T H E

L E
W i
A S S O C I A T I O N M E D I C A L E
C A N A D I E N N E
Volume 1 0 0 . N umber 6 .
F ebrua ry 8 , 1 9 6 9
P oly c y t h emi a : D i a g n os i s , P a t h op h y s i olog y
a n d
T h era p y
P a rt I
J .
H .
J E P S O N , M .D ., M .A ., C M , *
M on t rea l
rT , H E
et i olog y
of a n i n erea s ed
h emog lobi n
c on -
- -
c en t ra t i on a n d h ema t oc ri t i s a
p roblem
f re
q uen t ly
en c oun t ered i n c li n i c a l med i c i n e. I n
rec en t
y ea rs
t h e li s t of
p os s i ble
c a us es h a s
len g t h -
en ed t o s uc h a n ex t en t t h a t a n i n t en s i v e s ea rc h
i s
req ui red
t o es t a bli s h a
d i a g n os i s .
T h e t a s k i s
s i mp li f i ed by s ubd i v i d i n g
t h e
p oly c y t h emi a s
i n t o
t wo
ma j or g roup s a c c ord i n g
t o t h e mec h a n i s m
of t h e i n erea s ed
ery t h op oi es i s .
I n t h e f i rs t
g roup ,
p ri ma ry p oly c y t h emi a ( p oly c y t h emi a v era ) ,
s o
d es c ri bed bec a us e t h e
ma j or
d ef ec t s eems t o be
i n t h e bon e
ma rrow,
t h e i n erea s ed ra t e of
ery t h rop oi es i s
i s
i n d ep en d en t
of k n own h umora l
c on t rol. I n t h e s ec on d
g roup
t h e
p oly c y t h emi a
i s a ma n i f es t a t i on of a n
ex t ra med ulla ry
les i on
a n d i s t h eref ore t ermed
s ec on d a ry p oly c y t h emi a
( T a ble I ) ;
i t i s
c omp os ed
of s ev era l s ubd i v i s i on s
a n d
a p p ea rs
t o be
h umora l-d ep en d en t .
E a rly
i n t h e c li n i c a l
i n v es t i g a t i on
" rela t i v e"
p oly c y t h emi a
mus t be ex c lud ed f rom bot h c a t e
g ori es .
T h i s i n c lud es s t a t es of
d eh y d ra t i on ,
s t res s ,
a n d s uc h
en d oc ri n op a t h i es
a s
C us h i n g ' s
d i s ea s e a n d s ome
p h eoc h romoc y t oma s ;
i n a ll of
t h es e c on d i t i on s t h e
p oly c y t h emi a
i s d ue t o a
d ec rea s e i n
p la s ma
a n d i n t ot a l blood v olume.
T h e
et i olog y
of t h i s
p s eud o-p oly c y t h emi a
i s ob
s c ure,
but i n on e
g roup
of s uc h
p a t i en t s
a ld -
os t eron e ex c ret i on wa s d ec rea s ed a n d
un c h a n g ed
by
s a lt res t ri c t i on .1
F urt h ermore,
t h e
p res en c e
of a n orma l or red uc ed
h emog lobi n
c on c en t ra
t i on d oes n ot
p rec lud e
a n i n c rea s e i n t h e red -
F rom t h e D i v i s i on of
H ema t olog y , D ep a rt men t of M ed i
c i n e, R oy a l Vi c t ori a H os p i t a l, a n d M c Gi ll U n i v ers i t y
C li n i c , M on t rea l 2 , Q uebec .
*M ed i c a l R es ea rc h C oun c i l S c h ola r, a n d A s s i s t a n t P ro
f es s or of E x p eri men t a l M ed i c i n e, M c Gi ll U n i v ers i t y .
S up p ort ed by Gra n t M BT -1 6 6 4 f rom t h e M ed i c a l R es ea rc h
C oun c i l of C a n a d a .
R ep ri n t req ues t s t o: D r. J . H . J ep s on , D i v i s i on of
H ema t olog y , R oy a l Vi c t ori a H os p i t a l, M on t rea l
2 , Q uebec .
c ell ma s s s i n c e a c on c omi t a n t i n c rea s e i n
p la s ma
v olume h a s been obs erv ed i n s ome en d oc ri n e
s t a t es ,
i n h uma n
p reg n a n c y ,
a n d i n c i rrh os i s
of t h e li v er. T h eref ore t h e d et ec t i on of a t rue
i n c rea s e i n t h e red -c ell
ma s s , ea s i ly
d et ermi n ed
by
d i rec t mea s uremen t
us i n g ra d i oi s ot op e
d i lu
t i on
t ec h n i q ues ,
i s t h e f i rs t
s t ep
i n
i n v es t i g a t i n g
p a t i en t s
wi t h a lt ered
h emog lobi n
c on c en t ra t i on s .
O n c e a n i n c rea s e i n t h e red c ell ma s s i s es t a b
li s h ed ,
t h e
p a t i en t
c a n be c la s s i f i ed a s a c a s e of
p oly c y t h emi a
v era or a s
belon g i n g
t o t h e s ec
on d a ry p oly c y t h emi c g roup ,
t h e ba s i s of wh i c h
i s i n erea s ed
ery t h rop oi et i n p rod uc t i on . O n ly
a
f ew c a s es
ma y
be rela t ed t o ot h er c a us es . T h e
d i a g n os i s
of
p ri ma ry p oly c y t h emi a
i s
ea s i ly
ma d e wh en t h e i n erea s ed red c ell ma s s i s a c
c omp a n i ed by leuk oc y t os i s , t h romboc y t os i s ,
s p len omeg a ly
a n d i n erea s ed
leuk oc y t e
a lk a li n e
p h os p h a t a s e. S ec on d a ry p oly c y t h emi a
i s n ot a s
s oc i a t ed wi t h a n i n c rea s e i n c ellula r elemen t s
ot h er t h a n
ery t h roc y t es
or wi t h
s p len omeg a ly .
un les s t h ere i s a n ot h er d i s ea s e
p res en t
wh i c h
a c c oun t s f or t h em. I n a bout
2 5 %
of
p a t i en t s
wi t h
p ri ma ry p oly c y t h emi a s p len omeg a ly
i s a b
s en t . T h i s
g i v es
ri s e t o
ma j or
d i f f i c ult i es i n
d i a g n os i s
a t a
p a rt i c ula r s t a g e
of t h e d i s ea s e
wh en t h ere i s n o
leuk oc y t os i s , t h romboc y t os i s
or
i n erea s ed
leuk oc y t e
a lk a li n e
p h os p h a t a s e.
T h es e
p roblems
a re i n t en s i f i ed wh en c on d i t i on s
lea d i n g
t o d ec rea s ed a rt eri a l
0 2
s a t ura t i on a re n ot
p res
en t or wh en t h ei r ex i s t en c e i s n ot
ea s i ly
d emon
s t ra t ed ,
or i f f a c t ors
res p on s i ble
f or t i s s ue
h y -
p ox i a
a re loc a li z ed
s p ec i f i c a lly
t o t h e
k i d n ey .
T h i s
s ubj ec t
h a s been d i s c us s ed
by
s ev era l a u
t h ors 2 '
3
a n d t h e d a t a i n d i c a t e t h a t t h i s mea s ure
men t i s of t en n ot
c li n i c a lly h elp f ul.
M ore re
c en t ly
i t h a s been s h own t h a t un s a t ura t i on of
2 7 1
2 7 2
J ep s on :
P oly c y t h emi a
C a n a d . M ed . A s s . J .
F eb. 8 , 1 9 6 9 , v ol. 1 0 0
T A BL E I ..C la s s i f i c a t i on of t h e P oly c y t h bmi a s
/
P ri ma ry p oly c y t h emi a ( p oly c y t h emi a v era )
A C la s s i c a l
s y n d rome ( a s s oc i a t ed
wi t h
t h romboc y t o
s i s a n d
leuk oc y t os i s )
B
" Ben i g n " p oly c y t h emi a ( ? )
C " F a rn i li a l"
p oly c y t h emi a ( ? )
B C en t ra l n erv ous
s y s t em
1
H ema n g i obla s t oma
2
D ep res s ed res p i ra t ory
c en t re
C L i v er
1 C i rrh os i s
2
P ri ma ry
c a rc i n oma
2
S ec on d a ry
c a rc i n oma
D Gen i t a l
1 U t eri n e f i broi d s
2 P ros t a t i c c a rc i n oma
E E n d oc ri n e
1
C us h i n g ' s s y n d rome ( rela t i v e)
2
P ri ma ry
a ld os t eron i s m
3
H y p ert rop h y
of t h e
j ux t a g lomerula r
a p p a ra t us
4 T es t os t eron e-i n d uc ed
5
Va s op res s i n -i n d uc ed
6
P h eoc h romoc y t oma
7
Vi ri li z i n g
a d ren a l a d en oma
( ra t s )
F
T umours .( met a s t a t i c les i on s )
d es c ri bed wi t h
p oly c y t h emi a . E t i olog y
obs c ure.
