図1．前立腺癌患者の脳梗塞と非細菌性血栓性心内膜炎（NBTE）

頭部MRI拡散強調画像（A）では、両側大脳半球に多発性脳塞栓症を認め、経胸壁心エコー（B）では、僧帽弁に付着する巨大な疣贅が確認された（自験例）。
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図2．NBTEを合併しやすい悪性腫瘍

14の病理学的報告のメタアナリシスでは、NBTEは1.3％（613例）に認められ、その約半数（52.5％）に悪性腫瘍が認められたが、白血病を除いてその多くが腺癌であった。
出典
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1: Nonbacterial thrombotic endocarditis: a review.
著者: Lopez JA, Ross RS, Fishbein MC, Siegel RJ.
雑誌名: Am Heart J. 1987 Mar;113(3):773-84. doi: 10.1016/0002-8703(87)90719-8.
Abstract/Text: The entity of NBTE is reviewed in this article. Historic aspects, epidemiology, and pathogenesis are discussed. The clinicopathologic findings are emphasized as well as the potential for antemortem diagnosis and therapy. NBTE is diagnosed infrequently before death. Clinical suspicion is aroused in patients with an underlying process such as malignancy, DIC, or a spectrum of other diseases and evidence of pulmonary and/or systemic embolization. Systemic infection must be excluded. Two-dimensional echocardiography can be utilized to confirm the diagnosis. Anticoagulation therapy with heparin may prevent embolization.
Am Heart J. 1987 Mar;113(3):773-84. doi: 10.1016/0002-8703(87)90719-8....

図3．悪性腫瘍による血栓形成機序

ATⅢ: アンチトロンビンⅢ，DTI: 直接トロンビン阻害薬, FDP: フィブリン分解産物, ICAM: 細胞間接着分子, IL-1, 6, 8: インターロイキン-1, 6, 8, LMWH: 低分子ヘパリン, PAI-1: プラスミノゲン・アクチベーター・インヒビター-1, TGF: トランスフォーミング増殖因子, TNF: 腫瘍壊死因子, t-PA: 組織プラスミノゲン・アクチベーター, ⅩaI: Ⅹa阻害薬

図4．可溶性ムチンが関与する2つの血栓形成機序

血中に分泌されるムチンは2つの機序で血栓形成に関わっている。ひとつは、ムチンのシアル酸残基による直接的なプロトロンビン活性化であり、もう1つは、P-セレクチンを介する血小板同士の凝集、血小板あるいは単球と内皮との相互作用である。
出典
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1: Trousseau's syndrome: multiple definitions and multiple mechanisms.
著者: Varki A.
雑誌名: Blood. 2007 Sep 15;110(6):1723-9. doi: 10.1182/blood-2006-10-053736. Epub 2007 May 11.
Abstract/Text: In 1865, Armand Trousseau noted that unexpected or migratory thrombophlebitis could be a forewarning of an occult visceral malignancy. An analysis by Sack and colleagues in 1977 extended the term Trousseau's syndrome to include chronic disseminated intravascular coagulopathy associated with microangiopathy, verrucous endocarditis, and arterial emboli in patients with cancer, often occurring with mucin-positive carcinomas. In recent times the term has been ascribed to various clinical situations, ranging all the way from these classic descriptions to any kind of coagulopathy occurring in the setting of any kind of malignancy. These multiple definitions of Trousseau's syndrome are partly the consequence of multiple pathophysiologic mechanisms that apparently contribute to the hypercoagulability associated with cancer. Even the classic syndrome probably represents a spectrum of disorders, ranging from exaggerated fluid-phased thrombosis dependent on prothrombotic agents such as tissue factor to a platelet- and endotheliumum-based selectin-dependent microangiopathy associated with mucin-producing carcinomas, along with thrombin and fibrin production. Also considered here are recent hypotheses about genetic pathways within tumor cells that might trigger these thrombotic phenomena, and the reasons why therapy with heparins of various kinds remain the preferred treatment, probably because of their salutary actions on several of the proposed pathologic mechanisms.
Blood. 2007 Sep 15;110(6):1723-9. doi: 10.1182/blood-2006-10-053736. E...

