Y HQC V l f T NAM T H A N G 8 • 8 6 B A C B i f T / 2 0 1 2
MOT
sti
DAC D I I M2£
BAO MAUNG091 n, 16
GHUR; HOC TUYxinme
VA DOT BI^N GEN JAK2V617F TRtN BlNH N H A N TANG TIfiU cAu TICN PHAT
T 6 M T A T
Myc U f u : Nghifn cdu dfc difm t f bio m i u ngo^l vl, td chut hpc tuy xutjng v i d f t bifn gen MK2Vei7F d bfnh nhin t i n g b f u c i u b i n phit t^l Vifn Huyft Hpc TmySn M i u Tmng Lfdng. SSI tuVng v i phuUng p h i p n g h i i n c i h i : 59 bfnh nhin chan doin Ting Ufu cSu b f n phit theo b f u chuHn WHO 2008 dIfu ttj t^l Vifn Huyft Hpc Tniyen M i u Trung iTdng t d 01/2010 d f n 11/2011. Thiet ke nghifn cdu md t i c i t ngang.
K f t q u i v i kSt lu$n: Tuoi ttung binh i i 59 (26- 85), ty If gip cao d Ida tuoi tten 60 (50.8%), ty If nam/nii' la 0.51/1. Sd luUng Ufu cau ttung binh la 1453±476 x l O ' / L Hau het bfnh nhin cd ting sinh mau Ueu S u trong bJy (91.5%) kim roi ki^n hinh ttial. Ty If phit hlfn d f t bifn 3AK2V617F la 52.5%. Nong d f Hb v i so lupng Ueu (au d nhdm od dpt bien gen cao hdn nhdm khdng cd dpt bien ( P < 0 . 0 5 ) . .
Td' khda: T i n g Ueu ciu Ufn phit. Ting sinh tuy m^n i c b'nh, JAK2V617F.
S U M M A R Y
To shidy Uie chatacterisUc of peripheral blood, bone marrov* and JAK2V617F mutation stahis of essenUal Uirombocythemla patients In NaUonal Hematology and Blood Transfusion.
Patient and m e t h o d : a descriptive study carry out 59 paUents witti essenb'al thrombocythemla according to VKHO 2008 criteria was diagnosed and heated in NIHBT from 01/2010 to 11/2011.
Result and conclusion: mean age is 59 (26- 85), male/female raUo Is 0 . 5 1 / 1 , Incidence Is high In the age over 60. Mean platelet count is
(*) \l^ Huyet hoc-Truyin miu TW Phan bifn khoa hpc: TS. N g y i n Thj ND'
Nguyin Ngpc DOng, Nguyin VO Bio Anh Nguyin Dlnh Tuf, Nguyin Anh Trf(*)
14531476 X l O ' / L Bone manow showed proliferaUon of megakaryocytes (91.5%) with abnonnal shape. MK2Vei7F was found In 52.5%
of the patients. PaUents with mutaUon have Hb and platelet count higher than the others (P<0.05).
Key words: Essential thmmbocythemla.
Myeloproliferative neoplasms, JAK2Vie7F.
I.OATVANO£
Ting tiiu ciu tifn phit (Essential thromboeythemia) li mft bfnh thufc nhdm bfnh ting sinh tuy m ^ ic tinh (Myeloproliferative neoplasms), cd dfc diim ting sinh m^n tinh ddng tiiu ciu din din ting cao si lupng miu tiiu ciu di kim vdi hifn tupng ting sinh xo reticulin vi collagen ttong tuy xuong. Diy Ii mft bfnh hiim gip, chd yiu xuit hifn d ngudi Idn, chiim ty If cao nhit li biii 40-60, rit hiim gfp d trd em'-".
Ting tiiu ciu tifn phdt (TTCTP) dupe ghi nhfn lin dau tifn vio nim 1934 bdi eic nhi lim sing huyit hpc Epstein vi Goedel.
