今日の臨床サポート

凝固傾向

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:2021/01/20
参考ガイドライン:
  1. Guidance for the evaluation and treatment of hereditary and acquired thrombophilia.(2016)
患者向け説明資料

概要・推奨   

  1. 凝固傾向は、先天性あるいは後天性の原因により血栓症をきたしやすい状態である。
  1. 動脈血栓、静脈血栓をきたすが、臨床的には静脈血栓が問題となる場合が多い。
  1. 先天性の血栓性素因は、プロテインC欠損症、プロテインS欠損症、アンチトロンビン欠損症が問題となり、後天性の凝固傾向の原因は多岐にわたる
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧に
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります
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. 定期レビューを行い、参考文献を追加し、Clinical Questionを加えた。

病態・疫学・診察

疫学情報・病態・注意事項  
  1. 凝固傾向は、広義に血液が凝固しやすい状態を指す場合と、狭義に先天性あるいは後天性の原因により血栓症をきたしやすい状態を指す場合があるが、臨床的には狭義の意味で用いられ、血流の異常、血管壁の異常とともに血栓形成の重要な因子になる。
  1. 動脈血栓と静脈血栓では、基礎疾患、発症機序、治療が異なる。
  1. 動脈血栓は、血小板が主体の「血小板血栓」「白色血栓」であり、動脈硬化性病変を基盤として発症する。
  1. 静脈血栓は、血流の停滞や凝固活性の亢進を基礎として発症するフィブリンと赤血球が主体の「フィブリン血栓」「赤色血栓」である。
  1. 静脈⾎栓では、特に、深部静脈血栓症(deep vein thrombosis: DVT)と肺血栓塞栓症(pulmonary thromboembolism: PTE)が重要である。DVTの血栓が遊離してPTEをきたすことから、DVTとPEは一連の病態として捉らえられ、静脈血栓塞栓症(venous thromboembolism: VTE)と呼ばれる。
  1. DVTは、欧米人に比べてアジア人では頻度が少ないとされてきたが、わが国でも急速に増加してきている。
  1. 凝固傾向には、凝固阻止因子・線溶系因子の先天的異常による先天性の血栓性素因と、他の基礎疾患や病態による後天性の凝固傾向がある。
  1. 糖尿病、高血圧、高脂血症などの動脈硬化性病変を介して動脈血栓症をきたすリスクとなる疾患は通常は凝固傾向とせず、動脈硬化性病変がなくても血栓を形成するような病態を凝固傾向とする。
 
静脈血栓塞栓症のリスクとなる疾患(病態)

静脈血栓塞栓症の原因として先天性のものの頻度は高くないが、血栓性素因を示唆する所見があれば検査する。そのような所見がなければ後天性のリスクとなるものについて検討するが、複数のリスク因子が存在することが多い。

 
  1. 先天性の血栓性素因は、わが国ではプロテインC欠損症、プロテインS欠損症、アンチトロンビン欠損症が問題となる。
  1. 後天性の凝固傾向の原因は多岐にわたる。抗リン脂質抗体症候群が問題となることが多い。
  1. 骨髄増殖性腫瘍、発作性夜間ヘモグロビン尿症などの血液疾患も、後天性凝固傾向の原因となる。
 
  1. Clinical Question先天性血栓性素因の保因者が静脈血栓症を合併する頻度は?(参考文献:[1]
  1. 先天性血栓性素因の保因者が静脈血栓症を合併する頻度は、それぞれの先天性血栓性素因により異なる。
 
血栓性素因を有する患者に静脈血栓症が生ずるリスク

出典

img1:  Guidance for the evaluation and treatment of hereditary and acquired thrombophilia.
 
 J Thromb Thrombolysis. 2016 Jan;41(1):15・・・
 
  1. プロテインC(PC)欠損症、プロテインS(PS)欠損症、アンチトロンビン(AT)欠損症の保因者が、初めて静脈血栓症をきたす相対危険度は、いくつかの報告を総合すると、PC欠損症 10、PS欠損症 9.6、AT欠損症 10-30である。
  1. 先天性血栓性素因の保因者において静脈血栓症が再発する危険度は高くなく、再発には他の血栓症をきたす原因の関与が重要である。
 
