Synaptogenesis: Modulation by Availability of Membrane Phospholipid Precursors

NeuroMolecular Medicine

Volumn 18, Issue 3, 2016, Pages 426-440

  Cansev, Mehmet ^a  

^a ULUDAG UNIVERSITY   (Turkey)

Author keywords

Alzheimer s disease; Choline; Cognition; Docosahexaenoic acid; Synaptogenesis; Uridine

Indexed keywords

ARACHIDONIC ACID; CHOLINE; CITICOLINE; DOCOSAHEXAENOIC ACID; ICOSAPENTAENOIC ACID; LINOLENIC ACID; MEMBRANE PHOSPHOLIPID; POLYUNSATURATED FATTY ACID; POSTSYNAPTIC DENSITY PROTEIN 95; SYNAPSE RECEPTOR; SYNAPSIN I; SYNTAXIN; SYNTAXIN 3; UNCLASSIFIED DRUG; URIDINE; VITAMIN; PHOSPHOLIPID;

ARTICLE; BIOAVAILABILITY; BLOOD BRAIN BARRIER; BRAIN CELL; COGNITION; DENDRITIC SPINE; DIET SUPPLEMENTATION; HUMAN; LEARNING; LIPID ANALYSIS; MEMORY; NERVE DEGENERATION; NEUROPHYSIOLOGY; NEUROTRANSMISSION; NONHUMAN; PHOSPHOLIPID SYNTHESIS; PRIORITY JOURNAL; SYNAPSE; SYNAPTOGENESIS; ALZHEIMER DISEASE; ANIMAL; BRAIN; DIETARY SUPPLEMENT; METABOLISM; MOUSE; PATHOPHYSIOLOGY; PHYSIOLOGY; RAT;

ALZHEIMER DISEASE; ANIMALS; BRAIN; DIETARY SUPPLEMENTS; DOCOSAHEXAENOIC ACIDS; MICE; PHOSPHOLIPIDS; RATS; SYNAPSES;

EID: 84973115694     PISSN: 15351084     EISSN: 15591174     Source Type: Journal    
DOI: 10.1007/s12017-016-8414-x     Document Type: Article

References (84)