1
Bron c h og en i c
c a rc i n oma
2 R ec t a l a d en oc a rc i n oma
3 M ela n os a rc oma
4 C a rc i n oma of brea s t
p a t i en t s
wi t h
" ben i g n " ery t h roc y t os i s ,
a
s y n
d rome wh i c h d oes n ot i n c lud e t h e ot h er f ea t ures
of
p ri ma ry p oly c y t h emi a
or i t s
my elop roli f era -
t i v e
c omp li c a t i on s .5
T h i s
d i a g n os i s
s h ould be
res t ri c t ed t o t h os e
p a t i en t s
i n wh om n o s ec on d
a ry
c a us e i s d emon s t ra t ed .
S ome of t h e c ri t eri a us ed t o
s ep a ra t e
t h e
p ri ma ry
a n d
s ec on d a ry p oly c y t h emi a s
a re n ow
k n own t o
ov erla p .
A n
ex a mp le
of t h i s i s t h e
s li g h t
d ec rea s e of t h e a rt eri a l blood
s a t ura t i on ,
wh i c h
ma y
be d ue t o a red uc ed d i f f us i on
c a p a
c i t y
i n s ome
p a t i en t s
wi t h
p ri ma ry p oly c y t h e
mi a .6 9 S ome a ut h ors
s ug g es t
t h a t t h ere i s a n
i n erea s ed d i f f us i on
c a p a c i t y
wh en t h e red -c ell
ma s s i s i n erea s ed .1 0 T h e
p res en c e
of
h y p eruri -
c emi a or t h e
a p p ea ra n c e
of c li n i c a l
g out
d ue t o
i n erea s ed c ellula r
p roli f era t i on ,
t h e
s ubs eq uen t
i n erea s ed c ellula r t urn ov er a n d t h e
d eg ra d a t i on
of
n uc leop rot ei n s
a re n ot li mi t ed t o
p ri ma ry
p oly c y t h emi a s .1 1 " 1 4
I ron -k i n et i c
p a t t ern s ma y
n ot d i f f eren t i a t e be
t ween t h es e t wo
c a t eg ori es
bec a us e
t h ey a p p ea r
t o be s i mi la r i f t h e i ron s t ores a re
a d eq ua t e.1 5
A lt era t i on of t h e
li p i d
c on t en t of t h e
ery t h ro
c y t e
membra n e1 6 h a s been
rep ort ed
i n
p ri ma ry
p oly c y t h emi a
a s well a s a n i n erea s ed c on c en
t ra t i on of
g lut a mi c
ox a loa c et i c t ra n s a mi n a s e, g lu-
c os e-6
p h os p h a t e d eh y d rog en a s e
a n d h ex ok i n a s e
i n
ery t h roc y t es .1 7
H owev er,
i t wa s c on c lud ed
t h a t t h e i n erea s ed
en z y me
c on c en t ra t i on i s d ue
t o t h e
p res en c e
of a
y oun g er
c ell
p op ula t i on .
N o
c omp a ra ble
s t ud i es h a v e been d on e on
ery t h ro
c y t es
obt a i n ed f rom
p a t i en t s
wi t h
s ec on d a ry
p oly c y t h emi a .
D emon s t ra t i on of a s h ort en ed
ery t h roc y t e
s urv i v a l i n
p ri ma ry p oly c y t h emi a ,
d ue t o
i n t ra med ulla ry h emoly s i s
or
s p len i c
s e-
q ues t ra t i on
a s t h e d i s ea s e
p rog res s es , ma y
be of
v a lue
on ly
i n t h e la t er
s t a g es .1 8
I n s ome
p a t i en t s
wh o were
rec ei v i n g t h era p y ,
a n
a bn orma li t y
res embli n g
a d elet i on of a c h romos ome of t h e F
g roup 1 9 , 2 0
wa s obs erv ed i n t h e bon e-ma rrow
c ells ,
a s s oc i a t ed wi t h
h i g h
ex c ret i on of
t ry p t o-
p h a n e
met a boli t es .1 9
A s more
k n owled g e
i s
g a i n ed
of t h e c ells
p rod uc ed
i n
p ri ma ry p oly c y t h emi a , es p ec i a lly
of
t h e
en z y me c on f i g ura t i on
a n d
t y p es ,
a d i f f eren
t i a l
la bora t ory
t es t wi ll
un d oubt ed ly emerg e
wh i c h wi ll f a c i li t a t e t h e c la s s i f i c a t i on i n t o t h e
t wo
ma j or c a t eg ori es
of
p oly c y t h emi a .
S uc h d i f
f eren c es i n
en z y me c on f i g ura t i on
i n
p ri ma ry
a n d
s ec on d a ry p oly c y t h emi a s
c ould a ls o lea d t o a n
un d ers t a n d i n g
of t h e
p a t h og en es i s
of t h e f ormer.
a rt eri a l blood
ma y
be d et ec t ed
on ly
i n c ert a i n
c i rc ums t a n c es .4
D et ermi n a t i on of t h e
et i olog y
of a n i s ola t ed
i n c rea s e of t h e red -c ell ma s s i s f urt h er
c omp li
c a t ed
by
t h e
rec og n i t i on
of a n ot h er
g roup
of
1 . P ri ma ry P oly c y t h emi a
( i n d ep en d en t
of
ery t h rop oi et i n p rod uc t i on )
P a t h op h y s i olog y of P ri ma ry P oly c y t h emi a
T h i s
en t i t y
i s
g en era lly
c on s i d ered t o be a
C a n a d . M ed . A s s . J .
F eb. 8 , 1 9 6 9 , v ol. 1 0 0
J ep s on :
P oly c y t h emi a 2 7 3
my elop roli f era t i v e
d i s ea s e mos t of t en d et ec t ed
i n
p a t i en t s
ov er 5 0
y ea rs
of
a g e
a n d more f re
q uen t ly
i n men t h a n i n women
( 1 .4: 1 ) .
I t
ma y
p rog res s
t o
my elof i bros i s
a n d
my eloi d met a p la s i a
a n d , t ermi n a lly ,
i n a bout
1 0 % ,
t o a c ut e leu
k emi a . T h e mos t
f req uen t c omp li c a t i on s
i n un
t rea t ed
p a t i en t s
a re
h emorrh a g e
or t h rombos i s .
T h e
ov er-p rod uc t i on
of c ells
by
t h e bon e ma r
row d oes n ot
a p p ea r
t o be c on t rolled
by a n y
well-d ef i n ed h umora l f a c t or
or,
more
s p ec i f i c a lly ,
f a c t ors ,
s i n c e
g ra n ulop oi es i s
a n d
meg a k a ry o-
p oi es i s
a re a ls o
g en era lly
a f f ec t ed .
E ry t h rop oi -
et i c
a c t i v i t y
i n
p la s ma
h a s been d et ec t ed i n f re-
q uen t ly .2 0 '
2 1
A t
p res en t
t h e
s i g n i f i c a n c e
of t h i s
i s d i f f i c ult t o rela t e t o t h e h ormon e
ery t h rop oi -
et i n
( E S F ) .
I n mos t i n s t a n c es t h i s i s n ot i n
erea s ed i n t h e
p la s ma 2 2 2 3 *2 4
but h a s been
f oun d t o be
d ep res s ed
i n t h e uri n e of
p a t i en t s
wi t h a n elev a t ed red -c ell ma s s
( R C M ) , 2 5
s i mi
la r t o i t s
d ep res s i on
i n
p la s ma f ollowi n g h y p er-
t ra n s f us i on of n orma l
s ubj ec t s .2 0
T h a t t h e
ery
t h roi d t i s s ue of
p ri ma ry p oly c y t h emi a
i s i n d e
p en d en t
of
ery t h rop oi et i n
c on t rol i s a ls o
s ug
g es t ed by
t h e c on t i n ued a c t i v e
ery t h rop oi es i s
f ollowi n g h y p ert ra n s f us i on
of t h es e
p a t i en t s 2 2
.a
p roc ed ure
wh i c h
s up p res s es en d og en ous
E S F .
