Levels of Platelet-Leukocyte Aggregates in Women With Both Thrombophilia and Recurrent Pregnancy Loss

Abstract

The aim of our study was to investigate the significance of platelet-leukocyte aggregates (PLA) in women with recurrent pregnancy loss (RPL) as well as to identify association between common thrombophilic factors and whole blood levels of PLA in these patients. We measured PLA by whole blood flow cytometry in 66 nonpregnant women with hereditary and/or acquired thrombophilia and RPL, classified to 3 study groups, according to the type of losses (first, second, and third trimester) and 35 age-matched healthy controls. Platelet-leukocyte aggregates levels in all study groups were significantly increased compared to the control group (median values 2.13%, 2.32%, and 2.41%, vs median value in the control group 1.39%, P < .05 for all comparisons). Women with a single thrombophilic factor and women with combination of thrombophilic factors did not differ significantly as regards the PLA levels (2.13% vs 2.27%, P = .4). This study suggests that PLA may have a role in the pathogenesis of RPL in women affected by hereditary or acquired thrombophilia.

Keywords

platelet-leukocyte aggregates recurrent pregnancy loss thrombophilia flow cytometry

References

Hatasaka HH Recurrent miscarriage: epidemiologic factors, definitions, and incidence. Clin Obstet Gynecol. 1994;37(3): 625-634.

Kovalevsky G. , Gracia CR , Berlin JA , Sammel MD , Barnhart KT Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss. Arch Intern Med . 2004;164(5): 558-563.

Khan S. , Dickerman JD Hereditary thrombophilia. Thrombosis J. 2006 ;4(15): 15-32. http://www.thrombosisjournal.com/content/4/1/15; doi:10.1186/1477-9560-4-15.

Khong TY , Pearce JM , Robertson WB Acute atherosis in preeclampsia: maternal determinants and fetal outcome in the presence of the lesion. Am J Obstet Gynecol. 1987;157(2):360-363.

Redman CW , Sacks GP , Sargent IL Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol. 1999;180(2 pt 1):499-506.

Salafia CM , Pezzullo JC , López-Zeno JA , Simmens S. , Minior VK , Vintzileos AM Placental pathologic features of preterm preeclampsia. Am J Obstet Gynecol. 1995;173(4):1097-1105.

Blumenfeld Z. , Benjamin B. Thrombophilia-associated pregnancy wastage . Fertil Steril. 1999;72(5):765-74.

Koeleman BP , Reitsma PH , Allaart CF , Bertina RM Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood. 1994 ;84(4):1031-1035.

Gandrille S. , Greengard JS , Alhenc-Gelas M. , et al. Incidence of activated protein C resistance caused by the Arg506 Gln mutation in factor V in 113 unrelated symptomatic protein C deficient patients. Blood. 1995;86(1):219-224.

10.

Brenner B. , Zivelin A. , Lanir N. , Greengard JS , Griffin JH , Seligsohn U. Venous thromboembolism associated with double heterozygosity for R506Q mutation of factor V and for T298M mutation of protein C in a large family of a previously described homozygous protein C-deficient newborn with massive thrombosis. Blood. 1996;88(3):877-880.

11.

Zoller B. , Berntsdotter A. , Garcia de Frutos P. , Dahlback B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood. 1995;85(12): 3518-3519.

12.

Mandel H. , Brenner B. , Berant M. , et al. Coexistence of hyperhomocysteinemia and factor V Leiden mutation: impact on expression of thrombosis. N Eng J Med. 1996;334(12):763-768.

13.

Brenner B. , Vulfsons SL , Lanir N. , Nahir M. Coexistence of familial antiphospholipid syndrome and factor V Leiden-impact on thrombotic diathesis. Br J Haematol. 1996 ;94(1):166-167.

14.

Li N. , Hu H. , Lindqvist M. , Wikstrom-Jonsson E. , Goodall AH , Hjemdahl P. Platelet-leukocyte cross talk in whole blood. Arterioscler Thromb Vasc Biol. 2000;20(12):2702-2708.

15.

Larsen E. , Celi A. , Gilbert GE , et al. PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell. 1989;59(2):305-312.

16.

Hamburger SA , McEver RP GMP-140 mediates adhesion of stimulated platelets to neutrophils. Blood. 1990;75(3):550-554.

17.

Sako D. , Chang XJ , Barone KM , et al. Expression cloning of a functional glycoprotein ligand for P-selectin . Cell. 1993;75(6): 1179-1186.

18.

Cerletti C. , Evangelista V. , de Gaetano G. P-selectin-beta 2-integrin cross-talk: a molecular mechanism for polymorphonuclear leukocyte recruitment at the site of vascular damage. Thromb Haemost. 1999;82(2):787-793.

19.

Kaplar M. , Kappelmayer J. , Veszpremi A. , Szabo K. , Udvardy M. The possible association of in vivo leukocyte-platelet heterophilic aggregate formation and the development of diabetic angiopathy. Platelets . 2001;12(7):419-422.

