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  • Review Article
  • Published:

Novel drug development opportunities for heparin

Key Points

  • Heparin is a glycosaminoglycan that has long been used clinically as an anticoagulant. However, evidence indicating that this complex molecule possesses therapeutic potential in various unrelated settings continues to accumulate.

  • As an endogenous molecule, heparin is synthesized exclusively by mast cells, and is associated with allergy and inflammation. It is thought that heparin, which is released from these cells along with mediators such as histamine, might be involved in limiting the inflammatory response.

  • The closely related molecule heparan sulphate, which is expressed on the surfaces of mammalian cells and is an important component of extracellular matrices, is now known to regulate a wide range of biological processes through its ability to interact with an array of proteins, many of which are involved in inflammation, tumour growth and tumour cell metastasis.

  • Furthermore, the endoglycosidase heparanase, which digests heparan sulphate, is released by inflammatory and tumour cells and is implicated in the transport of these cells out of blood vessels and into tissue, as well as in tumour growth and angiogenesis.

  • Heparin therapy has been reported to confer benefit in human inflammatory disease and in cancer. The mechanisms by which heparin has an effect in these situations is not entirely understood, but is increasingly thought to involve interference with heparan sulphatea–protein binding interactions and inhibition of heparan digestion by heparanase.

  • Importantly, many of the effects of heparin in inflammatory and malignant disease and models thereof are independent of the well-characterized anticoagulant nature of the molecule, which indicates that isolation of specific activities of unfractionated heparin could yield novel therapeutics that do not affect haemostasis.

  • Given that the structural features of heparin that are responsible for its anticoagulant activity have long been understood and that, aside from the clotting cascade, the specifics of individual protein interactions with glycosaminoglycans are rapidly being determined, such novel therapeutic approaches might be a possibility in the not-too-distant future.

Abstract

The glycosaminoglycan heparin has been used in the clinic as an anticoagulant for more than 50 years. A fully characterized sequence in native heparin is known to be responsible for this activity. However, heparin is a complex polysaccharide, which has an array of properties that are unrelated to its anticoagulant activity. Recent research has provided us with an increased understanding of the specific structural requirements for the various actions of heparin, indicating that it might be possible to create 'tailor-made' sequences based on the heparin template to isolate specific therapeutic activities. This research should provide the basis for novel drug treatments for a range of diseases, including cancer and various inflammatory diseases.

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Figure 1: Similarities and differences between heparan sulphate and heparin.
Figure 2: Positive and negative effects of heparin anticoagulant therapy.
Figure 3: Possible sites of action for heparin in inhibition of cell extravasation.

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DATABASES

LocusLink

antithrombin

factor IXa

factor Xa

factor XIa

factor XIIa

fibrinogen

fibroblast growth factor 2

heparanase 1

heparanase 2

MAC1

PECAM1

PF4

L-selectin

P-selectin

thrombin

vWF

Medscape DrugInfo

pentosan polysuphate

FURTHER INFORMATION

fibrinogen and fibrin

glycosaminoglycan

thrombin

Glossary

MAST CELL

A type of leukocyte that has large secretory granules that contain histamine and various protein mediators.

FIBRINOPEPTIDE

The soluble plasma protein fibrinogen is cleaved by thrombin to release two peptides (fibrinopeptides A and B), thereby unmasking fibrin polymerization sites.

ZYMOGEN

A proenzyme (in this case) of the clotting cascade. Requires enzymatic activation to exert its effects.

VENOUS THROMBOEMBOLISM

The detachment and movement of a blood clot from, for example, a deep vein of the leg to another site, such as the pulmonary circulation.

PARENTERAL

The administration of a drug or substance other than through the gastrointestinal tract. Refers, in particular, to administration by injection.

PATENCY

Not being obstructed. In the case of a blood vessel, by blood clots or adherent cells.

ROLLING

The initial interaction between a leukocyte and the endothelium. Loose intercellular tethering results in the leukocyte rolling along the endothelium in the direction of blood flow.

TRANSMIGRATION

Adherent leukocytes are required to traverse the endothelium before they can migrate further, through the extracellular matrix, to the site of tissue inflammation.

TRIGGERING

The activation of a rolling leukocyte. Results in upregulation of the adhesion molecules that are required for firm adhesion.

ADHESION

A strong adhesive interaction is formed between a leukocyte and the endothelium, which results in the arrest of a previously rolling cell.

DIAPEDESIS

The process of a cell migrating across the endothelium out of a blood vessel.

EOSINOPHIL

A blood granulocyte that has a physiological role in the destruction of parasites. Eosinophils are strongly implicated in allergic inflammation, and are able to release an array of tissue-destructive mediators.

EXTRAVASATION

Movement of anything — for example, blood cells or plasma — out of a blood vessel.

HIGH ENDOTHELIAL CELL

An endothelial cell that lines specialized blood vessels (high endothelial venules) of lymphoid tissue.

ANGIOGENESIS

The growth of new blood vessels. For example, in pathology, the generation of a blood supply to a tumour.

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Lever, R., Page, C. Novel drug development opportunities for heparin. Nat Rev Drug Discov 1, 140–148 (2002). https://doi.org/10.1038/nrd724

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