Polycythemia vera (PV) and essential thrombocythemia (ET) are types of myeloproliferative neoplasms characterized by increased red blood cells in PV and increased platelets in ET. Both can involve increased white blood cells and risk of thrombosis, spleen enlargement, itching, and progression to acute myeloid leukemia or myelofibrosis. PV and ET involve an acquired abnormal clone with mutations in genes like JAK2 and MPL. The document discusses diagnostic criteria and distinguishing PV and ET from secondary causes of increased red blood cells or platelets. Bone marrow testing is often not required if criteria are met.

1. 真性多血症と血小板増加症
Polycythemia vera, essential thrombocythemia

2. PVとET
• PVとETは其々RBC, PLTが増加する骨髄増殖性疾患の1つ.
また,WBC上昇, 脾腫, 血栓症, 掻痒感(特に入浴後)を伴い,
AMLや骨髄線維症へ進展するリスクが少なからずある.
• Myeloproliferative neoplasm(MPN)
• BCR-ABL1陰性MPNに,
PV, ET, 骨髄線維症が含まれる.
TABLE I. World Health Organization (WHO) classification of
myeloid malignancies
1. Acute myeloid leukemia (AML) and related precursor neoplasmsa
2. Myeloproliferative neoplasms (MPN)
2.1. Classic MPN
2.1.1. Chronic myelogenous leukemia, BCR-ABL1 positive (CML)
2.1.2. Polycythemia vera (PV)
2.1.3. Primary myelofibrosis (PMF)
2.1.4. Essential thrombocythemia (ET)
2.2. Nonclassic MPN
2.2.1. Chronic neutrophilic leukemia (CNL)
2.2.2. Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS)
2.2.3. Mastocytosis
2.2.4. Myeloproliferative neoplasm, unclassifiable (MPN-U)
rymyelofibrosisa
datypiac
accompaniedby
enfibrosis,ord
ML,PV,MDS,orothermyeloidneoplasm
orotherclonalmarkerornoevidence
ythemiavera;PMF,primarymyelofibrosis;
osisrequiresmeetingallthreemajorcrite-
iatedwithasustainedincreaseof!2g/dL
annual clinical updates in hematological malignancies: a continuing medical education series
TABLE I. World Health Organization (WHO) classification of
myeloid malignancies
1. Acute myeloid leukemia (AML) and related precursor neoplasmsa
2. Myeloproliferative neoplasms (MPN)
2.1. Classic MPN
2.1.1. Chronic myelogenous leukemia, BCR-ABL1 positive (CML)
2.1.2. Polycythemia vera (PV)
2.1.3. Primary myelofibrosis (PMF)
2.1.4. Essential thrombocythemia (ET)
2.2. Nonclassic MPN
2.2.1. Chronic neutrophilic leukemia (CNL)
2.2.2. Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS)
2.2.3. Mastocytosis
2.2.4. Myeloproliferative neoplasm, unclassifiable (MPN-U)
3. Myelodysplastic syndromes (MDS)
3.1. Refractory cytopeniab
with unilineage dysplasia (RCUD)
3.1.1. Refractory anemia (ring sideroblasts < 15% of erythroid precursors)
3.1.2. Refractory neutropenia
3.1.3. Refractory thrombocytopenia
3.2. Refractory anemia with ring sideroblasts (RARS; dysplasia limited to
erythroid lineage and ring sideroblasts ! 15% of bone marrow erythroid
precursors)
3.3. Refractory cytopenia with multi-lineage dysplasia (RCMD; ring sideroblast
count does not matter)
3.4. Refractory anemia with excess blasts (RAEB)
3.4.1. RAEB-1 (2À4% circulating or 5À9% marrow blasts)
3.4.2. RAEB-2 (5À19% circulating or 10À19% marrow blasts or Auer rods
present)
3.5. MDS associated with isolated del(5q)
3.6. MDS, unclassifiable
4. MDS/MPN
4.1. Chronic myelomonocytic leukemia (CMML)
4.2. Atypical chronic myeloid leukemia, BCR-ABL1 negative
4.3. Juvenile myelomonocytic leukemia (JMML)
4.4. MDS/MPN, unclassifiable
4.4.1. Provisional entity: refractory anemia with ring sideroblasts associated
with marked thrombocytosis (RARS-T)
5. Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of
PDGFRA,c
PDGFRB,c
or FGFR1c
5.1. Myeloid and lymphoid neoplasms with PDGFRA rearrangement
5.2. Myeloid neoplasms with PDGFRB rearrangement
5.3. Myeloid and lymphoid neoplasms with FGFR1 abnormalities
annual clinical updates in hematological malignancies: a contin
Am. J. Hematol. 87:285-293, 2012.

