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HEMO
OPHILIA - PAST, PR
RESENT AND
A
A LOO
OK TO TH
HE FUTUR
RE
PART II
Margarett Heisel Ku
urth MD an
nd Nigel S. Key MD, F
FRCP
C
Co-Director
rs Fairview
w Universityy Hemophiliia and Throombosis
Center M
Minneapolis, Minnesota USA
Keyywords:
h
hemophilia,
bleeding ddisorder, pla
asma coagu
ulation facttor VIII, IX, treatment
Hem
mophilia is the
t most co
ommon seveere, inheriteed bleeding disorder in humans. It results from
ma
deficienncy of plassma coagulation facto r VIII (hem
mophilia A)
A or plasm
ma coagulattion factor IX
(hemophilia B). The second part of thiss review will
w describee the treatm
ment that iss available for
patientss with hemoophilia, som
me of the m
more commo
on complicaations that ooccur and possible
p
futture
developpments for thhese patientts in the new
w millenniu
um.
Treatm
ment
Oveer the past four
f
decades there havve been rem
markable chaanges in thee therapy th
hat is availaable
to patieents with heemophilia. Prior to 19960, treatmeent was primarily sym
mptomatic and
a as a ressult
patientss experiencced debilitaating and llife-threaten
ning complications reelated to their
t
bleeding
disorderrs [1, 2].
In 1965 Dr. J. Poole
P
reporrted that a pparticular plasma fraction could bee used to treeat hemophilia
A [2, 3]. Developm
ment of plasma-derivved factor concentrattes that couuld be used
d to treat both
hemophhilia A and В quickly followed. These prod
ducts effectively treateed bleeding episodes, but
b
they expposed their recipients to
t a variety of blood-borne pathog
gens, includding hepatitis A, B, andd С
and HIV
V. Viral inaactivation an
nd other purrification prrocesses of these produucts as welll as aggresssive
plasma testing were introduced
d in the 19880's and hav
ve improved
d the safety of these concentrates [4].
[
In thhe early 1980s, the gene responsiible for facttor VIM an
nd IX was ccloned and this led to the
producttion of faactor conccentrates uusing reco
ombinant technology.
t
. Recombinant factor
concenttrates are now
n
availab
ble for the treatment of
o patients with
w hemopphilia A and B. First and
a
second--generation recombinaant factor V
VIII produccts have co
ontinued to have small amounts of
human/bbovine plassma presentt in the mannufacturing process. Th
his was neccessary becaause the facctor
VIII prootein is unsstable. Third generatioon recombin
nant produccts, which w
were recenttly introducced,
are now
w free of booth bovine and humann plasma in
n the manuffacturing prrocess and final produuct.
Recombbinant factoor IX has no
ot required aany human or
o animal prrotein in thee product fo
or stability and
a
thus viral safety haas not been a concern w
with this pro
oduct [5-9] .
The facttor concentrrate product, dose and frequency are
a determin
ned by:
 The type and severity
y of hemophhilia
61



The site and
a severity
y of the bleeed
The respoonse of the individual
i
ppatient to fac tor conceentrate produ
ducts
The availability and price
p
of facctor concen trate produccts
Table I:: Initial Theerapy for Sp
pecific Hemoorrhages in Hemophilia
a
Type of Bleed
Hemoph
hilia A
Hemophilia В
Hemarthrrosis
20-50 units/kg FVIII ooncentrate
15 units/ kg if treated eearly
30
0 units/kg FIX
X concentrate
20
0 units/kg if treeated early
Muscle orr
Subcutaneeous hematom
ma
20 units/k
kg FVIII conccentrate
30
0 units/kg FIX
X concentrate
Mouth, deeciduous teethh
Dental exxtractions
20 units/k
kg FVIII conccentrate
Antifibrin
nolytics
Antifibrin
nolytics alonee are often
not sufficcient in severee hemophilia
30
0 units/kg FIX
X concentrate
An
ntifibrinolyticcs
An
ntifibrinolyticcs alone are offten
no
ot sufficient inn severe hemophilia
Epistaxis
Apply co
ontinuous presssure
for 20 miinutes
Packing with
w petrolatuum gauze
Antifibrin
nolytics
If this faiils then 20 uniits/kg
FVIII con
ncentrate
Ap
pply continuouus pressure
forr 20 minutes
Paacking with peetrolatum gauzze
An
ntifibrinolyticss
If this fails then 30 units/kg
FIX concentratee
Major surrgery
Life threaatening bleedss
50-75 units/kgFVIII cooncentrate
Follow with
w continuouus infusion
80
0 units/kg FIX
X concentrate
Fo
ollow with 20--40 units/kg every
12
2-24 hours
Monitor levels
Monitor levels
l
Hematuria
Bed rest
Fluid flussh
If not con
ntrolled in 1-2 days use 20 units/kg
u
FVIII con
ncentrate &/orr prednisone
for 3-5 daays







Beed reset
Flu
uid Flush
If not controlledd in 1-2 days th
he
30
0 units/kg
FIX concentratee &/or predniso
one
fo
or 3-5 days
C
Cryoprecipittate may be used
u
in hemoophilia A if factor VIII concentrate
c
iis not availab
ble. The dose is
ttypically 1 unit
u per 5-10 kg of body weight. Fressh frozen plaasma may alsso be used in
n hemophiliaa A.