Vi din nim 1960, eic trifu chtmg lim sing vi xft nghifm cda bfnh di dupe md ti khi diy dd'. Td nim 2005, mft dpt biin diim dfc trung cho cic bfnh ting smh tdy ndi chung vi TTCTP ndi rieng da dupe phit hifn, dd li dft biin trfn gen Janus kinase 2 (JAK2V617F), dpt biin nay xuat hifn d phin Idn cac bfnh nhan ting sinh tdy m?n tinh khdng cd nhilm sic thi Phi. Din nim 2008, sv ed mft cua dpt biin niy di dupe WHO
97
CHUYfN o£: HQI NOHI KHOA HQC HUYgT H0C«1iMY<N MAU TOAN QUCiC M12 dua vio mft tifu chuin chinh trong chin
doin xic djnh bfnh TTCTP''''''.
Theo hudng din cda WHO 2008, chin doin TTCTP ddi hdi phii ed diy dd tifu chuin td xft nghifm ti bio miu ngoji vi, ti chdc hpc biy xuong, dft biin gen cho din lo^i trit cic nguyfn nhin ting tiiu ciu thd phit. d Vift Nam hifn nay mdi chi cd mft si It CO sd cd thi dng dvmg diy dd cic k; thuft chin doin bfn. Do dd, chdng tdi tiin hinh di tii niy nhim myc tifu; Nghiin ciu dfc diim li bio miu ngopi vl, li chic hpc tiy xurang vi dft biin gen JAK2V617F 6 bfnh nhin ting tliu ciu Itln phil Ipi Vifn Huyit Hpc Truyin Miu Trung Vang.
IL 061 TOpNG VA PHUONO PHAP N6HliN COU 2.1. D i i t n ^ g nghifn cdu
Gim 59 bfnh nhan vio diiu ttj t?i Vifn Huyet Hpc Truyin Miu Trung LTong td thing 01/2010 din thing 11/2011, dupe chin doin xic djnh Ting tiiu ciu tifn phit theo tifu chuin cda WHO 2008.
Tieu chuin chin doin TTCTP (WHO 2008):
1. Tliu ciu ting duy tri lifn tvie ttfn 450 G/L.
2. Xit nghifm tdy xuong thiy ting sinh chu yiu ddng mau TC vdi ting si lupng miu TC kich thudc Idn, trudng thinh.
3. Khdng cd bing chihig cda Da hing ciu, Xo hiy, Lo-xf-mi kinh ddng hfit, Hfi chung rii l o ^ sinh tuy.
4. Cd bing chdng cua dpt biin gen JAK2V617F hofc marker don ddng khic, hoic khdng cd nguyfn nhin giy ting TC phin ung.
Chan doin xac dinh khi cd du ca 4 tieu chuan.
12. Phinmg p U p nghifn cAv Thiit ki nghifn cdu md t i cit ngang.
Cic phucmg phip chin doin dupe ti&i hinh;
• Phin tich tifu bin miu ngo^ vi, tiiu bin djch hdt tdy xuong, tifu bin sinh thiit biy xucmg dinh gii cic rii l o ^ hlnh thii ti bio; mft df ti bio Hiy xuong, mdc df xo tuy xuong. mft df vi hlnh thii miu TC.
• Thvrc hifn phin dng Allele - specific PCR (AS PCR) phit hifn dft biin gen JAK2V617F.
Cic thdng tin thu thfp duoc xu 1^ theo phuong phip thing kf y hpc vdi phin mim SPSS 18.0.
III. K i r QUA NGHllN COU
3.1. D$c diim chung ciia nhdm bfoh nhin nghifn ciiu
Tuii ttung binh cda 2 gidi li 59±12, ngudi it mii nhit li 26 v i nhiiu nhit li 85 hiii. Phin Idn gfp is Ida mii >60 (50.8%).
Bfnh gip d ci 2 gidi: 33.9% d nam vi 66.1%
d nfl. Ty If nam/nO li 0.51/1.