  1. Clinical Queston:すべての先天性血栓性素因患者の血縁者についてスクリーニング検査をする必要があるか?(推奨度2O(参考文献:[2][1]
  1. オランダにおいて、静脈血栓症を生じた先天性血栓性素因を持つ患者の2,479人の血縁者について、後ろ向きコホート研究を行った。
  1. 血栓症の年間発症率は、アンチトロンビン(AT)欠乏症1.77%(95%信頼区間:1.14-2.60)、プロテインC(PC)欠乏症1.52%(95%信頼区間:1.06-2.11)、プロテインS(PS)欠乏症1.90%(95%信頼区間:1.32-2.64)、血栓性素因を持つ血縁者のいないコントロールと比較して、修正相対リスクは、それぞれ、28.2(95%信頼区間:13.5-58.6)、24.1(95%信頼区間:13.7-42.4)、30.6(95%信頼区間:26.9-55.3)であった。高FVIII血症保因者の年間の血栓症発症率は0.49%(95%信頼区間:0.41-0.51)、修正相対的リスクは7.1(95%信頼区間:4.3-11.8)で、高IX血症、高XI血症、高トロンビン活性化線溶阻害因子(TAFI)血症、高ホモシステイン血症は独立した危険因子ではなかった。
  1. 静脈血栓症を生じたAT欠乏症、PC欠乏症、PS欠乏症患者の無症状の血縁者では、静脈血栓症発症のリスクが上昇する。若年発症の静脈血栓症患者や静脈血栓症の濃厚な家族歴がある場合には、これらのスクリーニング検査を考慮する。特に、他に血栓症のリスクとなる因子<図表>が存在する場合や、経口避妊薬、ホルモン補充療法を行う前、長時間の飛行機などよる移動の前などにはスクリーニング検査を考慮する。しかし、同じ遺伝子異常を有する保因者が静脈血栓症を生ずるリスクは保因者間で同等ではないために過剰な抗凝固療法が行われる可能性や、スクリーニング検査が陰性であっても血縁者の血栓症リスクは高く、スクリーニング陰性のために必要な静脈血栓症予防がなされなかったりすることがある可能性も念頭におく。血縁者スクリーニングの有用性についてはガイドラインにより異なっている。
 
  1. 静脈血栓塞栓症は、日本人では欧米人と比較して発症頻度が低いとされてきたが、生活習慣、食習慣の欧米化や高齢化の進行により、増加傾向にある。実際1990年代の検討では、アジア人は欧米人と比べて血栓症の頻度が低かったO(参考文献:[3]
  1. 米国において、National Hospital Discharge Surveyのデータから、1990~1999年の10年間におけるすべての退院患者の約1%の患者のなかで、深部静脈血栓症、肺梗塞、静脈血栓塞栓症と診断された患者について検討した。深部静脈血栓症と診断されたアジア/太平洋諸島出身者の人口当たりの頻度は、白人と比較して0.21(95%信頼区間:0.14-0.30)アフリカ系アメリカ人と比較して0.20(95%信頼区間:0.13-0.29)、肺梗塞はそれぞれ0.18(95%信頼区間:0.07-0.24)、0.16(95%信頼区間:0.17-0.31)、静脈血栓塞栓症は0.20(95%信頼区間:0.14-0.28)、0.19(95%信頼区間:0.13-0.27)で有意に低かった。
 
  1. Clinical Question:静脈血栓症の後天性リスク因子を多く有するほど静脈血栓症を起こしやすいか?O(参考文献:[4]
  1. マサチューセッツ州Worcester市のすべての住民の1999年の医療記録から587例の静脈血栓塞栓症患者を抽出して、観察研究を行った。
  1. 静脈血栓塞栓症の頻度と発症率はそれぞれ人口10万人当たり、104(95%信頼区間:95-114)と128(95%信頼区間:108-139)であった。発症前に存在していた因子で多かった6つの因子は、30日以内に48時間以上動けないことがあった、3カ月以内に入院した、3カ月以内に手術を受けた、3カ月以内に感染症に罹患した、悪性腫瘍がある、現在入院している、であった。これらの因子を1つも持たなかった患者は11%のみで、36%は1~2つ、53%は3つ以上のリスク因子を有していた。
  1. 静脈血栓症患者の90%は後天性リスク因子を有し、複数有することが多い。
 
  1. Clinical Question:先天性凝固異常は流産や死産のリスクと関連するか?O(参考文献:[5]
  1. 先天性凝固傾向が胎児死亡を増加させるかEuropean Prospective Cohort of Thrombophilia(EPCOT)に登録された1,384人で症例-対象研究を行った。
  1. プロテインS欠損症、プロテインC欠損症、アンチトロンビン欠損症、第V因子ライデン(Factor V Leiden)変異患者は843例で、571例が合計1,524回妊娠した。コントロール541人のうち395人が合計1,019回妊娠した。
  1. 先天性凝固傾向を有する患者において、流産あるいは死産により胎児死亡を来す頻度が有意に多く(オッズ比1.35、95%信頼区間:1.01-1.82)、流産よりも死産を来すリスクが高かった(オッズ比1.27 vs 3.6)。流産、死産に対するオッズ比をそれぞれの凝固傾向で検討したところ、有意であったのは、死産に対して複数の凝固異常を持つもののオッズ比が14.3(95%信頼区間:2.4-86.0)、アンチトロンビン欠損症が5.2(95%信頼区間:1.5-18.1)であった。
  1. 先天性凝固傾向を有する患者は流産あるいは死産を来しやすく、特にアンチトロンビン欠損症患者で死産のリスクが高い。
 
