The Heparins: Basic and Clinical Aspects
By David Green
()
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
David Green
David Green, MD, PhD, is Professor Emeritus in Medicine, Division of Hematology/Oncology, at Northwestern University Feinberg School of Medicine in Chicago, Illinois. He received his medical degree from Jefferson Medical College in Philadelphia, Pennsylvania and Doctorate in Biochemistry from Northwestern University, Evanston, Illinois. He is a clinician-investigator and author of more than 300 published scientific articles. His most recent book, Linked by Blood: Hemophilia and AIDS, describes the AIDS epidemic in the early 1980s that ravaged the hemophilia community and led to major changes in the collection and processing of blood and blood products. He is a Master of American College of Physicians and recipient of many other awards.
Read more from David Green
More Than a Hobby: How a $600 Startup Became America's Home and Craft Superstore Rating: 5 out of 5 stars5/5The Hundred Years War: A People's History Rating: 4 out of 5 stars4/5Giving It All Away…and Getting It All Back Again: The Way of Living Generously Rating: 4 out of 5 stars4/5A Generous Life: 10 Steps to Living a Life Money Can't Buy Rating: 0 out of 5 stars0 ratingsThe Black Prince Rating: 4 out of 5 stars4/5Dead Man Walking Rating: 0 out of 5 stars0 ratingsSamurai Castles: History / Architecture / Visitors' Guides Rating: 0 out of 5 stars0 ratingsBattle of Poitiers 1356 Rating: 0 out of 5 stars0 ratingsCurly Princess of the Rose Kingdom Rating: 0 out of 5 stars0 ratingsCaptured at the Imjin River: The Korean War Memoirs of a Gloster Rating: 0 out of 5 stars0 ratingsA Book About YOU: Finding Your True Purpose Rating: 0 out of 5 stars0 ratingsMaximising the Benefits of Psychotherapy: A Practice-based Evidence Approach Rating: 4 out of 5 stars4/5Hemophilia and Von Willebrand Disease: Factor VIII and Von Willebrand Factor Rating: 0 out of 5 stars0 ratingsPorto Lúa Rating: 0 out of 5 stars0 ratingsCurly Princess of the Daisy Kingdom Rating: 0 out of 5 stars0 ratingsCurly Princess of the Carnation Kingdom Rating: 0 out of 5 stars0 ratingsLinked by Blood: Hemophilia and AIDS Rating: 0 out of 5 stars0 ratingsCurly Princesses of the Sunflower Kingdom Rating: 0 out of 5 stars0 ratings
Related to The Heparins
Related ebooks
Pathophysiology of Ischemia Reperfusion Injury and Use of Fingolimod in Cardioprotection Rating: 0 out of 5 stars0 ratingsEndocrinology of the Heart in Health and Disease: Integrated, Cellular, and Molecular Endocrinology of the Heart Rating: 0 out of 5 stars0 ratingsManagement of Complex Cardiovascular Problems Rating: 0 out of 5 stars0 ratingsBlood Gases and Critical Care Testing: Physiology, Clinical Interpretations, and Laboratory Applications Rating: 0 out of 5 stars0 ratingsMedicines Management for Nurses at a Glance Rating: 0 out of 5 stars0 ratingsHandbook of Pediatric Hematology and Oncology: Children's Hospital and Research Center Oakland Rating: 4 out of 5 stars4/5Abdominal Organ Transplantation: State of the Art Rating: 0 out of 5 stars0 ratingsPharmacology of Antihypertensive Drugs Rating: 3 out of 5 stars3/5Cellular and Molecular Pathobiology of Cardiovascular Disease Rating: 0 out of 5 stars0 ratingsCardio-Hepatology: Connections Between Hepatic and Cardiovascular Disease Rating: 0 out of 5 stars0 ratingsAnesthesia for Congenital Heart Disease Rating: 0 out of 5 stars0 ratingsAlternatives to Blood Transfusion in Transfusion Medicine Rating: 0 out of 5 stars0 ratingsTorsades de Pointes Rating: 0 out of 5 stars0 ratingsHepatorenal Syndrome, A Simple Guide To The Condition, Diagnosis, Treatment And Related Conditions Rating: 0 out of 5 stars0 ratingsTeleStroke Rating: 0 out of 5 stars0 ratingsMathematical