Sunteți pe pagina 1din 58

FIZIOPATOLOGIA SERIEI

LEUCOCITARE

LEUCEMIA ACUTA
LEUCEMIA INTRODUCERE
 Leucemia este o afectiune maligna
characterizata prin proliferarea neregulata a
unui tip celular.
 Poate interesa oricare dintre liniile celulare,, una
sau mai multe linii celulare, sau celulele stem.
 Leucemiile sunt clasificate in doua grupe majore:
 Cronice, la care debutul
Cronice debutul, de regula,
regula este insidios,
insidios boala
este mai putin agresiva, iar celulele implicate sunt, de
regula, mature
 Acute, la care debutul, de regula, este rapid, boala este
foarte agresiva iar celulele implicate sunt slab
diferentiate cu multi blasti.
Modificari cantitative ale
seriei leucocitare
 Leucocitoza (cresterea numarului de leucocite peste
9.000/mmc) - poate apare in conditii fiziologice, prin
modificari de distributie in arborele circulator sau prin
solicitarea fiziologica a sistemului leucocitar (activitate fizica
intensa, expunere la frig, digestie intestinala, graviditate,
emotii, stres) sau patologice , prin intensificarea
leucopoiezei medulare si prin mobilizarea leucocitelor aflate
in circulatie sau in tesuturi ( infectii
infectii, hemoragii
hemoragii, inflamatii
inflamatii,
afectiuni endocrine, neurologice, leucemii).
 Leucopenia (scaderea numarului de leucocite sub
4000/mmc) - apare de obicei in conditii patologice: de
distributie ( soc anafilactic, frisoane), prin inhibitie
medulara ( infectii), de epuizare, prin inhibitia leucopoiezei
( dupa
d pa iradiere
i adie e cu
c raze
a e X,
X toxice
to ice chimice).
chimice)
 Neutrofilia ( cresterea numarului de granulocite neutrofile
peste 7000/mmc)-
7000/mmc) apare prin mobilizarea rezervelor
medulare sau prin cresterea productiei de granulocite (
infectii bacteriene, necroze inflamatorii, tulburari
metabolice, administrarea de corticosteroizi, hemoragii
acute si hemolize, afectiuni mieloproliferative).
 Neutropenia ( scaderea numarului de neutrofile sub
2500/mmc) - apare ca urmare a productiei scazute de
neutrofile ( prin proliferare medulara redusa,
granulocitopoieza ineficienta) sau ca urmare a scaderii
duratei de supravietuire in circulatie a neutrofilelor ( prin
accelerarea trecerii in tesuturi a neutrofilelor in infectii,
inflamatii, sau prin distrugerea neutrofilelor de catre
antico pi -hipersplenism,
anticorpi hipe splenism defecte de maturatie).
mat atie)
 Eozinofilia ( cresterea numarului de granulocite eozinofile peste 400/mmc)
-apare in afectiuni alergice, parazitare, dermatologice, hematologice,
t
tumori, i imunodeficiente,
i d fi i t sau asociatei t altor
lt afectiuni
f ti i ( sindrom
i d Loffler,
L ffl
aspergiloza bronhopulmonara, pleurezia cu eozinofile, poliartrita
reumatoida, poliarterita nodoasa, dermatomiozita, fasciita eozinofilica,
sindromul Churg
Churg-Strauss
Strauss, sarcoidoza
sarcoidoza, boli renale cronice,
cronice etc)
etc), postiradiere
postiradiere,
eozinofilia ereditara. Sindromul hipereozinofilic primar - defineste o
eozinofilie cu valori inalte, peste 1500/mmc, de etiologie neprecizata, care
persista peste 6 luni, asociata cu disfunctia unor organe, consecutiva
i filt ii lor
infiltrarii l cu eozinofile.
i fil
 Eozinopenia ( scaderea numarului de granulocite eozinofile sub
200/mmc)- datorata hiperfunctiei CSR. Apare in stari de stres,
posttraumatic post interventii chirurgicale,
posttraumatic, chirurgicale dupa corticoterapie,
corticoterapie vitamina C
in doze mari si insulina, in cursul infectiilor acute cu neutrofilie, dupa
expunere la frig, eforturi fizice mari. Aneozinofilia este patognomonica
pentru febra tifoida.
p
 Bazofilia ( cresterea numarului de granulocite bazofile peste 80/mmc)-
apare in sindroame mieloproliferative, colite ulcerative, artrite reumatoide,
urticarie,
ti i mixedem,
i d postsplenectomie.
t l t i
 Bazopenia - scaderea numarului de granulocite bazofile nu are nici o
semnificatie diagnostica, Apare in stari de stres, infectii acute, hipertiroidie,
administrare de corticosteroizi.
corticosteroizi
 Monocitoza ( cresterea numarului absolut de monocite peste
800/mmc) - apare ca urmare a stimularii productiei medulare de monocite
de catre FSC
FSC-M
M. Se intalneste in boli infectioase,
infectioase neoplazii,
neoplazii LES,
LES
sarcoidoza, sprue, colita ulceroasa, boli mieloproliferative, leucemii
monocitare, limfoame maligne, mielom multiplu, neutropenii cronice,
