Oct-4

POU5F1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPOU5F1, OCT3, OCT4, OTF-3, OTF3, OTF4, Oct-3, Oct-4, POU class 5 homeobox 1
External IDsOMIM: 164177 MGI: 101893 HomoloGene: 8422 GeneCards: POU5F1
Gene location (Human)
Chr.Chromosome 6 (human)[1]
Band6p21.33Start31,164,337 bp[1]
End31,180,731 bp[1]
RNA expression pattern




More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

5460

18999

Ensembl

ENSMUSG00000024406

UniProt

Q01860

P20263

RefSeq (mRNA)

NM_203289
NM_001173531
NM_001285986
NM_001285987
NM_002701

NM_001252452
NM_013633

RefSeq (protein)

NP_001239381
NP_038661

Location (UCSC)Chr 6: 31.16 – 31.18 MbChr 17: 35.51 – 35.51 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Oct-4 (octamer-binding transcription factor 4), also known as POU5F1 (POU domain, class 5, transcription factor 1), is a protein that in humans is encoded by the POU5F1 gene.[5] Oct-4 is a homeodomain transcription factor of the POU family. It is critically involved in the self-renewal of undifferentiated embryonic stem cells.[6] As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.[7]

Oct-4 is a member of the octamer transcription factor family, so named because they bind the octameric (8-unit) DNA nucleotide sequence "ATTTGCAT".[8]

Expression and function

Oct-4 transcription factor is initially active as a maternal factor in the oocyte and remains active in embryos throughout the preimplantation period. Oct-4 expression is associated with an undifferentiated phenotype and tumors.[9] Gene knockdown of Oct-4 promotes differentiation, demonstrating a role for these factors in human embryonic stem cell self-renewal.[10] Oct-4 can form a heterodimer with Sox2, so that these two proteins bind DNA together.[11]

Mouse embryos that are Oct-4 deficient or have low expression levels of Oct-4 fail to form the inner cell mass, lose pluripotency, and differentiate into trophectoderm. Therefore, the level of Oct-4 expression in mice is vital for regulating pluripotency and early cell differentiation since one of its main functions is to keep the embryo from differentiating.

Orthologs

Orthologs of Oct-4 in humans and other species include:

SpeciesEntrez GeneIDChromosomeLocationRefSeq (mRNA)RefSeq (protein)
Mus musculus (mouse)1899917,17 B1; 17 19.23 cMNC_000083.4, 35114104..35118822 (Plus Strand)NM_013633.1NP_038661.1
Homo sapiens (human)54606, 6p21.31NC_000006.10, 31246432-31240107 (Minus Strand)NM_002701.3NP_002692.2 (full length isoform)
NP_002692.1 (N-terminal truncated isoform)
Rattus norvegicus (rat)29456220NW_001084776, 650467-655015 (Minus strand)NM_001009178NP_001009178
Danio rerio (zebrafish)30333321NC_007127.1, 27995548-28000317 (Minus strand)NM_131112NP_571187

Structure

Oct-4 contains the following protein domains:

DomainDescriptionLength (AA)
POU domainFound in Pit-Oct-Unc transcription factors75
HomeodomainDNA binding domains involved in the transcriptional regulation of key eukaryotic developmental processes; may bind to DNA as monomers or as homodimers and/or heterodimers in a sequence-specific manner.59

Implications in disease

Oct-4 has been implicated in tumorigenesis of adult germ cells. Ectopic expression of the factor in adult mice has been found to cause the formation of dysplastic lesions of the skin and intestine. The intestinal dysplasia resulted from an increase in progenitor cell population and the upregulation of β-catenin transcription through the inhibition of cellular differentiation.[12]

Pluripotency in embryo development

Animal model

In 2000, Niwa et al. used conditional expression and repression in murine embryonic stem cells to determine requirements for Oct-4 in the maintenance of developmental potency.[7] Although transcriptional determination has often been considered as a binary on-off control system, they found that the precise level of Oct-4 governs 3 distinct fates of ES cells. An increase in expression of less than 2-fold causes differentiation into primitive endoderm and mesoderm. In contrast, repression of Oct-4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus, a critical amount of Oct-4 is required to sustain stem cell self-renewal, and up- or down-regulation induces divergent developmental programs. Changes to Oct-4 levels do not independently promote differentiation, but are also controlled by levels of Sox2. A decrease in Sox2 accompanies increased levels of Oct-4 to promote a mesendodermal fate, with Oct-4 actively inhibiting ectodermal differentiation. Repressed Oct-4 levels that lead to ectodermal differentiation are accompanied by an increase in Sox2, which effectively inhibits mesendodermal differentiation.[13] Niwa et al. suggested that their findings established a role for Oct-4 as a master regulator of pluripotency that controls lineage commitment and illustrated the sophistication of critical transcriptional regulators and the consequent importance of quantitative analyzes.

