Pleural mesothelioma and venous thrombosis:
The eosinophilia link
By Richard Julian Ames and Win Win Aye

Department of Haematology, West Suffolk Hospital, Hardwick Lane, Bury St Edmunds, IP33 2QZ, UK

Thrombosis Journal 2008, 6:3 doi:10.1186/1477-9560-6-3

The electronic version of this article is the complete one and can be found online at: http://www.thrombosisjournal.com/content/6/1/3

Received: 16 December 2007
Accepted: 28 April 2008
Published 28 April 2008

© 2008 Ames and Aye; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

Abstract
Peripheral blood eosinophilia and vascular occlusions are rare occurrences in patients with pleural
mesothelioma whereas eosinophilia may associate with thrombosis. We describe a patient with
mesothelioma who developed peripheral blood eosinophilia followed by deep vein thrombosis despite
being on low molecular weight heparin prophylaxis. We discuss the genesis of peripheral blood
eosinophilia and thrombosis in pleural mesothelioma.

Introduction
The latest nationwide census from the occupational United Kingdom physicians identified pleural
mesothelioma (PM) in 92% of lung cancers patients [1] whereas PM represented only 8% of histology
proven lung cancers accrued from an area without heavy industrial exposure to asbestos [2].
Peripheral blood eosinophilia (PBE) has been detected in 0.5% to 1.7% of patients with malignancy
[3]: it may occur in cancer of the lung, pancreas, uterus, liver, breast, kidney and thyroid [3,4], in
liposarcomas [5] in lymphomas and T-cell-leukemias [6,7] but it is quite rare in PM [8-11], PBE is
associated with metastatic spread, predicts a poor prognosis [12,13] may disappear with treatment of
the malignancy and reappear with tumour relapse [6,14]: We describe a patient who developed PBE
almost coincidentally with PM followed by deep vein thrombosis despite low molecular weight heparin
prophylaxis and in the absence of inherited thrombophilia.

Case report
A 75-year old gentleman was admitted to the Oncology/Haematology Ward in early September 2007
for severe shortness of breath. He had been fully investigated for a pleural effusion one month earlier
in a neighbouring hospital. At that time drained pleural fluid revealed reactive lymphocytes with
neither neutrophils nor eosinophils. However peripheral blood esosinophils were raised at 1.6 × 109/L,
C-reactive protein (CRP) at 33 mg/dl and fibrinogen at 568 mg/dl. Cultures for bacteria and stains for
acid-fast bacilli were negative. Several stool examinations and serologic tests were negative for
parasites as well as an autoimmune screen (antinuclear antibodies, antineutrophil-cytoplasmic
antibodies, anti myeloperoxidase antibodies). A right pleural biopsy done in mid August 2007 revealed
sheets of pleura infiltrated by malignant epithelioid cells that on immune staining expressed CK7
(cytokeratin) with focal expression of CK5/6 whereas staining for carcino-embriogenic antigen,
BerEP4, thyroid transcription factor-1 mesothelin, Wilms' tumour -1, CK20 or prostate specific antigen
was negative, confirming a diagnosis of epithelioid mesothelioma. A drain was inserted through the
right chest wall and opiates started (morphine sulphate 30 modified release bd, oxycodone). During
the current admission the drain was re-sited and fluid examination revealed only reactive lymphocytes
and few neutrophils. His peripheral blood eosinophils had risen to 21 × 109/L, CRP was up at 88 mg/dl
and fibrinogen at 880 mg/dl. The patient was started on a prophylactic dose of tinzaparin (3500
IU/day). On the fourth day after admission the patient developed a swollen calf, his D-dimer was
greater than 1000 mg/dl (cut-off normal >280 mg/dl) and an ultrasound scan confirmed a fresh
popliteal vein thrombosis. Tinzaparin was increased to therapeutic levels for five days until warfarin
brought the international normalised ratio within therapeutic range. A thrombophilia screen (including
factor V Leiden, prothrombin 20210, protein C, protein S, antithrombin, lupus anticoagulant and
anticardiolipin antibodies) arranged before commencing warfarin came back normal. Neither the
FIP1L1-PDGFRA fusion transcript (deletion 4q12) nor other cytogenetic abnormalities were found on a
cellular sample of peripheral blood. After 5 days later his general conditions deteriorated, he became
progressively confused with increasing hypoxia and passed away for respiratory failure. Post mortem
revealed a mesothelioma that had diffusely surrounded and invaded the left lung and pericardium
without directly affecting vascular structures. No asbestos bodies were found and no pulmonary
embolism was detected.

Discussion
PBE is rare finding in mesothelioma: a large survey found one case out of 4710 patients with pleural
involvement [8] whereas two more patients with pleural involvement [9,10] and one with peritoneal
involvement [11] have been described as case reports. In this setting PBE should be considered
reactive as the tumour itself produces factors that promote eosinophil generation such as interleukin
3, interleukin 5 and granulocyte-monocyte colony stimulating factor [15]: The negative cytogenetic
testing favours a reactive PBE in our patient.

Thrombosis development in PM is also rare: according to one series venous occlusions occurred in
6.5% (1/15) of cases [16], whereas an autopsy study on 111 patients with lung cancer identified 14
cases of PM of which 14% had evidence of clots in the venous circulation [17];isolated reports
documented occlusions of the superior vena cava [18,19], of the left jugular and subclavian veins [20]
and of the portal vein [21]. Arterial occlusions affected cerebral circulation in two cases [22,23], and
mesenteric vessels in one case (associated with nephrotic syndrome)[24],

The pathogenesis of thrombosis in PM is partly due to tumour tissue compressing veins [18,20] that at
times may progress to direct vessel infiltration [19] and partly due to a hypercoagulable state
characterised by elevated levels of plasma fibrinogen [25] and increased fibrin turnover leading to
disseminated intravascular coagulation [26].

Primary eosinophilic syndrome is strongly associated with thrombosis that may be recurrent despite
adequate heparin and warfarin anticoagulation [27]. Eosinophils store and express tissue factor and
once activated may initiate coagulation [28]. In addition eosinophils interfere with the activity of
natural anticoagulants: eosinophilic cationic protein (ECP) binding to thrombomodulin prevents
thrombin dependent activation of anticoagulant protein C [29] and binding to heparan sulphate (or
heparin) prevents the conformational change required for the anti-thrombin neutralisation of thrombin
[30]. Indeed an excess of ECP was able to override heparin binding to antithrombin [31] and may well
explain the few instances where apparently therapeutic or prophylactic doses of heparin failed to
prevent thrombosis [27,32]. This was the situation of our patient who developed deep vein thrombosis
being already on prophylactic low molecular weight heparin.

In conclusion we have reported an unprecedented patient with pleural mesothelioma in whom reactive
PBE contributed to the development of deep vein thrombosis more than the tumour itself on the
background of an inflammatory and eventually hypercoagulable state. Though difficult for
mesothelioma, tumour treatment may relieve the reactive PBE [6,14]. Clinicians should be aware of
the added thrombotic risk of hypereosinophilia in cancer patients [33] and consider prophylactic or
therapeutic anticoagulation according to clinical judgement and laboratory guidance, possibly with anti
factor Xa monitoring in the case of low molecular weight heparin.

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