Heparin: Applications and Future Prospects

Heparin: Applications and Future Prospects

Heparin: Applications and Future Prospects* Donald Quick, M.D.; and Arthur A Trowbridge, M.D. It is challenging to consider why a drug which has been...

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Heparin: Applications and Future Prospects* Donald Quick, M.D.; and Arthur A Trowbridge, M.D.

It is challenging to consider why a drug which has been in widespread clinical use for over 40 years and has been the subject of thousands of carefully conducted investigations at both the biochemical and clinical levels continues to generate the degree of controversy and intrigue surrounding the drug heparin. In his article 'The New Understanding of the Drug Heparin," (see page 751) DI: Jaques presents strong arguments in support of what he has termed "the new paradigm" of the drug heparin. This paradigm, evolved over a lifetime devoted to the study of heparin, proposes that heparin should be thought of in terms of a group of similar compounds (linear anionic polyelectrolytes) of varying molecular weight, each component possessing different anticoagulant properties. Moreover; these components also possess a variety of other biochemical properties, ranging from immunologic mediation to hormone suppression. Protection from thrombosis, he contends, is provided by heparin's ability to electrostatically protect vessel wall endothelium, the target organ of the drug. He proposes that heparin's anticoagulant and potentially hemorrhagic action is more or less an undesirable property or side effect of the drug and its antithrombotic ability lies in properties other than coagulation inhibition. The author further proposes that an alternative heparin administration technique (ie, intrapulmonary delivery) may possess the pharmacokinetic attributes necessary for the optimum delivery of this agent to its target organ without the concomitant undesirable systemic anticoagulant and hemorrhagic side effects. This article raises several interesting points which deserve comment, including (1) the properties and uses of heparin other than as an anticoagulant, (2) the heterogeneity of heparin' and how this relates to the study of heparin fractions and heparin analogs, and (3) the published work on intrapulmonary delivery as an alternative method of heparin administration. First, many clinicians do not well appreciate heparin smany biochemical properties distinct from its well known anticoagulant abilities. Jaques has elegantly summarized many of these properties in a recent extensive review 1 Heparin, for instance, has been *From the Division of Hematology/Oncology, Scott and White Clinic, Temple, Texas. Reptint requut&: Dr. Trowbridge, Scott and White Clinic, Temple, TemI 76508

shown to exhibit multiple immune-mediatory effects. These actions include stimulation of lymphocytes; inhibition of C' -esterase; antagonization of the action of histamine, bradykinin, and prostaglandin E 1; and attenuation of anaphylaxis. 1-3 There has been, however, a rather limited clinical applicability for these mediating effects of heparin. There are scattered reports of favorable effects on certain autoimmune disorders such as pulmonary alveolar proteinosis, experimental allergic encephalomyelitis, and certain subgroups of migraine.r" However, these claims are disputed by others; for instance, in the case of pulmonary alveolar proteinosis, heparin lavage has been felt by most authorities to be no more effective in this disorder than normal saline lavage." Perhaps one of the reasons for its limited use as an immune mediator (in fact, major immunology texts do not discuss any possible role for heparin) is the reported variability of the drug's effects on these immune processes. For example, findings conflict regarding heparin's effect on polymorphonuclear leukocyte aggregation and degranulization, with reports of both significant inhibitory and stimulatory effects. 7•8 In part, however; these conflicting drug effects may be either dose related, or may be due to the specific type of heparin (source, weight, etc) tested. 7 Such is true of immune-mediated thrombocytopenia, where it has been shown that beef lung heparin initiates immune-associated platelet aggregation at a rate of two to three times that of hog intestine heparin. 9 Similarly, fractions of high molecular weight heparin were found to be more reactive with the platelets than were fractions of low molecular weight. 10 Obviously, further studies defining the exact activities of specific heparin types on these immune processes must precede further clinical studies examining potential beneficial immune-mediation. Heparin possesses further properties which are often not appreciated but have prompted interesting studies. Some of the claims of heparin's activity are apparently overstated, while other drug actions of possible benefit might deserve closer attention. For example, early reports gave indication that heparin might prove effective in gallstone dissolution, though later work did not support this, and further investigation of heparin for this purpose was made obsolete by the favorable reports of the effectiveness of chenodeoxycholate and ursodeoxycholate for this purpose. n.1I On CHEST I 88 I 5 I NOVEMBER. 1885

