by Cifonelli and Dorfman [13] in 1962; the structures of D-glucosamine and L-iduronic acid are shown in Fig. 1.1.

      Figure 1.1 L-Iduronic acid and D-glucosamine. Images from https://pubchem.ncbi.nlm.nih,gov.

      In 1936, Hjalmar Holmgren, a histology assistant in Jorpes laboratory, was tasked with determining the cell of origin of heparin. He used toluidine blue staining to determine that the anticoagulant was located in the metachromatic granules of mast cells. In fact, glycosaminoglycans (GAGs) such as heparin account for as much as 25% of the total organic content of rat mature mast cells [14]. Mast cells from human lung are estimated to contain heparin in a concentration of 2.4–7.8 µg/106 cells [15]. Tissue mast cells have a very characteristic appearance with metachromatic dyes, displaying extensive grapelike clusters of granules (Fig. 1.2). Heparin is synthesized in the Golgi compartment of the mast cells and attached to the serglycin core protein [16]. A critical enzyme for the modification of the nascent heparin chains is N-acetylase/N-sulfatransferase 2 (NDST2), which is expressed in massive amounts in mast cells and is essential for the N-deacetylation and N-sulfation of the nascent polysaccharide chains. In the absence of this enzyme, mast cells are abnormal and lack heparin [17]. In contrast, heparan sulfate is made by cells throughout the body, and the key enzyme required for its synthesis is NDST1.

      Figure 1.2 Mast cell in the bone marrow, Giemsa stain, 1000×. Photomicrograph courtesy of Yi-Hua Chen, MD, Feinberg School of Medicine, Northwestern University.

      Glycosaminoglycans (GAGs) are linear polysaccharide chains consisting of repeating disaccharide groups. They are found in the extracellular matrix and bind to a core protein to form proteoglycans. The principal proteoglycans are hyaluronan and keratan, chondroitin, dermatan, and heparan sulfates. Heparan sulfate is located on the surfaces and basement membranes of most cells where it can bind a number of effectors. These include adhesion molecules, tyrosine kinase receptors, integrins, and complement receptors; growth factors such as vascular endothelial (VEGF), epidermal (EGF), and transforming growth factor-β (TGF-β); cytokines and chemokines; and the extracellular matrix components: collagens, fibronectin, and laminin [18,19]. Heparin differs from heparan sulfate in a number of respects (Fig. 1.3 and Table 1.1) [20]. Heparin has fewer chains and a small molecular mass (15 vs 30 kDa, and >80% of the glucosamine residues are N-sulfated, but the concentration of O-sulfates exceeds N-sulfates). In heparan, the numbers of N-sulfate and N-acetyl substituents are approximately equal and the number of O-sulfate groups can range from 20 to 75 per 100 disaccharide units [21]. Heparin also has a higher sulfate to disaccharide ratio and more iduronic acid [22]. In fact, heparin has the highest negative charge density and is the most acidic biologic macromolecule in the human body

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