1. Microangiopathic Hemolytic Anemia
Thrombotic microangiopathy

2. Microangiopathic Hemolytic Anemia
 Thrombotic microangiopathy; 微小血管の血栓症.
 微小血管の血栓症は3つの病型に分類される. TTP, HUS, DIC.
 このうち, TTPとHUSはMicroangiopathic hemolytic anemiaと呼ばれ,
微小血管内の血栓症 + 溶血, 塞栓症状を生じる病態.
全身性, 特に中枢神経に生じるものをTTP, もしくはTTP/HUS
腎臓に限局するものをHUSと呼ぶ.
 厳密に言えば, TTPは遺伝子異常を背景とし,
ADAMTS13という酵素欠損が基礎疾患にある場合が多い.
vWF因子の切断酵素であり, それが欠損すると血栓形成をし易い.
つまり全身の微小血管に血栓を生じる.
 HUSはO-157などの腸管病原性大腸菌感染後に生じるのが一般的で,
毒素が腎臓内の微小血管内皮を障害し, 腎臓のみを障害するパターン.
2 Clin J Am Soc Nephrol 7: 342–347, 2012

3. Thrombotic Thrombocytopenic Purpura
(TTP)
NEJM 2006;354:1927-35

4. Thrombotic Thrombocytopenic Purpura
 血漿交換に非常に良く反応するため, 診断することが重要
 未治療では死亡率90%と非常に高い疾患
 全身性の小血管閉塞を来し, 脳 塞, 心筋 塞, 腎不全を来す
 早期診断が重要だが, 特異的な所見に乏しく, 困難な場合が多い.
Microangiopathic hemolytic anemia, Thrombocytopeniaのみで
血漿交換に踏み切るのもアリ, 血漿交換で死亡率は10%に！
 TTP
 4-11/million/yrと稀な疾患
 通常成人に起こる疾患であり,
小児のMicroangiopathic Hemolytic anemia, Thrombocytopeniaは
HUS(Hemolytic-uremic syndrome)と考えるべき
(TTPと異なり, 対症療法のみで生存率91%と予後良好)

5.  微小血管の血栓症が全身性に生じる
 血小板凝集が主でフィブリンは関与しない.
又, 血管周囲炎, 内皮細胞障害もほとんど起こさない.
 血栓中にはvWF抗体を大量に含んでいる点が特徴.
 TTPの原因はADAMTS 13欠損
 通常, 多量体となったvWFを切断するための酵素
vWF-cleaving metalloprotease(ADAMTS 13)が働き,
巨大vWFが血小板凝集を来すのを防ぐが,
TTPではADAMTS 13の活性化が低下しており, 凝集を来す.
 TTPではADAMTS 13の欠損(<5% activity)が33-100%で認められる.
(Acronym for a disintegrin and metalloprotease with thrombospondin-1-like domains)
 ADAMTS 13は内皮細胞より産生される多量体.
欠損により, vWFの異常多量体を形成し, 小血管で血栓形成 TTP
 家族性のTTPではADAMTS 13の活性が0%.
9q34 geneがADAMTS 13をEncodeしており, 同部位の変位が原因.
 一過性のADAMTS 13に対する抗体上昇も原因の1つと考えられる.
NEJM 2002;347:589-600

6. NEJM 2002;347:589-600

7. Defect 疾患
ADAMTS 13 活性<5%
Familial TTP, Chronic relapsing TTP
乳児-小児期に起こる疾患
高齢者に起こる疾患
ADAMTS 13に対する自己抗体 Acquired idiopathic TTP, Single-episode TTP,
Recurrent TTP, Ticlopidine-associated TTP
一過性, 再発性, Ticlopidine-associated
一過性のADAMTS 13産生低下, 寿命低下 Acquired idiopathic TTP
ADAMTS 13は正常だが, 内皮細胞への結合が障害 Familial and acquired TTP
 健常人のADAMTS 13活性は50-178%.
肝障害, 播種性悪性腫瘍, 慢性代謝性疾患,
炎症性疾患, 妊婦, 新生児では低下している.
 ADAMTS 13 活性<5%を欠乏, 欠損のCutoffとする.
NEJM 2002;347:589-600

8. 抗血小板薬に伴うTTP-HUS N Engl J Med 2000;342:1773-7
 Ticlopidine-associated TTPの頻度は1600-5000例に1例,
ClopidogrelによるTTPはそれよりも低く,
20000例の使用では報告例無し.
 TiclopidineによるTTP
 95%は投薬開始後2-12wkで発症する.
 大半でADAMS13に対する自己抗体が誘発されており,
血漿交換が効果良好. 平均7回の血漿交換にて改善を示す.
また, 再発は少ない.
8

9. N Engl J Med 2000;342:1773-7
 ClopidogrelによるTTP 11例の解析
 平均年齢は55歳, 35-70歳まで様々, 女性例は6例.
 Clopidogrel開始から3-14日目で発症したのが10例.
1例はClopidogrel中止後3wk経過して発症している.
 Ticlopidineでは2-12wkでの発症が95%.
 2例は以前にTiclopidineの使用歴あるが, その際は発症していなかった.
 治療は全例で血漿交換を行い, 1例は発症後4日で死亡.
さらに1例では寛解後再発を認めた.
 血漿交換は1-30回. Ticlopidineよりも多い血漿交換が必要であり,
再発リスクも高い傾向がある.
 血中のADAMS13を測定したのは2例のみで,
双方とも活性は低下. ADAMS13抗体(IgG)も検出された.
9

