A. T. Phlegmasia alba dolens. Clin Med Hotel Dieu Paris. 1865;3:94.
Gross L FC. Nonbacterial thrombotic endocarditis. Classification and general description. Arch Intern Med. 1936;58:620–40.
BARRON KD, SIQUEIRA E, HIRANO A.
Cerebral embolism caused by nonbacterial thrombotic endocarditis.
Neurology. 1960 Apr;10:391-7. doi: 10.1212/wnl.10.4.391.
Abstract/Text
Callander N, Rapaport SI.
Trousseau's syndrome.
West J Med. 1993 Apr;158(4):364-71.
Abstract/Text
We report 4 cases of Trousseau's syndrome, in which spontaneous recurrent or migratory venous thromboses, arterial emboli caused by nonbacterial thrombotic endocarditis, or both, develop in a patient with a recognized or occult malignant tumor. The clinical course of 3 of the patients emphasizes a key point: The occurrence for no known reason of thromboses preventable by anticoagulation therapy with heparin but not with warfarin sodium should alert a physician to focus diagnostic efforts on uncovering an underlying malignant lesion. Thromboses may occur months to years before the tumor is discovered, and a thorough negative initial examination does not obviate the need for a continuing search. Patients with Trousseau's syndrome have persistent low-grade intravascular coagulation, and therapy with heparin should be continued indefinitely. Stopping heparin therapy for even a day may permit a new thrombosis to develop. Immunostaining a biopsy specimen from 1 patient provided evidence that 2 properties of a neoplastic lesion are required for the syndrome to develop: The malignant cells express surface membrane tissue factor, and structural features of the tumor permit the malignant cells or vesicles it sheds to be exposed to circulating blood.
Navi BB, Reiner AS, Kamel H, Iadecola C, Okin PM, Tagawa ST, Panageas KS, DeAngelis LM.
Arterial thromboembolic events preceding the diagnosis of cancer in older persons.
Blood. 2019 Feb 21;133(8):781-789. doi: 10.1182/blood-2018-06-860874. Epub 2018 Dec 21.
Abstract/Text
Cancer patients face an increased risk of arterial thromboembolism; however, it is uncertain when this excess risk begins. This study evaluated the risk of arterial thromboembolism before cancer diagnosis. Using the population-based Surveillance Epidemiology and End Results-Medicare linked dataset, we identified 374 331 patients ≥67 years of age with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, uterine, pancreatic, gastric cancer, or non-Hodgkin lymphoma from 2005 through 2013. Cancer patients were individually matched by demographics and comorbidities to Medicare beneficiaries without cancer, who served as controls. Validated diagnosis codes were used to identify arterial thromboembolic events, defined as a composite of myocardial infarction or ischemic stroke. The Mantel-Haenszel estimator was used to compare risks of arterial thromboembolic events between cancer and noncancer groups during 30-day periods in the 360 days before date of cancer diagnosis. From 360 to 151 days before cancer diagnosis, the 30-day interval risks of arterial thromboembolic events were similar between cancer patients and matched controls. From 150 to 1 day before cancer diagnosis, the interval 30-day risks of arterial thromboembolic events were higher in cancer patients vs matched controls, progressively increasing as the cancer diagnosis date approached and peaking during the 30 days immediately before cancer diagnosis, when 2313 (0.62%) cancer patients were diagnosed with an arterial thromboembolic event vs 413 (0.11%) controls (odds ratio, 5.63; 95% confidence interval, 5.07-6.25). In conclusion, the risk of arterial thromboembolic events begins to increase 150 days before the date of cancer diagnosis in older persons and peaks in the 30 days before.
© 2019 by The American Society of Hematology.
Lopez JA, Ross RS, Fishbein MC, Siegel RJ.
Nonbacterial thrombotic endocarditis: a review.
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.
Chaturvedi S, Ansell J, Recht L.
Should cerebral ischemic events in cancer patients be considered a manifestation of hypercoagulability?
Stroke. 1994 Jun;25(6):1215-8. doi: 10.1161/01.str.25.6.1215.
Abstract/Text
BACKGROUND AND PURPOSE: Previous studies, mainly autopsy-based, suggest that the spectrum of stroke in cancer patients differs from that of the general population. These studies also suggest that cerebrovascular events frequently are a manifestation of hypercoagulability. However, no studies that address this question in the adult oncological population from a clinical perspective are available. We therefore assessed the clinical impact of cerebral ischemic events in cancer patients and attempted to determine whether their occurrence represents a manifestation of Trousseau's syndrome.
