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And Plasminogen Activator Inhibitor-1 JBUON 2017; 22(4): 1022-1031 ISSN: 1107-0625, online ISSN: 2241-6293 • www.jbuon.com E-mail: [email protected] ORIGINAL ARTICLE Protein Z (PZ) and plasminogen activator inhibitor-1 (PAI-1) plasma levels in patients with previously untreated Hodgkin lymphoma (HL) Georgios Boutsikas1, Evangelos Terpos2, Athanasios Markopoulos3, Athanasios Papatheo- dorou4, Angeliki Stefanou3, George Georgiou1, Zacharoula Galani1, Veroniki Komninaka1, Vasileios Telonis1, Ioannis Anagnostopoulos5, Lila Dimitrakopoulou5, Konstantinos An- argyrou6, Konstantinos Tsionos6, Dimitrios Christoulas6, Maria Gonianaki6, Theophanis Giannikos1, Styliani Kokoris7, Kostas Konstantopoulos1, John Meletis1, Maria K. Angelo- 1 7 1 poulou , Anthi Travlou , Theodoros P. Vassilakopoulos 1Department of Hematology, National and Kapodistrian University of Athens; 2Department of Clinical Therapeutics, National and Kapodistrian University of Athens; 31st Propaedeutic Department of Internal Medicine, National and Kapodistrian Universi- ty of Athens; 4Department of Biomedical Research, 251 Air Force General Hospital of Athens; 5Immunology Laboratory, Laikon General Hospital of Athens; 6Department of Hematology, 251 Air Force General Hospital of Athens; 7Hematology Laboratory, National and Kapodistrian University of Athens, Athens, Greece Summary Purpose: The role of Protein Z (PZ) in conditions, such as PZ levels at diagnosis were associated with presence of B thrombosis, inflammation or cancer, is under investigation. symptoms and positive final positron emission tomography Plasminogen Activator Inhibitor-1 (PAI-1) is an acute phase (PET) and higher baseline PAI-1 levels with positive final reactant that promotes thrombosis and tumorigenesis. Sub- PET, too. PZ had a declining trend, but PAI-1 increased ini- ject of this work was to study PZ and PAI-1 in patients with tially and decreased thereafter, during the treatment period. Hodgkin Lymphoma (HL), a malignancy with inflamma- Conclusions: Conclusively, PAI-1, but not PZ, seems to be tory background and relatively low incidence of thrombosis. an acute phase protein in HL. Lower PZ and higher PAI-1 Methods: Newly diagnosed patients were enrolled in the levels at diagnosis may be indicative of aggressive disease. study. Healthy individuals were used as controls. These results need further verification. Results: PZ levels were higher in patients compared to con- trols (not significantly), while PAI-1 levels were significant- ly higher in patients. Both PZ and PAI-1 concentrations did Key words: Hodgkin lymphoma, plasminogen activator not correlate with most of patients’ characteristics. Lower inhibitor-1, protein Z Introduction Hemostasis is a protective process that has ated with diverse hemostatic disorders [1]. Cancer evolved to maintain homeostasis. It interacts with is a prothrombotic state and venous thrombosis is other defence mechanisms, such as inflammatory the most common hemostatic disorder observed response, but it is also associated with pathologi- in cancer patients affecting prognosis [2]. Cancer cal conditions, such as malignancy. patients have high levels of factors related with Inflammation is considered as a prothrom- thrombin generation, fibrin formation and fibri- botic stimulus. Chronic inflammation is associ- nolysis [3,4]. Tumor cells produce hemostatic fac- Correspondence to: Georgios Boutsikas, MD, MSc. Department of Hematology and Bone Marrow Transplantation, National and Kapodistrian University of Athens, Laikon General Hospital, 17, Agiou Thoma Street, Athens 11527, Greece Tel: +30 2132061702, Fax: +30 2132061498, E-mail: [email protected] Received: 01/02/2017; Accepted: 15/02/2017 PZ and PAI-1 levels in previously untreated Hodgin lymphoma 1023 tors [5-7], while it is believed that prothrombotic risk for thrombosis [56-60], while its deficiency conversion of tumor cells is related with oncogene has been correlated with bleeding tendency [61- expression [8-10]. Moreover, coagulation system 65]. It is considered to be an acute phase protein has a prominent role in tumor progression [11-25]. [66,67] and its levels increase in conditions with HL is a lymphoproliferative disease usually affect- acute phase response [67-71]. Furthermore, PAI- ing younger adults and presenting mainly with 1 seems to promote tumor metastasis and angio- lymphadenopathy. It is usually characterized by genesis [72] and its absence correlates with slow intense inflammatory response. Hodgkin/Reed- tumor proliferation rate in knock-out mice [73]. Sternberg (HRS) cells release cytokines, promot- The subject of this work was to study plasma PZ ing their proliferation and their immunologic es- and PAI-1 levels as hemostatic factors associated cape and attracting other inflammatory cells which