Immune Thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count due to increased platelet destruction and impaired production. The bone marrow findings in ITP show increased immature megakaryocytes with scant cytoplasm and absent lobulation in the nucleus. Dysplastic megakaryocytes with separated nuclei and micromegakaryocytes are also seen. Megakaryocytes in ITP frequently show emperipolesis of lymphocytes or lymphocytes and nucleated red blood cells within the cytoplasm. These bone marrow findings are sensitive and specific for diagnosing ITP.

1. Immune Thromobocytopenia
旧名; Idiopathic thromocytopenic purpura

2. Immune Thrombocytopenia
自己免疫機序による血小板破壊と産生障害
発症率は10/100000-yr. 男女差無し.
高齢者ほど多く, 小児では5-6/100000-yr程度.
PLT減少のみのPrimaryと,
HIV感染やSLEに合併するSecondaryがある.
診断からの経過により, 新規診断, 一過性(診断から3mo),
持続性(3-12mo), 慢性(>12mo)に分類される.
N Engl J Med 2011;365:734-41.

3. PLTに対する自己抗体.
GPIIb-IIIaに対する自己抗体が主で,
IgGが最も多いが, 一部IgMやIgAのこともある.
抗体が結合したPLTは急速に脾臓や肝臓でトラップされ,
消失する.
Cleveland Clinic Journal of Medicine 2012;79:641-650

4. ITPは基本的に除外診断
PLT以外のCBCに異常がないこと,
末梢血所見に問題ないこと,
出血以外の身体所見に問題がないこと(脾腫も無し),
2次性のPLT低下(膠原病, 薬剤, 感染症, 血液腫瘍)が
無いことを確認してITPと診断する.
膠原病; SLE, APS, 甲状腺疾患, Evans症候群.
感染症; HIV, H pylori, HCV, CMV
血液腫瘍; リンパ増殖性疾患
Hematol Oncol Clin N Am 23 (2009) 1329–1341

5. 感染症とPLT減少
小児では, IM, 風疹, 麻疹, 水痘などViral infectionで
PLT減少合併が多い.
その場合, PLT低下前(1-4wk)に感染症状を伴うため,
判別は比較低容易. また2-8wkで改善する.
成人例ではHCV, HIV, H pylori感染症が有名.
感染症状を伴わないため, ITPと勘違いする可能性がある.
Hematol Oncol Clin N Am 23 (2009) 1275–1297

6. HCV感染では肝硬変, 脾腫が無くても
PLT低下を来すことが知られている.
成人例のITP患者のうち, 20%でHCV陽性との報告あり.
またHCV感染者はITP発症リスクがHR 1.8[1.4-2.3].
機序は様々. 脾機能亢進, 肝でのThrombopoietin産生低下,
免疫機序によるPLT低下, IFNに伴うものなど.
ステロイド, IVIGの効果はHCV-ITPとITPで同等.
ただし, 免疫低下を考慮すると
Thrombopoietin-R agonistの方が良いかもしれない
Hematol Oncol Clin N Am 23 (2009) 1275–1297

7. HIVのPLT低下はいつ生じても良い.
HIV感染の初発症状としてもあり得る.
HAARTが導入される前はPLT低下合併頻度は5-30%
平均8.8%であった. 導入後の頻度は不明.
免疫機序による低下,
複合感染症(細菌, 寄生虫など)による低下
悪性腫瘍(Kaposi肉腫, NHLなど)に伴う低下
薬剤に伴う低下など, 色々機序はある.
PLT<5万となるような高度低下は少ない.
HIVへの治療がPLT低下の治療となる.
Hematol Oncol Clin N Am 23 (2009) 1275–1297

8. H pylori感染とITP
成人ITP患者でH pylori陽性者は62.3%だが,
ただ単に感染していただけな可能性もあるが,
除菌後に52.7%でPLT上昇を認めた報告がある.
日本からの報告では除菌施行した内56.2%でPLTが改善.
CagA陽性H pyloriが関連している可能性があり,
日本のH pyloriの殆どがCagA陽性.
機序や関連性は未だ議論があるが,
除菌でPLT改善すれば け物.
Hematol Oncol Clin N Am 23 (2009) 1275–1297

