今日の臨床サポート

赤血球破砕症候群

著者: 張替秀郎 東北大学 血液内科(血液・免疫病学分野)

監修: 木崎昌弘 埼玉医科大学総合医療センター

著者校正/監修レビュー済:2022/03/02
参考ガイドライン:
  1. 厚生労働科学研究費補助金(難治性疾患政策研究事業)「血液凝固異常症等に関する研究」班 TTP グループ:「血栓性血小板減少性紫斑病 (TTP)診療ガイド 2020」
患者向け説明資料

概要・推奨   

  1. 後天性血栓性血小板減少性紫斑病に対しては、血漿輸注ではなく血漿交換を行うことが推奨される(推奨度1
  1. 血栓性血小板減少性紫斑病においては、原則的に血小板輸血は適応とならないが、活動性出血を認める場合は、その施行を考慮すべきである(推奨度3)
  1. 血栓性血小板減少性紫斑病において、ADAMTS13の活性測定が推奨される(推奨度1)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
張替秀郎 : 講演料(中外製薬,ノバルティスファーマ),奨学(奨励)寄付など(協和キリン)[2022年]
監修:木崎昌弘 : 講演料(武田薬品工業,ヤンセンファーマ,小野薬品工業,ブリストル・マイヤーズスクイブ),研究費・助成金など(武田薬品工業),奨学(奨励)寄付など(協和キリン,旭化成ファーマ,第一三共,中外製薬,日本新薬,武田薬品工業)[2022年]

改訂のポイント:
  1. 厚生労働省研究班「血栓性血小板減少性紫斑病 (TTP)診療ガイド 2020」に沿って改訂を行った。 

病態・疫学・診察

疾患情報  
  1. 破砕赤血球は物理的損傷により断片化した赤血球であり、心臓弁置換術後や血栓性微小血管障害などで認められる。
  1. 一般的に、赤血球破砕症候群は血栓性微小血管障害により発症する疾患群を指し、血栓性血小板減少性紫斑病/溶血性尿毒症症候群がその代表である。
  1. 赤血球破砕症候群では、血栓形成による臓器障害・機械的溶血によりクレアチニン上昇、血小板減少、ヘモグロビン、ハプトグロビンの低下、間接ビリルビン・LDH・網赤血球数の上昇を認める。
  1. 血栓性血小板減少性紫斑病では、腎不全などの臓器障害のほか、発熱、精神症状などの症状を伴う。
  1. 溶血性尿毒症症候群は小児に多く、志賀毒素を産生する病原性大腸菌感染により発症することが多い。血性下痢などの消化器症状に引き続き、腎不全を発症する。
  1. 後天性血栓性血小板減少性紫斑病はvon Willebrand因子の切断酵素であるADAMTS13に対する中和抗体が産生され、活性が低下することにより発症する。
 
  1. 無尿期、乏尿期が長い溶血性尿毒症症候群では、長期的に腎機能が低下するリスクが高い(推奨度1O)
  1. まとめ:溶血性尿毒症症候群症例において腎不全が重篤であった場合、腎機能障害が非可逆的となる可能性がある。
  1. 代表事例の説明:長期の経過観察の結果、無尿期が8日以上、もしくは乏尿期が10日以上の症例は全例で慢性的な腎機能障害が認められた[1]
  1. 結論:重症の腎不全が長期にわたった症例では、腎機能障害が残存するため、継続的な経過観察が必要である。
問診・診察のポイント  
  1. 消化器症状の有無を確認する(特に小児例:腹痛、血性下痢、嘔吐など)。精神・神経症状の有無を確認する(例:頭痛、意識レベルの低下、混迷、けいれんなど)。腎不全の有無を確認する(例:排尿の有無、浮腫など)。発熱の有無を確認する。出血傾向の有無を確認する(例:皮下出血など)。

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文献 

R L Siegler, M K Milligan, T H Burningham, R D Christofferson, S Y Chang, L B Jorde
Long-term outcome and prognostic indicators in the hemolytic-uremic syndrome.
J Pediatr. 1991 Feb;118(2):195-200.
Abstract/Text We examined 61 patients an average of 9.6 years (range 5 to 18 years) after an episode of childhood hemolytic-uremic syndrome. Twenty-four (39%) had one or more abnormalities. Seven (11%) had proteinuria and six (10%) had low creatinine clearance as solitary abnormalities. Eight (13%) had both proteinuria and reduced creatinine clearance; three (5%) had a combination of hypertension, proteinuria, and low creatinine clearance. Abnormalities sometimes appeared after an interval of apparent recovery. Logistic regression analysis showed that duration of anuria was the best predictor of disease at follow-up. No patients who had anuria lasting longer than 8 days or oliguria exceeding 15 days escaped chronic disease. However, 45% of those with disease had no anuria, and a third had no oliguria. Physicians should therefore be cautious in assuming recovery from HUS on the basis of a single evaluation and should periodically evaluate patients for an extended period.

