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8/8/2019 Curs Hematologie
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v uMaiorescu
C U R S M E D I C
I N A I N T E R N A
R E U M A T O L O G I E
P r o f u n i v d r I o n C . i n t o i
u
Ț
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- Other
ConnectiveTissue Diseases
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Antiphospholipid
Syndrome• Triad: Any TEST plus: – Thrombotic events – Spontaneous
abortion(s) – Thrombocytopenia
• Others: Miraine!"aynauds! #ibman$Sac%s endocarditis! M"!Transverse myelitis!neuropathy
• Ab &ound in '* S#E!other CTD
• Correlates +ith ,- Ab
PTT/LAC
RPR Cardiolipin
3 Tests
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Reiter's Syndrome
• Arthritis that produces pain, swelling, redness andheat in the joints. It can afect the spine andcommonly involves the joints o the spine andsacroiliac joints. It can also afect many other
parts o the ody such as arms and legs. !aincharacteristic &eatures are in2ammation o&the 3oints! urinary tract! eyes! andulceration o& s%in and mouth4
• "he symptoms are ever, weight loss, s#in rash,in$ammation, sores, and pain.
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Reiter's Syndrome
• "eiter5s o&ten beins&ollo+in in2ammationo& the intestinal orurinary tract4 ,t sets o6a disease processinvolvin the 3oints!eyes! urinary tract! ands%in4 Many people haveperiodic attac%s thatlast &rom three to si0
months4 Some peoplehave repeated attac%s!+hich are usually&ollo+ed by symptom$&ree periods4
•
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%soriatic Arthritis
• Causes pain and s+ellin insome 3oints and scaly s%inpatches on some areas o& thebody4
• The symptoms are: – About 9* o& those +ith
psoriatic arthritis haves+ellin in 3oints outsidethe spine! and more than;* o& people +ithpsoriatic arthritis havenail lesions4 The course o&psoriatic arthritis varies!+ith most doinreasonably +ell4
– Silver or rey scaly spotson the scalp! elbo+s!%nees and<or lo+er end o&the spine4
– =ittin o&
>nernails<toenails – =ain and s+ellin in one or
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&egenerative oint
&isease• ,n early disease!
pain occurs onlya&ter 3oint use and
is relieved by rest
• As the diseaseproresses! pain
occurs +ithminimal motion oreven at rest
• @octurnal pain is
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reatment an ronos so& Deenerative oint
Disease• Meds• Early =T<e0ercises• 7eat<cold therapy
• oint protection• Surery
• Osteoarthritis is a slo+ly proressivedisease
• The eventual outcome is completedestruction o& the 3oint! andultimately surical intervention isre(uired
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A"T",TA UBE@,#A,D,O=AT,CA
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uvenile
IdiopathicArthritis )IA*and +therRheumatic&iseases inhildren
-
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tiology
• ,mmune mediated disease – Abnormal immunoreulation – Abnormal cyto%ine production in
the in2ammatory path+ay (T@!
,#$! ,#$/"! ,#$alpha)• Comple0 enetic
predispositions – 7#A associations
• Environmental triers – ,n&ections – Trauma – Stress
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&iagnostic "ests
• There is no lab test thatdianoses ,A
– – "heumatoid &actor – Antinuclear Antibody (A@A) F +ith
titer – ES" or C"=
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lassi/cation riteria or IA
• Ae at onset G years• Duration o& Arthritis: +ee%s• Arthritis in one or more 3oints
de>ned as s+ellin or e6usion! orpresence o& t+o or more o& the&ollo+in sins: (in or more 3oints) – #imitation o& "OM – Tenderness or pain on motion – ,ncreased heat
• E0clusion o& other diseases
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hronic arthritisin childhood0 IA
• It1s not a single disease, ut a groupo related, genetically
heterogeneous, phenotypicallydiverse immunoin2ammatorydisorders a6ectin 3oints and
other structures! possilyactivated y contact with an e2ternalantigen or antigens.
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%olyarticular IA - R3negative
• ive or more 3oints in the >rst months o&disease
• Asymmetric 3ointinvolvement• #are 3oints o&
%nees! +rists!elbo+s andan%les o&tena6ected
• Mornin sti6ness!
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%olyarticular - R3 positive
• Arthritis afecting 4 or more joints inthe /rst 5 months o disease.
• Similar to adult RA
• 3emales with onset in adolescence
• Rheumatoid nodules
• arly onset o erosive synovitis
• Symmetric joint involvement
• Small joints o hands or eet areafected
• "!0 micronathia
• ervical spine may e afected
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Rheumatoid Nodules• +ccur in 4-678 o
children with IA• !ost re(uently on elow• %ressure points, digital
$e2or tendon sheaths,Achilles tendons, ridgeo nose in child whowears glasses
• 3irm or hard, usuallymoile, nontender.
• Solitary or multiple, maychange in si9e, may lastmonths to years.
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IA0 %soriatic Arthritis• Arthritis and psoriasis or• Arthritis with : o the
ollowing0 – &actylitis - sausage li#e
swelling o toe or /nger – ;ail pitting – %soriasis in a /rst degree
relative )parents,
silings*• Slightly more emales• Symmetrical involving
large and small joints
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!edications
• ;SAI&s• &!AR&s0
!ethotre2ate,
%la(uenil,Sulasala9ine
• iologic responsemodi/ers
• <lucocorticosteroids
• !iscellaneous
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!ethotre2ate
• Standard dose0 67-64 mg=m: or 7.>-7.5 mg=#g=wee#, su?
• Improvement seen in 5-@ wee#s, utmay ta#e up to 5 months.
• as every 5 wee#s0 , !%
• @o alcohol
• Bsed or treatment o uveitis )C-5months to determine eDcacy*
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<lucocorticosteroids
• IE Solumedrol and daily oral%rednisone
• systemic $ares F pericarditis or persistentS2
• temporary measure until &!AR& isefective
• oint in3ections - usually undersedation
– "riamcinolone he2acetonide )Aristaspan*
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v uMaiorescu
C U R S M E D I C I N A I N T E R N A
H E M A T O L O G I E
P r o f u n i v d r I o n C . i n t o i u
Ț
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rsitatea HTitu MaiorescuI
MED,C,@A ,@TE"@A
toloie ,
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Topics
7ematopoiesisComplete blood count (C.C)Anemia
=olycythemia#eu%openia#eu%emia#ymphoma
MyelomaCoaulationTrans&usion
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7o+ much blood is in thehuman bodyJ
• About liters
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Composition o& blood
• . .lood is composed o&: –=lasma
–".C –1.C
–=latelets
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=lasma
• =lasma consists o&: –9* +ater4
* solutes:
– albumin! –electrolytes and proteins4 –clottin &actors !
–imuno$lobulins –circulatin antibodies and –>brinoen
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A.O blood roups:
A! .! A.! and O
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.lood Typin
35
ABO !ood "rou#s$ A% B% AB% &nd O
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,& a blood trans&usion is iven to
a person +ho has antibodies tothat type o& blood! then thetrans&used blood +ill be attac%edand destroyed (trans&usionreaction
36
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"h &actor
• The H"h &actorI is anotherma3or antien on the ".C!
called D F is autosomalrecessive –&& and
Dd: "hK Dd: "h$
37
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7ematopoiesis
HEMATOPOIE'A
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HEMATOPOIE'A
A!! (e!!s &rise fro) s&)e blood stem cell
*#!uri#otent +e)&to#oieti( ste) (e!!s,
Definiţie
- for)&re &! e!e)ente!or fi"ur&te &!e sn"e!ui$• #ro!ifer&re&
• diferen/iere&
• tre(ere& 0n (ir(u!&/ie
• (u#rinde$
• 12Eritro#oie& - for)&re& eritro(ite!or
• 42 Leu(o#oie& - for)&re& !eu(o(ite!or
• 32 Tro)o(ito#oie& - for)&re& tro)o(ite!or
S & bl d
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Summary o& blood&ormin orans
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.one Marro+
.one marro+ is the spony substance&ound in the center o& the bones4
• ,t manu&actures bone
marro+ stem cells!• +hich in turn produce blood cells4
• "ed blood cells F carry o0yen to tissue
Contain hemolobin!• =latelets F help blood to clot• 1hite blood cells F >ht in&ection
A
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A /4lymphoid stem cells
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ERITROPOIE'A
M&tur&re& eritro(ite!or$
redu(ere& di)ensiunii (re5tere& vo!u)u!ui (ito#!&s)&ti( 6 )&i #u/in &ofi!7% redu(ere& di)ensiunii nu(!eu!ui → e8#u!i& !ui.
Dur&t& de evo!u/ie CSP 2 reti(u!o(it - 9 2 : i!e.Produ(/i& eritro(ite;i - Distru"ere eritro(ite;i
- 9< )! sn"e.
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E",T"O=O,ELASubstane necesare eritropoieNei
A$=roteine
.4 Minerale: >er! cupru! cobalt!NincC4 Bitamine: ./! acid &olic!
.! C
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1hat does hemolobin
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1hat does hemolobindo
• Hemogloin pic#sup the o2ygenmolecules and
drops of +:
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#eu%ocyte types• Arti>cial division into
$-ranulocytes$ neutrophils!
$ eosinophils! $basophils
• /$Aranulocytes0 lymphocytes!
monocytes
48
# % l
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#eu%ocytes ranulocytes
49
neutro#+i! eosino#+i!
&so#+i!
s)&!! !=)#+o(=te )ono(=te
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Aranulocytes0 #ymphocytes
• /$P*• lymphoid
connectivetissue! e44
lymph nodes!tonsils! spleen• T+o main
types attac%antiens in
di6erent +ays• T cells• . cells
50
*
T ll
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T cells attac% &orein cellsdirectly
Qiller cells (Hcytoto0icI)! orCD;K is a main type
51
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. cells
• Di6erentiate into plasma cells• =lasma cells secrete antibodies
52
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Aranulocytes Monocytes
• P$;* o& 1.Cs• ,n connective
tissue theytrans&orm intomacrophages (phaocytic
cells +ithpseudopods*
53
*
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Disorders o& .loodcells
• .
55
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Disorders o& Erythrocytes
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,ntroduction
• The main &unction o& red blood cell•Trans&er o& O/ &rom luns to tissue•Trans&er o& CO/ &rom tissue to
luns• To accomplish this &unction red cells has
haemolobin (7b)
• Each red cell has P millionmolecules o& 7b
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Structure and &unction
o& 7aemolobin.
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Introduction• 7aemolobin (7b)! protein
constitutin < o& the red bloodcells
• Synthesis beins in proerythroblast• * at erythroblast stae• * at reticulocyte stae
T+o parts• 7aem• -lobin
Synthesis o&
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Synthesis o&7aemolobin (7b)• 7aem R lobin produced at t+o
di6erent sites in the cells
•7aem inmitochondria
•-lobin inpolyribosomes
Synthesis o&
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Synthesis o&7aemolobin
S & 7
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Structure o& 7aem
S nthesis o& lobin
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Synthesis o& lobin
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Synthesis o& lobin
• Barious types o& lobin combines withhaem to rom diferent haemogloin
• Eiht &unctional lobin chains!arraned in t+o clusters the•β
$ cluster (β
!γ
!δ
andε
lobin enes)on the short arm o& chromosome
•α
$ cluster (α
andζ
lobin enes) onthe short arm o& chromosome
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-lobin ene clusters
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Synthesis o& lobin
-lobin synthesis! starts at rd +ee% o& estation
• Embryonic
7aemolobin -o+er , (ζ
/ε
/) 7aemolobin =ortland ( ζ/γ/)
7aemolobin -o+er ,, (α/ε2)
• etal : 7b (α/γ/)! 7bA (
α/β/)• Adult : 7bA! 7bA/ ( α/δ/)! 7b4
Al h R b t h i
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Alpha R beta chains
unctions o&
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unctions o&7aemolobin• O0yen delivery to the tissues• "eaction o& 7b R o0yen
• O0yenation not o0idation• One 7b can bind to &our O/ molecules• #ess than 4 sec reuired &oro0yenation
•β chain move closer +hen o0yenated
• 1hen o0yenated /!$D=- is pushed out•β chains are pulled apart +hen O/ isunloaded! permittin entry o& /!$D=-resultin in lo+er anity o& O/
O0y R
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O0y Rdeo0yhaemolobin
Summary
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Summary• @ormal structure includin the
proportion o& lobin chains arenecessary &or the normal &unction o&haemolobin
• "educed haemolobin in the red bloodcells due to any abnormality o& any o&its constituents result into a clinicalsituation called anaemia
• Metabolic R other abnormalities resultinto abnormal o0yen supply to the
tissue
Disorders o& Erythrocytes
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Disorders o& Erythrocytes• $Anemia0 not enough cells
• /$De&ect in hemolobin• $=olycythemia0 too many
cells
71
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Disorders o& 7eme
synthesis
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Disorders o& 7eme
synthesis
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7EME$CO@TA,@,@- ="OTE,@S
• 7emolobin
• Myolobin
• Cytochromes
• Catalase
• Some pero0idases
ST"UCTU"E O 7EME
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ST"UCTU"E O 7EME
Ferrous iron (Fe2+)
Protoporphyrin IX:contains 4 pyrrolerings linkedtogether bymethenyl bridges
The t+o ma3or cell types that are active in hemesynthesis are hepatocytes and bone marro+
erythroblasts
;* o& total synthesis occurs in erythroid cells
He)e S=nt+esis
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&isorders o Heme metaolism
He)e ios=nt+esis
Por#+=ri&s
He)e de"r&d&tion
>&undi(e
BLOOD
CELLS Ster(oi!in
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LI?E
R
Bilirubin diglucuronid
!water-soluble"
2 #$P%glucuronic acid
via bile duct to intestines
e8(reted in fe(es
Uroi!ino"en
for)ed = &(teri&
@IDNE
Uroi!in
e8(reted in urine
C&
Bili'rdin ()α
He)e o8="en&se
&2
Bilirubin
!water-insoluble"
A$P+
A$P
,Bi!iverdin
redu(t&se
,-.lobin
,-oglobin
reabsorbed
into blood
Bilirubin
!water-insoluble"via blood to
the liver
INTESTINE
i"ure 4. C&t&o!is) of +e)o"!oin
l i/ ti th
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lassi/cation o the
%orphyrias• Multiple +ays to cateoriNe porphyrias: – 7epatic vs4 Erythropoietic: Oran in +hich
accumulation o& porphyrins and theirprecursors appears
– Cutaneous vs4 @on$ cutaneous – Acute and non$acute &orms
• Acute: – Aminolevulinate dehydratase de>ciency
porphyria (A#A$D) – Acute intermittent porphyria (A,=) – 7ereditary coproporphyria (7C=) – Barieate porphyria (B=)
• Chronic: – =orphyria cutanea tarda (=CT) – Erythropoietic protoporphyria (E==) – Conenital erythropoietic porphyria (CE=) – 7epatoerythropoietic porphyria (7E=*
n9ymatic
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n9ymatic&e/ciencies
• All o the hemepathway intermediatesare potentially to2ic.
• "heir overproductioncauses thecharacteristicneurovisceral and=orphotosensiti9ing
symptoms.
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%+R%HRIA B"A;A "AR&A
• Most (o))on #or#+=ri&
• He#&ti(% &utoso)&! do)in&nt
• Dise&se is (&used = & defi(ien(= in uro#or#+=rino"en
de(&ro8=!&se% +i(+ is invo!ved in t+e (onversion of
uro#or#+=rino"en III to (o#ro#or#+=rino"en III
• Uro#or#+=rino"en &((u)u!&tes in urine
• P&tients &re #+otosensitive *(ut&neous #+otosensitivit=,
A((u)u!&tion of #or#+=rino"ens resu!ts in t+eir
(onversion to #or#+=rins = !i"+t
Por#+=rins re&(t it+ )o!e(u!&r o8="en to for)o8="en r&di(&!s
O8="en r&di(&!s (&n (&use severe d&)&"e to t+e
sin
PORPHRIA
CUTANEA TARDA
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CUTANEA TARDA
Acute intermittent
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porphyria
!ary ?ueen o Scots
Ean <ogh
Jing <eorge III
Acute intermittent porphyria
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• The prevalence o& A,= in the United States is thouhtto be F per 4 – ,t is more common in northern European countries!
such as S+eden (F per )! .ritain and,reland4
• Acute intermittent porphyria =.-D ene mutation isinherited in an autosomal dominant &ashion4
• A6ects +omen more than men! +ith a ratio o& /:4• Most patients become symptomatic at ae ;$P
years4 – Attac%s occurrin be&ore puberty or a&ter ae P
years are unusual unless a ma3or provocation• Most patients are completely &ree o& symptoms
bet+een attac%s4• Course o& the neuroloical mani&estations is hihly
variable4
– Acute attac%s o& porphyria may resolve uite
Symptoms
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• Attac%s involve neuro$visceral symptoms but no s%inmani&estations0
– "he se(uence o events in attac#s usually is )6* adominalpain, ):* psychiatric symptoms, such as hysteria, and )>*peripheral neuropathies, mainly motor neuropathies.
• -astroenteroloical Symptoms most common: – onstipation )C@K@C8*, colic#y adominal pain )occurring in
@4KL48 cases*, vomiting )C>K@@8*, diarrhea )4K6:8*• =atients may have C@S sins consisting o sei9ures )67K
:78*, mental status changes, cortical lindness, and coma.
• =atients o&ten e0perience peripheral neuropathies )C:K
578* that are predominantly motor and can mimic <uillain-arrM
syndrome.
• =atients may develop &ever(9F8*)! hypertension (FP*) and tachycardia (/;F;*)4
y p
!echanism
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!echanism• The e0act mechanism underlyin these
complaints is not yet +ell understood!
various hypotheses have been put &or+ard:
– 2cess amounts o %< or AA may causeneuroto2icity )!eyer et al, 6LL@*
–Increased AA concentrations in the rain mayinhiit gamma-aminoutyric acid release)!ueller N Snyder, 6LOOP rennan N antrill,6LOL*
– Heme de/ciency may result in degenerative
changes in the central nervous system )Ghetsellet al, 6L@C*
– &ecreased heme synthesis in the liver results indecreased activity o hepatic tryptophanpyrrolase )"%*, a heme-dependent en9yme,
possily resulting in increased levels oserotonin
%recipitants
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%recipitants
• Drus: most common precipitate o acute attac#s 0 – ariturates and sulphonamides eing most
common
• "educed enery inta%e: even rie periods o
starvation during dieting, postoperative periods, orconcurrent illness.
