今日の臨床サポート

出血傾向

著者: 樋口敬和 獨協医科大学埼玉医療センター 輸血部

監修: 神田善伸 自治医科大学附属病院 血液科

著者校正/監修レビュー済:2021/04/21
患者向け説明資料

概要・推奨   

概要:
  1. 出血傾向は、出血後の止血が困難であったり止血後に再び出血を来す状態、およびわずかな外力で出血したり明らかな誘因がなく出血する状態で、血管とその周囲組織、血小板、凝固因子、線溶系の単独あるいは複合した異常により起こる。
  1. 出血傾向の症状は、皮下・粘膜出血、深在性(関節・筋肉・臓器)出血、止血困難、後出血などである。
 
推奨
  1. 出血傾向は、血管、血小板の数および機能の異常によるものと、凝固系の異常によるものに分けて考える
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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。
※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、実際の保険適用の査定において保険適用及び保険適用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用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:
樋口敬和 : 特に申告事項無し[2021年]
監修:神田善伸 : 未申告[2021年]

改訂のポイント:
  1. 定期レビューを行った。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 出血傾向は、出血後の止血が困難であったり止血後に再び出血を来す状態、およびわずかな外力で出血したり明らかな誘因がなく出血する状態である。
  1. 出血傾向は、血管とその周囲組織、血小板、凝固因子、線溶系の単独あるいは複合した異常により起こる。
  1. 先天性のものはほとんどが単独の異常で、後天性のものは単独あるいは複合した異常である。
  1. 出血傾向の症状は、①皮下・粘膜出血、②深在性(関節・筋肉・臓器)出血、③止血困難、④後出血などである。
  1. ①皮下・粘膜出血は、血管または血小板の異常に起因することが多く、②深在性(関節・筋肉・臓器)出血は凝固系の異常に起因することが多い。(原因による出血症状の相違:<図表>
  1. ③止血困難はすべての機序により起こる。
  1. ④後出血(一回止血した後に再出血する)は第XIII因子欠乏症や線溶系の異常でみられる。
  1. 出血部位が1つだけの場合は、局所的な原因も考慮する。
  1. 令和元年度血液凝固異常症全国調査によると、HIV非感染生存者は、血友病A 4,869人、血友病B 1,021人、von Willebrand病 1,356人、類縁疾患 1,051人であった。
問診・診察のポイント  
まとめ:
  1. 出血傾向は、血管、血小板の数および機能の異常によるものと、凝固系の異常によるものに分けて考える(原因による出血症状の相違:<図表>)。

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文献 

著者: A Tosetto, G Castaman, I Plug, F Rodeghiero, J Eikenboom
雑誌名: J Thromb Haemost. 2011 Jun;9(6):1143-8. doi: 10.1111/j.1538-7836.2011.04265.x.
Abstract/Text BACKGROUND: Quantitative bleeding assessment tools (BATs) have been used to describe the severity of the bleeding phenotype in patients with von Willebrand disease.
OBJECTIVES: To evaluate the clinical usefulness of a BAT for the diagnosis of mild bleeding disorders (MBDs) in previously undiagnosed patients.
METHODS: We prospectively assessed 215 patients who were consecutively referred for evaluation of bleeding symptoms (n=71), abnormal laboratory clotting test results (n=105) or family investigation (n=39) at two second-level centers. The bleeding history was assessed by a young investigator who administered the BAT instrument, and also by a senior physician who independently evaluated the patient and made the final diagnoses. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) were computed for a predefined bleeding score (BS) cut-off (BS of >3). Receiver operating characteristic curves were used to establish a diagnostic prediction rule.
RESULTS: Assuming the prevalence of MBD in the general population to be ∼1%, a normal BS (≤3) had a very high NPV (99.2%). The PPVs in patients referred for hemostatic or family evaluation at second-level clinics were estimated to be 71.0% and 77.5% (assuming MDB prevalences of 20% and 50%, respectively, in these settings). Measurement of BS in addition to activated partial thromboplastin time significantly increased the diagnostic efficiency of the BAT instrument (NPV of 99.6%).
CONCLUSIONS: BAT use improves the evaluation of patients with suspected MBD, and we propose its use in a clinical prediction guide based on BAT and activated partial thromboplastin time for the exclusion of patients with suspected MBD in a low-prevalence setting.

