Heparin, low-molecular-weight heparins, and heparin pentasaccharide: basic and clinical differentiation.
As a result of advanced technology, dramatic developments in the area of new anticoagulant and antithrombotic drugs appear to have made a profound impact on the use of LMWHs. Furthermore, because porcine mucosal heparin is used for the preparation of these agents, it is likely that alternative drugs with comparable pharmacologic and clinical efficacy are sought. Antithrombin drugs such as argatroban and hirudin are already approved for alternative management of heparin-compromised patients. Their efficacy in other indications is less superior. The development of specific anti-Xa drugs is slow. Although these agents may inhibit factor Xa and thrombin generation, none of them are capable of mimicking the polytherapeutic effects of LMWHs and thus can only be given in drug combinations. Synthetic and recombinant protein-derived anti-tissue factor agents have also been developed. These drugs only inhibit the tissue factor-mediated process and are limited in their therapeutic spectrum. Plasma-derived and recombinant serine protease inhibitors (serpins) are also available for the management of thrombotic and inflammatory disorders, but these agents cannot be given subcutaneously. Furthermore, because they are proteins, antibodies to these agents are generated. Nucleic acid derivatives (natural and synthetic aptomers) are developed for intravenous administration, but they are relatively weak antithrombotic agents. Dermatans, heparans, and chondroitin sulfates represent nonheparin GAGs, and, in mono-compositional and polycompositional form, these drugs are mainly used for the intravenous management of DVT prophylaxis. They can be given to patients who are heparin compromised. Synthetic heparinomimetics include heparin consensus-binding oligosaccharides and synthetic oligosaccharides with non-serpin affinity. In addition, binding oligosaccharides are conjugated with antithrombin agents to mimic the anti-Xa/anti-IIa activities of heparin. Biotechnology using bacterial and yeast cultures, aqua cultures for marine products, and plant carbohydrates have been the focus of developing heparin analogues. Development of these agents is in the early phase; however, it is likely that this approach may provide a reasonable alternative to LMWHs. Despite these developments, it is unlikely that any of these drugs will have a profound impact on the use of LMWHs in the near future. Unfractionated heparin and LMWHs collectively represent an important group of polypharmacologic drugs without which the management of thrombosis and vascular disorders would not be possible. The continual development of LMWHs in expanded indications did not comprise the use of unfractionated heparin in surgical and interventional cardiovascular indications. Ever since their introduction in the 1980s, the use of LMWHs has continually increased. This is primarily because of expanded indications and growing awareness among the clinicians. It is likely that once an antidote is developed and additional information is available on the mechanism of action of LMWHs, these drugs may gradualty be used for surgery patients. Despite these developments, it is likely that unfractionated heparin will continue to be used for specific indications. Drug combinations with heparins may necessitate dose adjustments, but it is unclear whether unilateral reduction of heparins will be optimal. The coming years will provide useful clinical and applied data on the improved use of unfractionated heparin. LMWHs, and pentasaccharide in the management of thrombotic and cardiovascular disorders. In addition, use of these drugs will be extended to many conditions, including cancer, inflammation, sepsis, and autoimmune diseases. Polytherapeutic approaches emphasizing LMWHs as primary and secondary drugs will also have an impact on the management of thrombotic and nonthrombotic disorders. Ultra-LMWHs and synthetic heparinomimetics, such as fondaparinux, that exhibit a narrow pharmacologic spectrum will only be useful in specific indications and in combination with other drugs.
Hoppensteadt
Debra
D
Hemostasis and Thrombosis Research Laboratories, Department of Pathology and Pharmacology, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA. dhoppen.lumc.edu
Walenga
Jeanine M
JM
Fareed
Jawed
J
Bick
Rodger L
RL
D005343:Fibrinolytic Agents / Q000737:chemistry / Q000627:therapeutic use*; D006493:Heparin / Q000737:chemistry / Q000627:therapeutic use*; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D009844:Oligosaccharides / Q000737:chemistry / Q000627:therapeutic use*; D013927:Thrombosis / Q000188:drug therapy*
D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D009844:Oligosaccharides; C049714:IC 831423; D006493:Heparin