Joyce M aria Annichino-8izzacchi, Valder R oberval Arruda, Tania Fátim a G om es M achado, Andrea M aria G al/izoni, C ristina C edran R ibeiro
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S tudies on the com ponents of the contact phase system in
patients w ith acute nonlym phoblastic leukem ia
D e p a r t m e n t o f C l i n i c a i M e d i c i n e , H e m a t o l o g y S e c t i o n , M e d i c i n e F a c u l t y , U N I C A M p ' C i d a d e U n i v e r s i t á r i a " Z e fe r i n o V a z " - C a m p i n a s , B r a z i lThe objective of the present study was to evaluate factors of the plasma kallikrein system in patients with acute nonlymphoblastic leukemia (ANLL), and compare the results to a normal control group. A prospective study was performed in the Tertiary Health Care Institution, Hemocentro, Campinas State University, Campinas, São Paulo, Brazil. Thirty-five patients, diagnosed as ANLL between 1988 and 1991, were considered for participation. Eleven patients were not elegible, according to the exclusion criteria: infection/ septicemia, previous treatment or blood transfusion. The study was performed with 24 ANLL patients, average age 34 years (16-69 years), 14 men and 10 women. Nineteen healthy volunteers, workers from the Hematology Center, average age 32 years (21-59 years), 11 men and 8 women, were .the control group. Plasmatic prekallikrein, C1-inhibitor, alpha 2-macroglobulin, activated partial thromboplastin time, prothrombin time, factor XII, factor XI, factor V and prealbumin were measured. Plasmatic prekallikrein (p=O.02) and prealbumin (p=O.03) were significantly decreased, and prothrombin time increased (p=O.003) in the patient group when compared to the control. Significantcorrelation (r=O.49,criticai value=O.43, p<O.05) between prekállikrein and prealbumin, and between prothrombin time and factor V (r=O.54, criticai value=O.44, p<O.05) was demonstrated in the patient group. No correlation was found between parameters analysed and circulant blast count or leukemia subgroups. Statistical analysis was performed by the W ilcoxon tes1.Correlation between the parameters was also verified. These results suggest activation of the contact system or impaired Iiver synthesis in patients with ANLL, and could contribute to disease complications.
UNITERMS: Plasmatic prekallikrein. Contact phase. Nonlymphoblastic leukemia.
INTRODUCTION
F
a c to r X II, p la s m a tic p re k a llik re in (P K ) a n d H M W -k in in o g e n p la y a n e s s e n tia l ro le in th e in itia tio n o fim p 9 rta n t b io lo g ic a l re a c tio n s , in c lu d in g in trin s ic
c o a g u la tio n p a th w a y . R e c e n tly ,- te c id u a l k a llik re in a n d
p re k a llik re in -k in in o g e n c o m p le x e s h a v e b e e n id e n tifie d in
n e u tro p h ils a n d m y e lo id p re c u rs o rs .I S tu d ie s " in v itro " d e m o n s tra te th a t g ra n u lo c y iic e la s ta s e is c a p a b le o f c le a v in g
H M W -k in in o g e n , P K a n d fa c to rs X II a n d X I. In a d d itio n ,
it c a n c le a v e C l-in h ib ito r to a n in a c tiv e fo rm .I
Address for correspondence:
Joyce M. A nnichino-Bizza cchi,
H em ocentro/U N IC AM P, C P 6198
C am pinas/SP - Brasil - C EP 13081-970
D is tu rb a n c e s o f h e m o s ta s is a re s till a m a jo r p ro b le m
in p a tie n ts w ith a c u te le u k e m ia , a n d a c tiv a tio n o f th e
c o n ta c t p h a s e o r p ro te o ly s is o f c o n ta c t s y s te m c o m p o n e n ts ,
if p re s e n t, c o u ld c o n trib u te to th e s e a lte ra tio n s .
A lth o u g h a re la tio n s h ip e x is ts b e tw e e n le u k o c y te s
a n d th e k a llik re in -k in in s y s te m , th e re a re fe w c lin ic a I
s tu d ie s o n le u k e m ia p a tie n ts .
C h ib a e t a I (1 9 7 9 ) s tu d ie d 1 4 a c u te m y e lo c y tic
le u k e m ia p a tie n ts . B e fo re a n d d u rin g th e tre a tm e n t th e y
fo u n d d e c re a s e d p la s m a tic P K a n d n o rm a l C I-IN H .
