(Chest. 2003;124:364S-370S.)
© 2003
American College of Chest Physicians
New Pentasaccharides for Prophylaxis of Deep Vein Thrombosis*
Pharmacology
Kenneth A. Bauer, MD
* From the Department of Medicine, Harvard Medical School, Hematology Section, VA Boston Healthcare System, and Beth Israel Deaconess Medical Center, Boston, MA.
Correspondence to: Kenneth A. Bauer, MD, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215; e-mail: kbauer{at}bidmc.harvard.edu
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Abstract
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Fondaparinux is the first of a new class of antithrombotic compounds, the synthetic pentasaccharides. By binding rapidly and strongly to antithrombin, its sole physiologic target in plasma, fondaparinux catalyzes specifically the inhibition of factor Xa, which results in effective and linear dose-dependent inhibition of thrombin generation. Fondaparinux does not bind to platelets. Its antithrombotic effect has been demonstrated in several animal models of arterial and venous thrombosis. At equivalent antithrombotic concentrations, fondaparinux induced less bleeding than unfractionated heparin in experimental bleeding models. Furthermore, it did not cross-react with sera from patients with heparin-induced thrombocytopenia. Administered subcutaneously, the absorption of fondaparinux is complete, rapid, and independent of dose. It has a linear pharmacokinetic profile, and its half-life of approximately 17 h allows for once-daily dosing. Fondaparinux is almost completely excreted by the kidneys. Owing to the limited intrasubject and intersubject variability, routine monitoring and dose adjustments should not be required for most patients. Fondaparinux has been approved for use in thromboprophylaxis after major orthopedic surgery, where it has demonstrated its efficacy compared to a low-molecular-weight heparin. Its clinical development in other indications is ongoing.
Key Words: fondaparinux • idraparinux • low-molecular-weight heparin • pentasaccharide • pharmacokinetics • thromboprophylaxis • venous thromboembolism
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Introduction
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Until very recently, pharmacologic prophylaxis of venous thromboembolism was based on three types of anticoagulant: vitamin K antagonists (eg, warfarin), unfractionated heparin, and low-molecular-weight heparin (LMWH). However, despite their use, venous thromboembolism continues to be a major cause of morbidity and mortality.1
For example, in major orthopedic surgery, the incidence of residual total deep vein thrombosis remains substantial, ranging between 19% and 49% with warfarin, 10% and 50% with unfractionated heparin, and 15% and 33% with LMWH.1
In addition, vitamin K antagonists and unfractionated heparin are inconvenient, requiring laboratory monitoring. New antithrombotic agents that are more effective in preventing thrombus formation, do not require laboratory monitoring, and are at least as safe, notably with respect to bleeding risk, are therefore needed.
Breakthroughs in polysaccharide chemistry made possible the synthesis of a new class of antithrombotic compounds, the synthetic oligosaccharides.2
3
Fondaparinux, the first of this new class, is a selective inhibitor of factor Xa and the most advanced in clinical development. Fondaparinux has been approved for use in thromboprophylaxis after major orthopedic surgery, where it has demonstrated its efficacy compared to a widely used LMWH in a number of clinical trials.4
5
6
7
8
9
Its benefit-to-risk ratio also appears promising in other clinical settings, including acute coronary syndromes10
11
12
and treatment of venous thromboembolism.13
This article reviews the mechanism of action of these synthetic oligosaccharides and describes more particularly the main pharmacologic characteristics of fondaparinux.
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The Path to the Design of Synthetic Oligosaccharides
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Coagulation is represented by a series of serine protease zymogens whose successive activation in "cascade fashion" leads to amplified thrombin production (Fig 1
).14
In vivo, this system is activated in response to vessel injury and exposure of the procoagulant tissue factor, which initiates the "extrinsic" pathway of coagulation. Once exposed, tissue factor immediately binds to activated factor VII (factor VIIa), and the tissue factor/VIIa complex activates factor X and factor IX directly to form factor Xa and factor IXa, respectively. Concomitantly, activation of the "intrinsic" pathway through the activation of factors XI augments factor IX activation and the efficient generation of more factor Xa. Factor Xa activates the conversion of factor II (prothrombin) into factor IIa (thrombin), which converts fibrinogen into fibrin. Fibrin threads constitute the matrix of the red clot, which traps circulating RBCs. The coagulation cascade thus leads to clot formation and growth.
