Curs Hematologie

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



- Other

ConnectiveTissue Diseases



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



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.



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

•



%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



&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



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



A"T",TA UBE@,#A,D,O=AT,CA



uvenile

IdiopathicArthritis )IA*and +therRheumatic&iseases inhildren

-



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



&iagnostic "ests

• There is no lab test thatdianoses ,A

– – "heumatoid &actor – Antinuclear Antibody (A@A) F +ith

titer – ES" or C"=



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



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.





%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!



%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





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.





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





!edications

• ;SAI&s• &!AR&s0

!ethotre2ate,

%la(uenil,Sulasala9ine

• iologic responsemodi/ers

• <lucocorticosteroids

• !iscellaneous



!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*



<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*





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



rsitatea HTitu MaiorescuI

MED,C,@A ,@TE"@A

toloie ,



Ba > reuJJJ



Topics

7ematopoiesisComplete blood count (C.C)Anemia

=olycythemia#eu%openia#eu%emia#ymphoma

MyelomaCoaulationTrans&usion



7o+ much blood is in thehuman bodyJ

• About liters



Composition o& blood

• . .lood is composed o&: –=lasma

–".C –1.C

–=latelets



=lasma

• =lasma consists o&: –9* +ater4

* solutes:

– albumin! –electrolytes and proteins4 –clottin &actors !

–imuno$lobulins –circulatin antibodies and –>brinoen



A.O blood roups:

A! .! A.! and O



.lood Typin

35

ABO !ood "rou#s$ A% B% AB% &nd O



,& 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



"h &actor

• The H"h &actorI is anotherma3or antien on the ".C!

called D F is autosomalrecessive –&& and

Dd: "hK Dd: "h$

37



7ematopoiesis

HEMATOPOIE'A



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



Summary o& blood&ormin orans



.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



A /4lymphoid stem cells



E",T"O=O,ELA



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.



E",T"O=O,ELASubstane necesare eritropoieNei

A$=roteine

.4 Minerale: >er! cupru! cobalt!NincC4 Bitamine: ./! acid &olic!

.! C



1hat does hemolobin



1hat does hemolobindo

• Hemogloin pic#sup the o2ygenmolecules and

drops of +:



#eu%ocyte types• Arti>cial division into

$-ranulocytes$ neutrophils!

$ eosinophils! $basophils

• /$Aranulocytes0 lymphocytes!

monocytes

48

# % l



#eu%ocytes ranulocytes

49

neutro#+i! eosino#+i!

&so#+i!

s)&!! !=)#+o(=te )ono(=te



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



T cells attac% &orein cellsdirectly

Qiller cells (Hcytoto0icI)! orCD;K is a main type

51



. cells

• Di6erentiate into plasma cells• =lasma cells secrete antibodies

52



Aranulocytes Monocytes

• P$;* o& 1.Cs• ,n connective

tissue theytrans&orm intomacrophages (phaocytic

cells +ithpseudopods*

53

*



=latelets

54

*



Disorders o& .loodcells

• .

55



Disorders o& Erythrocytes



,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



Structure and &unction

o& 7aemolobin.



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&



Synthesis o&7aemolobin (7b)• 7aem R lobin produced at t+o

di6erent sites in the cells

•7aem inmitochondria

•-lobin inpolyribosomes

Synthesis o&



Synthesis o&7aemolobin

S & 7



Structure o& 7aem

S nthesis o& lobin



Synthesis o& lobin



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



-lobin ene clusters



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



Alpha R beta chains

unctions o&



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



O0y Rdeo0yhaemolobin

Summary



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



Disorders o& Erythrocytes• $Anemia0 not enough cells

• /$De&ect in hemolobin• $=olycythemia0 too many

cells

71



Disorders o& 7eme

synthesis



Disorders o& 7eme

synthesis



7EME$CO@TA,@,@- ="OTE,@S

• 7emolobin

• Myolobin

• Cytochromes

• Catalase

• Some pero0idases

ST"UCTU"E O 7EME



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



He)e S=nt+esis



&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



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



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



n9ymatic&e/ciencies

• All o the hemepathway intermediatesare potentially to2ic.