B u z e ra k e t a I (1 9 8 2 ) s tu d ie d 3 9 p a tie n ts w ith a c u te
le u k e m ia a n d d e s c rib e d in c re a s e d k a llik re in -k in in s y s te m
a c tiv a tio n in p a tie n ts w ith a h ig h e r b la s t c o u n t.
. . T h is s tu d y w a s u n d e rta k e n to e v a lu a te s o m e c o n ta c t
s y s te m p a ra m e te rs in 2 4 p a tie n ts w ith A N L L a t d ia g n o s is ,
c o m p a re d to a c o n tro l g ro u p , a n d to v e rify c o rre la tio n
b e tw e e n p o s s ib le a lte ra tio n s a n d b la ~ t c o u n t, s o m e
c o a g u la tio n p a ra m e te rs a n d p re a lb u m in .
São Paulo Medicai Journal/RPM 115(4): 1490-1494, 1997
. {
P A T I E N T S
A N D M E T H O D S
Blood samples were collected by clean venipuncture,
in plastic
tubes containing
sodium
citrate
3,8% , in a 9: 1
proportion.
Following
its centrifugation,
the obtained
plasma
was kept at
-80
DC
until its use.
A prospective
study, including all new cases diagnosed
as ANLL in the Hemocentro
at Unicamp between
1988 to
1991, was developed.
Thirty-five
cases of ANLL
were
considered
for participation
in this study. Eleven patients
were
not elegible,
according
to the exclusion
cri teria:
infection/septicemia,
previous
treatment
or blood
transfusion.
Infection/septicemia
was ruled
out in the
absence of fever, negative blood and urine culture, normal
thorax X-ray and stable blood pressure. Finally, blood was
analysed from 24 ANLL patients, average age 34 years
(16-69 years),
14 men and 10 women.
Diagnosis
of renewed
ANLL
was based
on blood count, bone marrow
biopsy,
cytology and cytochemistry.
They were classified according
to the FAB-system
4(six M l,
nine M 2, one M 3, two M 4,
two M 5, two M 6 and two M 7 cases). ClinicaI bleeding was
present in 5 patients
(21 % of cases) and characterized
by
epistaxis (cases 4 and 13), ecchymosis
(cases 7 and 16) and
hematuria
(case 23). ClinicaI thrombosis
was not presente
Nineteen healthy volunteers, workers from the Hemocentro
at Unicamp,
average
age 32 years (21-59 years),
11 men
and 8 women, were the control group.
Plasmatic
PK was measured
after dextran
sulphate
activation,
using
an
amidolytic
assay~
with
Ac-Phe-Arg-pNA
chromogenic
substrate.~
"Kallikrein-Iike"
activity
was
evaIuated
in the
same
way
as the
prekallikrein
assay, substituting
dextran sulphate as buffer.
Cl-inhibitor
(CI-INH),
alpha 2-macrogIobuIin
(A2)
and
preaIbumin
(PA)
were
measured
by
rocket
immunoeIectrophoresis.
7Acti vated partiaI thromboplastin
time (APTT)
was measured
with kaolin and rabbit brain
cephalin.
8Prothrombin
time (PT) was obtained with rabbit
brain
thromboplastin.
9The APTT
and PT results
were
expressed
as' a ratio between
coagulation
time of patient
plasma
and a pool of 20 normal
plasmas.
Normal
and
prolonged
APTT and PT reference
plasmas were run daily
as a laboratory
quality
controI.
Factor XI and factor XII
were measured
by APTT corrrection
time, using deficient
plasma
in
factor
XI
and
XII
(Stago
diagnosis)
respectively.lO
Factor
V was .measured
by a described
procedure.
11Platelet
count
was determined
automatically
(CeII
dyn 1600, Unipath,
California,
USA).
Statistical
analysis
was
carried
out
using
the
W ilcoxon
teste Patients
and controIs were compared
to all
parameters
studied. Patients were .also separated according
to leukemia
subtypes,
into group 1 (M 1- 6 cases), group 2
(M 2- 9 cases) and group 3 (M 3 to M 7- 8 cases). This last
group was made up from 4 subgroups,
to achieve
a great
number
of patients,
making
statistical
analysis
possible.
