Csorba, Roland

Rath, Werner

Soliman, Amr A.

Tempelhoff, Georg-Friedrich von

Tsikouras, Panagioti

Ullrich, A.

Clinical and Applied Thrombosis/Hemostasis

DEA University of Debrecen Electronic Archive

Letter to the EditorAntiphopholipid Antibodies andFunctional Activated Protein C Resistancein Patients With Breast Cancer DuringAnthracycline-Based ChemotherapyAdministered Through an IntravenousPort-Catheter DeviceA. A. Soliman, MD1,2, R. Csorba, MD1,3, A. Ullrich, MD1,P. Tsikouras, MD1, W. Rath, MD4, and G.-F. von Tempelhoff, MD1Venous thromboembolic events (VTEs) are life-threateningcomplications in patients with cancer and remain the secondmost common cause of death in hospitalized patients with can-cer, after death from cancer itself.1 Patients with breast cancer,however, are considered to be at relatively low risk of develop-ing VTE.2 In a cohort of 108 255 patients with breast cancer,the 1- and 2-year cumulative incidence of VTE was estimatedto be 0.9% and 1.2%, respectively.3 Both chemotherapy in gen-eral and the agent used in particular were found to increase therisk of developing VTE. A systematic screening for thrombosisduring anthracycline-based regimens in adjuvant settingsrevealed a higher VTE (10%)4 rate when compared to the con-ventional cyclophosphamide methotrexate fluorouracil therapy(5.4%).5 The route of application of chemotherapeutic agentsrepresents another high risk factor for the development of VTE.Catheter-related thrombosis (CRT) involves 70% to 80% of allupper extremity thrombotic events and represents about 10% ofall cases of VTE in patients with cancer receiving chemother-apy.6 The role of acquired thrombophilia such as the inductionof antiphospholipid antibodies (aPL-abs) and lupus anticoagu-lant (LAC) in the pathogenesis of VTE in patients with breastcancer has been reported but is still a matter of debate.In a prospective, case-controlled study, we assessed the rate ofsymptomatic VTE in primary nonmetastatic, patients with breastcancerwho received adjuvant anthracycline-based chemotherapyregimens postoperatively via an intravenous port-catheter device(Hickman port, Celsite1Access Port venous low-profile compo-site access ports with titanium chamber, Braun Melsungen AG,Germany). The standard combination administered every 3weeks and for 6-treatment cycles was as follows: cyclophospha-mide 500 mg/m2, doxorubicin/epirubicin 15 mg/m2, and flurour-acil 1000mg/m.2 Prior to primary surgery and eachof the 6 cyclesof chemotherapy, laboratory tests for anticardiolipin antibodies(aCL-ab; immunoglobulin [Ig]G-, IgM-enzyme-linked immuno-sorbent assay [ELISA] >15 U/mL), LAC (partial thromboplastintime ratio > 1.2), resistance to activated protein C (APC, Coatest;Chromogenix, Mo¨lndal, Sweden; APC ratio < 2.0), and D-dimer(ELISA > 500 mg/L) were performed. None of the patientsreceived anticoagulants unless thrombosis was confirmed. Con-comitantly, clinical signs for thrombosis were assessed, namely,increasing girth, marked edema, vague pain, and redness in thecorresponding upper limb. The collected data were tabulated andanalyzed using PSPP-project version 0.7.9, released February2012.Over a period of 1.5 years, 42 patients with breast cancer(age: 60.6+ 7.5 years) were recruited; 49 age-matched healthywomen served as controls (age: 59.0+ 11.2 years; P ¼ .41).In the study period, 7.2% of the patients with breast cancer(n ¼ 3) developed symptomatic VTE, which were all localizedin the subclavian vein at the side of the port-catheter. All ofthem occurred after the first chemotherapy cycle and were pro-ven by contrast phlebography. Low-molecular-weight heparinat therapeutic dose was initiated and continued until removalof the device after the sixth cycle of chemotherapy. Sympto-matic thrombosis of the pelvic veins, lower extremities, or inother regions was not detected in any of the patients during the1 Department of Obstetrics and Gynecology, City Hospital of Aschaffenburg,Aschaffenburg, Germany2Department of Obstetrics and Gynecology, University of Alexandria,Alexandria, Egypt3 Department of Obstetrics and Gynecology, University of Debrecen,Debrecen, Hungary4Department of Obstetrics and Gynecology, University RWTH Aachen,Aachen, GermanyCorresponding Author:G.