PMID 1993944
A Pereira, R Mazzara, J Monteagudo, C Sanz, L Puig, A Martínez, A Ordinas, R Castillo
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: a multivariate analysis of factors predicting the response to plasma exchange.
Ann Hematol. 1995 Jun;70(6):319-23.
Abstract/Text The aim of this study was to investigate pretreatment prognostic factors that could be useful in predicting the response to plasma exchange in thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). Thirty-two patients with TTP/HUS, treated with plasma exchange at our institution from 1980 to 1994, were studied. The main clinical and laboratory data at the beginning of plasma exchanges were analyzed by the Cox stepwise logistic regression, applied to either treatment failure or death. Seventeen (53%) patients attained a complete remission and 22 (69%) survived (five in advanced renal failure and long-term hemodialysis). Longer delay in initiating plasma exchanges, presence of stupor or coma, and higher creatinine levels at the beginning of plasma exchanges were independent predictors of treatment failure. Stupor or coma at the beginning of plasma exchanges was the only predictor of mortality from unremitted TTP/HUS. Hemoglobin levels, platelet count, and LDH activity, traditionally envisaged as markers of disease activity, neither correlated with previous duration of TTP/HUS nor had any prognostic value. Early diagnosis of TTP/HUS and prompt initiation of intensive plasma exchange emerged from this study as the most effective interventions for improving the prognosis of TTP/HUS patients.

PMID 7632812
James N George
How I treat patients with thrombotic thrombocytopenic purpura: 2010.
Blood. 2010 Nov 18;116(20):4060-9. doi: 10.1182/blood-2010-07-271445. Epub 2010 Aug 4.
Abstract/Text Thrombotic thrombocytopenic purpura (TTP) is the common name for adults with microangiopathic hemolytic anemia, thrombocytopenia, with or without neurologic or renal abnormalities, and without another etiology; children without renal failure are also described as TTP. The diagnosis of TTP is an indication for plasma exchange treatment, but beginning treatment requires sufficient confidence in the diagnosis to justify the risk of plasma exchange complications. Documentation of a severe deficiency of plasma ADAMTS13 activity, defined as less than 10% of normal, is not essential for the diagnosis of TTP. Some patients without severe ADAMTS13 deficiency may benefit from plasma exchange treatment; in addition, some patients with severe ADAMTS13 deficiency may subsequently be diagnosed with another cause for their clinical features. However, severe acquired ADAMTS13 deficiency does define a subgroup of patients who appear to benefit from treatment with corticosteroids and other immunosuppressive agents in addition to plasma exchange but who have a high risk for relapse. Approximately 80% of patients survive their acute episode, a survival rate that has not changed since the introduction of plasma exchange treatment. Although recovery may appear to be complete, many patients have persistent minor cognitive abnormalities. More effective as well as safer treatment for TTP is needed.

PMID 20686117
B F Wyllie, A X Garg, J Macnab, G A Rock, W F Clark, Members of the Canadian Apheresis Group
Thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome: a new index predicting response to plasma exchange.
Br J Haematol. 2006 Jan;132(2):204-9. doi: 10.1111/j.1365-2141.2005.05857.x.
Abstract/Text Despite the favourable response of thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome (TTP/HUS) to plasma exchange, an early level of mortality persists. Non-response has been associated with a low frequency of exchange. The Rose index of TTP/HUS severity, occasionally used to predict the response of TTP/HUS to plasma exchange, remains unsatisfactory. The purpose of this study was to develop a new index predicting response of TTP/HUS to plasma exchange and to compare it with the Rose index. Retrospective analysis of 171 cases of TTP/HUS from 39 apheresis units across Canada between 1980 and 2001 was conducted. Logistic regression analysis was used to derive a model predicting 6-month mortality from presenting characteristics. The reduced model contained age >40 years, haemoglobin <9.0 g/dl and the presence of a fever at presentation. Gender, platelet count, creatinine and neurological signs were not part of the final model. This model predicted 13.4% of outcome variance. Predictive scores of 0, 2, 4 and 6 correlated with 6-month mortality rates of 12.5%, 14.0%, 31.3% and 61.5% respectively in our source population. This simple model may help identify those patients who would benefit from higher treatment intensity.