• "heir overproductioncauses thecharacteristicneurovisceral and=orphotosensiti9ing

symptoms.



%+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



CUTANEA TARDA

Acute intermittent



porphyria

!ary ?ueen o Scots

Ean <ogh

Jing <eorge III

Acute intermittent porphyria



• 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



• 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



!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



%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



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



=rotoporphyria ( i -o co--on cildood porpria ( i uuall 'idn b 2 ar o ag

Pathogenesisdicin aci'i o

rroclaa n-

L&. findin"$



"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 ,



* 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



%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



,-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



%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



%orphyria• Avoid sunlight @

• Iron chelation @

• lood Removal @

• Avoid drin#ing alcohol @

+ther "reatments



+ther "reatments

• Heme transusion 6

• !edication that induce cytochromepC47 have a chance o causing

porphyria attac#s 6

"ed Cell



"ed Cell

Disorders.



Anemia



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:



Anemia

Production !ur"i"al#Destruction

$R%&R'P'%&%(A

Anemia



Anemia

• DE,@,T,O@ -Decrease erytrocytes inblood

$Decreased production o&erythrocytes

/$,ncreased destruction o&erythrocytes

.lood loss19/04/2011 101

Anemia



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



AnemiaCaused by

Decreased Erythrocyte =roduction

AnemiaCaused by




$,ron De>ciency Anemia

/-Mealoblastic Anemias $Aplastic Anemia

19/04/2011 104

AnemiaCaused by




,ron De>ciencyAnemia

19/04/2011 105

,ron$De>ciency



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



,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



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




(CO.#AM,@)/B,TAM,@ . De>ciency

19/04/2011 109

M&(ro(=ti(

Ane)i& *COBLAMIN,14 ?ITAMIN B



* ,?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



#

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



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.



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.



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&



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(= .



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&



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&



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



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



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



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



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(=,.



!-'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



*

#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



M&(ro(=ti(

Ane)i& II2 Bone )&rro$



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!



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



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



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



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&



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



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 $



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



= = " % "

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



* ,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



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



/!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



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


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






• 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



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



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



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

http://en.wikipedia.org/wiki/Vitamin_B12

http://en.wikipedia.org/wiki/Pernicious_anemia




http://en.wikipedia.org/wiki/Vitamin_B12



• 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



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



• 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



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


Ț



Decreased production o&erythrocyte

Aplastic Anemia

• Aplastic anemia

• CharacteriNed by =ancytopenia

19/04/2011 148

Decreased production o& erythrocyteAplastic Anemia



• 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



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



• 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



• Dianosis –.lood tests

• C.C

–.one marro+ biopsy

19/04/2011 152

Aplastic Anemia



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



.lood lossanemia

•

154

Acute .lood #oss



• "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



• 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



Anemia causedby

,ncreased Erythrocyte Destruction

•

157



Anemia causedby

,ncreased Erythrocyte Destruction

7AEMO#WT,C A@AEM,AS

•

158

M&(ro(=ti(Ane)i&



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 .



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$



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



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@"



* 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"



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"



@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



* =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



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"



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



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



rminat X



Anemia o& chronic disease

and Erythropoietin

• .

Anemia o hronic &isease)A&*

Classical defnition



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



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



• 2cessive production o

cyto#ines

• Inefective erythropoiesis

• Interere with0

– fect o %+ on one marrow – Release o stored iron in

Reticuloendothelial system



Anemia o& ChronicDisease



/ajor steps of/ajor steps of erythropoiesiserythropoiesis andanderythropoietin dependenceerythropoietin dependence