-F. von Tempelhoff, MD, Department of Obstetrics and Gynecology, CityHospital of Aschaffenburg, Hospital of Aschaffenburg, Am Hasenkopf, Aschaf-fenburg 63739, Germany.Email: G-F.von.tempelhoff@gmx.deClinical and AppliedThrombosis/Hemostasis2014, Vol. 20(3) 338-340ª The Author(s) 2014Reprints and permission:sagepub.com/journalsPermissions.navDOI: 10.1177/1076029613508598cat.sagepub.comstudy period. Test results for aCL-ab (Figure 1A and B) andLAC were negative in all of the patients, prior to surgery, priorto the start of chemotherapy, and prior to each cycle ofchemotherapy. In one of the controls, however, aCL-ab waselevated, but her medical history was uneventful, and therewere no clinical signs of thrombosis.Mean D-dimer concentrations in patients with breast cancerprior to surgerywere elevated (but not above the cutoff level) com-pared to the concentrationsof thehealthyvolunteers (102+187vs37+ 21 mg/L; P < .001); however, in 1 patient the D-dimer levelcrossed the cutoff of 500 mg/L (970 mg/L) prior to chemotherapyand remained high (930 mg/L) throughout the follow-up withoutevidence of thrombosis.During chemotherapy,meanD-dimer con-centrations remained unchanged in all of the patients. We notedelevated D-dimer concentrations up to 620 and 760 mg/L, respec-tively, in only 2 patients, without evidence of thrombosis.None of the patients included in the present study hadelevated aPL-absat the time of primary diagnosis of breast,and we did not detect any increase in aCL-ab or LAC con-centrations in the follow-up during the chemotherapy cycles.We therefore assume that the induction of aCL-ab or LAC—inthe sense of an acquired thrombophilia—is an infrequent phe-nomenon in patients with breast cancer receiving standardanthracycline-based chemotherapy.The 7.2% incidence of CRT in our cohort is comparable tothat described in 1 study6 but contrary to others.7,8 Zuckermanet al reported that 22% of the patients presenting with malignan-cies in their cohort showed elevated aCL-ab concentrations,compared with 3% in the control group without malignancies.Moreover, the aCL-ab-positive patients had a significantlyhigher rate of VTE than aCL-ab-negative patients. Interestingly,the levels of aCL-ab decreased after successful treatment in 4patients who remained free of thrombotic events thereafter.7In a systematic review, Go´mez-Puerta et al concluded that theincrease in aCL-ab occurs in a wide range of different malignan-cies and that they decrease in more than one-third of the patientsafter cancer treatment.8 The APC resistance, either acquired orinherited (factor V Leiden mutation), was also incriminated asa possible cause ofVTE in patientswith cancer. Haim et al foundthat the prevalence of acquired functional APC resistance wassignificantly higher in patientswith cancerwho developedVTE.They concluded that resistance to APC is a risk factor for VTEand that acquired functional APC resistance is a common find-ing in patients with cancer having venous thromboembolismwhile the factor V Leiden mutation was unusual.9 These resultsare contradictory to our findings. We observed that none of ourpatients developed symptomatic VTE elsewhere apart fromCRT, and this made us to believe that most likely the mechan-isms inducing CRT are different from those causing pelvic orlower extremities thrombosis; therefore, the coagulation testsas used in this study may be inappropriate to predict CRT.Nijziel et al reported an increased resistance to APC in56 patients with node-positive breast cancer 1 year or moreafter chemotherapy in comparison with 28 healthy control par-ticipants.10 In our cohort, we could not find any elevation inAPC resistance before