PMID 16398654
Sarah L Allford, Beverley J Hunt, Peter Rose, Samuel J Machin, Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology
Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias.
Br J Haematol. 2003 Feb;120(4):556-73.
Abstract/Text
PMID 12588343
G A Rock, K H Shumak, N A Buskard, V S Blanchette, J G Kelton, R C Nair, R A Spasoff
Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group.
N Engl J Med. 1991 Aug 8;325(6):393-7. doi: 10.1056/NEJM199108083250604.
Abstract/Text BACKGROUND: Thrombotic thrombocytopenic purpura is an uncommon disease with a high mortality rate even with current treatment. The cause of the syndrome and its optimal treatment are unknown. Although both plasma exchange and plasma infusion have been useful treatments, it is not clear which is superior. In this report we describe a prospective randomized trial comparing plasma exchange with plasma infusion for the treatment of thrombotic thrombocytopenic purpura.
METHODS: One hundred two patients with thrombotic thrombocytopenic purpura were randomly assigned to receive either plasma exchange or plasma infusion with fresh-frozen plasma on seven of the first nine days after entry into the trial. The total volume of plasma received by patients undergoing plasma exchange was three times that received by patients undergoing plasma infusion. All the patients also received aspirin and dipyridamole. The outcomes in the two groups were compared at the end of the first treatment cycle (day 9) and after six months.
RESULTS: At the end of the first treatment cycle patients receiving plasma exchange had a higher rate of response as defined by an increase in the platelet count (24 of 51 patients) than those who received plasma infusion (13 of 51, P = 0.025). Of the 51 patients treated with plasma exchange, 2 died, whereas 8 of the 51 patients who received plasma infusion died (P = 0.035). After six months the outcome in the plasma-exchange group was still superior, with a response observed in 40 of 51 patients, whereas 25 of 51 patients in the plasma-infusion group responded (P = 0.002). Eleven patients in the plasma-exchange group died, as did 19 patients in the plasma-infusion group (P = 0.036). The overall mortality was 29 percent.
CONCLUSIONS: Plasma exchange is more effective than plasma infusion in the treatment of thrombotic thrombocytopenic purpura.

PMID 2062330
E Bobbio-Pallavicini, L Gugliotta, R Centurioni, C Porta, N Vianelli, A Billio, F Tacconi, E Ascari
Antiplatelet agents in thrombotic thrombocytopenic purpura (TTP). Results of a randomized multicenter trial by the Italian Cooperative Group for TTP.
Haematologica. 1997 Jul-Aug;82(4):429-35.
Abstract/Text BACKGROUND AND OBJECTIVE: Antiplatelet agents are often included in plasma exchange-based regimens for thrombotic thrombocytopenic purpura (TTP) patients; however, the opportuneness of their use in TTP is still controversial. The italian Cooperative Group for TTP carried out a randomized trial to investigate their actual effectiveness, both in acute TTP and as maintenance treatment.
METHODS: Seventy-two TTP patients were randomized to receive plasma exchange and steroids with (group B) or without (group A) aspirin and dipyridamole. Treatment efficacy was evaluated after 15 days and salvage treatments were also considered for non-responders. Upon disease remission, the patients already treated with antiplatelet agents received ticlopidine for one year.
RESULTS: Regarding the treatment of acute phase TTP, similar overall response rates were observed in the two groups (91.4% in group B vs. 75.6% in group A), but lower mortality rates were observed at 15 days in the patients treated with antiplatelet agents; as a matter of fact, 5 patients from arm A died in the first 15 days (13.5%) versus only one in arm B (2.8%). These figures, while not statistically significant, seem to suggest that antiplatelet agents might be useful in preventing deaths in acute TTP; moreover, bleeding did not worsen in antiplatelet agent-treated patients. As for the role of maintenance treatment, our results support the efficacy and safety of one-year ticlopidine therapy since the current relapse rate is significantly higher in non-treated patients; as a matter of fact, 6 patients (21.4%) in the non-ticlopidine group and only 2 (6.25%) in the ticlopidine group relapsed (P = .0182 in favor of maintenance treatment).
INTERPRETATION AND CONCLUSIONS: Our results suggest the usefulness of antiplatelet agents in the treatment of acute phase TTP patients. Moreover, one-year ticlopidine maintenance therapy appears to be beneficial in preventing TTP relapses; however, only the completion of an adequate follow-up for all patients will definitively confirm this observation.