3. • PVの好発年齢は60歳台. <50歳での発症はPVの1/3
• 臨床経過は3つに分類される;
① 検査にて偶発的に発見 (最も多い)
② 血栓症で発見 (~30%, 内12%が重度の血栓症)
③ 疾患による症状にて発見
• 血液検査は全血球が上昇していることが多く,
脾腫はPVの30-40%で認められ, 特に全血球の上昇パターン例で多い.
Blood. 2012;120(2):275-284

4. 二次性のRBC上昇
• PVを考慮した場合, 先ず二次性のRBC上昇をチェック.
ただし, 全血球が上昇している場合は先ずPVをチェックする.
• 喫煙歴, 睡眠時無呼吸, 肺疾患, 心疾患, 肝臓, 腎臓腫瘍.
• EPO値はPVでは低下し, 二次性では上昇する.

5. acquired abnormal clone, an erythrocytosis and
an increased white cell and platelet count. Ther
well-accepted diagnostic criteria7,8
for polycyth
The majority of patients have a clone of cells w
JAK2 where there is a gain-of-function mutatio
Val617Phe, which leads to a constitutively acti
A small minority of patients, who are negative
JAK2V617F mutation but have a polycythemia
phenotype, have been found to have mutations
of JAK2.10
Individuals with these mutations ten
predominately erythroid phenotype. Many were
idiopathic erythrocytosis before the discovery of
Secondary Erythrocytoses
The Oxygen-sensing Pathway
The human has sensitive mechanisms for the m
of erythropoiesis in response to hypoxia. This s
involves a number of proteins: the prolyl hydro
(PHDs), which exist in the isoforms PHD1, PHD
hypoxia-inducible factor (HIF), which is compo
unstable alpha subunit and a stable beta subun
von-Hippel-Lindau tumor suppressor protein (V
has three isoforms: HIF-1α, HIF-2α and HIF-3α
In normoxic conditions the PHDs hydroxylate t
subunits of HIF. This hydroxylation allows bin
Table 1. Causes of an erythrocytosis.
Primary ErythrocytosisPrimary ErythrocytosisPrimary ErythrocytosisPrimary ErythrocytosisPrimary Erythrocytosis
Congenital
Erythropoietin (EPO) receptor mutations
Acquired
Polycythemia vera (including JAK2 exon 12 mutations)
Secondary erythrocytosisSecondary erythrocytosisSecondary erythrocytosisSecondary erythrocytosisSecondary erythrocytosis
Congenital
Defects of the oxygen sensing pathway
VHL gene mutation (Chuvash erythrocytosis)
PHD2 mutations
HIF-2α mutations
Other congenital defects
High oxygen-affinity hemoglobin
Bisphosphoglycerate mutase deficiency
Acquired
EPO-mediated
Central hypoxia
Chronic lung disease
Right-to-left cardiopulmonary vascular shunts
Carbon monoxide poisoning
Smoker’s erythrocytosis
Hypoventilation syndromes including obstructive sleep
apnea
High-altitude
Local hypoxia
Renal artery stenosis
End-stage renal disease
Hydronephrosis
Secondary erythrocytosisSecondary erythrocytosisSecondary erythrocytosisSecondary erythrocytosisSecondary erythrocytosis
Congenital
Defects of the oxygen sensing pathway
VHL gene mutation (Chuvash erythrocytosis)
PHD2 mutations
HIF-2α mutations
Other congenital defects
High oxygen-affinity hemoglobin
Bisphosphoglycerate mutase deficiency
Acquired
EPO-mediated
Central hypoxia
Chronic lung disease
Right-to-left cardiopulmonary vascular shunts
Carbon monoxide poisoning
Smoker’s erythrocytosis
Hypoventilation syndromes including obstructive sleep
apnea
High-altitude
Local hypoxia
Renal artery stenosis
End-stage renal disease
Hydronephrosis
Renal cysts (polycystic kidney disease)
Post-renal transplant erythrocytosis
Pathologic EPO production
Tumors
Cerebellar hemangioblastoma
Meningioma
Parathyroid carcinoma/adenomas
Hepatocellular carcinoma
Renal cell cancer
Pheochromocytoma
Uterine leiomyomas
Drug associated
Erythropoietin administration
Androgen administration
Idiopathic erythrocytosisIdiopathic erythrocytosisIdiopathic erythrocytosisIdiopathic erythrocytosisIdiopathic erythrocytosis
Idiopathic erythrocytosis: a disappearing entity. Hematology 2009; 629-635

6. JAK 2遺伝子(Janus kinase 2; 9p24)
• PVではほぼ全例でJAK2遺伝子異常を認める.
exon14 (JAK2V617F)が96%, exon12が3%.
• 一方で, ETでは55%, 骨髄線維症では65%の陽性率.
また, ETや骨髄線維症ではexon12の変異は稀.
• MPL(myeloproliferative leukemia virus oncogene; 1p34)変異は
ETの4%, 骨髄線維症の8%で認められるが, PVでは稀.
Am. J. Hematol. 87:285-293, 2012.