3.2. B$c diim ti bio miu ngof I vi s i lupng HC d miu ngoji vi chd yiu ttong gidi h ^ binh thudng vi ting nh;
(74.6%). Cd 25.4% bfnh nhin giim si lupng HC. Ning df Hb cda phin Idn bfnh nhan ttong gidi h?n binh thudng (64.4%), cdn l(i li thiiu miu muc dp nhp din vda ( 3 5 . 6 ^ ^ Ttong 59 bfnh nhan nghifn cdu, so lupng BC ting cao ttfn 10 x lO'/L gip d 54.2%. Si lupng BC cao nhit la 46 x 10'/L.i Hau hit bfnh nhan cd si lupng TC ting rit cao ttfn 1000 G/L (83.1%), bfnh nhin ci si lupng TC cao nhit la 2890 G/L, thip nhit la 589 G/L. Si luong TC ttimg binh li 1453±476xl0'/L.
Y HOC VIJT NAiW THANB 8 • SO' BAC Bif T/2012
3.3. S$c diim ti chdc hf c tiiy xinmg Bing 3.1. Dfc dii
e$c diSm Mftdf t f bio
Mdc df xd
m to chuc hpc tdy xuonK qua smh thif t tdy Md'cdd
Nqhio tS bio Binh thudng
Giiu te bio Kbdno cd ting xd
Xd rii ric Xd tinq sinh manh
SdiBN(nr=59) 0 24 35 2 43 14
TVI«<Vi>
0%
40.7%
59.3%
3.4%
72.9%
23.7%
JVA^n xit: Mft df ti bio sinh miu ttfn tifu bin sinh thiit phin Idn li giiu ti bio (59.3%) vi binh thudng (40.7%). Khdng ed bfnh nhfin nio giim mft df ti bio. Hiu hit bfnh nhin cd ting sinh xo td mdc df rii ric (72.9%) cho din ting sinh xo mfuih (23.7%).
Bing 3.2. Die d i i m m i u t i f u cau ttfn b f u b e i c dliSm
Mat df I4TC
Roi loan hlnh ttiil MTC
Mdrcdf Binh thudnq Tinq Khdnq roi loan Kich tiiudc Idn Nhieu nhan Nhan tinq mui Kich thudc nhd
i n sum thif t tdy xuon SffBN(n=59]
5 51
0 48 10 49 3
[!
Tvlf % 8.5%
91.5%
0%
81.0%
16.9%
83.0%
5.1%
JVil^ xit. Hau hit bfnh nhan cd mau tiiu ciu ting (91.5%). Rii lojn hinh thii miu tiiu ciu thiy d tit ci cac bfnh nhin. Cac rii lo?n thudng gip; mau tiiu ciu kich thudc Idn (81%), nhin ting mdi (83%), mau tifu ciu nhiiu nhin (16.9%).
3.4. Kit qui xft nghifm dft biin gen JAK2V617F
Thvrc hifn xft nghifm tim ddt biin JAK2V617F d 59 bfnh nhin, chdng tdi thu dupe kit qui duong tinh d 31 bfnh nhan chiim 52.5%.
Bing 3.3. Dje diim xft nghifm cua nhdm ed dft biin JAK2V617F f>$c diem
Duong tinh Am tinh
Solu'dnqTC(G/U 1373±330 1191±456 P < 0.05
Soiu'anqBC(G/L) 18.38±14.25 15.17±12.98 P > 0.05
Nonq do Hb (q/L) 170.68±42.73 106.91±36.89
Nhpn xit. Si lupng TC ttung binh cua nhdm JAK2V617F (+) li 1373±330 xlO'/L cao hon cd f nghia thing ke (P < 0.05) so vdi nhdm khdng ed dpt biin. Ndng df Hb ttung binh cda nhdm JAK2V617F (+) la 170.68±42.73 g/L cao hon ed ^ nghia thing kf (P < 0.05) so vdi nhdm khdng ed dft bien.
99
CHUYEN Bi: HOI NOHI KHOA HOC HUYJt H f l ^ l ^ B f e l MAU TOAN OUgc M12 IV. BAN LUAN
4.1. S$c diim chung nhdm bfnh nhin nghifn clhi
Kit qui nghifn cdu cda chdng tSi vi df mii mic bfnh vi gidi eOng tuong ding vdi cic tie gii khic trong nude vi Quic Ti.
