How Did We Get Here?: A Historical Review and Critical Analysis of Anticoagulation Therapy Following Mechanical Valve Replacement.

Managing severe valvular heart disease with mechanical valve replacement necessitates lifelong anticoagulation with a vitamin K antagonist. Optimal anticoagulation intensity for patients with mechanical valves remains uncertain; current recommendations are inconsistent across guideline bodies and largely based on expert opinion. In this review, we outline the history of anticoagulation therapy in patients with mechanical heart valves and critically evaluate current antithrombotic guidelines for these patients. We conclude that randomized trials evaluating optimal anticoagulation intensity in patients with mechanical valves are needed, and that future guidelines must better justify antithrombotic treatment recommendations.

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 New indications, accompanied by longtime consecrated others, dismantle the idea of an outdated medication and create high expectations for the near future.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.

The paradox of the lupus anticoagulant: history and perspectives.

A unique coagulation inhibitor prolonging whole-blood clotting time was described more than 50 years ago in two patients with systemic lupus erythematosus (SLE). The immunoglobulin nature of the inhibitor and its interaction with antiphospholipid antibodies was later demonstrated and the term "lupus anticoagulant (LA)" was coined to describe this laboratory finding. It soon became apparent that LA was a misnomer as it is often found in plasma from patients with clinical conditions other than SLE and is associated with thromboembolic events that may occur in otherwise healthy individuals. Individuals with LA have circulating autoantibodies that inhibits blood coagulation. These are mostly of IgG or IgM class and mainly directed against a phospholipid (PL)-binding plasma protein, ß2-glycoprotein I (ß2GPI). The presence of ß2GPI-dependent LA represents a well-recognized risk factor for venous and arterial thromboembolism, as well as pregnancy loss and morbidity. ß2GPI-dependent LA in the presence of documented previous thromboembolism, or history of pregnancy loss/morbidity, identifies definite anti-PL syndrome. Laboratory diagnosis of LA is thus of particular importance, as it may assign patients with a common event (thrombosis) to a group with a high risk for recurrence, which is a prerequisite for long-term oral antithrombotic treatment.

The historical origins of modern international normalized ratio targets.

Prothrombin time (PT) and its derivative international normalized ratio (INR) are frequently ordered to assess the coagulation system. Plasma transfusion to treat incidentally abnormal PT/INR is a common practice with low biological plausibility and without credible evidence, yet INR targets appear in major clinical guidelines and account for the majority of plasma use at many institutions. In this article, we review the historical origins of INR targets. We recount historical milestones in the development of the PT, discovery of vitamin K antagonists (VKAs), motivation for INR standardization, and justification for INR targets in patients receiving VKA therapy. Next, we summarize evidence for INR testing to assess bleeding risk in patients not on VKA therapy and plasma transfusion for treating mildly abnormal INR to prevent bleeding in these patients. We conclude with a discussion of the parallels in misunderstanding of historic PT and present-day INR testing with lessons from the past that might help rationalize plasma transfusion in the future.

Blood transfusion; additional historical aspects. Part 2. The introduction of chemical anticoagulants; trials of 'Phosphate of soda'.

The pioneers of transfusion medicine around the turn of the 19th into the 20th centuries struggled with the awkward propensity of shed blood to clot. This article, a companion to a previous one (Boulton, 2013, Submitted for publication), describes in more detail how they recognised a potential for chemical anticoagulants which led to the introduction for a short period of sodium phosphate to aid blood transfusion: these cases preceded the introduction of citrate (Mollison, 2000, British Journal of Haematology, 108, 13-18).

[Warfarin - its synthesis and properties in a twenty-year retrospective*]. / Warfarín - jeho syntéza a vlastnosti v dvadsatrocnej retrospektíve*

The review paper deals with some aspects of warfarin history and its use, at the beginning as a rodenticide and later as an anticoagulant. It describes its principal physical-chemical properties and it analyzes schematically the possibilities of its preparation by both selective and non-selective synthesis from coumarin derivatives. A survey of syntheses and its results are tabulated, including the literary references, and the paper is concluded with an evaluation of the prospects of this agent in comparison with alternative anticoagulants and its advantages, disadvantages and prospects.

