Skip to main content
PMC home page
CNS Drug Reviews logoLink to CNS Drug Reviews
. 2006 Jun 7;8(1):1–30. doi: 10.1111/j.1527-3458.2002.tb00213.x

Neuroprotective Profile of Enoxaparin, a Low Molecular Weight Heparin, in In Vivo Models of Cerebral Ischemia or Traumatic Brain Injury in Rats: a Review

Jean‐Marie Stutzmann 1,✉, Veronique Mary 1, Florence Wahl 1, Odile Grosjean‐Piot 1, André Uzan 1, Jeremy Pratt 1
PMCID: PMC6741656  PMID: 12070524

ABSTRACT

The development of treatments for acute neurodegenerative diseases (stroke and brain trauma) has focused on (i) re‐establishing blood flow to ischemic areas as quickly as possible (i.e. mainly antithrombotics or thrombolytics for stroke therapy) and (ii) on protecting neurons from cytotoxic events (i.e. neuroprotective therapies such as anti‐excitotoxic or anti‐inflammatory agents for stroke and neurotrauma therapies). This paper reviews the preclinical data for enoxaparin in in vivo models of ischemia and brain trauma in rats. Following a photothrombotic lesion in the rat, enoxaparin significantly reduced edema at 24 h after lesion when the treatment was started up to 18 h after insult. Enoxaparin was also tested after an ischemic insult using the transient middle cerebral artery occlusion (tMCAO) model in the rat. Enoxaparin, 2 × 1.5 mg/kg i.v., significantly reduced the lesion size and improved the neuroscore when the treatment was started up to 5 h after ischemia. Enoxaparin, administered at 5h after insult, reduced cortical lesion size in a dose‐dependent manner. In permanent MCAO, enoxaparin (5 and 24 h after insult) significantly reduced lesion size and improved neuroscore. A slight and reversible elevation of activated partial thromboplastin time (APTT) suggests that enoxaparin is neuroprotective at a non‐hemorrhagic dose. Traumatic brain injury (TBI) is often accompanied by secondary ischemia due in part to edema‐induced compression of blood vessels. When enoxaparin, at 0.5 mg/kg i.v. + 4 × 1 mg/kg s.c., was administered later than 30h after TBI, it significantly reduced edema in hippocampus and parietal cortex. At one week after TBI the lesion size was significantly reduced and the neurological deficit significantly improved in enoxaparin treated animals. Finally, the cognitive impairment was significantly improved by enoxaparin at 48 h to 2 weeks after TBI. The anticoagulant properties of unfractionated heparin and specifically enoxaparin can explain their anti‐ischemic effects in experimental models. Furthermore, unfractionated heparin and specifically enoxaparin, have, in addition to anticoagulant, many other pharmacological effects (i.e. reduction of intracellular Ca2+ release; antioxidant effect; anti‐inflammatory or neurotrophic effects) that could act in synergy to explain the neuroprotective activity of enoxaparin in acute neurodegenerative diseases. Finally, we demonstrated, that in different in vivo models of acute neurodegenerative diseases, enoxaparin reduces brain edema and lesion size and improves motor and cognitive functional recovery with a large therapeutic window of opportunity (compatible with a clinical application). Taking into account these experimental data in models of ischemia and brain trauma, the clinical use of enoxaparin in acute neurodegenerative diseases warrants serious consideration.

Keywords: Enoxaparin, Low molecular weight heparin, Cerebral ischemia, Stroke, Traumatic brain injury, Brain edema, Memory, Neuroprotection

Full Text

The Full Text of this article is available as a PDF (723.7 KB).