METHODS: A computerized database that records all neurological admissions and consultations at a tertiary medical center was used to retrospectively identify all patients with cerebral ischemic events and cancer.
RESULTS: Thirty-three patients representing 3.5% of all stroke consultations and admissions seen at the University of Massachusetts Medical Center were identified during the period 1988 through 1992. Large-vessel atherosclerosis was the most frequent cause of stroke. Furthermore, although 30% were determined to have hypercoagulability as a cause using clinical criteria, in only one of nine patients in whom tests were done was sufficient evidence present to make a presumptive diagnosis of disseminated intravascular coagulation. Irrespective of therapy, recurrent cerebral ischemic events were noted in only 6% of patients during a follow-up period averaging greater than 9 months, a figure that is similar to that for the risk of repeated events in the noncancer population.
CONCLUSIONS: Recognizing the limitations of this retrospective study, it appears nonetheless that conventional stroke origins account for the majority of cerebral ischemic events in the adult cancer population. Although hypercoagulability is present to a greater extent than in the nononcological population, recurrent strokes seem to occur no more frequently than in the nononcological population, and antiplatelet agents seem sufficient therapy for most patients.
Planner RS, O'Sullivan EF, Campbell JJ, Ball DL.
The hypercoagulable state and pulmonary embolism in patients with ovarian carcinoma.
Aust N Z J Obstet Gynaecol. 1978 Aug;18(3):209-12. doi: 10.1111/j.1479-828x.1978.tb00052.x.
Abstract/Text
Fifty-nine patients with ovarian carcinoma were studied with particular reference to abnormalities of the coagulation mechanism. The notable findings were the high incidence of episodic thrombocytosis (73%) and the relation of these peaks of thrombocytosis to periods of expected maximum tumour break-down. The incidence of pulmonary embolism for the series was 44%, with the majority occurring in the group demonstrating significant thrombocytosis; in this latter group, pulmonary embolism constituted the major cause of death. The abnormalities in coagulation are discussed, together with pragmatic significance and methods of control.
野川茂：がんと脳梗塞－トルーソー症候群の臨床. 日本血栓止血学会誌. 2016;27:18-28.
Varki A.
Trousseau's syndrome: multiple definitions and multiple mechanisms.
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.
Donnellan E, Khorana AA.
Cancer and Venous Thromboembolic Disease: A Review.
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.
Nouh AM, Staff I, Finelli PF.
Three Territory Sign: An MRI marker of malignancy-related ischemic stroke (Trousseau syndrome).
Neurol Clin Pract. 2019 Apr;9(2):124-128. doi: 10.1212/CPJ.0000000000000603.
Abstract/Text
BACKGROUND: Multiple acute cerebral territory infarcts of undetermined origin are typically attributed to cardioembolism, most frequently atrial fibrillation. However, the importance of 3-territory involvement in association with malignancy is under-recognized. We sought to highlight the "Three Territory Sign" (TTS) (bilateral anterior and posterior circulation acute ischemic diffusion-weighted imaging [DWI] lesions), as a radiographic marker of stroke due to malignancy.
METHODS: We conducted a single-center retrospective analysis of patients from January 2014 to January 2016, who suffered an acute ischemic stroke with MRI-DWI at our institution, yielding 64 patients with a known malignancy and 167 patients with atrial fibrillation, excluding patients with both to eliminate bias. All DWI images were reviewed for 3-, 2-, and 1-territory lesions. Chi-square test of proportion was used to test significance between the 2 groups.
RESULTS: We found an association between the groups (malignancy vs atrial fibrillation) and the number of territory infarcts (p < 0.0001). Pairwise comparisons using the Holm p value adjustment showed no difference between 1- and 2-territory patterns (p = 0.465). However, the TTS was 6 times more likely observed within the malignancy cohort as compared to patients with atrial fibrillation (23.4% [n = 15] vs 3.5% [n = 6]) and was different from both 1-territory (p < 0.0001) and 2-territory patterns (p = 0.0032).
CONCLUSION: The TTS is a highly specific marker and 6 times more frequently observed in malignancy-related ischemic stroke than atrial fibrillation-related ischemic stroke. Evaluation for underlying malignancy in patients with the TTS is reasonable in patients with undetermined etiology.
丸藤哲, 的場敏明, 江口豊, 他：急性期DIC診断基準．多施設共同前向き試験結果報告．日救急医会誌. 2005;16:188-202.
