PROBLEMATICHE EMORRAGICHE E TROMBOTICHEIN EMATOLOGIA

Milano, 29 aprile 2011

LINFOMI E RISCHIO

TROMBOTICO

Maria Benedetta Donati, MD, PhDLaboratori di Ricerca

Università Cattolica, Campobassombdonati@rm.unicatt.it

CANCER AND THROMBOSIS:A DOUBLE MEANING

Thrombotic episodes as a complication ofthe clinical evolution of tumours,particularly of g.i. tract (A. Trousseau, 1865)

Hemostatic-thrombotic mechanisms as asupport to cancer cell growth andmetastasis formation (T. Billroth, 1878)

Principal pathways of Principal pathways of tumortumor cell cellinteractions with the interactions with the hemostatichemostatic system system

endothelial cellsplatelets

monocytes/macrophagesneutrophils

Interactions with host cellsProcoagulant activities

tissue factorcancer procoagulant

FV receptorFXIII-like activity

Fibrinolytic activities

t-PAPAI-1u-PA

u-PAR

Cytokines

IL1-βTNF-αVEGF

TUMOR CELLTUMOR CELL

Falanga and Donati, 2001Falanga and Donati, 2001

HAEMATOLOGIC MALIGNANCIESAND THROMBOSIS

PREVIOUS DOGMAS PRESENTLY QUESTIONED

THROMBOSIS NOT ONLY IN SOLIDTUMORS, BUT ALSO IN HEMATOLOGICALMALIGNANCIES

ACUTE LEUKEMIA: NOT ONLYHEMORRHAGIC,BUT ALSO THROMBOTICMANIFESTATIONS

BloodBlood 2006 2006

GroupsGroups ofof studiesstudies PopulatPopulat.. PatientsPatients EventsEvents IR %IR %((CICI 95% ) 95% )

ProspectiveProspectiveThrombosisThrombosis 1111 12321232 7171 5.65.6

(4.3-7.1)(4.3-7.1)

ProspectiveProspectiveTreatment prot.Treatment prot. 1313 520520 2020 3.93.9

(2.3-5.9)(2.3-5.9)

ProspectiveProspectiveLab. parametersLab. parameters 99 126126 00 00

(0-0.3)(0-0.3)

RetrospectiveRetrospective 99 55015501 8282 1.51.5(1.2-1.8)(1.2-1.8)

JTH 2007JTH 2007

ALL ALL lessless common, common, butbut thrombosisthrombosis more more frequentfrequentin in adultsadults, , alsoalso due due toto co-morbiditiesco-morbidities

13 13 prospectiveprospective studiesstudies323 323 patientspatients19 19 eventsevents ( (5.9%, 5.9%, 3.5-9.2 3.5-9.2 95%CI95%CI))

NON HODGKIN LYMPHOMA ANDDEEP VEIN THROMBOSIS

Retrospective study on 567 patients (2001-2006) in two Italian Centers

400 indolent, 167 aggressive DVT in 87 patients (15%) within 3 months

from diagnosis

Giordano Giordano etet al, al, ThrombThromb ResRes 2007 2007

Vascular compression by enlarged lymphonodesAge over 60Weekly chemotherapy

VTE IS A COMMON COMPLICATION IN PMBCL ANDNEGATIVELY INFLUENCES SURVIVAL

ANTITHROMBOTIC PROPHYLAXIS TO BE CONSIDEREDIN PATIENTS WITH BULKY MEDIASTINAL TUMOR MASS

Background

Incidence rates of thrombosis in subjects withlymphoma vary between 3% and 13% when studyingsystemic forms of the disease

No clinical subpopulation of patients with lymphoma hasbeen identified so far as being at higher risk forthrombosis, and no clear indications have been providedabout the need and the conditions required to preventthrombotic events in these patients

Aim To quantitatively combine and meta-analyze the

available data on thrombosis occurrence in patients withlymphoma and to obtain accurate estimates of thethrombotic risk

Several subgroup analyses were carried out trying toidentify lymphoma sub-populations at higher risk forthrombotic complications

Methods Articles were searched in the PubMed, Medline, Embase and

Cochrane databases

Studies on pediatric populations were excluded

The end point used for the analysis was the occurrence of“symptomatic” thrombotic events, defined as “symptomaticthrombotic event,” or “symptomatic thrombosis,” or “symptomaticvenous thrombosis,” or merely “thrombosis/thrombotic event”

Pooled Incidence rates (Irs) were calculated using exact maximumlikelihood binomial distribution

Results: type of studies

• The great majority of the patients were included in registries, where theIR of thrombotic events was significantly lower than in studiesspecifically designed to evaluate thrombotic complications in cancerpatients

• As recalling of events could be rather erratic, and many cases may notbe included into the databases, this group was excluded from furtheranalysis

Results: site of thrombosis

Results: types of lymphoma

Results:IR of thrombosis according to stage of disease, usingthe Ann Arbor staging system

0,00 5,00 10,00 15,00 20,00

STAGE I

STAGE II

STAGE III

STAGE IV

IR of thrombosis /%)

Results:IR of thrombosis for different subtypes of lymphoma

Further results 1 Ninety-five percent of events occurred during treatment,

whereas 3.8% took place at presentation of the disease,before initiating chemotherapy, and only 1.2% aftercompletion of the treatment

No study evaluated the effect of congenital thrombophiliaspecifically in lymphoma patients

Almost all patients included were treated according tocurrent chemotherapy protocols. Since data regardingtherapy were heterogeneous across studies, and not allpapers reported name and dosage of the employeddrugs, an evaluation of the effect of different treatmentinterventions in the risk of thrombosis was not possible

Further results 2

The presence of compression of venous vessels wasindicated as a risk factor in several studies; however, thecharacteristics of the available data did not allow us toinclude them in this meta-analysis

The contribution of central venous catheter (CVC) tothrombosis in lymphoma patients could not bethoroughly investigated in this meta-analysis, as only fewstudies reported the proportion of patients bearingCVCs, and less than half of venous thrombosis siteswere recorded

Conclusions 1

The global IR of thrombosis in lymphoma patients wasfound to be more than 6%

The estimated annual incidence of thrombosis in cancerpopulation is about 0.5%, compared with 0.1% in thegeneral population; thrombosis representing the secondleading cause of death in cancer patients

As in the majority of the studies patients were followed-up from diagnosis to an extent of 1-3 years, this pooledIR is to be considered particularly high

Conclusions 2

Since 95% of thromboses occurred during treatment, itis impossible to distinguish between thrombogeniceffects of lymphoma itself or its treatment. Nevertheless,the high rate of thrombotic events in lymphoma patientsstands as a problem in their clinical management,irrespective of the cause, either cancer or the treatments

Our meta-analysis shows that the IR of thrombosis inlymphoma patients is quite high especially in those withhgNHL at an advanced stage of the disease

The presence of vein compression, as well as the useof CVCs could be additional risk factors for thrombosis

Conclusions 3

These results may help better defining lymphomapopulations at high thrombotic risk, in whomprophylactic approaches, presently lacking, could bepreferentially developed

Confirmation of these findings, along with further studiesof prothrombotic risk factors in lymphoma, are needed inthe setting of well-designed prospective clinical studies

Research Laboratories, Catholic University, Campobasso, Italy