“Platelet-associated regulatory system (PARS)” with particular reference to female reproduction

Journal of Ovarian Research

Gábor L Kovács¹  Ioannis Hatzipetros³  Katalin Zámbó⁶  Bálint Farkas³  Péter Tamás³  Endre Sulyok²  István Vermes⁵  Szilárd Papp³  József Bódis⁴ 

[1] Szentagothai Research Centre, University of Pécs, 7624 Pécs, Ifjúsag u. 20., Hungary;Faculty of Health Sciences, University of Pécs, 7621 Pécs Vörösmarty u. 4, Hungary;Department of Obstetrics and Gynecology, University of Pécs, 7624 Pécs Édesanyák útja 17, Hungary;HAS-UP Human reproduction scientific research group, 7624 Pécs Édesanyák útja 17, Hungary;Institiute of Diagnostics, Faculty of Health Sciences, University of Pécs, 7400 Kaposvár, Szent Imre u. 14/b, Hungary;Department of Nuclear Medicine, University of Pécs, 7624 Pécs Ifjúság u. 13, Hungary

关键词: Hypothalamo-pituitary-ovarian system;    Endocrine organs;    Tumorgenesis;    Cardiovascular system;    Platelets;   

Others  :  801251
DOI  :  10.1186/1757-2215-7-55

 received in 2014-02-24, accepted in 2014-04-21,  发布年份 2014

【 摘 要 】

Background

Blood platelets play an essential role in hemostasis, thrombosis and coagulation of blood. Beyond these classic functions their involvement in inflammatory, neoplastic and immune processes was also investigated. It is well known, that platelets have an armament of soluble molecules, factors, mediators, chemokines, cytokines and neurotransmitters in their granules, and have multiple adhesion molecules and receptors on their surface.

Methods

Selected relevant literature and own views and experiences as clinical observations have been used.

Results

Considering that platelets are indispensable in numerous homeostatic endocrine functions, it is reasonable to suppose that a platelet-associated regulatory system (PARS) may exist; internal or external triggers and/or stimuli may complement and connect regulatory pathways aimed towards target tissues and/or cells. The signal (PAF, or other tissue/cell specific factors) comes from the stimulated (by the e.g., hypophyseal hormones, bacteria, external factors, etc.) organs or cells, and activates platelets. Platelet activation means their aggregation, sludge formation, furthermore the release of the for-mentioned biologically very powerful factors, which can locally amplify and deepen the tissue specific cell reactions. If this process is impaired or inhibited for any reason, the specifically stimulated organ shows hypofunction. When PARS is upregulated, organ hyperfunction may occur that culminate in severe diseases.

Conclusion

Based on clinical and experimental evidences we propose that platelets modulate the function of hypothalamo-hypophyseal-ovarian system. Specifically, hypothalamic GnRH releases FSH from the anterior pituitary, which induces and stimulates follicular and oocyte maturation and steroid hormone secretion in the ovary. At the same time follicular cells enhance PAF production. Through these pathways activated platelets are accumulated in the follicular vessels surrounding the follicle and due to its released soluble molecules (factors, mediators, chemokines, cytokines, neurotransmitters) locally increase oocyte maturation and hormone secretion. Therefore we suggest that platelets are not only a small participant but may be the conductor or active mediator of this complex regulatory system which has several unrevealed mechanisms. In other words platelets are corpuscular messengers, or are more than a member of the family providing hemostasis.