© 2011 International Society on Thrombosis and Haemostasis.
PMID 21435168  J Thromb Haemost. 2011 Jun;9(6):1143-8. doi: 10.1111/j.・・・
著者: Catherine P M Hayward, Karen A Moffat, Elizabeth Plumhoff, Elizabeth M Van Cott
雑誌名: Am J Hematol. 2012 May;87 Suppl 1:S45-50. doi: 10.1002/ajh.23124. Epub 2012 Feb 24.
Abstract/Text Bleeding disorders commonly result from deficiencies or defects in von Willebrand factor (VWF), platelets, coagulation factors, or fibrinolytic proteins. The primary goal of our study was to assess current North American coagulation laboratory practices for diagnosing bleeding disorders, using an on-line patterns-of-practice survey of diagnostic laboratory members of the North American Specialized Coagulation Laboratory Association. The survey examined laboratory approaches to evaluating bleeding disorders, with specific questions about the tests and test panels offered and compliance to recent guideline recommendations on diagnosing von Willebrand disease (VWD) and platelet function disorders. All laboratories responding to the survey performed a prothrombin time/international normalized ratio, an activated partial thromboplastin time, and coagulation factor assays, and many tested for VWD and platelet disorders. However, few laboratories had test panels that evaluated the more common bleeding disorders and few performed some assays, including VWF multimer assessments and assays for fibrinolytic disorders. Additionally, the cutoffs used by laboratories to diagnose type 1 VWD varied considerably, with only a minority following the National Heart Lung Blood Institute recommendations. In contrast, laboratories that tested for platelet function disorders mostly complied with aggregation testing recommendations, as published in the recent North American guidelines. Our results indicate that there are some gaps in the strategies used by laboratories to diagnose bleeding disorders that might be addressed by development of further guidelines and test algorithms that emphasize evaluations for common bleeding disorders. Laboratories may also benefit from guidelines on test interpretation, and external evaluation of their bleeding disorder testing strategies.

Copyright © 2012 Wiley Periodicals, Inc.
PMID 22367923  Am J Hematol. 2012 May;87 Suppl 1:S45-50. doi: 10.1002/・・・
著者: P Peterson, T E Hayes, C F Arkin, E G Bovill, R B Fairweather, W A Rock, D A Triplett, J T Brandt
雑誌名: Arch Surg. 1998 Feb;133(2):134-9.
Abstract/Text The major conclusions of this position article are as follows: (1) In the absence of a history of a bleeding disorder, the bleeding time is not a useful predictor of the risk of hemorrhage associated with surgical procedures. (2) A normal bleeding time does not exclude the possibility of excessive hemorrhage associated with invasive procedures. (3) The bleeding time cannot be used to reliably identify patients who may have recently ingested aspirin or nonsteroidal anti-inflammatory agents or those who have a platelet defect attributable to these drugs. The best preoperative screen to predict bleeding continues to be a carefully conducted clinical history that includes family and previous dental, obstetric, surgical, traumatic injury, transfusion, and drug histories. A history suggesting a possible bleeding disorder may require further evaluation; such an evaluation may include performance of the bleeding time test, as well as a determination of the platelet count, the prothrombin time, and the activated partial thromboplastin time. In the absence of a history of excessive bleeding, the bleeding time fails as a screening test and is, therefore, not indicated as a routine preoperative test.

PMID 9484723  Arch Surg. 1998 Feb;133(2):134-9.
著者: Roberto Stasi, Ameet Sarpatwari, Jodi B Segal, John Osborn, Maria Laura Evangelista, Nichola Cooper, Drew Provan, Adrian Newland, Sergio Amadori, James B Bussel
雑誌名: Blood. 2009 Feb 5;113(6):1231-40. doi: 10.1182/blood-2008-07-167155. Epub 2008 Oct 22.
Abstract/Text Whether the eradication of Helicobacter pylori infection can increase the platelet count in patients with immune thrombocytopenic purpura (ITP) is still a controversial issue. To provide evidence-based guidance, we performed a systematic review of the literature published in English, selecting articles reporting 15 or more total patients. We identified 25 studies including 1555 patients, of whom 696 were evaluable for the effects of H pylori eradication on platelet count. The weighted mean complete response (platelet count > or = 100 x 10(9)/L) and overall response (platelet count > or = 30 x 10(9)/L and at least doubling of the basal count) were 42.7% (95% confidence interval [CI], 31.8%-53.9%) and 50.3% (95% CI, 41.6%-59.0%), respectively. In 222 patients with a baseline platelet count less than 30 x 10(9)/L, the complete response rate was 20.1% (95% CI, 13.5%-26.7%) and the overall response rate was 35.2% (95% CI, 28.0%-42.4%). The response rate tended to be higher in countries with a high background prevalence of H pylori infection and in patients with milder degrees of thrombocytopenia. These findings suggest that the detection and eradication of H pylori infection should be considered in the work-up of patients with seemingly typical ITP.