  1. 日本における先天性血栓性素因の頻度について、国立循環器病センターが大阪府吹田市で32~89歳の住人を対象として行った調査があるO(参考文献:[6][7]
  1. プロテインC欠乏症の頻度は全体の0.13%、深部静脈血栓症患者の6.48%で、一般の住民に対するオッズ比は52.1(95%信頼区間:17.2-157.9)、アンチトロンビン欠乏症の頻度は全体の0.15%、深部静脈血栓症患者の5.56%、オッズ比は37.9(95%信頼区間:12.5-114.8)であった。またプロテインS欠乏症は全体の1.12%の頻度でみられた。
問診・診察のポイント  
 
  1. 凝固傾向を伴う患者は、通常は血栓症(特に静脈血栓症)を発症して受診する。

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文献 

著者: Scott M Stevens, Scott C Woller, Kenneth A Bauer, Raj Kasthuri, Mary Cushman, Michael Streiff, Wendy Lim, James D Douketis
雑誌名: J Thromb Thrombolysis. 2016 Jan;41(1):154-64. doi: 10.1007/s11239-015-1316-1.
Abstract/Text Thrombophilias are hereditary and/or acquired conditions that predispose patients to thrombosis. Testing for thrombophilia is commonly performed in patients with venous thrombosis and their relatives; however such testing usually does not provide information that impacts management and may result in harm. This manuscript, initiated by the Anticoagulation Forum, provides clinical guidance for thrombophilia testing in five clinical situations: following 1) provoked venous thromboembolism, 2) unprovoked venous thromboembolism; 3) in relatives of patients with thrombosis, 4) in female relatives of patients with thrombosis considering estrogen use; and 5) in female relatives of patients with thrombosis who are considering pregnancy. Additionally, guidance is provided regarding the timing of thrombophilia testing. The role of thrombophilia testing in arterial thrombosis and for evaluation of recurrent pregnancy loss is not addressed. Statements are based on existing guidelines and consensus expert opinion where guidelines are lacking. We recommend that thrombophilia testing not be performed in most situations. When performed, it should be used in a highly selective manner, and only in circumstances where the information obtained will influence a decision important to the patient, and outweigh the potential risks of testing. Testing should not be performed during acute thrombosis or during the initial (3-month) period of anticoagulation.

PMID 26780744  J Thromb Thrombolysis. 2016 Jan;41(1):154-64. doi: 10.1・・・
著者: Willem M Lijfering, Jan-Leendert P Brouwer, Nic J G M Veeger, Ivan Bank, Michiel Coppens, Saskia Middeldorp, Karly Hamulyák, Martin H Prins, Harry R Büller, Jan van der Meer
雑誌名: Blood. 2009 May 21;113(21):5314-22. doi: 10.1182/blood-2008-10-184879. Epub 2009 Jan 12.
Abstract/Text Thrombophilia screening is controversial. In a retrospective family cohort, where probands had thrombosis and a thrombophilic defect, 2479 relatives were tested for thrombophilia. In antithrombin-, protein C-, and protein S-deficient relatives, annual incidences of venous thrombosis were 1.77% (95% CI, 1.14-2.60), 1.52% (95% CI, 1.06-2.11), and 1.90% (95% CI, 1.32-2.64), respectively, at a median age of 29 years and a positive family history of more than 20% symptomatic relatives. In relatives with factor V (FV) Leiden, prothrombin 20210G>A, or high FVIII levels, these were 0.49% (95% CI, 0.39-0.60), 0.34% (95% CI, 0.22-0.49), and 0.49% (95% CI, 0.41-0.51), respectively. High FIX, FXI, and TAFI, and hyperhomocysteinemia were not independent risk factors. Annual incidence of major bleeding in antithrombin-, protein C-, or protein S-deficient relatives on anticoagulants was 0.29% (95% CI, 0.03-1.04). Cumulative recurrence rates in relatives with antithrombin, protein C, or protein S deficiency were 19% at 2 years, 40% at 5 years, and 55% at 10 years. In relatives with FV Leiden, prothrombin 20210G>A, or high levels FVIII, these were 7%, 11%, and 25%, respectively. Considering its clinical implications, thrombophilia testing should address hereditary deficiencies of antithrombin, protein C, and protein S in patients with first venous thrombosis at young age and/or a strong family history of venous thrombosis.