【 授权许可】

   
2014 Bódis et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Behnke O: The morphology of blood platelet membrane systems. Ser Haematol 1970, 3:3-16.
• [2]Cutler L, Rodan G, Feinstein MB: Cytochemical localization of adenylate cyclase and of calcium ion, magnesium ion-activated ATPases in the dense tubular system of human blood platelets. Biochim Biophys Acta 1978, 542:357-371.
• [3]Stenberg PE, Shuman MA, Levine SP, Bainton DF: Redistribution of alpha-granules and their contents in thrombin-stimulated platelets. J Cell Biol 1984, 98:748-760.
• [4]Harrison P, Savidge GF, Cramer EM: The origin and physiological relevance of alpha-granule adhesive proteins. Br J Haematol 1990, 74:125-130.
• [5]Wencel-Drake JD, Painter RG, Zimmerman TS, Ginsberg MH: Ultrastructural localization of human platelet thrombospondin, fibrinogen, fibronectin, and von Willebrand factor in frozen thin section. Blood 1985, 65:929-938.
• [6]Martin JH, Carson FL, Race GJ: Calcium-containing platelet granules. J Cell Biol 1974, 60:775-777.
• [7]Holmsen H, Weiss HJ: Secretable storage pools in platelets. Annu Rev Med 1979, 30:119-134.
• [8]White JG: A search for the platelet secretory pathway using electron dense tracers. Am J Pathol 1970, 58:31-49.
• [9]White JG: Identification of platelet secretion in the electron microscope. Ser Haematol 1973, 6:429-459.
• [10]White JG: Exocytosis of secretory organelles from blood platelets incubated with cationic polypeptides. Am J Pathol 1972, 69:41-54.
• [11]Bonfanti R, Furie BC, Furie B, Wagner DD: PADGEM (GMP140) is a component of Weibel-Palade bodies of human endothelial cells. Blood 1989, 73:1109-1112.
• [12]Horuk R: Molecular properties of the chemokine receptor family. Trends Pharmacol Sci 1994, 15:159-165.
• [13]Braquet P, Touqui L, Shen TY, Vargaftig BB: Perspectives in platelet-activating factor research. Pharmacol Rev 1987, 39:97-145.
• [14]Leslie M: Cell biology. Beyond clotting: the powers of platelets. Science 2010, 328:562-564.
• [15]Kaplan ZS, Jackson SP: The role of platelets in atherothrombosis. Hematology Am Soc Hematol Educ Program 2011, 2011:51-61.
• [16]Schnell O, Erbach M, Hummel M: Primary and secondary prevention of cardiovascular disease in diabetes with aspirin. Diab Vasc Dis Res 2012, 9:245-255.
• [17]Semple JW, Italiano JE Jr, Freedman J: Platelets and the immune continuum. Nat Rev Immunol 2011, 11:264-274.
• [18]Nguyen T, Ghebrehiwet B, Peerschke EI: Staphylococcus aureus protein A recognizes platelet gC1qR/p33: a novel mechanism for staphylococcal interactions with platelets. Infect Immun 2000, 68:2061-2068.
• [19]Peerschke EI, Yin W, Ghebrehiwet B: Platelet mediated complement activation. Adv Exp Med Biol 2008, 632:81-91.
• [20]Gay LJ, Felding-Habermann B: Contribution of platelets to tumour metastasis. Nat Rev Cancer 2011, 11:123-134.
• [21]Borsig L: The role of platelet activation in tumor metastasis. Expert Rev Anticancer Ther 2008, 8:1247-1255.
• [22]Stiegler G, Stohlawetz P, Brugger S, Jilma B, Vierhapper H, Hocker P, Panzer S: Elevated numbers of reticulated platelets in hyperthyroidism: direct evidence for an increase of thrombopoiesis. Br J Haematol 1998, 101:656-658.
• [23]Erem C, Kocak M, Hacihasanoglu A, Yilmaz M, Saglam F, Ersoz HO: Blood coagulation, fibrinolysis and lipid profile in patients with primary hyperparathyroidism: increased plasma factor VII and X activities and D-Dimer levels. Exp Clin Endocrinol Diabetes 2008, 116:619-624.
• [24]Falcon C, Pfliegler G, Deckmyn H, Vermylen J: The platelet insulin receptor: detection, partial characterization, and search for a function. Biochem Biophys Res Commun 1988, 157:1190-1196.