$rythropoietin$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;



carbohydrate

protein

protein K carbohydrate V lycoprotein

Er=t+ro#oietin



• .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



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



M&(ro#+&"e

6E#o

2E#o

CU2E

%hysiology o rythropoietin



co-binan

<rropoiin

iological efects o %+



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



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



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



,n advanced disease

To0icity &rom therapy

Therapy: Erythropoietin

%athogenesis o anemia in cancer



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




Anemia o hronic &isease

one !arrow Involvement

%ure Red ell Aplasia

!egaloglastic Anemia )6:, 3olate de.*


!icroangiopathic anemia Autoimmune Hemolytic Anemia

Therapy$induced Anemia

,mpact o& Anemia in=atients 1ith Cancer



• 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



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







.one Marro+ ,nvolvement





"herapy-induced Anemia

+; !ARR+G AS%IRA"



one marrow involvement



o!!i(u!&r !=)#+o)&

Neuro!&sto)&

Anemia Due to Marro+,n>ltration



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










=ure "ed Cell Aplasia



































y












y






!icroangiopathic anemia Autoimmune 7emolytic Anemia


Autoimmune Hemolytic Anemia







y






!icroangiopathic anemia

Autoimmune Hemolytic Anemia

Therapy$induced Anemia

Tre&t)ent O#tions forC&n(er2Re!&ted Ane)i&



Tr&nsfusion

• #d in ca o acu

an-ia

• @an aociad ri>

ERTHROPOIETIN,arrion !2000"

Types o& Trans&usion "eactions



,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



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



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


Ț

ersitatea Titu Maiorescu

S MED,C,@A ,@TE"@A



7ematoloie ,,



,ntrinsic hemolyticanemia 7emolobinopathies

Abnormal hemolobin

.

• 7emolobinopathies

• Over ; di6erent mutations o& lobin chains o&



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



y

anemia 7emolobinopathies

Abnormal hemolobin

Sic%le (secera) Cell Disease .





Sic%le (secera) CellDisease• The resultant cellular



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



•This results +henboth copies o& thehemolobin betaene have an S

mutation4

•All o& this personsbeta subunits are

replaced by betaS4

7emolobin

AlphaAlpha

.etaS

.etaS



ym"tomsOr"&ns t+&t (&n e &ffe(ted =

si(!e



• 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

•



•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



-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



,-oglobin C dia

Hemogloin



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)





7emolobin C disease



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



,-oglobin =C dia

7emolobin SC disease

"his disease is caused y having doule



"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



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)





Met+e)o"!oin

Methemolobin (M)



• ;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



• Drus ( nitrates)

• Endoenous products (reactive ointermediates)

• ,nherited de&ects (mutations)

• De>ciency o& @AD7$ 7b M reductase

E6ects and Symptoms

• unctional Anemia



Chocolate cyanosis Chocolate$cholored blood

• Tissue hypo0ia ^ an0iety!headache ! dyspnoea ! +ea%ness !lihtheadache 4

• "are cases ^ coma ! death4



Thalassemia



• Syndromes arising form

Decreased rate or absenceof globin chain synthesis.

How to name thalassemia?



• 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



7b$A Molecule4 7b$A is thema3or adult hemolobin4





mmon ty"es of thalassemia

•α-thalassemia

Reduced or absentα

-globin chain

•β-thalassemia

• Reduced or absent β-globin chain :



# Thalassemia



• 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&



• 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



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,.







β T7A#ASSEM,AS

h l



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 + !



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&.



$ thalassemia minor



_ Thalassemia Ma3or

• CharacteriNed by very severe



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



T halassemia !a"or



<;panion o B@





$ thalassemia ma&or%ale '( years

C!i(i(&! &v&!u&tionHe#&tos#!eno)e"&!=



.eta thalassemia ma3or• / de&ected .eta enes no betachains synthesis alpha chains

i i d h &



precipitate premature death o&".Cs4

•Complications•Enlarement

D&r sin due to iron over!o&d



T%*!T/*'T )7 T2!L!*/I!

1 CON?ENTIONAL TREATMENT



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



Anemiaby membrane

de&ects



BC @-bran

,ntroduction

•&eects due to



&eects due to• abnormalities in membraneproteins

• or lipids• &eects alter membranesstability! shape! de&ormabilityand permeability

• 7emolysis occurse0travascularl

Conditions Associated +ithMembrane De&ects



◦ Membrane proteins disorders

◦ $7ereditary spherocytosis◦

$7ereditary elliptocytocytosis◦ $7ereditary pyropoi%ilocytosis◦ Overhydrated and dehydrated hereditary

stomatocytosis

◦ Membrane lipid disorders

◦ $=aro0ysymal noctural hemolobinuria

.