The activity of coagulation factors is regulated by a variety of endogenous inhibitors that act by down-regulating thrombin production or neutralizing the enzymatic activity of thrombin. The protein C system, which interacts with the essential cofactors Va and VIIIa,15
and tissue factor pathway inhibitor, which inhibits extrinsic pathway activation,16
are two important inhibitors of coagulation. The heparan sulfate-antithrombin system is also an important physiologic mechanism for controlling the level of thrombin production.17
This system includes the serine protease inhibitor antithrombin (previously called antithrombin III [ATIII]) and molecules of heparan sulfate associated with the vascular endothelium. ATIII is normally present in a stable conformation with limited activity. The binding of ATIII to heparan sulfates leads to a conformational change in the serine protease inhibitor and a substantial enhancement of its basal inhibitory activity, notably toward factors Xa, IXa, and thrombin. This conformational change is also induced by the binding of ATIII to exogenously administered heparins used for prophylaxis or treatment of thrombosis.
The stimulation of the inhibitory reaction by heparin depends on both the chemical characteristics of heparin and the target protease. A critical pentasaccharide sequence within heparin molecules is required for their binding to ATIII and for promoting the change in conformation of ATIII.18
19
This pentasaccharide sequence is able to fully mediate the inhibitory effect of ATIII toward factor Xa. However, only longer polysaccharide chains of heparins that contain both the pentasaccharide and other critical thrombin-binding sites are able to form the ternary complex required for heparin-enhanced ATIII-mediated thrombin inactivation.20
As a result, unfractionated heparin, which has a molecular size distribution of 5,000 to 30,000 d, with the majority of chains containing 
18 saccharide units, enhances ATIII-mediated inhibition of various serine-proteases, notably factor Xa and thrombin.21
LMWHs, produced by chemical or enzymatic depolymerization of unfractionated heparin to yield molecular species that range from 1,000 to 10,000 d, have a more selective mechanism of action. They exert their anticoagulant effect primarily by inhibiting factor Xa, but also possess antithrombin activity to varying degrees, depending on the particular LMWH preparation.21
In addition, only approximately 30% of the molecules present in heparin preparations contain the ATIII-binding sequence. The remainder is composed of polyanionic chains that may bind nonspecifically, through electrostatic interactions, to a large number of other plasma proteins. This phenomenon possibly accounts for some of the undesirable pharmacokinetic characteristics and side effects of treatment by heparins.21
Progress in chemical synthesis has permitted the design and production of well-defined oligosaccharides constituting more potent, more selective, and consequently safer drugs.2
3
22
23
24
25
26
27
28
Their target and pharmacologic properties may be tailored by varying specific characteristics such as length or charge. For example, fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa.2
Idraparinux is another pentasaccharide selectively inhibiting factor Xa, with a longer half-life allowing once-weekly subcutaneous administration.22
Further oligosaccharides, inhibiting other coagulation factors or with different pharmacokinetic properties, have also been synthesized.22
23
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25
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27
28
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Fondaparinux, a Synthetic Modified Pentasaccharide
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The structure of fondaparinux was modeled on the pentasaccharide sequence in heparin responsible for binding to ATIII and enhancing its inhibitory activity.2
However, chemical modifications introduced into the pentasaccharide molecule (eg, a methyl group stabilizing the anomeric end and avoiding nonspecific binding to plasma proteins) render fondaparinux structurally distinct from its native counterpart and functionally more potent because of its higher affinity for ATIII.29
As shown in Figure 2
, fondaparinux is a single chemical entity (1,728 d) made up of three D-glucosamine units separated by one D-glucuronic acid unit and one L-iduronic acid unit, and bearing several sulfonate groups in key positions.
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Figure 2.. Structural formula of fondaparinux sodium. Fondaparinux is composed of three D-glucosamine units separated by one D-glucuronic acid unit and one L-iduronic acid unit, and bears several sulfonate groups in key positions.
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Mechanism of Action of Fondaparinux
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Fondaparinux was designed specifically to bind strongly (dissociation constant, Kd = 40 nM, approximately) and exclusively to its sole physiologic target in the plasma, ATIII.30
In plasma, 94% of fondaparinux is bound to plasma ATIII, and there is no detectable binding to albumin or other plasma proteins as 
1-acid glycoprotein.31
Each molecule of fondaparinux binds to one molecule of ATIII at a specific site and with very high affinity (Fig 3
). The binding is rapid, noncovalent, and reversible. It induces a critical conformational change in ATIII, exposing a loop containing an arginine residue that binds factor Xa. Exposure of the arginine-containing loop greatly increases the affinity of ATIII for factor Xa, potentiating the natural inhibitory effect of ATIII against factor Xa by a factor of approximately 300.2
19
30
Once ATIII binds to factor Xa, a further conformational change releases fondaparinux unchanged from its binding site. Once fondaparinux is released, it can catalyze the binding of further ATIII molecules to factor Xa. Each molecule of fondaparinux can therefore bind consecutively to several molecules of ATIII. The ATIII conformational change is permanent once the covalent complex with factor Xa has been formed, and the enzyme-inhibitor complex is then cleared from the circulation. ATIII acts as a buffer for the excess fondaparinux; once there is no free ATIII to which it can bind, the anticoagulant effect plateaus.32
In human volunteer studies,33
excess fondaparinux was eliminated in the urine.
