Gangguan

Myeloproliferatif Kronik

Definisi
Gangguan myeloproliferatif kronik :
gangguan akibat abnormalitas clonal
hematopoetic stem cell yg didapat (akuisita),
mengakibatkan peningkatan selularitas sum2
tulang yg diikuti peningkatan jumlah sel darah
perifer
gangguan ini berpotensi menjadi lekemia akut

_______________________________________
Hematopoetic stem cell : sel primitif sum2
tulang, asal dari seluruh jenis sel darah
Clonal/Monoclonal : propagasi sel yang
berasal dari sel progenitor tunggal

Gangguan Myeloproliferatif
Kronik
Polisitemia Vera (PV) : eritrosit
Trombositosis Esensial (TE) : trombosit
Myelofibrosis Idiopatik Kronik : fibrosis
sum2 tulang
Chronic Myelocytic Leukemia (CML) :
lekosit seri myeloid
CML memiliki abnormalitas kromosom unik
(kromosom Philadelphia) yg tidak didapat pd
kelainan lain, perjalanan klinis & implikasi
terapi berbeda CML dibicarakan dlm
keganasan hematologi

Perbandingan Gangguan
Myeloproliferatif
Morfologi Platelet
SDM

HCT

Lekosit

N atau N

AbN
N

Tdk khas N atau Tdk khas Myelo

fibrosis
N atau
N atau PV

CML

N atau TE

Polisitemia Vera
Kenaikan HCT > 54 () dan 51().
Evaluasi awal : massa eritrosit
(ml/kg) DD dgn hemokonsentrasi
(polisitemia spuria)
Klinis PV :, massa eritrosit tanpa
sebab sekunder
Saturasi oksigen arteri normal
Kadar eritropoetin (EPO) normal/rendah
splenomegali

Polisitemia Vera
Essentials of Diagnosis
Increased red blood cell mass.
Splenomegaly.
Normal arterial oxygen saturation.
Usually elevated white blood count
and platelet count.

DD Polisitemia Vera
Polisitemia spuria : cairan tubuh
pemakaian diuretik, sebab lain
Polisitemia sekunder :
Hipoksia : penyakit jantung, paru,
ketinggian
HbCO2 : merokok
Lesi ginjal
Tumor dgn sekresi EPO
Hb abnormal

Causes of
polycythemia.
Spurious polycythemia
Primary polycythemia : PV
Secondary polycythemia
Hypoxia: cardiac disease,
pulmonary disease, high
altitude
2. Carboxyhemoglobin: smoking
3. Renal lesions

1.

Sign and simptom

Symptoms related to expanded blood volume and
increased blood viscosity.
Common complaints: headache, dizziness, tinnitus,
blurred vision, and fatigue. Generalized pruritus,and
epistaxis.
60% are men, and the median age at presentation is
60 years. Polycythemia rarely occurs in persons under
age 40 years.
Physical examination: reveals plethora and engorged
retinal veins. Spleenomegaly in 75% of cases but is
nearly always enlarged when imaged
Thrombosis is the most common complication of
polycythemia vera and the major cause of morbidity
and death.
There is a high incidence of peptic ulcer disease.

Laboratory Finding

Hematocrit above normal, at times greater than 60%.

Red blood cell morphology is normal.
The red blood cell mass is elevated.
The white blood count is elevated to 10,000-20,000/uL
The platelet count is variably increased, sometimes to
counts exceeding 1,000,000/uL.
Platelet morphology is usually normal.
The bone marrow is hypercellular, with panhyperplasia
Iron stores are usually absent from the bone marrow
Overproduction of uric acid may lead to hyperuricemia.
Microcytosis, hypochromia, and poikilocytosis may result
from iron deficiency
Progressive hypersplenism may also lead to elliptocytosis.

Differensial Diagnosis
Laboratory features of myeloproliferative disorders.