DIC診断基準作成委員会：日本血栓止血学会 DIC診断基準 2017年版. 血栓止血誌. 2017;28(3):369-91.
Jovin TG, Boosupalli V, Zivkovic SA, Wechsler LR, Gebel JM.
High titers of CA-125 may be associated with recurrent ischemic strokes in patients with cancer.
Neurology. 2005 Jun 14;64(11):1944-5. doi: 10.1212/01.WNL.0000163850.07976.63.
Abstract/Text
In addition to etiologies common in the general population, strokes in cancer patients may be caused by hypercoagulable states, hyperviscosity, cardiogenic embolism, and neoplastic vessel infiltration. Intravascular mucins were reported in patients with recurrent thromboembolism. The authors report four patients with metastatic cancer, brain infarcts, and other thromboembolic disease with markedly elevated levels of the tumor marker CA-125 and explore possible associations between this mucinous protein and strokes.
Chen Y, Zeng J, Xie X, Wang Z, Wang X, Liang Z.
Clinical features of systemic cancer patients with acute cerebral infarction and its underlying pathogenesis.
Int J Clin Exp Med. 2015;8(3):4455-63. Epub 2015 Mar 15.
Abstract/Text
BACKGROUND: The increased incidence of cerebral infarction in patients with systemic cancer has been reported; however, the underline mechanisms remain unclear. Investigation regarding the clinical features of cerebral infarction in cancer patients could be helpful to understand its underlying pathogenesis.
METHODS: A total of 537 patients were recruited and divided into three groups: 1) stroke and cancer group (SCG), defined as active cancer patients with acute cerebral infarction; 2) stroke group (SG), defined as acute cerebral infarction patients without cancer; and 3) Cancer group (CG), defined as active cancer patients without cerebral infarction. These patients were age and gender-matched among groups.
RESULTS: 179 patients, including 128 male subjects (73.68%) were enrolled in each group. Compared to SG patients, more SCG patients lacked conventional vascular risk factors (CRFs), and had elevated plasma D-dimer, cancer antigen (CA) 125 and 199 levels with multiple lesions in multiple cerebral arterial territories. In addition, SCG patients were found to have poorer prognosis. Compared to CG patients, more SCG patients' cancer had metastasized. Multiple logistic regression analysis showed that the elevated plasma D-dimer, CA125 and CA199 levels may independently increase, but chemoradiotherapy decreased the risk of cerebral infarction in cancer patients.
CONCLUSIONS: Our study demonstrated that the clinical features of acute cerebral infarction in most active cancer patients can be identified as multiple lesions in multiple cerebral arterial territories with elevated plasma D-dimer and the elevated levels of cancer antigens.
渡邊雅男，渡邊照文，宮本伸和，他；担癌患者における脳梗塞の臨床的特徴：凝血学的マーカーの有用性. 脳卒中. 2006;28:351-9.
Rogers LR, Cho ES, Kempin S, Posner JB.
Cerebral infarction from non-bacterial thrombotic endocarditis. Clinical and pathological study including the effects of anticoagulation.
Am J Med. 1987 Oct;83(4):746-56. doi: 10.1016/0002-9343(87)90908-9.
Abstract/Text
The clinical and pathologic findings in 42 autopsy proved cases of cerebral infarction from cancer-associated non-bacterial thrombotic endocarditis were reviewed. Carcinoma of the lung was the most common malignancy. Most patients had disseminated cancer, but in six patients, the condition was stable or in remission, and six patients had localized cancer; two patients were not known to have cancer until neurologic symptoms developed. Neurologic symptoms were focal, suggesting stroke in 18; diffuse, suggesting metabolic encephalopathy in nine; and mixed in five. Neurologic signs were often the only evidence of thromboembolism. The definitive diagnostic test was cerebral angiography showing multiple arterial occlusions. Anticoagulation with heparin appeared to help some patients and did not promote brain hemorrhage. Early diagnosis and vigorous treatment of non-bacterial endocarditis may prevent severe neurologic disability.
Singhal AB, Topcuoglu MA, Buonanno FS.
Acute ischemic stroke patterns in infective and nonbacterial thrombotic endocarditis: a diffusion-weighted magnetic resonance imaging study.
Stroke. 2002 May;33(5):1267-73. doi: 10.1161/01.str.0000015029.91577.36.
Abstract/Text
BACKGROUND AND PURPOSE: Although infective endocarditis (IE) and nonbacterial thrombotic endocarditis (NBTE) are associated with cardioembolic stroke, differences in the nature of these conditions may result in differences in associated stroke patterns. We compared patterns of acute and recurrent ischemic stroke in IE and NBTE, using diffusion-weighted MRI (DWI).