10. Drug-associated TTP-HUS Medina et al. 287
他にTTP-HUSを来す薬剤一覧 (1) Current Opinion in Hematology 2001, 8:286–293
Table 1. Drugs and other exogenous substances reported to be associated with the development of thrombotic
thrombocytopenic purpura-hemolytic uremic syndrome
Antineoplastic drugs
mitomycin C (Mutamycinா) [Bristol-Myers Squibb; Princeton, NJ]
5-fluorouracil (Adrucilா) [Pharmacia; North Peapack, NJ]
cytarabine (Cytosar Uா) [Pharmacia; North Peapack, NJ]
chlorozotocin (DCNU)
cisplatin (Platinolா) [Bristol-Myers Squibb; Princeton, NJ]
daunorubicin [Bedford Laboratories; Bedford, OH]
deoxycoformycin (Nipentா) [Super Gen; Dublin, CA]
gemcitabine (Gemzarா) [Eli Lilly; Indianapolis, IN]
hydroxyurea (Hydreaா) [Bristol-Myers Squibb; Princeton, NJ]
Immunosuppressants
cyclosporin (Neoralா, Sandimmuneா) [Novartis; East Hanover, NJ]
OKT3 (Orthocloneா) [Ortho Biotech Products; Raritan, NJ]
tacrolimus (Prografா) [Fujisawa; Osaka, Japan]
Antiplatelet drugs
ticlopidine (Ticlidா) [Hoffmann-La Roche; Nutley, NJ]
clopidogrel (Plavixா) [Sanofi-Synthelabo; New York, NY]
defibrotide (Dasovasா, others) [Pharmacia Upjohn; Milan, Italy]
dipyridamole (Persantineா) [Boehringer Ingelheim; Ingelheim, Germany]
Antibiotics
ampicillin (Omnipenா, others) [Wyeth-Ayerst Pharmaceuticals; St. David’s, PA]
clarithromycin (Biaxinா) [Abbott Laboratories; Abbott Park, IL]
D-penicillamine (Cuprimineா, Merck; Whitehouse Station, New Jersey, USA), (Depenா, Wallace Laboratories; Cranbury, NJ)
metronidazole (Flagylா) [Searle Pharmaceuticals; Skokie, IL]
oxytetracycline (Terramycinா) [Pfizer; New York, NY]
penicillin (Pen Vee Kா, others) [Wyeth-Ayerst Pharmaceuticals; St. David’s, PA]
rifampicin (Rifadinா, Aventis Pharmaceuticals; Bridgewater, NJ), (Rimactaneா, Novartis; East Hanover, NJ)
sulfisoxazole (Gantrisinா) [Hoffmann-La Roche; Nutley, NJ]
H-2 receptor antagonists
cimetidine (Tagametா) [GlaxoSmithKline; Research Triangle Park, NC]
famotidine (Pepcidா) [Merck; Whitehouse Station, NJ]
Hormones 10
17-B estradiol patch (Climaraா, others) [Berlex Laboratories; Wayne, NJ]

11. H-2 receptor antagonists
cimetidine (Tagametா) [GlaxoSmithKline; Research Triangle Park, NC]
他にTTP-HUSを来す薬剤一覧 (2)
famotidine (Pepcidா) [Merck; Whitehouse Station, NJ] Current Opinion in Hematology 2001, 8:286–293
Hormones
17-B estradiol patch (Climaraா, others) [Berlex Laboratories; Wayne, NJ]
conjugated estrogens (Premarinா) [Wyeth-Ayerst Pharmaceuticals; St. David’s, PA]
danazol (Danocrineா) [Sanofi-Synthelabo; New York, NY]
ethinyl estradiol (Estinylா, various combination products) [Shering-Plough; Kenilworth, NJ]
ethynodiol acetate (Various combination products)
levonorgesterol (Norplantா) [Wyeth-Ayerst Pharmaceuticals; St. David’s, PA]
norethisterone (Aygestinா, various combination products) [ESI Lederle; St. David’s, PA]
Interferons
alpha interferon (Roferonா) [Hoffmann-La Roche; Nutley, NJ]
alpha 2b interferon (Intronா) [Shering-Plough; Kenilworth, NJ]
beta interferon (1a or 1b not specified)
Nonsteroidal antiinflammatory drugs
diclofenac (Cataflamா, Voltarenா) [Novartis; East Hanover, NJ]
ketorolac (Toradolா) [Hoffmann-La Roche; Nutley, NJ]
nimesulide (Algimesilா, others) [Francia; Milan, Italy]
piroxicam (Feldeneா) [Pfizer; New York, NY]
Vaccines
Hepatitis-B (Engerix-Bா, GlaxoSmithKline; Research Triangle Park, North Carolina, USA), (Recombivax HBா, Merck; Whitehouse Station, NJ
Influenza (Fluarixா) [SmithKline Beecham; Hertfordshire, United Kingdom]
MMR (MMR IIா) [Merck; Whitehouse Station, NJ]
triple-antigen/t.a.b. (diphtheria, tetanus, pertussis vaccine, various brands)
Miscellaneous
quinine (Formula Qா, various products available with some quinine content) [Major Pharmaceutical; Livonia, MI]
simvastatin (Zocorா) [Merck; Whitehouse Station, NJ]
albendazole (Albenzaா) [GlaxoSmithKline; Research Triangle Park, NC]
carbon tetrachloride (used as a hand washing agent in reported case)
cocaine (used illicitly)
heroin (used illicitly)
hair dyes (unspecified brands)
methapyrilene and salicylamide (Nytolா) [Block Drugs; Jersey City, NJ]
valacyclovir (Valtrexா) [GlaxoSmithKline; Research Triangle Park, NC]
11