Approaches to Liver Transplantation Rating: 0 out of 5 stars0 ratingsSitaraman and Friedman's Essentials of Gastroenterology Rating: 0 out of 5 stars0 ratingsDialysis: a Memoir Rating: 0 out of 5 stars0 ratingsDegenerative Aortic Valve Disease, its Mechanism on Progression, its Effect on the Left Ventricle and the Postoperative Results Rating: 0 out of 5 stars0 ratingsInterventional Cardiology: Principles and Practice Rating: 0 out of 5 stars0 ratingsGregory's Pediatric Anesthesia Rating: 4 out of 5 stars4/5Electrophysiologic Testing Rating: 0 out of 5 stars0 ratingsSurgical Inflammation Rating: 0 out of 5 stars0 ratingsUnderstanding Clinical Cardiac Electrophysiology: A Conceptually Guided Approach Rating: 0 out of 5 stars0 ratingsEthical Challenges of Organ Transplantation: Current Debates and International Perspectives Rating: 0 out of 5 stars0 ratingsIntelligence-Based Cardiology and Cardiac Surgery: Artificial Intelligence and Human Cognition in Cardiovascular Medicine Rating: 0 out of 5 stars0 ratingsHepatorenal Syndrome: Causes, Tests, and Treatment Options Rating: 5 out of 5 stars5/5Critical Decisions in Emergency and Acute Care Electrocardiography Rating: 0 out of 5 stars0 ratingsThe Metabolic Basis of Surgical Care Rating: 0 out of 5 stars0 ratingsRegenerative Medicine for Peripheral Artery Disease Rating: 0 out of 5 stars0 ratings
Medical For You
Tight Hip Twisted Core: The Key To Unresolved Pain Rating: 4 out of 5 stars4/5The Diabetes Code: Prevent and Reverse Type 2 Diabetes Naturally Rating: 4 out of 5 stars4/5The 40 Day Dopamine Fast Rating: 4 out of 5 stars4/5Mediterranean Diet Meal Prep Cookbook: Easy And Healthy Recipes You Can Meal Prep For The Week Rating: 5 out of 5 stars5/5WomanCode: Perfect Your Cycle, Amplify Your Fertility, Supercharge Your Sex Drive, and Become a Power Source Rating: 4 out of 5 stars4/5Working Stiff: Two Years, 262 Bodies, and the Making of a Medical Examiner Rating: 4 out of 5 stars4/5What Happened to You?: Conversations on Trauma, Resilience, and Healing Rating: 4 out of 5 stars4/5Holistic Herbal: A Safe and Practical Guide to Making and Using Herbal Remedies Rating: 4 out of 5 stars4/5Mating in Captivity: Unlocking Erotic Intelligence Rating: 4 out of 5 stars4/5Period Power: Harness Your Hormones and Get Your Cycle Working For You Rating: 4 out of 5 stars4/5The Vagina Bible: The Vulva and the Vagina: Separating the Myth from the Medicine Rating: 5 out of 5 stars5/5Adult ADHD: How to Succeed as a Hunter in a Farmer's World Rating: 4 out of 5 stars4/5Gut: The Inside Story of Our Body's Most Underrated Organ (Revised Edition) Rating: 4 out of 5 stars4/5Woman: An Intimate Geography Rating: 4 out of 5 stars4/5Healthy Gut, Healthy You: The Personalized Plan to Transform Your Health from the Inside Out Rating: 4 out of 5 stars4/5ATOMIC HABITS:: How to Disagree With Your Brain so You Can Break Bad Habits and End Negative Thinking Rating: 5 out of 5 stars5/5Women With Attention Deficit Disorder: Embrace Your Differences and Transform Your Life Rating: 5 out of 5 stars5/5Unhinged: The Trouble with Psychiatry - A Doctor's Revelations about a Profession in Crisis Rating: 4 out of 5 stars4/5Brain on Fire: My Month of Madness Rating: 4 out of 5 stars4/5Living Daily With Adult ADD or ADHD: 365 Tips o the Day Rating: 5 out of 5 stars5/5The Amazing Liver and Gallbladder Flush Rating: 5 out of 5 stars5/5"Cause Unknown": The Epidemic of Sudden Deaths in 2021 & 2022 Rating: 5 out of 5 stars5/5Hidden Lives: True Stories from People Who Live with Mental Illness Rating: 4 out of 5 stars4/5The Song of the Cell: An Exploration of Medicine and the New Human Rating: 4 out of 5 stars4/5
Related categories
Reviews for The Heparins
0 ratings0 reviews
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