References

  • 1. Bannon PG, Mi‐Jurng K, Dean RT, Dawes J. Augmentation of vascular endothelial barrier function by heparin and low molecular weight heparin. Thrombosis and Haemostasis 1995;73:706–712. [PubMed] [Google Scholar]
  • 2. Bara L, Bloch MF, Zitoun D, et al. Comparative effects of enoxaparin and unfractionated heparin in healthy volunteers on prothrombin consumption in whole blood during coagulation, and release of tissue factor pathway inhibitor. Thromb Res 1993;69:443–452. [DOI] [PubMed] [Google Scholar]
  • 3. Bareyre F, Wahl F, McIntosh TK, Stutzmann J‐M. Time course of cerebral edema after traumatic brain injury in rats: effects of riluzole and mannitol. J Neurotrauma 1997;14:839–849. [DOI] [PubMed] [Google Scholar]
  • 4. Bazzoni G, Beltran‐Nunez A, Mascellani G, Bianchini P, Dejana E, Del Maschio A. Effect of heparin, dermatan sulfate, and related oligo‐derivatives on human polymorphonuclear leukocyte functions. J Lab Clin Med 1993;121:268–275. [PubMed] [Google Scholar]
  • 5. Bellander BM, von Holst H, Fredman P and Svensson M. Activation of the complement cascade and increase of clusterin in the brain following cortical contusion in the adult rat. J Neurosurg 1996;85:468–475. [DOI] [PubMed] [Google Scholar]
  • 6. Bendetowicz AV, Kai H, Knebel R, et al. The effect of subcutaneous injection of unfractionated and low molecular weight heparin on thrombin generation in platelet rich plasma — A study in human volunteers. Thrombosis and Haemostasis 1994;72:705–712. [PubMed] [Google Scholar]
  • 7. Berge E, Sandset PM. Heparin in Acute Embolic Stroke Trial (HAEST). Cerebrovasc Dis 1999;S1:127. [Google Scholar]
  • 8. Bevilacqua MP, Nelson RM, Mannori G, Cecconi O. Endothelial‐leukocyte adhesion molecules in human disease. Annu Rev Med 1994;45:361–378. [DOI] [PubMed] [Google Scholar]
  • 9. Biagas KV, Uhl MW, Schiding JK, Nemoto EM, Kochanek PM. Assessment of posttraumatic polymorphonuclear leukocyte accumulation in rat brain using tissue myeloperoxidase assay and vinblastine treatment. J Neurotrauma 1992;9:363–371. [DOI] [PubMed] [Google Scholar]
  • 10. Black SC, Gralinski MR, Friedrichs GS, Kilgore KS, Driscoll EM and Lucchesi BR. Cardioprotective effects of heparin or N‐acetylheparin in an in vivo model of myocardial ischemic and reperfusion injury. Cardiovasc Res 1995;29:629–636. [PubMed] [Google Scholar]
  • 11. Bonmann E, Juttler E, Krestel HE, Sparnger M. Heparin inhibits induction of nitric oxide synthase by cytokines in rat brain microvasculature endothelial cells. Neurosc Lett 1998;253:95–98. [DOI] [PubMed] [Google Scholar]
  • 12. Cade JF, Buchanan MR, Boneu B, et al. A comparison of the antithrombotic and haemorrhagic effects of low molecular weight heparin fractions: the influence of the method of preparation. Thromb Res 1984;35:613–625. [DOI] [PubMed] [Google Scholar]
  • 13. Carlos TM, Clark RSB, Franicola‐Higgins D, Schiding JK, Kochanek PM. Expression of endothelial adhesion molecules and recruitment of neutrophils after traumatic brain injury in rats. J Leukoc Biol 1997;61:279–285. [DOI] [PubMed] [Google Scholar]
  • 14. Carlos TM and Harlan JM. Leukocyte‐endothelial adhesion molecules. Blood 1994;84:2068–2101. [PubMed] [Google Scholar]
  • 15. Carney JM, Tatsuno T, Floyd RA. The role of oxygen radicals in ischemic brain damage: free radicals production, protein oxidation, tissue dysfunction In: Krieglstein J, Oberplichler‐Schwenk H, Eds. Pharmacology of Cerebral Ischemia. Stuttgart : Wissenschaftliche Verlagsgesellschaft, 1992:321–332. [Google Scholar]