7. PV, ETの診断criteria
• PVに対するJAK2V617Fは感度97%, 特異度100%であり,
PVの診断には非常に有用な検査となる.
(他のHt上昇する疾患との鑑別において)
• Epoは85%で低値となる.
骨髄検査はMajorを満たす群では必須ではない.
hingPVfromother
;thepossibilityof
testresultiseffec-
surementofserum
ctedtobesubnor-
PV[27].Asubnor-
JAK2V617Fman-
orJAK2exon12
ximately3%ofPV
[4].Bonemarrow
diagnosisofPV
ediagnosticcriteria
ftheydisplaysub-
4].
thedetectionof
nunderlyingMPN
ssibilitysinceupto
AK2V617F-negative
rJAK2V617F-posi-
intheirpresenta-
andrefractoryane-
edthrombocytosis
examinationisof-
phologicdiagnosis
yeloidneoplasms,
ssificationof
neoplasmsa
positive(CML)
specified(CEL-NOS)
MPN-U)
RCUD)
oferythroidprecursors)
dysplasialimitedto
bonemarrowerythroid
(RCMD;ringsideroblast
blasts)
rowblastsorAuerrods
egative
gsideroblastsassociated
ndabnormalitiesof
rearrangement
t
bnormalities
include‘‘therapy-related
g/dL,absoluteneutrophil
wever,higherbloodcounts
uivocalhistological/cytoge-
owthfactorreceptora/b
1(FGFR1).
TABLE II. World Health Organization (WHO) Diagnostic Criteria for Polycythemia Vera, Essential Thrombocythemia and Primary Myelofibrosis
2008 WHO Diagnostic Criteria
Polycythemia veraa
Essential thrombocythemiaa
Primary myelofibrosisa
Major criteria 1 Hgb >18.5 g/dL (men), >16.5 g/dL (women), orb
1 Platelet count !450 3 109
/L 1 Megakaryocyte proliferation and atypiac
accompanied by
either reticulin and/or collagen fibrosis, ord
2 Presence of JAK2V617F or JAK2 exon 12 mutation 2 Megakaryocyte proliferation with large and mature morphology 2 Not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm
3 Not meeting WHO criteria for CML, PV, PMF, MDS,
or other myeloid neoplasm
3 Demonstration of JAK2V617F or other clonal marker or no evidence
of reactive marrow fibrosis
4 Demonstration of JAK2V617F or other clonal marker
or no evidence of reactive thrombocytosis
Minor criteria 1 BM trilineage myeloproliferation 1 Leukoerythroblastosis
2 Subnormal serum Epo level 2 Increased serum LDH level
3 EEC growth 3 Anemia
4 Palpable splenomegaly
BM, bone marrow; Hgb, hemoglobin; Hct, hematocrit; Epo, erythropoietin; EEC, endogenous erythroid colony; WHO, World Health Organization; CML, chronic myelogenous leukemia; PV, polycythemia vera; PMF, primary myelofibrosis;
MDS, myelodysplastic syndromes; LDH, lactate dehydrogenase.
a
PV diagnosis requires meeting either both major criteria and one minor criterion or the first major criterion and two minor criteria. ET diagnosis requires meeting all four major criteria. PMF diagnosis requires meeting all three major crite-
ria and two minor criteria.
b
or Hgb or Hct >99th percentile of reference range for age, sex, or altitude of residence or red cell mass >25% above mean normal predicted or Hgb >17 g/dL (men)/>5 g/dL (women) if associated with a sustained increase of !2 g/dL
from baseline that cannot be attributed to correction of iron deficiency.
c
Small to large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering.
d
or In the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation, and often decreased erythropoiesis (i.e., pre-fibrotic PMF).
Am. J. Hematol. 87:285-293, 2012.
PVは2 Major, 1 Minor もしくは 1 Major, 2 Minorで診断.

8. • PLT上昇患者でJAK2V617Fが認められれば,
MPNの関与が疑われるが, 陰性でも否定は困難.(感度60%)
• またJAK2V617Fが認められても, ETとは言えず,
Prefibrotic PMFやRARS-TではPLTが上昇することがあり, 鑑別を要す.
従って, ETを疑う場合は骨髄 刺が必要.
Figure 1. Diagnostic algorithm for myeloproliferative neoplasms. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
annual clinical updates in hematological malignancies: a continuing medical education series
Am. J. Hematol. 87:285-293, 2012.