anemii hemolitice autoimune, unele reactii medicamentoase.
 Monocitopenia ( scaderea numarului de monocite sub 150/mmc) -
apare in aplazia medulara, leucemia cu tricholeucocite, dupa
corticoterapie.
 Limfocitoza ( cresterea numarului de limfocite peste 3000/mmc) - apare in
modificari primare neoplazice ale seriei limfatice ( leucemia limfocitar
cronica,
i limfoame
li f maligne)
li ) ca limfocitoza
li f it reactiva
ti ( infectii
i f tii virale,
i l boli
b li
infectioase acute si cronice, rahitism, hipertiroidie).
 Limfocitopenia ( scaderea numarului de limfocite sub 1500/mmc) -
apare ca urmare a productiei scazute ( imunodeficiente
imunodeficiente, malnutritie
malnutritie, dupa
tratament citostatic, corticoterapie, boala hodgkin, mixedem, boala
Cushing), prin modificari in circulatia limfocitelor, tranzitorii, mediate de
cresterea g glucosteroizilor endogeni
g ( stres)) sau prin
p distructii crescute (
boli autoimune, infectii virale) ori pierderi ( rupturi sau fistule ale canalului
toracic, enteropatii cu pierdere de proteine, insuficiente cardiace grave).
 Plasmocitoza ( cresterea numarului de plasmocite peste 180/mmc)-
este
t expresia i uneii sinteze
i t crescutet de
d imunoglobuline.
i l b li Apare
A in
i boli
b li
infectioase, ciroza hepatica, alergia la penicilina, boala serului.
Modificari calitative ale
elementelor seriei leucocitare
 Defectele calitative ale neutrofilelor determina alterari ale
fagocitozei Anomaliile pot fi : congenitale ( deficitele lizei
fagocitozei.
microbiene - granulomatoza cronica familiala, deficienta
severa de G-6-PD, deficienta de MPO din granulatiile
neutrofile
fil sii monocite;
i anomalii
lii de
d structura celulara
l l -
sindromul Chediak-Higasi, anomalia Adler, anomalia Pelger-
Huet, anomalia MayMay-Hegglin,
Hegglin, deficitul de adeziune
leucocitara I) sau dobandite ( defecte intrinseci ale
neutrofilului - in leucemiile acute si cronice, HPN, sindromul
leucocitelor lenese; defecte extrinseci neutrofilului - diabet
zaharat, uremie, mielom multiplu, arsuri severe)
Disfunctii ale monocitelor si
macrofagelor
g
 apar in osteopetroza ( deficit izolat al
osteoclastelor, cu diminuarea resorbtiei
osoase si formarea " oaselor de marmura"),
marmura ),
boala granulomatoasa cronica, sindromul
Chediak-Higashi candidioza mucocutanata
Chediak-Higashi,
diseminata, terapia cu glucocorticoizi,
f
fumatul.
t l
SINDROAME
MIELODISPLAZICE (SMD)
 Sindroamele mielodisplazice (stări preleucemice) sunt afecţiuni clonale ale celulei
stem caracterizate prin citopenii periferice cu măduvă hiper- sau normocelulară, cu
semne de dishematopoieză uni- uni sau multilineară şi frecvente anomalii
cromozomiale.
 Factori de risc implicaţi în apariţia SMD:
 factori genetici şi constituţionali: sindromul Down, anemia Fanconi, boala von
Recklinghausen;
 iradierea cu doze mari sau repetate de radiaţii ionizante ( raze X sau gamma);
 substanţe chimice sau medicamentoase : benzen, agenţi alchilanţi;
 aplazia medulară tratată cu imunosupresoare, neutropenia congenitală tratată
cronic cu G-CSF.
 SMD sunt tulburări clonale dobândite, rezultând ca urmare a transformării
neoplazice a CSP
CSP, cu afectarea în special a celulei stem orientate mieloid (rar a
celor limfoide), care suferă o tulburare profundă a proceselor de maturare şi
diferenţiere celulară, cu hematopoieză ineficientă prin hiperapoptoză şi o producţie
inadecvată de celule sanguine mature cu modificări displazice.
 SMD pott fi primare
i şii secundare
d (terapiei
(t i i citostatice,
it t ti imunosupresoare
i , induse
i d de
d
factori ocupaţionali şi de mediu, HIV).
Leucemiile
 Leucemiile sunt afecţiuni maligne clonale,
caracterizate prin proliferarea nelimitată de
leucocite anaplazice, cu aberaţii cromozomiale,
având caracter invadant şi infiltrativ la nivelul
măduvei osoase hematogene şi teritoriilor
extramedulare. Leucemiile pot fi acute sau
cronice.
i
LEUCEMIA INTRODUCERE
 Atat cele cronice, cat si cele acute se clasifica functie de linia
celulara p
predominant proliferativa:
p
 Daca linia celulara predominanta apartine seriei mieloide este vorba
despre o leucemie mielocitara (denumita, uneori si leucemie
granulocitara)
 Daca linia celulara predominanta apartine seriei limfoide este vorba
despre o leucemie limfocitara
 Prin urmare, exista patru tipuri majore de leucemie
 Leucemia mieloida acuta (Acute Mielocytic leukemia – AML)-