12. of quinine-associated TTP-HUS in a report of exposure [41–46,48,50,57,58]. Other patients have given
nts from a reference laboratory for analysis of Current Opinion in Hematology 2001, 8:286–293
a history of recurrent fever, chills, nausea, and vomiting
ndent antibodies. Patients commonly were ex- with previous quinine ingestion. Many reports focused
the acute薬剤性TTP-HUSの特徴
 onset of fever, chills, nausea, vom-
on the demonstration of quinine-dependent antibodies
hea, and abdominal pain, beginning within 6 to multiple cell targets: platelets, neutrophils, lympho-
(Mytomycin C, Cyclosporine, Quinine, Ticlopidine, ClopidogrelによるTTP-HUS例)
inine ingestion. All patients had the diagnos- cytes, red cells, and endothelial cells [40•,41,42,44,
for TTP-HUS: thrombocytopenia, microan-
 39例の解析
emolytic anemia, and renal dysfunction. Two
Table 4. Clinical features of 39 reported patients with
d neurologic abnormalities. All patients un- associated thrombotic thrombocytopenic purpura-hemolytic
asma exchange (range, 2–11 days); most re- uremic syndrome
modialysis; all survived and renal function ap-
Clinical features Frequency
covered, although no long term follow-up was
Women 34/39 (87%)
Presenting symptoms
chills, fever 25/39 (64%)
ors’ experience, quinine is a common cause of abdominal pain, nausea, vomiting, diarrhea 37/39 (95%)
, accounting for 11% of all patients with clini- oliguric acute renal failure 35/38 (92%)
neurologic abnormalities 15/39 (38%)
cted TTP-HUS in their region (Kojouri et al.,
Laboratory abnormalities
hed data, July 2001). Further, quinine- leukopenia 14/37 (38%)
TTP-HUS has a high acute mortality (3 [18%] disseminated intravascular
nts) and a high risk for chronic renal failure (8 coagulation 13/36 (36%)
4 surviving patients). The difference between abnormal liver function test results 15/29 (52%)
Management
’ case series and the report of Gottschall et al.
plasma exchange 31/39 (79%)
at the authors see all patients with clinically dialysis 31/38 (82%)
TTP-HUS in their region, all patients are Outcome
ifically about quinine exposure, and all pa- death 4/39 (10%)
ollowed continuously after recovery (current chronic renal failure 12/35 (34%)
multiple episodes with repeat quinine exposure 14/39 (36%)
w-up, 3.8 years).
12

13. TTP 臨床症状
 TTSの症状は非特異的;
腹痛, 嘔気, 悪心, 微小血管障害に由来する症状
中枢症状は軽度で一過性のことも多い. 約半数で認める.
発熱はUncommon. 高熱, 悪寒がある場合はTTPよりもInfectionを疑う
 診断にはLabを
 Anemia + Thrombocytopenia – LeukocytopeniaでTTPを疑う
 Microangiopathic hemolytic anemiaは特異的ではないが
診断をサポートする因子ではある
 Fragmented RBC, 網赤血球, LDH↑, Bil↑, Coombs test陰性
 >2個/100倍視野でSchistocyteを認める Microangiopathic hemolysisを示唆
(Schistocyte = Fragmented RBC)
 腎不全は低頻度だが, 1/3で一過性のCr上昇は認める

14. *1(47名) 症状
Altered Mental Status 78.7%
Focal 29.7%
Hemiparesis 12.7%
Visual changes 6.3%
Seizure 36.9%
Renal involvement 85.1% J Bras Nefrol 2010;32(3):298-308
Heart involvement 36.1% Figure 1. Peripheral blood smear of a patient with TTP.
Abdominal Pain 39.1%
Prior TTP 17.0%
悪性腫瘍, Chemo 19.1%
膠原病 17.0%
E coli感染症 12.7%
Neurology 2009;73:66-70

15. TTP 画像検査
 頭部CT, MRI (Neurology 2009;73:66-70)
 47名のTTP患者のRetrospective study
 25%で頭部CTで急性変化を認め, その内半数がPRESであった
 MRIでは82%で所見(+). その半数(48%)がPRES.

16.  除外診断も重要
 Sepsis, Disseminated Cancer, Malignant Hypertension
 TTPと初期診断された10%がSepsis, Disseminated Cancerであった
 DICのLab所見はSepsisやDisseminated cancerを示唆するため注意
(TTPでもDICは認めることはあるが, 組織の虚血による影響)
 妊娠女性のTTP合併は有名であり,
妊娠可能女性でTTPを診た際はCheckが必要となる