1. Abumrad, N. A., Park, J. H., & Park, C. R. (1984). Permeation of long chain fatty acids into adipocytes. Journal of Biological Chemistry, 259(14), 8945–8953.
2. Bazan, N. G. (1990). Supply of n-3 polyunsaturated fatty acids and their significance in the central nervous system. In R. J. Wurtman & J. J. Wurtman (Eds.), Nutrition and the brain (Vol. 8, pp. 1–24). New York: Raven Press.
3. Bazan, N. G. (2005). Neuroprotectin D1 (NPD1): A DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress. Brain Pathology, 15(2), 159–166.
4. Bazan, H. E., Careaga, M. M., Sprecher, H., & Bazan, N. G. (1982). Chain elongation and desaturation of eicosapentaenoate to docosahexaenoate and phospholipid labeling in the rat retina in vivo. Biochimica et Biophysica Acta, 712(1), 123–128.
5. Brenna, J. T. (2002). Efficiency of conversion of alpha-linolenic acid to long chain n-3 fatty acids in man. Current Opinion in Clinical Nutrition and Metabolic Care, 5, 127–132.
6. Caner, B., Kafa, I. M., Bekar, A., Kurt, A., Cansev, M., & Ulus, I. H. (2012). Intraperitoneal administration of CDP-choline or a combination of cytidine plus choline improves nerve regeneration and functional recovery in a rat model of sciatic nerve injury. Neurological Research. doi:10.1179/1743132812Y.0000000003.
7. Cansev, M. (2006). Uridine and cytidine in the brain: Their transport and utilization. Brain Research Reviews, 52(2), 389–397.
8. Cansev, M. (2007). Involvement of uridine-nucleotide-stimulated P2Y receptors in neuronal growth and function. Central Nervous System Agents in Medicinal Chemistry, 7, 223–229.
9. Cansev, M., Ilcol, Y. O., Yilmaz, M. S., Hamurtekin, E., & Ulus, I. H. (2008a). Peripheral administration of CDP-choline, phosphocholine or choline increases plasma adrenaline and noradrenaline concentrations. Autonomic and Autacoid Pharmacology, 28(1), 41–58.
10. Cansev, M., Ilcol, Y. O., Yilmaz, M. S., Hamurtekin, E., & Ulus, I. H. (2008b). Choline, CDP-choline or phosphocholine increases plasma glucagon in rats: Involvement of the peripheral autonomic nervous system. European Journal of Pharmacology. doi:10.1016/j.ejphar.2008.05.017.
11. Cansev, M., Marzloff, G., Sakamoto, T., Ulus, I. H., & Wurtman, R. J. (2009). Giving uridine and/or docosahexaenoic acid orally to rat dams during gestation and nursing increases synaptic elements in brains of weanling pups. Developmental Neuroscience. doi:10.1159/000193394.
12. Cansev, M., Orhan, F., Yaylagul, E. O., Isik, E., Turkyilmaz, M., Aydin, S., et al. (2015a). Evidence for the existence of pyrimidinergic transmission in rat brain. Neuropharmacology. doi:10.1016/j.neuropharm.2014.12.019.
13. Cansev, M., & Ulus, I. H. (2011). Oral administration of phosphatide precursors enhances learning and memory by promoting synaptogenesis. In V. R. Preedy, R. R. Watson, & C. R. Martin (Eds.), Handbook of behavior, food and nutrition (pp. 489–504). New York: Springer.
14. Cansev, M., Ulus, I. H., Wang, L., Maher, T. J., & Wurtman, R. J. (2008c). Restorative effects of uridine plus docosahexaenoic acid in a rat model of Parkinson’s disease. Neuroscience Research. doi:10.1016/j.neures.2008.07.005.
15. Cansev, M., van Wijk, N., Turkyilmaz, M., Orhan, F., Sijben, J. W., & Broersen, L. M. (2015b). A specific multi-nutrient enriched diet enhances hippocampal cholinergic transmission in aged rats. Neurobiology of Aging. doi:10.1016/j.neurobiolaging.2014.07.021.
16. Cansev, M., Watkins, C. J., van der Beek, E. M., & Wurtman, R. J. (2005). Oral uridine-5′-monophosphate (UMP) increases brain CDP-choline levels in gerbils. Brain Research, 1058(1–2), 101–108.
17. Cansev, M., & Wurtman, R. J. (2007). Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils. Neuroscience, 148(2), 421–431.