care include mieloblasti, promielocite, monocite, mielomonocite,


eritrocite si megakariocite)
 Leucemia
L i LiLimfocitara
f i A
Acuta (Acute
(A lymphocytic
l h i leukemia
l k i –
ALL) care include celule T , B si celule NK (Natural Killer cell- Null
cell)
 Leucemia Mielocitara Cronica (Chronic myelocytic leukemia –

CML) – care include myelocite si mielomonocite)


LEUCEMIA INTRODUCERE
 Leucemia Limfocitara Cronica (Chronic lymphocytic
leukemia – CLL)) – care include pplasmocite {mielom
{ multiplu},
p },
celule paroase, prolimfocite, large granular cell lymphocytic,
Sezary’s syndrome, and circulating lymphoma)
 Etiologie – cauza exacta este frecvent necunoscuta
necunoscuta, dar
se cunosc factori predispozanti:
 Factori ai gazdei
g
 Some individuals have an inherited increased predisposition to
develop leukemia
 There is an increased incidence in those with an inherited tendency
for chromosome fragility or abnormality or those with increased
numbers of chromosomes (such as Down’s syndrome). Many of
these diseases are characterized by chromosomal translocations
translocations.
Leucemia Introducere
 Incidenta crescuta la cei cu imunodeficiente
ereditare.
ereditare
 Incidenta crescuta la cei cu disfunctii medulare
cronice cum ar fi boli mieloproliferative, sindr
mielodisplazice,
i l di l i anemiai aplastica,
l ti hemoglobinuria
h l bi i
paroxistica nocturna.
 Factori de mediu:
 Expunere radiatii ionizante
 Expunere la mutagene chimice si anumite subst
medicam
 Infectia virala
LEUCEMIA INTRODUCERE
 Incidenta
 Acute leukemias can occur in all age groups
 ALL (Acute Lymphoblastic Leukemia) is more common
in children
 AML (Acute Myeloid Leukemia) is more common in
adults
 Chronic leukemias are usually a disease of adults
 CLL (Chronic Lymphocytic Leukemia) is extremely rare
i children
in hild and
d unusuall before
b f the
h age off 40
 CML (Chronic Myeloid Leukemia) has a peak age of
30 50
30-50
LEUCEMIA INTRODUCERE
 Comparatie lecucemie acuta vs cronica:
Acute Chronic
Varsta all ages usually adults
Debut Clinic sudden insidious
Evolutie (netratata) 6 mo. or less 2-6 years
Celule Leucemice immature >30% blasts more mature cells
Anemia prominent mild
Thrombocytopenia prominent mild
Nr leucocite variable increased
Li h d
Limphadenopaie i mild
ild present;often
t ft prominent
i t
Splenomegalie mild present;often prominent
LEUCEMIA INTRODUCERE
 Leucemia Acuta –
 E
Este rezultatul:
l l
 Transformarii maligne a celulei stem conducand la proliferare
g
neregulata si
 Oprind maturarea la stadiul de blasti primitivi. Remember that
a blast is the most immature cell that can be recognized as
committed to a particular cell line.
 Aspecte clinice
 Proliferare Leucemica, accumulare si invasizie a tesuturilor
normale,
l incluzand
i l d ficatul,
fi t l splina,
li ggll limfatici,
li f ti i sist
i t nerv
central, pilele.
 Posibil un mediator umoral secretat de celulele leucemice ar
inhiba
h b proliferarea
lf celulelor
l l l normale.
l
LEUCEMIA INTRODUCERE
 Insuficienta maduvei si hematopoezei normale
poate conduce la pancitopenie si moarte prin
hemoragii si infectii.
 Evaluare de laborator
 Diagnosticul de laborator de bazeaza pe doua
aspecte
 Aparitia unei cresteri semnificative de elemente
imature in maduva incluzand blasti, promielocite,
p
promonocite (>30% blasti este semn diagnostic)
 Identificarea liniei celulare leucemice
LEUCEMIA INTRODUCERE
 Sangele periferic:
 Anemia
A i (normocroma,
( normocitara)
it )
 Scadere plachete
 Numar leucocite Variabil
 The degree of peripheral blood involvement determines
classification:
 Leukemic
Le kemic – increased
inc eased WBCs d duee to blasts
 Subleukemic – blasts without increased WBCs