• Tobacco smo%e: polycyclic aromatic hydrocarons,are #nown inducers o hepatic cytochrome %C47en9ymes and heme synthesis.
– An association etween cigarette smo#ing andrepeated attac#s o porphyria was ound in asurvey o 6CC patients with AI% in ritain )ip etal, 6LL6*.
• ,n&ections! surery and stress4
&iagnosi
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s • Demonstration o& porphyrinprecursors, such as AA and=or %<, is
essential or the diagnosis o acuteporphyrias.
• =orphyrin analysis is necessary &orthe dianosis o porphyrias withcutaneous photosensitivity.
– %< usually is not included in a urineporphyrin screen and must e orderedspecially
• Molecular dianostic testin:
– &etection o %<& mutations in AI%provides L48 sensitivity and around6778 speci/city
– %ossile to screen asymptomatic genecarriers.
– ess Bseul in acute attac#s
PBG in urine is
o8idied to #or#+oi!in
u#on st&ndin"% +i(+
"ives & d&r2ron
(o!or to urine% &nd often
referred to &s #ort2ine reddis+ urineF.
Erythropoietic= t h i
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=rotoporphyria ( i -o co--on cildood porpria ( i uuall 'idn b 2 ar o ag
Pathogenesisdicin aci'i o
rroclaa n-
L&. findin"$
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"Pla-a porprin l'l and luorcnc pcru-(ncrad r prooporprin in BC ool
CBC LTLi'r/gallbladdr i-aging
Con"enit&! Er=t+ro#oieti( #or#+=ri&
* G t+ di ,
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* Gunt+ers dise&se ,$
( i a 'r rar auoo-al rci' diordr
Pain uuall prn during inanc and rarl prn in adul li i
-ildr or-
Pathogenesis
( i caud b l'aion o bo ar%olubl and lipid%olubl porprin l'l
du o dicinc o uroporprinogn ((( na n-
Clinical features 1 :r 'r poonii'i i pooo;ic burning and bliring lading o -uilaion o lig ;pod par
2 <rrodonia3 =clro-alacia proran
4 ,prplni-5 ,-olic an-ia6 Tro-bocopnia
#roporprin and Coproporprin in urin
Corproporprin in ool
Lab. finding
epa oery ropo e c%orphyria
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%orphyriaIn+erit&n(e;P&t+o"enesis$
A$
#roporprinogn !#&.<" dcarbo;la dicinIn(iden(e$
:r rar %Prn a ag 1
Pro"nosis$
or-al li pan
=>in
=i-ilar o C<P?='r poonii'i i burning d-a
'icl/bulla roion incion
La cang?@uilaing car i dor-aion o no ar ingr
carring alopcia pig-nar cang clrodr-oid cang
,prricoi
T
d/bron color
<
Poopobia cropion conunci'ii
C!ini(&! #i(ture$
He)e
,-olic an-ia
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,-olic an-ia
GI
=plno-gal
GU$ar> urin a bir
Pla-a porprin l'l and
luorcnc pcru-
prooporprin in BCurinar uroporprin
cal coproporprin
CBC
L&. findin"
"reatment or Acute
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%orphyria• %anhematin 6
o >-C mg once a day 6
o Bsed to correct heme de/ciency in liver andstop production o porphyrin precursors 6
o Also acts as a mild anti-coagulant 6
• High carohydrate diet 6
• ast Resort0 iver transplant >
"reatment or utaneous
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%orphyria• Avoid sunlight @
• Iron chelation @
• lood Removal @
• Avoid drin#ing alcohol @
+ther "reatments
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+ther "reatments
• Heme transusion 6
• !edication that induce cytochromepC47 have a chance o causing
porphyria attac#s 6
"ed Cell
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"ed Cell
Disorders.
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Anemia is operationally defined as a reduction inone or more of the major RBC measurements:
hemoglobin concentration, hematocrit, or RBCcount
Keep in mind these are all concentration
measures
Definition:
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Anemia
Production !ur"i"al#Destruction
$R%&R'P'%&%(A
Anemia
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Anemia
• DE,@,T,O@ -Decrease erytrocytes inblood
$Decreased production o&erythrocytes
/$,ncreased destruction o&erythrocytes
.lood loss19/04/2011 101
Anemia
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Anemia
• Clinical Mani&estations:
4 =allor4
/4 atiue! +ea%ness4 4 Dyspnea4 P4 =alpitations! tachycardia4 4 7eadache! diNNiness! and
restlessness4
4 Slo+in o& thouht4 84 =aresthesia4
19/04/2011 102
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AnemiaCaused by
Decreased Erythrocyte =roduction
AnemiaCaused by
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Decreased Erythrocyte =roduction
$,ron De>ciency Anemia
/-Mealoblastic Anemias $Aplastic Anemia
19/04/2011 104
AnemiaCaused by
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Decreased Erythrocyte =roduction
,ron De>ciencyAnemia
19/04/2011 105
,ron$De>ciency
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yAnemia
Etioloy4 ,nadeuate dietary inta%e
• ound in * o& the+orlds population
/4 Malabsorption• Absorbed in duodenum• -, surery
4 .lood loss• / mls blood contain m
iron• -,! -U losses
P4 7emolysis106
,ron$De>ciency Anemia
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,ron$De>ciency Anemia
• Clinical Mani&estations – Most common: pallor – Second most common: in2ammation
o& the tonue (lossistis)
– CheilitisVin2ammation<>ssures o& lips – Sensitivity to cold – 1ea%ness and &atiue
• Dianostic Studies
– C.C – ,ron studies Dianostics: – ,ron levels: Total iron$bindin capacity
(T,.C)! Serum erritin4 – Endoscopy<Colonscopy
19/04/2011 107
Treatment o& ,ron$De>ciency
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Anemia
"eplacin iron – Diet – Dru Therapy
• ,ron replacement – Oral iron
» eosol! De0errum! etc» Absorbed best in acidic environemtn» -, e6ects
– =arenteral iron» ,M or ,B» #ess desirable than =
,ron therapy &or /$ months a&ter thehemolobin levels return to normal
19/04/2011 108
AnemiaCaused by
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Decreased Erythrocyte =roduction
(CO.#AM,@)/B,TAM,@ . De>ciency
19/04/2011 109
M&(ro(=ti(
Ane)i& *COBLAMIN,14 ?ITAMIN B
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* ,?it B14 is s=nt+esied = (ert&in )i(ro2
or"&nis).
Sour(es$ )e&t% fis+% e""s% &nd )i! ut not
#!&nts
It is not destro=ed = (ooin" .D&i!= reuire)ent is 124 )" ; d&=.
Stor&"e $ t+e &ver&"e &du!t stores 423 )" in t+e
!iver% it )&= t&e to =e&rs or )ore efore B14
defi(ien(=% deve!o#s &s t+e d&i!= !osses &re s)&!!
*124)",.
M&(ro(=ti(
Ane)i& Asor#tion$ ?it. B14 is !ier&ted in t+e
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#
sto)&(+% ound = intrinsi( f&(tor *I,
&nd &sored t+rou"+ t+e ter)in&! i!eu)%tr&ns#orted = tr&ns(o&!&)in I &nd to
!esser e8tend = tr&ns(o&!&)in II &nd
III.
It is essenti&! for$
12+&e)&to#oiesis
42GIT )u(os& inte"r&tion32or)&tion of )=e!in of nervous s=ste).
M&(ro(=ti(
Ane)i&CAUSES O ?IT. B14 DEICIENC
I T d fi i (D d i k
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I- True deficiency: (Decreased intake
2Poor so(ioe(ono)i( st&tus.
2?e"et&ri&ns% &!(o+o!i(
II-condition deficiency
!-Decreased absor"tion .
12De(re&sed intrinsi( f&(tors (o))onest (&use.
Perni(ious &n&e)i&.
Tot&! or #&rti&! "&stre(to)=
Atro#+i( "&stritis.G&stri( (&n(er.
Non2 Addisoni&n #erni(ious &n&e)i&
&2 In &sso(i&tion it+ +=#o"&))&"!ou!ine)i&%
"&stri( &tro#+=% &(+!or+=dri& &nd &sent intrinsi(
f&(tor ut no &ntiodies
2In inf&n(=$ Se!e(tive f&i!ure of I% nor)&! )u(os&.
C2 >uveni! PA f&i!ure of I se(retion it+ "&stri(
&tro#+= r&re!= it+ &ntiodies
M&(ro(=ti(
Ane)i& 42M&!&sor#tion s=ndro)e.
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32I!e&! dise&ses$
Ter)in&! i!eu) rese(tion TB enteritis.
C+ronFs dise&se.
B!ind !oo# s=ndro)e it+ &(teri&! over2
"rot+.
Infest&tion = fis+ t&#e or)
Di#+=!!oot+riu) !&tu).
M&(ro(=ti(
Ane)i&
#-Decreased utili$ation: R&re (on"enit&! en=)e defi(ien(=.
L&( of tr&ns(o!&)in II.
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L&( of tr&ns(o!&)in II.
III-%elative deficiency : (increased demand
Inf&n(=% #re"n&n(=% !&(t&tion
H&e)o!=!sis &nd &(tive +&e)&to#oiesis
M&!i"n&n(=.
T+=roto8i(osis
I&- Increased loss: He)odi&!=sis
&- Decrease of stores. &r &dv&n(ed (+roni( !iver
dise&ses
M&(ro(=ti(
Ane)i&
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PERNICIOUS ANAEMIA
*ADDISONIAN ANAEMIA,DEINITION
Perni(ious &n&e)i& *PA, is & (ondition in +i(+
t+ere is &tro#+= of t+e "&stri( )u(os& it+(onseuent f&i!ure of intrinsi( f&(tor #rodu(tion
&nd vit&)in B14 )&!&sor#tion.
M&(ro(=ti(
Ane)i&AETIOLOG
12Most #ro&!= &utoi))une dise&se it+ "eneti( tenden(= .
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42T+ere is &n &sso(i&tion it+ ot+er &utoi))une dise&se
*T+=roid dise&se% viti!i"o &nd AddisonFs dise&se,.
32Atro#+i( "&stritis *de(re&se HCL 6 I, &sso(i&ted it+
#rodu(tion of #&riet&! (e!! &ntiodies
J2Intrinsi( f&(tor &ntiodies +i(+ &re s#e(ifi( for t+e di&"nosis
&nd &re of to t=#es% !o(in" &ntiodies +i(+ in+iit t+eindin" of I to B14 &nd #re(i#it&tin" &ntiodies +i(+ in+iit
t+e indin" of B142I (o)#!e8 to its re(e#tor sites in t+e i!eu).
92It is (o))on in t+e e!der!= over K< =e&rs in f&ir +&ired &nd
!ue e=ed #eo#!e &nd in fe)&!es t+&n )&!es.
K2T+e re!&tives )&= +&ve (!ini(&! fe&tures of &utoi))une
dise&se
M&(ro(=ti(
Ane)i&
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PATHOPHSIOLOG
Bot+ vit Bi4 &nd fo!i( &(id &re essenti&! for DNA
s=nt+esis &nd )&tur&tion.
In (&ses of )e"&!o!&sti( &n&e)i& t+ere is & defi(ientDNA s=nt+esis% so t+e r&te of (e!! division of )&n=
(e!!s in t+e od= is r&te. T+e )ost &ffe(ted (e!!s &re
t+ose it+ r&#id r&te of division &nd "rot+. i.e.
+&e)&to#orti( (e!!s *RBC% BC% #!&te!et , &nd%
"&stri( )u(os& 6 in&i!it= to for) )=e!in s+e&t+
M&(ro(=ti(
Ane)i&
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RBCs *Me"&!o!&stosis - (e!!u!&r "i"&ntis),
12Me"&!o!&sts *(e!! "i"&ntis) ,$ t+ese &re !&r"e (e!!s
*)e"&!o, it+ re!&tive!= s)&!! nu(!eus *!&sts,.
T+e (=to#!&s) is )&red!= in (re&se e(&use RNA
s=nt+esis is nor)&! +i!e t+e nu(!eus is s!o!="roin" e(&use defi(ient DNA s=nt+esis.
42In BM% t+e nor)!&st &re re#!&(ed = t+ese
)e"&!o!&sts. So)e of t+ese &nor)&! (e!!s &re
destro=ed in BM. *intr&)edu!!&r= +&e)o!=sis,
M&(ro(=ti(
Ane)i& 32So)e of t+ese er=t+roid )e"&!o!&sts !ose t+eir
nu(!ei &nd oined #eri#+er&! !ood &s )&(ro(=tes
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nu(!ei &nd oined #eri#+er&! !ood &s )&(ro(=tes%
irre"u!&r s+&#e it+ re)n&nt of t+e nu(!eus .
t+ese (e!!s &re +&t(+ed &nd destro=ed = t+es#!een. Durin" its (ir(u!&tion.
J2So &n&e)i& is )u!tif&(tori&!
2 Defe(tive er=t+ro#oiesis
2 Intr&)edu!!&r= +&e)o!=sis.
2 Destru(tion = t+e s#!een .
92In(re&sed Seru) i!iruin2In(re&sed )edu!!&r= +&e)o!=sis.
2In(re&sed s#!eni( destru(tion of RBCs.
M&(ro(=ti(
Ane)i&BCs$ *!eu(o#eni&,
M=e!oid )e"&!o!&sts &re #resent in BM &nd "ive +=#erse")ented
PNL t t+ i + ! ! d
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PNL to t+e #eri#+er&! !ood.
Leu(o#eni& due to defi(ient DNA s=nt+esis
T+ro)o(=to#eni&
Due to defi(ient DNA s=nt+esis .
NB $ Sin(e t+e t+ree !ood e!e)ents &re effe(ted in
)e"&!o!&sti( &n&e)i&% it is etter to (&!! it)e"&!o!&sti( #&n(=to#eni&.
GIT
Is &ffe(ted in t+e s&)e )&nner% it+ se(ond&r=
&tro#+= e#it+e!i&! (e!!s of t+e ton"ue% sto)&(+ &ndeven intestine.
Nervous s=ste)
On!= it+ B14 defi(ien(=.% f&i!ure of s=nt+esis of
)=e!in s=nt+esis
M&(ro(=ti(
Ane)i&
CLINICAL EATURES
T+e onset is insidious
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T+e onset is insidious.
12 H&e)to!o"i(&! )&nifest&tions
2Gener&! )&nifest&tion of &n&e)i& .
2T+ro)o(=te#eni& B!eedin" tenden(ies
2Leu(#eni& ris of infe(tion
2He#&tos#!eno)e"&!=.
2Co!our of t+e sin is !e)on =e!!o oin" to
(o)in&tion of #&!!or &nd &undi(e.
M&(ro(=ti(
Ane)i&42 GIT )&nifest&tions
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2Atro#+i( "!ossitis% *red "!oed ton"ue,
2An"u!&r sto)&titis .
2G&stri( &tro#+= d=s#e#si&% &nore8i& n&use&%
vo)itin" .
2Intestin&! &tro#+= di&rr+oe& &nd )&!&sor#tion
C&n(er sto)&(+ on to# of &tro#+i( "&stritis
M&(ro(=ti(
Ane)i&
32 Neuro#s=(+&ti(e )&nifest&tions *on!= it+ vit B14
defi(ien(=,.
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!-'eurological manifestations (Ps:
Peri#+er&! neuro#&t+= *LMNL,
P=r&)id&! tr&(t &ffe(tion *UMNL, s#&sti( #&r&#!e"i&.
Posterior (o!u)n &ffe(tion !oss of dee# sens&tion &nd
sensor= &t&8i& .
NB$ Co)in&tion of t+e to !essons is (&!!ed su &(ute
(o)ined de"ener&tion of t+e s#in&! (ord *SCD,
b- Dementia
c- )"tic atro"hy
d- "sychosis rare
M&(ro(=ti(
Ane)i&J2 Asso(i&tion it+ ot+er &utoi))une fe&tures$ *in
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*
#erni(ious &n&e)i&,
12 T+=roto8(o&is
42 H&s+i)otoFs dise&se.
32?iti!i"o
J2R+eu)&toid dise&se
92Pri)&r= i!!i&rd (irr+osis
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M&(ro(=ti(
Ane)i& II2 Bone )&rro$
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S+o )e"&!o!&sti( er=t+ro#oiesis. T+e )ost(+&r&(teristi( is disso(i&tion eteen nu(!e&r
(=to#!&s)i( deve!o#)ent in er=t+ro!&sts it+ t+e
nu(!eus )&int&inin" & #ri)itive &##e&r&n(e des#ite
)&tur&tion &nd +&e)o"!oini&tion of t+e
(=to#!&s).
*rythroid hy"er"lasia+ maturation defect in
erythro"oiesis+ giant metamyelocytes+ aty"ical
megakaryocytes ,ith hy"ersegmented nuclei.
M&(ro(=ti(
Ane)i&III2 Esti)&tion of seru) B14 !eve!
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is !o usin" r&dioisoto#e di!ution or i))uno!o"i(&!
&ss&=s.
I?. Bio(+e)istr=
Seru) iron is +i"+% )ore t+&n 1:9 )(";1<< )!.
In(re&sed seru) indire(t i!iruin ref!e(t )i!d
+&e)o!=sis &nd ineffe(tive er=t+ro#oiesis.
In(re&sed seru) !&(ti( de+=dro"en&se *LDH,ref!e(tin" ineffe(tive )e"&!o!&sti(
er=t+ro#oiesis.
?. I))uno!o"=
P&riet&! (e!!s &ntiodies &nd "&strin re(e#tor&ntiodies% #resent in :< of #&tients. *not
s#e(ifi(,
Intrinsi( f&(tor &ntiodies t=#e I !o(in" *)ore
s#e(ifi(, &nd t=#e II #re(i#it&tin" &ntiodies.
M&(ro(=ti(
Ane)i&
?I2 ot+er investi"&tionsG&stri( io#s=$ #ro8i)&! 4;3 of sto)&(+ &tro#+i(.
!ugmented histamine test: achlorhydria.
chilling test
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chilling test.
!im
12 Di&"nosis of #erni(ious &n&e)i&.
42 To dete(t its (&use +et+er )&!&sor#tion or I defi(ien(=.
/ethodology
L&r"e dose of un!&e!!ed B14 *1<<<u", is "iven I? to s&tur&te
od= sores.