Correlation
between
various
parameters
was performed:
blast count or leucocyte
count and PK; CI-INH
or A2; PA
and PK, PT or factor V; and PK and PT or factor V. The
difference
at p
<0.05 was considered
significant.
R E S U L T S
Table 1 summarizes
peripheral
blood count found in
ANLL patients.
la b ia 1
B lo o d c o u n t o f A N L L p a t ie n t s
h e m o g lo b in le u c o c y t e s b la s t s p la t e le t s
g / d l / m m3 / m m3 / m m3
1.M1
8,1
3000
1500
62000
L
2.M1
10,0
3400
1600
55000
E
3.M1
7,5
1100
500
47000
U
4.M1
5,1
5100
1800
20000
K
5.M1
9,3
130000
111000
84000
E
6.M1
7,3
26000
18000
35000
M
7.M2
7,5
1500
900
15000
I
8.M2
7,6
2500
1900
21000
A
9.M2
8,8
6000
4000
90000
10.M2
7,5
11400
8700
102000
11.M2.
6,8
2100
1100
176000
S
12.M2
4,3
145000
110000
55000
U
13.M2
8,8
3500
1200
12000
B
14.M2
8,2
188000
165000
75000
G
15.M2
11,5
50000
38000
68000
R
16.M3
8,4
3500
2000
2000
O
17.M4
9,4
1900
1100
25000
U
18.M4
10,7
22200
12000
59000
P
19.M5
8,0
20000
15000
10000
S
20.M5
7,0
30000
18000
42000
21.M6
10,0
1200
800
40000
22.M6
6,1
157000
137000
35000
23.M7
5,0
73000
56000
36000
24.M7
6,3
4000
1800
10000
a v e r a g e
7.8
3P~66
29070
49000
A N N I C H I N O - B I Z Z A C C H I , J . M . ; A R R U D A , V . R . ; M A C H A D O , T . F . G . ; G A L L lZ O N I , A . M . ; R I B E I R O , C . C . - S t u d ie s o n t h e c o m p o n e n t s o f t h e c o n t a c t p h a s e s y s t e m in p a t ie n t s w it h a c u t e n o n ly m p h o b la s t ic le u k e m ia
1492
The results (tables 2 and 3) dem onstrated
that A PTT,
D IS C U S S IO NC I-IN H ,
A 2, factor X I, factor X II and factor V w ere not
different betw een patients and the controI group. K
allikrein-D isturbances ofhem ostasis
are still a frequent problem
Iike activity w as not increased in patients. PK w as decreased
in patients w ith acute Ieukem ia. Prekallikrein
or factor X II
(p=0.02)
and PT increased
(p=0.003)
in A N LL patients
deficiency
are associated
w ith an in vitro coagulopathy
w hen com pared
to the controI. PA w as significantly Iow er
(prolonged
A PTT),
in the absence
of clinicaI bleeding.
(p=O .03) in the patient group than in the controI one. W hen
H ow ever, if activation of the contact system or proteolysis
patients w ere separated into subgroups according to FA B -
of the com ponents
of this system is present in leukem ia,
classification,
no difference
w as verified in any variable
intrinsic blood coagulation pathw ay could be com prom ised,
m easured. There w as no correlation betw een circulant blast
contributing to the coagulopathy
seen in these patients.
count or Ieucocyte count and PK , A 2 or C I-IN H . A positive
The objective
of this study w as to evaluate
som e
correlation
betw een
PK and PA (~0.49,
criticaI value =
com ponents of the contact system in 24 A N LL patients. Patients
0.43, p<0.05), and betw een PT and factor V (r=0.54, criticaI
w ere studied at diagnosis, w ithout chem otherapy or infection,
value=0.44,
p<0.05), w as observed.
to avoid conditions w hich could, per se, alter the contact system .
T a b le 2
P a r a m e te r s o f th e c o n ta c t s y s te m , c o a g u la tio n a n d P A in A N L L
( R ) R a tio o f tim e o f c o a g u la tio n in s e c o n d s o f p a tie n t to a p o o l o f n o r m a l p la s m a .