9. リンパ増殖性疾患とITP
Hematol Oncol Clin N Am 23 (2009) 1261–1274
Table1
Biologic background, treatment options, and prognostic implications for ITP associated with LPDs
Origin of
Autoantibodies
Correlation
to LPDs
Presentation/
Activity/Tumor
Burden
Effect of ITP
Treatment
Effect of LPD
Treatment
Prognostic
Significance
CLL Normal B cells No Weak Good Yes
WM/MGUS Malignant B
cells
No No Good/weak Unknown
MZL Both
malignant
and normal
B cells
Not apparent Weak Good Yes
T-LGL Normal B cells Yes No Good Unknown
HL Normal B cells No Good Unknown No
Other LPDs
(DLBCL, FL,
MCL, HCL)
Normal B cells Yes Unknown Weak, may
trigger ITP
Unknown
Abbreviations: CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follic-
ularlymphoma; HCL,hairycellleukemia;HL,Hodgkinlymphoma; LPD,lymphoproliferative disorder;
ITP in Lymphoproliferative Disorders 1269

10. PLT低下患者144名の骨髄所見
MDS以外によるPLT低下を来す疾患 144例
ITP, 感染由来(IAT), 脾機能亢進, 再生不良性貧血,
Dimorphic anemia, 巨赤芽球性貧血, AML, ALL,
Lymphoma-leukemia syndrome, myeloma, 骨髄転移,
Blast crisis of CML
Megakaryocyteの増減
Indian Journal of Pathology and Microbiology 2009;52:490-4
young forms of megakaryocytes with scant bluish cytoplasm
and lacking lobulation of the nucleus which occupied most
of the cell.[1]
Dysplastic megakaryocytes were defined as those
with single/ multiple separate nuclei. Micromegakaryocytes
were defined as megakaryocytes whose size was that of a large
lymphocyte/monocyte and which had a single/bilobed nucleus.
The megakaryocytes were considered to show platelet budding if
there was budding of cytoplasmic processes from their surfaces.
Hypogranular forms were defined as megakaryocytes with pale
grey or water clear cytoplasm and sparse or no granules. The
type of cell seen within the megakaryocyte in emperipolesis was
also documented.
The number and morphology of the megakaryocytes in non-MDS
related thrombocytopenia were assessed. Their significance was
studied by comparing with the morphological changes in MDS.
The distribution of morphological changes in cases of non-MDS
conditions and MDS were compared using Fisher’s exact test. A P
value less than 0.05 was consideredsignificant. The sensitivity and
specificity for those morphological features which were significant
in the relevant hematological disorders was also calculated.
RESULTS
The commonest cause of thrombocytopenia for which bone
marrow examination was sought was AML (27 cases, 18.8%). The
secondmost common cause wasITP (19 cases, 13.15%) which was
followed by ALL and dimorphic anemia (18 cases each, 12.5%).
There were 17 casesof myeloma, 12 casesof megaloblastic anemia,
eight cases of aplastic anemia, five cases of IAT and LLS, three
cases of hypersplenism, two cases of bone marrow metastasis and
one case of blast crisis of CML. Maximum number of cases (38
cases, 26.4%) was seen in less than ten years of age group followed
The changes in number and morphology of megakaryocytes in
various hematological disorders are given in Tables 1 and 2. There
was an increase in the number of megakaryocytes in 18 cases
(94.7%) of ITP and immature megakaryocytes were seen in all the
cases (sensitivity = 100%, specificity = 68%, Figure 1). Dysplastic
forms were seen in 17 cases (89.5%), bare megakaryocytic nuclei in
16 cases (84.2%) and micromegakaryocytes in eight cases (42.1%)
of ITP, their sensitivity being 89%, 84% and 42% respectively and
specificity being 52%, 58% and 84% respectively. Emperipolesis
was seen in 13 cases (68.4%; sensitivity = 68%, specificity = 74%)
with lymphocytes in five cases and lymphocytes and nucleated red
blood cells in four cases.
In cases of IAT, immature megakaryocytes were observed in all the
five cases (sensitivity = 100%, specificity = 61%) and cytoplasmic
vacuolization was seen in two of the cases (sensitivity = 40%,
specificity = 86%).
Table 1: Incidence of changes in number of megakaryocytes in different
hematological disorders causing thrombocytopenia
Bone marrow Number per low-power field
Impression Normal Increased Decreased Absent
ITP * 1 18
IAT * 5
Hypersplenism 3
Aplasc anemia 2 6
Dimorphic anemia 9 6 3
Megaloblasc anemia 9 1 2
MDS * 1 6 1 1
ALL * 1 3 14
AML * 3 1 17 6
LLS * 1 1 3
Myeloma 4 5 7 1
Blast crisis of CML* 1
Metastasis 2
* ITP= Idiopathic thrombocytopenic purpura, IAT= Infecon-associated thrombocytopenia, MDS=

