Iron stores and coagulation parameters in patients with hypoxemic polycythemia secondary to chronic obstructive pulmonary disease: the effect of phlebotomies

Iron stores and coagulation parameters in patients with

hypoxem' c polycythemia secondary to chronic obstructive

pulmonary disease: The effect of phlebotomies

F r o m t h e R e s p i r a t o r y a n d He m a t o l o g y Di v i s i o n s , U n i v e r s i d a d e F e d e r a l d e S ã o P a u l o / E s c o l a P a u l i s t a t l e M e d i c i n a

-S ã o P a u l o , B r a z i l .

T h is s tu d y w a s d e s ig n e d to d e te rm in e th e e ffe c ts o f p h le b o to m y o n iro n b o d y c o n te n ts a n d c o a g u la tio n te s ts o f C O P O p a tie n ts w ith p o 'y c y th e m ia s e c o n d a ry to h y p o x e m ia . S e v e n te e n p a tie n ts w ith C O P O a n d h e m a to c rits h ig h e r th a n 5 4 p e rc e n t (m e a n H c t: 5 7 :t 0 .4 9 p e rc e n t ), w h o h a d n o t re c e iv e d a n ti-in fla m m a to ry o r a n tip la te le t a g g re g a tio n a g e n ts re c e n tly . T h e ir m e a n fo rc e d e x p ira to ry v o lu m e a t 1 s e c o n d (F E V1) w a s 0 .9 2 :t 0 .1 1 L . In te rv e n tio n : B lo o d w o rk w a s c o lle c te d to e v a lu a te th e fo llo w in g : s e ru m iro n a n d fe rritin le v e is , to ta l

iro n b in d in g c a p a c ity , tra n s fe rrin s a tu ra tio n in d e x , fib rin o g e n p la s m a le v e is , a c tiv a te d p a rtia l th ro m b o p la s tin tim e , p la te le t c o u n t, p la te -le t a g g re g a tio n m e a s u re m e n ts , a n d th ro m b o e la s to g ra p h y c o a g u la tio n p a ra m e te rs . T h e b lo o d s a m p le s w e re o b ta in e d b e fo re a n d a b o u t 7 d a y s a fte r th e h e m a to c rit c o rre c tio n b y 3 0 0 -4 0 0 m l p h le b o to m ie s d o n e e v e ry o th e r d a y . T h e m e a n n u m b e r o f p h le b o to m ie s d o n e fo r e a c h p a tie n t w a s 4 .4 . P o s tp h le b o to m y iro n s e ru m le v e is d e c re a s e d fro m 9 0 .1 :t 1 4 .8 to 5 9 .7 :t 9 .9 m g /d l a n d th e fe rritin s e ru m le v e is fro m 1 3 3 .8 :t 3 7 .9 to 7 0 .8 :t 3 2 .7 n g /m l (p < 0 .0 5 ). R e g a rd in g th e c o a g u la tio n s tu d ie s , th e re w e re s ig n ific a n t in c re a s e s in th e p la te le t c o u n t, fro m 2 2 7 ,3 0 0 :t 1 3 ,9 0 0 to 3 1 2 ,5 0 0 :t 3 0 ,2 0 0 p e r m m3_{, a n d in th e m a x im u m c lo t a m p litu d e (a ) o b ta in e d b y}

th ro m b o e la s to g ra p h y ( fro m 5 3 .6 :t 1 .4 p e rc e n t to 6 0 .4 :t 1 .1 p e rc e n t). T h e c o a g u la tio n tim e (k ) o f th e th ro m b o e la s to g ra p h y a ls o d e c re a s e d s ig n ific a n tly , fro m 7 .5 :t 0 .7 m m p re p h le b o to m y to 4 .5 :t 0 .3 m m p o s tp h le b o to m y . A lth o u g h th e c o a g u la tio n c h a n g e s w e re s m a ll a m o u n t, th e o b s e rv e d s ig n ific a n t d e c re a s e in iro n c o n te n ts m a y h a v e im p o rta n t c lin ic a i im p lic a tio n s .

U N IT E R M S : S e c o n d a ry p o ly c y th e m ia ; re p e titiv e p h le b o to m ie s ; iro n d e fic ie n c y ; c o a g u la tio n ; c h ro n ic o b s tru c tiv e p u lm o n a ry d is e a s e

IN T R O D U C T IO N

B

loodlettings,in the care of chronicor phlebotom ies,obstructiveare still adyocatedpulm onary

disease (C O PD ) patients w ith cor pulm onale and

severe secondary polycythem ia.1 Several authors have

show n that hem atocrit (H ct) reductions in hypoxem ic

patients w ith C O PD and polycythem ia are follow ed by

im provem ent in general sym ptom s,2-S m ental activity2-6 and

exercise perform ance.2-4.7.8

A d d re s s fo r c o rre s p o n d e n c e : J o s é A . B. M a rtin e z M O

D is c ip lin a d e P n e u m o lo g ia (L u n g D iv is io n ) U N IF E S P /E P M R u a B o tu c a tu , 7 4 0 - V ila C le m e n tin o