PMID 19139080  Blood. 2009 May 21;113(21):5314-22. doi: 10.1182/blood-・・・
著者: Paul D Stein, Fadi Kayali, Ronald E Olson, Creagh E Milford
雑誌名: Am J Med. 2004 Apr 1;116(7):435-42. doi: 10.1016/j.amjmed.2003.11.020.
Abstract/Text PURPOSE: To assess the rate of diagnosis of deep venous thrombosis, pulmonary embolism, and venous thromboembolism; the incidence in hospitalized patients; and mortality from pulmonary embolism among Asians/Pacific Islanders in the United States.
METHODS: The number of patients discharged from hospitals with a diagnostic code for pulmonary embolism or deep venous thrombosis from 1990 through 1999 was obtained from the National Hospital Discharge Survey. Population estimates and deaths from pulmonary embolism from 1990 through 1998 were obtained from the United States Bureau of the Census.
RESULTS: Rate ratios of 10-year age-adjusted rates of diagnosis of deep venous thrombosis, pulmonary embolism, and venous thromboembolism comparing Asians/Pacific Islanders with whites and African Americans ranged from 0.16 to 0.21. Rate ratios comparing incidences in hospitalized patients ranged from 0.32 to 0.42. The age-adjusted rate ratio of mortality in "others" (which included Asians/Pacific Islanders) was 0.29 (95% confidence interval [CI]: 0.01 to 0.87) compared with whites and 0.14 (95% CI: 0.0 to 0.58) compared with African Americans.
CONCLUSION: Rates of deep venous thrombosis, pulmonary embolism, and venous thromboembolism; incidences in hospitalized patients; and the mortality rate from pulmonary embolism were markedly lower in Asians/Pacific Islanders than in whites and African Americans. Clinical assessment of the prior probability of venous thromboembolic disease at the bedside should probably be adjusted based on these ethnic differences.

PMID 15047032  Am J Med. 2004 Apr 1;116(7):435-42. doi: 10.1016/j.amjm・・・
著者: Frederick A Spencer, Cathy Emery, Darleen Lessard, Frederick Anderson, Sri Emani, Jayashri Aragam, Richard C Becker, Robert J Goldberg
雑誌名: J Gen Intern Med. 2006 Jul;21(7):722-7. doi: 10.1111/j.1525-1497.2006.00458.x.
Abstract/Text BACKGROUND: While there have been marked advances in diagnostic and therapeutic strategies for venous thromboembolism, our understanding of its clinical epidemiology is based on studies conducted more than a decade ago.
OBJECTIVE: The purpose of this observational study was to describe the incidence and attack rates of venous thromboembolism in residents of the Worcester Statistical Metropolitan Area in 1999. We also describe demographic and clinical characteristics, management strategies, and associated hospital and 30-day outcomes.
DESIGN AND MEASUREMENTS: The medical records of all residents from Worcester, MA (2000 census=477,800), diagnosed with International Classification of Diseases, 9th revision (ICD-9) codes consistent with possible venous thromboembolism during 1999 were independently validated, classified, and reviewed by trained abstractors.
RESULTS: A total of 587 subjects were enrolled with validated venous thromboembolism. The incidence and attack rates of venous thromboembolism were 104 and 128 per 100,000 population, respectively. Three quarters of patients developed their venous thromboembolism in the outpatient setting - a substantial proportion of these patients had undergone recent surgery or had a recent prior hospitalization. Less than half of the patients received anticoagulant prophylaxis during high-risk periods before their venous thromboembolism. Thirty-day rates of venous thromboembolism recurrence, major bleeding, and mortality were 4.8%, 7.7%, and 6.6%, respectively.
CONCLUSION: These data provide insights into recent incidence and attack rates, changing patient profiles, management strategies, and subsequent outcomes in patients with venous thromboembolism. The underutilization of prophylaxis before venous thromboembolism, and relatively high 30-day recurrence rates, suggest a continued need for the improvement of venous thromboembolism prophylaxis and management in the community.