7ereditaryspherocytosis

H&e)o!=ti(Ane)i&

,<<$(TAM =P,<&CMT&=(=

Paogni



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



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'



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



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



"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



• Compensated hemolyticdisease

•@o anemia• ,ntermittent 3aundice

• Splenomealy

• Cholelithiasis: piment bilestones &rom increasedbilirubin brea%do+n

#ab eatures –Mild anemia



".C morpholoy – Spherocyte

– Baryin derees o&polychromasia!anisocytosis andpoi%ilocytosis

a 3eatures

• .one Marro+

– @ormoblastic erythroid hyperplasia



@ormoblastic erythroid hyperplasia – ,ncreased iron storae

• Chemistry – ,ncreased

• .ilirubin• ecal urobilinoen• #D

– Decreased• 7aptolobin

• ,mmunohematoloy – DAT neative

Dianostic tests &or 7ereditary spherocytosis

• Osmotic &raility $



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



• Splenectomy

–Corrects &or theanemia! but the

membrane de&ectremains

.



• 7ereditaryelliptocytosis

.

7ereditaryelliptocytosis



–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



E!!i#to(=tosis

#ab eatures

• !ild anemia



– !ild anemia

– Hg level increased

–

• R morphology – Elliptocytes or ovalocytes

Treatment o&7elliptocytosis



–Treatment is usually

not necessary! but i&patients havehemolysis!

splenectomy isbene>cial.

.



"ed cellenNymopathies

4 -lucose$$=hosphateDehydroenase ( -=D )

De>ciency



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:



Acute dru induced hemolysis:• Aspirin! primauine! uinine!

chlorouine! dapsone4

– Chronic compensated hemolysis – ,n&ection<acute illness – @eonatal 3aundice – avism

• Treatment:



–Stop the precipitatin dru ortreat the in&ection

–Acute trans&usions i& reuired

/4 =yruvate Qinase De>ciency –AR

–&e/cient A"% production Chronic



&e/cient A"% production, Chronichemolytic anemia

– InvP

• %. Smear0 %ric#le cells• &ecreased en9yme activity

– "reatment0

• "ransusion may e re(uired



=olycythemia.



=olycythemia Bera

!olcthemia Vera(lots o& red cells $ &or real)

• An uncommon disorder $distinuish &rom other causes o&



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



Secondary =olycythemia

• Appropriate E=O (tissue<%idneyhypo0ia)



hypo0ia) – pulmonary disease – hih altitude

– conenital heart disease – abnormal hemolobin

• hih anity

• carbo0yhemolobin

Secondary =olycythemia

• ,nappropriate E=O (ectopicproduction)



production) – Tumors (hepatoma! renal

carcinoma! leiomyoma! hamartoma)

– "enal disorders (transplantation!cysts)

– hemaniomas

– Androen abuse – E=O abuse – amilial polycythemia

!olcthemia Vera

• Clinical &eatures



– 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*



– 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



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



Treatment Options $Summary



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


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


P . e r a

P h l e b o t o m ! " e t o H # $ < % 5

7 h i



7emochromatosi

s .

Hemochromatosis

• ,ron overloaddi



,ron overloaddisease

• Over absorption andstorae o& ironcausin damaeespecially to liver!heart and pancreas

19/04/2011 296

•linical0



•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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ME D I C I N A I N