17. Clinical Categories of TTP
Category 原因 Risk 臨床的特徴 治療 経過
黒人 1/3で中枢症状(-) Plasma 80%が改善
特発性TTP ADAMTS 13欠損 女性 発熱は稀 exchange
免疫抑制療法 再発率~50%
肥満 腎障害も稀
妊娠 出産前 子癇発作 Plasma
妊娠 exchange 再発は稀にあり
ADAMTS 13欠損 産褥期 HELLPと酷似 免疫抑制療法
SLEの急性増悪 女性 免疫抑制療法
背景の膠原病 慢性の経過
自己免疫 抗リン脂質抗体症候群 若年 Plasma
腎障害は多い exchange 予後は悪い
Scleroderma 中年
小児; 対症療法
女性 小児ならばHUS 小児の12%が
Prodrome of Shiga toxin, O-157 成人では,
Bloody diarrhea 出血性腸炎 成人 成人では 腎不全 or 死亡
白人 神経, 腎障害多い Plasma 成人では45%
exchange
Quinineが最も多い 高齢者 急性の全身症状 死亡率は15%,
Acute, Plasma
immune-mediated Ticlopidine, 白人 ARF, 発熱, 下痢, exchange CRFは多い
drug toxicity Clopidogrelなども 免疫抑制療法
女性 肝障害, WBC低下 薬剤再開で再発
Chemo 薬剤の中止後も 原因薬剤の中止
Cumulative, 基礎疾患による
Dose-dependent (Mitomycin, Dose 進行する
gemcitabine) Duration Plasma CRFは多い
drug toxicity 免疫抑制療法 exchange
腎障害は多い
Hematooietic Donor 腎に限局した Plasma
Allogeneic
Stem-cell transplantaion HLA Thrombotic exchange 死亡率は高い
transplantation GVHD microangiopathy の効果は不明

18. TTP治療
 Plasma-Exchange Treatment
 効果が証明されている唯一の治療
 102名のTTP患者に対して, Plasma-Exchange vs Plasma infusionで比較し
6mo生存率は 78% vs 63% (p=0.04)
 治療への反応性, 改善までの時間もPlasma-Exchangeの方が良好
 Plasma ExchangeはPlasma vol.の1.0-1.5倍量を交換
 Plasma-Exchangeが出来ない場合はPlasma infusionで繋ぐ.
 ADAMTS 13低下例で血漿交換が著効しており,
ADAMTS 13正常例(自己免疫など)では効果は低下.
 その場合, 免疫抑制療法, ステロイド, 脾摘を必要とする可能性もあり
NEJM 2002;347:589-600

19.  血漿交換の期間は一致したCriteriaは無く, 寛解するまで行う
(PLTが正常値, 神経所見消失, LDHが正常値)
 一度改善した後も再燃するリスクはあるため,
慎重なフォローアップと再増悪時には速やかに再度血漿交換を考慮
 血漿交換の頻度を減少させてゆく方法がより実用的
(Blood 2000;96:1223-9)

20. Hematology 2011;16:73-79
 単一施設での42例の血漿交換の経験
 42例のTTP-HUSで血漿交換を施行.
そのうち38例(73.1%)が二次性.
 血漿交換は平均5回[1-32]
母集団 原因
80.7%が連日施行,
年齢 47歳[17-81] 特発性 26.9%
13.5%が隔日施行
男性 38.5% 血液幹細胞移植後 19.2%
 血漿交換での Hb 7.6g/dL[4.4-11.0] 妊娠 5.8%
寛解率は51.9%. PLT 3万[4-12.6]/µL 薬剤性 25.0%
Cre 2.5mg/dL[0.6-10.6] Mitomycin C 15.4%
 一次性TTP-HUSでは71.4%
発熱 44.2% Cyclosporin A 1.9%
二次性TTP-HUSでは42.1%
神経症状 61.6% Tacrolimus 3.8%
 再増悪は5.8%, 再燃は1.9% LDH 788IU/L[271-5176] Clopidogrel 1.9%
 平均余命は5.2ヶ月だが, Gemcitabine 1.9%
血便＋ 2.8%
基礎疾患による.
悪性腫瘍 11.5%
自己免疫疾患 5.8%
20
手術後 1.9%

21. than idiopathic patients (P50.001) not only in the paresthesia did not develop in the membrane filtra-
univariate analysis but also in the multivariate tion group. However, this difference was not statis-
Hematology 2011;16:73-79
analysis (Table 3). tically significant.
 血漿交換への反応性に関与する因子は
Between patients treated with the centrifugation
method and those treated with the membrane Discussion
filtration method,女性の方が反応性が良好.sig-
 性別; the remission rate was not The remission rate of patients with TTP–HUS who
nificantly different (51.1% versus 40.0%, P51.000). received therapeutic plasma exchange has been
基礎疾患; 特発性の反応性が良く, 幹細胞移植後はほぼ反応は無し.
Table 2 Analysis of factors associated with remission after therapeutic plasma exchange
Characteristics RR (%) P
Age (year) ,60 52.5 0.743
>60 41.7
Gender Male 25.0 0.009
Female 65.6
Hemoglobin (g/dl) ,9.0 46.2 0.523
>9.0 61.5
Baseline platelet (6109/l) ,20 47.1 1.000
>20 51.4
Creatinine (mg/dl) ,1.5 28.6 0.116
>1.5 57.9
Fever (.38uC) Absent 62.1 0.093
Present 34.8
Neurological symptoms Absent 55.0 0.776
Present 46.9
Etiology Idiopathic 71.4 0.003
HSCT 0
Pregnancy 100
Drugs 53.8
Bloody diarrhea 100
Presence of an additional disorder 40.0
Note: RR: remission rate; CI: confidence interval; HSCT: hematopoietic stem cell transplantation.
21

22. Hemolytic-Uremic Syndrome
(HUS)

23. Hemolytic-Uremic Syndrome
 溶血性貧血, 血小板低下, 腎障害を来す疾患
 <5yrの小児が>50%を占める. 頻度は6.1/100,000
全体の頻度は1-2/100,000
 E. coli O157:H7による感染性腸炎後に発症
 O157:H7, O111:H8, O103:H2, O123, O26が関与し,
E coli感染後のHUSが全体の90%を占める.
 O157では2-15%でHUSが合併する. 下痢後5-10日での発症が主
 O111では16.7%でHUSが合併し, 年齢による発症率に差は無し.
(2008年オクラホマでのOutbreak) (Arch Intern Med. 2010;170(18):1656-1663)
 小児では血性下痢後1wkに9-30%でHUSを併発すると言われる.
 他に Shigella dysenteriae, S pneumoniaeなどがHUSの原因となる
NEJM 2002;347:589-600