and during chemotherapy both inpatients affected with VTE and those who were not. It is worthmentioning that no other breast cancer study relating to thecourse of functional acquired thrombophilia (APC resistanceand aPL-ab) during chemotherapy considering the develop-ment of VTE has been published yet.From our results and through comparing them to the pub-lished relevant literature, we conclude that an increase inaCL-ab, LAC, hence antiphospholipid syndrome, and functionalresistance to APC as well are infrequent events in patients withbreast cancer receiving adjuvant anthracycline-containingFigure 1. A, Box plot showing the aCL-ab IgG levels before the breast operation and before each of the treatment cycles. Dots: outliers. B, Abox plot showing the aCL-ab IgM levels before the breast operation and before each of the treatment cycles. Dots: outliers. aCL-ab indicatesanticardiolipin antibody; Ig, immunoglobulin.Soliman et al 339chemotherapy combination, even in those patients who devel-oped port-catheter thrombosis.Authors’ NoteA. A. Soliman contributed to the concept and design of the study,shared in the data collection and its statistical analysis as well andshared in the critical writing of the manuscript; R. Csorba shared in theliterature search and critical writing of the manuscript; A. Ullrich tooka main part in the data collection, tabulation and statistical analysis;P. Tsikouras shared in the statistical analysis of the data and putting themanuscript in its final form to be published; W. Rath contributed to thesearch of literature and to the final revision of the intellectual content;and finally, G.-F. von Tempelhoff contributed substantially to the con-cept and design of the study, shared in the statistical analysis, and gaveapproval to the final version of the manuscript to be published.References1. Donati MB. Cancer and thrombosis. Haemostasis. 1994;24(2):128-131.2. Mandala M, Tondidni C. Adjuvant therapy in breast cancer andvenous thromboembolism. Thromb Res. 2012;1(suppl 1):s66-s70.3. Chew HK, Wun T, Harvey DJ, Zhou H, White RH. Incidence ofvenous thromboembolism and the impact on survival in breastcancer patients. J Clin Oncol. 2007;25(1):70-76.4. von Tempelhoff GF, Dietrich M, Hommel G, Heilmann L. Bloodcoagulation during adjuvant epirubicin/cyclophosphamide che-motherapy in patients with primary operable breast cancer. J ClinOncol. 1996;14(9):2560-2568.5. Saphner T, Tormey DC, Gray R. Venous and arterial thrombosisin patients who received adjuvant therapy for breast cancer. J ClinOncol. 1991;9(2):286-294.6. Kucher N.Clinical practice. Deep vein thrombosis of the upperextremities. N Engl J Med. 2011;364(9):861-869.7. Zuckerman E, Toubi E, Golan TD, et al. Increased thromboem-bolic incidence in anti cardiolipin positive patients with malig-nancy. Br J Cancer. 1995;72(2):447-451.8. Go´mez-Puerta JA, Cervera R, Espinosa G, et al. Antiphospholipidantibodies associated with malignancies: clinical and pathologicalcharacteristics of 120 patients. Semin Arthritis Rheum. 2006;35(5):322-332.9. Haim N, Lanir N, Hoffman R, Haim A, Tsalik M, Brenner B.Acquired activated protein C resistance is common in cancerpatients and is associated with venous thromboembolism. Am JMed. 2001;110(2):91-96.10. Nijziel MR, van Oerle R, Christella M, et al. Acquired resistanceto activated protein C in breast cancer patients. Br J Haematol.2003;120(1):117-122.340 Clinical and Applied Thrombosis/Hemostasis 20(3)

Antiphopholipid antibodies and functional activated protein C resistance in patients with breast cancer during anthracycline-based chemotherapy administered through an intravenous port-catheter device

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Antiphopholipid antibodies and functional activated protein C resistance in patients with breast cancer during anthracycline-based chemotherapy administered through an intravenous port-catheter device

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