WhiteCount Hematocrit Platelet Count

cellMorphology
Chronic myeloid leukemia
I
N
N or I
N
Myelofibrosis
N or D or I
N or I
D or N or I
Abn
Polycythemia vera
N or I
I
N or I
N
Essential thrombocytosis
N or I
N
I
N

Red

Terapi Polisitemia Vera

Terapi pilihan : flebotomi sd HCT <
45
Obat myelosupresan : hydoxyurea,
indikasi
keperluan flebotomi terlalu sering
trombositosis
terapi suportif: antitrombotik

Treatment
Phlebotomy. One unit of blood
(approximately 500 mL) weekly target:
less than 45%.
Myelosuppressive therapy : a high
phlebotomy requirement, thrombocytosis,
and intractable pruritus. Hydroxyurea >>
Alkylating because of less leukemogenic
potential. The usual dose is 500-1500
mg/d orally Target: platelets < 500,000/uL
and neutrophil count < 2000/uL.
Anagrelide is a new drug for trombositosis
Low-dose aspirin (81-325 mg daily) has
been shown to reduce the risk of
thrombosis.

Prognosis
Polycythemia is an indolent disease with
median survival of 11-15 years.
The major cause of morbidity and
mortality is arterial thrombosis.
Polycythemia vera may convert to
myelofibrosis or to chronic myelogenous
leukemia. In approximately 5% of cases,
the disorder progresses to acute
myelogenous leukemia, which is usually
refractory to therapy.

Trombositosis Esensial

Peningkatan trombosit tanpa sebab lain

Massa eritrosit N
Kromosom Philadelphia (-) DD dgn CML
Klinis berisiko trombosis, atau justru
terjadi perdarahan krn defek platelet
kualitatif
DD :
* Polisitemia Vera
* Trombositosis reaktif (pada infeksi, anemia
def besi, perdarahan)
Jumlah trombosit pd trombositosis reaktif
jarang > 1 juta/mmk

Essential Trombositosis
Essentials of Diagnosis
Elevated platelet count in absence of
other causes.
Normal red blood cell mass.
Absence of Philadelphia
chromosome.

Symptoms and Signs

Median age: 50-60 years, slightly
increased incidence in women.
Finding of an elevated platelet count.
First sign is thrombosis. Venous
thromboses may occur in unusual sites
such as the mesenteric, hepatic, or portal
vein.
Some patients experience
erythromelalgia(painful burning and
erythema)
Bleeding
Splenomegaly is present in at least 25% of
patients.

Laboratory Findings
Elevated platelet count is the hallmark of this
disorder, and may be over 2,000,000/uL.
WBC mildly elevated (not above 30,000/uL), but with
some immature myeloid forms.
The hematocrit is normal.
The peripheral blood smear reveals large platelets,
but giant degranulated forms seen in myelofibrosis
are not observed.
Red blood cell morphology is normal.
The bleeding time is prolonged in 20% of patients.
The bone marrow : increased megakaryocytes but no
other morphologic abnormalities.
The Philadelphia chromosome is absent to
differentiate from chronic myeloid leukemia.

Differensial Diagnosis
Laboratory features of myeloproliferative disorders.

WhiteCount Hematocrit Platelet Count

cellMorphology
Chronic myeloid leukemia
I
N
N or I
N
Myelofibrosis
N or D or I
N or I
D or N or I
Abn
Polycythemia vera
N or I
I
N or I
N
Essential thrombocytosis
N or I
N
I
N

Red

Terapi Trombositosis
Esensial
Terapi myelosupresan utk mencegah
trombosis : hydroxyurea target
terapi AT < 500.000/mmk
Low dose aspirin, untuk mencegah
trombosis belum disepakati

Treatment
Standard therapy has consisted of
hydroxyurea in a dose of 0.5-2 g/d.
Anagrelide is highly effective in a dose of
2-4 mg/d but may cause headache, mild
anemia, and peripheral edema, and in
high doses congestive heart failure.
Vasomotor symptoms such as
erythromelalgia and paresthesias respond
rapidly to aspirin and eventually to control
of the platelet count.
Plateletpheresis.

Prognosis
Essential thrombocytosis is an indolent
disorder
Average survival is longer than 15 years from
diagnosis
The major source of morbidity thrombosis
can be reduced by appropriate platelet control.
The bone marrow may become fibrotic, and
massive splenomegaly may occur, sometimes
with splenic infarction.
There is a 10-15% risk of progression to
myelofibrosis after 15 years, and a 1-5% risk of
transformation to acute leukemia over 20 year

IDIOPATHIC (AUTOIMMUNE)
THROMBOCYTOPENIC PURPURA
Essentials of Diagnosis
Isolated thrombocytopenia.
Other hematopoietic cell lines
normal.
No systemic illness.
Spleen not palpable.
Normal bone marrow with normal or
increased megakaryocytes.