11. 各骨髄所見のITP対する感度, 特異度
was75%alongwithspecificityof49%.Thesensitivi
emperipolesisincasesofdimorphicanemiawas44%[F
2].Howevernoplateletbuddingwasseeninanyoftheca
IncasesofMDS,dysplasticforms,baremegakaryocyticn
andmicromegakaryocyteswereseen.However,findi
micromegakaryocyteswasmostsignificantwhencomp
tonon-MDScausesofthrombocytopenia(specificity-8
Decreasedplateletbuddingandabsenceofcytoplasmicvac
wasalsonoted.
DISCUSSION
Thrombocytopenia,eitherpersistent,isolatedorinassoci
withpancytopeniarefractorytotreatmentisoneofthecomm
encounteredhematologicalproblemsforwhichabonema
studyissought.TheroutinelypreparedLeishmanstained
marrowaspiratesmearscanhelptoobservethedyspo
featuresofthemegakaryocytesassociatedwiththenon-
conditions.Thiscanimprovethediagnosticaccuracy
widerangeofhematologicaldisorderstherebyenablingp
therapeuticinterventions.
Normalmaturationandplateletformationresults
megakaryocyticdeoxyribonucleicacid(DNA)replic
thatoccurswithoutcelldivisionresultinginlargelobu
polypoidnucleus.Awidevarietyofgrowthfactors
thrombopoietinactsynergisticallywithotherhematop
cytokinesandtranscriptionalfactorsstimulatingthematur
andgrowthofmegakaryocytes.[3]
Adefectinanyofthesta
megakaryocytopoiesiscanleadtodysmegakaryocytopoiesi
thrombocytopenia.
Ashifttoyoung,immature,lesspolypoidmegakaryo
andfewermatureplatelet-producingmegakaryocyteswa
outstandingmorphologicalfeaturenotedinallthecaseso
inthepresentstudy(sensitivity=100%,specificity=6
SimilarfindingswereobservedbyHouwerzijletal,[2]
wh
theysaiditisbecauseofapoptoticandpara-apoptoticty
programmedcelldeath(PCD)ofmaturemegakaryocytes.
oftheabnormalmegakaryocytesweresurroundedbyneutro
andmacrophages,someinthestateofphagocytosis.Inappro
PCDofmaturemegakaryocytescandisruptplateletform
andapoptosis-likePCD(para-apoptosis)occursinITP.
findingisespeciallyusefulwhensomepatientsofMDSpr
withisolatedthrombocytopenia,thusmimickingITP.Dysp
formswereseenin17cases(89.5%),baremegakaryocyticn
in16cases(84.2%)andmicromegakaryocytesineight
(42.1%),theirsensitivitybeing89%,84%and42%respec
andspecificity,52%,58%and84%respectively.
Emperipolesis,seenin13ofthe19casesofITP(84
sensitivity=68%,specificity=74%)withlymphocytesi
andlymphocytesalongwithnucleatedredbloodcellsinTable 2: Incidence of changes in morphology of megakaryocytes in different hematological disorders causing thrombocytopenia
Bone marrow Immature Dysplasc Bare Emperipolesis Platelet Cytoplasmic Micromegakaryocytes Hypogranular Number of nuclear lobes
impression megakaryocytes forms megakaryocyc budding vacuolizaon forms
nuclei Normal Decreased
ITP* 19 17 16 13 12 4 8 0 18 1
IAT* 5 4 4 4 1 2 0 0 4 1
Hypersplenism 0 0 0 1 1 1 0 0 3
Aplasc anemia 2 1 2 2 1 1 0 0 1 1
Dimorphic anemia 10 13 13 8 0 7 2 0 18
Megaloblasc anemia 5 9 7 4 0 4 3 0 12
MDS* 4 7 6 4 1 0 5 0 9
ALL* 2 4 2 1 0 0 0 0 4
AML* 2 8 8 4 0 0 5 0 19 2
LLS* 1 2 1 1 0 0 0 0 2
Myeloma 8 10 8 3 1 2 5 0 16 1
* ITP= Idiopathic thrombocytopenic purpura, IAT= Infecon-associated thrombocytopenia, MDS= Myelodysplasc syndrome, ALL= Acute lymphoblasc lymphoma, AML= Acute myeloid leukemia, LLS= Leukemia-lymphoma syndrome
Indian Journal of Pathology and Microbiology 2009;52:490-4
感度 特異度
Megakaryocyte増加 94.7%
幼弱Megakaryocyte 100% 68%
Dysplastic from 89.5% 52%
Bare megakaryocytic nuclei 84.2% 58%
micromegakaryocyte 42.1% 84%
Emperipolesis 68.4% 74%
I N D I A N J O U R N A L O F P A T H O L O G Y A N D M I C R O B I O L O G Y - 5 2 ( 4 ) , O C T O B E R - D E C E M B E R 2 0 0 9 491
RESULTS
The commonest cause of thrombocytopenia for which bone
