Expanded Role of Low-Molecular-Weight Heparins in Hematologic and Oncologic Indications

This supplement to Seminars in Thrombosis and Hemostasis contains presentations originally given in December 2001 at a symposium preceding the Congress of the American Society of Hematology. The title of the symposium was “Expanded Role of Low-Molecular-Weight Heparins in Hematologic and Oncologic Indications: Laboratory and Clinical Perspectives.” All contributors to this supplement updated their presentation in the last 6 months, so that the contents present an up-to-date view.

In the first article, Hainer and coworkers review the role of newer anticoagulant drugs and use tinzaparin, a low-molecular-weight heparin (LMWH) as an example. They discuss briefly the production and pharmacokinetics, the methods of assaying the activity in plasma, and the advantages of LMWHs over unfractionated heparin (UFH). In addition, the clinical studies that have so far been conducted with tinzaparin are reviewed.

In the next article, Hull and Pineo discuss in detail the current management of venous thromboembolism. LMWHs have, for all practical purposes, replaced UFH as treatment modality. The advantages of LMWHs far outweigh their potential disadvantages. They are safer, easier to administer, need in most cases no monitoring, and were shown to be at least as effective, if not more so, than UFH. It is difficult to predict whether UFH will, in the long run, survive. If it does, it will be for limited clinical indications.

Mousa describes the relationship between LMWHs and cancer. LMWHs not only are useful for the prevention of thromboembolic diseases in cancer patients (who are in a hypercoagulable state), they also have provided evidence for inhibiting tumor growth and thus increase survival of cancer patients. Also in cancer patients, LMWHs have largely replaced UFH for treatment of thromboembolic complications. Several pathways in tumor growth appear to be modulated by LMWHs. These are extensively reviewed by the author.

Sutor and colleagues discuss the incidence of thromboembolism in children and the management options. In contrast to previous assumptions, thromboses are not rare in children, although they do occur less frequently than in adults. Most thromboses develop in association with central venous access lines, but other risk factors, acquired and congenital, are well recognized. Treatment options for pediatric patients are different from adult guidelines and the largest experience has been gained with UFH and, in rarer instances, with oral anticoagulants. In addition, in the pediatric populations LMWHs are increasingly used, again because of their ease of administration, the lack of need for monitoring, and their greater safety profile.

In the next article, Jeske and Fareed describe the results of an extensive study of tinzaparin in nonhuman primates. Comparisons were made with UFH. In addition to dose-finding by subcutaneous and intravenous routes of administration, the authors also studied the release of tissue factor pathway inhibitor (TFPI) in response to both heparins. The half-life of UFH was shorter than that of tinzaparin upon intravenous application, and the bioavailability of tinzaparin was greater with both routes of administration. Compared with UFH, tinzaparin released significantly more TFPI, again assessed after both routes of administration. The data indicate that tinzaparin has a better pharmacokinetic profile than UFH.

Hoppensteadt and coworkers report on laboratory testing of blood samples obtained from patients who were treated with UFH followed by warfarin, or tinzaparin followed by warfarin, or tinzaparin alone over a long period of time. These samples were tested with the activated partial thromboplastin time (aPTT), chromogenic anti-Xa and anti-IIa assays, and the Heptest. In addition, they measured thrombin/antithrombin (TAT) complexes and TFPI. They observed that the anti-Xa assay and the Heptest are equally useful in monitoring tinzaparin, should this become necessary. They reconfirm that TFPI antigen levels were higher under tinzaparin treatment and suggest that TAT levels could be useful in assessing resolution of the thrombosis.

Next, Walenga and associates report on mechanisms involved in the development of heparin-induced thrombocytopenia (HIT). This is the most serious side effect of UFH and is associated with a high degree of morbidity and even mortality. The nature of the antibody is well established, and so is its effect on the hemostasis system. The authors investigated the effect of these antibodies on endothelial cells, leukocytes, and the inflammatory cascade. Antiheparin antibodies bind directly to endothelial cells of the microvasculature, but require preactivation by platelets or tumor necrosis factor to bind to endothelial cells of the macrovasculature. This binding leads to the release of cytokines, coagulation activators, and adhesion molecules. The antibodies also facilitate the binding of neutrophils and monocytes to platelets, causing a procoagulant condition. They also amplify the inflammatory cascade. These studies demonstrate the complex role that these antibodies play in inducing procoagulant and proinflammatory states.

In the following article, Walenga and coworkers examine the frequency of HIT in relation to the various heparins presently in use. The heparin antibodies form when heparins complex with platelet factor 4. These antibodies are heterogeneous and can cause not only thrombocytopenia, but also severe arterial and venous thromboses. Key factors to their formation are the length of the polysaccharide chain and its overall charge. This explains why HIT is far less frequently encountered when LMWHs are used. Even if they form with LMWHs, they cause less HIT even though they may produce thrombocytopenia. Although HIT is less common with the use of LMWHs, it is advisable not to use LMWHs when antibodies against UFH have been demonstrated.

Messmore and colleagues expertly describe the history of heparin, its clinical development over the last decades, and the problems that lead to the search for alternative anticoagulants. Heparin's history is intimately tied to the discovery and characterization of antithrombin. HIT, the need for monitoring of UFH, and osteoporosis spurred the development of LMWHs as an alternative anticoagulant, and these, in turn, were further degraded into the pentasaccharide that is presently widely studied for its clinical usefulness.

In the last contribution, Fareed and coworkers discuss the differences that exist between the various LMWHs. Each LMWH is a distinct product with a different pharmacological profile. This is reflected in their different ways of manufacture, their anti-Xa/anti-IIa ratio, and their pharmacokinetics, so that no two LMWHs are identical. For this reason, they are not interchangeable. Each LMWH can be expected to have a different clinical efficacy so that clinical data obtained with one LMWH are not applicable to another. Although regulatory agencies and professional societies have all stressed this important fact, the authors point out that present regulations governing the production of generic products are not sufficient when it comes to LMWHs. Unless these regulations are made more stringent, generic LMWHs could turn into a major clinical problem.

Gratitude is expressed to all contributors for their excellent articles, and special thanks go to the guest editors, especially Dr. Hoppensteadt, for assembling this informative supplement.