PMID 18945961  Blood. 2009 Feb 5;113(6):1231-40. doi: 10.1182/blood-20・・・
著者: D A Westerman, A P Grigg
雑誌名: Med J Aust. 1999 Mar 1;170(5):216-7.
Abstract/Text OBJECTIVE: To assess the value of routine bone marrow biopsy (BMB) in adult patients less than 65 years of age with suspected idiopathic thrombocytopenic purpura (ITP).
DESIGN: Retrospective analysis. Data were collected from hospital medical records and laboratory results.
SETTING: Large tertiary-level metropolitan teaching hospital, Victoria.
PARTICIPANTS: Sixty-six patients who had undergone BMB for investigation of isolated thrombocytopenia between January 1992 and May 1997, according to defined eligibility criteria.
RESULTS: Sixty-one of the 66 patients had BMB findings consistent with ITP (i.e., normal or increased numbers of megakaryocytes and other haemopoietic lineages normal). Three of these patients' biopsies incidentally showed reduced or absent iron stores. In the remaining five patients, BMB in four showed mild hypocellularity and the subsequent course in these patients was consistent with chronic ITP. The fifth patient had neutrophil hypersegmentation and giant band cells on BMB, the cause of which was unclear. The subsequent course in this patient has also been consistent with chronic ITP.
CONCLUSIONS: Our data suggest that the routine performance of BMB for the diagnosis of ITP is not useful, provided that a thorough clinical history and physical examination are undertaken and that the blood count and peripheral blood smear show no abnormalities apart from thrombocytopenia.

PMID 10092918  Med J Aust. 1999 Mar 1;170(5):216-7.
著者: Y K Mak, P H Yu, C H Chan, Y C Chu
雑誌名: Clin Lab Haematol. 2000 Dec;22(6):355-8.
Abstract/Text We performed a retrospective analysis of bone marrow examination (BME) in the management of Chinese adult patients less than 60 years of age with isolated thrombocytopenia at presentation. Eighty-three patients with a median age of 39 years presenting with isolated thrombocytopenia (median platelet count: 38 x 10(9)/l) had routinely undergone BME as part of the laboratory investigations during the period from January 1996 to December 1999. All 83 patients had bone marrow findings of active marrow suggesting causes due to peripheral destruction. All of these patients responded to steroid or intravenous immunoglobulin (IVIg) therapy at presentation if their platelet counts were significantly low or if they had mucosal bleeding. Eighty-one of the 83 patients, after a median of 20 months follow-up, were finally diagnosed as having idiopathic thrombocytopenic purpura (ITP). The remaining two patients were finally confirmed as cases of systemic lupus erythematosus (SLE). Our results suggest that BME is not helpful in the diagnosis of isolated thrombocytopenia or suspected ITP in adult patients at presentation, provided that a thorough clinical history and physical examination are undertaken and that the blood count and peripheral blood smear show no abnormalities apart from the thrombocytopenia.

PMID 11318802  Clin Lab Haematol. 2000 Dec;22(6):355-8.
著者: C P M Hayward, M Pai, Y Liu, K A Moffat, J Seecharan, K E Webert, R J Cook, N M Heddle
雑誌名: J Thromb Haemost. 2009 Apr;7(4):676-84. doi: 10.1111/j.1538-7836.2009.03273.x. Epub 2009 Jan 17.
Abstract/Text BACKGROUND: Light transmission aggregometry (LTA) is commonly performed to assess individuals for bleeding disorders.
OBJECTIVES: The goal was to evaluate the incidence and spectrum of platelet function abnormalities in a prospective cohort of individuals referred for bleeding disorder assessments after exclusion of thrombocytopenia and von Willebrand disease.
PATIENTS/METHODS: Subjects were healthy controls and patients from a prospective cohort of individuals referred for bleeding disorder assessments after exclusion of thrombocytopenia and von Willebrand disease. LTA was performed by standardized methods using platelet-rich plasma adjusted to 250x10(9) platelets L(-1). Maximal aggregation data were analyzed to determine the likelihood of detecting a platelet function disorder by LTA, and the sensitivity and specificity of LTA for platelet disorders.
RESULTS: The incidence of false positive LTA among subjects excluded of having bleeding disorders was similar to healthy controls. Abnormal LTA was more common in subjects with bleeding disorders and the likelihood of a bleeding disorder was significantly increased (odds ratio 32) when maximal aggregation was reduced with two or more agonists. Receiver operator curve analyses indicated that LTA had high specificity and moderate sensitivity for detecting inherited defects in platelet function and that the LTA agonists 1.25 microg mL(-1) collagen, 6 microM epinephrine, 1.6 mM arachidonic acid and 1.0 microM thromboxane analogue U44619 detected most inherited disorders with abnormal LTA.
CONCLUSIONS: LTA is valuable for detecting platelet function abnormalities among individuals referred for bleeding problems, particularly when the test indicates abnormal responses to multiple agonists.