METHODS: Using ICD-9 diagnostic codes and medical record review, we identified 362 patients (387 episodes) with IE and 14 patients with NBTE. Thirty-five patients (with 27 episodes of IE, 9 NBTE) who underwent 36 initial and 29 follow-up DWI scans were selected for this study. DWI lesion size, number, and location were compared between groups and correlated with stroke syndromes and endocarditis features.
RESULTS: DWI was abnormal in all but 2 patients. Four acute stroke patterns were identified: (1) single lesion, (2) territorial infarction, (3) disseminated punctate lesions, and (4) numerous small (<10 mm) and medium (10 to 30 mm) or large (>30 mm) lesions in multiple territories. All patients with NBTE exhibited pattern 4, whereas those with IE exhibited patterns 1, 2, 3, and 4 (6, 2, 8 and 9 episodes, respectively). Seventy-five percent of patients with pattern 3 exhibited the clinical syndrome of embolic encephalopathy. Vegetation size, valve, and organisms had no correlation with stroke patterns.
CONCLUSION: DWI has utility in differentiating between IE and NBTE. Patients with NBTE uniformly have multiple, widely distributed, small and large strokes, whereas patients with IE exhibit a panoply of stroke patterns.
Klein I, Iung B, Wolff M, Brochet E, Longuet P, Laissy JP, Duval X.
Silent T2* cerebral microbleeds: a potential new imaging clue in infective endocarditis.
Neurology. 2007 Jun 5;68(23):2043. doi: 10.1212/01.wnl.0000266965.04112.bc.
Abstract/Text
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.
Abstract/Text
In an autopsy study of patients with cancer, 14.6% had pathologic evidence of cerebrovascular disease (CVD), and in 7.4% clinical symptoms of CVD had been present in life. The usual risk factors for CVD were overshadowed by pathophysiologic abnormalities related to the neoplasm, including direct effects of the tumor, coagulation disorders, infections and diagnostic or therapeutic procedures. In patients with leukemia, hemorrhages (72.4%) were much more common than ischemic infarcts. In lymphoma patients, the incidence of cerebral bleeding was lower (36.3%). In both groups, the leading causes of ischemic infarction were septic thrombi and intravascular coagulation. In patients with carcinoma, cerebral infarctions (54.1%) were more frequent than hemorrhages. NBTE (18.5%) and intravascular coagulation (9.6%) were the most common etiologies. Hemorrhages other than intratumoral bleeding in patients with melanoma or germ cell tumors were unusual. The clinical presentation of CVD in patients with cancer is more often a diffuse encephalopathy, with or without localizing signs, than the typical acute onset of a focal deficit. This was particularly true with intravascular coagulation, septic infarction and subdural hematoma. Our study suggests that by knowing the clinical setting, neurologic features and laboratory findings, one can, in many instances, make an accurate clinical diagnosis that, in some cases, leads to effective treatment.
野川茂：Trousseau症候群に対する抗血栓療法. In: 鈴木則宏 監修、伊藤義彰 編：脳卒中エキスパート 抗血栓療法を究める. 東京: 中外医学社; 2019. p.173-89.
Sack GH Jr, Levin J, Bell WR.
Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features.
Medicine (Baltimore). 1977 Jan;56(1):1-37.
Abstract/Text
Analysis of 182 patients with chronic disseminated intravascular coagulopathy and malignancy shows common features. Migratory thrombophlebitis occurred in 96 patients while at least a single episode of thrombophlebitis was noted in 113. Seventy-five of the patients bled and 45 had arterial emboli in various organs. Twelve patients had the triad of thrombophlebitis, hemorrhage, and arterial emboli, often sequentially. Hematologic data showed derangements associated with intravascular coagulation, the most prominent of which were hypofibrinogenemia and thrombocytopenia. Other abnormalities included prolonged prothrombin time, increased fibrinogen-fibrin degradation products, decreased levels of factors V and VIII, cryofibrinogenemia, and microangiopathic hemolytic anemia. Forty-one patients had lesions of non-bacterial thrombotic endocarditis at autopsy; 31 of these had arterial emboli during life. None of the lesions were infected. Mitral and aortic valves were most frequently involved. No single mechanism that causes the disseminated intravascular coagulopathy has been identified. However, cell products--secretions and enzymes--and the cells themselves have been proposed as the procoagulant(s) responsible for the syndrome. In addition to treatment of the underlying neoplasm, symptomatic disseminated intravascular coagulopathy should be controlled. Heparin is the drug of choice for treatment of this problem, very little benefit having been observed with warfarin therapy. Long-term use of anticoagulants is potentially feasible for control of chronic disseminated intravascular coagulopathy, but without effective control of the underlying tumor ultimately will be unsuccessful.