S ã o P a u lo /S P - B ra s il - C E P 0 4 0 2 3 -9 0 0

In a group of patients perform ing exercise studies in

ergom eter, the m axim um w orkload and oxygen

consum ption have increased 31 and 16 percent

respectively, w hen the m ean H tc had decreased from 62

to 50percent,x T hese effects are not secondary to changes

in respiratory m echanics or blood gases.2.4.S.7-10R ather, it

seem s they result from im provem ents in hem odynam ic

conditions related to a better blood viscosity.3.11-13

A lthough a great deal has been published in this field,

no attention has been paid to the potential hem atological

consequences of phlebotom ies. Sim ilarly to w hat happens

w ith blood donors and during the treatm ent of

hem ochrom atosis, repeated phlebotom ies in C O PD

patients could lead to reductions in their iron body

contents.14.1S Iron deficiency states m ay run w ith

decrem ents in w ork perform ance secondary to drops in

M A R T IN E Z , J .A .B .; G U E R R A ,C .C .C ,; N E R Y , L .E . e t a I. - lro n s to re s a n d c o a g u la tio n p a ra m e te rs in p a tie n ts w ith h y p o x e m ic p o ly c y th e m ia s e c o n d a ry to c h ro n ic o b s tru c tiv e p u lm o n a ry d is e a s e : T h e e ffe c t o f p h le b o to m ie s

helT Ioglobin leveIs, and disturbances in m uscular oxidative

m etaboIism .1ó In the case of reductions in iron body

contents actualIy deveIoping in C O P D patients folIow ing

phlebotom ies, the form er could act as lim iting factors for

expected exercise im provem ents.

In addition, polycythem ia is a w elI know n risk factor

for throm bosis,17 and lnany studies. suggest that C O P D

patients have a higher tendency to have throm boem bolic

episodes.IX_-20 _{S O lne studies of throm botic risk in C O P D}

have show n an increased tendency tow ards coagulation

w ith altered values in the throlnboelastogram ,

hyperfibrinogem ia and increased platelet aggregation.1x'21-23

T herefore, w e hypothesized that a reduction in H ct leveIs

by phlebotolnies could aIso have a favorable effect on

decreasing s'uch throm botic risk.

T he present study investigates the effects of the H ct

correction by repeated phlebotom ies on paralneters of

hem ostasis and body iron contents in C O P D patients w ith

severe secondary hypoxem ic polycythem ia.

P A T IE N T S A N D M E T H O D S

Patient Selection

S eventeen w ith C O P D and polycythelnia ( H ct 5 4

percent or m ore) patients w ere studied after signing an

inform ed consent form o A ll patients w ere in stable

respiratory conditions, w ithout clinicaI evidence of right or

left ventricular faiIure. T hey had not been under any

antiplatelet or anti-inflam m atory agent for at least the prior

1 0 days, and.during the study period there w ere no changes

in their daily m edications. N one of the patients show ed

clinicaI evidence ofblood loss or w ere using oxygen at that

tim e.

F ollow ing an initiallaboratory evaIuation, phlebotom ies

of 300 to 400 m l w ere perfonned every other day until a

venous H ct value around 4 5 percent w as reached (range: 4 1

-4 8 percent). A second set of laboratory tests w as then

perform ed about 7 days after the last phlebotom y 'session.

Iron Stores Measurements

V enous blood sam ples w ith no anticoagulant w ere

collected from fasting patients in the Inorning. Iron seruln

leveIs and seruln total iron binding capacity (T IB C ) w ere

m easured using a com m ercialIy available kit (Iron R oche@ )

w ith readings m ade w ith a C olelnan 6 /2 0

spectrophotom eter. F erritin serum leveIs w ere also

evaluated by a com m ercially available enzym atic

im m unoassay (F errizY lne T M @ - A bbot L aboratories). T he

transferrin saturation index (T S I) w as calculated as the

percentile ratio betw een serum iron leveIs and T IB C .

Coagulation Studies

C oagulation tests w ere perform ed on 3 .8 percent

sodium citrate venous blood sam ples collected

sim uItaneously w ith the iron blood w ork. T he follow ing

determ inations w ere m ade:

- A ctivated paltial throm boplastin tim e (A P T T ) using

hum an cephalin.24 T he results w ere expressed as the ratio

to the control values for the Iaboratory on that day.

- F ibrinogen plasm a leveIs, assessed by the R

atnoff-M enzie Inethocl.25

- P lateIet count, m ade in an autom atic counter C lay

A dam s m odeI U ltra-F Io.

- P latelet aggregation determ inations by the B orn

lnethod in a C hronolog aggregom eter.2ó T he aggregation

agents A D P in concentrations of 1 m M and 3 m M ,

epinephrine at 1: 1000 dilution, and hU lnan colIagen w ere

used in salnples froln each patient. T he percentage of

aggregated pIatelets w as caIculated at a curve point

corresponding to an interval of 5 m inutes from the initial.

stim ulus for each aggregation agent.

- T hrolnboelastography (T E G ), using a H artert

throlnboelastograph lnade by H elIige. T his test exalnines

the entire bloocl coaguIation process and the interaction

of alI involvecl cO lnponents.27 T he reaction tilne

r,

the

coagulation tim e

k,

and the lnaxil11um cIot alnpIitude

a ,

w ere lneasured using a special ruIer on the developed film o

Statistical Methods

A ll data are expressed as the m ean : tstandard error.

T he W iIcoxon test w as used in the statistical analysis for

the nonindependent variables. A . leveI of 5 percent w as

fixed as the litnit for rejection of the null hypothesis.

R E S U L T S

T hirteen m ale and four fem ale patients w ere studiecl.