F urt h ermore,
wh i le
ery t h roi d
t i s s ue of un
t rea t ed
p ri ma ry p oly c y t h emi a p a t i en t s
i s un -
res p on s i v e
t o
ery t h rop oi et i n
i n
v i t ro,
wi t h i n d uc
t i on of remi s s i on i t bec omes s en s i t i v e t o h umora l
reg ula t i on ( E S F ) .2 6
A ll t h es e obs erv a t i on s
s ug
g es t
t h a t a n
i n d ep en d en t
c lon e of c ells
emerg es
wh i c h i n t h e un t rea t ed s t a t e i s
i n d ep en d en t
of
h umora l c on t rol.
S i mi la rly ,
i n s ome c a s es of
a p la s t i c
a n emi a ,
a c lon e of c ells wi t h
s p ec i f i c
c h a ra c t eri s t i c s
d i f f eri n g
f rom t h os e of n orma l
ery t h roi d
c ells
emerg es
a n d res ult s i n t h e c li n i
c a l
s y n d rome
of
p a rox y s ma l
n oc t urn a l h emo-
g lobi n uri a .2 7
P a ra llel s t ud i es i n lower a n i ma ls s ubs t a n t i a t e
t h es e obs erv a t i on s . F i lt ra t es of F ri en d ' s v i rus
i n d uc ed
p oly c y t h emi a
i n
mi c e,
a n d a ls o s t i mu
la t ed
ery t h rop oi es i s
i n mi c e wh i c h were
p rev i
ous ly
ren d ered
p oly c y t h emi c , 2 8 *3 0 d emon s t ra t i n g
t h e
i n d ep en d en c e
of t h i s
t y p e
of
ery t h roi d p ro
li f era t i on f rom t h e
reg ula t ory
c on t rol of E S F .
N o E S F wa s d et ec t a ble i n t h e
p la s ma
or uri n e
of t h es e
mi c e,
n or wa s
ery t h rop oi es i s
i n h i bi t ed
by mult i p le i n j ec t i on s
of
a n t i -ery t h rop oi et i n
i n t o
p let h ori c
mi c e
i n j ec t ed
wi t h F ri en d ' s v i rus .3 0
T h es e res ult s
s ug g es t
t h a t i n t h e
g en et i c a lly
p red i s p os ed ,
a n un c on t rolled
t y p e
of
ery t h ro
p oi es i s
c a n be i n d uc ed wh i c h mi mi c s t h e
p i c t ure
of
p ri ma ry p oly c y t h emi a
i n t h e h uma n .
A lt h oug h
? C on c en t ra t i on of p la s ma 1 0 0 x a n d s ep a ra t i on on
S ep h a d ex G1 0 0 , wh i c h ord i n a ri ly res ult i n d et ec t i on of
s ma ll elev a t i on s of E S F , d i d n ot res ult i n d et ec t i on of
ery t h rop oi et i c a c t i v i t y i n p la s ma f rom
p a t i en t s wi t h
p ri ma ry p oly c y t h emi a .
n ot
c on c lus i v e,
t h es e s t ud i es c ould i n d i c a t e t h a t
i n ma n a lt era t i on of
n uc leo-p rot ei n s y n t h es i s
oc c urs ,
i n d uc ed
by
a
v i rus ,
a s oma t i c
mut a t i on ,
or s ome ot h er mec h a n i s m wh i c h lea d s t o a d e-
rep res s i on
of s t ruc t ura l
g en es , res ult i n g
i n un
c on t rolled
p roli f era t i on
or d i f f eren t i a t i on of c ells
wh i c h rema i n
i n d ep en d en t
of
a n y
k n own h u
mora l s t i mulus . I n v i ew of t h e a s s oc i a t i on of
p ri
ma ry p oly c y t h emi a
wi t h t h e
d ev elop men t
of t er
mi n a l leuk emi a or bon e-ma rrow
f a i lure,
a n d t h e
p red i s p os i t i on
of s ome et h n i c
g roup s
t o t h es e
d i s ea s es , 3 1 ,
3 2
i t i s
p os s i ble
t h a t on a molec ula r
lev el t h i s d i s ea s e i s d ue t o t h e
p res en c e
of
g en e( s )
wh i c h a re
p a rt
of a
" p oly c y t h emi a p oly -
op eron " . E x p la i n ed
on t h e ba s i s of obs erv a t i on s
of f et a l
ery t h rop oi es i s
wh i c h i n t h e
ea rly
c ours e
of
d ev elop men t a p p ea rs
t o be
i n d ep en d en t
of
h umora l
c on t rol,
t h e
g en e res p on s i ble
f or t h i s
more
p ri mi t i v e t y p e
of
ery t h rop oi et i c p roli f era
t i on
ma y ,
a t s ome
s t a g e,
bec ome
rep res s ed
a n d
t h eref ore " la t en t " .
N orma lly
s uc h
rep res s ed
g en es
would rema i n la t en t .
H owev er,
i n
g en et i
c a lly p red i s p os ed p ers on s
t h es e
g en es
c ould be
d erep res s ed
i n la t er li f e
by
un k n own f a c t ors
p erh a p s
rela t ed t o t h e
a g ei n g p roc es s .
I n t h os e
n ot s o
g en et i c a lly p red i s p os ed , d ev elop men t
of
p ri ma ry p oly c y t h emi a ma y
f ollow t h e i n v a s i on
of a v i rus or s oma t i c mut a t i on . U n d er s uc h c i r
c ums t a n c es a c lon e of c ells
ma y emerg e
wh i c h
i s
s i g n i f i c a n t ly
d i f f eren t f rom t h os e
res p on s i v e
t o h umora l
a g en t s .
S uc h a
h y p ot h es i s ma y
be
s up p ort ed by p rev i ous
i n v i v o a n d i n v i t ro ex
p eri men t s
a n d
p erh a p s by
t h e obs erv a t i on s of
t h e oc c urren c e of " f a mi li a l
p oly c y t h emi a , \ 3 3 -3 5
I n t h i s
s y n d rome
t h e
s p leen
i s
p a lp a ble,
a s i t i s
i n
p a t i en t s
wi t h
p ri ma ry p oly c y t h emi a .
T h e
mod e of i n h eri t a n c e of t h i s
s y n d rome
h a s n ot
been
c lea rly
es t a bli s h ed ;
i t d i f f ers f rom
f a mi ly
t o
f a mi ly , i n d i c a t i n g
t h e
h et erog en i c i t y
of t h e
t ot a l
g roup .
T h e f a c t t h a t n o i n c rea s e i n
ery t h ro
p oi et i n
h a s been f oun d i n on e
g roup
of
p a t i en t s
s ug g es t s
t h a t t h e d ef ec t i s a t t h e bon e-ma rrow
lev el.3 5 I n t h i s
s y n d rome, s y n t h es i s
of
s p ec i f i c
p rot ei n req ui red
f or t h e
p roli f era t i on
a n d
s p e
c i f i c f un c t i on a l
c a p a c i t y
of
ery t h roi d
t i s s ue
ma y
be
i n d ep en d en t
of
ery t h rop oi et i n .
A n ot h er
g roup
of a d ult
p a t i en t s
wi t h
" ben i g n " ery t h roc y t os i s
ma y
c on s t i t ut e a n
en t i t y s ep a ra t e
f rom t h e f a mi
li a l
t y p e.5
I n c on t ra s t t o t h e
la t t er,
t h e ma le-
f ema le ra t i o i n t h e f ormer
g roup
i s 5 .5 : 1 . T h i s
a ls o d i f f ers
s i g n i f i c a n t ly
f rom t h a t of
p a t i en t s
wi t h
p ri ma ry p oly c y t h emi a ( 1 .4: 1 ) .
T h e s ex
d i f f eren c e i s
s t ri k i n g
a n d c ould i n d i c a t e a
s p e
c i f i c mod e of i n h eri t a n c e f or t h i s
p a rt i c ula r
en t i t y , 3 6 , 3 7 p erh a p s
s i mi la r t o t h a t obs erv ed i n
p a t i en t s
wi t h
g luc os e-6 -p h os p h a t e d eh y d rog en
a s e
d ef i c i en c y .
H owev er,
bef ore
a d op t i n g
s uc h
a
h y p ot h es i s ,
ot h er f a c t ors mus t be ex c lud ed . I t
2 7 4
J ep s on :
P oly c y t h emi a
C a n a d . M ed . A s s . J .