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the other hand, heparin's proposed usefulness as a modifier of coronary artery disease probably deserves more attention. Heparin has been shown to liberate lipoprotein lipase, lower serum triglycerides, augment the level ofHDL, and favorably affect platelet aggregation in low doses. Studies are incomplete but, in a convincing summary of the drug's potential benefits on the atherogenic processes, Engelberg" concludes that heparins use merits wider application. A second point of discussion are implications expressed by Jaques regarding heparins heterogeneity. As pointed out, there are over 100 different "heparins" in each commercial preparation. Investigation and development of these various heparin fractions are underway. The excitement in this area lies in the potential development of an effective antithrombotic agent which possesses fewer undesirable side effects such as hemorrhage and thrombocytopenia. Heparin fractions with low-molecular weights tend to potentiate inactivation offactor Xa and factor XIIa but seem to show less reactivity with thrombin. I" These lowmolecular weight fractions also exhibit more specific antifactor Xa activity than anticoagulant activity, as measured by the traditional activated partial thromboplastin time. In vivo testing has shown lowmolecular weight heparins to be at least as effective as unfractionated heparin, and early clinical trials indicate that a single daily injection of low-molecular weight heparin is a convenient and apparently effective agent of thrombosis prophylaxis.":" Low-molecular weight heparins also have additional potential advantages. They have less platelet aggregating activity than their higher molecular weight counterparts yet retain some of the desirable properties of high molecular weight fractions, such as their inability to cross the placenta during pregnancy. 10.18 Heparin analogs are now being evaluated to find a drug with effective antithrombotic properties and no significant effect on overall clotting. The semi-synthetic heparin analog (SSHA) was noted by Thomas" to exhibit factor Xa inhibition without significant effect on overall clotting as measured by the APTI: In early clinical trials, this drug was as effective as continued low dose heparin, though more extensive studies are needed before safety and specific indications for use can be determined. Another heparin analog, pentosan polysulphate (SP54), offers similar hopes as an antithrombotic agent. This drug appears to act by a mechanism independent of antithrombin III, probably through potentiation of heparin cofactor II. 19 Again, early clinical trials show favorable results. in Due to its antithrombin-III independent mechanism, SP54 may offer an alternative form of treatment in patients with antithrombin-III deficiency. 21 The final point raised by Jaques is that of intrapulmonary heparin administration. The fact that 711

