Vaskulárna medicína 2/2016

Genetické pozadie syndrómu lepivých doštičiek u pacientok s abortami

prof. MUDr. Peter Kubisz, DrSc., MUDr. Juraj Chudej, PhD., MUDr. Juraj Sokol, PhD., RNDr. Mária Škereňová, RNDr. Jela Ivanková, prof.MUDr. Ján Staško, PhD.

Úvod: Spontánne potraty sú často zapríčinené anatomickými, hormonálnymi alebo genetickými abnormalitami. Podľa Bicka až 55 % je spôsobených defektmi koagulačných faktorov alebo krvných doštičiek, vyvolávajúcich trombotické infarkty placentárnych ciev. Vrodené a získané trombofilné stavy zvyšujú riziko výskytu venóznej trombózy počas gravidity a šestonedelia. Tiež bol dokázaný ich vzťah k syndrómu straty plodu, k ťažkej preeklampsii a k intrauterinnému úmrtiu plodu. K vrodenému trombofilnému stavu patrí okrem iných aj syndróm lepivých doštičiek (SPS). SPS je definovaný ako hyperagregabilita trombocytov po nízkych koncentráciách adenozíndifosfátu a/alebo adrenalínu. Po antifosfolipidovom syndróme predstavuje SPS druhý najčastejší trombofilný stav (21 %), zapríčiňujúci syndróm straty plodu. Pacienti a metódy: Vyšetrili sme 27 pacientok so SPS a anamnézou spontánneho potratu a 42 zdravých žien. Diagnóza SPS bola stanovená svetelnou agregometriou (PACKS-4 aggregometer, Helena Laboratories, USA) pomocou metódy a kritérií vypracovaných Mammenom et al. Predmetom záujmu boli štyri jednonukleotidové polymorfizmy (SNP) génu GAS6 (rs7400002, rs1803628, rs8191974, rs9550270), dva SNPs génu PEAR1 (rs12041331, rs12566888), dva SNPs génu MRVI1 (rs7940646, rs1874445) a pätnásť SNPs génu GP6 (rs1654410, rs1671153, rs1654419, rs11669150, rs1613662, rs12610286, rs1654431, rs4281840, rs12981732, rs10417943, rs1671152, rs1654433, rs1671215, rs10418743, rs8113032). Výsledky:Identifikovali sme šesť SNPs génu GP6 s vyššou frekvenciou výskytu u pacientok so SPS a potratom (rs1671153, rs1654419, rs1613662, rs1671152, rs1654433, rs1671215). Pri haplotypovej analýze sme rozpoznali štyri rizikové haplotypy génu GP6 vo vzťahu ku SPS ako možnej príčine spontánnych potratov (CGATAG, CTGAG, CCGT, ACGG). Pri PEAR1 géne boli identifikované dva SNPs, pri GAS6 géne jeden SNP s vyššou frekvenciou výskytu u pacientok so SPS a potratom (PEAR1: rs12041331; rs12566888; GAS6: rs9550270). Závery: Naše výsledky podporujú myšlienku, že genetická variabilita génov GP6, GAS6 a PEAR1 môže byť asociovaná s doštičkovou hyperagregabilitou. Štúdia zároveň poukazuje na možný polygénny (multifaktoriálny) typ dedičnosti pri SPS.

Kľúčové slová: jednonukleotidové génové polymorfizmy, hyperagregabilita trombocytov, syndróm straty plodu, trombofilné trombocytopatie

Genetic background sticky platelet syndrome in patients with abortion

Introduction:Spontaneous abortions are often caused by anatomical, hormonal or genetic abnormalities. According to Bick up to 55% of them are caused by defects in coagulations factors and platelets, which provoke thrombotic infractions of placental vessels. Hereditary and acquired thrombophilia increase risk of venous thrombosis during pregnancy and puerperium. Their connection to foetal loss syndrome, several preeclampsia, and intrauterine foetal death has also been proven. One of hereditary thrombophilia is Sticky Platelet Syndrome (SPS). SPS is defined as platelet hyperaggregability after low concentrations of adenosine diphosphate and/or epinephrine. After antiphospholipid syndrome, it is the second most frequent thrombophilia (21%) and it causes foetal loss syndrome. Patients and methods: We examined 27 female patients with SPS and history of spontaneous abortion, and 42 healthy women. SPS diagnosis was established by light transmission aggregometry (PACKS-4 aggregometer, Helena Laboratories, USA) according to methods and criteria developed by Mammen et al. We were interested in four single nucleotide polymorphisms (SNPs) of GAS6 gene (rs7400002, rs1803628, rs8191974, rs9550270), two SNPs of PEAR1 gene (rs12041331, rs12566888), two SNPs of MRVI1 gene (rs7940646, rs1874445), and fifteen SNPs of GP6 gene (rs1654410, rs1671153, rs1654419, rs11669150, rs1613662, rs12610286, rs1654431, rs4281840, rs12981732, rs10417943, rs1671152, rs1654433, rs1671215, rs10418743, rs8113032). Results: We identified six SNPs of GP6 gene with higher occurrence in patients with SPS and abortion (rs1671153, rs1654419, rs1613662, rs1671152, rs1654433, rs1671215). We also identified four high-risk haplotypes of GP6 gene in our haplotype analysis that are connected to SPS, a possible cause of spontaneous abortions (CGATAG, CTGAG, CCGT, ACGG). We identified two SNPs in PEAR1 gene and one SNP in GAS6 gene, both with higher occurrence in patients with SPS and abortion (PEAR1: rs12041331; rs12566888; GAS6: rs9550270). Conclusions:Our results support the idea that genetic variability of GP6, GAS6 and PEAR1 genes can be associated with platelet hyperaggregability. The study also suggests a possible polygenic (multifactorial) type of SPS heredity.

Keywords: single gene polymorphisms, platelet hyperaggregability, foetal loss syndrome, thrombophilic thrombocytopathies