marrow examination was sought was AML (27 cases, 18.8%). The
secondmost common cause wasITP (19 cases, 13.15%) which was
followed by ALL and dimorphic anemia (18 cases each, 12.5%).
There were 17 casesof myeloma, 12 casesof megaloblastic anemia,
eight cases of aplastic anemia, five cases of IAT and LLS, three
cases of hypersplenism, two cases of bone marrow metastasis and
one case of blast crisis of CML. Maximum number of cases (38
cases, 26.4%) was seen in less than ten years of age group followed
by 18.7% cases (27 cases) in 21-30 years of age. Least number of
cases was seen in more than 61 years of age (nine cases, 6.3%).
Figure 1: An immature megakaryocyte with cytoplasmic vacuolization
(arrow) in a case of idiopathic thrombocytopenic purpura (Leishman
stain, x 400)
Figure 2: A megakaryocyte showing emperipolesis of neutrophils
(arrows) in a case of dimorphic anemia (Leishman stain, x 400)
Impression Normal Increased Decreased Absent
ITP * 1 18
IAT * 5
Hypersplenism 3
Aplasc anemia 2 6
Dimorphic anemia 9 6 3
Megaloblasc anemia 9 1 2
MDS * 1 6 1 1
ALL * 1 3 14
AML * 3 1 17 6
LLS * 1 1 3
Myeloma 4 5 7 1
Blast crisis of CML* 1
Metastasis 2
* ITP= Idiopathic thrombocytopenic purpura, IAT= Infecon-associated thrombocytopenia, MDS=
Myelodysplasc syndrome, ALL= Acute lymphoblasc lymphoma, AML= Acute myeloid leukemia,
LLS= Leukemia-lymphoma syndrome, CML= chronic myeloid leukemia
The number and morphology of the megakaryocytes in non-MDS
related thrombocytopenia were assessed. Their significance was
studied by comparing with the morphological changes in MDS.
The distribution of morphological changes in cases of non-MDS
conditions and MDS were compared using Fisher’s exact test. A P
value less than 0.05 was consideredsignificant. The sensitivity and
specificity for those morphological features which were significant
in the relevant hematological disorders was also calculated.
RESULTS
The commonest cause of thrombocytopenia for which bone
marrow examination was sought was AML (27 cases, 18.8%). The
secondmost common cause wasITP (19 cases, 13.15%) which was
followed by ALL and dimorphic anemia (18 cases each, 12.5%).
There were 17 casesof myeloma, 12 casesof megaloblastic anemia,
eight cases of aplastic anemia, five cases of IAT and LLS, three
cases of hypersplenism, two cases of bone marrow metastasis and
one case of blast crisis of CML. Maximum number of cases (38
cases, 26.4%) was seen in less than ten years of age group followed
by 18.7% cases (27 cases) in 21-30 years of age. Least number of
cases was seen in more than 61 years of age (nine cases, 6.3%).
In cases of IAT, immature megakaryocytes were observed in al
five cases (sensitivity = 100%, specificity = 61%) and cytopla
vacuolization was seen in two of the cases (sensitivity = 4
specificity = 86%).
Table 1: Incidence of changes in number of megakaryocytes in diffe
hematological disorders causing thrombocytopenia
Bone marrow Number per low-power field
Impression Normal Increased Decreased Absen
ITP * 1 18
IAT * 5
Hypersplenism 3
Aplasc anemia 2 6
Dimorphic anemia 9 6 3
Megaloblasc anemia 9 1 2
MDS * 1 6 1 1
ALL * 1 3 14
AML * 3 1 17 6
LLS * 1 1 3
Myeloma 4 5 7 1
Blast crisis of CML* 1
Metastasis 2
* ITP= Idiopathic thrombocytopenic purpura, IAT= Infecon-associated thrombocytopenia, M
Myelodysplasc syndrome, ALL= Acute lymphoblasc lymphoma, AML= Acute myeloid leukem
LLS= Leukemia-lymphoma syndrome, CML= chronic myeloid leukemia
幼弱megakaryocyte
通常megakaryocyteの周囲はPLTが
多数認められるが, 幼弱では認めない. Emperipolesis