McNally, Roman, Cartwright nghifn cdu djch tl hpc cda cic bfnh miu ic tinh it nude Anh nhfn thiy df mii hay gip nhit cda ci ba thi bfnh ting sinh my m ^ ndi chung li 55 din 65 mii'''''. Oriesshammer, Bangerter, Sauer vi cfng svr nghifn cdu dfc diim lim sing cda 732 bfnh nhin TTCTP nhfn xft Ida mil hay gfp nhit li 50 din 60 mii".
Nguyin Thj Lan theo ddi 28 bfnh nhin TTCTP giai do?n 2000 - 2003 cho thiy d thdi diim dupe chin doin lin diu, cic bfnh nhin phin Idn trfn 60 tuii vdi trung binh li 55 mil'. Nghifn cdu cda Oriesshammer cflng nhu mft si tie gii khic vi bfnh TTCTP cho fliiy ttong bfnh niy nit cd xu hudng mic bfnh cao hon nam'. Nhu vfy, kit qui cua chung tdi cflng nhu cic nghifn cdu khic trong vi ngoii nude diu cho thiy bfnh TTCrrP cd thi gfp d ci hai gidi, chu yiu d ngudi Idn tuii, ty If mic bfnh cao sau 60 tuii.
4.2. S$c diim ti bio miu ngof i vi Tiiu ciu: 59/59 bfnh nhin TTCTP chdng tdi nghifn ciru cd ting si lupng TC d miu ngogi vi. Chdng tdi thiy 83.1% bfnh nhin ed si lupng TC ting ttfn 1000 G/1, ngudi ed TC cao nhit li 2890 G/1, nhihig bfnh nhin niy vio vifn chu yiu di ed diy dd ttifu chiing. Si lupng TC ttung binh khi vio vifn la 1453 G/L, cao hon tie gii Nguyin Thj Lan^ So vdi cic tic gii Quic ti, kit qui cda chdng tdi cflng cao hon: Bellucei quan sit 94 bfnh nhan TTCTP thay si lupng TC ttung bbih li 1200 G/1, Jensen vi cpng sif cho biit 96 bfnh nhan cua hp cd TC trung binh 1102 G/l'''''". Svi khic bift niy ed thi
do bfnh'idlln din Vifn Huyit hpc Trayio miu Trung Uomg - myin chuyf n khoa cuii cdng - khi da dr vio giai do^n toin phit cia bfnh.
Bfch ciu: Bfn cfnh si lupng TC ting cao, chdng tdi cflng thiy si lupng BC ting trfn 10 0/L gip d 54.2% bfnh nhin. Kit qui niy giing vdi mft si tic gii khic trong vi ngoii nude.
Hing ciu: Phin Idn bfnh nhin cOa chdng tdi cd ning df Hb binh thudng. Hb giim dudi 120 g/1 gfp d 35.6%, trong dd cd 7 trudng hpp Hb giim < 80 g/L chiim 11.9%.
s i lupng HC binh thudng ho$c ting nh« gjjp ttong 74.6%. Kit qui niy cflng mong tvi vdi tic gii Nguyin Thj Lan'.
43. fife diim xit nghifm ti chic kft tiiy xiivng
Nghifn ciiu tifu bin sinh thiit biy xuong cua 59 bfnh nhan, chdng tdi thiy 59.3%
trudng hprp ting sinh cic ddng ti bio, cdn l;i 40.7% cd mft df ti bio bhih thudng, khdng cd trudng hpp nao giim mft df te bio sinh miu. Bfn c^nh svi ting sinh cic ddng ti bio my, chung tdi nhfn thiy qui ttinh ting sinh xo xuit hifn d 96.6% bfnh nhin, bong di phin Idn li ting sinh xo muc dp via (72.9%). Nguyin Thj Lan nghifn cdu tiin bfnh nhin TTCTP cflng nhfn thiy 57.1% co ting sinh xo mdc df vda. Thiele J, Cerv^H F, Tefferi A cflng cd nhfn xft biong t v ' ^ W Ting miu TC gfp d hiu hit cic Iffi nhfin (91.5%). Nguyin Thj Lan nhfn xft 76.2% bfnh nhin TTCTP ting sinh niu TC d mdc df vda va m ^ ' . Kit qui nghi^.clhi cua ehiing tdi khic vdi tic gii ttfn cd IS do giai d o ^ bfnh t^ thdi diim duprc chin doin khong giing nhau. Cdng vdi syi ting sinh, tat ei bfnh nhan cda chdng tdi diu cd rii lo^
vi hinh thii mau TC. Trong dd hay gfp nhfc li kiiu rii loan mau tifu ciu kich thudc Idn
Y H p c V l f T NAM T H A N B 8 - S A B A C B I 6 T / 2 0 - | 2
(81%), nhfin ting mdi (83%), mau TC nhiiu nhin (16.9%). Nhflng dfc diim vi miu TC rit dfc trung ttong bfnh TTCTP. Theo tie gii Nguyin Thj Lan, 71.4% bfnh nhfin TTCTP cd thay dii vi hinh thii cda miu TC'.