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Disorders o& #eucocyte

=ro& univ dr ,on C4Tintoiu

O& !o&!o&!o&444444XXXX



)*+,*% /0*R0*1



)*+,*%De>nition



)eu2emia is a disease resulting fromthe neo"lastic "roliferation of

-hemo"oeitic

or

-lym"hoid cells

A

/4lymphoid stem cells



)*+,*%



t results from the mutation in asingle stem cell

The "rogeny of which form a clone ofleu2emic cells

)*+,*%

cute leu2emia

hronic leu2emia



•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



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



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



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



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



normal

lasts ( (

promyelocytes (myelocytes (

metamyelocytes (

ands (neutrophils ( U (

)eu2emia



Nor)&!"r&nu!o(=tes

ALL



CMLAML



+T* )*+,*%

+T* )*+,*%

A/5A55



+T* )*+,*%

)N) 3*T+R*S/NS*T



/NS*T

bru"t4 acute

nsidious4 slowly "rogressi5e 6one marrow malfunction

nemia4 infection 7 bleeding

Acute #eu%emia

• accumulation o& blasts in themarro+



Causes o& acuteleu%emias• idiopathic (most)• underlying hematologic disorders



• chemicals, drugs

• ioni9ing radiation

• viruses )H"E I*

• hereditary=genetic conditions

Clincal mani&estations

• symptoms due to: – marro+ &ailure



– tissue in>ltration – leu%ostasis

– constitutional symptoms – other (D,C)

• usually short duration o&

symptoms

Marro+ &ailure

• neutropenia:in&ections! sepsis



pin&ections! sepsis• anemia: &atiue!pallor

• thrombocytopenia:

bleedin

,n>ltration o&tissues<orans• enlarement o& liver! spleen!

lymph nodes



• um hypertrophy• bone pain• other orans: C@S! s%in! testis!

any oran

<um hypertrophy



A

hloromas



A

B

C <E@ 1998

#eu%ostasis

• accumulation o& blasts in

microcirculation +ith impairedper&usion



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



• blasts in peripheral blood• normocytic anemia• thrombocytopenia• neutropenia•

D,C

.one marro+ in acuteleu%emia• necessary &or dianosis• use&ul &or determinin type



• 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##)



• ae• curative vs palliative intent

=rinciples o& treatment

• combination chemotherapy – >rst oal is complete remission

& th " t t l



– &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



– 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



• 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



#cute meloblasticleu$emias,

=athophysioloy

•,n all AM#s,• the accumulation o& proli&eratin neoplasticmyeloid precursor cells in the marro+



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



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



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



>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



A!



A@L



Morpholoy

• Monoblasts oten have olded orloulated nuclei, lac# Auer rods,



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



Auer rods in AM# (pathomonomic &or myeloid lineae oriin)!A case o& AM#$M



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%



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,



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



Clinical eatures

• ,n&ections are &reuent,particularly in the oral cavity s#in



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



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.



• ?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



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



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



Acute lymphoblastic leu%emia (A##)

Acute lymphoblasticleu%emia• is a malinant (clonal)disease o& the bone

i hi h l



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



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



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



)ym"hadeno"athy

S"lenomegaly He"atomegally NS manifestations

Testicular in5ol5ement S2in

)*+,*%

)6/RT/R8 *0)+T/N

• nemia



• nemia• )eu2ocytosis:leu2o"enia:normal T)• Thrombocyto"enia• 6one marrow e;amination

s"irate 7 bio"sy



A##$#

Small and homogenous lasts. "hese may closely resemlelymphocytes ut are distinguished y their /ner chromatinstructure and the occasional presence o nucleoli



A##$#/ympholasts o varying si9e )small and large*



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.



!ature -A with prominent cytoplasmic vacuoles

Etioloy

• Epstein$.arr virus

• 7iher socioeconimic subroups• Trisomy / (Do+ns syndrome)



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



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



#ab Studies • .one marro+ aspiration and biopsy



Treatment stratey inA##



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



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



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!



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



arabinoside! hih dose

methotre0ate! hih dosecyclophosphamide4

/4 7ematopoietic stem cell

transplantation$ hih$dose therapy

$ reduced intencity conditionin

)*+,*%





Chronic Myeloid #eu%emia (CM#)

Chronic Myeloid #eu%emia

Clinical =resentation

Asymptomatic (f *)

atiue! +eiht loss! &ever



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



, = #

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 ( (



lasts ( (

promyelocytes (myelocytes (

metamyelocytes (

ands (neutrophils ( U (

Th ti O ti i



Therapeutic Options in

Chronic Myeloid #eu%emia

,matinib (-leevec! @ovartis)a small molecule tyrosine %inaseinhibitor



LeukemiaLeukemia

)

=ourc #ndr-ind

Treatment Options &or "esistantDisease

6* Dose Escalation o& imatinib



/) 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



• !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.