intrapulmonary heparin exerts a prolonged anticoagulant effect on blood raises further speculation about the true mechanism(s) of the drugs anticoagulation effects. Traditionally, heparin is considered to exert its effect via the activation of its cofactor antithrombin-III (ATIII), although the exact mechanism of heparin-ATIII interaction is still disputed. II It is perhaps less well recognized that heparin may act via a number of other mechanisms to prompt antithrombosis, including (as stated in the article) the drugs electrostatic effect on endothelial tissue lining. The work of Glimelius et al23 showing that heparin combines reversibly with cultured human endothelial cells; Sawyers demonstration of heparins protective effect on traumatized, damaged vessel endothelium; and recent studies in ultra-low dose heparin by Negus" and Hladovee" tend to support Jaques' proposal that heparin in low doses may act preferentially via endothelial cell uptake and redistribution. It is because of this mechanism that Jaques and coworkers propose that intrapulmonary heparin would be an effective alternative route ofheparin delivery. Intrapulmonary administration was first introduced over 20 years ago with initially disappointing results in terms of achieving what was felt to be significant anticoagulant levels. r1 In 1976, Jaques and co-worker~ successfully administered heparin intratracheally into dogs and later, via inhaled neubilizers into human volunteers. A dose of 1,300 units per kg body weight delivered to human subjects over lY2 hours of inhalation resulted in a prolonged state of moderate hypocoagulability for approximately two weeks. In subsequent studies, this method appeared safe and the hypocoagulability induced was easily reversed by repeated protamine adrninistration.P''" Phannacokinetic studies demonstrated a delayed endothelial cell uptake of heparin with slow release back into the plasma after several days. In theory, this delivery method would allow a single administration of heparin during hospitalization and avoid the need for uncomfortable twicea-day subcutaneous injections. In practice, however; clinical trials of intrapulmonary heparin have not been published and its advantages over other routes are uncertain. Intrapulmonary heparin will have to compete in terms of safety, efficacy, and cost effectiveness with other proven and unproven methods of thrombosis prophylaxis such as adjusted-dose heparin, ultralow dose IV heparin, dihydroergotamine-heparin prophylaxis, infusion pumps, and possibly even enteral administration of heparin (eg, via facilitation by CetomacrogollOOO).ss.34-37 Until such trials have been performed, intrapulmonary heparin administration will remain an interesting observation, but an uncertainty in terms of potential therapeutic applicability. We would, with the data available, strongly support DJ: Jaques' "new paradigm." Commercial heparin is in Heparin: AppIIcatIona and Future ProepecIa(QuIck, 7iowbtfdQe)

fact a mixture of complex, functionally multifaceted, individual molecules whose biologic properties are largely unknown. REFERENCES 1 Jaques LB. Heparins-anionic polyelectrolyte drugs. Pharmacol Rev 1980; 31:99-166 2 Ogston D, Murray }, Crawford GPM. Inhibition of the activated Cis subunit of the first component of complement by antithrombin-III in the presence of heparin. Thromb Res 1976; 9:217-22 3 Carr J. The antiinflammatory action of heparin: Heparin as an antagonist to histamine, bradykinin and prostaglandin E 1• Thromb Res 1979; 16:507-16 4 Altose MD. Pulmonary alveolar proteinosis. In: AP Fishman, ed. Pulmonary diseases and disorders. New York: McGraw-Hill Book Company, 1980, p 1341-45 5 Chelmicka-Szorc E, Amason BGW Partial suppression of experimental allergic encephalomyelitis with heparin. Arch Neurol 1972; 27:153-58 6 Thonnard-Newmann E, Neckers LM. Immunity in migraine: the effect of heparin. Ann Allergy 1981; 47:328-32 7 Laghi Pasini F, Pasqui AL, Ceccatelli L, Capecchi PL, Orrico A, DiPerri 1: Heparin inhibition of polymorphonuclear leukocyte activation in vitro. A possible pharmacological approach to granulocyte-mediated vascular damage. Thromb Res 1984; 35: 527-37 8 Cairo MS, Allen J, Higgins C, Baehner RL, Boxer LA. Synergistic effect of heparin and chemotactic factor on polymorphonuclear leukocyte aggregation and degranulation. AJP 1983; 113:67-73 9 Stead RD, Schafer AL, Rosenberg RD, Handin BI, J058 M. Heterogeneity ofheparin lots associated with thrombocytopenia and thromboembolism. Am J Med 1974; 77:185-87 10 Salzman E~ RosenbergRD, Smith MH, LindonJN, Favreau L. Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest 1980; 65:64-73 11 Gardner B. Experiences with the use of intracholedochal heparinized saline for the treatment of retained common duct stones. Ann Surg 1973; 177:240-44 12 Toouli J, Williamson BWA, Gooszen H, Blumgart LH. In vitro dissolution of human gallstones: the efficacy of heparinized solutions. Br J Surg 1979; 66:770-71 13 Engelberg H. Heparin and the atherosclerotic process. Pharmacol Rev 1984; 36:91-110 14 Holmer E, Kurachi K, Soderstrom G. The molecular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and Kallikrein by antithrombin. Biochem J 1981; 193:395400 15 Thomas D~ Merton RE, Lewis WE, Barrowclif£e TW Studies in man and experimental animals of a low molecular weight heparin fraction. Thromb Haemost 1981; 45:214-18 16 Thomas D~ Heparin. Clin Haematoll981; 10:443-58 17 KaIdcar vv. Djazaeri B, Fok}, Fletcher M, Scully MF, Westwick J. Low-molecular-weight heparin and prevention of post-operative deep vein thrombosis. Br Med J 1982; 284:375-79 18 Forestier F, DafIOs F, Capella-Pavlovsky M. Low-molecular-

