Journal of NeuroVirology

, 17:487

Platelet decline as a predictor of brain injury in HIV infection

  • Ann B. Ragin
  • Gypsyamber D’Souza
  • Sandra Reynolds
  • Eric Miller
  • Ned Sacktor
  • Ola A. Selnes
  • Eileen Martin
  • Barbara R. Visscher
  • James T. Becker


An association between platelet decline and increased risk of progression to dementia has been observed in an advanced HIV infection cohort study. This investigation evaluated the prognostic significance of platelet decline for dementia, for psychomotor slowing, and for brain injury, as quantified in vivo, in a much larger population of HIV+ men. Platelet counts and neurocognitive data were available from biannual visits of 2,125 HIV+ men participating in the prospective, Multicenter AIDS Cohort Study from 1984 to 2009. Brain volumetric data were also available from an imaging substudy of 83 seropositive participants aged 50 and older. The association of platelet counts with neurocognitive outcome was assessed using Cox proportional hazard models where change in platelet count from baseline was a time-updated variable. Marked platelet decline was associated with increased risk of dementia in univariate analysis (hazard ratio [HR] = 2.5, 95% confidence interval [CI] = 1.8–3.5), but not after adjustment for CD4 cell count, HIV viral load, age, study site, hemoglobin, race, education, smoking, and alcohol use (HR = 1.4, 95% CI = 0.78–2.5). Platelet decline did not predict psychomotor slowing in either univariate (HR = 0.79, 95% CI = 0.58–1.08) or multivariate (HR = 1.10, 95% CI = 0.73–1.67) analysis. Analysis of brain volumetric data, however, indicated a relationship between platelet decline and reduced gray matter volume fraction in univariate (p = 0.06) and multivariate (p < 0.05) analyses. Platelet decline was not an independent predictor of dementia or psychomotor slowing, after adjusting for stage of disease. Findings from a structural brain imaging substudy of older participants, however, support a possible relationship between platelet decline and reduced gray matter.