R&dio!&e!!ed B14 *!u", is "iven or&!!=% t+e &)ount of r&dio
!&e!!o! B14 on t+e urine.Urine of t+e ne8t 4J +ours is )e&sured
%esults
If r&dio!&e!!ed B14 e8(retion is !o t+ere )&= e
12 M&!&sor#tion
42 Perni(ious &n&e)i&.
Re#e&ted t+e test &fter "ivin" I or&!!= if it in(re&se in t+e urine%
t+is )e&ns t+&t t+e (&use is I defi(ien(=.
M&(ro(=ti(
Ane)i& TREATMENT
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Tre&t)ent of t+e (&use $ if #ossi!e .
Re#!&(e)ent t+er&#= .
Initi&! tre&t)ent is often &s t+e 1<<< )" B14
IM;d&= for 4 ees t+en in & dos&"e of
1<<< )" ti(e;ee ti!! (orre(tion of&n&e)i&. M&inten&n(e t+er&#= 1<<< )"
IM ever= 3 )ont+s.
Neuro!o"i(&! d&)&"e (&n e #re(i#it&ted =
tre&tin" in(orre(t!= it+ fo!i( &(id.Tr&nsfusion t+er&#= = #&(ed RBCs in t+e f!oin"
(onditionssever &n&e)i& *H Q : ");d! ,
He&rt f&i!ure .
M&red s=)#to)s .
M&(ro(=ti(
Ane)i&
OLATE DEICIENC
B&si( nutrition&! fe&tures &nd )et&o!is) of fo!&te
Di t f ! t
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Diet&r= fo!&te sour(e $
I)#ort&nt sour(es &re !iver% idne= &nd fres+ "reen ve"et&!es%
nuts+ yeast+ (ooin" #ro&!= destro=s% &t !e&st +&!f t+e fo!&te in
food%
Mini)u) d&i!= reuire)ents 1<<24<< u".
Asor#tion is (+ief!= in t+e eunu).
Tot&! od= store is &out 1< )" )&in!= in t+e !iver
Store is suffi(ient for J )ont+s.
un(tion
It is essenti&! for nu(!ei( &(id s=nt+esis )&tur&tion. It is defi(ien(=
!e&d to
Nu(!e&r )&tur&tion defe(t.% of !ood (e!!s &nd )e"&!o!&sti(er=t+ro#oiesis.
GIT$ )u(os&! (e!!s.
M&(ro(=ti(
Ane)i&
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CAUSES O OLATE DEICIENC$
I2 True defi(ien(= *de(re&sed int&e,
Poor ina> particularly in infancy, old ag poor
ocial condiion ar'aion alcool ;c
Poor ina> du o anor;ia a in .(T dia gParial garco- coliac dia CronD dia
cancr
M&(ro(=ti(Ane)i&
II2 Re!&tive defi(ien(= *in(re&sed de)&nd,
P i l i l l i
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Piological prgnanc lacaion
pr-auri
Paological ,a-aological dia i ;c rd cll
producion g a-oli
@alignan dia i incrad cllurno'r
(nla--aor dia g ru-aoid
arrii
CronD dia
@abolic dia g o-ocinuria !rar
congnial dc in con'rion o
o-ocin o caion ola"
M&(ro(=ti(
Ane)i&III 2 Conditioned defi(ien(= nor)&! int&e &nd
reuire)ent ut t+eir )&= e $
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a" $crad aborpion
* @alaborpion in -all bol dia
* $rug pill or anicon'ulan
b" $crad uiliaion
* Aniola drug anicon'ulan
-or;a pri-a-in and ri-opri-
I?2 In(re&sed !oss
* ,a-odiali or prional diali clol
bound o pla-a proin o ail r-o'd
Ane)i& CLINICAL EATURES
* M&= o((ur &t &n= &"e% de"rees of fo!&te
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= = " % "
defi(ien(= &re ver= (o))on &nd )i!d defi(ien(=
st&tes &re freuent!= unre(o"nised.
T+e (!ini(&! #i(ture is )u!tiv&rious e(&use of
t+e v&riet= of #ossi!e under!=in" (&uses.
T+e onset )&= e insidious or r&#id &s +enne"&tive fo!&te &!&n(e is #re(i#it&ted = e."
infe(tion
An&e)i& &nd so)eti)es s!i"+t &undi(e.
G!ossitis.
* o dind nurological cang
M&(ro(=ti(
Ane)i& * <niall a in 'i B12 dicinc
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* ,oll Eoll bodi and arg cll in
blood il- ould ugg plnic arop!coliac dia"
* Bon -arro o -galoblaic cang
* ducd ola l'l !F 25%25-g/-l"
ru- l'l ar labil and rd cll l'l ar
br rlcion o iu ola b radioioop
diluion or i--unological -od
'.# @icrobiological -od r ud in
pa bu a diad'anag a anibioic
rap could lad o all lo rul
M&(ro(=ti(
Ane)i&
Tre&t)ent
1" olic acid rap i conraindicad i
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r i an upicion o B12 dicinc
!urololgical cang -a b
prcipiad or orn"
2" olic acid 5-g dail i -or an
adGua
3" Proplacic olic acid i alo gi'n in
cronic -aological diordr r
r i rapid cll urno'r 5-g ac
>
4" Proplacic olic acid !400ug dail" i
rco--ndd in prgnanc
M&(ro(=ti(
Ane)i&
/!C%)C0T)I 1IT2)3T
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/!C%)C0T)I 1IT2)3T
/*4!L)#L!TIC C2!'4*
A raid @C: i -acrocoi on
pripral blood il- can occur i a
nor-ablaic B@ (n all condiion
l'l o :i B12 and ola ar nor-al
T ;ac -cani- ar uncrain bu
i - r i incrad lipid dpoiion in
rd cll --bran
M&(ro(=ti(
Ane)i& 1" Piological prgnanc and nborn
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2" Paological
* Alcool ;c
* Li'r dia
* iculocoi
* ,poroidi-
* =o- a-aological diordr !g aplaic
ana-ia idroblaic ana-ia
* $rug !g coo;ic a aaioprin"
* Aggluinad rd cll -aurd on rd counr
* Cold aggluini du o auoaggluinaion o rdcll @C: dcra o nor-al i ar-ing
o a-pl o 37&C
An incrad nu-br o riculoc lad o a
Decreased Erythrocyte =roduction
Mealoblastic Anemias
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Mealoblastic Anemias
• SUMA"W
19/04/2011 139
This picture sho+s lare! dense!oversiNed! red blood cells (".Cs) that
are seen in mealoblastic anemia4
Decreased Erythrocyte =roduction
Mealoblastic Anemias
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Mealoblastic Anemias
• CharacteriNed bylare ".Cs +hichare &raile andeasily destroyed
• Common &orms o&mealoblastic
anemia4 Cobalamin
de>ciency (Bitamin
./)19/04/2011 140
This picture sho+s lare! dense!oversiNed! red blood cells (".Cs) that
are seen in mealoblastic anemia4
Cobalamin (Bitamin ./)De>ciency pernicious anemia
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De>ciency pernicious anemia
• Cobalamin De>ciency$$&ormerly %no+n aspernicious anemia
• Vitamin B12 (cobalamin) is an importantwater-soluble vitamin.
• Intrinsic factor (,) is reuired &orcobalamin absorption• Causes o& cobalamin de>ciency
– -astric mucosa not secretin , – -, surery →loss o& ,$secretin astric mucosal
cells – #on$term use o& 7/$histamine receptor bloc%ers
cause atrophy or loss o& astric mucosa4 – @utritional de>ciency – 7ereditary de&ects o& cobalamine utiliNation
19/04/2011 141
Cobalamin (Bitamin ./)De>ciency
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De>ciency
• Clinical mani&estations – -eneral symptoms o& anemia – Sore tonue
– Anore0ia – 1ea%ness – =arathesias o& the &eet and hands
– Altered thouht processes• Con&usion → dementia
19/04/2011 142
Cobalamin De>ciencyDiagnostic
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Diagnostic
• ".Cs appear lare• Abnormal shapes• Structure contributes to erythrocyte
destruction• Schillin Test: a medical
investiation used &or patients +ith
vitamin ./ de>ciency4 The purposeo& the test is to determine i& thepatient has pernicious anemia4
19/04/2011 143
Cobalamin De>ciency
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• T"EATME@T – =arenteral administration o&
cobalamin – Q Dietary cobalamin does not
correct the anemia• Still important to emphasiNe
adeuate dietary inta%e
– ,ntranasal &orm o&
cyanocobalamin (@ascobal) isavailable
– 7ih dose oral cobalamin and S#
cobalamin can use be used19/04/2011 144
Decreased Erythrocyte =roductionolic Acid De>ciency
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olic Acid De>ciency
olic Acid De>ciency also causesmeablastic anemia (".Cs thatare lare and &e+er in number)
• olic Acid reuired &or ".C&ormation and maturationCauses
– =oor dietary inta%e – Malabsorption syndromes – Drus that inhibit absorption – Alcohol abuse
– 7emodialysis19/04/2011 145
olic Acid De>ciency
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• Clinical mani&estations are similar to those o&cobalamin de>ciency
• ,nsidious onset: proress slo+ly• Absence o& neuroloic problems
• Treated by &olate replacement therapy
• Encourae patient to eat &oods +ith lare amountso& &olic acid
• #ea&y reen veetables• #iver
• Mushrooms• Oatmeal• =eanut butter• "ed beans
19/04/2011 146
v uMaiorescu
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C U R S M E D I C I N A I N T E R N A
R E U M A T O L O G I E
P r o f u n i v d r I o n C . i n t o i u
Ț
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Decreased production o&erythrocyte
Aplastic Anemia
• Aplastic anemia
• CharacteriNed by =ancytopenia
19/04/2011 148
Decreased production o& erythrocyteAplastic Anemia
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• CharacteriNed by =ancytopenia – o& all blood cell types
• ".Cs• 1hite blood cells (1.Cs)• =latelets
– Hypocellular one marrow
• Etioloy – Conenital
• Chromosomal alterations
– Acuired• "esults &rom e0posure to ioniNin radiation!
chemical aents! viral and bacterial in&ections19/04/2011 149
Aplastic Anemia
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p
• Etioloy
– #o+ incidence
• A6ectin P o& every millionpersons
– Manaeable +ith erythropoietin
or blood trans&usion – Can be a critical condition• 7emorrhae• Sepsis19/04/2011 150
Aplastic Anemia
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• Clinical
Mani&estations – -radual development – Symptoms caused by suppression o&
any or all bone marro+ elements
– -eneral mani&estations o& anemia• atiue• Dyspnea• =ale s%in• reuent or proloned in&ections
• Une0plained or easy bruisin• @osebleed and bleedin ums• =roloned bleedin &rom cuts• DiNNiness
• headache19/04/2011 151
Aplastic Anemia
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• Dianosis –.lood tests
• C.C
–.one marro+ biopsy
19/04/2011 152
Aplastic Anemia
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Treatment – ,denti&yin cause – .lood trans&usions – Antibiotics – ,mmunosuppressants (neoral! sandimmune)
• Corticosteroids (Medrol! solu$medrol) – .one marro+ stimulants
• ilrastim (@eupoen)• Epoetin al&a (Epoen! =rocrit)
–.one marro+ transplantation – =ronosis is poor i& untreated• 8* &atal/
4
/
2
0
153
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.lood lossanemia
•
154
Acute .lood #oss
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• "esult o& sudden hemorrhae – Trauma! surery! vascular
disruption
• Collaborative Care4"eplacin blood volume
/$ ,denti&yin source o&hemorrhae
$Stoppin blood loss
155
Chronic .lood #oss
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• Sources<Symptoms – Similar to iron de>ciency anemia – -, bleedin! hemorrhoids!
menstrual blood loss• Dianostic Studies
– ,denti&yin source
– Stoppin bleedin• Collaborative Care
– Supplemental iron
administration 156
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Anemia causedby
,ncreased Erythrocyte Destruction
•
157
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Anemia causedby
,ncreased Erythrocyte Destruction
7AEMO#WT,C A@AEM,AS
•
158
M&(ro(=ti(Ane)i&
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HAEMOLTIC ANAEMIASDefinition $
T a-olic ana-ia ar a group o
dia in ic rd cll li pan i ornd
M&(ro(=ti(Ane)i&
PATHOPSIOLOG$
* H&e)o!=sis of RBC (&n o((ur eit+er .
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H&e)o!=sis of RBC (&n o((ur eit+er .
1, Intr&v&s(u!&r ie it+in t+e (ir(u!&tion .
4, E8tr& v&s(u!&r ie $ = #+&"o(=tes in RES in t+e
!iver% one% s#!een.
Bone )&rro (o)#ens&tor= re&(tions$
Er=t+riod +=#er#!&si& in BM% (&n in(re&se
er=t+ro#oiesis sever&! ti)es% so t+&t &n&e)i& )&=
not deve!o# ti!! RBCs !ife s#&n is !ess t+&n 4< d&=s
Reti(u=!o(=tosis is +&!!)&r.
S!i"+t )&(ro=tosis in t+e #eri#+er&!
!ood
M&(ro(=ti(Ane)i&
CAUSES$
A 2 CORPUSCULAR CAUSES$
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1, Con"enit&! Anor)&!ities$
@-bran dc
* ,rdiar procoi
* ,rdiar llipocoi• ,rdiar o-aocoi
,a-oglobinopai
* =ic>l cll ana-ia
* Talaa-ia
<n-opai1" Abnor-al arobic glcoli g .6P$ dicinc
2" Abnor-al anrobic glcoli g pru'a >ina
dicinc
3" on glcolic n-opai
H&e)o!=ti(Ane)i&
4, A(uired Anor)&!ities
1% Paro;-al nocurnal a-oglobinuria
2% :ia-in < dicinc
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B2 ETRACORPUSCULAR CAUSES$
12 I))une )e(+&nis)s
a !lloimmune antibodies (iso-immune:
* (nco-paibl blood ranuion
* ,a-olic dia o nborn
* Ar allognic B@ or organ ranplanaion
b !utoimmune haemolytic anaemias
1%Har- raci' anibodi !rac a 37 oC and do no
bring
aggluinaion p o ABF (g. "
* (diopaic
* =condar o CLL L-po-a =L< and ru-aoid
dia
* =condar o drug g -ldopa
H&e)o!=ti(Ane)i&
2% Cold raci' anibodi !rac a 32oCand uuall aggluina and a-ol rd
cll p o AB F (g@"
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* Cold a-oaggluinin dia% (diopaic- =condar !-copola-a pnun-ia
incion inciou -ononucloi
l-po-a
* Paro;-al cold a-oglobinuria
% (diopaic- =condar !o- 'iral incion
congnial I riar pili"
c Immunochemical mechanisms: drug
inducd a-olic ana-ia
H&e)o!=ti(Ane)i& 42 Me(+&ni(&! inur=
* Cardiac a-olic ana-ia !'al' proi"
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Cardiac a-olic ana-ia !'al' proi"
* @icroangiopaic a-olic ana-ia• @arc a-oglobinuria
32 C+e)i(&!s &nd Dru"s
* =na> 'no-* Lad
* apalin
* Pnacin
* =ulpa drug* ,popopaa-ia
H&e)o!=ti(Ane)i&
* Cloridiu- lcii pic-ia !=condar o
pic aborion"
* @alarial inaion !Blac> ar 'r"
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@alarial inaion !Blac> ar 'r"
92 Met&o!i( (&uses
* A balipoproin-ia A canocoi
* Li'r porpria
* =purr cll ana-ia* Ji'D ndro-
* Hilon dia
* ='r popopaa-ia
K2 Se(ond&r= to s=ste)i( dise&se $
* nal and li'r ailur
* Burn
H&e)o!=ti(Ane)i&
1,H&e)&!=ti( &undi(e .* @ild dgr
* =>in i l-on llo
* =clra ing o aundic
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* =clra ing o aundic
* $ar> ool* or-al urin ic dar>n on ;pour o
air
4,He&#&tos#!eno)e"&!=$
* Co--on in cronic a-oli ;cp in
ca o ic>l cll ana-ia r r l%plnco-
3, Bi!i&r= ostru(tion &nd ;or "&!! !&dder
stones.
* Pig-n on ;ra paic obrucion * :icid bil inrapaic obrucion
B (n i iuaion aundic bco- -i;d
! a-olic + obruci'" and abdo-inal pain
- b prn
H&e)o!=ti(Ane)i&
* 'r rigor progn rla ro- BC * .nralid bon pain
* Acu abdo-inal pain bac>ac -a b 'o-iing
* Aggra'aion o ana-ia !pallor" dpning a
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gg !p " p g
aundic and dar> colouraion o urin
* (n'igaion% $ar> urin a-oglobinuria
% (ncrad ru- biliurbin
% iculocoi
% B@ rroid prplaia* Cau -a b incion
#- ! "lastic crisis
* (nabili o B@ o rplacd drucd
BC
% ='r ana-ia iou aundic
% iculocopnia
% B@ rroid poplaia
* Cau 'iral incion pciall par'o'iru
B19 and
H&e)o!=ti(Ane)i&
C- e5uestration crisisTrapping and pooling o BC in pln
!-ainl and li'r"
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D- /egaloblastic crisis
* Ana-ia 'r iou aundic
* $crad riculocic coun
* @acrocic ana-ia
* B@ -gabloblaic
Cau olic acid dicinc
*- &aso-occlusive crisis (Thrombotic
"henomenon
* Painul* &nl in ca o ic>l cll ana-ia
H&e)o!=ti(Ane)i&
e&tures or t+e (&use
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e&tures or t+e (&use
e." t+&!&ss&e)i&% si(!e (e!! &n&e)i&.
COMPLICATIONS
H&e)o!=ti( (risis$.
A #!&sti( (risis$
o!&te defi(ien(= (&used = in(re&sed BM
reuire)ent
G&!! stones
In si(!e (e!! &n&e)i&$ si"ns &nd s=)#to)sof t+ro)oti(
#+eno)en&
& !ce reuX Si inca nu s$arminat X
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Anemia o& chronic disease
and Erythropoietin
• .