PMID 16808773  J Gen Intern Med. 2006 Jul;21(7):722-7. doi: 10.1111/j.・・・
著者: F E Preston, F R Rosendaal, I D Walker, E Briët, E Berntorp, J Conard, J Fontcuberta, M Makris, G Mariani, W Noteboom, I Pabinger, C Legnani, I Scharrer, S Schulman, F J van der Meer
雑誌名: Lancet. 1996 Oct 5;348(9032):913-6.
Abstract/Text BACKGROUND: A successful outcome of pregnancy requires an efficient uteroplacental vascular system. Since this system may be compromised by disorders of haemostasis associated with a prothrombotic state, we postulated that maternal thrombophilia might be a risk factor for fetal loss. We studied the relation between heritable thrombophilic defects and fetal loss in a cohort of women with factor V Leiden or deficiency of antithrombin, protein C, or protein S.
METHODS: We studied 1384 women enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). Of 843 women with thrombophilia 571 had 1524 pregnancies; of 541 control women 395 had 1019 pregnancies. The controls were partners of male members of the EPCOT cohort or acquaintances of cases. We analysed the frequencies of miscarriage (fetal loss at or before 28 weeks of gestation) and stillbirth (fetal loss after 28 weeks of gestation) jointly and separately.
FINDINGS: The risk of fetal loss was increased in women with thrombophilia (168/571 vs 93/395; odds ratio 1.35 [95% Cl 1.01-1.82]). The odds ratio was higher for stillbirth than for miscarriage (3.6 [1.4-9.4] vs 1.27 [0.94-1.71]). The highest odds ratio for stillbirth was in women with combined defects (14.3 [2.4-86.0]) compared with 5.2 (1.5-18.1) in antithrombin deficiency, 2.3 (0.6-8.3) in protein-C deficiency, 3.3 (1.0-11.3) in protein-S deficiency, and 2.0 (0.5-7.7) with factor V Leiden. The corresponding odds ratios for miscarriage in these subgroups were 0.8 (0.2-3.6), 1.7 (1.0-2.8), 1.4 (0.9-2.2), 1.2 (0.7-1.9), and 0.9 (0.5-1.5). Significantly more pregnancy terminations had been done in women with thrombophilia than in controls (odds ratio 2.9 [1.8-4.8]); this discrepancy was apparent in nine of 11 participating centres and for all thrombophilia subgroups.
INTERPRETATION: Women with familial thrombophilia, especially those with combined defects or antithrombin deficiency, have an increased risk of fetal loss, particularly stillbirth. Our findings have important implications for therapy and provide a rationale for clinical trials of thromboprophylaxis for affected women with recurrent fetal loss.

PMID 8843809  Lancet. 1996 Oct 5;348(9032):913-6.
著者: T Sakata, A Okamoto, T Mannami, H Matsuo, T Miyata
雑誌名: J Thromb Haemost. 2004 Mar;2(3):528-30.
Abstract/Text
PMID 15009480  J Thromb Haemost. 2004 Mar;2(3):528-30.
著者: T Sakata, A Okamoto, T Mannami, H Tomoike, T Miyata
雑誌名: J Thromb Haemost. 2004 Jun;2(6):1012-3. doi: 10.1111/j.1538-7836.2004.00742.x.
Abstract/Text
PMID 15140145  J Thromb Haemost. 2004 Jun;2(6):1012-3. doi: 10.1111/j.・・・
著者: Irene D Bezemer, Felix J M van der Meer, Jeroen C J Eikenboom, Frits R Rosendaal, Carine J M Doggen
雑誌名: Arch Intern Med. 2009 Mar 23;169(6):610-5. doi: 10.1001/archinternmed.2008.589.
Abstract/Text BACKGROUND: A positive family history of venous thrombosis may reflect the presence of genetic risk factors. Once a risk factor has been identified, it is not known whether family history is of additional value in predicting an individual's risk. We studied the contribution of family history to the risk of venous thrombosis in relation to known risk factors.
METHODS: In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis, a population-based case-control study, we collected blood samples and information about family history and environmental triggers from 1605 patients with a first venous thrombosis and 2159 control subjects.
RESULTS: A total of 505 patients (31.5%) and 373 controls (17.3%) reported having 1 or more first-degree relatives with a history of venous thrombosis. A positive family history increased the risk of venous thrombosis more than 2-fold (odds ratio [95% confidence interval], 2.2 [1.9-2.6]) and up to 4-fold (3.9 [2.7-5.7]) when more than 1 relative was affected. Family history corresponded poorly with known genetic risk factors. Both in those with and without genetic or environmental risk factors, family history remained associated with venous thrombosis. The risk increased with the number of factors identified; for those with a genetic and environmental risk factor and a positive family history, the risk was about 64-fold higher than for those with no known risk factor and a negative family history.
CONCLUSIONS: Family history is a risk indicator for a first venous thrombosis, regardless of the other risk factors identified. In clinical practice, family history may be more useful for risk assessment than thrombophilia testing.