18. Cansev, M., Yilmaz, M. S., Ilcol, Y. O., Hamurtekin, E., & Ulus, I. H. (2007). Cardiovascular effects of CDP-choline and its metabolites: Involvement of peripheral autonomic nervous system. European Journal of Pharmacology, 577(1–3), 129–142.
19. Carter, R. L., Fricks, I. P., Barrett, M. O., Burianek, L. E., Zhou, Y., Ko, H., et al. (2009). Quantification of Gi-mediated inhibition of adenylyl cyclase activity reveals that UDP is a potent agonist of the human P2Y14 receptor. Molecular Pharmacology. doi:10.1124/mol.109.058578.
20. Cetinkaya, M., Cansev, M., Cekmez, F., Tayman, C., Canpolat, F. E., Kafa, I. M., et al. (2013a). CDP-choline reduces severity of intestinal injury in a neonatal rat model of necrotizing enterocolitis. Journal of Surgical Research. doi:10.1016/j.jss.2012.11.032.
21. Cetinkaya, M., Cansev, M., Kafa, I. M., Tayman, C., Cekmez, F., Canpolat, F. E., et al. (2013b). Cytidine 5′-diphosphocholine ameliorates hyperoxic lung injury in a neonatal rat model. Pediatric Research. doi:10.1038/pr.2013.68.
22. Communi, D., Parmentier, M., & Boeynaems, J. M. (1996). Cloning, functional expression and tissue distribution of the human P2Y6 receptor. Biochemical and Biophysical Research Communications, 222(2), 303–308.
23. Communi, D., Pirotton, S., Parmentier, M., & Boeynaems, J. M. (1995). Cloning and functional expression of a human uridine nucleotide receptor. Journal of Biological Chemistry, 270(52), 30849–30852.
24. De Bruin, N. M., Kiliaan, A. J., De Wilde, M. C., & Broersen, L. M. (2003). Combined uridine and choline administration improves cognitive deficits in spontaneously hypertensive rats. Neurobiology of Learning and Memory, 80(1), 63–79.
25. De Theije, C. G., van den Elsen, L. W., Willemsen, L. E., Milosevic, V., Korte-Bouws, G. A., Lopes da Silva, S., et al. (2015). Dietary long chain n-3 polyunsaturated fatty acids prevent impaired social behaviour and normalize brain dopamine levels in food allergic mice. Neuropharmacology. doi:10.1016/j.neuropharm.2014.11.001.
26. De Waal, H., Stam, C. J., Lansbergen, M. M., Wieggers, R. L., Kamphuis, P. J., Scheltens, P., et al. (2014). The effect of souvenaid on functional brain network organisation in patients with mild Alzheimer’s disease: A randomised controlled study. PLoS One. doi:10.1371/journal.pone.0086558.
27. De Wilde, M. C., Penke, B., van der Beek, E. M., Kuipers, A. A., Kamphuis, P. J., & Broersen, L. M. (2011). Neuroprotective effects of a specific multi-nutrient intervention against Aβ42-induced toxicity in rats. Journal of Alzheimer’s Disease. doi:10.3233/JAD-2011-110635.
28. Gasser, T., Moyer, J. D., & Handschumacher, R. E. (1981). Novel single-pass exchange of circulating uridine in rat liver. Science, 213, 777–778.
29. Golczewski, J. A., Hiramoto, R. N., & Ghanta, V. K. (1982). Enhancement of maze learning in old C57BL/6 mice by dietary lecithin. Neurobiology of Aging, 3(3), 223–226.
30. Gundogdu, E. B., Bekar, A., Turkyilmaz, M., Gumus, A., Kafa, I. M., & Cansev, M. (2016). CDP-choline modulates matrix metalloproteinases in rat sciatic injury. Journal of Surgical Research. doi:10.1016/j.jss.2015.10.003.
31. Hartmann, T., van Wijk, N., Wurtman, R. J., Olde Rikkert, M. G., Sijben, J. W., Soininen, H., et al. (2014). A nutritional approach to ameliorate altered metabolism in Alzheimer’s disease. Journal of Alzheimer’s Disease. doi:10.3233/JAD-141137.
32. Hashimoto, M., Hossain, S., Shimada, T., Sugioka, K., & Yamasaki, H. (2002). Docosahexaenoic acid provides protection from impairment of learning ability in Alzheimer’s disease model rats. Journal of Neurochemistry, 81(5), 1084–1091.
33. Hashimoto, M., Tanabe, Y., Fujii, Y., Kikuta, T., Shibata, H., & Shido, O. (2005). Chronic administration of docosahexaenoic acid ameliorates the impairment of spatial cognition learning ability in amyloid beta-infused rats. Journal of Nutrition, 135(3), 549–555.