PMID 19143930  J Thromb Haemost. 2009 Apr;7(4):676-84. doi: 10.1111/j.・・・
著者: Yoshihiro Fujimura, Masanori Matsumoto
雑誌名: Intern Med. 2010;49(1):7-15. Epub 2010 Jan 1.
Abstract/Text BACKGROUND: Thrombotic microangiopathies (TMAs) are pathological conditions characterized by generalized microvascular occlusion by platelet thrombi, thrombocytopenia, and microangiopathic hemolytic anemia. Two typical phenotypes of TMAs are hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Severe deficiency of plasma ADAMTS13 activity (ADAMTS13: AC) is more specific for TTP, but not for HUS. Since 1998, our laboratory has functioned as a nationwide referral center for TMAs by analyzing ADAMTS13.
METHODS: Of 1,564 patients tested from 426 hospitals, 919 were positive for TMA. Levels of ADAMTS13: AC and the ADAMTS13 neutralizing autoantibody (ADAMTS13: INH) were determined by chromogenic act-ELISA and/or by classic von Willebrand factor multimer assay.
RESULTS: TMA patients consisted of two groups: severe (less than 3% of normal control) and non-severe deficiency of ADAMTS13: AC. Both groups were divided into congenital (n=65) and acquired (n=854) TMA. Of the former, 41 had congenital deficiency of ADAMTS13: AC, while the remaining 24 had disease of unknown etiology. The 854 patients with acquired TMA could be largely grouped into three categories: idiopathic TTP (n=284), idiopathic HUS (n=106), and secondary TMAs (n=464). The secondary TMAs were observed in heterogeneous patient groups and were associated with drugs, connective tissue diseases, malignancies, transplantation, pregnancy, E. coli O157: H7 infection, and other factors. All of the patients with acquired severe ADAMTS13: AC deficiency were positive for ADAMTS13: INH.
CONCLUSION: Although TMAs are highly heterogeneous pathological conditions, one-third of TMA patients have severe deficiency of ADAMTS13: AC. Platelet transfusions to such patients are contraindicated. Rapid ADAMTS13: AC assays are therefore prerequisite to appropriately treat TMA patients.

PMID 20045995  Intern Med. 2010;49(1):7-15. Epub 2010 Jan 1.
著者: P Harrison
雑誌名: Br J Haematol. 2000 Dec;111(3):733-44.
Abstract/Text
PMID 11122132  Br J Haematol. 2000 Dec;111(3):733-44.
著者:
雑誌名: J Clin Pathol. 1988 Dec;41(12):1322-30.
Abstract/Text
PMID 3225335  J Clin Pathol. 1988 Dec;41(12):1322-30.
著者: Francesca Palandri, Nicola Polverelli, Lucia Catani, Daria Sollazzo, Emanuela Ottaviani, Sarah Parisi, Michele Baccarani, Nicola Vianelli
雑誌名: Br J Haematol. 2012 Jan;156(2):281-4. doi: 10.1111/j.1365-2141.2011.08858.x. Epub 2011 Sep 21.
Abstract/Text
PMID 21936859  Br J Haematol. 2012 Jan;156(2):281-4. doi: 10.1111/j.13・・・
著者: Peter J Campbell, Cathy MacLean, Philip A Beer, Georgina Buck, Keith Wheatley, Jean-Jacques Kiladjian, Cecily Forsyth, Claire N Harrison, Anthony R Green
雑誌名: Blood. 2012 Aug 16;120(7):1409-11. doi: 10.1182/blood-2012-04-424911. Epub 2012 Jun 18.
Abstract/Text Essential thrombocythemia, a myeloproliferative neoplasm, is associated with increased platelet count and risk of thrombosis or hemorrhage. Cytoreductive therapy aims to normalize platelet counts despite there being only a minimal association between platelet count and complication rates. Evidence is increasing for a correlation between WBC count and thrombosis, but prospective data are lacking. In the present study, we investigated the relationship between vascular complications and 21 887 longitudinal blood counts in a prospective, multicenter cohort of 776 essential thrombocythemia patients. After correction for confounding variables, no association was seen between blood counts at diagnosis and future complications. However, platelet count outside of the normal range during follow-up was associated with an immediate risk of major hemorrhage (P = .0005) but not thrombosis (P = .7). Elevated WBC count during follow-up was correlated with thrombosis (P = .05) and major hemorrhage (P = .01). These data imply that the aim of cytoreduction in essential thrombocythemia should be to keep the platelet count, and arguably the WBC count, within the normal range. This study is registered at the International Standard Randomized Controlled Trials Number Registry (www.isrctn.org) as number 72251782.

PMID 22709688  Blood. 2012 Aug 16;120(7):1409-11. doi: 10.1182/blood-2・・・

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