PMID 19307525  Arch Intern Med. 2009 Mar 23;169(6):610-5. doi: 10.1001・・・
著者: M J Kupferminc, A Eldor, N Steinman, A Many, A Bar-Am, A Jaffa, G Fait, J B Lessing
雑誌名: N Engl J Med. 1999 Jan 7;340(1):9-13. doi: 10.1056/NEJM199901073400102.
Abstract/Text BACKGROUND: Obstetrical complications such as severe preeclampsia, abruptio placentae, fetal growth retardation, and stillbirth are associated with intervillous or spiral-artery thrombosis and inadequate placental perfusion. Whether these complications are associated with an increased frequency of thrombophilic mutations is not known.
METHODS: We studied 110 women who had one of the above-mentioned obstetrical complications and 110 women who had one or more normal pregnancies. The women were tested several days after delivery for the mutation of guanine to adenine at nucleotide 1691 [corrected] in the factor V gene (factor V Leiden), the mutation of cytosine to thymine at nucleotide 677 in the gene encoding methylenetetrahydrofolate reductase, and the mutation of guanine to adenine at nucleotide 20210 in the prothrombin gene. Two to three months after delivery the women were tested for deficiency of protein C, protein S, or antithrombin III and for the presence of anticardiolipin antibodies.
RESULTS: The mutation at nucleotide 1691 [corrected] in the factor V gene was detected in 22 of the women with obstetrical complications and in 7 of the women with normal pregnancies (20 percent and 6 percent, respectively; P=0.003). Twenty-four women with complications, as compared with nine women without complications, were homozygous for the C677T mutation in the gene encoding methylenetetrahydrofolate reductase (22 percent and 8 percent, respectively; P=0.005). The G20210A mutation in the prothrombin gene was found in 11 women with complications as compared with 3 women without complications (10 percent and 3 percent, respectively; P=0.03). Overall, 57 women with obstetrical complications had a thrombophilic mutation, as compared with 19 women with normal pregnancies (52 percent and 17 percent, respectively; P<0.001). Deficiency of protein S, protein C, or antithrombin III or anticardiolipin antibodies were detected in an additional 14 women with complications, as compared with 1 woman with a normal pregnancy (13 percent and 1 percent, respectively; P<0.001).
CONCLUSIONS: Women with serious obstetrical complications have an increased incidence of mutations predisposing them to thrombosis and other inherited and acquired forms of thrombophilia.

PMID 9878639  N Engl J Med. 1999 Jan 7;340(1):9-13. doi: 10.1056/NEJM・・・
著者: Gary H Lyman
雑誌名: Cancer. 2011 Apr 1;117(7):1334-49. doi: 10.1002/cncr.25714. Epub 2010 Nov 8.
Abstract/Text Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in patients with cancer. The risk of VTE varies over the natural history of cancer, with the highest risk occurring during hospitalization and after disease recurrence. Patient and disease characteristics are associated with further increased risk of VTE in this setting. Specific factors include cancer type (eg, pancreatic cancer, brain cancer, lymphoma) and the presence of metastatic disease at the time of diagnosis. VTE is a significant predictor of increased mortality during the first year among all types and stages of cancer, with metastatic disease reported to be the strongest predictor of mortality. VTE is also associated with early death in ambulatory patients with cancer. These data highlight the need for close monitoring, prompt treatment, and appropriate preventive strategies for VTE in patients with cancer. The American Society of Clinical Oncology and the National Comprehensive Cancer Network have issued guidelines regarding the prophylaxis and treatment of patients with cancer. This review summarizes the impact of VTE on patients with cancer, the effects of VTE on clinical outcomes, the importance of thromboprophylaxis in this population, relevant ongoing clinical trials examining the prevention of VTE, and new pharmacologic treatment options.