Patophysiology
ITP: autoimmune disorder in which
an IgG autoantibody is formed that
binds to platelets.
Platelets are not destroyed by direct
lysis.
Destruction takes place in the
spleen, where splenic macrophages
with Fc receptors bind to antibodycoated platelets.
Splenectomy is highly effective

Symptoms and Signs

ITP commonly in childhood
Precipitated by viral infection and usually
self-limited.
Adult form is usually a chronic disease and
only infrequently follows a viral infection.
Incidence between ages 20 and 50 years,
and there is a 2:1 female predominance.
Presenting complaint is mucosal or skin
bleeding (epistaxis, oral bleeding,
menorrhagia, purpura, and petechiae).
An enlarged spleen should lead one to
doubt the diagnosis.

Laboratory Findings
The hallmark of the disease is
thrombocytopenia, with platelet counts
that may be less than 10,000/uL.
Other counts are usually normal except for
occasional mild anemia, which can be
explained by bleeding or associated
hemolysis (Evans's syndrome).
Peripheral blood cell morphology is normal
except that platelets are slightly enlarged
(megathrombocytes).
The bone marrow will appear normal, with
a normal or increased number of
megakaryocytes.

Differensial Diagnosis
Causes of thrombocytopenia.
Bone marrow disorders
1.Aplastic anemia
2.Hematologic malignancies
3.Myelodysplasia
4.Megaloblastic anemia
5.Chronic alcoholism
. Nonmarrow disorders
1.Immune disorders
2.Idiopathic thrombocytopenic purpura
3.Drug-induced
4.Secondary (CLL, SLE)1

1.Posttransfusion purpura
2.Hypersplenism
3.Disseminated intravascular coagulation
4.Thrombotic thrombocytopenic purpura
5.Hemolytic-uremic syndrome
6.Sepsis
7.Hemangiomas
8.Viral infections, AIDS
9.Liver failure
10.CLL = chronic lymphocytic leukemia;
11.SLE = systemic lupus erythematosus.

Treatment
Initial treatment is with prednisone, 1-2
mg/kg/d. Prednisone works primarily by
decreasing the affinity of splenic
macrophages, reduces the binding of
antibody to the platelet surface, decrease
antibody production, enhanced vascular
stability.
the risk of bleeding is small with platelet
counts above 50,000/uL.
An alternative steroid regimen is the use
of high-dose dexamethasone, 40 mg/d for
4 days.
Splenectomy is the most definitive
treatment for idiopathic thrombocytopenic
purpura, Splenectomy is indicated if

Treatment
High-dose intravenous immunoglobulin, 1 g/kg
for 1 or 2 days, is highly effective in rapidly
raising the platelet count. Use for bleeding
emergencies or situations.
Danazol, vincristine, azathioprine,
cyclosporine, and cyclophosphamide.
Rituximab can produce good responses in
some patients with refractory disease.
Platelet transfusions are rarely used in the
treatment of idiopathic thrombocytopenic
purpura,

Prognosis
The prognosis for remission is good.
The major concern during the initial
phases is cerebral hemorrhage,
which becomes a risk when the
platelet count is less than 5000/uL.
Very low platelet counts caused fatal
bleeding is rare.

THROMBOTIC THROMBOCYTOPENIC PURPURA

Essentials of Diagnosis
Thrombocytopenia.
Microangiopathic hemolytic anemia.
Neurologic and renal abnormalities,
fever.
Reduced level of ADAMTS13.
Normal coagulation tests.
Elevated serum LDH.

Introducing
TTP is an uncommon syndrome with
microangiopathic hemolytic anemia,
thrombocytopenia, and a markedly elevated
serum LDH.
Deficiency of a von Willebrand factor-cleaving
protease, ADAMTS13, to platelet
agglutination and adhesion to endothelium.
TTP is seen primarily in young adults
between ages 20 and 50 years, female
predominance.
The syndrome is occasionally precipitated by
estrogen use, pregnancy, drugs, or
infections. The most common drugs
implicated are quinine and ticlopidine.