Chronic lymphocytic leu%emi

Chronic lymphocyticleu%emia ()

• Is characterised y the accumulationo& nonproli&eratin mature$appearin lymphocytes in the



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



&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



"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



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



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



• 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



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



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

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P r o f u n iv



A I N T E R N 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



staging* than the e2act histologicsutype

• @7# – approach is dictated mainly y the

histologic sutype rather than the

results o staging

ymphoma

7od%ins Disease



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



• >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



in other orans

(e0tramodaldisease)• =erson can be

asymptomatic• Common .

symptoms include&ever! drenchinniht s+eats! loss o&* o& body +eiht!

#ymphoma#ymphadenopathy – .



ymphadenopathy

• Enlared nodes

– tender V in&ectious – non$tender Vmalinant

• #ymphadenitis



• #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



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



A$ &sen(e of B s=)#to)s

B$ fever% ni"+t se&ts% ei"+t !oss

ymphomas



• ;eoplasms o lymphocytes orlympholasts that grow as nodular massesusually in lymph nodes

• Usually painless!non$tender enlaredlymph node in nec%

• 1eiht loss



• @iht s+eats

• ever• atiue• ,n&ection• -ood survival but at

ris% &or othermalinancies

S#in ymphoma and Shoulderymphoma



Hodg#in lymphoma

T , d >i



To-a ,odg>in

!1798%1866"

C!&ssi(&! Hod"in L=)#+o)&



7od%in lymphoma• cell o origin0 erminal centre .$

cell• "eed$Sternber cells )or RS

variants* in the afected tissues



variants* in the afected tissues

• most cells in afected lymph node arepolyclonal reactive lymphoid cells,not neoplastic cells

Reed-Sternerg ell



7od%in lymphoma7istoloic subtypes

• Classical 7od%in lymphoma –$nodular sclerosis (most

common subtype)



common subtype)

–/$mi0ed cellularity –$lymphocyte$rich

–P$lymphocyte depleted

lassic Hodg#in ymphoma



;odular SclerosingHodg#in ymphoma



7od%in #ymphoma

• Treatment – approach depends upon stae!

pronostic &actors! and co$



morbidities

– Stae ,$,,• consider "T! chemotherapy! or

combined therapy

– .ul%y stae ,$,,

• combined modality therapy – Stae ,,,$,B

• A.BD 0 $; cycles old standard



Hodg#in1s &isease

• Results o "reatment

• stage 4 year overall survival –I L78

–II L78



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



– 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

• .



;H

#ymphoma

• @on$7od%ins #ymphoma(@7#)

– 7eteroeneous roup o& cancersa6ectin lymphocytes• Usually classi>ed by histoloicrade (lo+ to hih)



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



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



– hih rade V aressive

• %rinciple

– indolent: slo+ ro+in! incurable – aressive: rapidly ro+in!

curable



;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



– combination chemotherapy

• CB=! C! @D! C7O= – chemotherapy K inter&eron – chemotherapy K monoclonal antibodies – monoclonal antibodies – radiolabeled monoclonal antibodies

– stem cell transplantation



Summary

•@7# incidence increasin! 7od%insdecreasin

• Hodg#in1s cure rate (uite highapproach is dictated mainly y disease stage



– 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



!ultiple !yeloma

• Malinant cells appear as

nodular masses in bone marro+• Xpunched outY lesions in s#ull N

spine



p

• 7ypoammalobinemia• Susceptible to in&ections• Elderly most commonly a6ected

!ultiple !yeloma

• Malinant neoplasm o& bone

marro+Tumor destroys bone Results in0



–%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



• "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.

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%latelet oagulation



Pete4h!ae/ Purura Hematoma/ Io!t bl.