HIV HIV dementia Hematologic Volumetric MRI Platelets 


  1. Achim CL, Adame A, Dumaop W, Everall IP, Masliah E, Neurobehavioral Research C (2009) Increased accumulation of intraneuronal amyloid beta in HIV-infected patients. J Neuroimmune Pharmacol 4:190–199PubMedCrossRefGoogle Scholar
  2. Angiolillo DJ, Ueno M, Goto S (2010) Basic principles of platelet biology and clinical implications. Circ J 74:597–607PubMedCrossRefGoogle Scholar
  3. Becker JT, Kingsley L, Mullen J, Cohen B, Martin E, Miller EN, Ragin A, Sacktor N, Selnes OA, Visscher BR, Multicenter ACS (2009) Vascular risk factors, HIV serostatus, and cognitive dysfunction in gay and bisexual men. Neurology 73:1292–1299PubMedCrossRefGoogle Scholar
  4. Becker JT, Maruca V, Kingsley LA, Sanders JM, Alger JR, Barker PB, Goodkin K, Martin E, Miller EN, Ragin A, Sacktor N, Selnes O (2011) Factors affecting brain structure in men with HIV disease in the post-HAART era. Neuroradiology (in press)Google Scholar
  5. Boehlen F, Clemetson KJ (2001) Platelet chemokines and their receptors: what is their relevance to platelet storage and transfusion practice? Transfus Med 11:403–417PubMedCrossRefGoogle Scholar
  6. Brass L (2010) Understanding and evaluating platelet function. Hematology 2010:387–396PubMedCrossRefGoogle Scholar
  7. Brown TT, Li X, Cole SR, Kingsley LA, Palella FJ, Riddler SA, Chmiel JS, Visscher BR, Margolick JB, Dobs AS (2005) Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study. AIDS 19:1375–1383PubMedCrossRefGoogle Scholar
  8. Conant K, Garzino-Demo A, Nath A, McArthur JC, Halliday W, Power C, Gallo RC, Major EO (1998) Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci USA 95:3117–3121PubMedCrossRefGoogle Scholar
  9. Conant K, McArthur JC, Griffin DE, Sjulson L, Wahl LM, Irani DN (1999) Cerebrospinal fluid levels of MMP-2, 7, and 9 are elevated in association with human immunodeficiency virus dementia. Ann Neurol 46:391–398PubMedCrossRefGoogle Scholar
  10. Depairon M, Chessex S, Sudre P, Rodondi N, Doser N, Chave JP, Riesen W, Nicod P, Darioli R, Telenti A, Mooser V, Swiss HIVCS (2001) Premature atherosclerosis in HIV-infected individuals–focus on protease inhibitor therapy. AIDS 15:329–334PubMedCrossRefGoogle Scholar
  11. Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Ruther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De Ryck M, Itri L, Prange H, Cerami A, Brines M, Siren AL (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8:495–505PubMedGoogle Scholar
  12. Ehrenreich H, Hasselblatt M, Knerlich F, von Ahsen N, Jacob S, Sperling S, Woldt H, Vehmeyer K, Nave KA, Siren AL (2005) A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain. Proc Natl Acad Sci USA 102:862–867PubMedCrossRefGoogle Scholar
  13. Ellis RJ, Deutsch R, Heaton RK, Marcotte TD, McCutchan JA, Nelson JA, Abramson I, Thal LJ, Atkinson JH, Wallace MR, Grant I (1997) Neurocognitive impairment is an independent risk factor for death in HIV infection. San Diego HIV Neurobehavioral Research Center Group. Arch Neurol 54:416–424PubMedGoogle Scholar
  14. Farinpour R, Miller EN, Satz P, Selnes OA, Cohen BA, Becker JT, Skolasky RL Jr, Visscher BR (2003) Psychosocial risk factors of HIV morbidity and mortality: findings from the Multicenter AIDS Cohort Study (MACS). J Clin Exp Neuropsychol 25:654–670PubMedCrossRefGoogle Scholar
  15. Gartner S (2000) HIV infection and dementia. Science 287:602–604PubMedCrossRefGoogle Scholar
  16. Gawaz M, Neumann FJ, Dickfeld T, Koch W, Laugwitz KL, Adelsberger H, Langenbrink K, Page S, Neumeier D, Schomig A, Brand K (1998) Activated platelets induce monocyte chemotactic protein-1 secretion and surface expression of intercellular adhesion molecule-1 on endothelial cells. [see comment]. Circulation 98:1164–1171PubMedGoogle Scholar
  17. Gawaz M, Brand K, Dickfeld T, Pogatsa-Murray G, Page S, Bogner C, Koch W, Schomig A, Neumann F (2000) Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an interleukin-1-dependent mechanism. Implications for atherogenesis. Atheroscler 148:75–85CrossRefGoogle Scholar
  18. Green DA, Masliah E, Vinters HV, Beizai P, Moore DJ, Achim CL (2005) Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients. AIDS 19:407–411PubMedCrossRefGoogle Scholar
  19. Hsue PY, Lo JC, Franklin A, Bolger AF, Martin JN, Deeks SG, Waters DD (2004) Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation 109:1603–1608PubMedCrossRefGoogle Scholar
  20. Janssen RS (1991) Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology 41:778–785Google Scholar
  21. Jurk K, Kehrel BE (2005) Platelets: physiology and biochemistry. Semin Thromb Hemost 31:381–392PubMedCrossRefGoogle Scholar
  22. Kaslow RA, Ostrow DG, Detels R, Phair JP, Polk BF, Rinaldo CR Jr (1987) The Multicenter AIDS Cohort Study: rationale, organization, and selected characteristics of the participants. Am J Epidemiol 126:310–318PubMedGoogle Scholar
  23. Klinger MH, Jelkmann W (2002) Role of blood platelets in infection and inflammation. J Interferon Cytokine Res 22:913–922PubMedCrossRefGoogle Scholar
  24. Kornbluth RS (2000) The emerging role of CD40 ligand in HIV infection. J Leukoc Biol 68:373–382PubMedGoogle Scholar
  25. Lin CI, Chen CN, Chen JH, Lee H (2006) Lysophospholipids increase IL-8 and MCP-1 expressions in human umbilical cord vein endothelial cells through an IL-1-dependent mechanism. J Cell Biochem 99:1216–1232PubMedCrossRefGoogle Scholar