12. 正常の巨核球
核は分葉し, 周囲に血小板産生を認める.

13. ちなみに, 感染症由来PLT低下に対しては,
幼弱megakaryocyteは感度100%, 特異度61%.
Cytoplasmic vacuolizationは感度40%, 特異度86%.
Dysplastic fromは巨赤芽球性貧血に対するSn 75%, Sp 49%
他にはDimorphic anemiaで認められる.
EmperipolesisはDimorphic anemiaの44%で陽性.
Indian Journal of Pathology and Microbiology 2009;52:490-4

14. ITPの治療
治療の目標は, 必要最低限の薬剤で,
出血リスクが低いレベルまでPLTを上げ維持すること.
成人例でPLT>3万で, 出血も軽度のみならば経過観察.
PLT<3万で出血(+), もしくはPLT<1万といった出血リスクが
大きい高度なPLT低下では治療が推奨される.
N Engl J Med 2011;365:734-41.

15. ITPの初期治療はステロイド ± IVIG
PSL 1mg/kg/dで開始し, 4-6wkかけてTapering.
もしくは, Dexamethasone 40mg/d 4d/moのパルス療法.
後者の方が効果は良好.
効果は良好だが, ステロイドの中止, 減量にて
ITPが再燃することが多く, 寛解持続するのは10-30%程度.
N Engl J Med 2011;365:734-41.
Cleveland Clinic Journal of Medicine 2012;79:641-650

16. PSL, IVIGで効果乏しい場合は脾摘が適応となる.
Rituximabも2nd-line treatmentとして用いられるが,
平均効果持続期間は10.5mo程度しかない.
近年Thrombopoietin-R agonistが効果高い報告があり,
期待されている.
N Engl J Med 2011;365:734-41.

17. 13 RCTsのMeta-analysis(N=646)
High-dose(HD) IVIG (総量2g/kg) と
Low-dose IVIG (総量<2g/kg)で効果を比較.
(投与方法としては0.2-0.4g/kg 5日間が最も多い方法. )
効果(PLT上昇までの期間, 上昇量, 出血リスク)は
両者有意差無し.
急性ITPに対するIVIGの量
Blood Coagulation and Fibrinolysis 2010, 21:713–721
716 Blood Coagulation and Fibrinolysis 2010, Vol 21 No 8
Fig. 2
0.1 0.2 0.5 1 2 5 10
Study
or subcategory
Xue [10]
Zhang [14]
Tang [15]
Cao and Ji [18]
Huang et al. [16]
Zhu et al. [18]
Ge [20]
Yang [21]
Total (95% Cl)
Total events: 199 (low-IVIG), 188 (HD-IVIG)
Test for heterogeneity: Chi
2
= 1.82, df = 7 (P = 0.97), I
2
= 0%
Test for overall effect: Z = 0.00 (P = 1.00)
23/23
12/15
9/10
23/31
24/28
38/54
52/55
18/25
241 228 100.00 1.00 (0.61, 1.63)
21/23
9/11
6/6
23/30
24/27
37/53
49/53
19/25
1.39
6.44
3.36
18.71
10.83
34.32
8.44
16.50
5.47 (0.25, 120.37)
0.89 (0.12, 6.48)
0.49 (0.02, 13.92)
0.88 (0.27, 2.81)
0.75 (0.15, 3.72)
1.03 (0.45, 2.35)
1.41 (0.30, 6.65)
0.81 (0.23, 2.88)
Low-IVIG
n/N
HD-IVIG
n/N
OR (fixed)
95% Cl
Weight
(%)
OR (fixed)
95% Cl