Walsh-McMonagle D, Green D.
Low-molecular-weight heparin in the management of Trousseau's syndrome.
Cancer. 1997 Aug 15;80(4):649-55.
Abstract/Text
BACKGROUND: Thrombophlebitis migrans is a major cause of morbidity in approximately 11% of patients with cancer. Thrombosis may predate the appearance of malignancy, and patients with thrombosis often respond poorly to warfarin.
METHODS: Four patients with extensive thrombosis and cancer are described in this article. Enoxaparin, a low-molecular-weight heparin, was administered subcutaneously to these patients for 5, 6, 26, and 27 months, respectively. The literature on the management of Trousseau's syndrome was reviewed and analyzed.
RESULTS: All four patients remained free of venous thromboembolism while being treated with low-molecular-weight heparin, acutely and during follow-up. Previously published studies suggest that therapy with low-molecular-weight heparin results in lower mortality than standard heparin therapy.
CONCLUSIONS: Further study to evaluate the safety and efficacy of low-molecular-weight heparin for both prophylaxis and treatment of thromboembolism in association with malignancy may lead to decreased morbidity and better quality of life for patients with this disorder.
Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Williamson RC.
Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS).
J Clin Oncol. 2004 May 15;22(10):1944-8. doi: 10.1200/JCO.2004.10.002.
Abstract/Text
PURPOSE: In experimental systems, interference with coagulation can affect tumor biology. Furthermore, it has been suggested that low molecular weight heparin therapy may prolong survival in patients with cancer. The primary aim of this study was to assess survival at 1 year of patients with advanced cancer.
PATIENTS AND METHODS: Patients with advanced malignancy (N = 385) were randomly assigned to receive either a once-daily subcutaneous injection of dalteparin (5,000 IU), a low molecular weight heparin, or placebo for 1 year.
RESULTS: The Kaplan-Meier survival estimates at 1, 2, and 3 years after randomization for patients receiving dalteparin were 46%, 27%, and 21%, respectively, compared with 41%, 18%, and 12%, respectively, for patients receiving placebo (P =.19). In an analysis not specified a priori, survival was examined in a subgroup of patients (dalteparin, n = 55; and placebo, n = 47) who had a better prognosis and who were alive 17 months after randomization. In these patients, Kaplan-Meier survival estimates at 2 and 3 years from randomization were significantly improved for patients receiving dalteparin versus placebo (78% v 55% and 60% v 36%, respectively, P =.03). The rates of symptomatic venous thromboembolism were 2.4% and 3.3% for dalteparin and placebo, respectively, with bleeding rates of 4.7% and 2.7%, respectively.
CONCLUSION: Dalteparin administration did not significantly improve 1-year survival rates in patients with advanced malignancy. However, the observed improved survival in a subgroup of patients with a better prognosis suggests a potential modifying effect of dalteparin on tumor biology.
Nakano K, Sugiyama K, Satoh H, Arifuku H, Fujimatsu T, Yoshida N, Watanabe H, Tokita S, Wakayama T, Tatewaki M, Souma R, Masuda H, Koyama K, Hirata H, Fukushima Y.
Effect of Thrombomodulin Alfa on Disseminated Intravascular Coagulation in Patients with Lung Cancer.
Intern Med. 2017;56(14):1799-1806. doi: 10.2169/internalmedicine.56.7143. Epub 2017 Jul 15.
Abstract/Text
Objective The mortality rate due to disseminated intravascular coagulation (DIC) is higher in patients with lung cancer than in those without. We examined the effect of treatment with thrombomodulin alfa (TM-α) for DIC in lung cancer patients. Methods Subjects were 57 patients with DIC (43 men, 14 women; mean age, 71.7 years), comprising 31 with lung cancer and 26 without. DIC patients with or without lung cancer did not differ significantly in their background characteristics. Results No significant difference was noted in the mortality rate between patients with lung cancer (61.3%) and those without (57.7%). However, the dose of TM-α was higher for survivors with lung cancer than for non-survivors (473.1 U/kg/day vs. 380.6 U/kg/day; p<0.01). Although no significant difference was noted in the DIC score between these four groups, the serum C-reactive protein level (6.9 mg/dL vs. 11.6 mg/dL; p<0.05) and prothrombin time-international normalized ratio (PT-INR; 1.10 vs. 1.52; p<0.05) were lower in survivors with lung cancer than in the non-survivors with lung cancer. The initial body temperature in non-survivors without lung cancer was lower than that in survivors without lung cancer (37.2°C vs. 37.9°C, p<0.01), and the platelet count and the time to recovery from DIC in patients without lung cancer showed a significant negative correlation (r2=0.438, p<0.05). Conclusion Our findings suggest that although 380 U/kg/day of TM-α is the recommended dose for DIC treatment, a higher dose may reduce the mortality rate of lung cancer patients with DIC. Furthermore, TM-α should be initiated before worsening of DIC parameters.