T
The dose is 10-15
1
cc/kg. Cyroprecipiitate is preferrred.
F
Fresh frozenn plasma may
y be used in hemophilia В if factor IX
X concentratte is not avaiilable. The dose
d
iis typically 1 0-15 cc/kg IV
D
Do not use antifibrinolyt
a
ics together w
with prothro
ombin complex concentraate (activated
d factor IX
cconcentrate)
A
Anlifibrinolyytics may bee used with rrecombinant factor IX, highly
h
purifieed factor IX
X and any facctor
V
VIII concenttrate
P
Prolonged therapy
t
with
h prothrombbin complex concentraate may cau
ause an increased risk of
tthrombosis.
F
For mild hem
mophilia A, DDAVP m
may be used instead of factor
f
concenntrate for miild to moderrate
bbleeds
Facttor VIII prooducts usuallly raise thee factor leveel 2 % for each
e
unit/kgg administered. Factor IX
productts raise the factor
f
level 1.1% for e ach unit/kg of factor product adm
ministered. The
T half-lifee of
factor V
VIM is 8-122 hours and
d the half-liffe of factor IX is 18-24
4 hours [10]]. This kinettic informattion
must alsso be taken into
i consideeration whenn determinin
ng the dose of factor prroduct used for a particuular
bleed. T
Table I sum
mmarizes som
me of the cuurrent recom
mmendation
ns for the treeatment of acute
a
bleedss in
patients with hemopphilia A or B. When cconsidering the use of factor
f
conceentrates, earrly treatmennt is
62
importannt to ensuree optimal response. Thhe goal of treatment of hemophiliia is promp
pt treatmentt to
minimizze complicattions and peermanent daamage to th
he musculoskeletal systeem. If facto
or concentraates
are not aavailable, crryoprecipitaate may be uused in hemo
ophilia A an
nd fresh frozzen plasma may
m be usedd in
hemophhilia A or B.
Whiile factor cooncentrate iss an importtant part of treatment of
o acute bleeeding episodes in patieents
with heemophilia, the
t role of adjuvant trreatments sh
hould not be
b ignored. Rest, ice, compression,
elevatioon and phyysical thera
apy can all assist in thee resolution
n of an acutte bleed inv
volving a joint,
muscle or soft tissuue and preveent its recurrrence. Rest and elevatiion are impoortant especcially while the
joint is ppainful. A lightly
l
com
mpressive baandage may be applieed if possibble. Ice shou
uld be applied
to the jooint or musscle as much as possibble both to help
h
control pain and tto decreasee the swellinng.
This is particularlyy helpful in
n the first 224 hours fo
ollowing thee injury. Im
mmobilizattion may h elp
decreasse the painn during an acute bleeed. This caan be accom
mplished w
with a posteerior splint or
other im
mmobilizing support. When the bbleed initiaally occurs,, the joint sshould be im
mmobilizedd in
the mosst comfortaable positio
on. As soonn as there is
i control of
o the bleedd, the patieent may beggin
gentle rrange of mootion and gradual
g
worrk toward full
f extensiion of the j oint. Once the bleed has
h
resolvedd, exercisees should be
b started tto maintain
n muscle strength
s
arround the joint that was
w
involveed. Lace-upp supports and bracees can be used in ch
hronically involved joints
j
to help
protect them from injury and
d recurrent bbleeding.
Desspite aggresssive treatm
ment, perm
manent dam
mage may still
s
follow hemarthro
osis. This iss a
result oof the inflammatory and degennerative prrocess that begins wiith the firsst episode of
hemarthhrosis. Oveer the past 30 years, p
primary prrophylaxiss (administrration of factor
fa
conceentrate tw
wo to three times per week) hass been offeered to children with ssevere hem
mophilia in an
attemptt to decreasse the numb
ber of jointt bleeds an
nd prevent hemophilic
h
c arthropath
hy. These reegimens aare clearly successfull in preventting hemop
philic arthropathy butt there are concerns
c
w
with
this treaatment, whhich includee factor conncentrate prrice, factor availability
ty and ease of peripheeral
venipunncture in sm
mall childreen [11].