F eb. 8 , 1 9 6 9 , v ol. 1 0 0
s h ould be
k ep t
i n mi n d t h a t more a n d more
c a us es of
ery t h roc y t os i s
a s s oc i a t ed wi t h ei t h er
p ri ma ry
or
s ec on d a ry
i n erea s ed
p rod uc t i on
of
ery t h rop oi et i n
a re
bei n g
f oun d .
A lt h oug h
d et a i ls
were n ot
a v a i la ble,
a rec en t a bs t ra c t would
a p p ea r
t o i n d i c a t e t h a t E S F ex c ret i on i n on e
f a mi ly
wa s i n erea s ed .3 8 T h e rec en t d et ec t i on of
a bn orma l
h emog lobi n s
wh i c h h a v e i n erea s ed
0 2
a f f i n i t y , res ult i n g
i n f a i lure t o relea s e
a d eq ua t e
ox y g en
t o t h e
t i s s ues , ma y
be
res p on s i ble
f or
ma n y
c a s es of f a mi li a l
p oly c y t h emi a .3 9 45
I n
ot h er
c a s es ,
" oc c ult "
h y p ox emi a ma y
be
p res en t
wh i c h i s d emon s t ra t ed
on ly
wh en a rt eri a l blood
g a s es
a re mea s ured a f t er ex erc i s e
or,
i n
s p ec i f i c
i n s t a n c es , f ollowi n g
res t i n t h e
s up i n e p os i t i on .4
T h us , ma n y
of t h es e c a s es
ma y
be d ue t o ot h er
f a c t ors wh i c h a re
d ep en d en t
on a h umora l
mec h a n i s m,
v i z .
ery t h rop oi et i n .
T h ei r d et ec t i on
c ould
ev en t ua lly
ex c lud e s ome of t h os e c a s es n ow
c la s s i f i ed a s
ben i g n
or
f a mi li a l,
a n d t h e
p a t t ern
of i n h eri t a n c e of t h os e wi t h a bon e-ma rrow d e
f ec t
ma y
t h en bec ome c lea rer.
K n owled g e
of t h e molec ula r
bi olog y
of
p ri
ma ry p oly c y t h emi a
i s s t i ll i n i t s
i n f a n c y .
H ow
ev er,
a
p ra c t i c a l a p p roa c h
wh en t h i s d i s ea s e i s
un a c c omp a n i ed by a c c es s ory
c lues ma k es a c li n i
c a l
d i a g n os i s p os s i ble,
a n d a s
t ec h n i q ues
a re
d ev elop ed
t o mea s ure
p la s ma ery t h rop oi et i n
rout i n ely
t h i s wi ll bec ome muc h ea s i er. A t
p res
en t i t i s
p os s i ble
t o mea s ure
s emi -q ua n t i t a t i v ely
t h e i n c rea s e or d ec rea s e of E S F i n uri n e c on -
c en t ra t es , emp loy i n g
t h e
p oly c y t h emi c
mous e
a s s a y .
U n les s
elev a t ed , p la s ma ery t h rop oi et i n
i s
n ot d et ec t a ble a n d ev a lua t i on of i t s
a c t i v i t y
i s
c omp li c a t ed by
t h e
p res en c e
of ot h er f a c t ors
wh i c h
ma y
en h a n c e or i n h i bi t t h e ef f ec t of
ery
t h rop oi et i n
i n t h e
a s s a y
mi c e.46
I t h a s been s h own i n bot h ma n a n d a n i ma ls
t h a t a n i n erea s ed R C M
ef f ec t i v ely
" t urn s of f "
E S F ,
wi t h a
c on s eq uen t
f a ll i n i t s c on c en t ra t i on
i n bot h t h e
p la s ma
a n d uri n e. T h i s oc c urs i n
n orma l h uma n s
wh o, h a v i n g
been a t a
h i g h
a lt i t ud e,
h a v e
ef f ec t i v ely
i n erea s ed t h ei r R C M
a s a res ult of i n erea s ed
p rod uc t i on
a n d t urn ov er
ra t e of E S F .
U p on ret urn i n g
t o s ea lev el f urt h er
or c on t i n ued E S F
p rod uc t i on
i s
s up p res s ed by
t h e ex i s t en t
h i g h
lev el of R C M .47 T h e s a me
ef f ec t f ollows
h y p ert ra n s f us i on
of n orma l s ub
j ec t s , 2 0
a n d c ould oc c ur i n t h e n ewborn i n f a n t
a n d i n
h y p ox i a -i n d uc ed p oly c y t h emi c
mi c e re
mov ed t o n orma l a mbi en t a i r.48 S i n c e
ery t h ro
p oi et i n p rod uc t i on
i s n ot i n erea s ed i n
p ri ma ry
p oly c y t h emi a
a n d t h e
ery t h roi d
ma rrow
p ro-
li f era t es wi t h out a
reg ula t ory
c on t rol
mec h a n i s m,
res ult i n g
i n a n i n c rea s e of R C M wi t h n o
p h y s i o
log i c a l p urp os e, en d og en ous
E S F bec omes
s up
p res s ed .
I t i s t h eref ore a bs en t or
ba rely
d et ec t
a ble i n uri n e c on c en t ra t es a n d
p res uma bly
i n
p la s ma
of s uc h
p a t i en t s .
T h i s i s i n c on t ra s t t o
wh a t oc c urs i n
p a t i en t s
wi t h
ery t h roc y t os i s
d ue
t o i n erea s ed
p rod uc t i on
of
E S F ,
wh o
ma y
ex
c ret e n orma l or i n erea s ed a moun t s of E S F i n
uri n e
( T a ble I I )
a n d h a v e
c on s i d era bly h i g h er
c on c en t ra t i on s of E S F i n t h ei r
p la s ma .
T h us ,
un d er c on t rolled
c on d i t i on s ,
d i f f eren t i a t i on be
t ween t h e t wo
ma j or g roup s
of
p oly c y t h emi a s
c a n be
t en t a t i v ely
ma d e. P a t i en t s wi t h a n i n
c rea s e of t h e R C M
i n d ep en d en t
of
E S F , i .e.,
t h os e wi t h
p ri ma ry p oly c y t h emi a ,
wi ll h a v e li t t le
or n o E S F i n t h ei r
uri n e,
wh i le t h e s ec on d c a t e
g ory
of
p a t i en t s
wi t h
ery t h roc y t os i s
wi ll h a v e
n orma l t o i n erea s ed lev els of E S F i n t h e uri n e.2 5
A s wi t h a ll
rules ,
t h ere i s a n
ex c ep t i on .
T h i s
ma y
oc c ur i n
p a t i en t s
wi t h c on c omi t a n t
c h a n g es
of t h ei r en d oc ri n e s t a t us
s ec on d a ry
t o d i s ea s es
s uc h a s
c i rrh os i s ,
or
v ery ra rely
bec a us e of a n
i n erea s ed R C M i n d uc ed
by
f a c t ors ot h er t h a n
ery t h rop oi et i n .
Ba s ed on t h es e
obs erv a t i on s ,
t h os e
p a t i en t s
wi t h
p ri ma ry p oly c y t h emi a
wi t h
out
s p len omeg a ly
or
a c c omp a n y i n g
t h rombo
c y t os i s a n d / or leuk oc y t os i s , ma y
be
t en t a t i v ely
d i f f eren t i a t ed
by
t h ei r red uc ed ex c ret i on of
ery
t h rop oi et i n ,
a n d
p erh a p s ,
i n t h e
f ut ure, by
d e
t ec t i on of low
p la s ma
c on c en t ra t i on s of
ery t h ro
p oi et i n .
T h e rec en t
d ev elop men t
of a
h ema g g lu
t i n a t i on i n h i bi t i on
a s s a y
f or
p la s ma
E S F
by
L a n g e,
M c D on a ld a n d
J ord a n 49 ma y p rov e
t o
be
ex t remely
v a lua ble i n
d i s t i n g ui s h i n g
t h e
p ri ma ry
f rom t h e
s ec on d a ry p oly c y t h emi a s .
T h e
d et ec t i on of ot h er bi oc h emi c a l les i on s of
ery
t h roc y t es p rod uc ed
i n t h es e
p a t i en t s
wi ll a ls o be
of v a lue i n
ma k i n g
t h i s d i f f eren t i a t i on . T h e
p res en c e
of met a boli c a lt era t i on s i n c ells
ma y
bec ome
a p p a ren t
wh en f et a l
ery t h rop oi es i s
i s
bet t er un d ers t ood .