A P T T P K C 1 A 2 X I X II P A P T
FV
(R ) ( U /m l) (%) (%) (%) (%) (%)
R
(%)1 .M 1 1 .3 5 0 .2 6 7 8 8 2 1 2 0 6 9 4 7 1 .2 7 0
L
2 .M 1 1 .1 8 0 .6 1 8 6 1 0 7 1 2 0 1 6 0 6 8 1 .1 7 0E
3 .M 1 1 .0 2 0 .1 7 8 9 9 3 6 3 7 7 4 2 1 .3 1 0 0U 4 .M 1 0 .9 4 0 .3 1 7 1 1 0 6 7 3 1 1 9 5 0 1 .4 1 2 0
K 5 .M 1 0 .9 6 0 .2 3 8 6 8 1 1 2 1 6 9 1 .0 8 0
E
6 .M 1 1 .0 0 0 .4 1 1 0 6 1 0 8 9 9 1 3 3 8 1 1 .0M 7 .M 2 0 .9 5 0 .4 0 1 0 0 1 0 0 1 1 2 1 6 0 1 0 0 1 .1 7 2
I 8 .M 2 1 .0 2 0 .4 1 9 4 1 0 8 1 0 3 1 5 3 5 6 1 .0 6 2
A 9 .M 2 ' 0 ~ 9 0 0 .4 1 7 9 9 6 1 0 1 8 6 5 0 1 .4 1 2 0
1 0 .M 2 1 .0 2 0 .6 2 9 2 7 5 1 0 8 6 6 5 0 1 .2 1 0 5
1 1 .M 2 1 .0 3 0 .3 5 9 2 6 7 1 0 3 1 5 3 4 0 1 .1 5 4
5 1 2 .M 2 0 .9 5 0 .4 3 8 7 1 2 9 7 4 1 0 9 4 0 1 .4 5 6
U 1 3 .M 2 0 .8 8 0 .7 6 8 7 9 2 1 7 5 1 1 8 1 0 0 1 .5 1 0 0
B 1 4 .M 2 0 .7 7 0 .3 6 9 5 7 5 4 8 1 2 8 7 0 1 .2 9 2
G
1 5 .M 2 1 .2 2 0 .1 2 9 0 1 6 7 6 5 4 4 1 .2 5 6R 1 6 .M 3 1 .2 0 0 .5 7 1 0 0 1 4 2 4 0 3 4 7 3 1 .2 1 1 0
O 1 7 .M 4 1 .1 4 0 .2 9 7 0 1 5 0 5 8 7 1 4 6 1 .5 3 5
U 1 8 .M 4 1 .0 2 0 .6 0 7 5 8 7 1 1 9 1 0 9 2 0 0 1 .2 1 4 0
P 1 9 .M 5 1 .3 5 0 .1 9 9 0 1 1 8 6 6 6 6 8 0 1 2 0
5 2 0 .M 5 1 .0 4 0 .2 0 9 0 1 5 7 1 0 0 1 9 0 4 3 1 .3 6 0
2 1 .M 6 0 .7 6 - 0 .6 2 8 1 1 0 8 1 3 9 1 7 1 8 7 1 .2 1 2 0
2 2 .M 6 1 .1 7 0 .4 6 1 0 0 1 5 4 5 8 9 4 1 .3 8 2
2 3 .M 7 1 .5 2 0 .5 3 9 3 8 6 1 6 0 1 2 0 6 7 1 .1 1 0 5
2 4 .M 7 1 .2 4 0 .6 7 7 0 1 7 5 1 7 5 1 3 5 1 0 0 1 .2 1 0 0
a v e r a g e 1 .0 7 0 .4 1 8 7 1 1 0 1 0 0 1 0 9 7 0 1 .2 2 8 7
5 D 0 .1 8 0 .1 7 9 3 1 3 7 4 2 3 6 0 .1 5 2 7
la b ia 3
P a ra m e te rs o f th e c o n ta c t s y s te m a n d c o a g u la tio n in A N L L a n d c o n tro l g ro u p
(R ) R a tio o f c o a g u la tio n tim e in s e c o n d s o f p a tie n t to a p o o l o f n o rm a l p la s m a s .