9. Figure 3. Diagnostic approach to erythrocytosis. Note 1 indicates familial erythrocyosis (eg, disorders of O2-sensing mechanisms, altered affinity of hemoglobin for O2);
note 2, primary familial and congenital polycythemia (PFCP).
Blood. 2012;120(2):275-284

10. pathway.44,45 Patients with primary familial and congenital polycy-
themia have isolated erythrocytosis, low EPO, no splenomegaly,
and a predisposition to severe cardiovascular (CV) problems.45 On
the other hand, the oxygen-sensing pathway consists of different
proteins involved in the regulation of erythropoietin production:
Risk factors for thrombosis
There is a general agreement among investigators to consider age
older than 60 years at diagnosis and a history of vascular events as
the 2 prognostic risk factors for thrombosis in PV (Table 3).54,55 The
European Collaboration on Low-Dose Aspirin in Polycythemia
Figure 1. Bone marrow histopathology in polycythe-
mia and postpolycythemia myelofibrosis. (A) Case of
PV showing hypercellular BM with trilineage proliferation
of all hematopoietic lineages, including prominent mega-
karyocytes (original magnification ϫ350). PAS indicates
periodic acid-Schiff reaction. (B) Case of PV by immuno-
histochemistry revealing red-stained neutrophil granulo-
poiesis and dark-blue nucleated erythropoietic precur-
sors as well as loose clusters of small to large
megakaryocytes (original magnification ϫ350; AS-D-
chloroacetate esterase reaction). (C) Case of post-PV
myelofibrosis showing decrease in overall cellularity and
only a few small and loose erythropoietic islets, abnormal
megakaryocytes, and greatly extended stroma compart-
ment (original magnification ϫ350). PAS indicates peri-
odic acid-Schiff reaction. (D) Case of post-PV myelofibro-
sis revealing effacement of hematopoiesis by dense
bundles of (yellow-brownish) collagen and reticulin fibers
associated with osteosclerosis enclosing few dispersed
megakaryocytes (original magnification ϫ350; Gomori
silver impregnation technique).
POLYCYTHEMIA VERA 277BLOOD, 12 JULY 2012 ⅐ VOLUME 120, NUMBER 2
For personal use only.by guest on August 15, 2013.bloodjournal.hematologylibrary.orgFrom
Blood. 2012;120(2):275-284

11. 家族性PVの評価
• MPN全例において, 家族歴のチェックは必要.
RBC増多では, 2つのタイプの家族性疾患に分類される
• EPO低値; primary familial and congenital PV
EPO正常, 高値; O2感受性障害, HbのO2結合障害, 先天性心疾患, 肺疾患
• 家族性PVでは, RBCの単独上昇を認め, EPOは低値で, 脾腫は伴わない.
また, 心血管障害の既往がある場合が多い.
Blood. 2012;120(2):275-284

12. • 家族性PVの評価
Figure 2. Approach to diagnose familial PV.
Blood. 2012;120(2):275-284