The transcription factors Oct-4, Sox2 and Nanog are part of a complex regulatory network with Oct-4 and Sox2 capable of directly regulating Nanog by binding to its promoter, and are essential for maintaining the self-renewing undifferentiated state of the inner cell mass of the blastocyst, embryonic stem cell lines (which are cell lines derived from the inner cell mass), and induced pluripotent stem cells.[11] While differential up- and down-regulation of Oct-4 and Sox2 has been shown to promote differentiation, down-regulation of Nanog must occur for differentiation to proceed.[13]

Role in reprogramming

Oct-4 is one of the transcription factors used to create induced pluripotent stem cells, together with Sox2, Klf4 and often c-Myc in mouse,[14][15][16] demonstrating its capacity to induce an embryonic stem cell-like state. These factors are often referred to as "Yamanaka reprogramming factors". This reprogramming effect has also been seen with the Thomson reprogramming factors, reverting human fibroblast cells to iPSCs through Oct-4, along with Sox2, Nanog, and Lin28. The use of Thomson reprogramming factors avoids the need to overexpress c-Myc, an oncogene.[17] It was later determined that only two of these four factors, Oct4 and Klf4, were sufficient to reprogram mouse adult neural stem cells.[18] Finally it was shown that a single factor, Oct-4 was sufficient for this transformation.[19]

In embryonic stem cells

In in vitro experiments of mouse embryonic stem cells, Oct-4 has often been used as a marker of stemness, as differentiated cells show reduced expression of this marker.

Oct3/4 can both repress and activate the promoter of Rex1. In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1.[20] However, in cells that are not actively expressing Oct3/4, exogenous transfection of Oct3/4 will lead to the activation of Rex1.[20] This implies a dual regulatory ability of Oct3/4 on Rex1. At low levels of the Oct3/4 protein, the Rex1 promoter is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.

In adult stem cells

Several studies suggest a role for Oct-4 in sustaining self-renewal capacity of adult somatic stem cells (i.e. stem cells from epithelium, bone marrow, liver, etc.).[21] Other scientists have produced evidence to the contrary,[22] and dismiss those studies as artifacts of in vitro culture, or interpreting background noise as signal,[23] and warn about Oct-4 pseudogenes giving false detection of Oct-4 expression.[24] Oct-4 has also been implicated as a marker of cancer stem cells.[25][26]