M ost of theln had severe or 1110derate C O P D w ith arterial

hypoxem ia (T able 1 ).T he m ean H ct fell frol115 7 percent

before phebotolnies to 4 5 percent at the tim e of the final

T a b l e 1 P a t i e n t S u m m a r y

A g e F E V₁ F V C / F E V₁ P a 0

2 H c t P r e H c t P o s t

N o . G e n d e r y r L %

m m H g % %

1 M 5 3 1 . 1 7 5 0 4 7 5 4 4 5

2 M 4 4 0 . 8 2 3 8 3 9 5 5 4 8

3 M ' 6 0 0 . 7 1 3 5 4 4 5 4 4 4

4 M 6 3 0 . 5 9 3 1 4 9 5 7 4 5

5 M 4 4 0 . 6 5 3 8 4 5 6 0 4 5

6 F 3 6 0 . 4 7 4 7 4 2 5 7 4 1

7 M 5 0 1 . 4 6 5 0 4 6 6 3 4 4

8 F 7 2 0 . 4 8 4 5 3 8 5 6 4 6

9 M 2 8 0 . 5 7 3 6 4 2 5 8 4 7

1 0 M 7 5 1 . 1 9 4 5 4 9 6 0 4 7

1 1 M 6 7 1 . 4 1 6 0 5 3 5 8 4 4

1 2 M 7 0 1 . 6 8 6 0 5 1 5 5 4 5

1 3 F 4 2 0 . 6 5 3 2 4 6 5 6 4 3

1 4 F 6 8 0 . 4 4 3 7 4 9 5 8 4 4

1 5 M 7 0 0 . 6 2 3 5 5 3 5 7 4 6

1 6 M 3 5 1 . 8 8 4 9 5 2 5 5 4 5

1 7 M 6 6 0 . 9 3 2 8 5 9 5 5 4 2

M e a n 5 5 : t 3 . 6 0 . 9 2 : t . 1 1 4 2 : t 2 . 4 4 7 : t 1 . 2 5 7 : t . 4 9 4 5 : t . 4 9

T I B C : s e r u m t o t a l ir o n b in d in g c a p a c it y ; T S I : t r a n s f e r in s a t u r a t io n in d e x o * p < 0 . 0 5

T a b l e 2

I r o n c o n t e n t s m e a s u r e m e n t s ( M e a n : ! :S E ) o b t a i n e d p r e - a n d p o s t p h l e b o t o m y

T h e re w e re s ig n ific a n t d e c re a s e s in th e s e ru n l le v e Is

o f iro n , fe rritin a n d T S I p o s tp h le b o to ln y (T a b le 2 ). T w e lv e

s tu d ie s . T h e s e c o n d s e t o f b lo o d te s ts w e re c o lle c te d 8 .7 : t

1 .3 d a y s a fte r th e Ia s t p h le b o to m y . T h e tim e b e tw e e n b lo o d

c o lle c tio n a n d a c tu a I s a m p le a n a ly s is w a s n o lo n g e r th a n

tw o h o u rs in e v e ry c a s e .

P o s t p h le b o t o m y 5 9 . 7 : t 9 . 9 * 3 9 9 . 9 : t 2 0 . 0

1 6 . 7 : t 3 . 6 * P r e p h le b o t o m y

9 0 . 1 : t 1 4 . 8 3 9 3 . 6 : t 2 7 . 6

2 5 . 4 : t 4 . 9

Coagulation Studies

C o a g u la tio n s tu d ie s o b ta in e d b e fo re a n d a fte r

p h le b o to m ie s a re lis te d in T a b le 3 . A li th e in itia l In e a n

v a lu e s w e re w ith in th e n o rln a l lim its ' o f th e a u th o rs '

la b o ra to ry e x c e p t fo r th e

r

p a ra ln e te r o f th e T E G , v v h ic h

w a s s lig h tly in c re a s e d . N o s ig n ific a n t d e c re a s e s w e re s e e n

in th e In e a n A P T T a n d fib rin o g e n le v e Is a fte r

p h le b o to ln ie s . T h e p la te le t c o u n t s ig n ific a n tly in c re a s e d

fro n l 2 2 7 ,3 0 0 1 In ln3

to 3 1 2 ,0 0 0 /m m3

a fte r th e p ro c e d u re .

F ifte e n p a tie n ts (8 8 .2 p e rc e n t) s h o w e d a n in c re a s e in th e

N o r m a l R a n g e 5 0 - 1 5 0 2 0 0 - 4 0 0 2 0 - 5 0 I r o n , m g / d l

T I B C , m g / d l T S I , %

a d e c re a s e i n i ro n

Iron Measurements

p a tie n ts (7 0 p e rc e n t) s h o w e d

c o n c e n tra tio n s a n d in 7 o f th e s e

it re m a in e d b e lo w 5 0 p e rc e n t o f

th e in itia l v a lu e . F a lls in fe rritin

le v e Is w e re s e e n i n 1 6 p a tie n ts

(9 4 p e rc e n t). S u c h d e c re a s e s

w e re g re a te r th a n 5 0 p e rc e n t

fro m th e b a s e lin e v a lu e s in 1 2

(7 0 p e rc e n t) o f th e s u b je c ts . In

8 p a tie n ts (4 7 p e rc e n t), th e fin a l

fe rritin v a lu e s w e re b e lo w 1 0 n g /

In l, in d ic a tin g s e v e re iro n

d e p le tio n (F ig . 1 ).