18. 副作用の頻度はLD-IVIGの方が少ない(OR0.39[0.18-0.83])
他に, 慢性ITPへの移行率も有意差無し(OR 1.62[0.62-4.21])
IVIGの投与量は0.2g/kg 5日間程度
(総量<2g/kg)でOK.
Blood Coagulation and Fibrinolysis 2010, 21:713–721

19. ITPの治療まとめ.
再発性で, PLT <20kとなる
場合は脾摘の適応となる
脾摘後は2/3は再発無し.
Rituximabや
Thrombopoetin-R agonistsは,
脾摘を回避可能な治療薬.
decreases once the dose is tapered or stopped;
remission is sustained in only 10% to 30% of
cases.30
Continuation of corticosteroids is lim-
ited by long-term complications such as op-
portunistic infections, osteoporosis, and emo-
tional lability.31
Intravenous immunoglobulin and
anti-D immunoglobulin are alternatives
Intravenous immunoglobulin is recom-
mended for patients who have not responded
to corticosteroids and is often used in preg-
nancy. It is thought to act by blocking Fc re-
ceptors in the reticuloendothelial system. In-
travenous immunoglobulin rapidly increases
platelet counts in 65% to 80% of patients,32
but the effect is transient and the drug requires
frequent administration. It is usually well tol-
erated, although about 5% of patients expe-
rience headache, chills, myalgias, arthralgias,
and back pain. Rare, serious complications
include thrombotic events, anaphylaxis (in
IgA-deficient patients), and renal failure.
Anti-D immunoglobulin, a pooled IgG
product, is derived from the plasma of Rh(D)-
negative donors and can be given only to
patients who are Rh(D)-positive. Response
rates as high as 70% have been reported, with
platelet effects lasting for more than 21 days.33
Studies have shown better results at a high
dose (75 µg/kg) than with the approved dose
of 50 µg/kg.34
Anti-D immunoglobulin can also be given
intermittently whenever the platelet count
falls below a specific level (ie, 30 × 109
/L).
This allows some patients to avoid splenec-
tomy and may even trigger long-term remis-
sion.32
TABLE 2
Treatment of immune thrombocytopenia
First-line
Prednisone (1 mg/kg/day in tapering doses × 4–6 weeks)
High-dose dexamethasone (Decadron) (40 mg daily × 4 days/month for
several cycles)
Intravenous immunoglobulin (0.8–1 g/kg)
Intravenous anti-D immunoglobulin (50–75 µg/kg)
Second-line
Rituximab (Rituxan) (375 mg/m2
weekly × 4 weeks)a
Splenectomya
Thrombopoietin receptor agonistsa
Romiplostim (Nplate) (1–10 µg/kg subcutaneously weekly)
Eltrombopag (Promacta) (25–75 mg orally daily)
Azathioprine (Imuran)
Cyclosporine A (Gengraf, Neoral, Sandimmune)
Cyclophosphamide (Cytoxan)
Danazol (Danocrine)
Dapsone
Mycophenolate mofetil (CellCept)
Vinca alkaloids
Third-line
Combination chemotherapy
Hematopoietic stem cell transplantationb
a
Commonly used
b
Warranted only for severe refractory immune thrombocytopenia with bleeding
complications unresponsive to other agentsCleveland Clinic Journal of Medicine 2012;79:641-650

20. Thrombopoietinは主に肝臓で産生されるホルモン.
MegakaryocyteのThrombopoietin-Rに結合し
PLT産生を亢進させる作用を持つ.
通常PLT低下患者ではThrombopoietin濃度が高くなるが,
ITP患者では原因は不明だが, 濃度が正常範囲のまま.
>> 外から補うことでPLT上昇効果が見込める.
RecombinantのThrombopoietinでは
自己抗体誘導してしまったため,
新しいRomiplostim(ロミプレート),
Eltrombopag(レボレート®)が開発された.
Thrombopoietin-R
N Engl J Med 2011;365:734-41.