See also

References

  1. 1 2 3 ENSG00000206454, ENSG00000204531, ENSG00000237582, ENSG00000229094, ENSG00000233911, ENSG00000235068 GRCh38: Ensembl release 89: ENSG00000230336, ENSG00000206454, ENSG00000204531, ENSG00000237582, ENSG00000229094, ENSG00000233911, ENSG00000235068 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024406 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Takeda J, Seino S, Bell GI (Sep 1992). "Human Oct3 gene family: cDNA sequences, alternative splicing, gene organization, chromosomal location, and expression at low levels in adult tissues". Nucleic Acids Research. 20 (17): 4613–20. doi:10.1093/nar/20.17.4613. PMC 334192. PMID 1408763.
  6. ↑ Young Lab- Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells Archived 2009-06-28 at the Wayback Machine. at MIT
  7. 1 2 Niwa H, Miyazaki J, Smith AG (Apr 2000). "Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells". Nature Genetics. 24 (4): 372–6. doi:10.1038/74199. PMID 10742100.
  8. ↑ Petryniak B, Staudt LM, Postema CE, McCormack WT, Thompson CB (Feb 1990). "Characterization of chicken octamer-binding proteins demonstrates that POU domain-containing homeobox transcription factors have been highly conserved during vertebrate evolution". Proceedings of the National Academy of Sciences of the United States of America. 87 (3): 1099–103. doi:10.1073/pnas.87.3.1099. PMC 53418. PMID 1967834.
  9. ↑ Looijenga LH, Stoop H, de Leeuw HP, de Gouveia Brazao CA, Gillis AJ, van Roozendaal KE, van Zoelen EJ, Weber RF, Wolffenbuttel KP, van Dekken H, Honecker F, Bokemeyer C, Perlman EJ, Schneider DT, Kononen J, Sauter G, Oosterhuis JW (May 2003). "POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors". Cancer Research. 63 (9): 2244–50. PMID 12727846.
  10. ↑ Zaehres H, Lensch MW, Daheron L, Stewart SA, Itskovitz-Eldor J, Daley GQ (Mar 2005). "High-efficiency RNA interference in human embryonic stem cells". Stem Cells. 23 (3): 299–305. doi:10.1634/stemcells.2004-0252. PMID 15749924.
  11. 1 2 Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, Robson P (Jul 2005). "Transcriptional regulation of nanog by OCT4 and SOX2". The Journal of Biological Chemistry. 280 (26): 24731–7. doi:10.1074/jbc.M502573200. PMID 15860457.
  12. ↑ Hochedlinger K, Yamada Y, Beard C, Jaenisch R (May 2005). "Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues". Cell. 121 (3): 465–77. doi:10.1016/j.cell.2005.02.018. PMID 15882627.
  13. 1 2 Thomson M, Liu SJ, Zou LN, Smith Z, Meissner A, Ramanathan S (June 2011). "Pluripotency factors in embryonic stem cells regulate differentiation into germ layers". Cell. 145 (6): 875–89. doi:10.1016/j.cell.2011.05.017. PMID 21663792.
  14. ↑ Okita K, Ichisaka T, Yamanaka S (Jul 2007). "Generation of germline-competent induced pluripotent stem cells". Nature. 448 (7151): 313–7. doi:10.1038/nature05934. PMID 17554338.
  15. ↑ Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R (Jul 2007). "In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state". Nature. 448 (7151): 318–24. doi:10.1038/nature05944. PMID 17554336.
  16. ↑ Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K (Jun 2007). "Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution". Cell Stem Cell. 1 (1): 55–70. doi:10.1016/j.stem.2007.05.014. PMID 18371336.
  17. ↑ Yu J, Vodyanik MA, et al. (2007). "Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells". Science. 318 (5858): 1917–1920. doi:10.1126/science.1151526. PMID 18029452.
  18. ↑ Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M, Schöler HR (Jul 2008). "Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors". Nature. 454 (7204): 646–50. doi:10.1038/nature07061. PMID 18594515.
  19. ↑ Kim JB, Sebastiano V, Wu G, Araúzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D, Meyer J, Hübner K, Bernemann C, Ortmeier C, Zenke M, Fleischmann BK, Zaehres H, Schöler HR (Feb 2009). "Oct4-induced pluripotency in adult neural stem cells". Cell. 136 (3): 411–9. doi:10.1016/j.cell.2009.01.023. PMID 19203577.
  20. 1 2 Ben-Shushan E, Thompson JR, Gudas LJ, Bergman Y (Apr 1998). "Rex-1, a gene encoding a transcription factor expressed in the early embryo, is regulated via Oct-3/4 and Oct-6 binding to an octamer site and a novel protein, Rox-1, binding to an adjacent site". Molecular and Cellular Biology. 18 (4): 1866–78. doi:10.1128/mcb.18.4.1866. PMC 121416. PMID 9528758.
  21. ↑ For example:
    • Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE (Feb 2005). "Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis". Carcinogenesis. 26 (2): 495–502. doi:10.1093/carcin/bgh321. PMID 15513931.
    • Kim JH, Jee MK, Lee SY, Han TH, Kim BS, Kang KS, Kang SK (2009). Mei L, ed. "Regulation of adipose tissue stromal cells behaviors by endogenic Oct4 expression control". PLoS ONE. 4 (9): e7166. doi:10.1371/journal.pone.0007166. PMC 2747014. PMID 19777066.
  22. ↑ Lengner CJ, Camargo FD, Hochedlinger K, Welstead GG, Zaidi S, Gokhale S, Scholer HR, Tomilin A, Jaenisch R (Oct 2007). "Oct4 expression is not required for mouse somatic stem cell self-renewal". Cell Stem Cell. 1 (4): 403–15. doi:10.1016/j.stem.2007.07.020. PMC 2151746. PMID 18159219.
  23. ↑ Lengner CJ, Welstead GG, Jaenisch R (Mar 2008). "The pluripotency regulator Oct4: a role in somatic stem cells?". Cell Cycle. 7 (6): 725–8. doi:10.4161/cc.7.6.5573. PMID 18239456.
  24. ↑ Zangrossi S, Marabese M, Broggini M, Giordano R, D'Erasmo M, Montelatici E, Intini D, Neri A, Pesce M, Rebulla P, Lazzari L (Jul 2007). "Oct-4 expression in adult human differentiated cells challenges its role as a pure stem cell marker". Stem Cells. 25 (7): 1675–80. doi:10.1634/stemcells.2006-0611. PMID 17379765.
  25. ↑ Kim RJ, Nam JS (Jun 2011). "OCT4 Expression Enhances Features of Cancer Stem Cells in a Mouse Model of Breast Cancer". Laboratory Animal Research. 27 (2): 147–52. doi:10.5625/lar.2011.27.2.147. PMC 3145994. PMID 21826175.
  26. ↑ Atlasi Y, Mowla SJ, Ziaee SA, Bahrami AR (Apr 2007). "OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer". International Journal of Cancer. 120 (7): 1598–602. doi:10.1002/ijc.22508. PMID 17205510.