Anemia o hronic &isease)A&*
Classical defnition
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Classical defnition
• Anemia occurring in Kchronic inectious, in$ammatoryor neoplastic disorders
• not due to Kmarrow replacement y tumor,leeding, or hemolysis
• characteri9ed y Khypoerremia in the presence oade(uate iron stores
Me&ns RT >un% @r&nt SB. #lood 14 <*:,$ 1K321KJ:
Ane)i& of C+roni( Dise&se
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Inf!&))&tion% neo#!&si&
B!unted er=t+ro#oietin res#onse
I)#&ired iron uti!i&tion
Bone )&rro stores &deu&te
Lo seru) iron
Ludig !1998"
Anemia o chronic disease
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• 2cessive production o
cyto#ines
• Inefective erythropoiesis
• Interere with0
– fect o %+ on one marrow – Release o stored iron in
Reticuloendothelial system
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Anemia o& ChronicDisease
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/ajor steps of/ajor steps of erythropoiesiserythropoiesis andanderythropoietin dependenceerythropoietin dependence
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$rythropoietin$rythropoietindependencedependence
)ematopoietic stem cell)ematopoietic stem cell
**B+B+--$$
..C+C+--$$
$rythroblasts$rythroblasts
ReticulocytesReticulocytes
* B+* B+--$ 0 burst$ 0 burst--forming unitforming unit 1 1erythroid2 . C+erythroid2 . C+--$ 0 colony$ 0 colony--forming unitforming unit 1 1erythroiderythroid
Bron, !e"ille 3444
R"HR+%+I"I;
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carbohydrate
protein
protein K carbohydrate V lycoprotein
Er=t+ro#oietin
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• .lcoproin o 34 >$a
• Producd in >idn and li'r rac a-oun in brain
• =i-ula ur'i'al and dirniaion o rroid prognior
Laco-b !1998 1999" Kran !1991" Brnaudin !2000"
A)ino A(id Seuen(e
of Er=t+ro#oietin
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10 201
16040
30
50
60
70
80
90
100
110
120
130
140150
%lin>d !3"
glcolaion
&%lin>d !1"
glcolaion
A-ino acid
==
=
=
<rl' !1991" @ulca !2001"
po prevents apoptosis oerythroid progenitors
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M&(ro#+&"e
6E#o
2E#o
CU2E
%hysiology o rythropoietin
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co-binan
<rropoiin
iological efects o %+
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Erthropoiesis
• ontrols R production
•%romotes survival, prolieration,and diferentiation o erythroidprogenitors
• 2erts efects on late erythroidprogenitors
@ulca ='ill 2000
Re"u!&tion of Er=t+ro#oietin
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H=#o8i& Inf!&))&tor= *HI21,
(=toines
%6
Er=t+ro#oietin
Ludig !1998" Laco-b !1999"HI21 - +=#o8i&2indu(ed f&(tor21
"he physiological role oerythropoietin in the healthy adult
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De(re&sed o8="en de!iver= to t+e idne=s
Perituu!&r interstiti&! (e!!s dete(t
!o o8="en !eve!s in t+e !ood
Pro2er=t+ro!&sts in red
one )&rro )&ture )oreui(!= into reti(u!o(=tes
More reti(u!o(=tes
enter (ir(u!&tin" !ood
L&r"er nu)er of red !ood (e!!s *RBC,
in (ir(u!&tion
In(re&sed o8="en de!iver= to tissues
Return to +o)eost&sis +en res#onse rin"s
o8="en de!iver= to idne=s &( to nor)&!
EPO
Perituu!&r interstiti&! (e!!s
se(rete er=t+ro#oietin *EPO, into
t+e !ood
Anemia o Renal 3ailure
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,n advanced disease
To0icity &rom therapy
Therapy: Erythropoietin
%athogenesis o anemia in cancer
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ANAEMIA
*Bone )&rro invo!ve)ent,
Iron distriution
defe(t
S+ortened er=t+ro(=tesurviv&! ti)e
De#ression of
er=t+ro#oiesis or
EPO #rodu(tion*(=toine2)edi&ted,
C=toto8i( (+e)ot+er&#=
H&e)o!=sis*NHL,
Ren&! f&i!ure*)u!ti#!e )=e!o)&,
Pure red (e!! &#!&si&
*T (e!! NHL,
An&e)i& of C+roni( Dise&s
Anemia in Cancer =atients
Iron &e/ciency Anemia
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Iron &e/ciency Anemia
Anemia o hronic &isease
one !arrow Involvement
%ure Red ell Aplasia
!egaloglastic Anemia )6:, 3olate de.*
Anemia o Renal 3ailure
!icroangiopathic anemia Autoimmune Hemolytic Anemia
Therapy$induced Anemia
,mpact o& Anemia in=atients 1ith Cancer
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• aigu
• =orn o bra
• Lac> o nrg o pror- dail uncion ↓ &L
• Co-plica co;iing dia
• Aociad i poor prognoi and incrad -orali
• @a co-pro-i icac and olrabili o ra-n
3actors involved in the cause anddevelopment o anaemia in cancer patients
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S+ortened
surviv&!
Tu)our (e!!s
RBCs
A(tiv&ted
i))une s=ste)
M&(ro#+&"esTN
An&e)i&
IN2α%β IN2γ IN2γ IL21 IL21 IL21
TN TN TN
α12&ntitr=#sin
Redu(ed I)#&ired Su##ressed
EPO iron BU2e
#rodu(tion uti!is&tion CU2e
Norousi&n MR. Med On(o! 119*Su##!. 1,$S14
Er=t+ro#+&"o(=tosis
D=ser=t+ro#oiesis
TN - tu)our ne(rosis f&(tor IN - interferon IL21 - inter!euin21
BU2e - er=t+roid urst2for)in" unit CU2e - er=t+roid (o!on=2for)in" unit
Anemia in Cancer =atients
Iron &e/ciency Anemia
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Iron &e/ciency Anemia
Anemia o hronic &isease
.one Marro+ ,nvolvement
%ure Red ell Aplasia
!egaloglastic Anemia )6:, 3olate de.*
Anemia o Renal 3ailure
!icroangiopathic anemia Autoimmune Hemolytic Anemia
"herapy-induced Anemia
+; !ARR+G AS%IRA"
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one marrow involvement
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o!!i(u!&r !=)#+o)&
Neuro!&sto)&
Anemia Due to Marro+,n>ltration
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2cept in hematological malignancies,
usually
associated with advanced disease.
reast and prostate a are an e2ception K
marrow
involvement oten with only mild anemia or
normal
H.
+; !ARR+G I+%S
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Anemia in Cancer =atients
Iron &e/ciency Anemia
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Iron &e/ciency Anemia
Anemia o hronic &isease
one !arrow Involvement
=ure "ed Cell Aplasia
!egaloglastic Anemia )6:, 3olate de.*
Anemia o Renal 3ailure
!icroangiopathic anemia Autoimmune Hemolytic Anemia
"herapy-induced Anemia
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Anemia in Cancer =atients
Iron &e/ciency Anemia
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Iron &e/ciency Anemia
Anemia o hronic &isease
one !arrow Involvement
%ure Red ell Aplasia
!egaloglastic Anemia )6:, 3olate de.*
Anemia o Renal 3ailure
!icroangiopathic anemia Autoimmune Hemolytic Anemia
"herapy-induced Anemia
Anemia in Cancer =atients
Iron &e/ciency Anemia
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Iron &e/ciency Anemia
Anemia o hronic &isease
one !arrow Involvement
%ure Red ell Aplasia
!egaloglastic Anemia )6:, 3olate de.*
Anemia o Renal 3ailure
!icroangiopathic anemia Autoimmune Hemolytic Anemia
"herapy-induced Anemia
Anemia in Cancer =atients
Iron &e/ciency Anemia
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y
Anemia o hronic &isease
one !arrow Involvement
%ure Red ell Aplasia
!egaloglastic Anemia )6:, 3olate de.*
Anemia o Renal 3ailure
!icroangiopathic anemia Autoimmune Hemolytic Anemia
"herapy-induced Anemia
Anemia in Cancer =atients
Iron &e/ciency Anemia
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y
Anemia o hronic &isease
one !arrow Involvement
%ure Red ell Aplasia
!egaloglastic Anemia )6:, 3olate de.*
Anemia o Renal 3ailure
!icroangiopathic anemia Autoimmune 7emolytic Anemia
"herapy-induced Anemia
Autoimmune Hemolytic Anemia
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Anemia in Cancer =atients
Iron &e/ciency Anemia
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y
Anemia o hronic &isease
one !arrow Involvement
%ure Red ell Aplasia
!egaloglastic Anemia )6:, 3olate de.*
Anemia o Renal 3ailure
!icroangiopathic anemia
Autoimmune Hemolytic Anemia
Therapy$induced Anemia
Tre&t)ent O#tions forC&n(er2Re!&ted Ane)i&
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Tr&nsfusion
• #d in ca o acu
an-ia
• @an aociad ri>
ERTHROPOIETIN,arrion !2000"
Types o& Trans&usion "eactions
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,mmediate• 7emolytic
• ebrile
• @on$cardioenic
pulmonary edema• Other alleric
Delayed
• Delayed hemolytic
• =ost$trans&usion purpura• ,n&ections
• -ra&t vs host disease
• Chronic immunosuppression
<uideline Recommendations or Anaemia!anagement in %atients with ancer
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ASCO<AS7• ,nitiate epoetin in patients +ith 7b Y
<dl (or7b ' to G/ <dl dependin on clinical
circumstances)• SC ,U ( ,U<%) once +ee%lyZ
double dose in absence o& response (7bincrease
GF/ <dl) a&ter P +ee%s• "aise 7b to / <dl and maintainZ
insucient evidence to support[normalisation o& 7b '/ <dl
Rio et &!. 6 Clin )ncol 4<<4 4<$ J<31<:
v uMaiorescu
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C U R S M E D I C I N A
I N T E R N A
H e ) & t o ! o " i e I I
P r o f u n i v d r I o n C . i n t o i u
Ț
ersitatea Titu Maiorescu
S MED,C,@A ,@TE"@A
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,ntrinsic hemolyticanemia 7emolobinopathies
Abnormal hemolobin
.
• 7emolobinopathies
• Over ; di6erent mutations o& lobin chains o&
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human hemolobin have been discovered• \ualitative
• (.eta subunits are replaced by
beta S!C!SC)4 Sic%le cell anemia replaced by beta S 7b C disease 7b SC disease
\auntitative Thalassemias (] and β
,ntrinsic hemolytic
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y
anemia 7emolobinopathies
Abnormal hemolobin
Sic%le (secera) Cell Disease .
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Sic%le (secera) CellDisease• The resultant cellular
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de&ect leads to • The main
mani&estations o& the
disease! +hichinclude: – $premature death
o& the cells
(hemolytic anemia) – /$vascular occlusiono& vessels andsubseuent tissuein&arction
S,CQ#E CE## D,SEASE
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•This results +henboth copies o& thehemolobin betaene have an S
mutation4
•All o& this personsbeta subunits are
replaced by betaS4
7emolobin
AlphaAlpha
.etaS
.etaS
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ym"tomsOr"&ns t+&t (&n e &ffe(ted =
si(!e
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• Br&in $ (ou!d (&use & stroe
• s#!een &nd idne= $ ren&! &nds#!eni( d=sfun(tion
• Mus(!e %one &nd oint
• Lun"s $ &(ute (+est s=ndro)e
Complications o& Sic%le CellDisease
•
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•pain episodes• stro%es
• increasedin&ections
•le ulcers• bone damae(osteo$necrosis)
• yello+ eyes or 3aundice
• early allstones• lun bloc%ae
• %idney damaeand loss o& body+ater in urine
• blood bloc%ae inthe spleen or liver(seuestration)
• eye damae
• anemia• delayed ro+th
Treatment o& Sic%le CellDisease• -eneral uidelines
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-eneral uidelines – Ta%in the vitamin &olic acid (&olate) daily
to help ma%e ne+ red cells – Daily penicillin until ae si0 to prevent
serious in&ection
– Drin%in plenty o& +ater daily (;$lasses &or adults) – Avoidin too hot or too cold temperatures – Avoidin over e0ertion and stress
– -ettin plenty o& rest – -ettin reular chec%$ups &rom%no+ledeable health care providers
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,-oglobin C dia
Hemogloin
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7emolobin C (7b C) is a betalobin chain mutation! it is causedy the amino acid substitution o&lysine instead o& lutamine at the.eta$ position, ma%in the 7b C a less soluble protein than 7b A+hich is the most abundant
hemolobin protein in adults(around 9* o& total hemolobinin adults4)
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7emolobin C disease
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Some characteristics o homo9ygoushemolobin C disease (7b CC) include0
• Cell dehydration• Taret cells• Mild hemolysis +ith no sini>cant
anemia (mild anemia*
Ghile hetero9ygous Hemogloin
patients are phenotypically normal andthe aove symptoms doesn1t apply
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,-oglobin =C dia
7emolobin SC disease
"his disease is caused y having doule
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"his disease is caused y having doulehetero9ygotes &or .eta S and .eta C in patients4
,n 7b SC disease! 7b C increases Q$Clcotransport activity! this causes the hihintraerythrocytic concentration o& 7b S toma%e polymers! ivin the red cell its sic%ledshape
,n 7b SC disease! the cell contains * o& 7bS and * o& 7b C! no normal hemolobin ispresent (7b A)
Some 7b SC symptoms
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Some o& the 7b SC disease symptomsinclude:• "etinopathy• ,schemic necrosis o& bone• Mild pain&ul crisis• =ossible asplenia (about P* o&
patients older than /) leadin to
sepsis (lo+erin .4=! dys&unction in%idneys! liver! luns and C@S)
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Met+e)o"!oin
Methemolobin (M)
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• ;ormal hemogloin contains &errousnon E",C ions on the center o&the heme roups
• Methemolobin is &ormed +hen&errous o0idiNed to &erric
• Our blood contains normallyabout * 7b Methemolobin
Causes
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• Drus ( nitrates)
• Endoenous products (reactive ointermediates)
• ,nherited de&ects (mutations)
• De>ciency o& @AD7$ 7b M reductase
E6ects and Symptoms
• unctional Anemia
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Chocolate cyanosis Chocolate$cholored blood
• Tissue hypo0ia ^ an0iety!headache ! dyspnoea ! +ea%ness !lihtheadache 4
• "are cases ^ coma ! death4
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• Syndromes arising form
Decreased rate or absenceof globin chain synthesis.
How to name thalassemia?
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• Named after globin chain that is abnormallysynthesized !!!!
• Reduced or absentα
-globin chain α
-thalassemia
• Reduced or absentβ
-globin chain β
-thalassemia• Reduced or absent
γ
-globin chain γ
-thalassemia• Reduced or absent
δ
-globin chain δ
-thalassemia• Reduced or absent γδβ-globin chains
γδβ
-thalassemia
Thalassemia
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7b$A Molecule4 7b$A is thema3or adult hemolobin4
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mmon ty"es of thalassemia
•α-thalassemia
Reduced or absentα
-globin chain
•β-thalassemia
• Reduced or absent β-globin chain :
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• Absence o& ] chains willresult in increase= e2cess o γ gloinchains during etal lie and e2cess T
gloin chains later in postnatal lie.• Severity o disease depends on
numer o genes afected.
• αα<αα (@ormal)
C!&ssifi(&tion Ter)ino!o"=
A!#+& T+&!&sse)i&
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• Nor)&! αα;αα
• Si!ent (&rrier 2 α;αα
•
Minor 2α
;2α
22;αα
• H H dise&se 22;2α
•B&rts +=dro#s fet&!is22;22
• *2, $ Indi(&tes & "ene de!etion$
H=dro#s et&!is
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T+e !ood fi!) of neon&te it+ +e)o"!oin B&rtFs +=dro#sfet&!is s+oin" &niso(=tosis% #oii!o(=tosis &nd nu)erous
nu(!e&ted red !ood (e!!s *NRBC,.
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β T7A#ASSEM,AS
h l
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β halassemia
2Asen(e or redu(ed of $ (+&ins 2 "ene )ut&tions in t+eβ
"ene in
(+ro)oso)e
i!! resu!t in in(re&se; e8(ess ofγ
"!oin (+&ins durin" fet&! !ife&nd e8(ess V "!oin (+&ins !&ter in #ostn&t&! !ife.
Severit= of dise&se de#ends on nu)er of "enes &ffe(ted.
C!&ssi(&! C!ini(&! S=ndro)es ofβ
T+&!&sse)i&β
t+&!&sse)i& (&n e #resented &s$
o Si! i i!d f f + !
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o Si!ent (&rrier st&te )i!dest for) ofβ
t+&!.oβ
t+&!&sse)i& )inor 2 +etero="ous disorder
resu!tin" in )i!d +=#o(+ro)i(% )i(ro(=ti( +e)o!=ti(
&ne)i&.oβ t+&!&sse)i& inter)edi& 2 Severit= !ies eteen t+e
)inor &nd )&or.
oβ t+&!&sse)i& )&or 2 +o)o="ous disorder
resu!tin" in severe !ife !on" tr&nsfusion2de#endent+e)o!=ti( &ne)i&.
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$ thalassemia minor
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_ Thalassemia Ma3or
• CharacteriNed by very severe
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microcytic! hypochromic anemia4• Detected early in childhood:• 7b level lies bet+een / and ; <d#4
• Severe anemia causes mar%ed bonechanes due to e0pansion o& marro+space &or increased erythropoiesis(Epo is increased)4
• See characteristic chanes in s%ull!lon bones! and hand bones4
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T halassemia !a"or
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$ thalassemia ma&or%ale '( years
C!i(i(&! &v&!u&tionHe#&tos#!eno)e"&!=
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.eta thalassemia ma3or• / de&ected .eta enes no betachains synthesis alpha chains
i i d h &
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precipitate premature death o&".Cs4
•Complications•Enlarement
D&r sin due to iron over!o&d
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T%*!T/*'T )7 T2!L!*/I!
1 CON?ENTIONAL TREATMENT
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1 CON?ENTIONAL TREATMENT2 BLOOD TRANSUSION
2 IRON CHELATION
4. HEMOGLOBIN STIMULATION
3. TREATMENT O COMPLICATION2 INECTIONS
2 HEART AILURE ETC.
J. CURE
2 BONE MARRO AND STEM CELLS TRANSPLANTATION
2 W GENE THERAP
i
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Anemiaby membrane
de&ects
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BC @-bran
,ntroduction
•&eects due to
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&eects due to• abnormalities in membraneproteins
• or lipids• &eects alter membranesstability! shape! de&ormabilityand permeability
• 7emolysis occurse0travascularl
Conditions Associated +ithMembrane De&ects
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◦ Membrane proteins disorders
◦ $7ereditary spherocytosis◦
$7ereditary elliptocytocytosis◦ $7ereditary pyropoi%ilocytosis◦ Overhydrated and dehydrated hereditary
stomatocytosis
◦ Membrane lipid disorders
◦ $=aro0ysymal noctural hemolobinuria
.