DDAV P is a syntthetic form
m of the horrmone desm
mopressin and is usedd to treat some bleediing
episodees in patiennts with mild
m
hemophhilia A. It raises the factor VIIII level by
y causing the
t
release of stored von
v Willebrand factorr and factorr VIII. Thee baseline ffactor VIII level must be
greaterr than 5% to be effeective and not all patients witth mild heemophilia A respond to
DDAV
VP. A DDA
AVP challlenge test is recomm
mended to determinee a particu
ular patiennt's
responsse. DDAV
VP can be administerred intra venously, su
ubcutaneouusly or nassally and will
w
result inn a 2-4 tim
mes increasee in the facttor VIII lev
vel over baseline [12] . This is offten sufficieent
to contrrol acute blleeding with
h trauma orr prevent blleeding with minor suurgical proccedures.
Anttifibrinolyttics such ass transexam
mic acid an
nd epsilon amino
a
caprooic acid aree used to trreat
mucouss membrane bleeding.. They funcction by inh
hibiting fibrinolysis att the site off injury. Thhey
can be administerred intraven
nously or oorally and are useful in the treeatment off noseblee ds,
mouth bbleeding orr with the bleeding
b
froom dental or
o otolaryngolic surgeery. They should
s
not be
used w
with hematuuria because they cann cause clott formation
n in the ureeter and uriinary obstruuction. Thhey should also not be used withh prothrom
mbin compleex concentr
trate (activaated factor IX
63
concenttrate) becauuse dissemiinated intravvascular co
oagulation and
a thrombbosis may occur.
o
Thee importancce of physiccal therapyy and regu
ular exercise should nnot be undeerestimatedd in
the prevvention of joint
j
and muscle
m
blee ds and in the rehabilitation of a joint follow
wing a bleeed.
Physicaal therapy can
c strength
hen muscless and impro
ove joint stability.
Thiss will decrrease the likelihood oof bleeding
g within a joint. Oncce a pattern
n of bleediing
begins in a particcular joint there is aatrophy of the surrounding musscles that leads
l
to jooint
instability. This inncreases thee risk of reebleeding in
nto the join
nt. Muscle sstretching exercises
e
heelp
preventt muscle blleeds. Orth
hotics is ussed to help
p improve joint stabillity and prrevent furthher
bleeding episodes. Icing is also
a
used too treat acutte bleeds but can be uused follow
wing physiccal
activityy to help deecrease thee likelihoodd of bleeding with ex
xercise. Ann aggressive program of
physicaal therapy is importan
nt for all pattients with hemophiliaa.
Co
omplicatioons treatm
ment of Heemophilia
Desspite thesee treatmentts patientss with hem
mophilia caan developp several complicatio
c
ons
related to recurrennt bleeds an
nd their
A pattern of reepeated join
nt bleeds inn patients with
w hemoph
hilia is assoociated with
h the develoopment off synovitis and will lead to degen
nerative arrthritis in the
t joint. D
Despite the availabilityy of
factor cconcentrate to treat hem
marthrosis, m
many patien
nts develop
p target joint
nts with chro
onic synoviitis.
In thesee patients aggressive
a
factor
f
replaacement maay break th
he cycle of rebleeding
g and synovvia!
proliferaation. If thiis is not su
uccessful theen these paatients often
n require a surgical, radioactive
r
or
chemicaal synovecctomy to control
c
the synovitis. Surgical synovectomyy may be accomplishhed
utilizingg either an open or arthroscopic approach. Recovery
R
reequires sevveral weeks of aggresssive
physicaal therapy and factorr replacemeent. Radioactive or chemical ssynovectom
my have beeen
perform
med utilizingg a variety of materialls, which deestroy the synovium.
s
T
The results are similarr to
those w
with surgical synovecctomy but there is a need for less rehabbilitation an
nd less facctor
replacem
ment [13, 14]. These in
nterventionns are often successful in controlliing synovitiis and slowing
the proggression of degenerativ
ve arthritis.. If the degenerative arrthritis proggresses, thee patients haave
chronic pain and looss of motio
on in the afffected jointt which may necessitatte a joint fu
usion or jooint
replaceement.