  26. Martin G, Roy J, Barat C, Ouellet M, Gilbert C, Tremblay MJ (2007) Human immunodeficiency virus type 1-associated CD40 ligand transactivates B lymphocytes and promotes infection of CD4+ T cells. J Virol 81:5872–5881PubMedCrossRefGoogle Scholar
  27. Mena ÁMM, Meijide H, Vázquez P, Castro Á, López S, Bello L, Serrano J, Baliñas J, Pedreira JD (2011) HIV increases mean platelet volume during asymptomatic HIV infection in treatment-naive patients. J Acquir Immune Defic Syndr: JAIDS 57:e112–e113PubMedCrossRefGoogle Scholar
  28. Nagata K, Tsuji T, Todoroki N, Katagiri Y, Tanoue K, Yamazaki H, Hanai N, Irimura T (1993) Activated platelets induce superoxide anion release by monocytes and neutrophils through P-selectin (CD62). J Immunol 151:3267–3273PubMedGoogle Scholar
  29. Nebuloni M, Pellegrinelli A, Ferri A, Bonetto S, Boldorini R, Vago L, Grassi MP, Costanzi G (2001) Beta amyloid precursor protein and patterns of HIV p24 immunohistochemistry in different brain areas of AIDS patients. AIDS 15:571–575PubMedCrossRefGoogle Scholar
  30. Price RW, Epstein LG, Becker JT, Cinque P, Gisslen M, Pulliam L, McArthur JC (2007) Biomarkers of HIV-1 CNS infection and injury. Neurology 69:1781–1788PubMedCrossRefGoogle Scholar
  31. Prodan CI, Ross ED, Vincent AS, Dale GL (2008) Rate of progression in Alzheimer’s disease correlates with coated-platelet levels–a longitudinal study. Transl Res 152:99–102PubMedCrossRefGoogle Scholar
  32. Prodan CI, Ross ED, Stoner JA, Cowan LD, Vincent AS, Dale GL (2011) Coated-platelet levels and progression from mild cognitive impairment to Alzheimer disease. Neurology 76:247–252PubMedCrossRefGoogle Scholar
  33. Ragin AB, Wu Y, Ochs R, Scheidegger R, Cohen BA, Edelman RR, Epstein LG, McArthur J (2010) Biomarkers of neurological status in HIV infection: a 3-year study. Proteomics Clin Appl 4:295–303PubMedCrossRefGoogle Scholar
  34. Ragin AB, Wu Y, Ochs R, Du H, Epstein LG, Conant K, McArthur JC (2011) Marked relationship between matrix metalloproteinase 7 and brain atrophy in HIV infection. J Neurovirol 17:153–158PubMedCrossRefGoogle Scholar
  35. Reitan R (1979) Manual for administration of neuropsychological test batteries for adults and children. Neuropsychology Laboratory, TucsonGoogle Scholar
  36. Schonbeck U, Libby P (2001a) CD40 signaling and plaque instability. Circ Res 89:1092–1103PubMedCrossRefGoogle Scholar
  37. Schonbeck U, Libby P (2001b) The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci 58:4–43PubMedCrossRefGoogle Scholar
  38. Sevigny JJ, Albert SM, McDermott MP, Schifitto G, McArthur JC, Sacktor N, Conant K, Selnes OA, Stern Y, McClernon DR, Palumbo D, Kieburtz K, Riggs G, Cohen B, Marder K, Epstein LG (2007) An evaluation of neurocognitive status and markers of immune activation as predictors of time to death in advanced HIV infection. Arch Neurol 64:97–102PubMedCrossRefGoogle Scholar
  39. Smith A (1982) The symbol digit modalities test manual. Western Psychological Services, Los AngelesGoogle Scholar
  40. Stellos K, Panagiota V, Kogel A, Leyhe T, Gawaz M, Laske C (2010) Predictive value of platelet activation for the rate of cognitive decline in Alzheimer’s disease patients. J Cereb Blood Flow Metab 30:1817–1820PubMedCrossRefGoogle Scholar
  41. Sui Z, Sniderhan LF, Schifitto G, Phipps RP, Gelbard HA, Dewhurst S, Maggirwar SB (2007) Functional synergy between CD40 ligand and HIV-1 Tat contributes to inflammation: implications in HIV type 1 dementia. J Immunol 178:3226–3236PubMedGoogle Scholar
  42. Valcour V, Shikuma C, Shiramizu B, Watters M, Poff P, Selnes O, Holck P, Grove J, Sacktor N (2004) Higher frequency of dementia in older HIV-1 individuals: the Hawaii aging with HIV-1 cohort. Neurology 63:822–827PubMedGoogle Scholar
  43. Wachtman LM, Skolasky RL, Tarwater PM, Esposito D, Schifitto G, Marder K, McDermott MP, Cohen BA, Nath A, Sacktor N, Epstein LG, Mankowski JL, McArthur JC (2007) Platelet decline: an avenue for investigation into the pathogenesis of human immunodeficiency virus-associated dementia. Arch Neurol 64:1264–1272PubMedCrossRefGoogle Scholar
  44. Wang J, Zhang W, Nardi MA, Li Z (2011) HIV-1 Tat-induced platelet activation and release of CD154 contribute to HIV-1-associated autoimmune thrombocytopenia. J Thromb Haemost 9:562–573PubMedCrossRefGoogle Scholar
  45. Weyrich AS, Zimmerman GA (2004) Platelets: signaling cells in the immune continuum. Trends Immunol 25:489–495PubMedCrossRefGoogle Scholar
  46. Weyrich AS, Elstad MR, McEver RP, McIntyre TM, Moore KL, Morrissey JH, Prescott SM, Zimmerman GA (1996) Activated platelets signal chemokine synthesis by human monocytes. J Clin Investig 97:1525–1534PubMedCrossRefGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2011

Authors and Affiliations

  • Ann B. Ragin
    • 1
    • 8
  • Gypsyamber D’Souza
    • 2
  • Sandra Reynolds
    • 2
  • Eric Miller
    • 3
  • Ned Sacktor
    • 4
  • Ola A. Selnes
    • 4
  • Eileen Martin
    • 5
  • Barbara R. Visscher
    • 6
  • James T. Becker
    • 7
  1. 1.Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  2. 2.Johns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  3. 3.Semel Institute for NeuroscienceUniversity of California Los AngelesLos AngelesUSA
  4. 4.The Johns Hopkins University School of MedicineBaltimoreUSA
  5. 5.University of Illinois at ChicagoChicagoUSA
  6. 6.School of Public HealthUniversity of California Los AngelesLos AngelesUSA
  7. 7.University of Pittsburgh School of MedicinePittsburghUSA
  8. 8.Department of RadiologyNorthwestern UniversityChicagoUSA

Personalised recommendations