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7ereditaryspherocytosis
H&e)o!=ti(Ane)i&
,<<$(TAM =P,<&CMT&=(=
Paogni
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Paogni
A rdiar auoo-al do-inan
diordr in ic corpucular --bran i
abnor-all l dor-abl and -or
pr-abl o odiu- Ti i du o an
abnor-ali o proin a pcrin in
corpucular --bran ic cau ar
i-bibiion and rupur or rd blood cll
H&e)o!=ti(Ane)i&
CL((CAL P(CT#<
1" =-po- uuall appar during ir dcad
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1" =-po- uuall appar during ir dcado
li bu -a b dlad
2" Co--on aur o a-olic ana-ia
3" =lig or -odra nlarg-n o pln
4" Pig-n biliar on in long anding ca
5" Cronic lg ulcr
H&e)o!=ti(Ane)i& 1% CBC
* =procoi rd cll ar prical inad o
bing N
biconca'
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biconca'* iculocoi
* Ana-ia o -odra dgr
2% Os)oti( fr&"i!it=
i caracriicall incrad a-oli uuall
bgin a podiu- clorid concnraion o 06 O or
'n igr
3% Dire(t (oo)Fs i ngai' ;cluding an
auoi--un cau o procoi and a-oli
H&e)o!=ti(Ane)i&
TREATMENT $
T principal or- o ra-n i
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T principal or- o ra-n i
plnco- aloug i ould no b
pror-d unl clinicall indicad bcau o
ana-ia
=plnco- lngn li pan ordcll corrc ana-ia pr'n
a-ocro-aoi bu do no ac
caracr o rd cll
.
7ereditary spherocytosis )HS*
De&ect in an%yrin R spectrin
"esults in the &ormation o& &raile spherocytic red cells
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"esults in the &ormation o& &raile spherocytic red cells4Spherocyte becomes less 2e0ible and more permeable to @aK
Clinical indins
• Baries in severity
d h l i
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• Compensated hemolyticdisease
•@o anemia• ,ntermittent 3aundice
• Splenomealy
• Cholelithiasis: piment bilestones &rom increasedbilirubin brea%do+n
#ab eatures –Mild anemia
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".C morpholoy – Spherocyte
– Baryin derees o&polychromasia!anisocytosis andpoi%ilocytosis
a 3eatures
• .one Marro+
– @ormoblastic erythroid hyperplasia
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@ormoblastic erythroid hyperplasia – ,ncreased iron storae
• Chemistry – ,ncreased
• .ilirubin• ecal urobilinoen• #D
– Decreased• 7aptolobin
• ,mmunohematoloy – DAT neative
Dianostic tests &or 7ereditary spherocytosis
• Osmotic &raility $
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Osmotic &raility $ – Cells are incubated in decreasin
concentrations o& @aCl4 Spherocyteslyse sooner than normal red cells4
• Autohemolysis test – "ed cells are incubated at 8 C &or P;
hours4 Deree o& hemolysis isincreased +hen spherocytes arepresent4
• "ed cell membrane studies – Membrane proteins are analyNed
usin el electrophoresis4
Treatment o& 7ereditaryspherocytosis 7S
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• Splenectomy
–Corrects &or theanemia! but the
membrane de&ectremains
.
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• 7ereditaryelliptocytosis
.
7ereditaryelliptocytosis
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–A de&ect o& one o& the s%eletal
proteins –"esults in the &ormation o&
&raile elliptocytic red cells thatare sensitive to mechanicalstress4
–More permeable to @aK
–Tends to a6ect blac%s! especiallyin A&rica
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E!!i#to(=tosis
#ab eatures
• !ild anemia
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– !ild anemia
– Hg level increased
–
• R morphology – Elliptocytes or ovalocytes
Treatment o&7elliptocytosis
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–Treatment is usually
not necessary! but i&patients havehemolysis!
splenectomy isbene>cial.
.
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"ed cellenNymopathies
4 -lucose$$=hosphateDehydroenase ( -=D )
De>ciency
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De>ciency
–=ivotal enNyme in 7M= Shunt R
produces @AD=7 to protect ".Caainst o0idative stress
–Most common enNymopathy
$* +orlds population –=rotection aainst Malaria –$lin%ed
• Clinical eatures:– Acute dru induced hemolysis:
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Acute dru induced hemolysis:• Aspirin! primauine! uinine!
chlorouine! dapsone4
– Chronic compensated hemolysis – ,n&ection<acute illness – @eonatal 3aundice – avism
• Treatment:
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–Stop the precipitatin dru ortreat the in&ection
–Acute trans&usions i& reuired
/4 =yruvate Qinase De>ciency –AR
–&e/cient A"% production Chronic
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&e/cient A"% production, Chronichemolytic anemia
– InvP
• %. Smear0 %ric#le cells• &ecreased en9yme activity
– "reatment0
• "ransusion may e re(uired
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=olycythemia Bera
!olcthemia Vera(lots o& red cells $ &or real)
• An uncommon disorder $distinuish &rom other causes o&
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distinuish &rom other causes o&erythrocytosis
• &iagnosis depends on #nowledge o
erythropoeisis
• "omplications most commonlfrom thrombosis and vascular
incidents• ong natural history with treatment
=athophysioloy o&=olycythemia
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Secondary =olycythemia
• Appropriate E=O (tissue<%idneyhypo0ia)
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hypo0ia) – pulmonary disease – hih altitude
– conenital heart disease – abnormal hemolobin
• hih anity
• carbo0yhemolobin
Secondary =olycythemia
• ,nappropriate E=O (ectopicproduction)
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production) – Tumors (hepatoma! renal
carcinoma! leiomyoma! hamartoma)
– "enal disorders (transplantation!cysts)
– hemaniomas
– Androen abuse – E=O abuse – amilial polycythemia
!olcthemia Vera
• Clinical &eatures
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– Attributed to increased bloodviscosity and poor o0yen
delivery to orans (brain) – =oor O/ delivery leads to
ischemia and thrombosis
– E0panded blood volume andviscosity leads to increasedcardiac +or% load
=4 Bera $ Symptoms RSins• Symptoms
– 7eadache
• Sins
– Splenomealy8*
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– 1ea%ness – =ruritis
(auaenic) – DiNNiness – Diaphoresis – Bisual
disturbance – 1eiht loss
p y8*
– S%in plethora8*
– 7epatomealyP* – Con3unctival
plethora 9*
– Systolic7ypertension8/*
=4 Bera $ Dianosis(=BS- criteria)
• Criteria – ".C mass
• Sini>cance – True vs4 spurious
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elevated
– SaO/ ' 9/*
– Splenomealy(or)
• thrombocytosis• #eu%ocytosis• hih #A=
• hih ./
p – "<O most /°
causes – Evidence &or M=D
• alse =ositive
4* – smo%ers! drin%ers
%. vera - one !arrowiopsy
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Treatment Options $Summary
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A g e > 7 0
H y d r o x y u r e a
3 2 P ?
A g e 5 0 - 7 0
H y d r o x y u r e a
P h l e b o t o m y
A g e < 5 0
P h l e b o t o m y
H y d r o x y u r e a
P . e r a
P h l e b o t o m ! " e t o H # $ < % 5
7 h i
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7emochromatosi
s .
Hemochromatosis
• ,ron overloaddi
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,ron overloaddisease
• Over absorption andstorae o& ironcausin damaeespecially to liver!heart and pancreas
19/04/2011 296
•linical0
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•linical0• &isease penetrance very variale
&rom early symptoms and severedisease to no symptoms Fenetic dianosis very common F
but the disease syndrome muchless so
O& !ce reuX .ine ca s$a terminatX
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v u
Maiorescu C U R S M E
H e)
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ME D I C I N A I N
T E R N A
He ) & t o ! o " i e I I
P r o f u n i v d r I o n C . i n t o i u
Ț
ersitatea Titu MaiorescuS MED,C,@A ,@TE"@A
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v u
Maiorescu C U R
S M E D IC
H ePr
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DI C I N A I N T E R N A
He ) & t o ! o " i e
P r o f u n i v d r I o n C . i n t o i u
Ț
ersitatea "itu !aiorescu
S MED,C,@A ,@TE"@A
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Disorders o& #eucocyte
=ro& univ dr ,on C4Tintoiu
O& !o&!o&!o&444444XXXX
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)eu2emia is a disease resulting fromthe neo"lastic "roliferation of
-hemo"oeitic
or
-lym"hoid cells
A
/4lymphoid stem cells
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t results from the mutation in asingle stem cell
The "rogeny of which form a clone ofleu2emic cells
)*+,*%
cute leu2emia
hronic leu2emia
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•cute %yeloid )eu2emia• cute )ym"hoid )eu2emia
• hronic %yeloid )eu2emia• hronic )ym"hoid )eu2emia
Acute leu%emia
• Acute leu%emia is characteriNed by an
abnormal proli&eration o& immature +hiteblood cells! called blasts or proenitor cells
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T+o main &orms o& acute leu%emia
–Acute lymphoblastic leu%emia• A cancer at the earliest staes o& lymphocytematuration
• Occurs more o&ten in the youn
–Acute nonlymphoblastic leu%emia• Usually a malinancy o& the myeloblast• More common in adults
Classi>cation o&leu%emias
A(ute Cronic
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M=e!oid
ori"in
L=)#+oid
ori"in
A(ute M=e!oid
Leue)i& *AML,
A(ute L=)#+o!&sti(
Leue)i& *ALL,
C+roni( M=e!oid Leue)i&
*CML,
C+roni( L=)#+o(=ti( Leue)i&
*CLL,
L-poid
prognior
B2!=
)#+o(=tes
T2!=)#+o(=tes
P!&s)&
(e!!s
germinal centernaïveALL
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He)&to#oieti(
ste) (e!!
Neutro#+i!s
Eosino#+i!s
B&so#+i!s
Mono(=tes
P!&te!ets
Red (e!!s
M=e!oid
#ro"enitor
A@L
L-poid
prognior
B2!=
)#+o(=tes
T2!=)#+o(=tes
P!&s)&
(e!!s
germinal centernaïveCLL
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He)&to#oieti(
ste) (e!!
Neutro#+i!s
Eosino#+i!s
B&so#+i!s
Mono(=tes
P!&te!ets
Red (e!!s
M=e!oid
#ro"enitor
C@L
7o+ to distinuish AM# vs CM#&rom loo%in at peripheral blood
Myeloid cell CM# AM#normal
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normal
lasts ( (
promyelocytes (myelocytes (
metamyelocytes (
ands (neutrophils ( U (
)eu2emia
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Nor)&!"r&nu!o(=tes
ALL
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+T* )*+,*%
+T* )*+,*%
A/5A55
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+T* )*+,*%
)N) 3*T+R*S/NS*T
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/NS*T
bru"t4 acute
nsidious4 slowly "rogressi5e 6one marrow malfunction
nemia4 infection 7 bleeding
Acute #eu%emia
• accumulation o& blasts in themarro+
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Causes o& acuteleu%emias• idiopathic (most)• underlying hematologic disorders
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• chemicals, drugs
• ioni9ing radiation
• viruses )H"E I*
• hereditary=genetic conditions
Clincal mani&estations
• symptoms due to: – marro+ &ailure
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– tissue in>ltration – leu%ostasis
– constitutional symptoms – other (D,C)
• usually short duration o&
symptoms
Marro+ &ailure
• neutropenia:in&ections! sepsis
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pin&ections! sepsis• anemia: &atiue!pallor
• thrombocytopenia:
bleedin
,n>ltration o&tissues<orans• enlarement o& liver! spleen!
lymph nodes
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• um hypertrophy• bone pain• other orans: C@S! s%in! testis!
any oran
<um hypertrophy
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A
B
C <E@ 1998
#eu%ostasis
• accumulation o& blasts in
microcirculation +ith impairedper&usion
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per&usion• luns: hypo0emia! pulmonary
in>ltrates• C@S: stro%e• only seen +ith 1.C '' 0
9<#
#aboratory &eatures
• 1.C usually elevated! but can
be normal or lo+bl i i h l bl d
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• blasts in peripheral blood• normocytic anemia• thrombocytopenia• neutropenia•
D,C
.one marro+ in acuteleu%emia• necessary &or dianosis• use&ul &or determinin type
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• use&ul &or pronosis• Acute leu%emias are de>ned by
the presence o& ' /* blasts inbone marro+ (* o& nucleatedmarro+ cells)
Treatment o& acuteleu%emiasChoice o& "0 is in2uenced by:• type (AM# vs A##)
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• ae• curative vs palliative intent
=rinciples o& treatment
• combination chemotherapy – >rst oal is complete remission
& th " t t l
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– &urther "0 to prevent relapse
• supportive medical care – trans&usions! antibiotics! nutrition
• psychosocial support – patient and &amily
Chemotherapy &or acuteleu%emias• =hases o& A## treatment
– induction– intensi>cation
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– intensi>cation – C@S prophyla0is
– maintenance• =hases o& AM# treatment – induction – consolidation (post$remission
therapy)
#ost2re)ission t+er&#=
7ematopoietic stem celltransplantation
• permits HrescueI &rom other+ise
e0cessively to0ic treatmentdditi l d t & &t
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• additional advantae o& ra&t$vs$leu%emia e6ect in alloeneic
transplants• trade$o6 &or alloeneic
transplantation: reater anti$
leu%emic e6ect but more to0ic
#cute meloblastic
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#cute meloblasticleu$emias,
=athophysioloy
•,n all AM#s,• the accumulation o& proli&eratin neoplasticmyeloid precursor cells in the marro+
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myeloid precursor cells in the marro+suppresses remainin normal hematopoietic
progenitor cells y physical replacement as well asy other un#nown mechanisms.
• The &ailure o& normal hematopoiesis results inanemia! neutropenia! and thrombocytopenia!
+hich cause most o& the ma3or clinicalcomplications o A!.
ChromosomalAbnormalities
• =articular chromosomalabnormalities correlate +ith
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abnormalities correlate +iththe clinical settin in +hich
the tumor occurs4• AM# arisin de novo in
patients +ith no ris% &actors
are o&ten associated +ithbalanced chromosomaltranslocations! particularly
ren(+2A)eri(&n2Britis+ *AB, C!&ssifi(&tion of AML
+AB
subtype (ame
Appro6imate 7 of
adult patients Prognosis/4 ndifferentiated acute
myeloblastic leu8emia5& 9orse
/ Acute myeloblasticleu8emia ;ith minimal
maturation
<7 A'erage
/3 Acute myeloblasticleu8emia ;ith maturation
25& (etter
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leu8emia ;ith maturation
)3 Acute promyelocyticleu8emia
*0& (e+t
/= Acute myelomonocyticleu8emia
20& A"erage
/= eos Acute myelomonocyticleu8emia ;itheosinophilia
5& Better
/< /onocytic leu8emia 47 A"erage
/> Acute erythroid leu8emia 5& ,or+e
/? Acute mega8aryoblastic <7 9orse
Morpholoy
• The dianosis o& AM# is based on>ndin that myeloid blasts ma%e
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>ndin that myeloid blasts ma%eup more than /* o& the cells in
the marro+
Diffuse re#!&(e)ent of nor)&! +&e)&to#oiesis in one
)&rro = !eue)i( (e!!s
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Morpholoy
• Monoblasts oten have olded orloulated nuclei, lac# Auer rods,
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and are pero2idase negative andnonspeci/c esterase positive.
• In some A!s, blasts e0hibitmea%aryocytic di6erentiation! which is oten accompanied y
marrow /rosis caused y therelease o /rogenic cyto#ines.
• Rarely, the lasts o A! showevidence o er throid diferentiation
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Auer rods in AM# (pathomonomic &or myeloid lineae oriin)!A case o& AM#$M
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Auer rods in an M<M/ AM#
Clinical eatures
• Most patients present within weeks
or a ew months o the onset osymptoms related to anemia%
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symptoms related to anemia%neutropenia, and
thromoboctopenia! most notaly&atiue! &ever, and spontaneousmucosal and cutaneous bleedin4
•
Clinical eatures• +ten, the bleedin diathesis
caused by thrombocytopenia is the
most stri#ing clinical eature.utaneous petechiae and ecchymoses,
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p yserosal hemorrhaes into the
linins o& the body cavities andviscera! and mucosal hemorrhaes into the gingivae and urinary tract arecommon. %rocoagulants and /rinolyticactors released y leu#emic cells,especially in acute promyelocyticleu#emia !> , e0acerbate the
Cut&neous #ete(+i&e &nd e((+=)oses
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Clinical eatures
• ,n&ections are &reuent,particularly in the oral cavity s#in
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particularly in the oral cavity, s#in,lungs, #idneys, urinary ladder, and
colon, and are oten caused yopportunists such as ungi,Pseudomonas, and commensals.
Clinical eatures
• Signs and symptoms related toin/ltration o tissues are usually less
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ystri#ing in A!.
• Mild lymphadenopathy andoranomealy can occur. In tumorswith monocytic diferentiation )!C and
!4*, in>ltration o& the s%in)leu#emia cutis* and the gingiva can eoserved, li#ely re$ecting the normal
-
Clinical eatures
• entral nervous system spread is lesscommon than in A ut still seen.
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• ?uite uncommonly, patients present withlocali9ed masses composed o myelolasts in
the asence o marrow or peripheral loodinvolvement. "hese tumors, #nown variouslyas myelolastomas, granulocytic sarcomas,or chloromas, inevitaly progress to systemicA! over a period o up to several years.
=ronosis
• A! is a diDcult disease to treat.
• Appro2imately 578 o the patientsachieve complete remission with
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achieve complete remission withchemotherapy, ut only 648 to >78
remain ree rom disease or 4 years.• A!s associated with t)@P:6* or
inv)65* have a relatively good
prognosis with conventionalchemotherapy.