• [25]Murdoch WJ: Accumulation of thromboxane B2 within periovulatory ovine follicles: relationship to adhesion of platelets to endothelium. Prostaglandins 1986, 32:597-604.
• [26]Li XM, Sagawa N, Ihara Y, Okagaki A, Hasegawa M, Inamori K, Itoh H, Mori T, Ban C: The involvement of platelet-activating factor in thrombocytopenia and follicular rupture during gonadotropin-induced superovulation in immature rats. Endocrinology 1991, 129:3132-3138.
• [27]Maki N, Hoffman DR, Johnston JM: Platelet-activating factor acetylhydrolase activity in maternal, fetal, and newborn rabbit plasma during pregnancy and lactation. Proc Natl Acad Sci U S A 1988, 85:728-732.
• [28]Pritchard PH: The degradation of platelet-activating factor by high-density lipoprotein in rat plasma. Effect of ethynyloestradiol administration. Biochem J 1987, 246:791-794.
• [29]Bodis J, Tinneberg HR, Schwarz H, Papenfuss F, Torok A, Hanf V: The effect of histamine on progesterone and estradiol secretion of human granulosa cells in serum-free culture. Gynecol Endocrinol 1993, 7:235-239.
• [30]Bodis J, Torok A, Tinneberg HR, Hanf V, Hamori M, Cledon P: Influence of serotonin on progesterone and estradiol secretion of cultured human granulosa cells. Fertil Steril 1992, 57:1008-1011.
• [31]Bodis J, Koppan M, Kornya L, Tinneberg HR, Torok A: The effect of catecholamines, acetylcholine and histamine on progesterone release by human granulosa cells in a granulosa cell superfusion system. Gynecol Endocrinol 2002, 16:259-264.
• [32]Koppan M, Bodis J, Verzar Z, Tinneberg HR, Torok A: Serotonin may alter the pattern of gonadotropin-induced progesterone release of human granulosa cells in superfusion system. Endocrine 2004, 24:155-159.
• [33]Vasiljevic M, Prorocic M, Tasic L, Stanimirovic B, Dikic S, Mandic V, Jeremic D: The significance of the ovarian arteriolar vasodilatation in pathogenesis of the ovarian hyperstimulation syndrome. Srp Arh Celok Lek 2006, 134:344-347.
• [34]Fujiwara H, Maeda M, Imai K, Fukuoka M, Yasuda K, Horie K, Takakura K, Taii S, Mori T: Differential expression of aminopeptidase-N on human ovarian granulosa and theca cells. J Clin Endocrinol Metab 1992, 74:91-95.
• [35]Varnagy A, Bodis J, Manfai Z, Wilhelm F, Busznyak C, Koppan M: Low-dose aspirin therapy to prevent ovarian hyperstimulation syndrome. Fertil Steril 2010, 93:2281-2284.
• [36]Krabbe KS, Nielsen AR, Krogh-Madsen R, Plomgaard P, Rasmussen P, Erikstrup C, Fischer CP, Lindegaard B, Petersen AM, Taudorf S, Secher NH, Pilegaard H, Bruunsgaard H, Pedersen BK: Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 2007, 50:431-438.
• [37]Hashimoto K: Sigma-1 receptor chaperone and brain-derived neurotrophic factor: emerging links between cardiovascular disease and depression. Prog Neurobiol 2013, 100:15-29.
• [38]Rasmussen P, Brassard P, Adser H, Pedersen MV, Leick L, Hart E, Secher NH, Pedersen BK, Pilegaard H: Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp Physiol 2009, 94:1062-1069.
• [39]Karege F, Schwald M, Cisse M: Postnatal developmental profile of brain-derived neurotrophic factor in rat brain and platelets. Neurosci Lett 2002, 328:261-264.
• [40]Radka SF, Holst PA, Fritsche M, Altar CA: Presence of brain-derived neurotrophic factor in brain and human and rat but not mouse serum detected by a sensitive and specific immunoassay. Brain Res 1996, 709:122-301.
• [41]Mattson MP, Maudsley S, Martin B: A neural signaling triumvirate that influences ageing and age-related disease: insulin/IGF-1, BDNF and serotonin. Ageing Res Rev 2004, 3:445-464.