P ri ma ry p oly c y t h emi a
of t en
p rog res s es
t o
my eloi d met a p la s i a
wi t h
ery t h ro
p oi es i s
loc a t ed i n
org a n s
wh i c h i n f et a l li f e were
n orma lly res p on s i ble
f or t h e
p rod uc t i on
of t h es e
c ells . T h i s
ma y
i n d i c a t e t h a t t h e d i s ea s e i s a
rev ers i on t o
p ri mi t i v e
f et a l-li k e
ery t h rop oi es i s
d ue t o t h e f a i lure of
rep res s i on
of a la t en t
ery t h rop oi et i c c a p a c i t y .
T h era p y
S i n c e
p a t i en t s g en era lly
f a ll i n t o a n old er
a g e
g roup
wh ere t h e i n c i d en c e of a rt eri os c lerot i c
c h a n g es
i s
g rea t er, p h lebot omy p la y s
a more
p romi n en t
role i n
bri n g i n g
a bout
ea rly
reli ef of
s y mp t oms .
I n t h i s
s i t ua t i on ,
t h e i n erea s ed t ot a l
h emog lobi n
ma s s d oes n ot a i d t i s s ue
ox y g en a
t i on ,
s i n c e
h y p ox emi a
i s n ot t h e
p ri ma ry
s t i mu
lus . T h e i n c rea s e i n blood
v i s c os i t y
wi t h t h e ri s e
of t h e h ema t oc ri t t en d s t o d ec rea s e t h e ra t e of
blood f low.
P ri ma ry p oly c y t h emi a
wh i c h i s
g en
era lly
a s s oc i a t ed wi t h a
h y p erv olemi c
s t a t e5 0
res ult s i n i n erea s ed c a rd i a c
out p ut
a n d a d e-
C a n a d . M ed . A s s . J .
F eb. 8 , 1 9 6 9 , v ol. 1 0 0
J ep s on :
P oly c y t h emi a 2 7 5
T A BL E I I ..E x c ret i on of E ry t h rop oi et i n i n P a t i en t s wi t h D i s ea s es F req uen t ly A s s oc i a t ed wi t h P oly c y t h emi a
H b. R C M U ri n e E S F O t h er E S F * U ri c a c i d . A rt . O 2 ( % s a t .)
C a t eg ory ( g .% ) ( ml./ k g .) ( U / H h rs .) ( U / ml.) S p leen ( mg .% )
a n d P a w ( mm. H g ) C ommen t s
______
o" . 1 9 .1 411 .0
. .
6 .0
.
N orma l H b. elec t ro
p h ores i s
9 . 1 6 .3 3 5 0 .2 5
.
+ 8 .8 9 1 % ( 6 0 mm.) L euk oc y t os i s ; t ermi n a l
my elof i bros i s
9 . 1 8 3 7 .3N eg .
.
+ 7 .5 9 4% ( 8 0 mm.) L euk oc y t os i s
9 . 2 3
.
N eg .
.
+
.
9 4% ( 7 0 mm.) L euk oc y t os i s ,
L A P 3 0 0 ; **
+ ov a ri a n t umour
9 . 1 7 .5 7 0 N eg .
.
+
.
9 4% L euk oc y t os i s
o" . 1 9 .2
.
0 .8
.
9 5 % + Von R ec k li n g h a us en ' s
d i s ea s e; n ormot en s i v e
H YP O XE M I A
P i c k wi c k i a n s y n d rome
o" . 2 0 .8 6 2 6 .5
.
9 .9 -1 2 .9 7 9 % ( 43 mm.) U ri n e p H 5 ; res p . a c i d os i s ,
H +46 m/ *E q ., P c o2
8 5 mm.; H C 0 8 ,
44 mM / 1 .
E mp h y s ema
c f . 1 7 .4 4.6
. .
8 .7 9 5 % ( 7 3 mm.)
T run c us a rt eri os us a n d i ron
d ef i c i en c y o" . 1 2 .2 2 6 .0
.
5 0 % _
R E N A L
H y p ern ep h roma o" . 2 2
.
4.5
. . . .
C lea r c ell c a rc i n oma
R en a l c y s t o" . 1 8 .5 3 5 6 .0
.
5 .7 9 4% ( 7 3 mm.)
M i ld p oly c y t h emi a
R en a l c y s t o" . p l.
=
.4
p re-a s p i ra t i on .
1 7 .3 434.0 c y s t
f l. =5 .5 9 .6 9 5 % ( 7 6 mm.)
p os t -a s p i ra t i on . 1 5 .1 3 1
. .. .
T uberc ulous
n ep h ri t i s of L .
,
k i d n ey 9 . 1 7 .3 40
.
L . ren a l v ei n , .3 8 .1 5 9 1 % ( 5 1 mm.) P ulmon a ry h y p ert en s i on ,
R . ren a l v ei n , .1 5 c or p ulmon a le,
a s s oc .
a rt . h y p ox emi a
E XT R A R E N A L
S up ra t en t ori a l h ema n g i obla s t oma 1 1 y rs .
9 . 1 8 .4 3 6 1 .2 5
. .
4.8 9 6 % ( 8 8 mm.) E x t en s i on i n t o t h a la mi ,
d i s p la c emen t
of t h e
bra i n s t em. U ri n e p H : 6
O v a ri a n c y s t a d en o-c a rc i n oma
p re-s urg i c a l
9 . 1 7 .4
.
0 .3 5
. .
L a p
n orma l
p os t -s urg i c a l. 1 2 .8
. ..
Bron c h og en i c c a rc i n oma
o" . 1 8 .8 2 .8
.
+ 9 3 % ( 6 6 mm.) L a p n orma l, ren a l met a s -
t a s i s a n d h y p ox emi a .
P oly c y t h emi a
n ot
p rov ed
N orma l a d ult
o" . 1 4-1 8 3 0 1 2 .5 -4.5 N ot d et ec t ed 4-6 >9 4% ( 8 0 -9 0 )
E S F a t uri n e p H of
5 -6 .5
N orma l a d ult
9 . 1 2 -1 4 2 4 1 0 .8 -1 .2 N ot d et ec t ed
. .
P rep ubert a l
c f a n d 9 . 1 2 -1 4 2 4 1 0 .3 -0 .8 N ot d et ec t ed
._--_
A L K A L O S I S *
( n o p oly c y t h emi a )
R es p i ra t ory
o* . 1 7 2 9 1 3 .4
. .
6 .3 9 3 % ( 6 8 mm.)
U ri n e p H 4-7 .5 ; p la s ma
H C O 3
=
2 0 .5 mM / 1 .; P c O a
=
3 2 .5 ; H +=3 8 n E q .
M et a boli c 0 * . 1 5 .2
.
2 8
. .
8 .7
9 6 % ( 6 8 mm.) U ri n e p H =7 .5 ; p la s ma
H C O 3
=
3 8 mM / l.
P C 0 2 =40
? E ry t h rop oi et i n ( E S F )
i n
p la s ma by p res en t a s s a y p roc ed ures i s n ot d et ec t ed a n d i s i n f luen c ed by
t h e p res en c e
of ot h er s ubs t a n c es .46 H emoly s i s
of s p ec i men i n c rea s es
i n c orp ora t i on of M F e i n t o ery t h roc y t es of t es t mi c e i n d ep en d en t
of E S F c on t en t . A la rg e p erc en t a g e
of p la s ma h emoly z es
mous e
ery t h roc y t es . S p ec i f i c ex t ra c t i on of p la s ma eli mi n a t es t h es e ef f ec t s , but req ui res c on c en t ra t i on .
f O c c urren c e of uri c a c i d emi a i n t h e g en era l p op ula t i on ,
or t h a t a s s oc i a t ed wi t h ren a l d i s ea s e or s ec on d a ry p oly c y t h emi a , p rec lud es us i n g
t h i s d et ermi n a t i on s p ec i f i c a lly i n t h e d i a g n os i s of
p ri ma ry p oly c y t h emi a .
**L A P
=
leuk oc y t e a lk a li n e p h os p h a t a s e, n orma l 3 0 .