M A R T I N E Z , J . A . B . ; G U E R R A , C . C . C , ; N E R Y , L . E . e t a I . - lr o n s t o r e s a n dc o a g u la t io n p a r a m e t e r s in p a ~ ie n t s w it h h y p o x e m ic p o ly c y t h e m ia s e c o n d a r y t o c h r o n ic o b s t r u c t iv e p u lm o n a r y d is e a s e : T h e e f f e c t o f p h le b o t o m ie s

'O S T P K .E B O T O M Y

r-P C O .o s -,

P R E P H E L E B O T O M Y ,-- p c0 .0 5 -,

300 ₄₁₀

400 250

1

_ 350 E

200 .5._

I

z

z t=

o

~ 250

e: 150 _~

200

100 150

100 50

50

P R E 'O S T P H E L E B O T O M Y P K .E B O T O M Y

2 ). S e ru m fe rritin is a g o o d in d ic a to r o f

iro n b o d y sto re s, a n d th e d ro p in its le v e Is

d e n o te s th a t th e tissu e iro n c o n te n ts2 8 ,2 9

w e re a lso a ffe c te d .

Iro n d e fic ie n c y sta te s m a y h a v e

e ffe c ts o n re d b lo o d c e lls a n d so lid o rg a n

tissu e s. A lth o u g h it w o u ld b e e x p e c te d

th a t iro n d e fic ie n c y c o u ld h a v e a n

in h ib ito ry e ffe c t o n C O P D h y p o x ic

h e m o p o ie tic re sp o n se , th is is n o t a lw a y s

th e c a se . S e c o n d a ry p o ly c y th e m ia

a sso c ia te d to iro n d e fic ie n c y in C O P D

p a tie n ts h a s b e e n d e sc rib e d .3 0

,3 1 S o m e

a u th o rs re p o rt th a t iro ,n d e p le tio n m a y n o t

b e a n im p e d in g fa c to r to in c re a se s in re d

c e ll m a ss, a n d th a t in su c h c a se s

p o ly c y th e m ia is a sso c ia te d w ith

h y p o c h ro m ic e ry th ro c y te s.3 2

A n iro n d e fic ie n c y sta te m a y a lso

F ig u re 1 - Iro n a n d fe rritin in d iv id u a l v a lu e s fo rC O P Op a tie n ts s u b m itte d to s e q u e n c ia l d i stu rb th e m u sc u la r o x id a ti v e

p h le b o to m ie s . m e ta b o lism , in te rfe rin g w ith th e p a tie n t's

w o rk p e rfo rm a n c e . 16T h e tissu e h a e m iro n

c o m p o u n d s in c lu d e th e c y to ç h ro m e s, m y o g lo b in , c a ta la se

a n d p e ro x id a se . In a d d itiQ D , m u sc le s h a rb o r n o n -h a e m

iro n -c o n ta in in g e n z y m e s su c h a s N A D H d e h y d ro g e n a se ,

su c c in ic d e h y d ro g e n a se a n d x a n th in e o x id a se . F in a lly ,

so m e e n z y m e s su c h a s a c o n ita se a n d try p to p h a n p y rro la se

re q u ire iro n o r h a e m a s a c o fa c to r.

E x p e rim e n ta l stu d ie s o n ra ts h a v e fo u n d th a t m ild

a n d se v e re iro n d e fic ie n c y a re a sso c ia te d w ith d e fic its 9 f

c y to c h ro m e c a n d m io g lo b in in sk e le ta l m u sc le .3 3 _{F IN C H}

e t a 1 .3 4

c o m p le te d stu d ie s o f w o rk p e rfo rm a n c e o n iro n

-d e fic ie n t ra ts, k e e p in g h e m o g lo b in le v e Is c o n sta n t th ro u g h

e x c h a n g e tra n sfu sio n s. It w a s se e n th a t iro n -d e fic ie n t ra ts

h a d a sig n ific a n t sh o rte r ru n n in g tim e th a n ç o n tro ls w ith

sim ila r h e m o g lo b in le v e Is. A fte r 4 d a y s o f iro n

a d m in istra tio n , th e iro n -d e fic ie n t g ro u p a c h ie v e d n o rm a l

ru n n in g tim e s.

B io c h e m ic a l a n a ly sis d o n e a t th a t tim e su g g e ste d th a t

a n in c re a se in th e ra te o f o x id a tiv e p h o sp h o ry la tio n w ith

a -g ly c e ro p h o sp h a te a s a su b stra te p la y e d a k e y ro le in th e

im p ro v e m e n t o f w o rk p e rfo rm a n c e . N o n -p u b lish e d d a ta

fro m o u r la b o ra to ry h a v e sh o w n sm a ll b u t sig n ific a n t

in c re a se s in th e m a x im a l w o rk lo a d a n d o x y g e n

c o n su m p tio n re a c h e d b y 1 5 iro n -d e fic ie n t, a n e m ic w o m '

4 d a y s a fte r a d m in istra tio n o fIV iro n -d e x tra n , e v ~ n th o u g h

th e ir h e m o g lo b in le v e Is h a d n o t c h a n g e d .

T h e re fo re , w e c a n h y p o th e siz e th a t C O P D p a tie n ts

w h o sh o w a m e Iio ra tio n o f e x e rc ise p e rfo rm a n c e a fte r

p h Ie b o to m ie s ln ig h t h a v e th is e ffe c t a tte n u a te d if

sim u Ita n e o u s iro n d e fic ie n c y sta te s d e v e Io p . T h e

D IS C U S S IO N

p la te le t c o u n t, 4 o f th e m w ith fin a l m e a su re m e n ts b e y o n d

4 0 0 ,O O O /m m .3 _{S tu d ie s o f p la te le t a g g re g a tio n m a d e w ith}

d iffe re n t stim u la n t a g e n ts d id n o t sh o w a n y sig n ific a n t

p o stp h le b o to m ie s c h a n g e .

