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Editorials
Arterial thrombosis and cancer: the neglected side of the coin of Trousseau syndrome
Valerio De Stefano
Fondazione Policlinico Universitario A. Gemelli IRCCS, Istituto di Ematologia, Università Cattolica, Roma, Italia
E-mail: valerio.destefano@unicatt.it doi:10.3324/haematol.2018.197814
The clinical observation of the association between cancer and thrombosis was first reported in 1823 by Jean Baptiste Bouillaud when he was still a medical student.1 However, Armand Trousseau in 1865 was the first to study systematically clinical and autopsy findings and formulate the theory of the close and fre- quent association between cancer and increased risk of thrombosis. He re-examined the previous observations: “I have just reperused the memoir of Dr. Bouillaud, and have pleasure in stating that the work of my colleague is as complete as if it had been written yesterday.”2 In his 95th lecture on clinical medicine, delivered at the Hôtel Dieu in Paris, he noted: “I have long been struck with the frequency with which cancerous patients are affected with painful oedema in the superior or inferior extremi- ties, whether one or other was the seat of cancer. [...] I have since that period had an opportunity of observing other cases of painful oedema, in which, at the autopsy, I found visceral cancer, but in which during life, there was
no appreciable cancerous tumor; and in which there exist- ed a cachexia referable neither to the tubercular diathesis, the puerperal state, nor chlorosis. I have thus been led to the conclusion, that when there is a cachectic state not attributable to the tuberculous diathesis or to the puerper- al state, there is most probably a cancerous tumor in some organ. [...] So great, in my opinion, is the semiotic value of phlegmasia in the cancerous cachexia, that I regard this phlegmasia as a sign of the cancerous diathesis as certain as sanguinolent effusion into the serous cavi- ties.”2
The procoagulant mechanisms underlying cancer-asso- ciated thrombophilia are complex and multifactorial. However, the expression of tumor cell-associated clot promoting properties leads to the activation of the clot- ting cascade, with the generation of thrombin and fibrin, and the stimulation of platelets, leukocytes and endothe- lial cells, enhancing their cellular procoagulant features.3 A possible particular role of neutrophil extracellular traps
Table 1. Studies investigating the incidence of arterial thrombosis conducted in patient cohorts composed of different cancer groups.
Reference
Khorana et al.10
Di Nisio et al.11
Zoller et al.12,13
Navi et al.14
Brenner et al.15 Grilz et al.8
Cancer Time patients, n frame
66,106 1995-2002
1934 2003-2009
820,491 1987-2008
279,719 2002-2011
5717 2009-2014
1880 2003-2013
Design
Multicenter retrospective cohort
Multicenter retrospective cohort
Nationwide retrospective cohort
Risk vs. controls
N/A
N/A
At 6 months 1.7 (AMI) 2.2 (IS)
At 6 months 2.2 (ATE) 2.9 (AMI) 1.9 (IS)
N/A
N/A
Inclusion criteria
Diagnosis of cancer, hospitalization, chemotherapy, neutropenia
Diagnosis of cancer, ambulatory follow up, chemotherapy,
no history of ATE
Diagnosis of cancer
Age >65 years,
primary breast, lung, prostate, colorectal, bladder, pancreatic, gastric cancer or non-Hodgkin lymphoma
Active cancer, previousVTE
Age >18 years, newly diagnosedorrelapsed cancer, no indication to long-term anticoagulation
Source of information
Discharge database
Medical records
National computerized registry (MigMeg2 database) based on unique person number
ATE, n (%)
1135 (1.72%)
5 (0.27%)
N/A
Cumulative incidence at 1 yr: 6.5% at 2 yrs:9.1%
63 (1.10%)
48 (2.55%) Cumulative Incidence at 1 yr: 1.7% at 2 yrs:2.6%
AMI, n (%)
577 (0.87%)
4 (0.20%)
IS, n (%)
VTE, n (%)
422
(0.64%) (6.44%)
0 38 (1.96%)
4255
Retrospective matched cohort
Multicenter prospectivecohort
Monocenter prospective cohort
SEER-Medicare dataset
RIETE registry
CATS dataset
34,666 31,524 (4.2%) (3.8%)
Cumulative Cumulative Incidence Incidence at 1 yr: 2.6% at 1 yr: 4.3% at 2 yrs:3.7% at 2 yrs:5.8%
N/A
N/A
15 (0.26%)
20 (1.06%)
42 499 (0.73%) (8.72%)
16 157 (0.85%) (8.35%)
n: number; yr/yrs: year(s); N/A: not available; AMI: acute myocardial infarction; ATE: arterial thromboembolic event; CATS: Vienna Cancer and Thrombosis Study; IS: ischemic stroke; RIETE: Registro Informatizado de Enfermedad TromboEmbolica; SEER: Surveillance Epidemiology and End Results-Medicare;VTE: venous thromboembolism.
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