• [42]Bhuiyan MS, Tagashira H, Fukunaga K: Sigma-1 receptor stimulation with fluvoxamine activates Akt-eNOS signaling in the thoracic aorta of ovariectomized rats with abdominal aortic banding. Eur J Pharmacol 2011, 650:621-628.
• [43]Fujimoto M, Hayashi T, Urfer R, Mita S, Su TP: Sigma-1 receptor chaperones regulate the secretion of brain-derived neurotrophic factor. Synapse 2012, 66:630-639.
• [44]Bhuiyan MS, Tagashira H, Fukunaga K: Dehydroepiandrosterone-mediated stimulation of sigma-1 receptor activates Akt-eNOS signaling in the thoracic aorta of ovariectomized rats with abdominal aortic banding. Cardiovasc Ther 2011, 29:219-230.
• [45]Lommatzsch M, Zingler D, Schuhbaeck K, Schloetcke K, Zingler C, Schuff-Werner P, Virchow JC: The impact of age, weight and gender on BDNF levels in human platelets and plasma. Neurobiol Aging 2005, 26:115-123.
• [46]Linher-Melville K, Li J: The roles of glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor and nerve growth factor during the final stage of folliculogenesis: a focus on oocyte maturation. Reproduction 2013, 145:R43-R54.
• [47]Andrae J, Gallini R, Betsholtz C: Role of platelet-derived growth factors in physiology and medicine. Genes Dev 2008, 22:1276-1312.
• [48]Smith S, Francis R, Guilbert L, Baker PN: Growth factor rescue of cytokine mediated trophoblast apoptosis. Placenta 2002, 23:322-330.
• [49]Ohlsson R, Falck P, Hellstrom M, Lindahl P, Bostrom H, Franklin G, Ahrlund-Richter L, Pollard J, Soriano P, Betsholtz C: PDGFB regulates the development of the labyrinthine layer of the mouse fetal placenta. Dev Biol 1999, 212:124-136.
• [50]Escalante-Alcalde D, Hernandez L, Le Stunff H, Maeda R, Lee HS Jr, Gang C, Sciorra VA, Daar I, Spiegel S, Morris AJ, Stewart CL: The lipid phosphatase LPP3 regulates extra-embryonic vasculogenesis and axis patterning. Development 2003, 130:4623-4637.
• [51]Shivdasani RA, Rosenblatt MF, Zucker-Franklin D, Jackson CW, Hunt P, Saris CJ, Orkin SH: Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell 1995, 81:695-704.
• [52]Suh TT, Holmback K, Jensen NJ, Daugherty CC, Small K, Simon DI, Potter S, Degen JL: Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice. Genes Dev 1995, 9:2020-2033.
• [53]Iwaki T, Sandoval-Cooper MJ, Paiva M, Kobayashi T, Ploplis VA, Castellino FJ: Fibrinogen stabilizes placental-maternal attachment during embryonic development in the mouse. Am J Pathol 2002, 160:1021-1034.
• [54]Palumbo JS, Zogg M, Talmage KE, Degen JL, Weiler H, Isermann BH: Role of fibrinogen- and platelet-mediated hemostasis in mouse embryogenesis and reproduction. J Thromb Haemost 2004, 2:1368-1379.
• [55]Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R: Proteinase-activated receptors. Pharmacol Rev 2001, 53:245-282.
• [56]Sato Y, Fujiwara H, Zeng BX, Higuchi T, Yoshioka S, Fujii S: Platelet-derived soluble factors induce human extravillous trophoblast migration and differentiation: platelets are a possible regulator of trophoblast infiltration into maternal spiral arteries. Blood 2005, 106:428-435.
• [57]Zarbock A, Polanowska-Grabowska RK, Ley K: Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev 2007, 21:99-111.
• [58]Sato Y, Fujiwara H, Konishi I: Role of platelets in placentation. Med Mol Morphol 2010, 43:129-133.
• [59]James AH, Brancazio LR, Price T: Aspirin and reproductive outcomes. Obstet Gynecol Surv 2008, 63:49-57.
• [60]Peitsidis P, Datta T, Pafilis I, Otomewo O, Tuddenham EG, Kadir RA: Bernard Soulier syndrome in pregnancy: a systematic review. Haemophilia 2010, 16:584-591.
