Lost in (Clinical) Translation: Recent Advances in Heparin Neutralization and Monitoring

Abstract

The heparin family, which includes unfractionated heparin, low-molecular heparin and fondaparinux, is a class of drugs clinically used as intravenous blood thinner. To date, issues related to both to the reversal of anticoagulation and the blood level determination of the anticoagulant at the point-of-care remain: while the only U.S. Food and Drug Administration (FDA) approved antidote for heparin displays serious efficacy and safety drawbacks, the current assays for heparin monitoring are indirect measurements subject to their own limitations and variations. Herein, we provide an update on the numerous recent chemical approaches to tackle these issues, from which it is clear that some new antidotes and sensors for heparin certainly have the potential to exceed current clinical standards. This review aims to review a field that requires close collaborations between physicians, biologists and chemists in order to foster advances toward clinical translation. Context and challengesHeparin, which belongs to the family of glycosaminoglycans (GAGs), is a linear sulfated polysaccharide and consists of repeating disaccharide subunits of α-1,4 linked uronic acid and D-glucosamine (Figure 1). As a consequence, heparin displays the highest density of negative charges among biomacromolecules. This polyanion is widely used as an intravenous anticoagulant due to its ability to accelerate the rate at which antithrombin (AT) inhibits serine proteases within the blood coagulation cascade, most notably factor Xa and thrombin. [1][2][3][4] Polymers of various lengths such as unfractionated heparin (UFH, Mw ~ 15 kDa), low-molecular-weight heparins (LMWHs, Mw = 3.6-6.5 kDa), and the synthetic pentasaccharide fondaparinux (Mw = 1.7 kDa) are routinely delivered to patients. While UFH is used during acute thrombotic events or to maintain blood fluidity during procedures requiring extracorporeal circulation (i.e., cardio-pulmonary bypass or hemodialysis), 5,6 LMWHs and fondaparinux are prescribed to treat and/or prevent deep vein thrombosis and pulmonary embolism. 7,8 With an estimated one billion doses of heparin produced every year, heparin's market is rapidly growing, driven by the ageing of populations and the increasing incidence of cardiovascular diseases. 9 KeywordsAnticoagulants: commonly known as blood thinners, they are chemical substances that retard or inhibit the coagulation of the blood.

Porous Polymers as Universal Reversal Agents for Heparin Anticoagulants through an Inclusion–Sequestration Mechanism

“…[ 4,10,11 ] This neutralization is fully realized through multivalent electrostatic attraction between its positively charged guanidinium groups and the negatively charged sulfate and carboxylate groups of heparin. [ 11 ] However, protamine only partially neutralizes LMWHs, [ 12 ] with a maximal efficiency of ≈60%, in case of accidental overdose or serious bleeding caused by LMWHs, thereby increasing the risks of bleeding and limit their use for the treatment of thrombotic events. [ 13 ] Moreover, protamine has no neutralization activity against fondaparinux.…”

A Turn‐On Sensor for Highly Sensitive and Selective Detect Heparin in Human Serum Albumin

“…[3] At present, Hep has been widely employed as both prophylactic and therapeutic agents in clinics, especially as an anticoagulant in thromboembolic diseases, myocardial infarction, DIC hemodialysis and cardiopulmonary bypass, etc. [4][5][6] As a natural anticoagulant substance in animals, heparin can not only promote the secretion of tissue factor pathway inhibitor from vascular endothelium to reduce coagulation factors, but also combine with antithrombin to greatly enhance itself effect. For this reason, an overdose of Hep will have a tendency to cause thrombocytopenia, bleeding, and other side effects in clinics.…”

“…Hep is necessary in regulating various pathological and physiological processes, such as immune defense, blood coagulation, lipid transport and metabolism, and cell growth and differentiation [3] . At present, Hep has been widely employed as both prophylactic and therapeutic agents in clinics, especially as an anticoagulant in thromboembolic diseases, myocardial infarction, DIC hemodialysis and cardiopulmonary bypass, etc [4–6] . As a natural anticoagulant substance in animals, heparin can not only promote the secretion of tissue factor pathway inhibitor from vascular endothelium to reduce coagulation factors, but also combine with antithrombin to greatly enhance itself effect.…”

Heparin reversal by an oligoethylene glycol functionalized guanidinocalixarene

“…[5][6][7] Given these issues, there has been a medical need for alternative, safe UFH neutralizers that can specically counteract UFH without causing serious adverse effects. 8 Discovering and developing new heparin neutralizers has been a popular area of research. 8,9 During the past two decades, a variety of different UFH neutralizers including small molecules, 10 cationic polymers (e.g.…”

“…8 Discovering and developing new heparin neutralizers has been a popular area of research. 8,9 During the past two decades, a variety of different UFH neutralizers including small molecules, 10 cationic polymers (e.g. polybrene), [11][12][13][14] peptides, 11,15 and nanoparticles 16,17 have been designed and evaluated in vitro and/or in vivo.…”