P a tie n t C o n tro l
A P T T
R
1 .0 1 .0 6P K (U /m l) 0 .4 1 0 .5 2 *
C 1 (% ) 8 7 9 3
A 2 (% ) 1 1 0 1 0 9
X I (% ) 1 0 0 1 0 1
X II (% ) 1 0 9 1 0 0
P T
R
1 .2 2 1 .1 0 * *V (% ) 9 2 8 7
P A (% ) 7 0 1 1 1 * * *
* p = O .0 2 **p = O .O O 3 ***p = O .0 3
B le e d in g w a s p re s e n t in 2 1
%
o f c a s e s , a little le s sth a n th a t d e s c rib e d b y o th e rs , a n d th ro m b o c y to p e n ia w a s
p ro b a b ly th e m a jo r re s p o n s ib le fa c to r. T h e e x c lu s io n o f
p a tie n ts w ith in fe c tio n /s e p tic e m ia , a c o n d itio n th a t
in c re a s e s th e ris k o f b le e d in g in p a tie n ts w ith
th ro m b o c y to p e n ia , c o u ld e x p la in th e lo w e r in c id e n c e o f
h e m o rrh a g ia in o u r p a tie n ts .
W e h a v e d e m o n s tra te d th a t A N L L p a tie n ts h a v e lo w
b io lo g ic P K a c tiv ity . T h is fa c t c o u ld s u g g e s t a n a c tiv a tio n
o f th e c o n ta c t p h a s e , a s d e s c rib e d in p re v io u s re p o rts . 2 ,3
O th e rw is e , th e la c k o f re d u c tio n o f th e m a in P K
in h ib ito r, c o u ld d is p ro v e th a t th e k a llik re in -k in in s y s te m
h a s b e e n a c tiv a te d in le u k e m ia p a tie n ts . 5 tu d ie s
d e m o n s tra te d in c re a s e d s y n th e s is o f C 1 -IN H in
in fla m m a to ry p ro c e s s e s , m e d ia te d b y in te rle u c in -6 ,
in fe rrin g th a t it c o u ld b e a n a c u te p h a s e p ro te in .1 2 -1 3 T h e n o rm a l le v e I o f C 1 -IN H in o u r p a tie n ts d o e s n o t ro le o u t
in c re a s e d tu rn o v e r, s in c e s y n th e s is c o u ld b e in c re a s e d ,
a s s o c ia te d w ith s im u lta n e o u s c o n s u m p tio n , b y k a llik re in
-k in in s y s te m a c tiv a tio n . C 1 -IN H a n tig e n fre q u e n tly is n o t.
re d u c e d e v e n a fte r c o n s u m p tio n o f th e in h ib ito r b y a n
a c tiv e e n z y m e ; th e a n tig e n m a y e v e n a p p e a r in c re a s e d in
L a u re ll a s s a y , d u e to fa s te r e le c tro p h o re tic m o b ility o f th e
e n z y m e -in h ib ito r c o m p le x o In d e e d , th e im m u n o lo g 'ic
m e th o d e m p lo y e d fo r C 1 -IN H m e a s u re m e n t c a n re v e a l
le v e Is o f in a c tiv e in h ib ito rs .6,1 4 -1 5
K a llik re in is p re s e n t in le u c o c y te s a n d m y e lo id
p re c u rs o rs . 5 0 , in le u k e m ia , a d is e a s e w ith a n in c re a s e d
n u m b e r o f th e s e c e lls , w e c o u ld e x p e c te d a c o rre la tio n
b e tw e e n b la s t c e ll c o u n t a n d P K , C 1 o r A 2 le v e Is . H o w e v e r,
o u r re s u lts d id n o t c o n firm th is h y p o th e s is .
K a llik re in -lik e a c tiv ity w a s n o t in c re a s e d in o u r
p a tie n ts , s u g g e s tin g th e re w a s n o s p o n ta n e o u s p ro te o ly s is
trig g e re d b y e n z y m e s lib e ra te d fro m b la s ts c e lls .
P K is s y n th e tiz e d in li v e r, a n d it c a n b e a re lia b le
in d e x o f liv e r fu n c tio n .'6 Im p a ire d liv e r fu n c tio n c o u ld
c o n trib u te to th e d e c re a s e d P K le v e I in o u r p a tie n ts . T h e
fin d in g o f d e c re a s e d P A , a s e n s itiv e p a ra m e te r o f liv e r
s y n th e s is , a n d a s ig n ific a tiv e c o rre la tio n b e tw e e n P K a n d
P A in o u r A N L L p a tie n ts , c o rro b o ra te th is h ip o th e s is .