Yoshii Y, Numata T, Ishitobi W, Takahashi N, Wakui H, Kojima J, Shimizu K, Hara H, Ishikawa T, Kawaishi M, Saito K, Araya J, Kaneko Y, Nakayama K, Kuwano K.
Lung adenocarcinoma complicated by Trousseau's syndrome successfully treated by a combination of anticoagulant therapy and chemotherapy.
Intern Med. 2014;53(16):1835-9. doi: 10.2169/internalmedicine.53.1315. Epub 2014 Aug 15.
Abstract/Text
A 63-year-old woman was diagnosed with advanced lung adenocarcinoma complicated by Trousseau's syndrome characterized by non-bacterial thrombotic endocarditis, asymptomatic brain infarction, deep venous thrombosis, and low-grade disseminated intravascular coagulation (DIC). The patient's DIC rapidly became widespread, and multiple micropulmonary embolisms led to severe respiratory failure. She received a blood transfusion and anticoagulant treatment with heparin and recombinant human soluble thrombomodulin, which modestly ameliorated her symptoms, and additional chemotherapy led to tumor shrinkage with concomitant resolution of Trousseau's syndrome. Although there are no established medical approaches for managing Trousseau's syndrome, intensive anticoagulant treatment may be effective for improving the patients' general condition in order for them to be able to undergo subsequent combination chemotherapy.
Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JRE, Wells P, Woller SC, Moores L.
Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report.
Chest. 2016 Feb;149(2):315-352. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7.
Abstract/Text
BACKGROUND: We update recommendations on 12 topics that were in the 9th edition of these guidelines, and address 3 new topics.
METHODS: We generate strong (Grade 1) and weak (Grade 2) recommendations based on high- (Grade A), moderate- (Grade B), and low- (Grade C) quality evidence.
RESULTS: For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) over vitamin K antagonist (VKA) therapy, and suggest VKA therapy over low-molecular-weight heparin (LMWH; Grade 2C). For VTE and cancer, we suggest LMWH over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). We have not changed recommendations for who should stop anticoagulation at 3 months or receive extended therapy. For VTE treated with anticoagulants, we recommend against an inferior vena cava filter (Grade 1B). For DVT, we suggest not using compression stockings routinely to prevent PTS (Grade 2B). For subsegmental pulmonary embolism and no proximal DVT, we suggest clinical surveillance over anticoagulation with a low risk of recurrent VTE (Grade 2C), and anticoagulation over clinical surveillance with a high risk (Grade 2C). We suggest thrombolytic therapy for pulmonary embolism with hypotension (Grade 2B), and systemic therapy over catheter-directed thrombolysis (Grade 2C). For recurrent VTE on a non-LMWH anticoagulant, we suggest LMWH (Grade 2C); for recurrent VTE on LMWH, we suggest increasing the LMWH dose (Grade 2C).
CONCLUSIONS: Of 54 recommendations included in the 30 statements, 20 were strong and none was based on high-quality evidence, highlighting the need for further research.
Copyright © 2016 American College of Chest Physicians. All rights reserved.
Agnelli G, Bergqvist D, Cohen AT, Gallus AS, Gent M; PEGASUS investigators.
Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery.
Br J Surg. 2005 Oct;92(10):1212-20. doi: 10.1002/bjs.5154.
Abstract/Text
BACKGROUND: The aim of this study was to assess whether the synthetic factor Xa inhibitor fondaparinux reduced the risk of venous thromboembolism more efficiently than the low molecular weight heparin dalteparin in patients undergoing major abdominal surgery.