34. Hirsch, M. J., Growdon, J. H., & Wurtman, R. J. (1978). Relations between dietary choline or lecithin intake, serum choline levels, and various metabolic indices. Metabolism, 27, 953–960.
35. Holguin, S., Huang, Y., Liu, J., & Wurtman, R. (2008a). Chronic administration of DHA and UMP improves the impaired memory of environmentally impoverished rats. Behavioural Brain Research. doi:10.1016/j.bbr.2008.02.042.
36. Holguin, S., Martinez, J., Chow, C., & Wurtman, R. (2008b). Dietary uridine enhances the improvement in learning and memory produced by administering DHA to gerbils. FASEB Journal. doi:10.1096/fj.08-112425.
37. Holub, B. J. (1978). Differential utilization of 1-palmitoyl and 1-stearoyl homologues of various unsaturated 1,2-diacyl-sn-glycerols for phosphatidylcholine and phosphatidylethanolamine synthesis in rat liver microsomes. Journal of Biological Chemistry, 253, 691–696.
38. Ilcol, Y. O., Cansev, M., Yilmaz, M. S., Hamurtekin, E., & Ulus, I. H. (2007). Intraperitoneal administration of CDP-choline and its cholinergic and pyrimidinergic metabolites induce hyperglycemia in rats: involvement of the sympathoadrenal system. Archives of Physiology and Biochemistry, 113(4–5), 186–201.
39. Ilcol, Y. O., Cansev, M., Yilmaz, M. S., Hamurtekin, E., & Ulus, I. H. (2008). Peripheral administration of CDP-choline and its cholinergic metabolites increases serum insulin: Peripheral muscarinic and nicotinic acetylcholine receptors are both involved in its action. Neuroscience Letters, 431(1), 71–76.
40. Ilcol, Y. O., Yilmaz, Z., Cansev, M., & Ulus, I. H. (2009). Choline or CDP-choline alters serum lipid responses to endotoxin in dogs and rats: Involvement of the peripheral nicotinic acetylcholine receptors. Shock. doi:10.1097/SHK.0b013e3181971b02.
41. Isbil-Buyukcoskun, N., Ilcol, Y. O., Cansev, M., Ozluk, K., Hamurtekin, E., & Ulus, I. H. (2008). Central choline suppresses plasma renin response to graded hemorrhage in rats. Clinical and Experimental Pharmacology and Physiology, 35(9), 1023–1031.
42. Kamp, F., & Hamilton, J. A. (1993). Movement of fatty acids, fatty acid analogues, and bile acids across bilayers. Biochemistry, 32(41), 11074–11086.
43. Kaplan, T., Kafa, I. M., Cansev, M., Bekar, A., Karli, N., Taskapilioglu, M. O., et al. (2014). Investigation of the dose-dependency of citicoline effects on nerve regeneration and functional recovery in a rat model of sciatic nerve injury. Turkish Neurosurgery. doi:10.5137/1019-5149.JTN.8451-13.0.
44. Kennedy, E. M., & Weiss, S. B. (1956). The function of cytidine coenzymes in the biosynthesis of s. Journal of Biological Chemistry, 222, 193–214.
45. Klein, J., Koppen, A., & Loffelholz, K. (1990). Small rises in plasma choline reverse the negative arteriovenous difference of brain choline. Journal of Neurochemistry, 55, 1231–1236.
46. Knobloch, M., & Mansuy, I. M. (2008). Dendritic spine loss and synaptic alterations in Alzheimer’s disease. Molecular Neurobiology. doi:10.1007/s12035-008-8018-z.
47. Knott, G. W., Holtmaat, A., Wilbrecht, L., Welker, E., & Svoboda, K. (2006). Spine growth precedes synapse formation in the adult neocortex in vivo. Nature Neuroscience, 9(9), 1117–1124.
48. Koivisto, H., Grimm, M. O., Rothhaar, T. L., Berkecz, R., Lütjohann, D. D., Giniatullina, R., et al. (2014). Special lipid-based diets alleviate cognitive deficits in the APPswe/PS1dE9 transgenic mouse model of Alzheimer’s disease independent of brain amyloid deposition. Journal of Nutritional Biochemistry. doi:10.1016/j.jnutbio.2013.09.015.
49. Kotani, S., Sakaguchi, E., Warashina, S., Matsukawa, N., Ishikura, Y., Kiso, Y., et al. (2006). Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neuroscience Research, 56(2), 159–164.
50. Lai, M. K., Tan, M. G., Kirvell, S., Hobbs, C., Lee, J., Esiri, M. M., et al. (2008). Selective loss of P2Y2 nucleotide receptor immunoreactivity is associated with Alzheimer’s disease neuropathology. Journal of Neural Transmission (Vienna). doi:10.1007/s00702-008-0067-y.