H o w e v e r, w e h a v e to ta k e in to a c c o u n t th a t p re a lb u m in
c a n b e d e c re a s e d in c lin ic a I s itu a tio n s w ith o u t liv e r
s y n th e s is in s u ffic ie n c y , in w h ic h a m o d u la tio n o f p ro te in
s y n th e s is o c c u rs , w ith a n in c re a s e in a c u te p h a s e p ro te in s
a n d re d u c tio n in o th e rs . T h e g re a t m a jo rity o f th e s e
~ lte ra tio n s a re m e d ia te d b y c y to k in e s th a t a c t o n
h e p a to c y te s .1 7
T h e e v a lu a tio n o f o th e r p ro te in s th a t a re
in v o lv e d in a c u te p h a s e re s p o n s e , lik e fib rin o g e n , re a c tiv e
. p ro te in C a n d a lp h a 1 -a n titrip s in , w o u ld b e a n im p o rta n t
a id in th e a n a ly s is o f o u r re s u lts .
P re v io u s s tu d ie s d e s c rib e d c o a g u la tio n
a b n o rm a litie s in m y e lo c y tic Ie u k e m ia , p a rtic u la rly in th e .
s u b ty p e M 3 . B la s t c e lls a re ric h in p ro c o a g u la n ts w h ic h
c a n trig g e r b lo o d c o a g u Ia tio n b y d ire c t fa c to r X
a c tiv a tio n , o r b y tis s u e fa c to r-lik e a c tiv ity . In s o m e
p a tie n ts th e a c tiv a tio n o f b lo o d c o a g u la tio n c a n d e te rm in e
a n in c re a s e o f A P T T , P T a n d th ro m b in tim e . A c tiv a tio n
m a rk e rs o fb lo o d c o a g u la tio n , lik e th ro m b in -a n tith ro m b in
c o m p le x e s , fib rin o g e n d e g ra d a tio n p ro d u c ts a n d D
-d im m e rs , a re o f in te re s t in c o n firm in g th is a c tiv a tio n o r
n o t. In o u r p a tie n ts , P T a n d P T T A w e re m e a s u re d a n d
P T w a s th e o n ly p a ra m e te r a lte re d .
P T in c re a s e s b y re d u c tio n o f fa c to r 1 1 , V II, X o r
fib rin o g e n . 5 0 , im p a ire d liv e r s y n th e s is , v ita m in K
d e fic ie n c y , is o la te d re d u c tio n o f o n e o f th e s e fa c to rs , o r
in c re a s e d c o n s u m p tio n , c o u ld ra is e P T .
T h e re fo re , im p a irm e n t o f liv e r s y n th e s is c o u ld
c o n trib u te to th e in c re a s e d P T v e rifie d .in o u r p a tie n ts ,
fa v o re d b y s im u Ita n e o u s P K a n d P A d e c re a s e . A n
in c re a s e d tu rn o v e r, d u e to a c ti v a tio n o f b lo o d c o a g u la tio n
c o u ld a ls o h a v e c o n trib u te d to th is fin d in g .
T b e re .w a s n o c o rre la tio n b e tw e e n P K a n d P T ,
s u g g e s tin g th e k a llik re in -k in in s y s te m d o e s n o t p la y a n
im p o rta n t ro le in th is a lte ra tio n .
In s o m e p a tie n ts (c a s e s 1 , 1 5 a n d 1 9 ) a c tiv a tio n o f
th e b lo o d c o a g u la tio n in trin s ic p a th w a y b y k a llik re in is
s u g g e s te d b y s im u lta n e o u s P K a n d fa c to r X II d e c re a s e .
F u rth e r in v e s tig a tio n s a re n e e d e d to c la rify th e
c o n ta c t s y s te m in A N L L . D e te rm in a tio n o f k a llik re in -C 1
-IN H c o m p le x e s o r a c tiv ity a n d a n tig e n le v e Is o f P K a n d
C 1 -IN H s h o u ld b e e m p lo y e d to e lu c id a te th e s e p o in ts .
A N N IC H IN O -B IZ Z A C C H I, J .M .;'A R R U D A , V .R .; M A C H A D O , T .F .G .; G A L L lZ O N I, A .M .;
R IB E IR O , C .C . - S tu d ie s o n th e c o m p o n e n ts o f th e c o n ta c t p h a s e s y s te m in p a tie n ts
w ith a c u te n o n lv m o h o b la s tic le u k e m ia
1494
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