weight heparin (PK 10169)does not cross the placenta during the second trimester of pregnancy. Study by direct fetal blood sampling under ultrasound. Thromb Res 1984; 34:557-60 19 Scully MF, Kakkar vv. Identification ofbepann cofactor II as the principal plasma cofactor for the antithrombin activity of pentosan polysuImte (SP54). Thromb Res 1984; 36:187-94 20 Fredin HO, Nillius SA, Bergqvist D. Prophylaxis of deep vein thrombosis in patients with fracture of the femoral neck. A prospective comparison between dextran and a sulphated polysaccharide. Acta Orthop Scand 1982; 53:413-17 21 Fischer AM, Dautzenberg MD, Aurousseau MH, Beguin S, Goudemand J, Hemker HC. Comparison between the effect of pentosan polysulfate heparin and antithrombin-III injections in antithrombin-III deficient patients. Thromb Res 1985; 37:

295-307 22 Wessler S, Gitel SN. Heparin: New concepts relevant to clinical use. Blood 197~; 53:525-44 23 Glimelius B, Busch C, Hook M. Binding of heparin on the surface of cultured human endothelial cells. Thromb Res 1978; 12:773-82 24 Sawyer PN, Stanczewski B, Pomerance A, Lucas 'I: Stoner G, Srinivasan S. Utility of anticoagulant drugs in vascular thrombosis: electron microscopic and biophysical study. Surgery 1973; 74:263-75 25 Negus D, Friedgood A, Cox 8J. Ultra-low dose intravenous heparin in the prevention of post-operative deep vein thrombosis. Lancet 1980; 1:891-94 26 Hladovec J. The effect of heparin on endothelial stability. Thromb Res 1984; 35:347-52 27 Wmdsor E, Freeman L. An investigation of routes of administration of heparin other than injection. Am J Med 1964; 37:408-16 28 Kavanagh L~ Jaques LB. A new route of heparin administration-the lung. Arzneim-Forsch Drug Res 1976; 26:389-92 29 Jaques LB, Mahadoo J, Kavanagh LW Intrapulmonary heparin. A new procedure for anticoagulant therapy. Lancet 1976; 2: 1157-61 30 Wright ~ Jaques LB. Heparin via the lung. Can J Surg 1979; 22:317-19 31 Wright C}, Mahadoo J, Jaques LB. Anticoagulant activity and operative blood loss after intrapulmonary heparin. Br J Surg 1979; 66:844-47 32 Wright CJ, Mahadoo J, Jaques LB. Reversal by protamine of the prolonged response to intrapulmonary heparin. Can J Surg 1981; 24:130-32 33 Mahadoo}, Jaques LB. Effects of long-term treatment of mice with intrapulmonary heparin. Arzneim-Forsch Drug Res 1981; 31:976-78 34 Hull R, Hirsh J. Long-term anticoagulant therapy in patients with venous thrombosis. Arch Intern Moo 1983; 143:2061-63 35 Sasabara AA, Diserio FJ, Singer JM. Dihydroergotamineheparin prophylaxis of post-operative deep vein thrombosis. A multicenter 'trial. JAMA 1984; 251(22):2960-66 36 Carson J, Schwartz JS. Implantable and external infusion pumps for the treatment of thromboembolic disease in outpatients. Ann Intern Med 1984; 100:305-06 37 Kidron M, Eldor A, Lichtenberg D, Touitou E, Ziv E, Bar-On H. Enteral administration of heparin. Thromb Res 1979; 16:833-35

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