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Figure 3.. Mechanism of action of fondaparinux. Factor Xa is located at the intersection of the intrinsic and extrinsic pathways. 1: Fondaparinux binds to ATIII. 2: ATIII undergoes a conformational change after binding to fondaparinux. 3: Bound to fondaparinux, ATIII selectively and rapidly inhibits factor Xa. By inhibiting factor Xa, thrombin generation and fibrin formation are blocked. 4: Fondaparinux is released to act on other molecules of ATIII.
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Fondaparinux is a selective inhibitor of factor Xa, devoid of nonspecific interactions.28
30
The rationale for designing specific factor Xa inhibitors was based on the fact that factor Xa is positioned at the start of the common pathway of the extrinsic and intrinsic coagulation systems, and therefore plays a central role in thrombin generation (Fig 1)
. Furthermore, it was hypothesized that, as the amount of serine-protease is amplified at each step of the coagulation cascade, anticoagulants that target coagulation factors located high up in the cascade such as factor Xa may be more effective than those directly targeting thrombin. For example, it has been estimated that the inhibition of one factor Xa molecule prevents the generation of about 50 molecules of thrombin.34
Finally, experimental and clinical data indicated that the antithrombotic effect of heparins could be mediated by their anti-factor Xa inhibitory effect alone.30
35
Although fondaparinux has no direct activity against thrombin (or other coagulation factors), inhibition of factor Xa results in effective and linear dose-dependent inhibition of thrombin generation, whether triggered by the extrinsic or intrinsic pathway.36
37
38
Fondaparinux also prolongs the lag time of thrombin generation in a dose-dependent manner. Moreover, in contrast to heparins, and probably due to its lack of sensitivity to inactivation by platelet-released heparin-neutralizing proteins such as platelet factor 4, fondaparinux inhibits thrombin formation in the presence of platelets.36
Fondaparinux was also shown to inhibit clot-bound factor Xa as well as a direct inhibitor of factor Xa, which does not require ATIII for exerting its effect, but is unable to effectively inhibit factor Xa within the assembled prothrombinase complex.39
In contrast to direct thrombin inhibitors, fondaparinux does not inhibit thrombin activity, allowing traces of thrombin to escape neutralization and thereby facilitate hemostasis. It is therefore possible that selective factor Xa inhibitors may be safer, with respect to bleeding risk, than direct thrombin inhibitors. This original mode of action (pure anti-factor Xa activity) has been acknowledged by health authorities who did not categorize fondaparinux in the class of "heparins" but in the class of "other antithrombotic agents."
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Pharmacodynamics of Fondaparinux
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The effect of therapeutic doses of fondaparinux on routine hemostasis tests, including activated partial thromboplastin time, prothrombin time, activated clotting time, and bleeding time, is very limited.30
35
When necessary, fondaparinux may be assayed in plasma using a specific anti-factor Xa chromogenic method. This assay is different from that used for heparins. Only fondaparinux, and not the international standards of heparin or LMWH, may be used to calibrate this assay. Accordingly, whereas heparin dosages are expressed in anti-Xa units, dosages of fondaparinux, a pure compound, are expressed in milligrams.
Unlike unfractionated heparin and, to a lesser extent, LMWH, fondaparinux does not bind to platelets and has no effect on platelet function; consequently, its administration may result in a lower risk of bleeding and heparin-induced thrombocytopenia.30
35
Moreover, fondaparinux (like idraparinux) did not cross-react with serum samples from patients with heparin-induced thrombocytopenia.40
41
In another study,42
using serum samples of patients with heparin-induced thrombocytopenia containing anti-platelet factor 4/heparin antibodies, fondaparinux did not enhance antibody binding to platelet factor 4, regardless of its concentration. To my knowledge, no immunoallergic thrombocytopenia has been reported in clinical studies with fondaparinux.
The antithrombotic effect of fondaparinux has been extensively studied in several animal models of venous thrombosis.30
35
Overall, fondaparinux was active against not only thrombus formation but also thrombus growth. The antithrombotic effect of fondaparinux was dose dependent, and it was closely correlated with the onset and duration of its ex vivo inhibitory effect on factor Xa. Fondaparinux was also a potent antithrombotic agent in arteriovenous shunt models in which thrombi are composed of RBCs, fibrin strands, and a large number of platelets, suggesting that it may be an effective treatment in arterial thrombosis. In addition, although fondaparinux does not in itself possess any thrombolytic activity, it was able to enhance clot lysis induced by thrombolytic agents, suggesting that it could be a valuable adjunctive antithrombotic therapy during thrombolysis in occluded vessels.
