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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, 8:286–293Table 1. Drugs and other exogenous substances reported to be associated with the development of thromboticthrombocytopenic purpura-hemolytic uremic syndromeAntineoplastic 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]
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, 8:286–293Hormones 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
of quinine-associated TTP-HUS in a report of exposure [41–46,48,50,57,58]. Other patients have givennts from a reference laboratory for analysis of Current Opinion in Hematology 2001, 8:286–293 a history of recurrent fever, chills, nausea, and vomitingndent 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 antibodieshea, 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 syndromemodialysis; 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 abnormalitieshed data, July 2001). Further, quinine- leukopenia 14/37 (38%)TTP-HUS has a high acute mortality (3 [18%] disseminated intravascularnts) 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
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;16:73-79analysis (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 centrifugationmethod and those treated with the membrane Discussionﬁltration 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 whoniﬁcantly 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 exchangeCharacteristics RR (%) PAge (year) ,60 52.5 0.743 >60 41.7Gender Male 25.0 0.009 Female 65.6Hemoglobin (g/dl) ,9.0 46.2 0.523 >9.0 61.5Baseline platelet (6109/l) ,20 47.1 1.000 >20 51.4Creatinine (mg/dl) ,1.5 28.6 0.116 >1.5 57.9Fever (.38uC) Absent 62.1 0.093 Present 34.8Neurological symptoms Absent 55.0 0.776 Present 46.9Etiology Idiopathic 71.4 0.003 HSCT 0 Pregnancy 100 Drugs 53.8 Bloody diarrhea 100 Presence of an additional disorder 40.0Note: RR: remission rate; CI: confidence interval; HSCT: hematopoietic stem cell transplantation. 21
Figure 2 Frequency of neurologic symptoms and signs over the course of 42 days after the onset of diarrheaFor 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 thedisease 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 attentionhort 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 andmaximum rate (40%) reported for children with apraxia. Increasing cognitive dysfunction was accom- 32 Neurology® 2012;79:1466–1473HUS in the past. Several aspects might be respon- panied by decreasing alertness and alterations of con- 6–8
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 renalNCT/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.