アルゴリズム

担がん患者に脳梗塞が見られた場合、あるいは3つの脳主幹動脈領域にわたり脳梗塞がみられ（3 territory sign＊）、D-dimerあるいはFDPが高値の場合、トルソー症候群を疑う。腹部CT・エコーあるいは消化管内視鏡（GIF**）で頻度の高い腺癌・婦人科系腫瘍・転移性腫瘍の検索を行う。また、腫瘍マーカー（CEA、SLX、PSA、CA19-9、CA125など）、および凝固系マーカー（TATA，PICなど）のチェックを行う。さらに、下肢静脈ドップラー・エコーでVTEを、経胸壁（あるいは経食道）心エコーでNBTEおよびPFOの検索を行う。トルソー症候群と診断されれば、原発巣および転移巣に対する癌治療と並行して、出血のリスクを勘案して、低分子量ヘパリンまたは遺伝子組換えトロンボモジュリン製剤などのDICの治療を行う。また、VTEが存在する場合、未分画（海外では低分子量）ヘパリンまたはDOACを開始する。さらに、エビデンスは乏しいが、脳梗塞予防治療としてヘパリン（またはDOAC）の投与を考慮する。
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表1．悪性腫瘍による凝固能亢進機序

表2．担がん患者の静脈血栓症の危険因子

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1: Cancer and Venous Thromboembolic Disease: A Review.
著者: Donnellan E, Khorana AA.
雑誌名: Oncologist. 2017 Feb;22(2):199-207. doi: 10.1634/theoncologist.2016-0214. Epub 2017 Feb 7.
Abstract/Text: Venous thromboembolism (VTE), including deep-vein thrombosis and pulmonary embolism, represents a major cause of morbidity and mortality in cancer patients. Patients with cancer are six times more likely to develop VTE than their noncancer counterparts, and VTE is the second leading cause of death in cancer patients. Despite the publication of major consensus guidelines setting out recommendations for thromboprophylaxis in cancer patients, there remains a gulf between these guidelines and clinical practice. In general, thromboprophylaxis is recommended for most patients hospitalized with active cancer. Furthermore, outpatient thromboprophylaxis may be used in carefully selected high-risk ambulatory patients. Certain areas of controversy still remain. Although low-molecular-weight heparin has been shown to be superior to vitamin K antagonists in cancer patients, the role of direct oral anticoagulants is still uncertain. Moreover, recurrent thromboembolism, bleeding, and thrombocytopenia are frequently seen in cancer patients. Optimal anticoagulation in such instances presents a major challenge to clinicians. Modern computed tomography techniques have resulted in an increase in the detection of "incidental" VTE. Despite a growing body of evidence promulgating standard anticoagulant treatment in such cases, these cases present further challenges for members of the multidisciplinary team. The Oncologist 2017;22:199-207Implications for Practice: This article discusses venous thromboembolism (VTE) in patients with malignancy. Practical guidance is offered on how to prevent, diagnose, and treat VTE in cancer patients. The management of "challenging" cases of VTE is also discussed.

© AlphaMed Press 2017.
Oncologist. 2017 Feb;22(2):199-207. doi: 10.1634/theoncologist.2016-02...

表3．Khoranaスコア

出典
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1: Cancer and Venous Thromboembolic Disease: A Review.
著者: Donnellan E, Khorana AA.
雑誌名: Oncologist. 2017 Feb;22(2):199-207. doi: 10.1634/theoncologist.2016-0214. Epub 2017 Feb 7.
Abstract/Text: Venous thromboembolism (VTE), including deep-vein thrombosis and pulmonary embolism, represents a major cause of morbidity and mortality in cancer patients. Patients with cancer are six times more likely to develop VTE than their noncancer counterparts, and VTE is the second leading cause of death in cancer patients. Despite the publication of major consensus guidelines setting out recommendations for thromboprophylaxis in cancer patients, there remains a gulf between these guidelines and clinical practice. In general, thromboprophylaxis is recommended for most patients hospitalized with active cancer. Furthermore, outpatient thromboprophylaxis may be used in carefully selected high-risk ambulatory patients. Certain areas of controversy still remain. Although low-molecular-weight heparin has been shown to be superior to vitamin K antagonists in cancer patients, the role of direct oral anticoagulants is still uncertain. Moreover, recurrent thromboembolism, bleeding, and thrombocytopenia are frequently seen in cancer patients. Optimal anticoagulation in such instances presents a major challenge to clinicians. Modern computed tomography techniques have resulted in an increase in the detection of "incidental" VTE. Despite a growing body of evidence promulgating standard anticoagulant treatment in such cases, these cases present further challenges for members of the multidisciplinary team. The Oncologist 2017;22:199-207Implications for Practice: This article discusses venous thromboembolism (VTE) in patients with malignancy. Practical guidance is offered on how to prevent, diagnose, and treat VTE in cancer patients. The management of "challenging" cases of VTE is also discussed.

© AlphaMed Press 2017.
Oncologist. 2017 Feb;22(2):199-207. doi: 10.1634/theoncologist.2016-02...

表4．担がん患者における脳梗塞発症機序

Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore). 1985 Jan;64(1):16-35. doi: 10.1097/00005792-198501000-00002. PMID: 3965856.などより作成
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表5．凝固能亢進（DIC）に対する治療薬

表6．VTE再発予防のための薬剤