Anoother methood of treatm
ment for tar
arget joints is intra-arrticular steeroid injecttion. In these
cases paatients are treated
t
with
h 1-2 injecti ons of stero
oids 2-4 weeks apart w
with immobiilization of the
joint in between thhe two injections. Thiss decreases the synoviitis and redduces the nu
umber of jooint
bleeds. Aggressivee physical th
herapy is neeeded to maintain
m
strength in the muscles su
urrounding the
joint. Thhis proceduure is similaar to the raddioactive orr chemical synovectom
s
my in requirring less facctor
replacem
ment when compared to
t surgical ooptions [15]].
Inhibitoors are IgG
G antibodiees formed aagainst the deficient factor
f
and occur in 15 to 30 % of
patientss with hemoophilia A an
nd 1 to 4 % of patien
nts with hem
mophilia B.. These inhibitors tendd to
occur inn the first 50-100
5
expo
osure days bbut have beeen seen latter in life w
when there are
a changess in
the facttor product that is adm
ministered. They are seen more frequently
f
iin severe heemophilia and
a
64
with certain genetiic mutation
ns. They aree more com
mmon in ceertain hemoophilia kind
dreds [16, 17].
1
Inhibitoors in patiennts with hem
mophilia В are likely to be assocciated with anaphylactic reactionss to
factor cconcentrate, which furth
her compliccate therapy
y [18]. The majority off inhibitors in hemophilia
A and В are high tiiter and mak
ke treatmennt with tradittional factor concentrat
ate impossib
ble.
For patients with
w
high titter inhibitoors, immunee tolerance (IT) therap
apy may bee attemptedd to
render tthe individdual immun
nologically tolerant to the deficieent clottingg factor. IT
T involves the
frequennt administraation of facctor concenttrate to toleerize the immune systeem so that the
t antibodyy is
no longer producedd. IT is succcessful in 800 % of patieents with inh
hibitors butt there are major
m
conceerns
with its use includding the pro
ohibitive cossts, venous access, and
d psychologgical stress on the patiient
and fam
mily [19]. An intern
national stuudy is currently ongoing to coompare hig
gh dose (2200
units/kgg/day) and low
l
dose (5
50 units/kgg three timees per week
k) regimenss to determiine safety and
a
efficacyy for patientts with hemophilia A.
If IT
T therapy iss not attem
mpted or is uunsuccessfu
ul, aggressiv
ve symptom
matic treatm
ment (rest, ice,
i
compresssion and elevation)
e
an
nd bypassin
ng agents (activated
(
prothromb
p
bin complex
x concentrate
or recombinant Vila)
V
are useed to treat bbleeds. Desp
pite these treeatments, bbleeding episodes are very
difficultt to treat annd many of these patiients have much greatter short- aand long-terrm disabilitties
related tto their hem
mophilia [20
0].
Hepatitiis continuess to be a major concerrn for patien
nts with hem
mophilia. H
Hepatitis А, В and С can
c
all be trransmitted through bloo
od productss. Plasma deerived facto
or concentraates are viraally inactivaated
but stilii carry an acctual and/orr theoreticaal risk of heepatitis. Vacccinations aare currently
y available for
the prevvention of hepatitis A and В annd are stron
ngly recom
mmended foor patients with bleeding
disorderrs. Vaccinaation for heepatitis С iis not possiible and a high perceentage of th
he hemophilia
populatiion, particuularly those transfused with factor concentratee before 19 88, have beeen exposedd to
hepatitiss С and rem
main virally positive [21]. This indolent infection cann result in cirrhosis,
c
liver
failure aand hepatoccellular carccinoma.
Pseuudotumor iss an uncomm
mon compllication in hemophilia
h
patients
p
andd it is felt to
o be causedd by
repeatedd bleeding episodes in a particuular area which
w
then slowly enllarge and encapsulate.
e
. It
appears as an expaanding masss and mayy invade nearby structu
ures includi
ding bone, muscle
m
or soft
s
tissue oorgans. It iss often asso
ociated withh inadequate treatmen
nt of bleediing episodees. It produces
symptom
ms by its expansion
e
and pressurre against structures that
t
it is innvading. It is treated by
operativve removal but the procedure can be difficultt with a sign
nificant moorbidity and
d mortality and
a
it requirres aggressiive factor reeplacement [22].
Compreh
hensive treeatment cen
nters
Com
mprehensivee treatment centers havve been esttablished in
n many coun
untries to co
oordinate caare,
educatioon, diagnossis and treatment of patients with
w
hemoph
hilia and oother bleed
ding disordeers.