=ronosis
• In contrast, the prognosis is dismal
or patients with AM# +ith priormyelodysplastic syndrome or
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myelodysplastic syndrome orollowing genoto2ic therapy, possily
ecause o damage to normalhematopoietic stem cells. "heseVhigh-ris#V orms o A!, as well as
relapsed A! o all types, areincreasingly eing treated withallogeneic one marrow
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Acute lymphoblastic leu%emia (A##)
Acute lymphoblasticleu%emia• is a malinant (clonal)disease o& the bone
i hi h l
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marro+ in +hich early
lymphoid precursorsproli&erate and replace the normal hematopoietic
cells o& the marro+4
=athophysioloy
• The malinant cells o& A## are
lymphoid precursor cells (ie!lymphoblasts) that are arrested in anearly stae o& development This
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early stae o& development4 Thisarrest is caused by an abnormal
e0pression o& enes! o&ten as a resulto& chromosomal translocations4 Thelymphoblasts replace the normalmarro+ elements! resultin in a
mar%ed decrease in the production o&normal blood cells4 The lymphoblastsalso proli&erate in orans other thanthe marro+! particularly the liver!
Acute lymphatic leu%aemia Cont4
Signs and symptoms
Anaemia! bleedin!lymphadenopathy! in&ection
Clinicalmani&estation
Clinicalmani&estation
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mani&estation mani&estation
3ever%allorleedingAnore2ia3atigue
Gea#nessone, joint andadominal painIncrease intracranial
<enerali9edlymphadenopathyInection o respiratorytractAnaemia and leeding
o mucus memranecchymosesGeight lossHepatomegaly
+T* )8%9H/6)ST )*+,*%
)N) 3*T+R*S 6one "ain 7 tenderness ) h d th
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)ym"hadeno"athy
S"lenomegaly He"atomegally NS manifestations
Testicular in5ol5ement S2in
)*+,*%
)6/RT/R8 *0)+T/N
• nemia
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• nemia• )eu2ocytosis:leu2o"enia:normal T)• Thrombocyto"enia• 6one marrow e;amination
s"irate 7 bio"sy
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A##$#
Small and homogenous lasts. "hese may closely resemlelymphocytes ut are distinguished y their /ner chromatinstructure and the occasional presence o nucleoli
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A##$#/ympholasts o varying si9e )small and large*
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arge last cells with mar#ed cytoplasmic udding
)leing*. "he diferential diagnosis will e0 A!-!O and A.
3arther cytochemical and immunophenotyping studiesshowed to e case o -lineage A.
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!ature -A with prominent cytoplasmic vacuoles
Etioloy
• Epstein$.arr virus
• 7iher socioeconimic subroups• Trisomy / (Do+ns syndrome)
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y ( y )• 7ih$enery radiation
• ,ndustrial e0posure• E0posure to aricultural
chemicals
• Smo%in• =ree0istin myeloproli&erative
disorder
Clinical eatures• .one pain• 7epatosplenomealy! lymphadenopathy4• "ashes
• #e&t upper uadrant &ullness and earlysatiety due to splenomealy4
• Symptoms related to a lare mediastinal
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Symptoms related to a lare mediastinalmass! such as shortness o& breath4
• Symptoms o& leu%ostasis (e! respiratory
distress! altered mental status)• Anemic syndrome• ,ncrease ris% o& in&ection• ever•
Disseminated intravascular coaulation(hemorrhaic or thrombotic complications)
#ab Studies • A C.C count: anemia!thrombocytopenia! a
hih! normal! or lo+ 1.C count!neutropenia! blasts
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#ab Studies • .one marro+ aspiration and biopsy
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Treatment stratey inA##
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A##
Medical Care • A$,nduction therapy:P$dru reimen o& vincristine! prednisone!
anthracycline! and cyclophosphamide or #$
asparainase or a$dru reimen o& vincristine! prednisone!
anthracycline! cyclophosphamide! and #$i i th & P
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asparainase iven over the course o& P$+ee%s4
• .$Consolidation therapy:a standard P$ to $dru induction usuallyinclude consolidation therapy +ith Ara$C incombination +ith an anthracycline orepipodophylloto0in4
• C$Maintenance• C@S prophyla0is
Supportive Care
• "eplacement o& blood products: pac%ed
red blood cells! platelets! &resh &roNenplasma• Antibiotics: a third$eneration
cephalosporin (or euivalent) +ith an
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cephalosporin (or euivalent) +ith anaminolycoside4 =atients +ith persistent&ever a&ter $ days o& antibacterialantibiotics have amphotericin added totheir reimen4
• The use o& prophylactic antibiotics inneutropenic patients +ho are not &ebrile iscontroversial4 A commonly used reimen
includes cipro2o0acin ( m orally t+icedaily! 2uconaNole (Di2ucan) (/ m orallydaily)! and acyclovir (/ m orally times<d)4
=ost$remission therapy instandard$ris% A##
6. Chemotherapy
a<4 Maintenance therapy: $mercaptopurine!
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p p
methotre0ate $ &or /$ years4
b<4 ,ntensi>cation treatmentperiodically
repeated: daunorubicin<adriablastin!
prednisone! vincristine!cyclophosphamide4
/4 C@S prophyla0is
=ost$remission therapy inhih$ris% A##4 ,ntensi>cation treatment:
amsacrine! mito0antrone!idarubicine! hih dose cytosine
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arabinoside! hih dose
methotre0ate! hih dosecyclophosphamide4
/4 7ematopoietic stem cell
transplantation$ hih$dose therapy
$ reduced intencity conditionin
)*+,*%
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Chronic Myeloid #eu%emia (CM#)
Chronic Myeloid #eu%emia
Clinical =resentation
Asymptomatic (f *)
atiue! +eiht loss! &ever
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Abdominal &ullness! pain and<or early
satiety due to splenomealy (f $9*)
Easy bruisin and purpura
#eu%ostasis
=ulmonary symptoms @euroloic symptoms
CM# F =eripheral .lood and .Mindins
Peri#+er&! s)e&r (&n on!= "ive & #resu)#tive
di&"nosis of CML X=ou need to (onfir) t+e t*44,Y$
1, !euo(=tosis it+ & !eft s+iftF
4, nor)o(=ti( &ne)i&
3, t+ro)o(=tosis in 9< of #ts
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, = #
J, &so!ute eosino#+i!i& it+ & nor)&! of Eos.
9, &so!ute &nd re!&tive in(re&se in &so#+i!s
K, LAP s(ore is !o *not freuent!= e)#!o=ed,
=ourc #ndr-ind
7o+ to distinuish AM# vs CM#&rom loo%in at peripheral blood
Myeloid cell CM# AM#normal
lasts ( (
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lasts ( (
promyelocytes (myelocytes (
metamyelocytes (
ands (neutrophils ( U (
Th ti O ti i
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Therapeutic Options in
Chronic Myeloid #eu%emia
,matinib (-leevec! @ovartis)a small molecule tyrosine %inaseinhibitor
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LeukemiaLeukemia
)
=ourc #ndr-ind
Treatment Options &or "esistantDisease
6* Dose Escalation o& imatinib
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/) Second -eneration TQ,s
) .one Marro+ Transplant
P) Clinical Trial =articipation
one !arrow "ransplant
• &onor is placed under anesthesia.
• !arrow is aspirated out o the iliaccrest.
! i /lt d d t t d t
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• !arrow is /ltered and treated to
remove its o one and otherunwanted cells and deris,transerred to a lood ag, and isinused into the patient1s lood just
li#e at transusion.
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Chronic lymphocytic leu%emi
Chronic lymphocyticleu%emia ()
• Is characterised y the accumulationo& nonproli&eratin mature$appearin lymphocytes in the
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appearin lymphocytes in theblood! marro+! lymph nodes! andspleen
• ,n most cases! the cells aremonoclonal . lymphocytes that areCDK
tiology )6*
• The cause o& C## is un%no+n
• There is increased incidence in
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&armers! rubber manu&acturin
+or%ers! asbestos +or%ers! andtire repair +or%ers
• -enetic &actors have beenpostulated to play a role in hihincidence o& C## in some &amilies
linical /ndings ):*
• !ost symptomatic patients have enlared
lymph nodes (more commonly cervicaland supraclavicular) and splenomealy• "he lymph nodes are usually discrete reely
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"he lymph nodes are usually discrete, reelymovale, and nontender
• 7epatomealy may occure• ess common maniestation are in/ltration
o tonsils, mesenteric or retroperitoneal
lymphadenopathy! and s%in in>ltration• %atients rarely present with eatures o
anemia, and ruising or leeding
aoratory /ndings )6*
• The blood lymphocyte count above ! -<#
• ,n most patients the leu%emic cells havethe morpholoic appearance o& normalsmall lymphocytes
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small lymphocytes• ,n the blood smears are commonly seen
ruptured lymphocytes (Hbas%etI orHsmudeI cells)
• Care&ul e0amination o& the blood smearcan usually di6erentiate C##! and thedianosis can be con>rmed byimmunophenotypin
The dianostic criteria &orC##
6* A peripheral blood lymphocyte
count o& reater than -<#! +ithless than * o& the cells beinatypical
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atypical
:* "he cell should have the presenceo& .cell$speci>c di6erentiationantiens )&6L, &:7, and &:C*and e &4)W*
>* A bone marro+ aspiratessho+in reater than *
&iferential diagnosis
• ,n&ectious causes
– bacterial (tuberculosis) – viral (mononucleosis)
• Malinant causes
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• Malinant causes
– .$cell – T$cell• leu%emic phase o& non$7od%in
lymphomas
• 7airy$cell leu%emia• 1aldenstrom macrolobulinemia• lare ranular lymphocytic leu%emia
Stain ()"ai Classi>cation &or C##
– $ lymphocytosis (' -<#)
– , $ lymphocytosis K lymphadenopathy – ,, $ lymphocytosis K splenomealy K<$
lymphadenopathy
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lymphadenopathy
– ,,, $ lymphocytosis K anemia (7b G*)K<$lymphadenopathy or splenomealy – ,B $ lymphocytosis K thrombocytophenia
(=lt G-<#) K<$ anemia K<$
lymphadenopathy K<$ splenomealy
"reatment• "reatment is reserved or patients with low-
or intermediate ris# disease who are
symptomatic or have progressive disease)increasing organomegaly or lymphocytedouling time o less than 6: months* andpatients with high -ris# disease
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patients with high ris# disease – Al%ylatin aents (chlorambucil!
cyclophosphamide) – @ucleoside analos (cladribine! 2udarabine) – .ioloical response modi>ers – Monoclonal antibodies – .one marro+ transplantation – And systemic complications reuirin
therapy• antibiotics• immunolobulin
v u
Maiorescu C U
R S M E D I C I N A IN
H e ) & t o ! o " i e ?
P r o f u n iv
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A I N T E R N A
? ni v d r I o n C . i n t o i u
Ț
ersitatea "itu !aiorescu
S MED,C,@A ,@TE"@A
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H Hematologie E III# #ymphom
=ro& univ dr ,on C4Tintoiu
Approach to the %atient
• 7od%ins Disease
– approach dictated mainly y where thedisease is located rather )results ostaging* than the e2act histologic
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staging* than the e2act histologicsutype
• @7# – approach is dictated mainly y the
histologic sutype rather than the
results o staging
ymphoma
7od%ins Disease
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7od%in s Disease
.
ymphoma
• #ymphomas are a
malinant proli&eration o&lymphocytes F either . or T• >8 o all cancers in the BS result rom
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• >8 o all cancers in the BS result romlymphomas
• "he lymphomas are classi/ed y theappearance o malignant lymphocyteson iopsy o tumor
• cateories – #o+$rade – ,ntermediate$rade – 7ih$rade
3unctional %resentation oymphoma
• =eople present +iths+ollen! ro+inlymph lands (nodaldisease) or tumors
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in other orans
(e0tramodaldisease)• =erson can be
asymptomatic• Common .
symptoms include&ever! drenchinniht s+eats! loss o&* o& body +eiht!
#ymphoma#ymphadenopathy – .
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ymphadenopathy
• Enlared nodes
– tender V in&ectious – non$tender Vmalinant
• #ymphadenitis
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• #ymphadenitis
– lymph node isin&ected
• Reactive hyperplasia – acute
• dental in&ections! sore
throat! enitalin&ections
– chronic• T.
Staging o ymphoma• Stae , F involvement o& a sinle lymph node
reion or sinle e0tranodal oran or site
• Stae ,, F involvement limited to one side o&the diaphram +ith / or more lymph node
i
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reions
• Stae ,,, F involvement o& lymph node reionson both sides o& the diaphram
• Stae ,B F di6use or disseminated involvement
o& one or more e0tralymphatic orans
St&"e I St&"e II St&"e III St&"e I?
Ann Aror Staging System
Stain o& #ymphoma
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A$ &sen(e of B s=)#to)s
B$ fever% ni"+t se&ts% ei"+t !oss
ymphomas
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• ;eoplasms o lymphocytes orlympholasts that grow as nodular massesusually in lymph nodes
• Usually painless!non$tender enlaredlymph node in nec%
• 1eiht loss
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• @iht s+eats
• ever• atiue• ,n&ection• -ood survival but at
ris% &or othermalinancies
S#in ymphoma and Shoulderymphoma
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Hodg#in lymphoma
T , d >i
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To-a ,odg>in
!1798%1866"
C!&ssi(&! Hod"in L=)#+o)&
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7od%in lymphoma• cell o origin0 erminal centre .$
cell• "eed$Sternber cells )or RS
variants* in the afected tissues
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variants* in the afected tissues
• most cells in afected lymph node arepolyclonal reactive lymphoid cells,not neoplastic cells
Reed-Sternerg ell
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7od%in lymphoma7istoloic subtypes
• Classical 7od%in lymphoma –$nodular sclerosis (most
common subtype)
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common subtype)
–/$mi0ed cellularity –$lymphocyte$rich
–P$lymphocyte depleted
lassic Hodg#in ymphoma
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;odular SclerosingHodg#in ymphoma
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7od%in #ymphoma
• Treatment – approach depends upon stae!
pronostic &actors! and co$
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morbidities
– Stae ,$,,• consider "T! chemotherapy! or
combined therapy
– .ul%y stae ,$,,
• combined modality therapy – Stae ,,,$,B
• A.BD 0 $; cycles old standard
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Hodg#in1s &isease
• Results o "reatment
• stage 4 year overall survival –I L78
–II L78
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II L78
–III @78 –IE 548
Hodg#in1s0 uture directions
• imited stage and good prognosis
advanced stage – cure rate high
– current goal is to minimi9e late complications
trials loo#ing at !" with less chemotherapy
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– trials loo#ing at !" with less chemotherapy
and less radiation• Advanced stage
– cure rate around 47-O78
– trial comparing AE& to Stanord E
• linical "rials
;on-Hodg#in ymphoma
• .
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;H
#ymphoma
• @on$7od%ins #ymphoma(@7#)
– 7eteroeneous roup o& cancersa6ectin lymphocytes• Usually classi>ed by histoloicrade (lo+ to hih)
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rade (lo+ to hih)
–ollicular lymphoma –Small lymphocytic lymphoma –Di6use lare .$cell lymphoma –.ur%itts lymphoma –Many others
ymphoma iology• ,ndolent vs4 Aressive @7#
– %ey principle in understandin bioloy!and approach to the patient – ,ndolent V incurable– Aressive V curable
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Aressive V curable
– 17WJ• Chromosomal Abnormalities in @7#
– &reuent chromosomal translocations into, ene loci
• t(;ZP)! t(/Z;)! t(;Z//) .ur%itts• t(PZ;) &ollicular @7#
@7#: Classi>cation• Terminoloy (re&ers to natural
history) – lo+ rade V indolent – intermediate rade V aressive
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– hih rade V aressive
• %rinciple
– indolent: slo+ ro+in! incurable – aressive: rapidly ro+in!
curable
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;H0 Approach to the%atient• ,ndolent @7#: treatment options
– +atch&ul +aitin – radiation to involved >elds – sinle aent chemotherapy
• chlorambucil K prednisone! 2udarabine
bi ti h th
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– combination chemotherapy
• CB=! C! @D! C7O= – chemotherapy K inter&eron – chemotherapy K monoclonal antibodies – monoclonal antibodies – radiolabeled monoclonal antibodies
– stem cell transplantation
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Summary
•@7# incidence increasin! 7od%insdecreasin
• Hodg#in1s cure rate (uite highapproach is dictated mainly y disease stage
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– approach is dictated mainly y disease stage
• @7# cure rate mediocre – approach is dictated mainly by histoloic
subtype – indolent vs4 aressive
• indolent: +atch&ul +aitin per&ectly acceptable&or asymptomatic patients
• aressive: reuire aressive treatment ASA=to achieve cure
Multiple Myeloma
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!ultiple !yeloma
• Malinant cells appear as
nodular masses in bone marro+• Xpunched outY lesions in s#ull N
spine
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p
• 7ypoammalobinemia• Susceptible to in&ections• Elderly most commonly a6ected
!ultiple !yeloma
• Malinant neoplasm o& bone
marro+Tumor destroys bone Results in0
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–%ain – ractures
– 7ypercalcemia – S%eletal de&ormities
– Qidney problems#oyr!ght 2007/ 200/ 200*/ *11% by )o+by/ 4./ a a!l!ate o 6l+e'!er 4.
!ultiple !yeloma
• &iagnosed y0
– Z-ray – lood studies – iopsy
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• "reatment – hemotherapy – Radiation
– one marrow transplant
#oyr!ght 2007/ 200/ 200*/ *11% by )o+by/ 4./ a a!l!ate o 6l+e'!er 4.
!yeloma+steolytic lesions
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O& !ce reuX ,ncepe alt curs J
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v u
Maiorescu C U R
S M E D I C I N A I N T ER
H e ) & t o ! o " i e I ?
P r o f u n i v d r I
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TE R N A
r I o n C . i n t o i u
Ț
.#EED,@- D,SO"DE"SJ
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.#EED,@- D,SO"DE"S
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T+e nor)&! +&e)ost&sis #revents$
Z s#ont&neous +&e)orr+&"e &nd undue !ood !oss
fro) inured vesse!s
Z intr&v&s(u!&r t+ro)us
for)&tion.
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!eedin"
t+ro)osis
7EMOSTAS,S
@ A!C5AR P)A!$3@ P5A&$5$& P)A!$
C'A5A&%'( P)A!$
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@ C'A5A&%'( P)A!$
=@ +%BR%('5&%C P)A!$
Hemostasis
B: (nur
P!&te!et
Aggrgaion
B!ood ?esse!