At equivalent antithrombotic concentrations, fondaparinux induced less bleeding than unfractionated heparin in experimental bleeding models.30
35
Protamine sulfate does not inhibit the anticoagulant activity of fondaparinux.35
A recent study43
performed in healthy volunteers suggests that recombinant activated factor VII may be an effective and safe candidate to overcome the anticoagulant effect of fondaparinux.
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Pharmacokinetics of Fondaparinux
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Fondaparinux has a linear pharmacokinetic profile (Table 1
).33
44
Administered subcutaneously, the absorption of fondaparinux is complete, rapid, and independent of the dose. Its distribution volume is close to that of plasma. Fondaparinux reaches a maximum concentration within 1.7 h of dosing. Its half-life of approximately 17 h is independent of the dose and allows for once-daily dosing. There is no evidence that fondaparinux is metabolized. Fondaparinux is almost completely excreted by the kidneys as the unchanged compound, and plasma clearance of fondaparinux is therefore delayed in patients with moderate or severe renal insufficiency. The intrasubject and intersubject variability is very limited, suggesting that routine monitoring and dose adjustments should not be required for the majority of the population. These results contrast with those obtained with unfractionated heparin which, by binding, nonspecifically, via electrostatic interactions, to a large number of other plasma proteins, have unpredictable pharmacokinetics.21
Importantly, fondaparinux did not undergo placental transfer in vitro at plasma concentrations corresponding to therapeutic levels.45
No interactions were observed between fondaparinux and other drugs, including warfarin, aspirin, piroxicam, a nonsteroidal anti-inflammatory drug, and digoxin.46
47
48
These results are consistent with the fact that, in vitro, fondaparinux does not inhibit the oxidative metabolism of seven isoform-selective cytochrome P450 substrates commonly implicated in the metabolism of drugs.49
They are also consistent with the absence of binding of fondaparinux to plasma proteins other than ATIII,31
in particular those frequently involved in drug binding.
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Contribution of Fondaparinux Relative to Conventional Anticoagulants
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Table 2
summarizes the main advantages of fondaparinux as compared to vitamin K antagonists, unfractionated heparin, and LMWH. The selective action of fondaparinux toward factor Xa contrasts with the action of heparins and vitamin K antagonists, which act on a number of coagulation factors. Heparins act notably on factors IIa and Xa, but also on factors IXa, XIa, and XIIa; vitamin K antagonists impair the synthesis of biologically active procoagulant (coagulation factors II, VII, IX, and X) and anticoagulant (proteins C and S) proteins. Overall, as compared to heparins, fondaparinux is a homogeneous molecule and its chemical synthesis eliminates the theoretical risk of pathogen contamination and assures batch-to-batch consistency. In plasma, it binds only to ATIII and, consequently, its pharmacokinetics are very predictable with little intersubject variability. Its administration requires once-daily subcutaneous injection with no monitoring of coagulation parameters. In addition, in contrast to heparins, fondaparinux does not bind to platelet factor 4 and does not cross-react with antibodies involved in heparin-induced thrombocytopenia. In contrast to vitamin K antagonists, fondaparinux has a fast onset of action. Finally, its therapeutic response is not subject to drug interactions and change in dietary intake, in contrast to vitamin K antagonists.
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Conclusion
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Progress in oligosaccharide chemistry has allowed the design and synthesis of well-defined oligosaccharides. First, these synthetic oligosaccharides represent unique tools for defining structure activity relationships related to ATIII function. Second, some of them may be developed as antithrombotic drugs. Fondaparinux is the first of this new class. Idraparinux is another pentasaccharide currently in clinical development. Other compounds comprising this pentasaccharide sequence prolonged by saccharide chains of various lengths and charges are in preclinical development. Results obtained with fondaparinux and promising data shown with idraparinux indicate that synthetic oligosaccharides may have superior benefit-to-risk ratios relative to conventional therapies for preventing venous thromboembolism. Furthermore, by offering improved pharmacokinetics, they may facilitate the treatment of patients at risk of thrombosis.
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Footnotes
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Dr. Bauer served as consultant to Sanofi-Synthelabo and NV Organon, and has received an honorarium from the American College of Chest Physicians for the preparation of this article.
Abbreviations: ATIII = antithrombin III; LMWH = low-molecular-weight heparin
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TOP
Abstract
Introduction