• [61]Tamás PIZ, Szilágyi A: Discordant clinical characteristics suggest different pathogenesis of preeclampsia. J Perinat Med 2007, 35(suppl. 2):278.
• [62]Tamás PVB, Szabó I: Distinct fetal growth and clinical indices in preeclampsia. Magy Nőorv L 2003, 66:211-215.
• [63]Abildgaard U, Heimdal K: Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review. Eur J Obstet Gynecol Reprod Biol 2013, 166:117-123.
• [64]Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA: Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Investig 2003, 111:649-658.
• [65]Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA: Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med 2006, 12:642-649.
• [66]Gotsch F, Romero R, Friel L, Kusanovic JP, Espinoza J, Erez O, Than NG, Mittal P, Edwin S, Yoon BH, Kim CJ, Mazaki-Tovi S, Chaiworapongsa T, Hassan SS: CXCL10/IP-10: a missing link between inflammation and anti-angiogenesis in preeclampsia? J Matern Fetal Neonatal Med 2007, 20:777-792.
• [67]Aly AS, Khandelwal M, Zhao J, Mehmet AH, Sammel MD, Parry S: Neutrophils are stimulated by syncytiotrophoblast microvillous membranes to generate superoxide radicals in women with preeclampsia. Am J Obstet Gynecol 2004, 190:252-258.
• [68]Holthe MR, Staff AC, Berge LN, Lyberg T: Leukocyte adhesion molecules and reactive oxygen species in preeclampsia. Obstet Gynecol 2004, 103:913-922.
• [69]Marques FK, Campos FM, Filho OA, Carvalho AT, Dusse LM, Gomes KB: Circulating microparticles in severe preeclampsia. Clin Chim Acta 2012, 414:253-258.
• [70]Knight M, Redman CW, Linton EA, Sargent IL: Shedding of syncytiotrophoblast microvilli into the maternal circulation in pre-eclamptic pregnancies. Br J Obstet Gynaecol 1998, 105:632-640.
• [71]Hahn S, Holzgreve W: Fetal cells and cell-free fetal DNA in maternal blood: new insights into pre-eclampsia. Hum Reprod Update 2002, 8:501-508.
• [72]Taylor RN, Crombleholme WR, Friedman SA, Jones LA, Casal DC, Roberts JM: High plasma cellular fibronectin levels correlate with biochemical and clinical features of preeclampsia but cannot be attributed to hypertension alone. Am J Obstet Gynecol 1991, 165:895-901.
• [73]Minakami H, Takahashi T, Izumi A, Tamada T: Increased levels of plasma thrombomodulin in preeclampsia. Gynecol Obstet Investig 1993, 36:208-210.
• [74]Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK: Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 1989, 161:1200-1204.
• [75]Redman CW, Bonnar J, Beilin L: Early platelet consumption in pre-eclampsia. Br Med J 1978, 1:467-469.
• [76]Dekker G, Robillard PY: The birth interval hypothesis-does it really indicate the end of the primipaternity hypothesis. J Reprod Immunol 2003, 59:245-251.
• [77]Robertson SA, Ingman WV, O’Leary S, Sharkey DJ, Tremellen KP: Transforming growth factor beta–a mediator of immune deviation in seminal plasma. J Reprod Immunol 2002, 57:109-128.
• [78]Weyrich AS, Zimmerman GA: Platelets: signaling cells in the immune continuum. Trends Immunol 2004, 25:489-495.
• [79]Austgulen R, Lien E, Vince G, Redman CW: Increased maternal plasma levels of soluble adhesion molecules (ICAM-1, VCAM-1, E-selectin) in preeclampsia. Eur J Obstet Gynecol Reprod Biol 1997, 71:53-58.
• [80]Moncada S, Higgs EA: The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol 2006, 147(Suppl 1):S193-S201.
• [81]Tamás P, Bódis J, Sulyok E, Kovács L, Hantosi E, Molnár G, Leben-Hoffer J, B-B SM: L-arginin metabolism in early-onset and late-onset pre-eclamptic pregnancies. Scand J Clin Lab Invest 2013, 73:436-443.