24.  Shiga toxin; 70-kDの外毒素であり, S dysenteriae DNAにCode
 A subunit(33-kD)1つとB subunit(7.7-kD) 5つで構成
Toxinは血液を介して
糸球体内皮, Mesangial cell,
尿細管に沈着 TNF-α, IL-1,6を分泌
異常な巨大vWFを産生し,
血栓形成を来す NEJM 2002;347:589-600

25. O157:H7によるHUS発症リスク因子
 E coli O157:H7による下痢 発症1wk以内の
小児259名のProspective cohort. (10歳未満を対象)
 上記のうち36名(14%)でHUS*を発症
(*溶血性貧血 Ht<30%, PLT <150k, Cre上昇を満たす)
Table 4. Multivariable Analysis for Risk Factors Associated With
Hemolytic Uremic Syndrome
 HUS発症に関与する因子は,
Multivariable OR P
初期に嘔吐, a
Risk Factor (95% CI)b Value
初期評価のWBC高値, Agec 0.89 (0.77–1.04) .15
抗生剤使用. Vomiting before enrollment 3.05 (1.23–7.56) .02
Initial leukocyte count c 1.10 (1.03–1.19) .008
Days from onset of diarrhea to first 0.87 (0.63–1.20) .40
leukocyte count determination
Days from onset of diarrhea to stool 0.98 (0.65–1.48) .94
culture
Acetaminophen 1.39 (0.58–3.34) .46
Antibiotics 3.62 (1.23–10.6) .02
25 Abbreviation: CI, confidenceInfectious Diseases 2012;55(1):33–41
Clinical interval; HUS, hemolytic uremic syndrome; OR,
odds ratio.

26.  このStudyでの使用抗生剤は,
 ST合剤(44%でHUS発症, p=0.02)
β-lactam(22%でHUS発症, p=0.29)
MTZ(67%でHUS発症, p=0.04)
AZT(25%でHUS発症, p=0.40)
 このデータより, Leukocytosis, Abx使用の有無から
Table 6. Probabilities of Hemolytic Uremic Syndrome (HUS) by
HUS発症率を求めると, no HUS → Nonoligoanuric HUS → Oligoanuric HUS
No HUSa Nonoligoanuric Oligoanuric
Grouping (%) HUSa (%) HUSa (%)
No antibiotics + low 92.3 5.6 2.1
leukocyte count
No antibiotics + high 84.0 11.3 4.7
leukocyte count
Antibiotics + low 77.4 15.5 7.0
leukocyte count
Antibiotics + high 60.0 25.3 14.7
leukocyte count
Abbreviation: HUS, hemolytic uremic syndrome.
26 a
Clinical Infectious Diseases 2012;55(1):33–41
Probabilities are given as percentages by the ordinal logistic regression

27. STEC O157とHUS CID 2009;49:1480-5
 Foodborne Disease Active Surveillance Networkにおいて,
 2000-2006年でO157による食中毒症例は3464例.
 その内, 218例(6.3%)でHUSを発症. 平均年齢は3-4yr.
 年齢<5yrはHUS発症OR 5.37[4.04-7.14]
女性はHUS発症OR 1.70[1.27-2.27]
 死亡率は全体で0.6%だが, HUS発症例では4.6%と予後不良
 死亡リスクは>=60yrで最悪で1.9%
 HUS合併例では33.3%と高い.
15.3%
 <5yrではHUS合併例でも
死亡率は3.0%程度.
年齢 HUS(+) HUS(-)
<5yr 3.0% 0.3%
7.9%
5-9yr 2.4% 0.0%
10-17yr 0.0% 0.2% 3.4% 3.8%
18-59yr 0.0% 0.1% 1.2%
>60yr 33.3% 1.9%
All 4.6% 0.4%

28. ドイツにおける
Shiga-Toxin産生O104:H4 outbreak N Engl J Med 2011;365:1771-80.
 2011年5月-7月にドイツにてO104-H4が流行.
 3816例の腸炎症例が発症し, 54例が死亡.
HUSを発症したのは845例(22%)と高頻度.
 腸炎での死亡率は0.6%[0.4-1.0],
HUSでの死亡率は4.2%[3.0-5.8].
 HUSは今までと異なり, 88%が成人例であった. 平均年齢は42歳.
 O104:H4 の平均潜伏期間は8d[6-10].
下痢発症∼HUS発症までの期間は5d[4-7].
28