  • 16. Clark RSB, Kochanek PM, Schwarz MA, et al. Inducible nitric oxide synthase expression in cerebrovascular smooth muscle, neutrophils after traumatic brain injury in immature rats. Pediatr Res 1996;39:784–790. [DOI] [PubMed] [Google Scholar]
  • 17. Clark WM, Madden KP, Rothlein R, Zivin JA. Reduction of central nervous system injury in rabbits using leukocyte adhesion antibody treatment. Stroke 1991;22:877–883. [DOI] [PubMed] [Google Scholar]
  • 18. Clark RSB, Schiding JK, Kaczorowski SL, Marion DW, Kochanek PM. Neutrophil accumulation after traumatic brain injury in rats: comparison of weight drop, controlled cortical impact models. J Neurotrauma 1994;11:499–506. [DOI] [PubMed] [Google Scholar]
  • 19. Choudhri TF, Hoh BL, Solomon RA, Connolly ES, Pinsky DJ. Use of a spectrophotometric hemoglobin assay to objectively quantify intracerebral hemorrhage in mice. Stroke 1997;28:2296–2302. [DOI] [PubMed] [Google Scholar]
  • 20. Dagenais P, Théorêt J‐F, Merhi Y, Latour J‐G. Comparative study of unfractionated and a low molecular weight heparin (enoxaparin) as P‐selectin inhibitors. FASEB J 1997;11:A311. [Google Scholar]
  • 21. Del Zoppo GJ, Copeland BR, Harker LA, et al. Experimental acute thrombotic stroke in baboons. Stroke 1986;17:1254–65. [DOI] [PubMed] [Google Scholar]
  • 22. Del Zoppo GJ, Schmid‐Schonbein GW, Mori E, Copeland BR, Chang CM. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion, reperfusion in baboons. Stroke 1991;22:1276–1283. [DOI] [PubMed] [Google Scholar]
  • 23. Dietrich WD, Alonso A, Halley M. Early microvascular, neuronal consequences of traumatic brain injury: a light and electron microscopic study in rats. J Neurotrauma 1994;11:289–301. [DOI] [PubMed] [Google Scholar]
  • 24. Dippel DW. The results of CAPRIE, IST, CAST. Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events. International Stroke Trial. Chinese Acute Stroke. Trial. Thromb. Res 1998;92 (1 Suppl 1): S13–S16. [DOI] [PubMed] [Google Scholar]
  • 25. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischemic stroke: an integrated view. TINS 1999;22:391–397. [DOI] [PubMed] [Google Scholar]
  • 26. Fareed J, Haas S, Sasahara J. Differentiations of LMWH: Applied, clinical considerations. Seminars in Thromb Hemost 1999;25 (Suppl 3): 1–147. [PubMed] [Google Scholar]
  • 27. Feuerstein GZ, Liu T, Barone FC. Cytokines, inflammation, and brain injury: role of tumor necrosis factor‐alpha. Cerebrovasc Brain Metab Rev 1994;Winter;6:341–360. [PubMed] [Google Scholar]
  • 28. Fisher M, Francis R. Altered coagulation in cerebral ischemia. Platelet, thrombin, plasmin activity. Arch Neurol 1990;47:1075–1079. [DOI] [PubMed] [Google Scholar]
  • 29. Finneman I, Hovda DA, Smith M, Yoshino A, Becker DP. Concussive brain injury is associated with a prolonged accumulation of calcium; a 45Ca autoradiographic study. Brain Res. 1993;624:94–102. [DOI] [PubMed] [Google Scholar]
  • 30. Friedrichs GS, Kilgore KS, Manley PJ, Gralinski MR, Lucchesi BR. Effects of heparin and N‐acetyl heparin on ischemia/reperfusion‐induced alterations in myocardial function in the rabbit isolated heart. Circ Res 1994;75:701–710. [DOI] [PubMed] [Google Scholar]
  • 31. Gikakis N, Khan MD, Hiramatsu Y, et al. Effect of factor Xa inhibitors on thrombin formation, complement, neutrophil activation during in vitro extracorporeal circulation. Circulation 1996;14:341–346. [PubMed] [Google Scholar]
  • 32. Grady MS, Cody RF, Maris DO, et al. P‐selectin blockade following fluid‐percussion injury: behavioral, immunochemical sequelae. J Neurotrauma 1999;16:13–25. [DOI] [PubMed] [Google Scholar]