J ln f luen c e of a c i d -ba s e ba la n c e i n p a t i en t s a p p ea rs i mp ort a n t i n ev a lua t i n g t h e c on c en t ra t i on of E S F i n uri n e, 1 2 1 a s well a s t h e a moun t of blood
remov ed bef ore t h e d et ermi n a t i on of uri n e
ery t h rop oi et i n .8 6
P o2
n orma l ra n g e d ep en d en t on a g e of p a t i en t .
c rea s e of
p eri p h era l res i s t a n c e, 5 1 i n c rea s i n g
t h e
t ot a l
ox y g en t ra n s p ort . H owev er,
i n
p a t i en t s
wi t h
a rt eri os c lerot i c v a s c ula r
d i s ea s e,
t h e i n erea s ed
blood f low i s
li mi t ed ,
a n d t h e i n erea s ed blood
v i s c os i t y ma y
res ult i n loc a l i s c h emi a . P h lebo-
t omy
i s t h eref ore of
g rea t i mp ort a n c e
i n t h e
t rea t men t of
p ri ma ry p oly c y t h emi a , es p ec i a lly
i n t h e
p res en c e
of
i mp en d i n g
c erebra l or
p eri
p h era l
t i h rombos i s . T h e f i rs t ef f ec t of
p h lebot omy
i s t o red uc e t h e blood v olume a n d c a rd i a c out
p ut ,
a n d
on ly
la t er i s t h e
v i s c os i t y
of t h e blood
red uc ed
by
d i lut i on wi t h
p la s ma .
I t i s t h eref ore
un d es i ra ble t o red uc e
g rea t ly
t h e blood v olume
wi t h a
s i n g le p h lebot omy ,
a n d c a ut i on i s re
q ui red
i n
p a t i en t s
wi t h a d v a n c ed a rt eri os c leros i s .
S i mult a n eous i n f us i on of
a g ed p la s ma
or d ex t ra n
p la s ma ex p a n d ers ma y
be
a d v a n t a g eous
i n
p ro-
mot i n g
h emod i lut i on a n d
p rev en t i n g h y p ot en -
s i on . A
s p ec i f i c p h lebot omy p rog ra m
wi ll
v a ry
wi t h t h e
req ui remen t s
a n d t olera n c e of t h e
p a
t i en t ,
but i t i s
g en era lly
a d v i s a ble t o red uc e t h e
h ema t oc ri t t o
5 0 %
or les s . I n mos t
c a s es ,
c h emo-
2 7 6 J E P S oN : P O L YC YT R E M I A C a n a d . M ed . A s s . J .
F eb. 8 , 1 9 6 9 , v ol. 1 0 0
t h era p y or ra d i ot h era p y wi ll a ls o be n ec es s a ry
s i n c e ma n y of t h e s y mp t oms of p ri ma ry p oly -
c y t h emi a a re li n k ed t o t h e blood h i s t a mi n e lev el,
wh i c h i n t urn i s rela t ed t o t h e ba s op h i le c on -
c en t ra t i on .5 2 I n a d d i t i on , t h romboc y t os i s i s f re-
q uen t ly a s s oc i a t ed wi t h t h i s d i s ea s e. F ormerly ,
t h era p y wa s p ri ma ri ly d ep en d en t on t h e us e of
3 2 . g i v en i n d os es wh i c h red uc e t h e red c ell
ma s s , leuk oc y t es a n d p la t elet s t o n orma l lev els .
T h i s t rea t men t h a s un d oubt ed ly p rolon g ed t h e
li f e of p a t i en t s wi t h p ri ma ry p oly c y t h emi a t o a
med i a n of ov er 1 3 y ea rs ..' 5 4 H owev er, rec en t
rep ort s h a v e emp h a s i z ed t h e i n c rea s ed f req uen c y
of a c ut e or c h ron i c my eloc y t i c leuk emi a i n p a -
t i en t s rec ei v i n g 3 2 1 ? c omp a red wi t h t h e i n c i d en c e
i n t h os e n ot on ra d i a t i on t h era p y . T h e i n c i d en c e
of leuk emi a s eems t o be rela t ed t o t h e t ot a l d os e
of 3 2 .*5 5 I n v i ew of t h es e obs erv a t i on s i t h a s
been s ug g es t ed t h a t y oun g er p a t i en t s s h ould n ot
rec ei v e t h i s t y p e of t h era p y .5 5 47 O t h ers p oi n t
out , h owev er, t h a t t h e ex t en d ed s urv i v a l of
p a t i en t s t rea t ed wi t h ra d i ot h era p y ma y be
res p on s i ble f or t h e i n c rea s ed i n c i d en c e of
leuk emi a .5 8 ' . . M oreov er, t h e med i a n li f e
s p a n of p a t i en t s t rea t ed by ot h er mea n s d i d n ot
d i f f er f rom t h a t of p a t i en t s t rea t ed wi t h c h emo-
t h era p y . A lt h oug h n o leuk emi a d ev elop ed i n a
g roup of A n g lo-S a x on p a t i en t s t rea t ed wi t h
c h emot h era p y a lon e, t h e i n c i d en c e of bon e-ma r-
row f a i lure a n d t h e s urv i v a l t i me of t h es e p a -
t i en t s were t h e s a me a s i n p a t i en t s t rea t ed wi t h
3 2 P ; t h ey were d es c ri bed a s h a v i n g a " leuk e-
moi d " blood p i c t ure.6 2 T h ere a re ot h er rep ort s
of a low i n c i d en c e of leuk emi a i n A n g lo-S a x on
p a t i en t s t rea t ed wi t h ra d i ot h era p y .6 0 F urt h er-
more, a c ut e my eloc y t i c leuk emi a h a s been re-
p ort ed i n p a t i en t s rec ei v i n g n o t h era p y or s ome
f orm of c h emot h era p y . T h e d ev elop men t of
a n emi a , i n c rea s i n g s p len omeg a ly a n d t h e p res -
en c e of y oun g c ells of t h e my eloc y t e s eri es on
p eri p h era l s mea r h a s been c a lled leuk emi a by
s ome a ut h ors a n d a leuk emoi d rea c t i on by
ot h ers .5 9 6 ' T h e la t t er d o n ot a p p ly t h e t erm
" leuk emi a " t o wh a t t h ey beli ev e a re t h e ma n i -
f es t a t i on s of bon e-ma rrow f a i lure, t h a t i s , t h e
blood p i c t ure a s s oc i a t ed wi t h my elos c leros i s a n d
ex t ra -med ulla ry h emop oi es i s . T h i s i n c lud es a
" leuk emoi d rea c t i on " , t h e ev en t ua l d ev elop men t
of t h romboc y t op en i a , a n emi a a n d , i n s ome, t h e
a p p ea ra n c e of " bla s t " c ells on ly s h ort ly bef ore
d ea t h .5 9 I t h a s been s ug g es t ed t h a t t h e d i a g n os i s
of c h ron i c my elog en ous leuk emi a be res t ri c t ed
t o p a t i en t s wi t h a s p ec i f i c P h i la d elp h i a c h romo-
s ome.5 9 P erh a p s i t i s s i g n i f i c a n t t h a t p ri ma ry
p oly c y t h emi a a s well a s a c ut e leuk emi a i s more
wi d es p rea d i n p eop le of E urop ea n J ewi s h ori -
g i n , 3 1 a f a c t n ot ed i n a n ep i d emi olog i c a l s t ud y
of t h i s d i s ea s e.3 2 I n t h e s eri es a lrea d y ref erred
t o wh i c h wa s ma d e up p red omi n a n t ly of A n g lo-
S a x on s t h ere were n o c a s es of leuk emi a a f t er
ra d i a t i on t h era p y .6 0 T h i s s ug g es t ed t h a t t h e f or-
mer g roup ma y be un d uly s us c ep t i ble t o leuk e-
mog en i c a g en t s , a n d p erh a p s t h i s a c c oun t s f or
t h e h i g h er i n c i d en c e of leuk emi a i n p a t i en t s of
on e s eri es t rea t ed wi t h 3 2 p , T h e us e of c h emo-
t h era p eut i c a g en t s i n t h es e p a t i en t s ma y a ls o
p rov e t o be leuk emog en i c un d er s uc h c i rc um-
s t a n c es . I t i s a p p a ren t t h a t t h e a rg umen t h a s n ot
been s a t i s f a c t ori ly s et t led . S i n c e t h e t h rea t of
leuk emi a ma y be p res en t wi t h t h e us e of 3 2 p ,
i t i s p erh a p s wi s er t o t emp ori z e by us i n g c h emo-
t h era p y ea rli er i n t h e c ours e of t h e d i s ea s e a n d
t o res erv e ..l? f or old er p a t i en t s . H owev er,
c h emot h era p eut i c a g en t s t h ems elv es a re n ot
wi t h out c omp li c a t i on s ; t h ey req ui re c los e s up er-
v i s i on a n d ma y h a v e lon g -t erm s i d e ef f ec t s . D i f -
f us e i n t ers t i t i a l f i bros i s ma y f ollow bus ulf a n
t h era p y , 41 . p a n c y t op en i a ma y oc c ur, a n d t h e
rep ort ed remi s s i on s f ollowi n g c h emot h era p y a re
of t en s h ort er t h a n t h os e wi t h 3 2 p , 5 4
C h emot h era p eut i c a g en t s s uc h a s bus ulf a n ,
c h lora mbuc i l a n d c y c lop h os p h a mi d e h a v e been
emp loy ed s uc c es s f ully . T h ei r us e i s wa rra n t ed
i n t h e p res en c e of i n c rea s ed p la t elet c oun t s ,
t h rombos i s or h emorrh a g i c ma n i f es t a t i on s , p er-
s i s t en t s y mp t oms wh i c h a re n ot reli ev ed by
p h lebot omy , or i n t h e p res en c e of c omp li c a t i on s
f rom i n c rea s ed d eg ra d a t i on of n uc leo-p rot ei n
res ult i n g i n h y p eruri c emi a .6 4' ( .
