A Century of Heparin.

The year 2018 was the centennial of the naming of heparin by Emmett Holt and William Howell and the 102nd anniversary of Jay McLean's discovery of an anticoagulant heparphosphatide at Johns Hopkins Hospital in Baltimore. This article discusses recently discovered historical artifacts that shed new light on heparin's christening, including McLean's unpublished letter written in 1950 that represents one of the most complete accounts of heparin's discovery before his untimely death. In addition, the article describes the finding of a plaque dedicated to McLean and explores the circumstances of its removal from public display, as learned from interviews with present and former staff members.

The Development of Extracorporeal Membrane Oxygenation.

Evolving from the development of heart-lung machines for open-heart surgery, extracorporeal membrane oxygenation has reemerged as a rescue modality for patients with acute respiratory failure that cannot be supported by conventional modes of ventilation. The history of extracorporeal membrane oxygenation begins with the discovery of heparin, fundamental to the success of extracorporeal circulation and membrane lungs. Engineers and scientists created suitable artificial membranes that allowed gas exchange while keeping gas and blood phases separate. Special pumps circulated blood through the devices and into patients without damage to delicate red cells and denaturing plasma. Initial attempts in adults ended in failure, but Robert Bartlett, first at Loma Linda, CA, then at Ann Arbor, MI, succeeded in applying the technology in newborn infants with persistent pulmonary hypertension. Preserved in the critical care of infants, the technology in time could be reapplied in the life support of older children and adults.

Advances in Heparins and Related Research. An Epilogue.

The discovery of heparin in 1916 by Jay McLean, a medical student at Johns Hopkins University, not only provided a universal anticoagulant, but also laid the foundation for the discipline of hemostasis and thrombosis[...].

Remembering Professor Benito Casu (1927-2016).

Heparin and related drugs have contributed in so many different ways to the drug discovery process, and have provided a platform to understand the pathophysiology of vascular and inflammatory diseases for nearly 100 years.

HITs and misses in 100 years of heparin.

Heparin was discovered 100 years ago, and the heparin-induced thrombocytopenia syndrome was described 40 years ago. That the most powerful anticoagulant of the last century can also produce the most extreme prothrombotic diathesis is but one of the paradoxes that surround heparin-induced thrombocytopenia. Standard treatment is alternative anticoagulation. Advances continue to be made regarding pathophysiology, prevention, and treatment. Currently, an epidemic of overdiagnosis threatens the well-being of patients, so efforts to educate clinicians on when and how to make this diagnosis are pressing.

Jay McLean, 100 años de heparina / Jay McLean: 100 years of heparin

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The History of Antithrombotic Therapy: The Discovery of Heparin, the Vitamin K Antagonists, and the Utility of Aspirin.

The administration of intravenous heparin to postoperative patients by Barritt and Jordan reduced the incidence of fatal and nonfatal pulmonary embolism and established heparin as the standard for parenteral anticoagulation. The coumarin family of vitamin K antagonists quickly became the standard for long-term oral anticoagulation. Aspirin became a widely used antithrombotic agent after the discovery that chronic oral administration reduced the incidence of secondary strokes and myocardial infarction. This article gives a brief history of antithrombotic therapy, including the discovery of heparin, the vitamin k antagonists, and the utility of aspirin.

The evolution of anticoagulant therapy.

Arterial and venous thromboembolism are leading causes of morbidity and mortality around the world. For almost 70 years, heparins (unfractionated heparin and low molecular weight heparins) and vitamin K antagonists have been the leading therapeutic medical options for the treatment and prevention of thromboembolic disorders. Nevertheless, the many limitations of these traditional anticoagulants have fuelled the search for novel agents over the past 15 years, and a new class of oral anticoagulants that specifically target activated factor X and thrombin has been developed and is now commercially available. In this narrative review, the evolution of anticoagulant therapy is summarised, with a focus on newer oral anticoagulants.

Heparin: 100 years of pleiotropic effects.

Heparin is a glycosaminoglycan with anticoagulant properties and antiinflammatory effects. The discovery of heparin approaches its 100th year and its antiinflammatory properties still draws much attention and anticipation to new possibilities of use and the likelihood of developing heparin-like drugs that lacked the anticoagulation effects. It is known that heparins limit the embolization and the extension of the thrombus, although they do not promote its complete lysis in most cases. The complexity and pleiotropic characteristics of these glycosaminoglycans still challenge science, to the point in which approaches hitherto unusual appear repeatedly in the literature. New indications, accompanied by longtime consecrated others, dismantle the idea of an outdated medication and create high expectations for the near future. The objective of this review is to analyze the pleiotropic effects of heparin and its use in several diseases, highlighting its safety and effectiveness.