13. PV, ETのリスク評価と治療
• PV, ETのリスク評価 = 血栓症のリスク評価の意味であり,
生存率やMPFへの進展リスクの評価ではない.
• 生存率に関与する因子としては,
• 高齢, 血栓症既往, Leukocyte >11000/µL, 貧血, PLT上昇が挙げられる.
• ETの15年生存率は80%,AML, MF進展率1%未満と予後は良好
PVでは10年生存率>75%,AML転化 <5%, MF進展率 <10%.
transformation.Usingage!60years,hemoglobinbelow
normalvalueandleukocytecount>153109
/L,onestudy
demonstratedamediansurvivalof>20yearsintheab-
senceofallthreeriskfactorsand$9yearsinthepresence
oftwoofthethreeriskfactors[39].AsimilarstrategyinPV
revealedmediansurvivalsof$23and9yearsintheab-
senceofadvancedageandleukocytosisorpresenceof
bothriskfactors,respectively[36].Leukocytosishasalso
beenassociatedwithleukemic[36]andJAK2V617Fallele
burdenwithfibrotic[19]transformationinPV[19].Therela-
tionshipbetweenthrombosisandleukocytosis[40,41],
thrombosis,andJAK2V617F[5]orpregnancy-associated
complicationsandJAK2V617F[42À44]havebeenexam-
inedbydifferentgroupsofinvestigatorswithfindingsthat
wereconflictingandinconclusive.
Risk-Adaptedtherapy
BecausesurvivalinstrictlyWHO-definedETisnear-nor-
mal(15-yearsurvivalof$80%)andthe10-yearriskof
AMLorMFlessthan1%[20],itwouldbeinappropriateto
suggestthatanycurrenttreatmentmodifiesthenaturalhis-
toryofthedisease.Similarly,inWHO-definedPV,the10-
yearprojectedratesforsurvival,leukemictransformation,
andfibroticprogressionwere>75,<5,and<10%,respec-
tively[45].Incontrast,theriskofthrombosis,inbothPV
andET,exceeds20%andasubstantialproportionof
patientsexperiencevasomotordisturbances(e.g.,head-
aches,lightheadedness,acralparesthesias,erythromelal-
gia,atypicalchestpain)[46],andincaseofPV,pruritus
[47].Inaddition,inbothPVandET,somepatientsmayde-
velopacquiredvonWillebrandsyndrome(AvWS),espe-
ciallyinthepresenceofextremethrombocytosis(platelets
>1,0003109
/L),andbeatriskforaspirin-associated
bleeding[48].Accordingly,thegoalofcurrenttherapyinPV
andETisprimarilytopreventthrombohemorrhagiccompli-
cations,withoutincreasingbleedingrisk,andsecondarilyto
controltheaforementionedsymptoms.Inthisregard,treat-
mentistailoredtoindividualpatientsaccordingtotheirrisk
forthrombosisorbleeding(TableIV).
Managementoflow-riskPVorET,intheabsenceof
extremethrombocytosis
Controlledstudieshaveconfirmedtheanti-thrombotic
valueoflow-doseaspirininPV,amongallriskcategories
[49].Inaretrospectivestudy,aspirinusehasalsobeen
reportedtobebeneficialinJAK2V617F-positivelow-risk
ET,inpreventingvenousthrombosis,andalsoinpatients
withcardiovascularriskfactors,inpreventingarterialthrom-
bosis[50].Thereisalsouncontrolledevidencethatsup-
portsphlebotomyforallpatientswithPV[51]andtwo
recentstudiessuggestedahematocrittargetofeither
<55%[37]or<48%[45]asbeingacceptableinpatients
receivingaspirintherapy.
Low-doseaspirintherapyhasalsobeenshowntobe
effectiveinalleviatingvasomotor(microvascular)disturban-
cesassociatedwithETorPV[52].Vasomotorsymptomsin
ETconstituteheadaches,lightheadedness,transientneuro-
logicoroculardisturbances,tinnitus,atypicalchestdiscom-
fort,paresthesias,anderythromelalgia(painfulandburning
sensationofthefeetorhandsassociatedwitherythema
andwarmth).Thesesymptomsarebelievedtostemfrom
smallvessel-basedabnormalplatelet-endothelialinterac-
tions[53].Histopathologicalstudiesinerythromelalgiahave
revealedplatelet-richarteriolarmicrothrombiwithendothe-
lialinflammationandintimalproliferationaccompaniedby
increasedplateletconsumptionthatiscoupledwithabun-
dantVWfactordeposition[53À55].
Aspirintherapyisalsoconsideredtobeadequate,and
potentiallyusefulinpreventingcomplicationsduringpreg-
TABLE IV. Risk Stratification in Polycythemia Vera and Essential Thrombocythemia and Risk-Adopted Therapy
Risk categories Essential thrombocythemia Polycythemia vera Management during pregnancy
Low-risk without extreme thrombocytosis (age
<60 years and no thrombosis history)
Low-dose aspirin Low-dose aspirin 1 phlebotomy Low-dose aspirin 1 phlebotomy if PV
Low-risk with extreme thrombocytosis (platelets >1,000 3 109
/L) Low-dose aspirin provided ristocetin
cofactor activity >30%
Low-dose aspirin provided ristocetin cofactor
activity >30% 1 phlebotomy
Low-dose aspirin provided ristocetin cofactor
activity >30% 1 phlebotomy if PV
High-risk (age !60 years and/or presence of thrombosis history) Low-dose aspirin 1 hydroxyurea Low-dose aspirin 1 phlebotomy 1 hydroxyurea Low-dose aspirin 1 phlebotomy if PV 1 interferon-a
High-risk disease that is refractory or intolerant to hydroxyurea Low-dose aspirin 1 interferon-a (age <65
years) or busulfan (age !65 years)
Low-dose aspirin 1 phlebotomy 1 interferon-a
(age <65 years) or busulfan (age !65 years)
Low-dose aspirin 1 phlebotomy if PV 1 interferon-a
Am. J. Hematol. 87:285-293, 2012.