Symptoms and Signs

Anemia, bleeding, or neurologic
abnormalities.
Neurologic symptoms include headache,
confusion, aphasia, and alterations in
consciousness from lethargy to coma. With
more advanced disease, hemiparesis and
seizures may occur.
On examination, the patient appears acutely
ill and is usually febrile. Pallor, purpura,
petechiae,
Patients may have abdominal pain and
tenderness due to pancreatitis.

Differential Diagnosis

The normal values of coagulation

tests differentiate TTP from DIC.
Other conditions causing
microangiopathic should be excluded
Evans's syndrome is the
combination of autoimmune
thrombocytopenia and autoimmune
hemolytic

Laboratory Findings
Anemia
Reticulocytosis and circulating nucleated
red blood cells.
The hallmark is a microangiopathic blood
picture with fragmented red blood cells
Thrombocytopenia is invariably present
and may be severe.
Increasing indirect bilirubin
LDH is markedly elevated in proportion
to the severity of hemolysis;
Coombs test is negative.

 Coagulation tests (prothrombin time,

partial thromboplastin time, fibrinogen)
are normal unless ischemic tissue damage
causes secondary disseminated
intravascular coagulation
(DIC) present elevated fibrin degradation
products may be seen.
ADAMTS13 is usually absent during active
disease.
Pathologically, there may be thrombi in
capillaries and small arteries, with no
evidence of inflammation.

Differensial Diagnosis
Evans's syndrome is the combination of
autoimmune thrombocytopenia and
autoimmune hemolytic anemia, but the
peripheral smear will show spherocytes
and not red blood cell fragments.
TTP and hemolytic-uremic syndrome are
not distinct disease entities, TTP
characterized by more neurologic and
severe thrombocytopenia and hemolyticuremic syndrome with more renal failure.

Treatment
Plasmapheresis. 60 to 80 mL/kg of plasma should
be removed and replaced with fresh-frozen
plasma.
Treatment should be continued daily until the
patient is in complete remission.
Prednisone and antiplatelet agents (aspirin [325
mg three times daily] and dipyridamole [75 mg
three times daily])
The combination of splenectomy, corticosteroids,
and dextran has been used with success.
Splenectomy performed in remission may prevent
subsequent relapses.
Immunosuppression with drugs such as
cyclophosphamide has also been effective.

Prognosis
With plasmapheresis, 80 to 90
percent of patients now recover
completely.
Neurologic abnormalities are almost
always completely reversed.
Most complete responses are
durable, but in 20% of cases the
disease will be chronic and relapsing.

Myelofibrosis Idiopatik
Kronik
Adanya proses fibrosis pd sum2 tulang, yg diduga
dipicu pelepasan platelet-derived growth factor
(PDGF) dan sitokin lain
Fibrosis sum2 tulang hematopoesis ekstra
meduler (hepar, splen, dan lnn) gagal sum2
tulang (bone marrow failure) pd tahap akhir
Klinis : splenomegali masif dgn anemia
gambaran drh tepi leukoeritroblastik (AL, eritrosit
berinti , skistosit)
hapusan sum2 tulang : hiperselular sum2 tulang dgn
fibrosis retikuler/kolagen

Prognosis terburuk di antara gangguan

myeloproliferatif

Terapi Idiopatik
Myelofibrosis
Suportif : mengatasi anemia
Thalidomide
Transplantasi sum2 tulang allogenik
(berasal dari orang lain)

Sindrom Myelodisplasia
(MDS)

Definisi
Kelainan clonal stem cell akuisita dgn ciri
Sitopenia
Sum2 tulang hiperselular
Adanya abnormalitas sitogenetik dan
morfologi sel

Kausa : idiopatik, sebagian kasus terjadi

pasca kemoterapi sitotoksik
Preleukemic state menjadi AML pd
10-50% kasus
Tidak terdapat abnormalitas kromosom
spesifik

Sindrom Myelodisplasia (Pembagian

WHO)

Refractory anemia (RA)

RA with ringed sideroblast (RARS)
RA with excess blast-1 (RAEB-1)
RA with excess blast-2 (RAEB-2)
MDS, unclassified
MDS with isolated del(5q)

Terapi MDS
Suportif dan allotransplan

ALHAMDULILLAH