A d e q u a te th ro m b o e la sto g ra p h y stu d ie s b e fo re a n d

a fte r p h Ie b o to m ie s c o u ld n o t b e o b ta in e d in 4 p a tie n ts d u e

to te c h n ic a l p ro b le m s. In th e 1 3 stu d ie d su b je c ts, a

sig n ific a n t d e c re a se w a s n o tic e d in

k

d u rin g th e fin a l

stu d ie s. A lth o u g h

r

a lso e x p e rie n c e d a d e c re a se , su c h

c h a n g e d id n o t re a c h sta tistic a l sig n ific a n c e . F in a lly ,

a

v a lu e s sh o w e d a sig n ific a n t p o stp h le b o to m ie s in c re a se .

P h le b o to m y m a y b e u se d in th e c a re o f C O P D

p a tie n ts in a n a tte m p t to re d u c e d e trim e n ta l c a rd io v a sc u la r

e ffe c ts o f b lo o d h y p e rv isc o sity d u e to p o ly c y th e m ia . T h e

b a sis fo r th is p ro c e d u re is th e e ffe c t o f p h Ie b o to m y in

im p ro v in g h e m o d y n a m ic c o n d itio n s a n d e x e rc ise

p e rfo rm a n c e in su c h p a tie n ts.2_-4_{,7 ,8 ,1 1 -1 3 H o w e v e r, th e e ffe c ts}

o f th is k in d o f th e ra p y o n h e m o sta sis a n d iro n re se rv e s o f

C O P D p a tie n ts h a d n o t b e e n th o ro u g h Iy e x a m in e d b e fo re .

O u r p re se n t re su Its sh o w e d th a t th e n o rm a liz a tio n o f

h e m a to c rits b y p h le b o to m ie s le d to a n im p o rta n t re d u c tio n

in iro n b o d y c o n te n ts. T h is b e c a m e a p p a re n t b y th e

sig n ific a n t d e c re a se s in se ru m iro n , fe rritin a n d T S I (T a b le

T a b le 3

R e s u lt s o f c o a g u la t io n s t u d ie s ( M e a n : ! :S E ) o b t a in e d p r e - a n d p o s t p h le b o t o m y

N o r m a l R a n g e P r e p h le b o t o m y P o s t p h le b o t o m y

A P T T 0 . 9 0 - 1 . 2 5 1 . 1 4 : t 0 . 0 6 1 . 0 6 : t 0 . 0 4

F ib r in o g e n , m g / d l 2 0 0 - 4 0 0 2 6 2 : t 1 2 2 3 6 . 5 : t 1 3 . 2

P la t e le t s / m m3 _{2 0 0 , 0 0 0 - 4 0 0 , 0 0 0}

2 2 7 , 3 0 0 : t 1 3 , 9 0 0 3 1 2 , 5 0 0 : t 3 0 . 2 *

P la t e le t A g g r e g a t io n

A D P 3 m M , % 6 0 - 8 0 6 5 . 8 : t 5 . 1 _{7 4 . 1 : t 3 . 9}

A D P 1 m M , % _{6 0 - 8 0 6 3 . 0 : t 6 . 4 6 9 . 8 : t 4 . 7}

E p in e p h r in e , % 6 0 - 8 0 6 3 . 3 : t 6 . 4 6 4 . 6 : t 5 . 9

C o lla g e n , % 6 0 - 8 0 8 0 . 0 : t 2 . 8 _{7 8 . 2 : t 3 . 2}

T h r o m b o e la s t o g r a p h y #

', m m 7 . 2 - 9 . 6 9 . 9 : t 0 . 7 9 . 0 : t 0 . 5

k,mm

5 . 8 - 7 . 8 7 . 5 : t 0 . 7 4 . 5 : t 0 . 3 *

a , m m 4 8 - 6 0 5 3 . 6 : t 1 . 4 6 0 . 4 : t 1 . 1 *

A P T T : a c t iv a t e d p a r t ia l t h r o m b o p la s t in t im e ; A D P : a d e n o s in e d ip h o s p h a t e ; r : r e a c t io n t im e ;

k

c o a g u la t io n t im e ; a : m a x im u m c lo t a m p lit u d e

* p < 0 . 0 5 ; # d a t a f r o m 1 3 p a t ie n t s

d e v e lo p m e n t o f h y p o c h ro m ic re d c e Ils in su c h situ a tio n s

c o u ld im p a ir o x y g e n tra n sp o rt to th e tissu e s, e v e n w ith

th e p re se n c e o f a h ig h h e m a to c rit. F u rth e rm o re , iro n

d e p le tio n a t th e sk e le ta l m u sc le le v e I c o u ld le a d to p o o r e n z y m a tic fu n c tio n a n d o x y g e n u tiliz a tio n .