20.

Freedman JE , Joseph L. Platelet-monocyte aggregates bridging thrombosis and inflammation. Circulation. 2002;105(18):2130-2132.

21.

Zeller JA , Lenz A. , Eschenfelder CC , Zunker P. , Deuschl G. Platelet-leukocyte interaction and platelet activation in acute stroke with and without precedeing infection. Arterioscler Thromb Vasc Biol. 2005;25(7):1519-1523.

22.

Evangelista V. , Manarini S. , Dell’Elba G. , et al. Clopidogrel inhibits platelet-leukocyte adhesion and platelet-dependent leukocyte activation. Thromb Haemost. 2005;94(3):568-577.

23.

Furman MI , Barnard MR , Krueger LA , et al. Circulating monocyte-platelet aggregates are an early marker of acute myocardial infarction. J Am Coll Cardiol. 2001;38(4):1002-1006.

24.

Htun P. , Fateh-Moghadam S. , Tomandl B. , et al. Course of platelet activation and platelet-leukocyte interaction in cerebrovascular ishemia. Stroke. 2006;37(9):2283-2287.

25.

Yngen M. Platelet Function in Diabetes Mellitus. Relationship to Hyperglycaemia, Antidiabetic Treatment, and Microangiopathy. Stockholm ; Sweden: Karolinska University Press; 2005.

26.

Arellano-Rodrigo E. , Alvarez-Larran A. , Reverter J. , et al. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with JAK2 mutational status. Haematologica. 2006; 91(2):169-175.

27.

Falanga A. , Marchetti M. , Evangelista V. , et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood . 2000;96(13): 4261-4266.

28.

Ashman N. , Macey M. , Fan S. Increased platelet-monocyte aggregates and cardiovascular disease in end-stage renal failure patients. Nephrol Dial Transplant. 2003;18(10):2088-2096.

29.

Michelson AD , Barnard MR , Krueger LA , Valeri CR , Furman MI Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin. Studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation. 2001;104(13): 1533-1537.

30.

Isermann B. , Kashif M. , Nawroth P. Platelet activation impairs placental function . Thromb Res. 2009;123(suppl 2):S85-S87.

31.

Harding SA , Din JN , Sarma J. , et al. Flow cytometric analysis of circulating platelet-monocyte aggregates in whole blood: methodological considerations. Thromb Haemost . 2007;98(2): 451-456.

32.

Ivanov P. , Komsa-Penkova R. , Kovacheva K. , et al. Impact of genetic factors on pulmonary embolism - early onset and recurrent incidences. Lung. 2008;186(1):27-36.

33.

Preston FE , Rosendaal FR , Walker D. , et al. Increased fetal loss in women with heritable thrombophilia. Lancet. 1996;348(9032): 913-916.

34.

Rai R. , Shlebak A. , Cohen H. , et al. Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage. Hum Reprod. 2001;16(5):961-965.

35.

Bick RL Recurrent miscarriage syndrome due to blood coagulation protein/platelet defects: prevalence, treatment and outcome results. DRW Metroplex Recurrent Miscarriage Syndrome Cooperative Group. Clin Appl Thromb Hemost. 2000;6(3):115-125.

36.

Kaptan K. , Beyan C. , Ifran A. , Pekel A. Platelet-derived microparticle levels in women with recurrent spontaneous abortion. Int J Gynaecol Obstet. 2008;102(3):271-274.

37.

Smith GC , Pell JP , Walsh D. Spontaneous loss of early pregnancy and risk of ischaemic heart disease in later life: retrospective cohort study. BMJ. 2003;326(7386):423-424.

38.

Shishehbor MH , Bhat DL Inflammation and atherosclerosis. Curr Atheroscler Rep. 2004;6(2):131-139.

39.

Pitchford SC Novel uses for anti-platelet agents as antiinflammatory drugs. Br J Pharmacol. 2007;152(7):987-1002.

40.

Martinelli I. , Taioli E. , Cetin I. , et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med. 2000;343(14):1015-1018.

41.

Ridker PM , Henekens CH , Selhub J. , Miletich JP , Malinow MR , Stampfer MJ Interrelation of hyperhomocysteinemiq, factor V Leiden and risk of future venous thromboembolism. Circulation. 1997;95(7):1777-1782.

42.

Brenner B. , Sarig G. , Weiner Z. , Younis J. , Blumenfeld Z. , Lanir N. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost. 1999;82(1):6-9.

43.

Hohlagschwandtner M. , Unfried G. , Heinze G. , Huber JC , Nagele F. , Tempfer C. Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage. Fertil Steril. 2003;79(5):1141-1148.

44.

Sotiriadis A. , Vartholomatos G. , Pavlou M. , et al. Combined thrombophilic mutations in women with unexplained recurrent miscarriage. Am J Reprod Immunol. 2007;57(2):133-141.