[Fifty years of clinical use of warfarin]. / Cincuenta años de uso clinico de la warfarina.

Warfarin is the most utilized oral anticoagulant for the long term prophylaxes of thrombosis. Its use has been increased as new clinical conditions, capable of leading to thrombosis, have been detected. Due to the special characteristics of warfarin, such as the variability of doses for each individual, the narrow margin between adequate and inadequate doses, interaction with multiple pharmaceutical products, interference of its action by vitamin K present in the diet and the possibility of hemorrhagic complications or thrombotic recurrence, this drug requires a very careful dosage and strict laboratory and clinical monitoring. Despite being in the market for more than de fifty years and its many disadvantages, warfarin has not been substituted for the new oral anticoagulants. In 1999, warfarin was positioned eleventh on the list of the most used medicines in the world.

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.

Fifty years of research on antithrombotic therapy: Achievements and disappointments.

The achievements with antithrombotic therapy over the past 50 years have been monumental and the disappointments relatively few. In this review, we will discuss, chronologically, the major developments of the two recognized classes of antithrombotics - anticoagulants and antiplatelet agents.

The story of the discovery of heparin and warfarin.

Heparin and coumarins have been the mainstay of anticoagulant therapy throughout our working lives. As we stand on the threshold of a new era of anticoagulants it is timely to look back upon their discovery and development. Both have fascinating stories to tell. Jay McLean claimed to have discovered heparin whilst a medical student, although this is disputed. The story of warfarin leads us from a mysterious haemorrhagic disease of cattle to the development of a rat poison which became one of the most commonly prescribed drugs in history. Many people were involved in both stories and we owe them all a debt of gratitude.

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.

Vitamin K antagonist therapy: changes in the treated populations and in management results in Italian anticoagulation clinics compared with those recorded 20 years ago.

Vitamin K antagonists (VKA) are the most widely used anticoagulants in the world. An appropriate management of treated patients is crucial for their efficacy and safety. The prospective, observational, multicenter, inception-cohort FCSA-START Register, a branch of START Register (NCT02219984) included VKA-treated patients managed by centers of Italian Federation of anticoagulation clinics (AC). Baseline patient characteristics and data during treatment were analyzed and compared with those of ISCOAT study, performed by the Federation and published in 1996/7. 5707 naïve patients [53% males, mean age 73.0 years (28.1% >80 years)], 61.6% treated for atrial fibrillation (AF), and 28.0% for venous thromboembolism were included. During the 8906 patient-years (pt-yrs) of observation, 123 patients had major bleeding (MB) (1.38% pt-yrs; fatal: 0.11% pt-yrs), while non-major clinically relevant bleeds were 144 (1.62% pt-yrs). Bleeding was more frequent in elderly (≥70 years; p = 0.04), and during initial 3-month therapy (p = 0.02). Bleeding rate was 2.5% pt-yrs for temporally related INR results <3.0, increasing to 12.5% for INR ≥ 4.5. Thrombotic events were 47 (0.53% pt-yrs; 4 fatal 0.04% pt-yrs). Compared with ISCOAT-1996/7 results, patients older than 80 y are increased from 8 to 28% (p < 0.01), and those treated for AF are increased from 17 to 61%. The quality of anticoagulation control and incidence of MB are not different. However, thrombotic complications fell drastically from 3.5 to 0.53% pt-yrs (p < 0.01), with lower mortality (p = 0.01). VKA-treated patients monitored in Italian AC have good clinical results, with low bleeding and thrombotic complications rates. Important changes in the treated population and improvement in thrombotic complications are detected compared with the ISCOAT-1996/7 study.

Anticoagulation in Pulmonary Embolism: Update in the Age of Direct Oral Anticoagulants.

The emergence of direct oral anticoagulants (DOACs) represents a major advancement and paradigm shift in the treatment of venous thromboembolism. Currently, dabigatran, rivaroxaban, apixiban, and edoxoban are approved and used routinely for the prevention and treatment of patients with venous thromboembolism. Because each of the DOACs has different doses and dosing regimens, clinicians need to become familiar with their use. This article focuses on the practical considerations of how and when to use the DOACs. It also aims to explore follow-up monitoring, use in special populations, reversal agents, periprocedural management, and how to handle bleeding complications with the DOACs.