R E F E R E N C E S
1 . P R A N K E R D , T . A . J .: P roc . R oy . S oc . M ed ., 5 9 : 1 0 8 9 ,
1 9 6 6 .
2 . GA R D N E R , F . H .: S emi n a rs H ema t ., 3 : 2 3 2 , 1 9 6 6 .
3 . M U R R A Y, J . F .: A n n . I n t ern . M ed ., 6 4: 8 9 2 , 1 9 6 6 .
4. Bi oE L ow, D . B., W A R D , H . P . A N D P E T T Y, T . L .: O li n .
R es .. 1 6 : 1 3 2 , 1 9 6 8 ( a bs t ra c t ) .
5 . M O D A N , B. A N D M O D A N , M .: Bri t . J . H a ema t ., 1 4:
3 7 5 , 1 9 6 8 .
6 . M U R R A Y, J . F .: A mer. R ev . R es p . D i s ., 9 2 : 43 5 , 1 9 6 5 .
7 . W A S S E R M A N , L . R ., D oBs oN , R . L . A N D L A W R E N C E ,
J . H .: , J . O li n . I n v es t ., 2 8 : 6 0 , 1 9 49 .
8 . C A S S E L S , D . E . A N D M O R S E , M .: I bi d ., 3 2 : 5 2 . 1 9 5 3 .
9 . L E R T E M A N M . et a l.: A n n . I n t ern . M ed ., 6 0 : 40 9 , 1 9 6 4.
1 0 . H E R BE R T , S . J . et a l.: E ) a s . O h es t , 48 : 40 8 , 1 9 6 5 .
1 1 . C A M E R O N , E . A .: Bri t . M ed . , T ., 1 : 3 4, 1 9 6 1 .
1 2 . L E W I s , 3 . G.: I bi d ., 1 : 2 4. 1 9 6 1 .
1 3 . T A L BO T T , J . H .: M ed i c i n e ( Ba i t .) , 3 8 : 1 7 3 , 1 9 5 9 .
1 4. VI D E BA E K , A .: A c t a M ed . S c a n d ., 1 3 8 : 2 3 9 , 1 9 5 0 .
1 5 . E L L I s , L . D ., W E S T E R M A N , M . P . A N D BA L C E R E A K ,
S . P .: Bri t . .1 . H a ema t ., 1 3 : 8 9 2 , 1 9 6 7 .
1 6 . D H O P E S H W A R K A R , G. A . A N D S T J K H A T A N K A R , U . N .:
I bi d ., 1 4: 5 1 . 1 9 6 8 .
1 7 . BA R T O S , H . R . A N D D E S F O R GE S , 3 . F .: Blood , 2 9 : 9 1 6 ,
1 9 6 7 .
1 8 . P oL L Yc ov E , M ., W I N C H E L L , H . S . A N D L A W R E N C E ,
.J . H .: I bi d ., 2 8 : 8 0 7 , 1 9 6 6 .
1 9 . M I L L A R D , R . B. et a l.: Bri t . .T . H a ema t ., 1 4: 3 6 3 , 1 9 6 8 .
2 0 . P E N I N GT O N , D . G.: P roc . R oy . S oc . M ed ., 5 9 : 1 0 9 1 ,
1 9 6 6 .
2 1 . L I N M A N , J . W . A N D BE T H E L L , F . H .: J . L a b. O li n .
M ed ., 49 : 1 1 3 . 1 9 5 7 .
2 2 . S T O H L M A N , F ., J R .: S emi n a rs H ema t ., 3 : 1 8 1 , 1 9 6 6 .
2 3 . J E P S O N , 3 . H .: U n p ubli s h ed d a t a .
2 4. VA N D YK E , D ., N O H R , M . L . A N D L A W R E N C E , J . H .:
Blood , 2 8 : 5 3 5 , 1 9 6 6 .
2 5 . A D A M S O N , J . W . A N D F I N C H , C . A .: A n n . N .Y. A c a d .
S c i ., 1 49 : 5 6 0 , 1 9 6 8 .
2 6 . K R A N T Z , S . B.: I bi d .. 1 49 : 43 0 , 1 9 6 8 .
2 7 . L E W I S , S . M . A N D D A C I E , 3 . V.: Bmt . J . H a ema t ., 1 3 :
2 3 6 , 1 9 6 7 .
2 8 . M I R A N D , B. A .: A n n . N .Y. A c a d . S c i ., 1 49 : 48 6 , 1 9 6 8 .
2 9 . S A S S A , S ., T A K A K U , F . A N D N A K A O , K .: Blood , 3 1 :
7 5 8 , 1 9 6 8 .
3 0 . M I R A N D , B. A . et a l.: P roc . S oc . E x p . Bi ol. M ed ., 1 2 8 :
8 44, 1 9 6 8 .
C a n a d . M ed . A s s . J .
F eb. 8 , 1 9 6 9 , v ol. 1 0 0 M ulut A Y A N D W O O D : L U M BO P E R I T O N E A L S mi N T s 2 7 7
3 1 . N A T H A N , D . G.: S emi n a rs H ema t ., 3 : 2 3 0 , 1 9 6 6 .
3 2 . M O D A N , B.: Blood , 2 6 : 6 5 7 , 1 9 6 5 .
3 3 . D A VE Y, M . G. et a l.: A c t a H a ema t . ( Ba s el) , 3 9 : 6 5 ,
1 9 6 8 .
3 4. C A S S I L E T H , P . A . A N D H YM A N , G. A .: A mer. , T . M ed .
S c i ., 2 5 1 : 6 9 2 , 1 9 6 6 .
3 5 . A BI L D GA A R D , C . F ., C O R N E T , J . A N D S C H U L M A N , I .:
J . P ed i a t ., 6 3 : 1 0 7 2 , 1 9 6 3 .
3 6 . L YO N , M . F .: N a t ure ( L on d on ) , 1 9 0 : 3 7 2 , 1 9 6 1 .
3 7 . D A VI D S O N , H . G., N : T ows K y , H . M . A N D C H I L D S , B.:
P roc . N a t . A c a d . S c i . U .S .A ., 5 0 : 48 1 , 1 9 6 3 .
3 8 . A L P E R I N , J . B. et a l.: O li n . R es ., 1 6 : 40 , 1 9 6 8 ( a b-
s t ra c t ) .
3 9 . C H A R A C H E , S ., W E A T H E R A L L , D . G. A N D C L E O G, J . B.:
J . O li n . I n v es t ., . 45 : 8 1 3 , 1 9 6 6 .
40 . R E E D , C . S . et a l.: Blood , 3 1 : 6 2 3 , 1 9 6 8 .
41 . J oN E s , H . T . et a l.: J . O li n . I n v es t ., 46 : 1 8 40 , 1 9 6 7 .
42 . N ov ., M . J ., E D W A R D S , M . J . A N D M E T O A L F E , J .: I bi d .,
46 : 1 8 48 , 1 9 6 7 .
43 . R U C K N A GE L , D . L ., GL YN N , K . P . A N D S M I T H , J . R .:
O li n . R es ., 1 5 : 2 7 0 , 1 9 6 7 ( a bs t ra c t ) .