Patientss treated att compreheensive hemoophilia cen
nters have shown rem
markable im
mprovement in
quality of life andd a decreasse in comp lications an
nd health care
c
costs [[23]. Thesee centers haave
becomee models for the treatment off other ch
hronic diseeases. Perssonnel invo
olved incluude
65
hematollogists, nurrse case maanagers, phyysical theraapists, sociaal workers, orthopedists, geneticists,
and phaarmacists. Patients
P
atttend yearly comprehen
nsive assesssments at these centeers. Treatm
ment
center sstaff are avaailable durin
ng the rest oof the year by
b phone to answer pattient questio
ons and to talk
t
with priimary care physicians to guide thhe treatmentt of these patients. Theese centers are a valuaable
asset to the hemopphilia comm
munity to asssist in prov
viding the best
b and moost efficientt treatment for
bleedingg and other health issuees that thesee patients may
m develop
p.
Eduucation has played an important role in the care of patients
p
witth hemophilia and other
bleedingg disorderss. From thee time a bbaby is firsst diagnoseed with hem
mophilia th
he nurses and
a
physiciaans spend tiime at each clinic visit educating the
t patient and
a family aabout their disease andd its
treatmennt. This information allows
a
the patient to recognize bleeds
b
and other med
dical probleems
early. IIt also givees them thee informatiion that wiill help theem make innformed deecisions about
activitiees to help minimize their
t
chancce of injury
y. Maintain
ning open communicaation betweeen
patientss and their health
h
care providers
p
is very imporrtant in the treatment
t
off hemophiliia.
The Future Gene therapy
y
The concept of
o gene therrapy has hheld great hope
h
for th
he hemophillia community since the
cloning of the facttor VIII and
d IX gene inn the early 1980s. Currrently hum
man phase one
o studies are
ongoingg using a vaariety of veectors to acccomplish geene transferr. Unexpectted difficultties have beeen
encounttered, but thhe scientificc communitty continuess to aggresssively pursuue gene therrapy as a 211stcentury reality for patients
p
witth hemophillia [24].
Neew factor products
p
Effoorts are undderway to provide
p
an adequate su
upply of saafe product that can efffectively trreat
bleedingg episodes in patients with
w hemopphilia. Imprroved viral safety and a stable or decreased rate
r
of inhibbitor formattion are the objective inn developin
ng new prod
ducts. Perhaaps most im
mportant is the
assurancce of an addequate and
d safe factorr product su
upply at a reasonable
r
price to alll patients with
w
hemophhilia.
Oveer the past 40
4 years theere has beenn a revolutio
on in the treeatment of ppatients witth hemophilia.
A once fatal disease can now
w be effectivvely treated
d so that the patients hhave the po
otential to leead
relativelly normal liives. As wee enter the nnew millenn
nium, the go
oal is to conntinue to work
w
to provvide
safe, reaasonably prriced factor concentratees to all patiients with hemophilia.
h
While mosst patients with
w
hemophhilia in Nortth America and Europpe have acceess to this care,
c
it is esstimated thaat 70 % of the
world's hemophiliaa patients have
h
limitedd access to
o factor products for thheir diseasee. Clearly this
t
inequityy of treatmeent will need
d to be addrressed in coming years.
66
ГЕМОФ
ФИЛИЯ - ПРОШЛО
П
ОЕ, НАСТО
ОЯЩЕЕ И ВЗГЛЯД В БУДУЩ
ЩЕЕ
Маргрет Г
Гейзел Керт
т, Нигель С.
С Кей
Обссуждаются проблемы
ы, связанны
ые с патофизиологией
й, клиничеескими про
оявлениями
и и
развити
ием наиболлее частых
х осложненний, а такж
же методы
ы лечения ггемофилии
и, по данны
ым
мировоой научной литературы.
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REFERE
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nce obtainedd from norm
mal plasma
effective in acceleratting the clottting of hem
mophilic blood, J Clinn. Invest., 1937;
1
16:113124.
2. Pool J.G., Hershgold
d E.J. High potency antti-haemoph
hilic factor cconcentrate prepared
from cryooglobulin prrecipitate, N
Nature, 1964
4; 203:312.
3. Tullis J.L., Melin M.,, Jurigian P
P. Clinical use
u of humaan prothrom
mbin compleexes. N. Enggl.
J. Med., 1965;
1
273:667-674.
4. Fricke W.A.,
W. Lamb M.A.
M Viral s afety of clo
ot ting factorr concentrattes., Semin
n. Thromb.
Hemost., 1993; 19:54
4-61.
5. Gitschier J., Wood W.I.,
W Goralkka T.M. et all. Characterrization of tthe human factor VIII
gene, Naature, 1984;; 312:326-3 30.
6. Vehar G.A.,
G
Keyt В., Eatonn D. et al.
a Structure of human ffactor VIII., Nature,
1984; 3122:326-330.
7. Yoshitakee S., Schach
h B.G., Fostter D. С et al.
a Nucleotide sequencee of the gen
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