29. Shiga-Toxin–Producing E. coli Outbreak in Germany
N Engl J Med 2011;365:1771-80.
Table 1. Demographic and Clinical Characteristics and Laboratory Test Values of Patients Positive for Shiga-Toxin–Producing Escherichia coli
at First Presentation.*
Total Adults Children
Variable (N = 166) (N = 142) P Value† (N = 23) P Value†
Without HUS With HUS Without HUS With HUS
(N = 119) (N = 23) (N = 6) (N = 17)
Age — yr 0.12 0.42
Median 38 37 38 12 10
Range 18–87 20–84 18–87 1–17 1–15
Male sex — no. (%) 63 (38) 45 (38) 4 (17) 0.06 4 (67) 10 (59) 0.74
Bloody diarrhea — no./total no. (%) 141/161 (88) 106/116 (91) 20/22 (91) 0.94 3/5 (60) 11/17 (65) 0.85
Abdominal pain — no./total no. (%) 134/152 (88) 102/115 (89) 19/22 (86) 0.76 5/5 (100) 8/9 (89) 0.44
Nausea — no./total no. (%) 38/115 (33) 23/84 (27) 9/19 (47) 0.09 3/4 (75) 3/7 (43) 0.30
Vomiting — no./total no. (%) 33/133 (25) 14/94 (15) 6/20 (30) 0.11 4/5 (80) 9/13 (69) 0.65
Temperature — °C 36.7±0.5 36.6±0.5 36.8±0.5 0.31 36.9±0.5 37.0±0.6 0.80
Hemoglobin — g/dl 13.4±2.2 14.2±1.3 11.8±2.8 <0.001 13.7±1.6 10.1±1.9 <0.001
Leukocytes — ×10−9/liter 11.3±4.1 11.0±3.5 12.4±5.8 0.11 12.2±5.3 12.1±5.0 0.98
Platelets — ×10−9/liter 209.3±90.0 245.2±51.3 111.7±91.9 <0.001 295.7±35.5 63.6±56.8 <0.001
Creatinine — mg/dl 1.4±1.9 0.8±0.2 2.0±1.7 <0.001 0.7±0.3 4.7±4.3 0.04
Bilirubin — mg/dl 0.9±0.7 0.8±0.5 1.8±1.0 <0.001 0.8±0.5 1.3±0.8 0.24
Lactate dehydrogenase — U/liter 424±575 193±92 671±464 <0.001 235±39 1707±860 <0.001
C-reactive protein — mg/liter 18.1±28.8 14.4±26.0 29.9±32.6 0.02 39.0±61.2 18.5±18.9 0.22
* Plus–minus values are means ±SD. Data are for patients who presented to the Hamburg University Medical Center between May 19 and
29
June 11, 2011. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for bilirubin to micro-

30. HUSのその他の原因
 家族性HUS
 5-10%を占め, 死亡率は54%と通常のHUSよりも高い(3-5%)
 生存者の半数に再発を認め, 1/3以上がHDを必要とする
 家族性HUS患者の中に, Factor Hの欠損を認める例がある
Factor Hは150-kDの蛋白で, C3bBb C3b, Bbへ分解する作用
 Factor Hの欠損によりC3が活性化され, 細胞障害を来す
糸球体内皮細胞の障害を来し, 血栓形成を起こす.
 Unknown causes
 薬剤; Mitomycin, cyclosporine, tacrolimus, 化学療法, 放射線療法
 Quinine-induced immune thrombocytopeniaなど
NEJM 2002;347:589-600

31. HUSによる神経症状 Neurology® 2012;79:1466–1473
 ESEC O104:H4によるHUS 48名の解析
 42例で神経学的評価を施行. >> 神経学的異常は41例で認められた.
所見
MMSE<28 24/42 パニック発作 13/42 Dysdiadochokinesis 14/42
見当識障害 14/39 焦燥感 5/42 Dysmetria 10/42
Working memory 21/39 妄想 6/42 Intension tremor 9/42
短期記憶 18/39 Pseudohallucinations 5/42 小脳失調 6/42
失語 22/42 抑うつ 6/42 構音障害 5/42
失行 14/42 多幸感 2/42 複視 15/42
失書 13/42 反射亢進 23/42 めまい 7/42
保続 9/42 不全対麻痺 7/42 静止時振戦 10/42
神経運動遅延 20/42 四肢麻痺 4/42 運動振戦 4/42
嗜眠 6/42 Rigor 1/42
昏睡 10/42 頭痛 11/42
痙攣, ミオクローヌス 8/42
31

32. Figure 2 Frequency of neurologic symptoms and signs over the course of 42 days after the onset
of diarrhea
For the first days the graph summarizes symptoms reported from the patients, their relatives, or the first attending physi-
cian since the patients were referred to our hospital with delay. Thus the graph gives an estimation of the course of the
disease rather than a precise description.
発症10-15日で最も高頻度となり,
rologic complications is not yet known. In our co- symptoms was similar in all patients. Slight attention
hort and another recently described cohort from this deficits and trouble finding words were followed by
その後改善を認めてゆく経過.
outbreak with neurologic symptoms in 56%11 the alterations of working memory and short-term mem-
rate of neurologic symptoms exceeded by far the ory and then disorientation for time and place and
maximum rate (40%) reported for children with apraxia. Increasing cognitive dysfunction was accom-
32 Neurology® 2012;79:1466–1473
HUS in the past. Several aspects might be respon- panied by decreasing alertness and alterations of con-
6–8

33. HUSの治療
 対症療法が基本
 補液, 電解質補正
 尿量モニタリング, 必要があれば透析導入
 TTPのような血漿交換, 血漿輸血は効果認めない.
 抗凝固薬, ヘパリンも効果無し.
 O157:H7感染に対する抗生剤は毒素放出を促進
 HUSのRiskを増加させる可能性が示唆されている
 抗生剤を投与することで下痢症のOutcomeも変わらず,
基本抗生剤は投与する必要なし.
 急性期の死亡率は3-5%. 生存例でも20%でESRDになり得る.
NEPHROLOGY 2006; 11, 213–218 NEJM 2002;347:589-600