  • 33. Graham DI, Ford I, Adams JH, et al. Ischemic brain damage is still common in fatal non‐missile head injury. J Neurol Neurosurg Psychiatry 1989;52:346–350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Grosjean‐Piot O, Wahl F, Gobbo O, Stutzmann J‐M. Assessment of sensori‐motor, cognitive deficits induced by a moderate traumatic injury in the right parietal cortex in the Rat, Neurobiology Dis 2001;8:1082–1093. [DOI] [PubMed] [Google Scholar]
  • 35. Hall ED, Braughler JM. Free radical CNS in jury. Res. Publ. Assoc Res Nerv Ment Dis 1993;71:81–105. [PubMed] [Google Scholar]
  • 36. Heimann A, Takeshima T, Kempski OS. C1‐esterase inhibitor reduces neuronal damage in a venous infarct model. J Cereb Blood Flow Metab 1999;19:S163. [Google Scholar]
  • 37. Hommel M for the FISS bis Investigators Group. Fraxiparine in ischemic Stroke Study (FISS bis) (Abstract). Cerebrovasc Dis 1998;8(Suppl 4): 19. 9767195 [Google Scholar]
  • 38. . INTERNATIONAL STROKE TRIAL Collaborative Group. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischemic stroke. Lancet 1997;349:1569–1581. [PubMed] [Google Scholar]
  • 39. Jonas S, Sugimori M, Llinas R. Is low molecular weight heparin a neuroprotectant Ann NY Acad Sci 1997;825:389–393. [DOI] [PubMed] [Google Scholar]
  • 40. Kaczorowski SL, Schiding JK, Toth CA, Kochanek PM. Effect of soluble complement receptor‐1 on neutrophil accumulation after traumatic brain injury in rats. J Cereb Blood Flow Metab 1995;15:860–864. [DOI] [PubMed] [Google Scholar]
  • 41. Kalsbeek WD, McLaurin RL, Harris BSH, Miller JD. The national head, spinal cord injury survey: major findings. J Neurosurg 1980;53:S19–S31. [PubMed] [Google Scholar]
  • 42. Kay R, Wong KS, Yu YL, et al. Low‐molecular‐weight heparin for the treatment of acute ischemic stroke. N Engl J Med 1995;333:1588–1593. [DOI] [PubMed] [Google Scholar]
  • 43. Lafont F, Prochiantz A, Valenza C, et al. Defined glycosaminoglycan motifs have opposite effects on neuronal polarity in vitro. Dev Biol 1994;165:453–468. [DOI] [PubMed] [Google Scholar]
  • 44. Lafuente JV, Cervós‐Navarro J. Craniocerebral trauma induces hemorrheological disturbances. J Neurotrauma 1999;16:425–430. [DOI] [PubMed] [Google Scholar]
  • 45. Lashley KS. Integrative functions of the cerebral cortex. Physiol Rev 1933;13:1–42. [Google Scholar]
  • 46. Lee KR, Betz AL, Keep RF, Chenevert TL, Kim S, Hoff JT. Intracerebral infusion of thrombin as a cause of brain edema. J Neurosurg 1995;83:1045–50. [DOI] [PubMed] [Google Scholar]
  • 47. Libersan D, Khalil A, Dagenais P, et al. The low molecular weight heparin enoxaparin limits infarct size at reperfusion in the dog. Cardiovasc Res 1998;37:656–666. [DOI] [PubMed] [Google Scholar]
  • 48. Maeda T, Katayama Y, Kawamata T, Aoyama N, Mori T. Hemodynamic depression, microthrombosis in the peripheral areas of cortical contusion in the rat: role of platelet activating factor. Acta Neurochir 1997; Suppl 70:102–105. [DOI] [PubMed] [Google Scholar]
  • 49. Mary V, Wahl, F , Uzan A, Stutzmann J‐M. Enoxaparin reduces lesion size, improves functional outcome after transient, permanent ischemia in rats. Stroke 2001;32:993–999. [DOI] [PubMed] [Google Scholar]
  • 50. McIntosh TK, Juhler M, Wieloch T. Novel pharmacologic strategies in the treatment of experimental traumatic brain injury. J Neurotrauma 1998;15:731–769. [DOI] [PubMed] [Google Scholar]