In o rd e r to e v a lu a te th e e ffe c ts o f H e t c o rre c tio n b y

p h le b o to m ie s o n th e h e m o sta sis o f C O P D p o ly c y th e m ic

p a tie n ts, te sts w e re d o n e to a sse ss th e in trin sic p a th w a y , p la te le t a n d fib rin o g e n c o n c e n tra tio n s, p la te le t a g g re g a tio n

a n d T E G . A re n e w e d in te re st in T E G m o n ito rin g h a s b e e n

se e n re c e n tly b e c a u se its tra c in g re p re se n ts th e sh e a r

e la stic ity o f a b lo o d c lo t a s it fo rm s, m a tu re s, re tra c ts a n d

e v e n tu a IIy ly se s. T h is te st is e x tre m e ly se n sitiv e to id e n tify h y p e rc o a g u la b i lity . 2 7

T h e in itia l e v a lu a tio n p re p h le b o to m y d id n o t sh o w

a n y e v id e n c e o f h y p e rc o a g u la b ility , sin c e m o st o f th e te st

re su Its w e re w ith in th e n o rm a l ra n g e fo r o u r c o a g u la tio n

la b o ra to ry (T a b le 3 ). T h e o n ly e x c e p tio n w a s th e re a c tio n

tim e

r,

w h ic h re p re se n ts th e tim e re q u ire d fo r in itia I fib rin

fo rn la tio n , w h ic h w a s slig h tly in c re a se d . T h is la st fin d in g in d e e d is ln o re c o m p a tib le w ith a h y p o c o a g u la b ility

c o n d itio n .

T h e m e a n p la te le t c o u n t in c re a se d sig n ific a n tly a fte r

p h le b o to m y fro m 2 2 7 ,3 0 0 to 3 1 2 ,5 0 0 m m3 _{(T a b le 3 ).}

In c re a se s in p la te le t n u m b e r h a v e b e e n re p o rte d a fte r c h ro n ic a n d a c u te b lo o d 1 0 ss.3 5 .3 6T h e ln e c h a n ism s in v o lv e d

in su c h rise s m a y b e re la te d to iro n d e p le tio n , sin c e a n

in h ib ito ry e ffe c t o f th is m e ta l in th ro b o p o ie sis h a s b e e n

d e sc rib e d .3 5 O th e r stu d ie s su g g e st th e p re se n c e o f a n

h u m o ra l fa c to r, th e th ro m b o p o ie tin , in p la sm a fro m a n im a Is

w ith p o sth e m o rrh a g ic th ro m b o c y to sis.3 7

In o p p o sitio n to p re v io u s re p o rts o n C O P D p a tie n ts,

w e d id n o t o b se rv e a n in c re a se in p la te le t a g g re g a tio n a fte r

p h le b o to m y .'X JX -4 0T h o se re p o rts a tte m p te d to re la te th e ir

fin d in g s to in c re a se s in c irc u la tin g c a th e c o la m in e s,

e sp e c ia l1 y se ro to n in , se c o n d a ry to th e b le e d in g . T h e

d iffe re n c e s b e tw e e n p re se n t a n d fo rm e r re su lts ln a y b e

e x p la in e d b y th e fa c t th a t o u r b lo o d sa m p le s w e re c o lle c te d la te r, a ro u n d o n e w e e k a fte r th e Ia st p h le b o to m y , w h e n

n o rm a liz a tio n o f c a th e c o la m in e le v e Is p ro b a b ly h a d

a lre a d y o c c u rre d .

O th e r sig n ific a n t p o stp h le b o to m y c h a n g e s w e re a n

e x te n sio n o f

a

a n d sh o rte n in g o f

k

in th e T E G tra c in g s

(T a b le 3 ). T h e p a ra ln e te r

a

re p re se n ts th e ln a x im u ln c lo t

stre n g th . T h e p a ra m e te r

k

re p re se n ts th e ~ p e e d o f c lo t

fo rln a tio n , fib rin c ro sslin k in g a n d p la te le t-fib rin in te ra c tio n . B o th p a ra m e te rs m a y b e d e c re a se d in c a se s o f

th ro ln b o c y to p e n ia o r h y p o fib rin o g e n e m ia . A lth o u g h w ith

n o sta tistic a l sig n ific a n c e , th e

r

v a lu e a lso d e c re a se d p o stp h le b o to m y .

T h e se la st re su lts su g g e st th a t im p ro v e m e n ts in

th ro m b in fo n n a tio n h a v e o c c u rre d p o stp h le b o to m y . T h is

c o u ld b e a n o n -sp e c ific re a c tio n to b le e d in g , a s in c re a se s in c o a g u la tio n a c tiv ity m e a su re d b y T G E fo llo w in g b lo o d

M A R T I N E Z , J . A . B . ; G U E R R A , C . C . C , ; N E R Y , L . E . e t a I . - I r o n s t o r e s a n d c o a g u la t io n

p a r a m e t e r s in p a t ie n t s w it h h y p o x e m ic p o ly c y t h e m ia s e c o n d a r y t o c h r o n ic o b s t r u c t iv e

p u lm o n a r y d is e a s e : T h e e f f e c t o f p h le b o t o m ie s

losses during surgery have been described.

Such changes

were documented

even 2 hours after surgery and could

have accounted for cathecolamine

releases related to stress,

and the entry into circulation

of coagulation

factors froln

the hepatic interstitial fluido However, our final coagulation

tests

were

performed

about

7 days

after

the

last

phlebotomy, again making this interpretation less probable.

Another possibility

is that decreased

helnatocrits

led to

falls

in viscosity

with

better

liver

perfusion

and

oxygenation,

promoting

improvelnent

its production

of

coagulation

factors.

The increase

in

a

Inay also

be related

to the

en)argement'

of the platelet

counting.

Although

the

fibrinogen

leveIs have not changed,

the growth

in

a

postphlebotomy

may also be in part secondary to a higher

availability

of fibrinogen

for the fibrin network making.

In high Hct samples, the total alnount of fibrinogen may

not be enough to make a fibrin network capable of strongly

containing

an increased

nUlnber of red cells. Low Hct

samples may have proportionally

Inore fibrinogen

to be

used in the fibrin network,

producing

clots with greater

texture.