34. E coli O104:H4によるHUSの治療 BMJ 2012;345:e4565
 289例のRetrospective case-control study.
 160例(54%)で一次透析となり, 最終的に維持透析となったのは3例のみ.
 37例(12%)で痙攣(+), 54例(18%) 挿管管理, 12例(4%)が死亡.
 血漿交換±大量ステロイド治療は予後に影響を及ぼさない.
 抗生剤治療はE coliの便中排泄期間を短縮させ,
痙攣発症率, 腸管壊死を低下させるという単一施設の報告がある.
 Eculizumabの効果は有意差が見いだせず.
34

35.  血漿交換をすべきかどうかは原因により異なる.
 下痢症に関連したHUSは基本的に対症療法.
 他の原因(= Atypical HUS)では基本的には血漿交換を行う.
Table 1 CLASSIFICATION AND TREATMENT OF THE DIFFERENT FORMS OF HUS
Disease Causes Treatment
D+ HUS Stx-producing Escherichia coli Support
Shigella dysenteriae type 1 Support and antibiotics
Non-Stx HUS (sporadic) Bacterium (Streptococcus pneumoniae) Antibiotics and plasma
Virus (HIV) Plasma
Drugs (antineoplastic, antiplatelet,
Drug interruption and plasma
immunosuppressive drugs)
Pregnancy Delivery, plasma
Post-partum Plasma
Systemic diseases
Lupus Steroids and plasma
Scleroderma Blood pressure control
Antiphospholipid syndrome Oral anticoagulant agents
Idiopathic Plasma
Genetic (CFH, MCP CFI)
, Plasma
Familial Genetic (CFH, MCP CFI), plasma
, Plasma
J Bras Nefrol 2010;32(3):298-308

36. the approach outlined in Fig. 1 is more detailed and
attempts to avoid biasing children with TTP from hav-
ing plasma therapy withheld and adults with HUS due
 典型的なTypical HUSのみ血漿交換を行わないと考えるべし TTP.
to E. coli O157:H7 being mislabeled as suffering
 初期ではHUSかTTPかの判別は困難な場合が多い.
TABLE 1. Thrombotic microangiopathy and plasma treatment
 小児例ではほとんどがHUS.
Thrombotic thrombocytopenic purpura ⁄ hemolytic uremic syndrome
明らかな腸炎の既往があり, (majority adults)
Primary
その後の発症であれば Idiopathic or acquireda
Hereditarya
行わない選択もありだが, Secondary
Collagen vascular diseaseb
Typical HUSが確定困難ならば Drugsa except mitamycin C
原則行う形をとる事が多い. Infectionb except E. coli O157:H7 (NR)
Pregnancyb
Pancreatitisb
Stem cell transplant (NR)
Occult or disseminated malignancy (NR)
Malignant hypertension (NR)
Hemolytic uremic syndrome (majority children)
Primary
Atypical hemolytic uremic syndrome (abnormalities in
cComplement regulation)
Complement factor Hb, complement factor Ib, complement
factor Bb,
C3 convertaseb, thrombomodulinb except membrane co-factor
protein (NR)
Seminars in Dialysis 2012;25:214-219 Secondary
Diarrheal hemolytic uremic syndrome (NR)
E. coli O157:H7
36 a
80–90% response; b50–70% response; NR, 0% response.

37. Atypical HUS
 HUSの10%がAtypical HUSに属し,
 Shiga-like toxin産生菌, S pneumoniae感染に関与しない発症
 死亡率が25%と高く, 20%が末期腎不全へ移行し, 予後不良な病態
 Familial form
 家族性は<20%を占める. 末期腎不全, 死亡Riskは50-80%と高い.
 Sporadic form
 家族性に属さないものを孤発性と呼び, HIV感染, 悪性腫瘍,
臓器移植, 妊娠, 化学療法, 免疫抑制剤, 抗血小板剤に由来する.
 女性のAtypical HUSの10-15%が妊娠, 出産後に発症する
 Sporadic formの50%が原因不明の”特発性”
NEPHROLOGY 2006; 11, 213–218 NEJM 2009;361:1676-87

38. Atypical HUSの特徴
 補体はC3が消耗性の低下を示し, C4は正常値をとる
 Complement factor H(CFH); Alternative pathwayに関連する因子
Atypical HUSではCFHの遺伝子異常を有する割合が高く,
家族性では40-45%, 孤発性では10-20%で変異を認める
Gene Protein Effect 頻度 Plasma Therapy 長期反応 腎移植後
短期反応 死亡, 腎不全 再発率
CFH Factor H 内皮結合障害 20-30% 寛解率60% 70-80% 80-90%
CFHR1/3 Factor HR1,R3 抗FH抗体 6% 寛解率70-80% 30-40% 20%
MCP Membrane 細胞膜表現異常 10-15% 治療適応なし <20% 15-20%
cofactor protein
CFI Factor I 低値, 欠損 4-10% 寛解率30-40% 60-70% 70-80%
CFB Factor B C3安定化 1-2% 寛解率30% 70% 稀
C3 C3 C3b不活化抑制 5-10% 寛解率40-50% 60% 40-50%
THBD Thrombomodulin C3b不活化抑制 5% 寛解率60% 60% 稀
NEJM 2002;347:589-600

39. Atypical HUS 臨床所見
 遺伝子異常が原因の場合, 67%は小児期に発症する
 急性の血小板減少, 溶血性貧血, 腎障害を特徴とし,
腎外症状(CNSなど)は20%で認められる.
 予後, 治療反応性は原因遺伝子異常により異なる
CFH変異の10年生存率は50%, Anti-CFH抗体, CFI, C3変異は80-90%
 MCP変異の予後は良好で, 80-90%の寛解率を認める
 Atypical HUSの治療
 血漿交換は死亡率は50% 25%へ低下させる
 Guidelineでは診断後24hr以内に血漿交換を行うことを推奨.
(血漿量の1-2倍を交換, もしくは20-30mL/kgを補充)
 腎移植後も再発を認める
NEJM 2002;347:589-600