with thrombosis, inflammation and malignancy in contribute to the inflammatory background by patients with HL, a disease with intense inflam- further cytokine production. This microenviron- matory components. More specifically, the aim ment is responsible for B symptoms and elevated of this study was to compare plasma PZ and PAI- inflammatory markers frequently observed in HL 1 levels of newly diagnosed HL patients to age- [26-38]. Furthermore, the incidence of thrombosis and sex-matched controls, to correlate them with in HL patients is about 4.7% [39]. clinical and laboratory baseline characteristics, PZ is a vitamin-K-dependent glycoprotein prognosis and outcome of patients and to evaluate synthesized by the liver. It was identified in bovine their alterations during chemotherapy. plasma in 1977 [40], consists of 360 amino-acids [41] and its plasma concentration is in the order Methods of 2.9 pg/ml [42], although normal range varies widely among studies. PZ functions as cofactor From January of 2013 to April of 2014, 16 patients diagnosed with HL and treated in the Department of for Protein Z dependent Protease Inhibitor (PZPI) Hematology of National and Kapodistrian University for inhibition of FXa in the presence of calcium of Athens, as well as 16 age- and sex-matched healthy and phospholipids [42], implying an anticoagulant controls were enrolled prospectively in this study, role. However, the exact role of PZ in hemostasis which was approved by the Ethics Committee of the is not clear, since observations suggest contradic- University. All patients and controls gave written in- tory effects. It has been proposed that PZ bound formed consent. According to Departmental policy to phospholipids microparticles interacts with patients had undergone lymph node biopsy, baseline thrombin predisposing to thrombosis [43], but PZ blood counts, biochemical and “inflammatory marker” levels in lower normal limits are not associated profile, and clinical staging with physical examination, computed tomography (CT) of the neck, chest and ab- with bleeding tendency [44], that PZ is an inde- domen and bone marrow biopsy. Patients were treated pendent prognostic factor for ischaemic stroke with 4-8 cycles of ABVD-based chemotherapy or com- [45], acts as acute phase protein in ischaemic bined modality therapy according to clinical stage and/ stroke or contributes to its pathogenesis [46]. Ad- or the German Hodgkin Study Group (GHSG) [74-77]. ditionally, low PZ levels correlate with increased The standard ABVD regimen consisted of adriamycin risk for thrombotic complications [47], although 25 mg/m2, bleomycin 10 IU/m2, vinblastine 6 mg/m2 this is not confirmed by all studies [48]. Regarding and dacarbazine 375 mg/m2, all on days 1 and 15 of 28- inflammation, PZ was thought to be a “negative” day cycles (day 1 part A and day 15 part B). Advanced- acute phase reactant [49-51], i.e. had negative cor- stage patients <60 years old received 2 ABVD cycles relation with acute phase marker levels. However, followed by interim PET. If interim PET was negative, they received 6 further ABVD cycles, but if positive they experimental studies in murine models have dem- were treated with 6 cycles with BEACOPP-escalated onstrated that PZPI, and not PZ, functions as acute (bleomycin, etoposide, adriamycin, cyclophosphamide, phase protein and that the observed PZ increase oncovin, procarbazine, prednisone) [78-80]. in acute phase depends on PZPI, which prolongs Four blood samples were collected using free flow- PZ half-time by complex formation [52]. Similarly, ing technique from each patient before ABVD cycles IA, the exact role of PZ in cancer remains obscure. PZ IB, IIA and IIB and one sample from healthy controls (for is expressed in breast cancer [53] and non-small- each patient a control of the same gender and of simi- cell lung cancer, but less intensely compared to lar age was chosen). Blood samples were centrifuged at prothrombotic factors [54]. Its concentration in 1500 rounds per min (RPM) for 15 min and plasma was collected in aliquots and stored at -20oC. acute leukemia was found to be lower in compari- Enzyme-Linked Immunosorbent Assays (ELISA) son to controls [55]. were standardized for determination of PZ and PAI-1 PAI-1 is a fibrinolysis inhibitor that belongs to plasma levels. These molecules were measured using the family of serine protease inhibitors (SERPIN). commercially available ELISA kits according to manu- High PAI-1 levels are associated with increased facturer’s instructions (HYPHEN Biomed, Paris, France). JBUON 2017; 22(4): 1023 1024 PZ and PAI-1 levels in previously untreated Hodgin lymphoma Their levels before IA ABVD (in fact at diagnosis) were Table 1. Characteristics of patients and controls compared to the corresponding ones
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