21. N Engl J Med 2011;365:734-41.

22. RomiplostimのRCT
ITP患者(PLT<3万/µL, 脾摘後63名, 脾摘未62名)
Romiplostim SC vs Placeboに2:1で割り付け.
薬剤はPLT 5-20万となるように調節. 24wk継続.
Outcome
Lancet 2008; 371: 395–403
B
A Splenectomised
Non-splenectomised
200
150
100
50
0
0
Number available
for measurement
Placebo
Romiplostim
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
21 21 21 21 21 21 21
Romiplostim
Placebo
21 21 21 11 12 20 20 20 20 20 20 18 19 18 18 19 17 19
42 42 42 42 42 42 41 42 41 41 40 39 41 39 40 40 39 40 39 39 40 38 38 39 40
21 21 21 21 21 21 21 20 18 19 19 19 18 18 18 18 18 18 18 18 18 18 17 16 17
41 41 41 41 41 41 40 41 41 40 40 37 40 38 40 38 39 39 38 39 38 36 38 39 39
Number available
for measurement
Placebo
Romiplostim
0 2 3 4 5 6 7 8 9 10 11 12
Study week
Medianplateletcount(×109
/L)Medianplateletcount(×109
/L)
13 14 15 16 17 18 19 20 21 22 23 24 25
200
150
100
50
0
PLT上昇を認めたのは,
Romiplostim投与群では
脾摘群で78.6%
脾摘未で87.8%
Placebo群では7.1%のみ.

23. RomiplostimのRCT
脾摘されていないITP患者234名のOpen-labeled RCT.
Romiplastim vs Placeboに割り付け52wk継続.
Romiplastimは3µg/kgより開始し, PLT5-20万を目標に調節. Max 10µg/kg
Outcome; PLT>5万を達成したのは
Romiplastim群で71-92%, Placebo群で26-51%.
Treatment failureは11% vs 30%, OR 0.31[0.15-0.61]
脾摘施行例は9% vs 36%, OR 0.17[0.08-0.35]
N Engl J Med 2010;363:1889-99.

24. EltrombopagのRCT
既存の治療に不応性のITP患者118名のRCT. (PLT<3万/µL)
Eltrombopag vs Placeboに割り付け, PLT上昇を比較.
Eltrombopagは30mg, 50mg, 75mgを使用.
Day 43でのPLT>5万達成率; 28% vs 70% vs 81% vs 11%(PL)
PLT数; 2.6万 vs 12.8万 vs 18.3万 vs 1.6万(PL)
N Engl J Med 2007;357:2237­47.
Eltrombopag for Chronic Idiopathic Thrombocytopenic Purpura
100
80
90
70
60
40
30
10
50
20
0
8 15 22 29 36 43
400
300
200
100
0
1 8 15 22 29 4336
Placebo Eltrombopag,
30 mg
Eltrombopag,
50 mg
Eltrombopag,
75 mg
Placebo
Eltrombopag, 30 mg
Eltrombopag, 50 mg
Eltrombopag, 75 mg

25. EltrombopagのRCT
PLT<3万/µLの慢性ITP患者114名のDB-RCT.
通常の治療 + Eltrombopag vs Placeboを6wk継続.
50mg/dより開始し, 3wk目でPLT<5万ならば75mgに増量
Outcome; Day43において, PLT>5万達成率.
Eltrombopag群で59% vs 16%, OR 9.61[3.31-27.86]
出血リスクはOR 0.49[0.26-0.89]
投薬終了後2wkでPLTは基礎値まで低下.
国内ではエボレート®12.5mg, 25mg錠が使用可能
Lancet 2009; 373: 641–48

26. 臨床での使用方法
既存の治療で改善しないITPを対象とする.
(レボレートは50mgで約5千円, ロミプレートは250µgで6万円也)
Romiplostim; 初期投与量は1µg/kg SC. 1回/wk.
PLT値に応じて調節し, 平均使用量は3-4µg/kg.
最大投与量は10µg/kg
Eltrombopag; 初期投与量は50mg/d PO.
PLT値に応じて調節し, 25-75mg/dの範囲で調節.
肝障害やアジア人では血中濃度が上昇するため,
初期投与量は25mg/dより開始する.
また, 食事に影響されるため, 食後1-2hrで内服し,
制酸剤, Ca, Mgなど併用患者では
4hr以上あけて内服する必要あり.
N Engl J Med 2011;365:734-41.