14. thrombosis. The most remarkable and relatively novel finding is the
fact that only male sex (P ϭ .04; hazard ratio [HR] ϭ 2) predicted
venous thrombosis. Although it is possible that sex differences in
vascular anatomy and response to inflammation explain the in-
creased risk of venous events in males,8 additional studies are
according to their JAK2V617F mutational status, leukocyte count,
and presence or absence of cardiovascular risk factors.
Finally and somewhat unexpectedly, the presence of extreme
thrombocytosis (platelet count Ͼ 1000 ϫ 109/L) independently as-
sociated with a lower risk of arterial thrombosis, in both the entire
Table 2. Multivariate analysis for risk factors predicting fatal and nonfatal thrombotic events in the follow-up of 891 WHO-ET patients
Parameters at diagnosis
Major thrombosis (n ‫؍‬ 109) Arterial thrombosis (n ‫؍‬ 79) Venous thrombosis (n ‫؍‬ 37)
HR (95% CI) P HR (95% CI) P HR (95% CI) P
Age Ͼ 60 y 1.50 (1.00-2.25) 0.049 1.69 (1.05-2.73) 0.031 1.26 (0.63-2.52) .506
Previous thrombosis 1.93 (1.27-2.91) 0.002 2.07 (1.28-3.34) 0.003 1.78 (0.86-3.66) .119
Male sex 1.34 (0.91-1.95) 0.135 0.98 (0.62-1.54) 0.919 1.99 (1.03-3.83) .039
CV risk factors* 1.56 (1.03-2.36) 0.038 1.91 (1.19-3.07) 0.007 0.77 (0.33-1.83) .556
WBC Ͼ 11 ϫ 109/L 1.14 (0.72-1.79) 0.583 1.66 (1.01-2.72) 0.044 0.52 (0.19-1.38) .516
Hemoglobin Ͻ 12 g/dL 1.36 (0.58-3.18) 0.479 1.53 (0.60-3.93) 0.376 0.48 (0.06-3.72) .479
Platelet count Ͼ 1000 ϫ 109/L 0.50 (0.30-0.84) 0.009 0.42 (0.22-0.78) 0.007 0.97 (0.44-2.15) .943
JAK2V617F 2.04 (1.19-3.48) 0.009 2.57 (1.27-5.19) 0.009 1.43 (0.65-3.11) .372
Analysis adjusted also for chemotherapy and antiplatelet needs during follow-up.
CV indicates cardiovascular; and WBC, white blood cell count.
*Smoking, arterial hypertension, and diabetes (at least one).
血栓症のリスク因子; ET 891名の解析
Blood. 2011;117(22): 5857-5859

15. • リスクに応じた治療;
• 前述の通り, PV, ETは生命予後は悪くないが,
血栓症や血管症状(頭痛, めまいなど)は20%以上で認める為,
血栓症リスクに応じた治療が必要となる.
• Low-risk PV, ETで著明なPLT上昇が無い患者群への治療
• アスピリンは全PV症例と,
JAK2V617F陽性Low-risk ET患者と, 心血管リスク(+)群への投与が推奨.
• 瀉血療法は全PV患者へ推奨され, 目標Ht値は<55%, もしくは<48%.
• 妊娠可能女性や妊婦でも同様の治療方針をとるが,
ヘパリンやPLT低下させる薬剤(Hydroxyurea)は避ける.
• Hydroxyureaは症状がとれれば, PLT 400k/µLを達成する必要は無い.
Am. J. Hematol. 87:285-293, 2012.

16. • Low-risk PV, ETで著明なPLT上昇がある,
もしくは出血リスクのある患者群への治療
• PV, ETで出血傾向を示すのは, 様々な因子が関連する.
1つはvWF multimerの低下が関連しているとされる.
• 上記理由より, この患者群へのアスピリンの使用は注意が必要.
特にPLT>1000k/µLの患者群へアスピリンを使用することで,
後天性vWF症候群が生じ, 出血リスクが上昇する可能性がある.
• このような患者群では, 先ず凝固因子をチェックし,
活性が<30%ならばアスピリンを控える方が良いと考えられる.
Am. J. Hematol. 87:285-293, 2012.

17. • High-risk PV, ETの治療
• AlkylatingTherapy (Hydroxyurea, pipobroman)はAMLへの転化率を低下させる
• IFN治療はRBC, PLT増加を抑制し得る (3MU SC 3回/wk).
また, 脾腫の改善効果や, 掻痒感の改善効果が期待できる治療.
• peg-INF-α ~90µg SC/wkの投与にて, 寛解率80%を見込め,
さらにJAK2V617Fの低下が認められた(CR 5-10%).
Am. J. Hematol. 87:285-293, 2012.

18. se aspirin (100 mg daily)
ested double-blind, place-
al trial carried out in the
Five hundred and eighteen
P study population) with-
ndication to aspirin were
nt was 61 years and 59%
ardiovascular events were
o that this trial included
k population. Median fol-
nificantly lowered the risk
including cardiovascular
tion, nonfatal stroke and
relative risk 0.4 [95% CI
cardiovascular mortality
59%, respectively. Major
htly increased by aspirin
Fig. 1 Flow-chart of recommended treatment for patients with
polycythaemia vera (PV)
Intern Emerg Med (2007) 2:13–18

19. Polycythemia veraの治療目標
• CYTO-PV trial; JAK-2陽性のPV患者365名のRCT.
• 瀉血療法, Hydroxyureaにて治療.
治療目標Ht <45%群 vs 45-50%群に割り付け,
心血管イベント, 死亡, 血栓症リスクを比較.
• 治療は抗血小板薬(84.4%), 瀉血(68%), Hydroxyurea(52.6%), 降圧薬(48.2%)
• アウトカム;(31mフォロー)
N Engl J Med 2013;368:22-33.
Outcome <45% 45-50% HR
心血管イベント 4.4% 10.9% 2.69[1.19-6.12]
全死亡 1.6% 3.3% 2.15[0.54-8.62]
心血管死亡 0 2.2% NA
MI死亡 0 0.5% NA
Stroke死亡 0 1.1% NA
肺塞栓死亡 0 0.5% NA
心血管イベントは増加.
両群で死亡リスクは同等.