40. Cancer-related
microangiopathic hemolytic anemia Medicine 2012;91: 195-205
 Microangiopathic hemolytic anemia(MAHA)は
典型的なのはTTPやAtypical HUSのことを差す.
 TTP/aHUSは薬剤や膠原病, 手術治療, 骨髄幹細胞移植, 悪性腫瘍に
続発して生じることもあり,
悪性腫瘍が原因になるものをCR-MAHAと呼ぶ.
 CR-MAHA 168例の解析
 原発癌の頻度は,
原発巣 胃癌によるMAHAの平均年齢は52歳. 男女差無し
胃癌 44 腹腔内 10 乳癌によるMAHAの平均年齢は54歳[19-82].
乳癌 36 泌尿生殖器 3
内分泌腫瘍では, 褐色細胞腫が3例,
前立腺癌 23 内分泌 6
下垂体腫瘍が2例, 神経内分泌腫瘍が1例.
肺癌 16 他 4
リンパ腫はHL, IVL, NHL, Myeloma, hairy cell leukemia
原発不明癌 12 リンパ腫 14
40

41. TABLE 2. Clinical and Hematologic Data of Patients With CR-MAHA
Characteristic All Solid Cancers Gastric Breast Prostate Lung CUP Other*
No. of patients 154 44 36 23 16 12 23
CR-MAHA at recurrence 30/154 (19.4%) 10 13 7 0 0 0
Metastatic, no. (%)† 134/146 (91.8%) 39 33 21 13 12 16
Nonmetastatic, no. (%)† 12/146 (8.2%) 3 0 2 3 0 4
Patients with TTP-like clinical picture 11 1 3 2 1 0 4
Patients with HUS-like clinical picture 26 3 1 17 0 1 4
BM infiltration‡ 90/111 (81.1%) 33 24 4 7 10 12
No BM infiltration‡ 21/111 (18.9%) 5 1 7 3 0 5
Leukoerythroblastic blood presentation 36 11 11 3 6 4 1
Hypofibrinogenemia (G200 mg/dL) 39/108 (36.1%) 13/28 8/17 5/21 2/13 4/9 7/20
Pulmonary complications 49 16 13 4 8 3 5
Abbreviation: BM = bone marrow.
*Other tumors include abdominal, genitourinary, endocrine, and various cancers.
†No data for 8 patients.
‡No data for 43 patients.
Medicine & Volume 91, Number 4, July 2012 Cancer-Related Microangiopathic Hemolytic Anemia
CR-MAHAを認める例は予後不良.
 that themany cases with only limited (focal) and MAHA after successful lymphoma,of MAHA and antibodies 195-205
clear
occurred in
extent of infiltration was not uniform,
infiltration. associated with
treatment cancer. In MAHA
ADAMTS 13 2012;91: were de-
Medicine
Most cases with bone marrow infiltration also had bone me- tected in a few cases and disappeared after successful lymphoma
tastases. Survival of CR-MAHA Patients sometimes associated According to Treatment*
TABLE 4. Bone marrow infiltration was With Various Cancers treatment (see below).
with bone marrow necrosis25,78,109,124,135,141 or fibrosis.38,106
Tumor emboli in the marrow have been found in some cases at Survival, MedianEndocrine Tumors
MAHA in (Range)
autopsy.141 MAHA occurred in 3 cases of pheochromocytoma,51,127,132
All 2 cases of pituitary tumor,74,75 and 1 case of neuroendocrine tu-
Pulmonary Abnormalities in CR-MAHA
Cancers Gastric Breastmor. 38 Two of Lung tumors were malignant, 38,127 and both had
these CUP Prostate
Clinical, radiologic, or histologic evidence of pulmonary = 26)
(n = 99)* (n = 34) (n (n = 13) Clinically, 2 = 11) were TTP like and15)
bone marrow infiltration. (n cases (n = 2
involvement was documented in 49 cases.(mo)
Treatment (mo) Clinical findings in-(mo) were HUS like. (mo) 2 cases of pheochromocytoma, 1 patient in
In the (mo) (mo)
cluded noncardiac 4 (0.5Y31) respiratory distress syndrome.(0.5Y31)
CT/CS dyspnea and 3 (0.5Y2) 4 whom the tumor was removed had (2Y9)
5 (0.5Y15) 3.5 complete remission,132 the
10.5 (2Y26)
Radiologic findings were reticulonodular infiltration of the lung. other had complete remission of MAHA but persistent renal
NCT/CS
43,67,89,126,135,156 0.5 (0.5Y84) 0.5 (0.5Y1.5) involvement(0.5Y16)
Histologic findings of pulmonary 0.5 0.5 (0.5Y1) 0.5 (0.5Y2.0) 4 (0.5Y84)
failure.51 Both patients with pituitary tumors had no bone mar-
(most at autopsy) were=pulmonary carcinomatous lymphangitis, = no row infiltration. Prolactin was elevated (prolactin is often secreted
Abbreviations: CT/CS chemotherapy or cancer surgery, NCT/CS chemotherapy or cancer surgery.
14,92,115,151 12,28,43,151
pulmonary microvascular tumor emboli,
*Only patients with survival data available. with growth hormone in this tumor). Plasma exchange was not
and pulmonary thrombotic microangiopathy.47,108,115,116,131 effective; both patients died within a few days.