Dr Abdul Mannan FRCPath FCPS

Blood 🩸 Doctor

From Heparin Discovery to Synthetic Innovation

Fondaparinux represents a significant milestone in anticoagulant therapy, emerging from decades of research into heparin and its derivatives. This document explores the scientific journey that led to its development, the key researchers involved, and its impact on modern medicine.

The drug’s origins trace back to fundamental discoveries about heparin and antithrombin interactions that began in the early 20th century. The foundation for fondaparinux development was laid in 1916 when Jay McLean, a medical student at Johns Hopkins University, discovered heparin while studying the putative prothrombotic properties of dog liver and heart extracts. However, the mechanism by which heparin exerted its anticoagulant effects remained unclear for decades.

A critical breakthrough came in 1932 when scientists demonstrated that heparin requires a plasma factor, now known as antithrombin (AT), for its anticoagulant action. Understanding the Antithrombin-Heparin Interaction: The 1970s marked a pivotal period in heparin research when scientists from Harvard University and the University of Uppsala explained the mechanism of interaction between heparin and antithrombin. This work established that heparin accelerates the antithrombin-mediated inhibition of coagulation enzymes by approximately 1000-fold. The discovery revealed that antithrombin is a serine protease inhibitor that primarily antagonizes thrombin and Factor Xa, two pivotal components within the coagulation cascade. Identification of the Pentasaccharide Binding Domain: A major breakthrough occurred in the early 1980s with the discovery that only a specific pentasaccharide sequence within heparin was responsible for high-affinity binding to antithrombin. This discovery was particularly significant because it demonstrated that a characteristic pentasaccharide domain in certain heparin chains activated the serine protease inhibitor antithrombin III, which inhibits thrombin and Factor Xa in the coagulation cascade. The critical period from 1976 to 1983 proved instrumental in understanding heparin’s antithrombin binding site. Research groups discovered that only a fraction of heparin molecules were capable of binding with high affinity to antithrombin, and this fraction essentially accounted for the anticoagulant activity of the unfractionated material. Through selective, partial depolymerization of heparin and fractionation on immobilized antithrombin columns, researchers isolated the smallest high-affinity molecules and subjected them to structural analysis. Building on the discovery of Lindahl and associates, who had isolated heparin fragments with high affinity for AT, Choay and colleagues demonstrated that the minimum heparin fragment necessary for high-affinity binding to antithrombin consisted of a pentasaccharide. Choay and associates then isolated this high-affinity pentasaccharide and demonstrated that it formed an equimolar complex with antithrombin and enhanced AT-mediated inhibition of Factor Xa. Chemical Synthesis and Development: The first synthetic pentasaccharide was reported in 1987 when Maurice Petitou at Institut Choay in Paris, working with collaborators at Laboratoire de Biochimie Structurale in Orléans, France, and Istituto di Chimica e Biochimica “G. Ronzoni” in Milan, Italy, described the synthesis of a methyl α-pentoside with high affinity for antithrombin III. This achievement represented the culmination of years of structure-function studies that revealed the pentasaccharide sequence comprised a binding site for antithrombin constituted by five sugar units with an internal unique 3-O-sulfated glucosamine unit, in addition to sugar residues and sulfate groups present elsewhere in the polysaccharide. The synthetic pentasaccharide, initially designated as SR90107A/Org31540, was characterized as a synthetic and selective Factor Xa inhibitor and became the first of a new class of antithrombotic drugs. This compound was developed through a cooperative effort between Sanofi-Synthélabo and Organon, ultimately becoming fondaparinux sodium, marketed under the trade name Arixtra. Structural Characteristics: Fondaparinux is a synthetic pentasaccharide that mimics the antithrombin-binding site of heparin. Apart from the O-methyl group at the reducing end of the molecule, the identity and sequence of the five monomeric sugar units contained in fondaparinux is identical to a sequence of five monomeric sugar units that can be isolated after either chemical or enzymatic cleavage of the polymeric glycosaminoglycans heparin and heparan sulfate. The molecule exists in two forms: a neutral polyacid called heparin pentasaccharide that includes sulfonic, oxysulfonic, and carboxylic acids, and the decasodium salt of those acids, with fondaparinux being the preferred salt form due to its superior bioavailability. Clinical Development and Approval: The clinical development of fondaparinux progressed through extensive phase II and III trials. Phase IIb clinical studies identified a fixed dose of 2.5 mg once daily for prophylaxis of venous thrombosis without monitoring. Four phase III studies involving more than 7,000 patients demonstrated a combined 55% relative risk reduction of venous thromboembolic events in orthopedic surgery patients compared to the low molecular weight heparin enoxaparin. Fondaparinux received approval from the US FDA and the European CPMP for prophylaxis of venous thrombosis after orthopedic surgery, with marketing beginning in Spring 2002. The drug was marketed as Arixtra by Sanofi-Synthélabo and Organon, representing a significant advancement in anticoagulant therapy by offering the first synthetic, selective Factor Xa inhibitor distinct from heparin and low molecular weight heparins. Significance and Innovation The development of fondaparinux marked a paradigm shift in anticoagulant therapy. In 2005, researchers described fondaparinux as the first of a class of antithrombotic agents distinct from heparin and its low molecular weight derivatives. The synthetic compound mimics the site of heparin that binds to antithrombin but exhibits only Factor Xa inhibitor activity, which maximizes the inhibition of thrombin generation while avoiding some of the side effects associated with traditional heparin therapy. The creation of fondaparinux represents a successful example of rational drug design based on detailed understanding of molecular mechanisms. The achievement demonstrated how fundamental research into glycosaminoglycan biochemistry could be translated into clinically useful therapeutics, paving the way for further development of synthetic anticoagulants with improved safety profiles and more predictable pharmacological properties.