  • 51. Mena MA, Casarejos MJ, Gimenez‐Gallego G, Garcia de Yebenes J. Fibroblast growth factors: structure‐activity on dopamine neurons in vitro. J Neural Transm Park Dis Dement 1995;9:1–14. [DOI] [PubMed] [Google Scholar]
  • 52. Nagy Z, Kolev K, Csonka E, Pék M, Machovich R. Contraction of human brain endothelial cells induced by thrombogenic, fibrinolytic factors: An in vitro cell culture model. Stroke 1995;26:265–270. [DOI] [PubMed] [Google Scholar]
  • 53. Nelson RM, Cecconi O, Roberts WG, Aruffo A, Linhardt RJ, Bevilacqua MP. Heparin oligosaccharides bind L‐, P‐selectin, inhibit acute inflammation. Blood 1993;82:3253–3258. [PubMed] [Google Scholar]
  • 54. Obrenovitch TP, Urenjak J. Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury J Neurotrauma 1997;14:677–698. [DOI] [PubMed] [Google Scholar]
  • 55. Okada Y, Copeland BR, Fitridge R, Koziol JA, del Zoppo GJ. Fibrin contributes to microvascular obstructions, parenchymal changes during early focal cerebral ischemia, reperfusion. Stroke 1994;25:1847–1853. [DOI] [PubMed] [Google Scholar]
  • 56. Oyanagui Y, Sato S. Heparin, a potent releasing agent of extracellular superoxide dismutase (EC‐SOD C), suppresses ischemic paw edema in mice. Free Radic Res Commun 1990;9:87–99. [DOI] [PubMed] [Google Scholar]
  • 57. Pratt J, Boudeau P, Uzan A, Imperato A, Stutzmann J‐M. Enoxaparin reduces cerebral edema after photothrombotic injury in the rat. Haemostasis 1998;28:78–85. [DOI] [PubMed] [Google Scholar]
  • 58. Royo NC, Wahl F, Stutzmann J‐M. Kinetics of polymorphonuclear leukocytes infiltration after traumatic brain injury in rat. Neuroreport 1999;10:1363–1367. [DOI] [PubMed] [Google Scholar]
  • 59. Shapira Y, Yadid G, Cotev S, Shohami E. Accumulation of calcium in the brain following head trauma. Neurol Res 1989;11:169–172. [DOI] [PubMed] [Google Scholar]
  • 60. Schoettle RJ, Kochanek PM, Margargee M‐J, Uhl MW, Nemoto EM. Early polymorphonuclear leukocyte accumulation correlates with the development of posttraumatic cerebral edema in rats. J Neurotrauma 1990;7:207–217. [DOI] [PubMed] [Google Scholar]
  • 61. Sherman DG. Heparin, heparinoids in stroke. Neurology 1998;51 (Suppl 3): S56–S58. [DOI] [PubMed] [Google Scholar]
  • 62. Shohami E, Gallily R, Mechoulam R, Kohen R. Oxidative stress in close‐head injury: brain antioxidant capacity as an indicator of functional outcome. J. Cereb. Blood Flow Metab 1997;17:1007–1019. [DOI] [PubMed] [Google Scholar]
  • 63. Smith DR, Ducker TB, Kempe LG. Temporary experimental intracranial vascular occlusion. Effect of massive doses of heparin on brain survival. J Neurosurg 1969;30:537–544. [DOI] [PubMed] [Google Scholar]
  • 64. Soares HD, Hicks RR, Smith D, McIntosh TK. Inflammatory leukocyte recruitment, diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. J Neurosc 1995;15:8223–8233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Von Sprecht BU, Bieber B, Uzan A. Comparison of the effects of enoxaparin, unfractioned heparin on acidic fibroblast growth factor (aFGF) mediated cell proliferation in vitro, in vivo angiogenesis in the chicken allantois membrane. Thrombosis, Haematosis , abstract XVIII Congress, Suppl, July, 2001.
  • 66. Stahel PF, Morganti‐Kossmann MC, Kossmann T. The role of complement system in traumatic brain injury. Brain Res Rev 1998;27:243–256. [DOI] [PubMed] [Google Scholar]
  • 67. Sugimori M, Cherksey BD, Llinas R. Dendritic apoptosis: a new mechanism for restricted neuronal death. Soc. Neurosci Abst 1995;21:2019. [Google Scholar]
  • 68. Tamura A, Graham DI, McCulloch J, Teasdale GM. Focal cerebral ischemia in the rat: 1. Description of technique, early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab 1981;1:53–60. [DOI] [PubMed] [Google Scholar]