%urpura



%etechiae



%etechiaeCty!4al o latelet d!+order+D



Do not blanch withpressure

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3A"+R &3II;IS)$/'P)%5%A A FClassic )emophiliaD

• F0-F5& o all Hemoh!l!a4+• Deficiency of +actor %%%

• 8ab =e+ult+ - Prologed P$$



)$/'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)



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!

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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



– 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



– 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



–Hepatitis B Human parvovirus

–Hepatitis C Hepatitis A

–HIV Other

Treatment of hemophilia B

• Agent

–High purity factor IX –Recombinant human factor IX

• Dose



–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



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



special &reeNin. – Second generation o &actor B,,, are

made with animal or human proteins.

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A C . i n t o i u Ț

Clinical Features of Bleeding

Disorders



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



'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



deficiencies deficiency/warfarinoverdose

– DIC





Laboratory evaluation of

von Willebrand disease• Classification

– Type 1 Partial quantitative deficiency

– Type 2 Qualitative deficiency

– Type 3 Total quantitative deficiency

• Diagnostic tests:

vonWillebrandtype



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



– 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



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



• 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



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



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



• Fresh frozen plasma

• Coagulation inhibitor concentrate (ATIII)

Classification of platelet disorders

• Quantitativedisorders

– Abnormal distribution

– Dilution effect

– Decreased

production

• Qualitative disorders

– Inherited disorders(rare)

Acquireddisorders



production

– Increaseddestruction

– Acquired disorders• Medications

• Chronic renal failure

• Cardiopulmonarybypass

Thrombocytopenia

Immune-mediated

IdioapthicDrug-inducedCollagen vascular diseaseLymphoproliferative disease

SarcoidosisN i ditd



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



)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



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)



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



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



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)



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



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



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



Measure time to clot

• Variables: – Source and quantity of thrombin

Causes of prolonged Thrombin Time

• Heparin

• Hypofibrinogenemia• Dysfibrinogenemia

• Elevated FDPs or paraprotein

• Thrombininhibitors(Hirudin)



Thrombin inhibitors (Hirudin)• Thrombin antibodies

Classification of thrombocytopenia• Associated with

leeding – Immune-mediated

thromocytopenia)I"%*

– !ost others

• Associated withthromosis – "hromotic

thromocytopenicpurpura

– Heparin-associated

thromocytopenia



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



surgical blood loss

• Not recommended for routine testing inpreoperative patients

• Drugs and blood productsused for bleeding



Treatment Approaches to

the Bleeding Patient

• Red blood cells

• Platelet transfusions

• Fresh frozen plasma

• Cryoprecipitate

• Amicar

• DDAVP



DDAVP• Recombinant Human factor VIIa

RBC transfusion therapy

Indications

• Improve oxygen carrying capacity of blood

–Bleeding

–Chronic anemia that is symptomatic

–Peri-operativemanagement



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



CMV negative patients Prevents transmission

Washed RBC PNH patients Prevents hemolysis

IgA deficient recipient Prevents anaphylaxis


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



g y y pulmonary edema


Adverse reactions

Non-immunologic reactions

Congestive heart failure Volume overload

Fever and shock Bacterial contamination



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



,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)



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



• 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



• Note – Viral screened product

– ABO compatible

Cryoprecipitate• Prepared from FFP

• Content – Factor VIII, von Willebrand factor, fibrinogen

• Indications – Fibrinogen deficiency

– UremiavonWillebranddisease



– 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



• 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



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



– 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



• Use non-transfusional drugs whenever possible

• RBC transfusions for surgical procedures or large

blood loss

.leedin Disorders 7emophilia



.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 ,



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



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



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



p – Second generation o &actor B,,, are

made with animal or human proteins.

