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Limitations of conventional anticoagulant therapy and the promises of non-heparin based conformational activators of antithrombin

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Abstract

An elevated prothrombotic state is a major risk factor for venous thromboembolism, atrial fibrillation and cardiac strokes. The regulation of various coagulation cascade proteases plays an important role in determining a prothrombotic state. Clinically used anticoagulants are inhibitor of enzymes that are involved in the coagulation pathway, primarily thrombin and factor Xa. The conformational activation of antithrombin by heparin is a critical step in the inhibition of factor Xa by antithrombin. Despite heparin being the most potent physiological activator which enhances the otherwise very lethargic antithrombin inhibition of factor Xa by approximately 1,000-fold, the conventional heparin therapy poses serious complications because of heparin’s polyanionic nature and its cross-reactivity. A number of attempts have been carried out in designing alternative non-heparin based conformational activators of antithrombin for factor Xa inhibition. Studies have demonstrated appreciable activation of antithrombin by small organic molecules, but not much is known about the specificity and effects of these molecules on structure and stability. It is assumed that these activators of antithrombin perform their function by binding to heparin binding site. A recently identified cavity which links the heparin binding site to the strand 2A for antithrombin activation also seems to be an ideal target apart the heparin binding site of antithrombin. There are opportunities in discovering more activators from naturally available organic scaffolds and also for modifying such scaffolds for designing better conformational activators with minimum associated complications. This review summarizes the current literature on the mainstay anticoagulants and non-heparin based antithrombin conformation modulators.

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Abbreviations

ATIII:

Antithrombin

Serpin:

Serine protease inhibitor

RCL:

Reactive center loop

HIT:

Heparin induced thrombocytopenia

LMWH:

Low molecular weight heparin

INR:

International normalized ratio

UFH:

Unfractionated heparin

QTS:

Quercetin 3,7,3′,4′-tetrasulfate

ATS:

Quercetin 3-acetyl-7,3′,4′-trisulfate

aPTT:

Activated partial thromboplastin time

PT:

Prothrombin time

TT:

Thrombin time

PAAs:

Polyacrylic acids

HINT:

Hydropathic interaction technique

ECS:

Epicatechin sulfate

DHP:

Dehydrogenation polymer

CDSO3:

Sulfated dehydropolymer of caffeic acid

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Acknowledgments

The research in the lab is supported by grants from Department of Biotechnology, University Grant Commission and Indian Council of Medical Research, Government of India. QR is supported by CSIR Senior Research Fellowship. PS is supported by a grant from Rajiv Gandhi National Fellowship.

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Authors and Affiliations

  1. Protein Conformation and Enzymology Lab, Department of Biosciences, Jamia Millia Islamia (A Central University), Jamia Nagar, New Delhi, 110025, India

    Qudsia Rashid, Poonam Singh & Mohamad Aman Jairajpuri

  2. Organic Synthesis Lab, Department of Biosciences, Jamia Millia Islamia (A Central University), Jamia Nagar, New Delhi, 110025, India

    Mohammad Abid

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  1. Qudsia Rashid
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  2. Poonam Singh
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Correspondence to Mohamad Aman Jairajpuri.

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Rashid, Q., Singh, P., Abid, M. et al. Limitations of conventional anticoagulant therapy and the promises of non-heparin based conformational activators of antithrombin. J Thromb Thrombolysis 34, 251–259 (2012). https://doi.org/10.1007/s11239-012-0712-z

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