In summary,

the coagulation

tests

made

after

phlebotolny

have

shown

slnall

changes

towards

an

augmented coagulability.

Such changes could be the result

of an organic reaction to bleeding, especially the increase

in platelet counting. Although the precise clinicaI meaning

of these findings are unknown,

the literature

contains

a

reference to a patient with pulmonary

artery thrombosis

following phlebotomies.

42

_However,

_{alnong the different}

tests done, only

k

_{reached a final value out of our normal}

laboratory range. Therefore, we speculate that the detected

changes do not represent a harmful thrombotic

risk related

to the phlebotomies

Based in the present

results,

we do oot think the

prophylactic

adlninistration

of anticoagulant

agents after

phlebotomies

in COPD patients is necessary. In addition,

we

recolnmend

oral

iron

supplementation

after

phlebotolnies

for polycythelnic

COPD patients

in order

to avoid iron deficiency.

S ã o P a u lo M e d ic a i J o u rn a l/R P M 1 1 5 (2 ): 1 3 9 5 -1 4 0 2 , 1 9 9 7 M A R T IN E Z , J .A .B .; G U E R R A ,C .C .C ,; N E R Y , L .E . e t a I. - Iro n s to re s a n d c o a g u la tio n

1. K ingler JR , H iU N S. R ight ventricular dysfunction in chronic

obstructive pulm onary disease. C hest 1991 ;99:715-23.

2. H arrison B D W , G regory R J, C lark T JH , ScoU B W . E xchange

transfusion w ith D extran 40 in polycythaem ia secondary to

hypoxic lung disease. B r M ed J 1971 ;4:7136.

3. H arrison B D W , D aw s J, M adgw ick R G , E vans M . T he effects

of therapeutic decrease in packed cell volum e on the

responses to exercise of patients w ith polycythaem ia

secondary to lung disease. C lin Sci 1973;45:833-47.

4. W edzicha JA , R udd R M , A pps M C P, C otter FE , N ew land

A C , E m pey D W . E rythrapheresis in patients w ith

polycythaem ia secondary to hypoxic lung disease. B r M ed J

1983;286:511-4.

5. D ayton L M , M cC ullough R E , Scheinhorn D J, W ell JV .

Sym ptom atic and pulm onary response to acute phlebotom y

in secondary polycythem ia. C hest 1975;68:785-90.

6. B ornstein R , M eron D , Y ork E , Sproule B , Z ak C . E ffects of

venesection on cerebral function in chronic lung disease. C an

J N eurol Sci 1980;7:293-6.

7. C hetty K G , B row n SE , L ight R W . Im proved exercise

tolerance of the polycythem ic lung patient follow ing

phlebotom y. A m J M ed 1983;74:415-20.

8. C hetty K O , L ight R W , Stansbury D W , M ilne N . E xercise

perform ance of polycythem ic chronic obstructive pulm onary

disease: E ffect of phlebotom ies. C hest 1990;98: 1073-7.

9. M assaro D , K atz F. E ffect of venesection on arterial gas

values and ventilatory function in patients w ith chronic

bronchitis. T horax 1965 ;20:441-6.

10. Patakas D A , C hristaki PI, L ouridas G E , Sproule B J. C ontrol

of breathing in patients w ith chronic obstructi ve lung disease

and secondary polycythem ia after venesection. R espiration

1986;49:257-62.

11. R akita L , G illespie D G , Sancetta SM . T he acute and chronic

effects of phlebotom y on general hem odynam ics and

pulm onary functions of patients w ith pulm onary elnphysem a. A m H eart J ] 965;70:466-75.

12. Segel N , B ishop JM . T he circulation in patients w ith chronic

bronchitis and em physenla at rest and during exercise, w ith special reference to the influence of changes in blood

viscosity and blood volum e on the pulm onary circulation. J C lin Invest 1966;45: 1555-68.

13. W eisse A B , M oschos C B , Frank M J, L evinson G E , C annila

JE , R egan T 1. H em odynam ic effects of staged helnatocrit

reduction in patients w ith stable cor puhnonale and severel

elevated hem atocrit leveIs. A m J M ed 1975;58:92-8.

14. L ieden G . Iron state in regular blood donors. Scand J I-Iaem atol.1973;11 :342-9.

15. Propper R , N athan D . C linicaI rem oval of iron. A nn R ev

M ed 1982;33:509-19.

16. D allm an PR o M anifestations of iron deficiency. Sem in

H em atol 1982; 19: 19-30.

research on the platelet hyperaggregation in patients w ith

chronic respiratory failure. B ulI E urop Physiopatol R espir

1980;16:113-5.

19. M itchelI R S, Silvers G , D art G A , Petty T L , V icent T N , R yan

SF, FilIey G F. C linicaI and m orphologic correlations in

chronic airw ay obstruction. A m R ev R espir D is

1968;97:54-62.

20. R yan SF. Pulm onary em bolism and throm bosis in chronic

obstructive em physem a. A m J Pathol 1963;43:767-73.

21. B alsano F, C ordova C , M usca A , Perone A , V ioli F. R uolo

deI m etabolism o pulm onary sull'em ocoagulazione in

fisiologia in clinica ed in terapia. C I T erap 1977;80:513-7.

22. B run J, B iot N , Perryn-FayolIe M , Sab H . L es troubles de la

coagulation sanguine au cours de I'insuffisance respiratoire

cronique: D eductions therapeutiques. Poum on C ouer

1962;18:181-194.