Copyright © 2010 American Cancer Society.
PMID 21425133  Cancer. 2011 Apr 1;117(7):1334-49. doi: 10.1002/cncr.25・・・
著者: P Prandoni, A W Lensing, H R Büller, A Cogo, M H Prins, A M Cattelan, S Cuppini, F Noventa, J W ten Cate
雑誌名: N Engl J Med. 1992 Oct 15;327(16):1128-33. doi: 10.1056/NEJM199210153271604.
Abstract/Text BACKGROUND: In contrast to the established relation between overt cancer and subsequent venous thromboembolism, it is unclear whether symptomatic deep-vein thrombosis is associated with a risk of subsequent overt malignant disease.
METHODS: Two hundred sixty consecutive patients with symptomatic, venographically proved deep-vein thrombosis were enrolled in a study, of whom 250 were followed during a two-year period. Among those assessed during follow-up, the incidence of subsequently detected cancer in the 105 patients with secondary venous thrombosis (i.e., thrombosis associated with a well-recognized risk factor other than cancer) was compared with the incidence of cancer in the 145 patients with idiopathic venous thrombosis.
RESULTS: Routine examination at the time of diagnosis of the venous thrombosis revealed cancer in 5 of the 153 enrolled patients with idiopathic venous thrombosis (3.3 percent) and in none of the 107 enrolled patients with secondary venous thrombosis. During follow-up, overt cancer developed in 2 of the 105 patients with secondary venous thrombosis (1.9 percent) and in 11 of the 145 patients with idiopathic venous thrombosis (7.6 percent; odds ratio, 2.3; 95 percent confidence interval, 1.0 to 5.2; P = 0.043). Of the 145 patients with idiopathic venous thrombosis, 35 had confirmed recurrent thromboembolism. Overt cancer subsequently developed in 6 of the 35 (17.1 percent). The incidence of cancer in the patients with recurrent idiopathic venous thrombosis was higher than that in the patients with secondary venous thrombosis (P = 0.008; odds ratio, 9.8; 95 percent confidence interval, 1.8 to 52.2) or in the patients with idiopathic venous thrombosis that did not recur (P = 0.024; odds ratio, 4.3; 95 percent confidence interval, 1.2 to 15.3).
CONCLUSIONS: There is a statistically significant and clinically important association between idiopathic venous thrombosis and the subsequent development of clinically overt cancer, especially among patients in whom venous thromboembolism recurs during follow-up.

PMID 1528208  N Engl J Med. 1992 Oct 15;327(16):1128-33. doi: 10.1056・・・
著者: Marc Carrier, Alejandro Lazo-Langner, Sudeep Shivakumar, Vicky Tagalakis, Ryan Zarychanski, Susan Solymoss, Nathalie Routhier, James Douketis, Kim Danovitch, Agnes Y Lee, Gregoire Le Gal, Philip S Wells, Daniel J Corsi, Timothy Ramsay, Doug Coyle, Isabelle Chagnon, Zahra Kassam, Hardy Tao, Marc A Rodger, SOME Investigators
雑誌名: N Engl J Med. 2015 Aug 20;373(8):697-704. doi: 10.1056/NEJMoa1506623. Epub 2015 Jun 22.
Abstract/Text BACKGROUND: Venous thromboembolism may be the earliest sign of cancer. Currently, there is a great diversity in practices regarding screening for occult cancer in a person who has an unprovoked venous thromboembolism. We sought to assess the efficacy of a screening strategy for occult cancer that included comprehensive computed tomography (CT) of the abdomen and pelvis in patients who had a first unprovoked venous thromboembolism.
METHODS: We conducted a multicenter, open-label, randomized, controlled trial in Canada. Patients were randomly assigned to undergo limited occult-cancer screening (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) or limited occult-cancer screening in combination with CT. The primary outcome measure was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period.
RESULTS: Of the 854 patients who underwent randomization, 33 (3.9%) had a new diagnosis of occult cancer between randomization and the 1-year follow-up: 14 of the 431 patients (3.2%) in the limited-screening group and 19 of the 423 patients (4.5%) in the limited-screening-plus-CT group (P=0.28). In the primary outcome analysis, 4 occult cancers (29%) were missed by the limited screening strategy, whereas 5 (26%) were missed by the strategy of limited screening plus CT (P=1.0). There was no significant difference between the two study groups in the mean time to a cancer diagnosis (4.2 months in the limited-screening group and 4.0 months in the limited-screening-plus-CT group, P=0.88) or in cancer-related mortality (1.4% and 0.9%, P=0.75).
CONCLUSIONS: The prevalence of occult cancer was low among patients with a first unprovoked venous thromboembolism. Routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit. (Funded by the Heart and Stroke Foundation of Canada; SOME ClinicalTrials.gov number, NCT00773448.).