Conricion
Co&"u!&tion
C&s(&de
Tiu
acor ural
Lab T
• CBC%Pl• BT!CT"• PT• PTT
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Aggrgaion
Plal
Aci'aion
Conricion C&s(&de
=abl ,-oaic Plug
ibrin
or-aion
ducd
Blood lo
Pri-ar -oaic plug
Pl =ud@orpologuncionAnibod
@O"MA# C#OTT,@-Res#onse to vess!e inur=
1 ?&so(onstri(tion o rduc blood lo
2 P!&te!et #!u" for)&tion !'on illbrand acor
bind da-agd 'l and plal"
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g p "
3 A(tiv&tion of (!ottin" cacad i gnraion
o ibrin clo or-aion
4 irin!=sis !clo bra>don"
S(reenin" tests of !ood (o&"u!&tion• Disorders of vesse!s$
– Ru)#e!2Leede test
• Disorders of #!&te!ets$ – P!&te!et (ount &nd )or#+o!o"=
– B!eedin" ti)e *Iv=,
• Co&"u!o#&t+ies$
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Co&"u!o#&t+ies$
– Co&"u!&tion ti)e – Ativ&ted #&rti&! t+ro)o#!&stin
ti)e *APTT,
– Prot+ro)in *INR2
,nternational @ormaliNed"atio)
– T+ro)in ti)e *TT,
BASCU#A" =7ASE
,H6 A (899: 6;;68 ;
:A)A6:/ A;9#9;$=#$9
=6;>8$;
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=6;>8$;.
=#ATE#ET =7ASE
P8A$686$; A:H6=6 $9 $H6
:A)A6: ;>=?A#6 A:
?9=) A $6)P9=A=@ P8>
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?9=) A $6)P9=A=@ P8>.
+A<BA"I+; %HAS
$H=9>H $,9 ;6PA=A$6
PA$H,A@; $H6 #96=;9 9?
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%latelet oagulation
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Pete4h!ae/ Purura Hematoma/ Io!t bl.
%urpura
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%etechiaeCty!4al o latelet d!+order+D
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Do not blanch withpressure
(cf. angiomas)Not palpable (cf. vasculitis)
Henoch-Schonlein purpura
•
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cchymoses
Cty!4al o
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Intr&)us(u!&r ine(tion )&= e ver= d&n"erous to
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ACTO" DE,C,E@C,ES (CO@-E@,TA#)
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H6)9PH8A (
'o ,886(=A:J; :;6A;6
3A"+R &3II;IS)$/'P)%5%A A FClassic )emophiliaD
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)$/'P)%5%A B FChristmasDiseaseG*0-*5& o all Hemoh!l!a4+Deficiency of +actor %H8ab $e+t - Prologed P$$
)emophiliaClinical manifestations (hemophilia A & Bare indistinguishable)
Hemarthrosis (most common)Fixed joints
Soft tissue hematomas (e.g., muscle)
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Muscle atrophyShortened tendons
Other sites of bleedingUrinary tractCNS, neck (may be life-threatening)
Prolonged bleeding after surgery or dentalextractions
Pete4h!ae ! at!etB!th =o4Ky )outa!
;otted ?e'er
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Hemarthro+!+ Ca4uteD
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Treatment of hemophilia A
• Intermediate purity plasma products – Virucidally treated – May contain von Willebrand factor
• High purity (monoclonal) plasma products – Virucidally treated
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– No functional von Willebrand factor
• Recombinant factor VIII – Virus free/No apparent risk – No functional von Willebrand factor
Dosing guidelines for hemophilia A• Mild bleeding
– Target: 30% dosing q8-12h; 1-2 days (15U/kg) – Hemarthrosis, oropharyngeal or dental, epistaxis, hematuria
• Major bleeding – Target: 80-100% q8-12h; 7-14 days (50U/kg) – CNS trauma, hemorrhage, lumbar puncture – Surgery
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– Retroperitoneal hemorrhage – GI bleeding
• Adjunctive therapy – ε-aminocaproic acid (Amicar) or DDAVP (for mild disease only)
Complications of therapy
• Formation of inhibitors (antibodies)
–10-15% of severe hemophilia A patients –1-2% of severe hemophilia B patients
• Viral infections
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–Hepatitis B Human parvovirus
–Hepatitis C Hepatitis A
–HIV Other
Treatment of hemophilia B
• Agent
–High purity factor IX –Recombinant human factor IX
• Dose
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–Initial dose: 100U/kg –Subsequent: 50U/kg every 24 hours
Hemophilia A and BHemophilia A HemophiliaB
Coagulation factor deficiency Factor VIII Factor IX
Inheritance X-linked X-linkedrecessive recessive
Incidence 1/10,000 males 1/50,000 males
S it Rltdtf t l l
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Severity Related to factor level<1% - Severe - spontaneous bleeding1-5% - Moderate - bleeding with mild injury5-25% - Mild - bleeding with surgery or trauma
Complications Soft tissue bleeding
"reatment• %roducts used to treat hemophilia
are0 – resh &roNen plasma andcryoprecipitate +hich are &romsinle blood donors and reuire
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special &reeNin. – Second generation o &actor B,,, are
made with animal or human proteins.
H!A"++< -;&
• .
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• .
v u
Maiorescu C U R S
M E D I C I N A I N T E R N
H e ) & t o ! o " i e I I
P r o f u n i v d r I o n iȚ
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A C . i n t o i u Ț
Clinical Features of Bleeding
Disorders
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Clinical Features of Bleeding Disorders Platelet #oagulat!o
d!+order+
a4tor d!+order+
;!te o bleed!g ;K! :ee ! +ott!++ue+
)u4ou+ membrae+ CLo!t+/
mu+4le+D
Ce!+tax!+/ gum/
ag!al tra4tD
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'ag!al/ tra4tDPete4h!ae @e+ o
644hymo+e+ CMbru!+e+ND ;mall/ +uer!4!al 8arge/ dee
Hemarthro+!+ E mu+4le bleed!g 6xtremely rare #ommo
(leed!g ater 4ut+ G +4rat4he+ @e+ o
(leed!g ater +urgery or trauma mmed!ate/ :elayed C*-2
day+D/
Coagulation factor disorders• Inherited bleedingdisorders – Hemophilia A and B
– vonWillebrandsdisease
– Other factordfii i
• Acquired bleedingdisorders – Liver disease
– Vitamin Kdfii / fi
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deficiencies deficiency/warfarinoverdose
– DIC
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Laboratory evaluation of
von Willebrand disease• Classification
– Type 1 Partial quantitative deficiency
– Type 2 Qualitative deficiency
– Type 3 Total quantitative deficiency
• Diagnostic tests:
vonWillebrandtype
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vonWillebrand typeAssay 1 2 3
vWF antigen ⇓ Normal ⇓⇓vWF activity ⇓ ⇓ ⇓⇓
Multimer analysis Normal Normal Absent
$reatmet o 'o ,!llebrad :!+ea+e
• Cryoprecipitate – Source of fibrinogen, factor VIII and VWF
– Only plasma fraction that consistently contains VWF multimers
• DDAVP (deamino-8-arginine vasopressin) – ↑ plasma VWF levels by stimulating secretion from endothelium – Duration of response is variable
Notgenerallyusedintype2disease
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– Not generally used in type 2 disease – Dosage 0.3 µg/kg q 12 hr IV
• Factor VIII concentrate (Intermediate purity) – Virally inactivated product
Vitamin K deficiency• Source of vitamin K Green vegetables
Synthesized by intestinal flora
• Required for synthesis Factors II, VII, IX ,XProtein C and S
• Causes of deficiency MalnutritionBiliaryobstruction
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Biliary obstructionMalabsorption Antibiotic therapy
• Treatment Vitamin KFresh frozen plasma
Common clinical conditions associated with
Disseminated Intravascular Coagulation
• Sepsis
• Trauma – Head injury
– Fat embolism
• Obstetricalcomplications – Amniotic fluid embolism – Abruptio placentae
• Vasculardisorders
Activation of both coagulation and fibrinolysis
Triggered by
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• Malignancy• Vascular disorders• Reaction to toxin (e.g.snake venom, drugs)
• Immunologic disorders – Severe allergic reaction – Transplant rejection
Disseminated Intravascular Coagulation (DIC)
Mechanism
Systemic activationof coagulation
Intravasculardeposition of fibrin
Depletion of plateletsand coagulation factors
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BleedingThrombosis of small
and midsize vesselswith organ failure
Pathogee+!+ o :#
Coagulation Fibrinolysis
Fibrinogen
Thrombin Plasmin
Release ofthromboplasticmaterial into
circulation
Consumption of
coagulation factors;presence of FDPs↑ aPTT↑ PT↑ TT
↓ Fibrinogen
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FibrinMonomers
FibrinClot
(intravascular)
Fibrin(ogen)DegradationProducts
Plasmin
Presence of plasmin↑ FDP
Intravascular clot↓ Platelets
Schistocytes
Disseminated Intravascular Coagulation
Treatment approaches
• Treatment of underlying disorder
• Anticoagulation with heparin
• Platelet transfusion
• Freshfrozenplasma
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• Fresh frozen plasma
• Coagulation inhibitor concentrate (ATIII)
Classification of platelet disorders
• Quantitativedisorders
– Abnormal distribution
– Dilution effect
– Decreased
production
• Qualitative disorders
– Inherited disorders(rare)
Acquireddisorders
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production
– Increaseddestruction
– Acquired disorders• Medications
• Chronic renal failure
• Cardiopulmonarybypass
Thrombocytopenia
Immune-mediated
IdioapthicDrug-inducedCollagen vascular diseaseLymphoproliferative disease
SarcoidosisN i ditd
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SarcoidosisNon-immune mediatedDICMicroangiopathic hemolytic anemia
8!'er :!+ea+e ad Hemo+ta+!+
1.Decreased synthesis ofII, VII, IX, X, XI, and fibrinogen
2.Dietary Vitamin K deficiency (Inadequate intake or
malabsortion)3.Dysfibrinogenemia
4.Enhanced fibrinolysis (Decreased alpha-2-antiplasmin)
5.DIC
6.Thrombocytoepnia due to hypersplenism
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)aagemet o Hemo+tat!4
:ee4t+ ! 8!'er :!+ea+eTreatment for prolonged PT/PTT
Vitamin K 10 mg SQ x 3 days - usually ineffective
Fresh-frozen plasma infusion 25-30% of plasma volume (1200-1500 ml) immediate but temporary effect
Treatment for low fibrinogen Cryoprecipitate (1 unit/10kg body weight)
Treatment for DIC (Elevated D-dimer, low factor VIII, thrombocytopenia Replacement therapy
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Vitamin K deficiency due to warfarin overdose
Managing high INR values
Clinical situation Guidelines
INR therapeutic-5 Lower or omit next dose;Resume therapy when INR is therapeutic
INR 5-9; no bleeding Lower or omit next dose;Resume therapy when INR is therapeutic
OmitdoseandgivevitaminK(125mgpo)
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Omit dose and give vitamin K (1-2.5 mg po)
Rapid reversal: vitamin K 2-4 mg po (repeat)
INR >9; no bleedingOmit dose; vitamin K 3-5 mg po; repeat as necessar
Resume therapy at lower dose when INR therapeutic
Chest 2001:119;22-38s (supplement)
Vitamin K deficiency due to warfarin overdoseManaging high INR values in bleeding patients
Clinical situation Guidelines
INR > 20; serious bleeding Omit warfarinVitamin K 10 mg slow IV infusionFFP or PCC (depending on urgency)Repeat vitamin K injections every 12 hrs as needed
Anylife-threateningbleeding OmitwarfarinVitaminK10mgslowIVinfusion
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Any lifethreatening bleeding Omit warfarinVitamin K 10 mg slow IV infusionPCC ( or recombinant human factor VIIa)Repeat vitamin K injections every 12 hrs as needed
Chest 2001:119;22-38s (supplement)
Aroa4h to Po+t-oerat!'e bleed!g
1.Is the bleeding local or due to a hemostatic failure?1. Local: Single site of bleeding usually rapid with minimal coagulation test
abnormalities2. Hemostatic failure: Multiple site or unusual pattern with abnormal
coagulation tests
2.Evaluate for causes of peri-operative hemostatic failure1. Preexisting abnormality2. Special cases (e.g. Cardiopulmonmary bypass)
3.Diagnosis of hemostatic failure1. Review pre-operative testing2. Obtain updated testing
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Laboratory Evaluation of BleedingOverview
CBC and smearPlatelet count ThrombocytopeniaRBC and platelet morphology TTP, DIC, etc.
CoagulationProthrombin time Extrinsic/common pathwaysPartial thromboplastin time Intrinsic/common pathwaysCoagulation factor assays Specific factor deficiencies50:50 mix Inhibitors (e.g., antibodies)Fibrinogen assay Decreased fibrinogenThrombin time Qualitative/quantitative
fibrinogendefectsFDP Ddi Fibili(DIC)
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fibrinogen defectsFDPs or D-dimer Fibrinolysis (DIC)
Platelet functionvon Willebrand factor vWDBleeding time In vivo test (non-specific)Platelet function analyzer (PFA)Qualitative platelet disorders
and vWDPlatelet function tests Qualitative platelet disorders
Laboratory Evaluation of the
Coagulation PathwaysPartial thromboplastin time
(PTT)Prothrombin time
(PT)
Intrinsicpathway Extrinsicpathway
Surface activating agent (Ellagic acid, kaolin)PhospholipidCalcium
Thromboplastin Tissue factor PhospholipidCalcium
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Intrinsic pathway Extrinsic pathway
Common pathwayThrombin timeThrombin
Fibrin clot
Coagulation factor deficiencies
Summary
Sex-linked recessive Factors VIII and IX deficiencies cause bleeding
ProlongedPTT;PT normal
Autosomal recessive(rare) Factors II, V, VII, X, XI, fibrinogen deficiencies cause bleedingProlongedPT and/orPTT
FactorXIIIdeficiencyisassociatedwithbleedingand
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Factor XIII deficiency is associated with bleeding andimpaired wound healingPT/ PTT normal;clot solubility abnormal
Factor XII, prekallikrein, HMWK deficiencies
do not cause bleeding
Thrombin Time
• Bypasses factors II-XII
• Measures rate of fibrinogen conversion to fibrin
• Procedure: – Add thrombin with patient plasma
– Measuretimetoclot
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Measure time to clot
• Variables: – Source and quantity of thrombin
Causes of prolonged Thrombin Time
• Heparin
• Hypofibrinogenemia• Dysfibrinogenemia
• Elevated FDPs or paraprotein
• Thrombininhibitors(Hirudin)
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Thrombin inhibitors (Hirudin)• Thrombin antibodies
Classification of thrombocytopenia• Associated with
leeding – Immune-mediated
thromocytopenia)I"%*
– !ost others
• Associated withthromosis – "hromotic
thromocytopenicpurpura
– Heparin-associated
thromocytopenia
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thromocytopenia – "rousseau1s
syndrome
– &I
Bleeding time and bleeding• 5-10% of patients have a prolonged bleedingtime
• Most of the prolonged bleeding times are due toaspirin or drug ingestion
• Prolonged bleeding time does not predict excess
surgicalbloodloss
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surgical blood loss
• Not recommended for routine testing inpreoperative patients
• Drugs and blood productsused for bleeding
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Treatment Approaches to
the Bleeding Patient
• Red blood cells
• Platelet transfusions
• Fresh frozen plasma
• Cryoprecipitate
• Amicar
• DDAVP
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DDAVP• Recombinant Human factor VIIa
RBC transfusion therapy
Indications
• Improve oxygen carrying capacity of blood
–Bleeding
–Chronic anemia that is symptomatic
–Peri-operativemanagement
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Perioperative management
Red blood cell transfusions
Special preparation
CMV-negative CMV-negative patients Prevent CMVtransmission
Irradiated RBCs Immune deficient recipientPrevent GVHD
or direct donor
Leukopoor Previous non-hemolytic Prevents reaction transfusion reaction
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CMV negative patients Prevents transmission
Washed RBC PNH patients Prevents hemolysis
IgA deficient recipient Prevents anaphylaxis
Red blood cell transfusions
Adverse reactions
Immunologic reactions
Hemolysis RBC incompatibilityAnaphylaxis Usually unknown; rarely against IgAFebrile reaction Antibody to neutrophilsUrticaria Antibody to donor plasma proteins
Non-cardiogenic Donor antibody to leukocytespulmonaryedema
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g y y pulmonary edema
Red blood cell transfusions
Adverse reactions
Non-immunologic reactions
Congestive heart failure Volume overload
Fever and shock Bacterial contamination
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Hypocalcemia Massive transfusion
Transfusion-transmitted disease
Infectious agent Risk
HIV ~1/500,000Hepatitis C 1/600,000Hepatitis B 1/500,000Hepatitis A <1/1,000,000
HTLV I/II 1/640,000CMV 50%donorsaresero-positive
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,CMV 50% donors are seropositiveBacteria 1/250 in platelet transfusionsCreutzfeld-Jakob disease UnknownOthers Unknown
Platelet transfusions• Source
– Platelet concentrate (Random donor)
– Pheresis platelets (Single donor)
• Target level
– Bone marrow suppressed patient (>10-20,000/µl)Bleeding/surgicalpatient(>50000/µl)
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pp p ( , µ) – Bleeding/surgical patient (>50,000/µl)
Platelet transfusions - complications• Transfusion reactions
– Higher incidence than in RBC transfusions
– Related to length of storage/leukocytes/RBC mismatch
– Bacterial contamination
• Platelet transfusion refractoriness – Alloimmune destruction of platelets (HLA antigens)
– Non-immune refractoriness
• Microangiopathic hemolytic anemia• Coagulopathy
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• Coagulopathy
• Splenic sequestration
• Fever and infection
• Medications (Amphotericin, vancomycin, ATG, Interferons)
Fresh frozen plasma• Content - plasma (decreased factor V and VIII)
• Indications
– Multiple coagulation deficiencies (liver disease, trauma) – DIC
– Warfarin reversal
– Coagulation deficiency (factor XI or VII)
• Dose (225 ml/unit) – 10-15 ml/kg
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• Note – Viral screened product
– ABO compatible
Cryoprecipitate• Prepared from FFP
• Content – Factor VIII, von Willebrand factor, fibrinogen
• Indications – Fibrinogen deficiency
– UremiavonWillebranddisease
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– von Willebrand disease
• Dose (1 unit = 1 bag) – 1-2 units/10 kg body weight
Hemostatic drugs
Aminocaproic acid (Amicar)• Mechanism
– Prevent activation plaminogen -> plasmin
• Dose
– 50mg/kg po or IV q 4 hr
• Uses – Primary menorrhagia
– Oral bleeding
– Bleeding in patients with thrombocytopenia
– Blood loss during cardiac surgery
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• Side effects – GI toxicity
– Thrombi formation
Hemostatic drugs
Desmopressin (DDAVP)• Mechanism
– Increased release of VWF from endothelium
• Dose – 0.3µg/kg IV q12 hrs
– 150mg intranasal q12hrs
• Uses –Most patients with von Willebrand disease – MildhemophiliaA
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Mild hemophilia A
• Side effects – Facial flushing and headache
– Water retention and hyponatremia
Recombinant human factor VIIa (rhVIIa;
Novoseven)• Mechanism
– Direct activation of common pathway
• Use – Factor VIII inhibitors – Bleeding with other clotting disorders – Warfarin overdose with bleeding
– CNS bleeding with or without warfarin
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– Dose – 90 µg/kg IV q 2 hr – “Adjust as clinically indicated”
• Cost (70 kg person) - $1 per µg – ~$5,000/dose or $60,000/day
Approach to bleeding disordersSummary
• Identify and correct any specific defect ofhemostasis – Laboratory testing is almost always needed to establish the causeof bleeding
– Screening tests (PT,PTT, platelet count) will often allow placementinto one of the broad categories
– Specialized testing is usually necessary to establish a specificdiagnosis
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• Use non-transfusional drugs whenever possible
• RBC transfusions for surgical procedures or large
blood loss
.leedin Disorders 7emophilia
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.leedin Disorders• "hree types Hemophilia0 males only
– Type A most common K &actor B,,,de>ciency
– Type . - lac# o actor , (ChristmasDisease*
– Type C K lac# o &actor ,
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yp
Eon Gillerand &isease K 68 o
population K men or women K prolongedleeding time
Hemophilia• Hemophilia is a se0$lin%ed
hereditary bleedin disorder• "ransmitted on the Z chromosome
• emale is the carrier
• Gomen do not sufer rom thedisease itsel
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o e do o su e o edisease itsel
3unctional %resentation oHemophilia• =eople +ith
hemophilia can
bleed any+here! utleeding into joints)hemarthrosis*, sottissue )such asmuscle*, urine
)hematuria*, and the i
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rain are common
• hronic leeding into joints or an acute
leed into the rain orspinal canal can leadto chronic disailities,
"reatment• %roducts used to treat hemophilia
are0 – resh &roNen plasma and
cryoprecipitate +hich are &romsinle blood donors and reuire
special &reeNin.Second generation o &actor B,,, are
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p – Second generation o &actor B,,, are
made with animal or human proteins.