20. N Engl J Med 2013;368:22-33.
Outcome <45% 45-50% HR
非致死的MI 1.6% 0 NA
非致死的Stroke 0 2.2% NA
非致死的動脈血栓症 0 1.6% NA
非致死的DVT 0.5% 2.2% 4.11[0.46-36.74]
非致死的PE 0 0.5% NA
TIA 0.5% 2.2% 4.24[0.47-37.97]
血栓性静脈炎 2.2% 1.1% 0.51[0.09-2.79]
出血 1.1% 2.7% 2.53[0.49-13.06]
MI, Stroke, DVT, PE, 塞栓症どれも個別には有意差ないが,
まとめると若干の有意差を認め, Ht<45%群の方が
治療目標として優れていると判断される
N Engl J Med 2013;368:22-33.

21. 0.50 1.00 2.00 4.00 8.00 16.00
High HCT Better Low HCT Better
Sex
Female
Male
Age
≤66.8 yr
>66.8 yr
Thrombosis
No
Yes
Risk
Low
High
Platelet count
≤364,000/mm3
>364,000/mm3
White-cell count
≤8600/mm3
>8600/mm3
Splenomegaly
Yes
No
Diabetes
Yes
No
Hypertension
Yes
No
Type of therapy
Phlebotomy
Drug therapy
Both
Aspirin use
Yes
No
Anticoagulant use
Yes
No
Overall
Hazard Ratio (95% CI)High HCT Low HCTSubgroup
0.25
19.90 (1.13–349.0)
3.91 (1.45–10.53)
3.68 (1.21–11.18)
4.62 (0.52–41.35)
6.60 (0.79–54.86)
2.66 (0.52–13.72)
10.81 (1.38–84.43)
2.17 (0.65–7.21)
0.91 (0.06–14.83)
4.89 (1.07–22.34)
4.70 (1.58–13.99)
3.76 (0.75–18.81)
5.76 (1.68–19.78)
1.08 (0.15–7.69)
4.30 (0.89–20.71)
4.85 (1.06–22.15)
3.24 (0.86–12.21)
2.04 (0.51–8.14)
6.85 (1.53–30.60)
5.02 (1.44–17.46)
2.15 (0.39–11.72)
4.61 (1.32–16.19)
3.02 (0.58–15.88)
5.72 (1.27–25.83)
2.49 (0.64–9.62)
2.06 (0.69–6.14)
P Value for
Interaction
9/72
9/111
7/91
11/92
13/130
5/53
4/60
14/123
12/90
6/93
8/86
10/96
7/70
10/110
1/15
17/168
10/100
8/83
5/67
6/48
6/54
14/140
4/43
2/24
16/159
18/183
0/66
5/116
3/91
2/91
3/130
2/52
2/60
3/122
2/93
3/89
3/95
2/87
2/79
2/99
1/17
4/165
1/103
4/79
2/64
1/46
2/63
4/139
1/43
2/25
3/157
5/182
0.11
0.41
0.65
0.44
0.24
0.70
0.88
0.28
0.17
0.85
0.84
0.17
P Value
0.04
0.20
0.19
0.02
0.02
0.19
0.38
0.01
0.01
0.32
0.08
0.04
0.07
0.04
0.95
0.01
0.02
0.21
0.24
0.08
0.11
0.02
0.17
0.94
0.01
0.007
no. of events/total no. (%)
特に心血管
イベントリスクが
高い患者群に
おいてはHt<45%を
目指すべき.
N Engl J Med 2013;368:22-33.

22. PV; 状況に応じた治療
• 内臓血管 血栓症(Splanchnic vein thrombosis)
• SVTがある場合, 脾機能亢進や出血によりPVがMaskされている可能性あり
SVTの治療として, ヘパリン, ワーファリンが必要となる.
また, High-risk群としてHydroxyureaを使用する(妊婦には注意)
• 外科手術患者
• PV, ET患者の8%が周術期に致命的な血栓症を来し得る.
待機的手術の場合, 術前に可能な限り正常な血球に近づける.
(Hydroxyureaを使用, もしくはRBC高値だけならば瀉血)
Blood. 2012;120(2):275-284

23. • 妊婦の場合
• PVでは60台発症が主であり, 妊娠には影響しないことが多い.
ETは若年が多いため, 妊娠可能女性にあり得る.
• HydroxyureaやCytotoxic agentは避けるべき.
• 瀉血にてHt <45%を維持しつつ, 出産後6wkはLMWHを投与.
Major thrombosisや重度の妊娠合併症がある場合,
妊娠中もLMWHを投与.
• PLT>1500k/µLや重度の出血がある場合はINFの投与を考慮する.
• 掻痒感への対応
• 抗ヒスタミンは効果乏しい. 決まった治療は無い.
Blood. 2012;120(2):275-284