METHODS: In a double-blind double-dummy randomized study, patients scheduled for major abdominal surgery under general anaesthesia received once-daily subcutaneous injections of fondaparinux 2.5 mg or dalteparin 5000 units for 5-9 days. Fondaparinux was started 6 h after surgery. The first two doses of dalteparin, 2500 units each, were given 2 h before surgery and 12 h after the preoperative administration. The primary outcome measure was a composite of deep vein thrombosis detected by bilateral venography and symptomatic, confirmed deep vein thrombosis or pulmonary embolism up until day 10. The main safety outcome measure was major bleeding during treatment.
RESULTS: Among 2048 patients evaluable for efficacy, the rate of venous thromboembolism was 4.6 per cent (47 of 1027) with fondaparinux compared with 6.1 per cent (62 of 1021) with dalteparin, a relative risk reduction of 24.6 (95 per cent confidence interval -9.0 to 47.9) per cent (P = 0.144), which met the predetermined criterion for non-inferiority of fondaparinux. Major bleeding was observed in 49 (3.4 per cent) of 1433 patients given fondaparinux and 34 (2.4 per cent) of 1425 given dalteparin (P = 0.122).
CONCLUSION: Postoperative fondaparinux was at least as effective as perioperative dalteparin in patients undergoing high-risk abdominal surgery.
Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators.
Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism.
N Engl J Med. 2018 Feb 15;378(7):615-624. doi: 10.1056/NEJMoa1711948. Epub 2017 Dec 12.
Abstract/Text
BACKGROUND: Low-molecular-weight heparin is the standard treatment for cancer-associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear.
METHODS: In this open-label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low-molecular-weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration.
RESULTS: Of the 1050 patients who underwent randomization, 1046 were included in the modified intention-to-treat analysis. A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, -3.4 percentage points; 95% CI, -7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6).
CONCLUSIONS: Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682 .).
Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, Hale D, Dunn JA, Lyman GH, Hutchinson C, MacCallum P, Kakkar A, Hobbs FDR, Petrou S, Dale J, Poole CJ, Maraveyas A, Levine M.
Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D).
J Clin Oncol. 2018 Jul 10;36(20):2017-2023. doi: 10.1200/JCO.2018.78.8034. Epub 2018 May 10.
Abstract/Text
Purpose Venous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous low molecular weight heparin has been standard treatment for such patients. The purpose of this study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for VTE in patients with cancer. Patient and Methods In this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample size of 400 patients would provide estimates of VTE recurrence to within ± 4.5%, assuming a VTE recurrence rate at 6 months of 10%. Results A total of 203 patients were randomly assigned to each group, 58% of whom had metastases. Twenty-six patients experienced recurrent VTE (dalteparin, n = 18; rivaroxaban, n = 8). The 6-month cumulative VTE recurrence rate was 11% (95% CI, 7% to 16%) with dalteparin and 4% (95% CI, 2% to 9%) with rivaroxaban (hazard ratio [HR], 0.43; 95% CI, 0.19 to 0.99). The 6-month cumulative rate of major bleeding was 4% (95% CI, 2% to 8%) for dalteparin and 6% (95% CI, 3% to 11%) for rivaroxaban (HR, 1.83; 95% CI, 0.68 to 4.96). Corresponding rates of CRNMB were 4% (95% CI, 2% to 9%) and 13% (95% CI, 9% to 19%), respectively (HR, 3.76; 95% CI, 1.63 to 8.69). Conclusion Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with dalteparin.
Agnelli G, Becattini C, Meyer G, Muñoz A, Huisman MV, Connors JM, Cohen A, Bauersachs R, Brenner B, Torbicki A, Sueiro MR, Lambert C, Gussoni G, Campanini M, Fontanella A, Vescovo G, Verso M; Caravaggio Investigators.
Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer.
N Engl J Med. 2020 Apr 23;382(17):1599-1607. doi: 10.1056/NEJMoa1915103. Epub 2020 Mar 29.
Abstract/Text
BACKGROUND: Recent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these oral agents is limited by the increased risk of bleeding associated with their use.
METHODS: This was a multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. We randomly assigned consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or subcutaneous dalteparin (at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily). The treatments were administered for 6 months. The primary outcome was objectively confirmed recurrent venous thromboembolism during the trial period. The principal safety outcome was major bleeding.
RESULTS: Recurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P = 0.60).
CONCLUSIONS: Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding. (Funded by the Bristol-Myers Squibb-Pfizer Alliance; Caravaggio ClinicalTrials.gov number, NCT03045406.).
Copyright © 2020 Massachusetts Medical Society.
野川茂：トルソー症候群. In: 伊藤義彰 編：症例から学ぶ 戦略的急性期脳卒中診断・治療. 東京: 南山堂; 2019. p.151-61.