23. G aida A , G hio G . E m ocoagulazione e fibrinolisi

nelI'enfisem a polm onare. M inerva M ed 1964;55:2122-5.

24. C hanarin LL aboratory haem atology: an account of laboratory

techniques, 1 st ed. E dinburgh: C hurchill L ivingstone,

1989:274-5.

25. R atnoff O D , M enzie C . A new m ethod for determ ination of

fibrinogen in sm all sam ples of plasm a. J L ab C lin M ed 1951 ;37:316-20.

26. B orn G V R . A ggregation of blood platelets by adenosine

diphosphate and its reversal. N ature 1962; 194:327-9.

27. Spiess B D , D avalIe M . C oagulation m onitoring in the surgical

intensive care unit. C rit C are C lin 1988;4:605-20.

28. M ilnan N , Pedersen N S, V isfeldt 1. Serum ferritin in healthy

D anes: R elation to m arrow haem osiderin iron stores. D an

M ed B ulI 1983;30: 116-20.

29. W alters G O , M iller FE , W orw ood M . Serum ferritin

concentration and iron stores in norm al subjects. J C lin Path 1973;26:770-2.

30. T ura S, Pollycove M , G elpi A P. E rythrocyte and ironkinetics

in patients w ith chronic pulm onary em physem a. J N ucl M ed 1962;3: 110-25.

31. Shaw D B , Sim pson T . Polycythem ia in em physem a. QJ M ed

1961 ;30: 135-52.

32. Stradling JR , L ane D J. D evelopm ent of secondary

polycythaem ia in chronic airw ays obstruction. T horax 1981 ;36:321-5.

33. Siim es M A , R efino C , D allm an PR o M anifestations of iron

deficiency at various leveIs of dietary iron intake. A m J C lin

N utr 1980;33:570-4.

34. Finch C A , M iller L R , Inam dar A R , Person R , Seiler K ,

M ackler B . Iron deficiency in the rat: Physiological and

biochem ical studies of m uscle dysfunction .. J C lin Invest 1976;58:447-53.

35. K rizsa A . Study on the developm ent of posthaem orrhagic

throm bocytosis in rats. A cta H aem at 1971 ;46:228-31.

M A R T IN E Z , J .A .B .; G U E R R A ,C .C .C ,; N E R Y , L .E . e t a I. - lro n s to re s a n d c o a g u la tio n

p a ra m e te rs in p a tie n ts w ith h y p o x e m ic p o ly c y th e m ia s e c o n d a ry to c h ro n ic o b s tru c tiv e p u lm o n a ry d is e a s e : T h e e ffe c t o f p h le b o to m ie s

3 6 . K a rp a k tin S , G a rg S K , F re d m a n M L . R o le o f iro n a s a re g u la to r o f th ro m b o p o ie s is .A m J M e d 1 9 7 4 ;5 7 :5 2 1 -5 . 3 7 . W e in tra u b A , K h a n I, K a rp a tk in S . A s p le n ie d e p e n d e n t

th ro m b o p o ie tie fa e to r in e h ro n ie b lo o d lo s s p la s ln a . C lin R e s 1 9 7 4 ;2 2 :4 1 1 A .

3 8 . C o rd o v a C , M u s e a A , V io li F , A le s s a n d ri A , P e rro n e A , B a ls a n o F . P la te le t h y p e rfu n e tio n in p a tie n ts w ith e h ro n ie a irw a y s o b s tru e tio n . E u r J R e s p ir D is 1 9 8 5 ;6 6 :9 -1 2

3 9 . M u s e a A , C o rd o v a C , V io li F . T h e th ro m b o g e n ie ris k in e h ro n ie re s .ra to ry fa ilu re . A d v E x p M e d B io 1 1 9 8 4 ; 1 6 4 :3 6 9 -3 7 5 .

4 0 . C o rd o v a C , M u s e a A , P e rro n e A , V io li F , A le s s a n d ri C , M a rig lia n o V . P o s s ib ile ru o lo d e Ila s e ro to n in a n e l d e te rm in is m o d e Ila ip e ra g g re g a z io n e p ia s trin ie a d o p o s a l a s s o in p a z ie n ti e o n in s u fie ie n z a re s p ira to ria e ro n ie a . C I T e ra p

1 9 7 9 ;9 0 :4 8 9 -5 0 1 .

4 1 . T u m a n K J , S p ie s s B D , M e C a rth y R J , Iv a n k o v ie h A D . E tfe e ts o f p ro g re s s iv e b lo o d Io s s o n e o a g u la tio n a s m e a s u re s b y th ro m b o e la s to g ra p h y . A n e s th A n a Ig 1 9 8 7 ;6 6 :8 5 6 -6 3 . 4 2 . C h a m b e rla in D A , M ilIa rd F J C . T h e tre a tm e n t o f p o ly e y th a e m ia

s e e o n d a ry to h y p o x ie lu n g d is e a s e b y c o n tin u o u s o x y g e n a d m in is tra tio n . QJ M e d 1 9 6 3 ;3 2 :3 4 1 -5 0 .

S ã o P a u lo M e d ic a i J o u rn a l/R P M 1 1 5 (2 ): 1 3 9 5 -1 4 0 2 , 1 9 9 7 M A R T IN E Z , J .A .B .; G U E R R A ,C .C .C ,; N E R Y , L .E . e t a I. - lro n s to re s a n d c o a g u la tio n p a ra m e te rs in p a tie n ts w ith h y p o x e m ic p o ly c y th e m ia s e c o n d a ry to c h ro n ic o b s tru c tiv e