PMID 26095467  N Engl J Med. 2015 Aug 20;373(8):697-704. doi: 10.1056/・・・
著者: A Delluc, D Antic, R Lecumberri, C Ay, G Meyer, M Carrier
雑誌名: J Thromb Haemost. 2017 Oct;15(10):2076-2079. doi: 10.1111/jth.13791. Epub 2017 Aug 29.
Abstract/Text
PMID 28851126  J Thromb Haemost. 2017 Oct;15(10):2076-2079. doi: 10.11・・・
著者: M Coppens, J H Reijnders, S Middeldorp, C J M Doggen, F R Rosendaal
雑誌名: J Thromb Haemost. 2008 Sep;6(9):1474-7. doi: 10.1111/j.1538-7836.2008.03055.x. Epub 2008 Jun 6.
Abstract/Text BACKGROUND: Inherited thrombophilia is only weakly associated with recurrence in patients with a first venous thrombosis (VT). In spite of this, thrombophilia testing is often performed in these patients. Positive results may influence patient management such as prolonged anticoagulant treatment or intensified prophylaxis in high-risk situations.
OBJECTIVE: To investigate whether thrombophilia testing reduces the risk of recurrent VT by virtue of these management alterations.
METHODS: From a large case-control study of patients (MEGA study), aged 18-70 years, with a first VT between 1999 and 2004, we selected 197 patients who had had a recurrence during follow-up. We compared the incidence of thrombophilia testing to that of a control cohort of 324 patients. We calculated the odds ratio (OR) for recurrent thrombosis in tested vs. non-tested patients. Only patients who were tested before recurrence were regarded as tested. All first and recurrent thrombotic events were objectively confirmed.
RESULTS: Thrombophilia tests were performed in 35% of cases and in 30% of controls. The OR for recurrence was 1.2 [95% confidence interval (CI) 0.9-1.8] for tested vs. non-tested patients. After correction for age, sex, family history, geographic region, presence of clinical risk factors, and year of first VT, the OR remained unchanged.
DISCUSSION: Thrombophilia testing in patients with a first VT does not reduce the incidence of recurrence in clinical practice.

PMID 18540999  J Thromb Haemost. 2008 Sep;6(9):1474-7. doi: 10.1111/j.・・・
著者: Chad M Thorson, Robert M Van Haren, Mark L Ryan, Emiliano Curia, Danny Sleeman, Joe U Levi, Alan S Livingstone, Kenneth G Proctor
雑誌名: J Am Coll Surg. 2013 Apr;216(4):580-9; discussion 589-90. doi: 10.1016/j.jamcollsurg.2012.12.006. Epub 2013 Jan 11.
Abstract/Text BACKGROUND: The hypercoagulable state associated with cancer imparts considerable risk for venous thromboembolism. Surgical resection of malignancies should theoretically reverse tumor-induced hypercoagulability. However, coagulation changes in cancer patients postresection have not been described thoroughly. Conventional coagulation tests are unable to detect hypercoagulable states. In contrast, rotational thromboelastography (ROTEM) can detect hypo- or hypercoagulable conditions. We hypothesized that the cancer-induced hypercoagulable state would improve after surgical resection.
METHODS: After informed consent, blood samples of patients undergoing surgical resection for curative intent were analyzed with serial ROTEM.
RESULTS: Thirty-five patients (mean ± SD age 66 ± 17 years; 67% male) had cancers involving the pancreas (n = 12 [34%]), esophagus (n = 10 [29%]), stomach (n = 7 [20%]), bile ducts (n = 3 [9%]), and duodenum (n = 3 [9%]). Preoperative ROTEM identified 14 (40%) who were hypercoagulable. After surgical resection, patients became progressively hypercoagulable with more rapid clot formation time (low clot formation time, high alpha) and higher maximum clot firmness. By week one, 86% (n = 30) had abnormal ROTEM values, including 17 of 21 (81%) who had normal coagulation profiles preoperatively. Most (n = 30 [86%]) remained hypercoagulable at 3 to 4 weeks.
CONCLUSIONS: Rotational thromboelastography identifies baseline hypercoagulability in more than one third of patients with intra-abdominal malignancies. This is among the first studies to demonstrate progressive hypercoagulability that persists for at least 1 month after resection. These data support postdischarge thromboprophylaxis regimens in high-risk cancer patients.

Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.
PMID 23313542  J Am Coll Surg. 2013 Apr;216(4):580-9; discussion 589-9・・・
著者: Jody L Kujovich
雑誌名: Br J Haematol. 2004 Aug;126(4):443-54. doi: 10.1111/j.1365-2141.2004.05041.x.
Abstract/Text During their lifetimes, women face several unique situations with an increased risk of venous thromboembolism (VTE). Doctors in a variety of specialties must advise women on the risks of oral contraceptives (OC), hormone replacement or pregnancy. Modern 'low dose' OC are associated with a three to sixfold increased relative risk of VTE. Hormone replacement and selective oestrogen receptor modulators confer a similar two to fourfold increase in thrombotic risk. However, because the baseline incidence of thrombosis is higher in older postmenopausal women, the absolute risk is higher than in younger OC users. The risk of venous thrombosis is six to 10-fold higher during pregnancy than in non-pregnant women of similar age. Thrombophilic disorders increase the thrombotic risk of OC, hormone replacement and pregnancy, especially in women with homozygous or combined defects. This review focuses on recent data estimating the thrombotic risk of hormonal therapies and pregnancy in women with and without other thrombotic risk factors.

PMID 15287937  Br J Haematol. 2004 Aug;126(4):443-54. doi: 10.1111/j.1・・・

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