51. Lands, W. E. (1958). Metabolism of glycerolipides: A comparison of lecithin and triglyceride synthesis. Journal of Biological Chemistry, 231(2), 883–888.
52. Lecca, D., & Ceruti, S. (2008). Uracil nucleotides: From metabolic intermediates to neuroprotection and neuroinflammation. Biochemical Pharmacology. doi:10.1016/j.bcp.2007.12.009.
53. Lustig, K. D., Shiau, A. K., Brake, A. J., & Julius, D. (1993). Expression cloning of an ATP receptor from mouse neuroblastoma cells. Proceedings of the National Academy of Sciences (USA), 90, 5113–5117.
54. Mantel, C. R., Schulz, A. R., Miyazawa, K., & Broxmeyer, H. E. (1993). Kinetic selectivity of cholinephosphotransferase in mouse liver: The Km for CDP-choline depends on diacylglycerol structure. Biochemical Journal 289, 815–820.
55. Mapstone, M., Cheema, A. K., Fiandaca, M. S., Zhong, X., Mhyre, T. R., MacArthur, L. H., et al. (2014). Plasma s identify antecedent memory impairment in older adults. Nature Medicine. doi:10.1038/nm.3466.
56. Marszalek, J. R., Kitidis, C., DiRusso, C. C., & Lodish, H. F. (2005). Long-chain acyl-CoA synthetase 6 preferentially promotes DHA metabolism. Journal of Biological Chemistry, 280(11), 10817–10826.
57. Masliah, E., Mallory, M., Alford, M., DeTeresa, R., Hansen, L. A., McKeel, D. W, Jr., et al. (2001). Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology, 56(1), 127–129.
58. Mi, W., van Wijk, N., Cansev, M., Sijben, J. W. C., & Kamphuis, P. J. G. H. (2013). Nutritional approaches in the risk reduction and management of Alzheimer’s disease. Nutrition. doi:10.1016/j.nut.2013.01.024.
59. Nitsch, R. M., Blusztajn, J. K., Pittas, A. G., Slack, B. E., Growdon, J. H., & Wurtman, R. J. (1992). Evidence for a membrane defect in Alzheimer disease brain. Proceedings of the National Academy of Sciences (USA), 89(5), 1671–1675.
60. Olde Rikkert, M. G., Verhey, F. R., Blesa, R., von Arnim, C. A., Bongers, A., Harrison, J., et al. (2015). Tolerability and safety of Souvenaid in patients with mild Alzheimer’s disease: Results of multi-center, 24-week, open-label extension study. Journal of Alzheimer’s Disease. doi:10.3233/JAD-141305.
61. Oldendorf, W. H., & Braun, L. D. (1976). [H]Tryptamine and 3Hwater as diffusible internal standards for measuring brain extraction of radio-labeled substances following carotid injection. Brain Research, 113, 219–224.
62. Ramirez-Amaya, V., Balderas, I., Sandoval, J., Escobar, M. L., & Bermudez-Rattoni, F. (2001). Spatial long-term memory is related to mossy fiber synaptogenesis. Journal of Neuroscience, 21(18), 7340–7348.
63. Richardson, U. I., Watkins, C. J., Pierre, C., Ulus, I. H., & Wurtman, R. J. (2003). Stimulation of CDP-choline synthesis by uridine or cytidine in PC12 rat pheochromocytoma cells. Brain Research, 971(2), 161–167.
64. Robinson, P. J., Noronha, J., DeGeorge, J. J., Freed, L. M., Nariai, T., & Rapoport, S. I. (1992). A quantitative method for measuring regional in vivo fatty-acid incorporation into and turnover within brain phospholipids: Review and critical analysis. Brain Research Reviews, 17, 187–214.
65. Sakamoto, T., Cansev, M., & Wurtman, R. J. (2007). Oral supplementation with docosahexaenoic acid and uridine 5′-monophosphate increases dendritic spine density in adult gerbil hippocampus. Brain Research, 1182, 50–59.
66. Savci, V., Goktalay, G., Cansev, M., Cavun, S., Yilmaz, M. S., & Ulus, I. H. (2003). Intravenously injected CDP-choline increases blood pressure and reverses hypotension in hemorrhagic shock: effect is mediated by central cholinergic activation. European Journal of Pharmacology, 468(2), 129–139.
67. Savelkoul, P. J., Janickova, H., Kuipers, A. A., Hageman, R. J., Kamphuis, P. J., Dolezal, V., et al. (2012). A specific multi-nutrient formulation enhances M1 muscarinic acetylcholine receptor responses in vitro. Journal of Neurochemistry. doi:10.1111/j.1471-4159.2011.07616.x.