 Aleukemic – decreased WBCs with no blasts

 Clasificarea celulelor imature implicate trebuie


facuta prin:
LEUCEMIA INTRODUCERE
 Morfologie – an experienced morphologist
can look at the size of the blast, the amount
of cytoplasm, the nuclear chromatin pattern,
the presence of nucleoli and the presence of
auer rods (are a pink staining
staining, splinter
shaped inclusion due to a rod shaped
alignment of primary granules found only in
myeloproliferative processes) to identify the
blast type:
 AML – mieloblastul este un blast mare cu
cantitate moderata de citoplasma, cromatina
fina, nucleoli proeminenti. 10-40% dintre
mieloblasti contin corpi Auer.

Myeloblast cu corpi Auer


LEUCEMIA INTRODUCERE
 ALL (Leuc Limfoblastica acuta) – in contrast cu cea
mieloblastica limfoblastul este un blast mic cu
mieloblastica,
insuficienta citoplasma, cromatina densa, nucleoli
nedistinctivi si fara corpii Auer.

Limfoblast
LEUCEMIA INTRODUCERE

 Citocimia – ajuta la
clasificarea liniei celulare
leucemice (mieloida
versus limfoida)
 Mieloperoxidaza
Mi l id – se
afla in granulatiile
primare ale cel
granulocitare incepand
cu stadiul de blast
tarziu. Monocitele pot fi
slab positive
positive.
Negru Sudan
 Negru Sudan coloreaza
phospholipidele grasimile neutre si
phospholipidele,
sterolii aflati in granulele primare si
secundare ale celulei granulocitare
si mai putin in lizozomii
monocitelor. Rareori apare
positivitate in celulele limfoide
Esteraza Nonspecifica