PMID 9299856
K Ikeda, O Ida, K Kimoto, T Takatorige, N Nakanishi, K Tatara
Effect of early fosfomycin treatment on prevention of hemolytic uremic syndrome accompanying Escherichia coli O157:H7 infection.
Clin Nephrol. 1999 Dec;52(6):357-62.
Abstract/Text OBJECTIVE: To clarify the effect of early fosfomycin treatment, an antimicrobial agent in common use in Japan, on children with E. coli O157 with the aim of preventing hemolytic uremic syndrome (HUS).
PATIENTS AND METHODS:
DESIGN: Non-randomized prospective study for development of HUS among inpatients with E. coli O157.
SETTING: The hospitals where the 292 inpatients were treated.
CASES: A total of 292 inpatients aged six to eleven years with E. coli O157 infection, 36 (12.3%) of whom were HUS cases.
RESULTS: Most of the HUS inpatients (91.7%) developed this complication between the sixth and ninth day of illness. We therefore analyzed the effects of antimicrobial therapy, especially that of fosfomycin, on prevention of HUS within the first five days of illness, because fosfomycin was the most frequently used (88.0%). To clarify the effect of fosfomycin alone on prevention of HUS, we carried out an analysis using the data for 130 inpatients who received fosfomycin alone or did not receive any antimicrobial agents, within the first five days of illness. multivariate analysis, controlled for age, gender and presence of fever, showed that all adjusted odds ratios for the development of HUS with the use of fosfomycin within the first three days of illness were less than 1.0, with the use of fosfomycin on the second day of illness achieving statistical significance (adjusted OR, 0.09; 95% CI, 0.01-0.79). Furthermore, inpatients who took fosfomycin within the first two days of illness developed HUS significantly less often than those who did not (adjusted OR, 0.15; 95% CI, 0.03-0.78). On the other hand, fosfomycin therapy on and after the third day of illness was not associated with the prevention of HUS.
CONCLUSION: The early use of fosfomycin within the first two days of illness might prevent the development of HUS.

PMID 10604643
C S Wong, S Jelacic, R L Habeeb, S L Watkins, P I Tarr
The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections.
N Engl J Med. 2000 Jun 29;342(26):1930-6. doi: 10.1056/NEJM200006293422601.
Abstract/Text BACKGROUND: Children with gastrointestinal infections caused by Escherichia coli O157:H7 are at risk for the hemolytic-uremic syndrome. Whether antibiotics alter this risk is unknown.
METHODS: We conducted a prospective cohort study of 71 children younger than 10 years of age who had diarrhea caused by E. coli O157:H7 to assess whether antibiotic treatment in these children affects the risk of the hemolytic-uremic syndrome and to assess the influence of confounding factors on this outcome. Estimates of relative risks were adjusted for possible confounding effects with the use of logistic-regression analysis.
RESULTS: Among the 71 children, 9 (13 percent) received antibiotics and the hemolytic-uremic syndrome developed in 10 (14 percent). Five of these 10 children had received antibiotics. Factors significantly associated with the hemolytic-uremic syndrome were a higher initial white-cell count (relative risk, 1.3; 95 percent confidence interval, 1.1 to 1.5), evaluation with stool culture soon after the onset of illness (relative risk, 0.3; 95 percent confidence interval, 0.2 to 0.8), and treatment with antibiotics (relative risk, 14.3; 95 percent confidence interval, 2.9 to 70.7). The clinical and laboratory characteristics of the 9 children who received antibiotics and the 62 who did not receive antibiotics were similar. In a multivariate analysis that was adjusted for the initial white-cell count and the day of illness on which stool was obtained for culture, antibiotic administration remained a risk factor for the development of the hemolytic uremic syndrome (relative risk, 17.3; 95 percent confidence interval, 2.2 to 137).
CONCLUSIONS: Antibiotic treatment of children with E. coli O157:H7 infection increases the risk of the hemolytic-uremic syndrome.