68. Savran, M., Bekar, A., Cansev, M., Tolunay, S., Ulus, I. H., & Taskapilioglu, M. O. (2012). Prevention of epidural fibrosis in rats by local or systemic administration of citicoline. Turkish Neurosurgery. doi:10.5137/1019-5149.JTN.6008-12.0.
69. Scheltens, P., Kamphuis, P. J., Verhey, F. R., Olde-Rikkert, M. G., Wurtman, R. J., Wilkinson, D., et al. (2010). Efficacy of a medical food in mild Alzheimer’s disease: A randomized, controlled trial. Alzheimer’s and Dementia. doi:10.1016/j.jalz.2009.10.003.
70. Scheltens, P., Twisk, J. W., Blesa, R., Scarpini, E., von Arnim, C. A., Bongers, A., et al. (2012). Efficacy of Souvenaid in mild Alzheimer’s disease: Results from a randomized, controlled trial. Journal of Alzheimer’s Disease. doi:10.3233/JAD-2012-121189.
71. Selkoe, D. J. (2002). Alzheimer’s disease is a synaptic failure. Science, 298(5594), 789–791.
72. Soderberg, M., Edlund, C., Kristensson, K., & Dallner, G. (1991). Fatty acid composition of brain s in aging and in Alzheimer’s disease. Lipids, 26(6), 421–425.
73. Sweet, D. H., Miller, D. S., & Pritchard, J. B. (2001). Ventricular choline transport: A role for organic cation transporter 2 expressed in choroid plexus. Journal of Biological Chemistry, 276, 41611–41619.
74. Teather, L. A., & Wurtman, R. J. (2006). Chronic administration of UMP ameliorates the impairment of hippocampal-dependent memory in impoverished rats. Journal of Nutrition, 136(11), 2834–2837.
75. Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., et al. (1991). Physical basis of cognitive alterations in Alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment. Annals of Neurology, 30(4), 572–580.
76. Toni, N., Teng, E. M., Bushong, E. A., Aimone, J. B., & Zhao, C. (2007). Synapse formation on neurons born in the adult hippocampus. Nature Neuroscience, 10(6), 727–734.
77. Ulus, I. H., Watkins, C. J., Cansev, M., & Wurtman, R. J. (2006). Cytidine and uridine increase striatal CDP-choline levels without decreasing acetylcholine synthesis or release. Cellular and Molecular Neurobiology, 26(4–6), 563–577.
78. Wang, L., Albrecht, M. A., & Wurtman, R. J. (2007). Dietary supplementation with uridine-5′-monophosphate (UMP), a membrane phosphatide precursor, increases acetylcholine level and release in striatum of aged rat. Brain Research, 1133(1), 42–48.
79. Wang, L., Pooler, A. M., Albrecht, M. A., & Wurtman, R. J. (2005). Dietary uridine-5′-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. Journal of Molecular Neuroscience, 27(1), 137–145.
80. Wiesmann, M., Jansen, D., Zerbi, V., Broersen, L. M., Garthe, A., & Kiliaan, A. J. (2013). Improved spatial learning strategy and memory in aged Alzheimer AβPPswe/PS1dE9 mice on a multi-nutrient diet. Journal of Alzheimer’s Disease. doi:10.3233/JAD-130179.
81. Wurtman, R. J., Cansev, M., & Ulus, I. H. (2009). Choline and its products acetylcholine and phosphatidylcholine. In A. Lajtha (Ed.), Neural lipids, handbook of neurochemistry and molecular neurobiology (pp. 443–501). Berlin: Springer.
82. Wurtman, R. J., Regan, M., Ulus, I., & Yu, L. (2000). Effect of oral CDP-choline on plasma choline and uridine levels in humans. Biochemical Pharmacology, 60(7), 989–992.
83. Wurtman, R. J., Ulus, I. H., Cansev, M., Watkins, C. J., Wang, L., & Marzloff, G. (2006). Synaptic proteins and s are increased in gerbil brain by administering uridine plus docosahexaenoic acid orally. Brain Research, 1088(1), 83–92.
84. Yilmaz, Z., Ozarda, Y., Cansev, M., Eralp, O., Kocaturk, M., & Ulus, I. H. (2010). Choline or CDP-choline attenuates coagulation abnormalities and prevents the development of acute disseminated intravascular coagulation in dogs during endotoxemia. Blood Coagulation and Fibrinolysis. doi:10.1097/MBC.0b013e328338ce31.