,diopathicthrombocytopenicpurpura
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I"%• Idiopathic thromocytopenic purpura
– Idiopathic ^ cause is un#nown
– "hromocytopenic ^ lood does nothave enough platelets
– %urpura ^ e2cessive leeding = ruising
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Symptoms• Random purpura
•pista2is, hematuria, hematemesis,and menorrhagia
• %etechiae and hemorrhagic ullae inmouth
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Cuanou pcia and cc-o
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&iagnostic "ests• ow platelet count
•%eripheral lood smear• Antiplatelet antiodies
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;ormal platelet count0 647,777 toC77,777
!anagement• IE gamma gloulin to loc# antiody
production, reduce autoimmuneprolem
• Corticosteroids to reducein2ammatory process
• IE anti-& to stimulate platelet
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pproduction
Heparin-Induced "hromocytopenia
)HI"* – HI"
• Associated with administration o heparin
• &evelops when the ody develops an antiody, or allergy
to heparin• Heparin )parado2ically* causes thromosis
• Immune mediated response that casues intense plateletactivation and relaese o procoaggulation particles.
– linical eatures
• "hromocytopenia• %ossile thromosis ater heparin therapy
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• %ossile thromosis ater heparin therapy – an e triggered y any type, route or amount o heparin
19/04/2011 544
+ ,ce greu[
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B!ood (o&"u!&tion disorders
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Dr. @!&r& ?eendi
Se"ed Universit=Tr&nsfusio!o"= De#&rt)ent
T+e nor)&! +&e)ost&sis #revents$
Z s#ont&neous +&e)orr+&"e &nd undue !ood !oss
fro) inured vesse!s
Z intr&v&s(u!&r t+ro)us
for)&tion.
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!eedin"
t+ro)osis
T+ere &re t+ree (o)#onents of !ood (o&"u!&tion
s=ste)$
HAEMOSTASIS
1.
C&#i!!&ries
4.P!&te!ets
3.
P!&s)&
(o&"u!&tionf&(tors
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1. 4$ Pri)&r= +&e)ost&sis *it is enou"+ to sto# !eedin" fro)
s)&!! inuries,
3$ Se(und&r= +&e)ost&sis *it is ne(ess&r= to sto# !eedin"
definite!
Pri)&r= +&e)ost&sis I$
Z C&#i!!&ries &nd !&r"er !ood vesse!s re&(t to inur= = &ni))edi&te !o(&! te)#or&r= vasoconstriction *& ref!e8 nervous
)e(+&nis), to redu(e t+e &)ount of !ood !ost.
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Pri)&r= +&e)ost&sis II$
Z P!&te!ets$
2 adhere to t+e site of inur=
2 aggregation
2 release sust&n(es fro) t+eir (=to#!&s)s to initi&te !ood
(o&"u!&tion ⇒ haemostatic "lug is formed.
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Se(und&r= +&e)ost&sis$
B!ood (o&"u!&tion f&(tors &re ne(ess&r= to sto# !eedin"
definite!=.• I$ firino"en
• II$ #rot+ro)in
• III$ tissue t+ro)o#!&stin *tissue f&(tor% T,
• I?$ C&66 • ?$ #ro&((e!erin
• ?I$ 2
• ?II$ #ro(onvertin
• ?III$ &nti+e)o#+i!i( f&(tor *AH,• I$ C+rist)&s f&(tor *#!&s)& t+ro)o#!&stin (o)#onent,
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*# # # ,
• $ Stu&rt f&(tor
• I$ #!&s)& t+ro)o#!&stin &nte(edent *PTA,
• II$ H&"e)&n f&(tor *(ont&(t f&(tor,• III$ firin st&i!iin" f&(tor *L&i2Lor&nd f&(tor,
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Disorders of t+e +&e)ost&ti( )e(+&nis) &re
devided into t+ree )&in "rou#s$
• Disorders of t+e vesse!s
• Disorders of t+e #!&te!ets
• Disorders of t+e (o&"u!&tion )e(+&nis)
„ "ur"uric
diseases9
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"
(8coagulo"athies9
T+e investi"&tion of & #&tient it+ &
sus#e(ted disorder of +&e)ost&sis
– (&se +istor= *#erson&! det&i!s% f&)i!=
+istor=,
– ins#e(tion *t=#e of !eedin",
– #+=si(&! e8&)in&tion
–ot+er non dise&ses – dru"s &nd )edi(&tions
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"
– !&or&tor= tests
Cert&in si"ns &nd s=)#to)s &re virtu&!!= di&"nosti( of
disordered +&e)ost&sis.
T+e )&in s=)#to) of &!! dise&ses is t+e !eedin"$
Z in t+e [#ur#uri( disorders\ (ut&neous &nd )u(os&!!eedin" usu&!!= is #ro)inent
Z in different t=#es of [(o&"u!o#&t+ies\ +e)&rt+roses%
+&e)&to)&s &re t+e (+&r&(teristi( !eedin" )&nifest&tions.
T+e onset of !eedin" fo!!oin" tr&u)& freuent!= is delayed
* i tt f + ,
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*re(ur in & )&tter of +ours,
*t+e te)#or&r= +e)ost&ti( &deu&(= of t+e #!&te!et #!u"
)&= e8#!&in t+is #+eno)enon,.
Pete(+i&e% #ur#ur&s$s)&!! (&#i!!&r= +&e)orr+&"es r&n"in" fro) t+e sie of & #in+e&d to )u(+ !&r"er
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Pete(+i&e% #ur#ur&s
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H&e)&to)&s$
)&= e s#ont&neous *in & serious +e)orr+&"i( dise&se, or )&= o((ur
&fter tr&u)& *in & )i!d +e)orr+&"i( dise&se,.
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Intr&)us(u!&r ine(tion )&= e ver= d&n"erous to
t+e #&tient it+ & !eedin" disorder
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?eni#un(ture *if si!fu!!=
#erfor)ed, is it+out d&n"er
e(ouse t+e e!&sti(it= of t+e venous&!!s.
S(reenin" tests of !ood (o&"u!&tion• Disorders of vesse!s$
– Ru)#e!2Leede test
• Disorders of #!&te!ets$
– P!&te!et (ount &nd )or#+o!o"= – B!eedin" ti)e *Iv=,
• Co&"u!o#&t+ies$
– Co&"u!&tion ti)e
– Ativ&ted #&rti&! t+ro)o#!&stin
ti *APTT,
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ti)e *APTT,
– Prot+ro)in *INR,
–T+ro)in ti)e *TT,
L&or&tor= di&"nosis of t+e (o&"u!o#&t+ies
Cont&(t &(tiv&tion Tissue t+ro)o#!&stin *T,
II
I
I
?III
?II
INTRIN
SIC
ETRINSI
C
B!ood
(o&"u!&tion
ti)e
Prot+ro)2
in
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?
II
I
COMM
ON
APTI
P!&te!et(ount
B!eedin"ti)e
APTI Prot+ro)2in
Presu)#tivedi&"nosis
De(re&sed Pro!on"ed Nor). Nor). Thrombocyto"enia
Nor). Pro!on"ed Pro!on"ed Nor). von 1illebrands disease
Nor).; in(re&sed
Pro!on"ed Nor). Nor). Thrombocyto"athia
Nor). Nor). Pro!on"ed Nor). 8intrinsic9 "ath,ay
abnormality
*?III. I. I. II,
Nor). Nor). Nor). Pro!on"ed 8e;trinsic9"ath,ay
Di&"nosis of !eedin" disorders = t+e s(reenin" tests
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abnormality *?II,
Nor). Nor). Pro!on"ed Pro!on"ed 8common9 "ath,ay
abnorm. *I. II. ?. .,
Nor). Nor). Nor). Nor). - <7=III deficiency< milde
bleeding disorder
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H&e)o#+i!i&A !eedin" disorder in +i(+ (!ottin" f&(tor ?III
*ei"+t, <2aemo"hilia !< or I *nine, <2aemo"hilia #<
in & #ersons !ood #!&s)& is )issin" or is &t & !o
!eve!.
Prev&!en(e$+&e)o#+i!i& A$ 1<9;)i!!ion )en
+ +i!i B 4; i!!i
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+&e)o#+i!i& B$ 4;)i!!ion )en
• In +&e)o#+i!i&% ?IIIor I (!ottin" f&(tor is)issin"% or t+e !eve! of
t+&t f&(tor is !o.
• T+is )&es itdiffi(u!t for t+e !ood
to for) & (!ot% so!eedin" (ontinues! t+ !
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!on"er t+&n usu&!.
T+e +e)o#+i!i& "ene is (&rried on t+e (+ro)oso)e
⇒ in )&!es +o !&( & nor)&! &!!e!e% t+e defe(t is )&nifested =
(!ini(&! +&e)o#+i!i&. o)en )&= e (&rriers.
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H&e)o#+i!i& is & !ife!on" dise&se
• A #erson orn it++&e)o#+i!i& i!!
+&ve it for !ife.
• T+e !eve! of f&(tor
?III or I in +is
!ood usu&!!= st&=s
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!ood usu&!!= st&=s
t+e s&)e t+rou"+out
+is !ife.
C!ini(&! )&nifest&tions
T+e )ost dr&)&ti( )&nifest&tion of +&e)o#+i!i& is
e8tensive !eedin" into t+e soft tissue &nd )us(!es after
only negligible trauma+ or even no kno,n trauma.
T+e freuen(= &nd severit= of !eedin" "ener&!!= isre!&ted to t+e !ood !eve! of ?III or I.
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H&e)o#+i!i& (&n e )i!d% )oder&te% or severe% de#endin" on t+e !eve! of (!ottin" f&(tor.
T+ree (&te"or= of severit=$
• Severe$ ?III;I Q 1
– Re#e&ted &nd severe +e)&rt+roses &nd s#ont&neous!eedin"% (ri##!in" (o))on.
• Moder&te$ ?III;I$ 129 – S#ont&neous !eedin" &nd +e)&rt+roses infreuent.
Serious !eedin" fro) trivi&! inuries.• Mi!de$ ?III;I$ 92J< S t ! di if t ti t
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– S#ont&neous !eedin" )&nifest&tions )&= e &sent%&!t+ou"+ serious !eedin" )&= fo!!o sur"i(&!#ro(edures or tr&u)&ti( inur=.
>oint !eedin"
As !ood fi!!s t+e (&#su!e% t+e oint
se!!s &nd e(o)es #&infu! &nd +&rd to
)ove.
T+e )ost (o))on oint !eeds +&##en
in &n!es% nees% &nd e!os.
B!eeds into ot+er oints (&n &!so +&##en.
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T+e !on"2ter) effe(ts of oint
!eeds$Re#e&ted !eedin" into & oint (&uses t+e
s=noviu) to se!! &nd !eed ver= e&si!=.
So)e !ood re)&ins in t+e oint &fter e&(+
!eed. T+e s=noviu) sto#s #rodu(in" t+e
s!i##er=% oi!= f!uid t+&t +e!#s t+e oint )ove.T+is d&)&"es t+e s)oot+ (&rti!&"e t+&t
(overs t+e ends of t+e ones. T+e oint
e(o)es stiff% #&infu! to )ove% &nd unst&!e.
It e(o)es )ore unst&!e &s )us(!es &round
t+e oint e&en.
it+ ti)e% )ost of t+e (&rti!&"e re&s don
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&nd so)e one e&rs &&=. So)eti)es t+e
oint (&nnot )ove &t &!!.
T+e +o!e #ro(ess is (&!!ed$+e)o#+i!i( &rt+ritis.
H&e)o#+i!i( &rt+ro#&t+= *r&dio"r&#+s,
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Ot+er t=#es of !eedin"$su(ut&neous% intr&)us(u!&r +e)&to)&s% "&strointestin&!
!eedin"% +e)&turi&% (erer&! +e)orr+&"e
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?o!)&nnFs (ontr&(ture
L&r"e +&e)&to)& of t+e(eree!!u)*(o)#uter to)o"r&#+=,
Pseudotu)or
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Life2t+re&tenin" !eedin"$
2 !eedin" it+in t+e +e&d is &)&or (&use of de&t+ in
+&e)o#+i!i&
- B!eedin" into t+e t+ro&t )&=
(&use se!!in"% &s e!! &sdiffi(u!t= s&!!oin" &nd
re&t+in"
- G&strointestin&! !eedin" *often
due to #e#ti( u!(er&tion,
Serious ut usu&!!= not
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Serious% ut usu&!!= not
!ife2t+re&tenin" !eedin"$
2 !eeds into t+e e=es% s#ine &nd#so&s )us(!e
T+er&#=
T+e on!= )ode of tre&t)ent is re#!&(e)ent t+er&#=$ to
in>ect the missing clotting factor into a vein.
C!ottin" f&(tor (&nnot e "iven = )out+.
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&(tor sustitution
• On de)&nd$ – in t+e event of !eedin"
e#isodes
• Profi!&8is$ to#revent !eedin"s &nd t+eir(onseuen(es
– #ri)&r=
– se(und&r=
• Ho)e tre&t)ent$
– t+e #&tient or +is re!&tives &ret&u"+t to "ive iv. ine(tion oft+e f&(tor (on(entr&te
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t+e f&(tor (on(entr&tei))edi&te!= +en t+ere &res=)#to)s of !eedin".
C&!(u!&tion of t+e dose of f&(tor re#!&(e)ent
H&e)o#+i!i& A$
*desired !eve! ?III 2 #&tient ?III !eve! , 8 od=ei"+t";4
H&e)o#+i!i& B$
*desired !eve! I 2 #&tient I !eve! , 8 od=ei"+t"
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Re(o))ended doses of ?III;I forv&rious t=#es of +&e)orr+&"e
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&(tor re#!&(e)entat the consulting
room
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2ome thera"y:
is infusion it+ (!ottin" f&(torre#!&(e)ent &&= fro) t+e +os#it&!.
A #erson it+ +&e)o#+i!i& (&n infuse &t
+o)e% s(+oo!% or% or e!se+ere.
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s+&r#s (ont&iner
dis#os&!e i#es
&!(o+o! i#e
&nd&"e
(otton &!!st&#e
tourniuet
utterf!= need!e
s=rin"e
tr&nsfer need!e;
fi!ter need!e
f&(tor (on(entr&te
!&te "!o es
Su##!ies needed for tre&t)ent it+ f&(tor (on(entr&te$
A ritten re(ord
of &!! tre&t)ents
)ust e e#t.
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!&te8 "!oves
di!uent *steri!e &ter, su##!ied
it+ t+e (on(entr&te
Medi(&! tre&t)ent is on!= one #&rt of "ood +e&!t+.
Peo#!e it+ +e)o#+i!i& s+ou!d$
2 E8er(ise &nd st&= fit.
2 e&r #rote(tion t+&t is &##ro#ri&te for t+e s#ort or &(tivit=.2 Get re"u!&r (+e(2u#s t+&t in(!ude oint &nd )us(!e
e8&)in&tion.
2 Get &!! v&((in&tions re(o))ended% in(!udin" +e#&titis A
&nd +e#&titis B #rote(tion.
2 M&int&in & +e&!t+= od= ei"+t. Peo#!e +o do not e8er(ise&re )ore !ie!= to #ut on e8tr& ei"+t. A #erson it+
+ +i!i d t t ! +i i +t t+ t + d t
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+e)o#+i!i& needs to (ontro! +is ei"+t so t+&t +e does not
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ersitatea "itu !aiorescu
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• Dissolution ofibrin "lots
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prur
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Hemarthro+!+ Ca4uteD
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+arge pseudocst involving the left
pro*imal femur
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Pathogee+!+ o :#
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irin
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