27. RomiplostimのDose調節方法
Lancet 2008; 371: 395–403より
1µg/kg/wkより開始し,
PLT 5-20万を達成する前は,
PLT<1万/µL → 2µg/kg/wkで増量
PLT 1-5万/µL → 2µg/kg/2wkで増量.
PLT 5-20万を達成した後は, 維持アルゴリズムへ.
PLT<1万/µL → 1µg/kg/wkで増量
PLT 1-5万/µL → 1µg/kg/2wkで増量.
2wk連続でPLT 20-40万/µL → 1µg/kg減量
PLT>40万/µL → 中断し, PLT<20万となってから
1µg/kg減量して再開
最大投与量は15µg/kg/wk

28. Romiplostim, Eltrombopag使用中の患者では,
Dose調節無しでPLT>5万が4wk以上持続するまで,
毎週PLTをチェックする必要あり.
その後は1ヶ月毎のチェックでOK.
PLT 20-40万となるようならば治療は一時中断.
PLTを元に戻すことが目標ではない.
Eltrombopagでは肝障害が報告されているため,
Dose調節中は2wk毎に肝酵素チェック.
その後は1ヶ月毎のチェックでOK
N Engl J Med 2011;365:734-41.

29. Thrombopoietin-R agonistの副作用
最も多いのは頭痛, 悪心, 嘔吐, 怠感, 下痢,
関節痛, 鼻咽頭炎.
薬剤中断後にITPが増悪するのは8-10%で認められる.
中断後4wkは出血リスクが上昇し得る.
中止時はTaperingが他薬剤への切り替えが推奨される.
Eltrombopagによる肝障害は11%(Placeboで7%).
肝酵素が3ULN程度, Bilは1.6ULN程度上昇.
薬剤継続しても改善することがあるが,
ALT>3ULN, 4wk以上持続, 急速進行例では中断が必要.
N Engl J Med 2011;365:734-41.

30. Thrombopoietin-R agonistと血栓症リスク
Romiplostimを使用した291名中,
17名で25例の静脈, 動脈血栓症を併発.(8.6%)
Eltrombopagを使用した299名中,
16名で21例の静脈, 動脈血栓症を併発.(7.0%)
薬剤の使用期間で頻度は変わらず.
また血栓症を来した患者は1つ以上の血栓リスクを
有しており, リスクがある患者では要注意となる.
骨髄線維症の合併も報告されている.
N Engl J Med 2011;365:734-41.

31. TABLE 3
Newer therapies for immune thrombocytopenia
refractory to first-line treatment in adults
RITUXIMAB (RITUXAN) ROMIPLOSTIM (NPLATE) ELTROMBOPAG (PROMACTA)
Drug class Anti-CD20 monoclonal
antibody
Thrombopoietin receptor
agonist
Thrombopoietin receptor
agonist
Route Intravenous Subcutaneous Oral
Dosing 375 mg/m2
weekly × 4 1–10 mg/kg weekly 25–75 mg daily
Approximate
platelet count
response rate*
60%41
79%
(splenectomized patients)47
88%
(nonsplenectomized patients)47
70%
(receiving 50-mg dose)
80%
(receiving 75-mg dose) 51
Approximate time
to response
1–8 weeks35
1–4 weeks 2 weeks
Duration
of response
Up to 2 years
(median 10.5 months) 43
Platelet count returns to base-
line 2 weeks after discontinuing
treatment
Platelet count returns to
baseline 2 weeks after
discontinuing treatment
Safety concerns Mild infusion reaction
Rare: infections, serum
sickness, bronchospasm
Bone marrow reticulin
formation, thrombosis
Elevated liver enzymes,
bone marrow reticulin
formation, thrombosis
*Platelet count > 50 x 109
/L
Cleveland Clinic Journal of Medicine 2012;79:641-650

32. 2nd lineでも効果が無い場合,
多剤併用療法を考慮する.
Azathioprine, cyclosporine, cyclophosphamide,
mycophenolateといった免疫抑制剤を併用.
もしくは幹細胞移植を考慮する.
Cleveland Clinic Journal of Medicine 2012;79:641-650