Impact for Muslim Patients:

Fondaparinux represents a significant advancement for Muslim patients requiring anticoagulation therapy. Unlike traditional heparin products, which are often derived from porcine intestinal mucosa and thus raise religious concerns for many Muslims, fondaparinux is completely synthetic. This synthetic pentasaccharide anticoagulant provides an important halal alternative that aligns with Islamic dietary restrictions while delivering effective anticoagulation therapy.

The development of this synthetic anticoagulant addresses a critical need in healthcare for culturally sensitive medications. For Muslim patients who previously faced difficult decisions between their religious obligations and medical necessities, fondaparinux offers a solution that respects their faith while providing the essential therapeutic benefits of anticoagulation.

Additionally, the availability of fondaparinux has improved medication adherence among Muslim patients requiring long-term anticoagulation, as it eliminates religious concerns that might otherwise lead to suboptimal treatment or treatment refusal.

References

Choay, J., Petitou, M., Lormeau, J. C., Sinay, P., Casu, B., & Gatti, G. (1983). Structure-activity relationship in heparin: A synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochemical and Biophysical Research Communications, 116(2), 492-499.

Hirsh, J., O'Donnell, M., & Eikelboom, J. W. (2007). Beyond unfractionated heparin and warfarin: Current and future advances. Circulation, 116(5), 552-560.

Lindahl, U., Bäckström, G., Höök, M., Thunberg, L., Fransson, L. A., & Linker, A. (1979). Structure of the antithrombin-binding site in heparin. Proceedings of the National Academy of Sciences, 76(7), 3198-3202.

McLean, J. (1916). The thromboplastic action of cephalin. American Journal of Physiology, 41, 250-257.

Petitou, M., Duchaussoy, P., Lederman, I., Choay, J., Jacquinet, J. C., Sinaÿ, P., & Torri, G. (1987). Synthesis of heparin fragments: A chemical synthesis of the pentasaccharide O-(2-deoxy-2-sulfamido-6-O-sulfo-α-D-glucopyranosyl)-(1→4)-O-(β-D-glucopyranosyluronic acid)-(1→4)-O-(2-deoxy-2-sulfamido-3,6-di-O-sulfo-α-D-glucopyranosyl)-(1→4)-O-(2-O-sulfo-α-L-idopyranosyluronic acid)-(1→4)-2-deoxy-2-sulfamido-6-O-sulfo-D-glucopyranose decasodium salt, a heparin fragment having high affinity for antithrombin III. Carbohydrate Research, 167, 67-75.

Turpie, A. G., Gallus, A. S., & Hoek, J. A. (2001). A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. New England Journal of Medicine, 344(9), 619-625.

Warkentin, T. E., & Crowther, M. A. (2002). Reversing anticoagulants both old and new. Canadian Journal of Anaesthesia, 49(6), S11-S25.

Key Milestones in Fondaparinux Development