Smh thiit Uy xuong li mft xit nghifm rit cd i nghia trong chin doin bfnh TTCTP;
k^ thuit niy li phuong tifn khdng thi thay thi gidp phfin tich df giiu ti bio vi nhOng biin dii cda hf xo lifn vdng, miu TC.
4.4. Dfc diim dft biin gen JAK2V617F
4.4.1. T} If Oft biin JAK2V617F Chdng tdi phit hifn dupe mft t^ If khi cao bfnh nhin cd dft biin JAK2V617F, cd 52.5% bfnh nhin TTCTP mang dft biin niy.
Kit qui niy cflng mong tvr vdi cic tic gii trong vi ngoii nude, nhu; Phan Thj Xinh, Nguyin Thien Lfi, Baxter EJ, Levine RL va James tf-"''''".
4.4.2. Liin quan gilta dft biin JAK2V617F vii mft si xit nghifm
So sinh ning 0Hba nhdm ed dft biin gen JAK2V617F vdi nhdm fim tinli, chung tdi nhfn thiy ed svr khic bift rd tft. 6 nhdm TTCTP, bfnh nhin JAK2V617F(+) cd Hb trung bmh la 170 g/L cao hon d bfnh nhin JAK2V617F(-) li 106 g/1, sv khic bift ed f nghia thing kf (P < 0.05). Kit qui cua chung tdi tuong tvi vdi nhin xet cda Guido Finazzi va Tiziano Barbui khi nghifn cdu ttfn cic bfnh nhfin TTCTP''*.
Tiip tpc 6m hiiu su khic bifl vi si lupmg BC, chdng tdi thiy bfnh nhfin JAK2V617F (+) cd si lupng BC cao hon bfnh nhan khdng mang dot biin gen; 18.38 G/L so vdi 15.17 xlO'/L. Tuy nhifn svi khac bift niy khdng ed y nghia thing kf vdi (P >
0.05). Kit qui niy cung Wong tvi nhin djnh cda Baxter EJ vi cpng svi khi nghifn ciiu ve TTCTP. Theo Guido Finazzi vi Tiziano
Barbui thi si lupng BC trung binh cda bfnh nhfin TTCTP cd JAK2V617F li 9.9 xlO'/L cao ban cd ^ nghia thing kf so vdi nhdm khdng cd biin dii gen li 8.1 xlO'/L'''.
vi si lupmg TC, bfnh nhfin TTCTP vdi JAK2V617 (+) ed si lupng TC ttung bhih li 1373 xlO'/L, cao ban nhdm JAK2V617F (-) li 1191 xlO'/L. Mft si tic gii: Tiziano Barbui, Vannucchi AM, Tefferi A, Barosi vi cf ng SVI nghifn cdu vdi si lupng Idn cic bfnh nhin TTCTP diu kit lufn s i lupng TC d nhdm JAK2V617F (+) cao hon cd ^ nghia thing kf so vdi nhdm JAK2V617F (-)«•'»•"
V. Kh LUAN
Qua nghifn cdu eic dfc diim Ifim sing vi xft nghifm d 59 bfnh nhfin dupe chin doin TTCTP chdng tdi nit ta mft si kit lufn:
Bfnh gfp d ei hai gidi, nO nhiiu hon nam, t^ If gfp ting din theo mil vi dfc bift cao d Ida mii tren 60.