  • 69. . TOAST‐Investigators‐Publications‐Committee. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke. A randomized controlled trial. JAMA 1998;279:1265–1272. [PubMed] [Google Scholar]
  • 70. Toulmond S, Duval D, Serrano A, Scatton B, Benavides J. Biochemical, histological alterations induced by fluid percussion brain injury in the rat. Brain Res 1993;620:24–31. [DOI] [PubMed] [Google Scholar]
  • 71. Tyrell DJ, Kilfeather S, Page CP. Therapeutic uses of heparin beyond its traditional role as an anticoagulant. TIPS 1995;16:198–204. [DOI] [PubMed] [Google Scholar]
  • 72. Uhl MW, Biagas KV, Grundl PD, et al. Effects of neutropenia on edema, histology, and cerebral blood flow after traumatic brain injury in rats. J Neurotrauma 1994;11:303–315. [DOI] [PubMed] [Google Scholar]
  • 73. Upchurch GR, Welch GN, Freedman JE, et al. High‐dose heparin decreases nitric oxide production by cultured bovine endothelial cells. Circulation 1997;95:2115–2121. [DOI] [PubMed] [Google Scholar]
  • 74. Wada K, Chatzipanteli K, Busto R, Dietrich WD. The role of nitric oxide in traumatic brain injury. J Neurosurg 1998;89:109–120. [DOI] [PubMed] [Google Scholar]
  • 75. Wahl F, Grosjean‐Piot O, Bareyre F, Uzan A, Stutzmann J‐M. Enoxaparin reduces brain edema, cerebral lesions, improves motor, cognitive impairments induced by a traumatic brain injury in rats. J Neurotrauma 2000;17:1055–1065. [DOI] [PubMed] [Google Scholar]
  • 76. Wahl F, Allix M, Plotkine M, Boulu RG. Neurological, behavioral outcomes of focal cerebral ischemia in rats. Stroke 1992;23:267–272. [DOI] [PubMed] [Google Scholar]
  • 77. Wahl F, Renou E, Mary V, Stutzmann J‐M. Riluzole reduces brain lesions, improves neurological function in rats after a traumatic brain injury. Brain Res 1977;756:247–255. [DOI] [PubMed] [Google Scholar]
  • 78. Wahl F, Parmentier S, Damour D, Plotkine M, Stutzmann J‐M, Böhme GA. Inhibition of inducible NO‐synthase reduced the brain edema induced by a traumatic brain injury with a large therapeutic window. J Cereb Blood Flow Metab 1999;19:S379. [Google Scholar]
  • 79. Whalen MJ, Carlos TM, Kochanek PM, et al. Neutrophils do not mediate blood‐brain barrier permeability early after controlled cortical impact in rats. J Neurotrauma 1999;16:583–594. [DOI] [PubMed] [Google Scholar]
  • 80. Ward PA, Warren JS, Johnson KJ. Oxygen radicals, inflammation, and tissue injury. Free Rad. Biol Med 1988;5:403–408. [DOI] [PubMed] [Google Scholar]
  • 81. Warlow CP. Epidemiology of stroke. Lancet 1998;352(Suppl III): 1–4. [DOI] [PubMed] [Google Scholar]
  • 82. Yanaka K, Spellman SR, McCarthy JB, Oegema TR Jr, Low WC, Camarata PJ. Reduction of brain injury using heparin to inhibit leukocyte accumulation in a rat model of transient focal cerebral ischemia. I. Protective mechanism. J Neurosurg 1996;85:1102–1107. [DOI] [PubMed] [Google Scholar]
  • 83. Yanaka K, Spellman SR, McCarthy JB, Low WC, Camarata PJ. Reduction of brain injury using heparin to inhibit leukocyte accumulation in a rat model of transient focal cerebral ischemia. II. Dose‐response effect, the therapeutic window. J Neurosurg 1996;85:1108–1112. [DOI] [PubMed] [Google Scholar]
  • 84. Young E, Cosmi B, Weitz J, Hirsh J. Comparison of the non‐specific binding of unfractionated heparin, low molecular weight heparin (enoxaparin) to plasma proteins. Thromb Haemost 1993;70:625–630. [PubMed] [Google Scholar]

Articles from CNS Drug Reviews are provided here courtesy of Wiley

RESOURCES