Historia de la heparina / History of heparin

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History of heparin.

The history of heparin is described from its initial discovery in 1916 to recent developments in knowledge of its mechanism of action and clinical use. Commercial production started soon after its discovery, in the 1920s, and improved purification methods led to animal studies and the first clinical trials in the 1930s. Research into heparin's chemical structure proved difficult, with uncertainty about the uronic acid moiety and the N-acetyl content, but the structure of the basic disaccharide unit was established by the 1960s, though knowledge of the heterogeneity and fine structure of heparin chains continued to accumulate over the next 20 years. In 1976, it was found that only one third of heparin chains bound with high affinity to antithrombin, and subsequent studies identified a unique pentasaccharide sequence, which was essential for antithrombin binding and anticoagulant activity - this pentasaccharide was synthesised in 1983. Clinical usage of heparin continued to increase and two major developments were the use of low- dose heparin for prevention of deep vein thrombosis and pulmonary embolism, and the development of low-molecular-weight heparin as a separate drug.

Discovery of anticoagulant drugs: a historical perspective.

The history of the traditional anticoagulants is marked by both perseverance and serendipity. The anticoagulant effect of heparin was discovered by McLean in 1915, while he was searching for a procoagulant in dog liver. Link identified dicumarol from spoiled sweet clover hay in 1939 as the causal agent of the sweet clover disease, a hemorrhagic disorder in cattle. Hirudin extracts from the medicinal leech were first used for parenteral anticoagulation in the clinic in 1909, but their use was limited due to adverse effects and difficulties in achieving highly purified extracts. Heparins and coumarins (i.e.: warfarin, phenprocoumon, acenocoumarol) have been the mainstay of anticoagulant therapy for more than 60 years. Over the past decades, the drug discovery paradigm has shifted toward rational design following a target-based approach, in which specific proteins, or "targets", are chosen on current understandings of pathophysiology, small molecules that inhibit the target's activity may be identified by high-throughput screening and, in selected cases, these new molecules can be developed further as drugs. Despite the application of rational design, serendipity has still played a significant role in some of the new discoveries. This review will focus on the discovery of the main anticoagulant drugs in current clinical use, like unfractionated heparin, low-molecular-weight heparins, fondaparinux, coumarins (i.e.: warfarin, acenocoumarol, phenprocoumon), parenteral direct thrombin inhibitors (DTIs) (i.e.: argatroban, recombinant hirudins, bivalirudin), oral DTIs (i.e.: dabigatran) and oral direct factor Xa inhibitors (i.e.: rivaroxaban, apixaban).

A tale of two anticoagulants: warfarin and heparin.

This article relays the story of 3 men, Karl Paul Link, who is the discoverer of warfarin, and William Henry Howell and Jay McLean, who are the discoverers of heparin.

A history of pulmonary embolism and deep venous thrombosis.

Although enormous progress has been made in understanding the physiology of pulmonary embolism, developing new diagnostic modalities and strategies, and constant refinement in the use of heparin therapy and thrombolytic therapy, venous thromboembolism remains a common and lethal process. As the history of this disease illustrates, advances continue to be made and it is anticipated that with newer diagnostic studies and anticoagulants under development, diagnosis and treatment of pulmonary embolism will continue to improve.

The history of phenotypic testing in thrombosis and hemostasis.

This article takes the reader through a journey of the history of the phenotypic tests for hemostasis and thrombosis starting from the most simple (which were based on the visual inspection and recording of the time needed for native whole blood to clot) to the more complex ones based on the addition to plasma of exogenous substances, use of sophisticated coagulometers or synthetic substrates, and use of computer software to record coagulation times or visualize coagulation tracings and thrombin generation curves. One can see how the simple tests evolved over the years and how such old and time-honored tests as thrombin generation and thromboelastography, devised more than 50 years ago and neglected for many years, are now gaining momentum thanks to the progress made by the technology combined with a better understanding of the coagulation mechanisms. This progress notwithstanding, it should be realized that current tests are still somewhat far from being adequate to investigate hemostasis and thrombosis. The challenge in the future will be to devise newer tests mimicking more closely what occurs in vivo.