Phin Idn benh nhin ed s i lupng TC ting cao > 1000 xlO'/L kim theo ting si lupng BC. Da si cd ning df Hb ttong gidi h?n binh thudng.
Hiu hit bfnh nhin cd ting sinh miu TC kim theo rii lo^in hlnh thii. Mat df ti bio my xuong ting di cdng vdi hifn Mpmg ting sinh xo mdc dp vda din m^nh gip d phin Idn bfnh nhan nghien cdu.
Phit hifn dft biin gen JAK2V617F d 52.5% bfnh nhin nghifn cdu.
Khi so sinh giiia hai nhdm, ching tdi nhfn thiy ning dd Hb vi si lupng TC d nhdm ed dft biin gen cao ban nhdm khdng cd dft biin (P<0.05).
TAI Ulu THAM KHAO
1. Nguyen Vu Bao Anh (2010), "NghiSn cihi die diem lam sang, huyet hpc vi budc diu nh§n xet ve dft bien gen Janus Kinase
101
CHUYEN Bi: HOI NGHI KHOA HQC HUYgX HOC • TWUYJNIHAU TOAN QUgC MM (JAK2V617F) trong mft s i thi bfnh Ong
sinh biy man tinh", Lufn vin bic s j nfl tri, DaihQcYHiNfi.
2. Nguyin Thiin Lit, Ph«m Quang Vinh, VS Quic Vinh, Nguyin Tuin Ting, Nguyin Thj Lan Hwmg (2012), "Triin khai k;
thuit ASO-PCR xic djnh dft biin gen JAK2V6I7F d bfnh nhin ling sinh tdy man tinh tai khoa Huyit hpc - Triyin miu Bfnh vifn Bach Mai", Tpp chi Y hpc Vlft Nam, tl.
9-12.
3. Nguyin Thj Lan (2003), "Nghiin cdu dfc diim lim sing, xit nghifm huyit hpc vi budc diu dinh gii phuang phip gan tliu ciu phii hpp Hydrea bong diiu tn bfnh ting tiiu ciu tiin phit tai Vifn Huyit hpc Truyin miu", Luin vin bic sp chuyin khoa c4>//,tt.3-78.
4. Pban Tb| Xinh, Hoing Anh VO, Nguyin Tin Binh (2010), "iTng dung ky thuft ASO- PCR xic djnh dft bien gen JAK2V6I7F trong nhitng rii loan ting sinh tuy", r<ip chi Yhpc Viet Nam, tr. 351-356.
5. Barbui T, Barosi G, Gross! A, el al (2004),
"Evidence- and consensus-based practice guidelines for the therapy of essential thromboeythemia. A statement from the Italian Society of Hematology".
Haematologica; 89; 215 - 232.
6. Baiter EJ, Scott LM, Campbell PJ, et al.
(2005), 'Acqutavd mutation of the tyratifit kinase JAK2 In human myeloproliferative diiorden". Lancet 365 (9464), pp I0S4 • 1061.
7. Elliott MA, Tefferi A (200S), "Thrombosii and haemorrhage in polycythemia vera and essential thrombocythaemia*. Br I Haematol; 128:275-290.
8. Guido Finazzi c« al (2007), "Risk of thrombosis in patients with essential thromboeythemia and polycythemia vera according to JAJC2V617F mutation status".
Hematologka; 92: 135-136.
9. James C.Ugo V,Cit»lev4 N, CoDiUntineKa SN, Valnchenker W (200S), "A JAK2 mutation In myeloproliferative disorders: Pathogeneai and therapeutic and scientific prospect^.
Trends Moi Med 11( I2):S46.
10. Uvine RL, Wadleigh M,Cooli J,el ll (2005), "Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thromboeythemia, and myeloid metaplasia with myelofibrosis". Cancer Cell; 7:391.
11. Vannucchi AM, Antonioli E, Gnglielmdll P, Rambaldi A, Barosi G, Marchioli R et al (2007). 'Clinical profile of homozygo^
JAK2V6I7F mutation in patients with polycythemiaveia or essential thromboeythemia*. Blood, 110: 840 - 846.