44. N A GE L , H . L ., GI BS O N , Q . H . A N D C H A R A C H E , S .: Bi o-
c h emi s t ry ( W a s h .) . 6 : 2 3 9 5 , 1 9 6 7 .
45 . A D A M S O N , J . W . A N D S T A M A T O YA N N O P O U L O S , G.: Blood ,
3 0 : 8 48 , 1 9 6 7 ( a bs t ra c t ) .
46 . J E P S O N , J . H .: J ourn a l of t h e R oy a l O olleg e of P h y s i -
c i a n s , L on d on , 2 : 3 8 1 . 1 9 6 8 .
47 . R E YN A F A R J E , C ., L oz A N o, H . A N D VA L D I VI E S O , J .:
Blood , 1 4: 43 3 , 1 9 5 9 .
48 . C oT E S , P . M . A N D BA N GH A M , D . H .: N a t ure ( L on -
d on ) , 1 9 1 : 1 0 6 5 , 1 9 6 1 .
49 . L A N GE , R . D ., M C D O N A L D , T . P . A N D J O R D A N , T .:
P a p ers p res en t ed a t t h e 1 2 t h C on g res s of t h e I n -
t ern a t i on a l S oc i et y of H ema t olog y , N ew York , S ep -
t ember 1 -6 , 1 9 6 8 .
5 0 . H U BE R , H ., L E W I S , S . M . A N D S E U R , L .: Bri t . J .
H a ema t ., 1 0 : 5 6 7 , 1 9 6 4.
5 1 . GU YT O N , A . C . et a l.: A mer. J . P h y s i oL , 1 9 4: 2 6 3 ,
1 9 5 8 .
5 2 : GI L BE R T , H . S ., W A R N E R , R . A N D W A S S E R M A N , L . R .:
Blood , 2 8 : 7 9 5 , 1 9 6 6 .
5 3 . O s a ooD , E . E .: I bi d ., 2 6 : 2 43 , 1 9 6 5 .
5 4. S Z U R , L ., L E W I S , S . M . A N D P A T H , M . C .: Bri t . J .
R a d i ol., 3 9 : 1 2 2 . 1 9 6 6 .
5 5 . M O D A N , B. A N D L I L I E N F E L D , A . M .: M ed i c i n e ( Ba i t .) ,
44: 3 0 5 , 1 9 6 5 .
5 6 . D A M E S H E K , W .: S emi n a rs H ema t ., 3 : 2 2 6 , 1 9 6 6 .
5 7 . E d i t ori a l: L a n c et , 1 : 8 49 . 1 9 6 5 .
5 8 . GA R D N E R , F . H .: D M , 1 , J un e 1 9 6 2 .
5 9 . I d em: S emi n a rs H ema t ., 3 : 2 2 0 , 1 9 6 6 .
6 0 . H A L N A N , K . B. A N D R U S S E L L , M . H .: L a n c et , 2 : 7 6 0 ,
1 9 6 5 .
6 1 . H A R M A N , J . B., K A Y. H . B. M . A N D L E D L I E , E . M .:
L a n c et , 1 : 1 1 1 5 , 1 9 6 5 .
6 2 . P E R K I N S , J ., I S R A E L S . M . C . G. A N D W I L K I N S O N , J . F .:
Q ua rt . J . M ed ., 3 3 : 49 9 . 1 9 6 4.
6 3 . O L I N E R , H . et a l.: A mer. J . M ed ., 3 1 : 1 3 4, 1 9 6 1 .
6 4. W A S S E R M A N , L . R . A N D GI L BE R T , H . S .: S emi n a rs
H ema t ., 3 : 2 2 8 , 1 9 6 6 .
6 5 . BR O D S K Y, I ., K A H N , S . B. A N D BR A D Y, L . XV.: Bri t . , T .
H a ema t ., 41 : 3 5 1 , 1 9 6 8 .
M y elos c i n t i g ra ms i n t h e A s s es s men t of L umbop eri t on ea l
S h un t s
S H I R L E Y M U R R A Y, M .D ., F .R .C .P . [ C ] a n d
D . E . W O O D , M .D ., F .R .C .P . [ C ] , T oron t o
C O M M U N I C A T I N G h y d roc ep h a lus h a s been
t rea t ed wi t h lumbop eri t on ea l s h un t s t o
en a ble t h e c erebros p i n a l f lui d ( GS F ) t o d ra i n
f rom t h e s p i n a l s uba ra c h n oi d s p a c e t o t h e p en -
t on ea l c a v i t y by mea n s of a p oly et h y len e t ube.
Bloc k a g e of t h e t ube i s a f req uen t c omp li c a t i on .1
S i n c e t h e c on d i t i on of s y mp t oma t i c oc c ult c om-
mun i c a t i n g h y d roc ep h a lus wi t h n orma l C S F
p res s ure h a s been d es c ri bed , t h e i n t rod uc t i on
of a lumbop eri t on ea l s h un t h a s been p erf ormed
on a n umber of p a t i en t s .2 4 T h i s c ommun i c a t i on
d es c ri bes a met h od f or a s s a y i n g t h e p a t en c y of
t h e t ube by ex t ern a l s c a n n i n g a f t er a ra d i o-
p h a rma c eut i c a l h a s been i n s t i lled i n t o t h e
lumba r s uba ra c h n oi d s p a c e. T h e p roc ed ure wa s
ut i li z ed i n n i n e p a t i en t s . I n ei g h t of .t h es e t h e
es t a bli s h ed d i a g n os i s wa s c ommun i c a t i n g h y d ro-
c ep h a lus wi t h n orma l C S F p res s ure. I n t h e
n i n t h p a t i en t t h ere wa s a i r ov er t h e s ulc i on t h e
p n eumoen c ep h a log ra m, wh i c h s ug g es t ed t h a t
t h e d i a g n os i s ma y h a v e been h y d roc ep h a lus ex
v a c uo. H owev er, a lumbop eri t on ea l s h un t wa s
p erf ormed on t h i s p a t i en t a s well.
F rom t h e D ep a rt men t of N uc lea r M ed i c i n e, T oron t o Gen -
era l H os p i t a l, T oron t o, O n t a ri o.
R ep ri n t req ues t s t o: D r. S h i rley M urra y , T oron t o Gen era l
H os p i t a l, i oi c olleg e S t reet , T oron t o 2 , O n t a ri o.
M E T H O D
U n d er s t eri le c on d i t i on s , 1 3 1 J s erum a lbumi n ,
1 0 0 d c ., or 9 9 mT c a lbumi n , 1 mc ., d i lut ed i n 1 0
ml. E lli ot B s olut i on , wa s i n j ec t ed i n t o t h e s ub-
a ra c h n oi d s p a c e a t L 3 -L 4. T h e ra d i a t i on d os e
wa s c on s i d ered t o be wi t h i n a c c ep t a ble li mi t s .5 ' 8
T h e a moun t of a lbumi n us ed wi t h 1 3 1 1 wa s 1
t o 2 mg . T h e q ua n t i t y a d mi n i s t ered wi t h 9 9 mT c
wa s h i g h er t h a n wh a t wa s c on s i d ered d es i ra ble
( 3 0 mg .) , but n o i ll ef f ec t s were n ot ed i n t h e
p a t i en t s rec ei v i n g t h i s a moun t of a lbumi n . T h e
c urren t p rod uc t of 9 9 mT c a lbumi n h a s a s p eef f i c
a c t i v i t y of 1 mi lli c uri e p er mg .
1 3 1 1 s erum a lbumi n wa s us ed ex c lus i v ely f or
t h e n on -s c a n n i n g t ec h n i q ue. F ollowi n g t h e i n -
j ec t i on , a g ri d wa s ma rk ed on bot h t h e ba c k a n d
a bd omen . P oi n t c oun t s were obt a i n ed a t f i x ed
d i s t a n c es f rom t h e s i t e of i n j ec t i on . C oun t s ov er
t h e t ube were c omp a red wi t h c oun t s on t h e
op p os i t e s i d e eq ui d i s t a n t f rom t h e i n j ec t i on s i t e.
T en s uc h s t ud i es were d on e. Bec a us e ev a lua t i on
of t h e res ult s p rov ed d i f f i c ult , s c a n n i n g wa s
i n s t i t ut ed .
T h e s c a n n er us ed wa s a .D y n a p i x " .* T h i s 1 0 -
c ry s t a l s c a n n er a c q ui res 1 0 s i mult a n eous li n es of
i n f orma t i on wi t h on e-i n c h s ep a ra t i on . D ep en d -
*P i c k er N uc lea r.