• [82]Tamas P, Csermely T, Ertl T, Vizer M, Szabo I, Prievara FT: Calcium dobesilate lowers the blood pressure in mild to moderate midtrimester hypertension: a pilot study. Gynecol Obstet Investig 1999, 47:210-213.
• [83]Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA: Pathophysiology of preeclampsia: linking placental ischemia/hypoxia with microvascular dysfunction. Microcirculation 2002, 9:147-160.
• [84]Harlow FH, Brown MA, Brighton TA, Smith SL, Trickett AE, Kwan YL, Davis GK: Platelet activation in the hypertensive disorders of pregnancy. Am J Obstet Gynecol 2002, 187:688-695.
• [85]von Hundelshausen PW, Weber C: Platelets as immune cells. Bridging inflammation and cardiovascular disease. Circ Res 2007, 100:27-40.
• [86]Tamás P, Gresele P, Bódis J, Polidori D, Nenci GG, Csaba I: The reduced erythrocyte deformability in preeclampsia is due to altered plasma to red blood cell interaction. In Hypertension in Pregnancy Bologna: Monduzzi Edited by Cosmi AV, DiRenzo GC. 1991, 399-402.
• [87]Weinstein L: Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982, 142:159-167.
• [88]Aarts PA, Heethaar RM, Sixma JJ: Red blood cell deformability influences platelets–vessel wall interaction in flowing blood. Blood 1984, 64:1228-1233.
• [89]Heilmann L, Rath W, Pollow K: Hemorheological changes in women with severe preeclampsia. Clin Hemorheol Microcirc 2004, 31:49-58.
• [90]Fitzgerald JR, Loughman A, Keane F, Brennan M, Knobel M, Higgins J, Visai L, Speziale P, Cox D, Foster TJ: Fibronectin-binding proteins of Staphylococcus aureus mediate activation of human platelets via fibrinogen and fibronectin bridges to integrin GPIIb/IIIa and IgG binding to the FcgammaRIIa receptor. Mol Microbiol 2006, 59:212-230.
• [91]Yeaman MR, Bayer AS: Antimicrobial peptides from platelets. Drug Resist Updat 1999, 2:116-126.
• [92]Youssefian T, Drouin A, Masse JM, Guichard J, Cramer EM: Host defense role of platelets: engulfment of HIV and Staphylococcus aureus occurs in a specific subcellular compartment and is enhanced by platelet activation. Blood 2002, 99:4021-4029.
• [93]Faas MM, Schuiling GA, Baller JF, Visscher CA, Bakker WW: A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats. Am J Obstet Gynecol 1994, 171:158-164.
• [94]Mittendorf R, Lain KY, Williams MA, Walker CK: Preeclampsia. A nested, case–control study of risk factors and their interactions. J Reprod Med 1996, 41:491-496.
• [95]Heine RP, Ness RB, Roberts JM: Seroprevalence of antibodies to Chlamydia pneumoniae in women with preeclampsia. Obstet Gynecol 2003, 101:221-226.
• [96]Conteras A, Herrern JA, Soob JE, Aree RM, Jaramillo A, Botero J: Periodontitis is associated with preeclampsia in pregnant women. J Periodontal Res 2006, 77:182-188.
• [97]Todros T, Verdiglione P, Ogge G, Paladini D, Vergani P, Cardaropoli S: Low incidence of hypertensive disorders of pregnancy in women treated with spiramycin for toxoplasma infection. Br J Clin Pharmacol 2006, 61:336-340.
• [98]Martin JN Jr, Files JC, Blake PG, Perry KG Jr, Morrison JC, Norman PH: Postpartum plasma exchange for atypical preeclampsia-eclampsia as HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Am J Obstet Gynecol 1995, 172:1107-1125. discussion 1125–1107
• [99]Villa PM, Kajantie E, Raikkonen K, Pesonen AK, Hamalainen E, Vainio M, Taipale P, Laivuori H: Aspirin in the prevention of pre-eclampsia in high-risk women: a randomised placebo-controlled PREDO Trial and a meta-analysis of randomised trials. BJOG 2013, 120:64-74.
• [100]Ruggeri ZM, Orje JN, Habermann R, Federici AB, Reininger AJ: Activation-independent platelet adhesion and aggregation under elevated shear stress. Blood 2006, 108:1903-1910.