 Esteraza Nespecifica– este utilizata


pentru a identifica cel monocitare
care suntt dif
difuz pozitive.
iti Limfocitele
Li f it l
T pot avea colorari focale
Fosfataza Acida
 Fosfataza Acida poate fi gasita in
mieloblasti si limfoblasti.
limfoblasti Limfocitele T
au un nivel cresut de fosfataza acida si
pot fi utilizate pentru a ajuta
diagnosticul leucemiei acute T
limfocitare.
Fosfataza alcalina leucocitara
 Fosfataza alcalina leucocitara– este
localizata in granulele tertiare ale
neutrofilelor segmentate si in
metamielocite. Scorul FAL este
determinat numarand 100 neutrofile
mature scorand de la 0 la 5 fiecare
celula. The total LAP score is
calculated by adding up the scores for
each cell.
Fosfataza alcalina leucocitara
LEUCEMIA INTRODUCERE
 Markerii imunologici (imunofenotiparea) – sunt utilizati mai ales
pentru lymphocytes,
p y p y , i.e.,, pentru
p determinarea liniilor B sau T.
Se bazeaza pe anticorpii anti markeri specifici de suprafata.
Constituie ceea ce numim anticorpi primari . Fluorescently
labeled antibodyy ((secondaryy antibody)
y) against
g the primary
p y
antibody is added and allowed to react and then unbound
secondary antibody is washed away. The cells are then sent
through a flow cytometer that will determine the number of
cells that have a fluorescent tag and which are thus positive for
the presence of the surface marker to which the primary
antibody was made. In a direct assay, the primary antibody is
fl
fluorescently
tl labeled.
l b l d
Direct versus indirect labeling
of antigens
Flow cytometer
Deoxytidyl transferaza
terminala
 Este o DNA polimeraza unica prezenta
in celulele stem si in precursorii B si T
limfoizi celulari. Niveluri crescute se
gasesc in 90% din leucemia
limfoblastica It can also be detected
limfoblastica.
using appropriate antibodies and flow
cytometry.
t t
LEUCEMIA INTRODUCERE
 Citogeneza – studiile citogenetice pot fi cum utilizate
pentru diagnostic si pentru prognosticul afectiunilor
hematologice maligne.
 Many leukemias (and lymphomas) are characterized by
specific
ifi chromosomal
h l abnormalities,
b li i including
i l di specific
ifi
translocations and aneuploidy. The specific type of
malignancy can be identified based on the specific
abnormality
b lit or translocation.
t l ti Th
These may be b identified
id tifi d by
b
 Looking at the karyotypes of the chromsomes from the

abnormal cells
 DNA based tests – these tests are very useful for

following the course of the disease


 A normal karyotype
y yp is usuallyy associated with a better
prognosis.
Chromosomal translocation
Chromosome karyotyping
Leucemiile acute
 Leucemia limfoblastica acuta
 They may b
Th be classified
l ifi d on theh
basis of the cytological features
of the lymphoblasts into;
 L1 - This is the most common
form found in children and it has
the best prognosis
prognosis. The cell size
is small with fine or clumped
homogenous nuclear chromatin
and absent or indistinct nucleoli.
The nuclear shape is regular,
occasionally clefting or indented.
The cytoplasm
y p is scant,, with slight
g
to moderate basophilia and
variable vacuoles.
LLeucemia
i limfoblastica
li f bl i
ALL-L2 acuta:
L2 – This is the most