PMID 10874060
Kirk E Smith, Peter R Wilker, Paul L Reiter, Erin B Hedican, Jeff B Bender, Craig W Hedberg
Antibiotic treatment of Escherichia coli O157 infection and the risk of hemolytic uremic syndrome, Minnesota.
Pediatr Infect Dis J. 2012 Jan;31(1):37-41. doi: 10.1097/INF.0b013e31823096a8.
Abstract/Text BACKGROUND: Infection with Escherichia coli O157 (O157) can lead to the development of hemolytic uremic syndrome (HUS). Treating O157 infections with antibiotics is a possible risk factor for HUS development; however, previous studies evaluating this relationship have yielded conflicting results. The objective of this study was to further evaluate this issue.
METHODS: An age-matched case-case comparison study comprising Minnesota residents less than 20 years of age with culture-confirmed O157 infection who did (n = 66) or did not (n = 129) subsequently develop HUS was conducted. Subjects were identified through statewide surveillance activities by the Minnesota Department of Health from 1996 to 2002.
RESULTS: Overall antibiotic treatment was not associated with the development of HUS. Self-reported vomiting and female gender were significantly associated with the development of HUS. After adjustment for illness severity and gender, subjects who developed HUS were more likely to have been treated only with bactericidal antibiotics within the first 3 days (adjusted matched odds ratio [OR], 12.4; 95% confidence interval [CI], 1.4-110.3) or within the first 7 days (OR, 18.0; 95% CI, 1.9-170.9) after the onset of diarrhea. In particular, the use of β-lactams (penicillins or cephalosporins) in the first 3 days after diarrhea onset was also significant after adjustment (OR, 11.3; 95% CI, 1.2-106.7).
CONCLUSIONS: Individuals infected with O157 infection presenting with a more severe illness were at an increased risk of developing HUS. The use of bactericidal antibiotics, particularly β-lactams, to treat O157 infection was associated with the subsequent development of HUS.

PMID 21892124
Marie Scully, Vickie McDonald, Jamie Cavenagh, Beverley J Hunt, Ian Longair, Hannah Cohen, Samuel J Machin
A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura.
Blood. 2011 Aug 18;118(7):1746-53. doi: 10.1182/blood-2011-03-341131. Epub 2011 Jun 2.
Abstract/Text The safety and efficacy of weekly rituximab 375 mg/m(2) (×4), given within 3 days of acute TTP admission, with standard therapy (PEX and steroids) was evaluated. Clinical outcomes were compared to historical controls (n = 40) who had not received rituximab. Within the trial group, 15 of 40 required ICU admission and 15% of all cases with the highest troponin T levels on admission were ventilated. Before the second rituximab infusion, 68% of cases had a platelet count > 50 × 10(9)/L and 38% > 150 × 10(9)/L. Fewer PEX were required in whites compared to nonwhite in the rituximab group (mean 14 vs 21, P = .0095). Inpatient stay was reduced by 7 days in the non-ICU trial cases compared to historical controls (P = .04), especially in whites, with a mean reduction of 7 days (P = .05). Ten percent of trial cases relapsed, median, 27 months (17-31 months), compared to 57% in historical controls, median 18 months (3-60 months; P = .0011). There were no excess infections or serious adverse events with rituximab. In conclusion, rituximab appears a safe and effective therapy. Inpatient stay and relapse are significantly reduced in the rituximab cohort. Rituximab should be considered in conjunction with standard therapy on acute presentation of TTP. This study was registered at www.clinicaltrials.gov as NCT009-3713.

PMID 21636861
Yoshitaka Miyakawa, Kazunori Imada, Tatsuo Ichinohe, Kenji Nishio, Takayuki Abe, Mitsuru Murata, Yasunori Ueda, Yoshihiro Fujimura, Masanori Matsumoto, Shinichiro Okamoto
Efficacy and safety of rituximab in Japanese patients with acquired thrombotic thrombocytopenic purpura refractory to conventional therapy.
Int J Hematol. 2016 Aug;104(2):228-35. doi: 10.1007/s12185-016-2019-x. Epub 2016 May 17.
Abstract/Text Thrombotic thrombocytopenic purpura (TTP), while rare, is a potentially life-threatening disorder. Plasma exchange (PE) is considered the primary treatment for TTP. In Western countries, rituximab, an anti-CD20 antibody, is recommended with PE for the treatment of refractory/relapsed TTP, and as up-front therapy in newly diagnosed TTP with neurological/cardiac pathology. The present open-label, single-arm, multicenter study evaluated the efficacy and safety of rituximab in Japanese patients with refractory/relapsed TTP. Patients received rituximab 375 mg/m(2) intravenously, once weekly for a total of four treatments, with PE and steroids. Of six evaluable patients in the full analysis set, two met the primary efficacy endpoint (platelet count >150 × 10(9)/L at week 4), yielding a 33.3 % response rate (95 % confidence interval: 4.3-77.7). While the lower confidence limit of the primary efficacy endpoint failed to reach the pre-specified threshold of 30 %, clinically significant recovery of platelet count with discontinuation of PE, increase of ADAMTS13 activity, disappearance of ADAMTS13 inhibitor, and improvement of TTP-associated clinical manifestations were observed after rituximab therapy in all patients. No safety concerns were identified in this study; therefore, rituximab is considered a useful treatment option in Japanese TTP patients who are refractory to conventional therapy. Trial registration JMA-IIA00160.

PMID 27188338

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