24. 治療反応性
の評価
Table 2. Response criteria for PV
Criteria
Complete remission
A Durable* resolution of disease-related signs
including palpable hepatosplenomegaly, large
symptoms improvement† AND
B Durable* peripheral blood count remission, defined
as Ht lower than 45% without phlebotomies;
platelet count #400 3 109
/L, WBC count ,10
3 109
/L, AND
C Without progressive disease, and absence of any
hemorrhagic or thrombotic event, AND
D Bone marrow histological remission defined as the
presence of age-adjusted normocellularity and
disappearance of trilinear hyperplasia, and
absence of .grade 1 reticulin fibrosis
Partial remission
A Durable* resolution of disease-related signs
including palpable hepatosplenomegaly, large
symptoms improvement† AND
B Durable* peripheral blood count remission, defined
as Ht lower than 45% without phlebotomies;
platelet count #400 3 109
/L, WBC count ,10
3 109
/L, AND
C Without progressive disease, and absence of any
hemorrhagic or thrombotic event, AND
D Without bone marrow histological remission
defined as persistence of trilinear hyperplasia.
No response Any response that does not satisfy partial
remission
Progressive disease Transformation into post-PV myelofibrosis,
myelodysplastic syndrome or acute leukemia‡
Molecular response is not required for assignment as complete response or
partial response. Molecular response evaluation requires analysis in peripheral
blood granulocytes. Complete response is defined as eradication of a preexisting
abnormality. Partial response applies only to patients with at least 20% mutant
allele burden at baseline. Partial response is defined as $ 50% decrease in allele
burden.
WBC, white blood cell.
*Lasting at least 12 wk.
†Large symptom improvement ($10-point decrease) in MPN-SAF TSS.10
‡For the diagnosis of post-PV myelofibrosis, see the IWG-MRT criteria12
; for the
diagnosis of myelodysplastic syndrome and acute leukemia, see WHO criteria.
ed the operative context, and
ocess aimed at providing the
escribed.1
During the initial
roject was to revise the def-
used for evaluating the results
y of drugs intended to modify
. To achieve this goal, ques-
panel asking the member to
isting evidence and personal
naires were returned and the
heir priority votes. The final
n a consensus meeting using
on the concept that stan-
nse to therapies in ET and
e antiproliferative activity
w and experimental drugs.
tions should be limited to
t they are not warranted in
ies of response criteria to
te or partial remissions in
The definition of response
nd signs of the disease,
bsence of vascular events
and bone marrow histol-
quality-of-life instrument
ion of symptoms through
orpoliferative Neoplasm-
mptom Score [MPN-SAF
g response durability (12
remission differed from
f correction of histological
ate drug had not been able
process. Besides response,
ncluded also the definition
12,13
ovide response definitions
Table 1. Response criteria for ET
Criteria
Complete remission
A Durable* resolution of disease-related signs
including palpable hepatosplenomegaly, large
symptoms improvement,† AND
B Durable* peripheral blood count remission, defined
as: platelet count #400 3109
/L, WBC count
,10 3 109
/L, absence of leukoerythroblastosis,
AND
C Without signs of progressive disease, and
absence of any hemorrhagic or thrombotic
events, AND
D Bone marrow histological remission defined as
disappearance of megakaryocyte hyperplasia
and absence of .grade 1 reticulin fibrosis.
Partial remission
A Durable* resolution of disease-related signs
including palpable hepatosplenomegaly, and
large symptoms improvement, AND
B Durable* peripheral blood count remission, defined
as: platelet count #400 3 109
/L, WBC count
,10 3 109
/L, absence of leukoerythroblastosis,
AND
C Without signs of progressive disease, and
absence of any hemorrhagic or thrombotic
events, AND
D Without bone marrow histological remission,
defined as the persistence of megakaryocyte
hyperplasia.
No response Any response that does not satisfy partial
remission
Progressive disease Transformation into PV, post-ET myelofibrosis,
myelodysplastic syndrome or acute leukemia‡
Molecular response is not required for assignment as complete response or
partial response. Molecular response evaluation requires analysis in peripheral
blood granulocytes. Complete response is defined as eradication of a preexisting
abnormality. Partial response applies only to patients with at least 20% mutant
allele burden at baseline. Partial response is defined as $50% decrease in allele
burden.
WBC, white blood cell.
*Lasting at least 12 wk.
†Large symptom improvement ($10-point decrease) in MPN-SAF TSS.10
‡For the diagnosis of PV see World Health Organization criteria (WHO)13
; for
the diagnosis of post-ET myelofibrosis, see the IWG-MRT criteria12
; for the
diagnosis of myelodysplastic syndrome and acute leukemia, see WHO criteria.13
Blood.2013;121(23):4778-4781