frequent ALL found in


adults. The cell size is large
andd heterogenous
h with
ih
variable nuclear chromatin
and prominent nucleoli. The
nucleus is irregular, clefting
and indented. The
cytoplasm is variable and
often moderate to abundant,
the basophilia
p is variable
and may be deep, and
vacuoles are variable.
Leucemiile acute
 L3 – This is the rarest form of
ALL The cell size is large
ALL. large,
with fine, homogenous
nuclear
uc ea cchromatin
o at co containing
ta g
prominent nucleoli. The The
nucleus is regular oval to
round. The cytoplasm is
moderately abundant and is
deeply basophilic and
vacuolated.
Leucemiile acute
 ALL may also be classified on the basis of
immunologic markers into:
 Early pre-B ALL
 Pre-B ALL
 B ALL
 T ALL
 Null or unclassified ALL (U ALL) - lack B or T
markers and may be the committed lymphoid
stem cell)
B cell maturation
T cell maturation
Leucemiile acute
 Incidenta – ALL este caracteristica copiilor
mici (2-5 ani), dar poate aparea si la adulti
 Clinica– pancitopenia cu astenia, paloare,
febra, scadere in greutate, iritabilitate,
infectii, anorexie, dureri osoase, sangerari.
 L1 occurs in children, L2 in adults, and L3
is called Burkitts leukemia
Leucemiile acute
 Prognoza – varsta, nr de leucocite si tipul de
celula sunt cei mai importanti indicatori de
prognostic
 Patients younger then 1 and greater than 13 have a poor
prognosis
 If the WBC count is < 10 x 109/L at presentation, the
prognosisi is
i good;
d If the
th WBC countt is
i > 20 x 109/L att
presentation the prognosis is poor
 T cell ALL ((more common in males)) has a poorer
p
prognosis than any of the B cell ALLs which have a cure
rate of 70%
Leucemiile acute
 Acute leukemias with mixed lineage – there
are occasionally acute leukemias that are
biphenotypic and display phenotypes for two
different lineages
 B lymphoid/myeloid
 T lymphoid/myeloid
 B/T lymphoid
 Myeloid/Natural killer
 A rare trilineage leukemia has also been seen
(was B/T lymphoid/myeloid!)
Leucemiile acute
 Leucemia mieloblastica acuta (sau Leucemia
granulocitara acuta) – clasificarea se bazeaza
pe
 Morfologia blastilor medulari
 Gradul maturarii celulare
 Reactii citochimice
 Imunofenotipare
 AML is divided into 7 different classifications:
 M1 – myeloblastic without maturation
 The bone marrow shows  90% blasts and < 10%
promyelocytes
 The disease occurs in older adults
AML – M1
 Note the myeloblasts and the auer rod:
Leucemiile acute
 M2 – myeloblastic with maturation
 The bone marrow shows 30 30-89%
89% blasts and > 10%
promyelocytes;
 This is characterized by an 8,21 chromosomal translocation
 This occurs in older adults
 M3 – hypergranular promyelocytic
 This form of AML has a bone marrow with >30% blasts
 Is more virulent than other forms
 Occurs with a medium age of 39
 The WBC count is decreased
 T t
Treatment t causes a release
l off th
the granules
l and
d may send d
the patient into disseminated intravascular coagulation and
subsequent bleeding
 It is characterized by a 15,17
15 17 chromosomal translocation
AML – M2
 Note myeloblasts and hypogranulated
PMNs:
AML – M3
 Note hypergranular promyelocytes:
Leucemiile acute
 M3m – hypogranular promyelocytic –
 The bone marrow has > 30% blasts
 The WBC count is increased.
 Like the M3 type, treatment causes a release of the
granules
l and d may sendd the
th patient
ti t into
i t disseminated
di i t d
intravascular coagulation and subsequent bleeding and
 It is characterized by a 15,17 translocation
 M4 – acute myelomonoblastic leukemia
 Both myeloblasts and monoblasts are seen in the bone
marrow and peripheral blood
 Infiltration of extramedullary sites is more common than
with the pure granulocytic variants
AML – M3m
 Note hypogranular promyelocytes:
AML – M4
 Note monoblasts and promonocytes:
Leucemiile acute
 M5 – acute monoblastic leukemia
 >80% of the nonerythroid cells in the bone marrow are
monocytic
 There is extensive infiltration of the gums, CNS, lymph nodes and
extramedullary sites
 Thi form
This f is
i further
f h divided
di id d into
i
 M5A - Poorly differentiated (>80% monoblasts)
 M5B - Well differentiated (<80% monoblasts)
 M6 – erythroleukemia
th l k i
 This is rare and is characterized by a bone marrow having a
predominance of erythroblasts
 It has 3 sequentially morphologically defined phases;
 Preponderance of abnormal erythroblasts
 Erythroleukemia – there is an increase in both erythroblasts
and myeloblasts
 Myeloblastic leukemia – M1, M2, or M4
 Anemia is common
AML – M5A
 Note monoblasts:
AML-M5B
 Note monoblasts, promonocytes, and
monocytes:
AML – M6
 Note M1 type monoblasts
Leucemiile acute
 M7 - Acute megkaryoblastic leukemia
 This is a rare disorder characterized by extensive
proliferation of megakaryoblasts, atypical megakaryocytes
and thrombocytopenia
 Tratamentul leucemiilor –
 Are doua scopuri:
 Eradicarea masei celulare leucemice
 Actiuni de suport
 Except for ALL in children, cures are not common
b t complete
but l t remission
i i (absence
( b off any leukemia
l k i
related signs and symptoms and return of bone
marrow and peripheral blood values to within
normal values) is
Leucemiile acute
 Exista patru tipuri generale de terapie
 Chimioterapia – usually a combination of drugs
is used
 Transplantul de maduva
 Radioterapia
 Immunoterapia – stimulate the patients own
immune system to mount a response against
the malignant cells

S-ar putea să vă placă și