Nakao S, Masuda T, Sakamoto S, Yamaguchi K, Horimasu Y, Miyamoto S, Nakashima T, Iwamoto H, Fujitaka K, Hamada H, Hattori N.
Cerebral embolism during edoxaban administration for venous thromboembolism in a patient with lung adenocarcinoma: A case report.
Medicine (Baltimore). 2019 Mar;98(12):e14821. doi: 10.1097/MD.0000000000014821.
Abstract/Text
RATIONALE: The efficacy of direct oral anticoagulants (DOACs) in the treatment and prophylaxis of cancer-related venous thromboembolism (VTE) is reportedly similar to that of heparin. However, the effect of DOACs on the prophylaxis of cancer-related arterial thromboembolism (ATE) remains unclear. To our knowledge, we present the 1st case where cerebral ATE was encountered during edoxaban administration for VTE in a patient with lung adenocarcinoma.
PATIENT CONCERNS: In March 2017, a 63-year-old female was diagnosed with lung adenocarcinoma (cT2aN3M1b stage IVa) along with having asymptomatic VTE; thus, 60 mg/day edoxaban administration was initiated. In addition, 1st-line chemotherapy generated a partial antitumoral response. However, owing to lung cancer progression, a secondary treatment with pembrolizumab administration was initiated. The patient suddenly experienced aphasia 11 days after pembrolizumab administration.
DIAGNOSIS: The patient was diagnosed as multiple cerebral ATE using brain magnetic resonance imaging. However, VTE recurrence was not observed. Based on the findings of lung cancer progression and increased coagulation, cerebral ATE was diagnosed as Trousseau syndrome.
INTERVENTIONS: DOAC administration was switched to heparin administration.
OUTCOMES: Coagulation profile normalized and aphasia improved without any further disease symptoms.
LESSONS: We considered that DOACs are effective for the treatment and prophylaxis of VTE but may be insufficient for ATE prevention. Therefore, DOACs should be replaced with heparin to prevent ATE when cancer and coagulation become uncontrollable with DOAC.
Yamaura G, Ito T, Miyaji Y, Ueda N, Nakae Y, Momoo T, Nakano T, Johmura Y, Higashiyama Y, Joki H, Doi H, Takeuchi H, Takahashi T, Koyano S, Yamaguchi S, Yokoyama M, Tanaka F.
Therapeutic efficacy of heparin and direct factor Xa inhibitors in cancer-associated cryptogenic ischemic stroke with venous thromboembolism.
Thromb Res. 2021 Oct;206:99-103. doi: 10.1016/j.thromres.2021.08.016. Epub 2021 Aug 23.
Abstract/Text
BACKGROUND: Anticoagulation therapy, especially using heparin or recently developed oral direct factor Xa inhibitors (DiXals), is recommended as first-line treatment for cancer-related venous thromboembolism (VTE). However, the preventive efficacy of these anticoagulants for cancer-associated ischemic stroke is still unknown. We retrospectively investigated the efficacy of subcutaneous unfractionated heparin (UFH) and DiXals for preventing the recurrence of cancer-associated cryptogenic ischemic stroke with VTE.
METHODS: We retrospectively studied consecutive patients with cancer-associated cryptogenic ischemic stroke and comorbid VTE who received subcutaneous UFH or oral DiXaIs at 9 hospitals.
RESULT: Fifty-three patients (24 treated with UFH and 29 treated with DiXaIs) were enrolled. Of these, 47 demonstrated systemic metastasis (cancer stage IV). During 30-day follow-up after initiation of anticoagulation therapy, recurrent ischemic stroke was observed in only 1 patient (4%) in the UFH group and in 9 patients (31%) in the DiXal group. The incidence of major bleeding complications was similar between the 2 groups (4% and 10%, respectively). The cumulative risk of ischemic stroke recurrence within 30 days was lower with UFH than with DiXals (competing risk analysis, p = 0.008). In the DiXal group, patients who experienced recurrence showed significantly higher D-dimer levels than those without recurrence.
CONCLUSION: In patients with cancer-associated cryptogenic ischemic stroke and comorbid VTE, UFH demonstrated a lower rate of recurrent ischemic stroke than DiXaIs, and there were no differences in bleeding risk between the 2 treatments. D-dimer levels at stroke onset increased the risk of recurrence in the DiXal group but not in the UFH group.
Copyright © 2021 Elsevier Ltd. All rights reserved.