,diopathicthrombocytopenicpurpura



I"%• Idiopathic thromocytopenic purpura

– Idiopathic ^ cause is un#nown

– "hromocytopenic ^ lood does nothave enough platelets

– %urpura ^ e2cessive leeding = ruising



Symptoms• Random purpura

•pista2is, hematuria, hematemesis,and menorrhagia

• %etechiae and hemorrhagic ullae inmouth



Cuanou pcia and cc-o



&iagnostic "ests• ow platelet count

•%eripheral lood smear• Antiplatelet antiodies



;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



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



• %ossile thromosis ater heparin therapy – an e triggered y any type, route or amount o heparin

19/04/2011 544

+ ,ce greu[



B!ood (o&"u!&tion disorders



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.



!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



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.



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.



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,



*# # # ,

• $ 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,















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



"

(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



"

– !&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 + ,



*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



Pete(+i&e% #ur#ur&s



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,.



H&e)&to)&s



Intr&)us(u!&r ine(tion )&= e ver= d&n"erous to

t+e #&tient it+ & !eedin" disorder



?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,



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



?

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



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



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



+&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+ !



!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.



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



!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.



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



– 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.





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



&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,





Ot+er t=#es of !eedin"$su(ut&neous% intr&)us(u!&r +e)&to)&s% "&strointestin&!

!eedin"% +e)&turi&% (erer&! +e)orr+&"e



?o!)&nnFs (ontr&(ture

L&r"e +&e)&to)& of t+e(eree!!u)*(o)#uter to)o"r&#+=,

Pseudotu)or



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



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+.



&(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



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"



Re(o))ended doses of ?III;I forv&rious t=#es of +&e)orr+&"e



&(tor re#!&(e)entat the consulting

room



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.



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.



!&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



+e)o#+i!i& needs to (ontro! +is ei"+t so t+&t +e does not

#ut e8tr& stress on +is oints% es#e(i&!!= if +e +&s &rt+ritis.

Dent&! +e&!t+ is ver= i)#ort&nt in +&e)o#+i!i&$

2 He&!t+= teet+ &nd "u)s redu(e t+e need for +&e)o#+i!i&

tre&t)ent.

2 Re"u!&r dent&! (&re redu(es t+e need for ine(tions &nd

sur"er=.

- Dent&! (&re s+ou!d in(!ude rus+in"% f!ossin"% &nd (+e(2u#s

= & dentist.

- Coo#er&tion eteen +e)&to!o"ists *+e)ost&seo!o"ists, &nd

dentists is ne(ess&r=.



=




S MED,C,@A ,@TE"@A

Hematologie E

#ymphomas

%ro univ dr Ion ."intoiu



;ormal Hemostasis

=rimary 7emostasis• BascularSub

endthel• von 1illebrand

&actor(v1)

• =latelets

&econdar'emost asis

• #ctivation ofibrinogen toibrin( IntrinsicE*trinsi

c "lotting"ascades)

Di l ti f



• Dissolution ofibrin "lots



H%%a

Coagulation cascade

%ntrinsic system C+ura4e 4ota4tD

H%%

H% H%a

&issue factor

%H %Ha %%a %%

%%% %%%a

$6trinsic system Ct!++ue damag

H Ha



%%a

a

%%

+ibrinogen +ibrin

F&hrombinG%%a

itamin K dependant factors

%etechiae

$o no blanc i

Ftypical of platelet disordersG



prur

!c angio-a"

o palpabl !c 'aculii"

<cc-o

*t=#i(&! of(o&"u!&tion

f&(tor

disorders,



Hemarthro+!+ Ca4uteD





+arge pseudocst involving the left

pro*imal femur



Pathogee+!+ o :#

Co&"u!&tion irino!=sis

irino"en

irin

Mono)ers irin*o"en,

D d ti

T+ro)in P!&s)in

Re!e&se oft+ro)o#!&sti()&teri&! into(ir(u!&tion

Consu)#tion of

(o&"u!&tion f&(tors

↑ &PTT

↑ PT

↑ TT

↓ irino"en

Presen(e of #!&s)in↑ DP

I t ! ! t



irin

C!ot

*intr&v&s(u!&r,

De"r&d&tion

Produ(ts

P!&s)in

Intr&v&s(u!&r (!ot

↓ P!&te!ets

S(+isto(=tes

• "H ;&



Documents

Curs Hematologie