Journal of Thrombosis and Thrombolysis

, Volume 34, Issue 2, pp 251–259

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

  • Qudsia Rashid
  • Poonam Singh
  • Mohammad Abid
  • Mohamad Aman Jairajpuri
Article

DOI: 10.1007/s11239-012-0712-z

Cite this article as:
Rashid, Q., Singh, P., Abid, M. et al. J Thromb Thrombolysis (2012) 34: 251. doi:10.1007/s11239-012-0712-z

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.

Keywords

Serine protease inhibitor Antithrombin Heparin Flavonoids Coagulation 
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

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Qudsia Rashid
    • 1
  • Poonam Singh
    • 1
  • Mohammad Abid
    • 2
  • Mohamad Aman Jairajpuri
    • 1
  1. 1.Protein Conformation and Enzymology Lab, Department of BiosciencesJamia Millia Islamia (A Central University)New DelhiIndia
  2. 2.Organic Synthesis Lab, Department of BiosciencesJamia Millia Islamia (A Central University)New DelhiIndia

Personalised recommendations