Further reading

  • Lamoury FM, Croitoru-Lamoury J, Brew BJ (2006). "Undifferentiated mouse mesenchymal stem cells spontaneously express neural and stem cell markers Oct-4 and Rex-1". Cytotherapy. 8 (3): 228–42. doi:10.1080/14653240600735875. PMID 16793732.
  • Hough SR, Clements I, Welch PJ, Wiederholt KA (Jun 2006). "Differentiation of mouse embryonic stem cells after RNA interference-mediated silencing of OCT4 and Nanog". Stem Cells. 24 (6): 1467–75. doi:10.1634/stemcells.2005-0475. PMID 16456133.
  • Feldman N, Gerson A, Fang J, Li E, Zhang Y, Shinkai Y, Cedar H, Bergman Y (Feb 2006). "G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis". Nature Cell Biology. 8 (2): 188–94. doi:10.1038/ncb1353. PMID 16415856.
  • Boyer LA, Lee TI, Cole MF, Johnstone SE, Levine SS, Zucker JP, Guenther MG, Kumar RM, Murray HL, Jenner RG, Gifford DK, Melton DA, Jaenisch R, Young RA (Sep 2005). "Core transcriptional regulatory circuitry in human embryonic stem cells". Cell. 122 (6): 947–56. doi:10.1016/j.cell.2005.08.020. PMC 3006442. PMID 16153702.
  • Gerrard L, Zhao D, Clark AJ, Cui W (2005). "Stably transfected human embryonic stem cell clones express OCT4-specific green fluorescent protein and maintain self-renewal and pluripotency". Stem Cells. 23 (1): 124–33. doi:10.1634/stemcells.2004-0102. PMID 15625129.
  • Reményi A, Lins K, Nissen LJ, Reinbold R, Schöler HR, Wilmanns M (Aug 2003). "Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers". Genes & Development. 17 (16): 2048–59. doi:10.1101/gad.269303. PMC 196258. PMID 12923055.
  • Schoorlemmer J, Kruijer W (Dec 1991). "Octamer-dependent regulation of the kFGF gene in embryonal carcinoma and embryonic stem cells". Mechanisms of Development. 36 (1–2): 75–86. doi:10.1016/0925-4773(91)90074-G. PMID 1723621.
  • Wey E, Lyons GE, Schäfer BW (Mar 1994). "A human POU domain gene, mPOU, is expressed in developing brain and specific adult tissues". European Journal of Biochemistry / FEBS. 220 (3): 753–62. doi:10.1111/j.1432-1033.1994.tb18676.x. PMID 7908264.
  • Crouau-Roy B, Amadou C, Bouissou C, Clayton J, Vernet C, Ribouchon MT, Pontarotti P (May 1994). "Localization of the OTF3 gene within the human MHC class I region by physical and meiotic mapping". Genomics. 21 (1): 241–3. doi:10.1006/geno.1994.1249. PMID 8088794.
  • Guillaudeux T, Mattei MG, Depetris D, Le Bouteiller P, Pontarotti P (1993). "In situ hybridization localizes the human OTF3 to chromosome 6p21.3-->p22 and OTF3L to 12p13". Cytogenetics and Cell Genetics. 63 (4): 212–4. doi:10.1159/000133537. PMID 8500351.
  • Abdel-Rahman B, Fiddler M, Rappolee D, Pergament E (Oct 1995). "Expression of transcription regulating genes in human preimplantation embryos". Human Reproduction. 10 (10): 2787–92. doi:10.1093/oxfordjournals.humrep.a135792. PMID 8567814.
  • Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M (Sep 1996). "Generation and analysis of 280,000 human expressed sequence tags". Genome Research. 6 (9): 807–28. doi:10.1101/gr.6.9.807. PMID 8889549.
  • Inamoto S, Segil N, Pan ZQ, Kimura M, Roeder RG (Nov 1997). "The cyclin-dependent kinase-activating kinase (CAK) assembly factor, MAT1, targets and enhances CAK activity on the POU domains of octamer transcription factors". The Journal of Biological Chemistry. 272 (47): 29852–8. doi:10.1074/jbc.272.47.29852. PMID 9368058.
  • Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Schöler H, Smith A (Oct 1998). "Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4". Cell. 95 (3): 379–91. doi:10.1016/S0092-8674(00)81769-9. PMID 9814708.
  • Gonzalez MI, Robins DM (Mar 2001). "Oct-1 preferentially interacts with androgen receptor in a DNA-dependent manner that facilitates recruitment of SRC-1". The Journal of Biological Chemistry. 276 (9): 6420–8. doi:10.1074/jbc.M008689200. PMID 11096094.
  • Butteroni C, De Felici M, Schöler HR, Pesce M (Dec 2000). "Phage display screening reveals an association between germline-specific transcription factor Oct-4 and multiple cellular proteins". Journal of Molecular Biology. 304 (4): 529–40. doi:10.1006/jmbi.2000.4238. PMID 11099378.
  • Ezashi T, Ghosh D, Roberts RM (Dec 2001). "Repression of Ets-2-induced transactivation of the tau interferon promoter by Oct-4". Molecular and Cellular Biology. 21 (23): 7883–91. doi:10.1128/MCB.21.23.7883-7891.2001. PMC 99954. PMID 11689681.
  • Guo Y, Costa R, Ramsey H, Starnes T, Vance G, Robertson K, Kelley M, Reinbold R, Scholer H, Hromas R (Mar 2002). "The embryonic stem cell transcription factors Oct-4 and FoxD3 interact to regulate endodermal-specific promoter expression". Proceedings of the National Academy of Sciences of the United States of America. 99 (6): 3663–7. doi:10.1073/pnas.062041099. PMC 122580. PMID 11891324.
  • Looijenga LH, Stoop H, de Leeuw HP, de Gouveia Brazao CA, Gillis AJ, van Roozendaal KE, van Zoelen EJ, Weber RF, Wolffenbuttel KP, van Dekken H, Honecker F, Bokemeyer C, Perlman EJ, Schneider DT, Kononen J, Sauter G, Oosterhuis JW (May 2003). "POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors". Cancer Research. 63 (9): 2244–50. PMID 12727846.
  • Wang P, Branch DR, Bali M, Schultz GA, Goss PE, Jin T (Oct 2003). "The POU homeodomain protein OCT3 as a potential transcriptional activator for fibroblast growth factor-4 (FGF-4) in human breast cancer cells". The Biochemical Journal. 375 (Pt 1): 199–205. doi:10.1042/BJ20030579. PMC 1223663. PMID 12841847.
  • Reményi A, Lins K, Nissen LJ, Reinbold R, Schöler HR, Wilmanns M (Aug 2003). "Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers". Genes & Development. 17 (16): 2048–59. doi:10.1101/gad.269303. PMC 196258. PMID 12923055.
  • Rajpert-De Meyts E, Hanstein R, Jørgensen N, Graem N, Vogt PH, Skakkebaek NE (Jun 2004). "Developmental expression of POU5F1 (OCT-3/4) in normal and dysgenetic human gonads". Human Reproduction. 19 (6): 1338–44. doi:10.1093/humrep/deh265. PMID 15105401.
  • Matin MM, Walsh JR, Gokhale PJ, Draper JS, Bahrami AR, Morton I, Moore HD, Andrews PW (2005). "Specific knockdown of Oct4 and beta2-microglobulin expression by RNA interference in human embryonic stem cells and embryonic carcinoma cells". Stem Cells. 22 (5): 659–68. doi:10.1634/stemcells.22-5-659. PMID 15342930.
  • Baal N, Reisinger K, Jahr H, Bohle RM, Liang O, Münstedt K, Rao CV, Preissner KT, Zygmunt MT (Oct 2004). "Expression of transcription factor Oct-4 and other embryonic genes in CD133 positive cells from human umbilical cord blood". Thrombosis and Haemostasis. 92 (4): 767–75. doi:10.1160/TH04-02-0079. PMID 15467907.
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