Soluble endothelial protein C receptor and coagulation parameters as prognostic factors in non‐small cell lung carcinoma

The association between cancer and thrombosis is well known, and the occurrence of thrombotic complications in patients with malignancies commonly correlates with poor prognosis [1]. The protein C pathway is the main natural in vivo anticoagulant mechanism, and abnormalities such as acquired activated protein C (APC) resistance and congenital APC resistance, mostly resulting from the factor V Leiden G1691A mutation, are major risk factors for venous thromboembolism (VTE), with odds ratios (ORs) of 2.5 and 2.0–7.0, respectively [2–4]. Our previous study demonstrated the association of acquired APC resistance (APC resistance without FV Leiden) with VTE in cancer patients [5]. Moreover, high levels of FVIII, FV, FII and FX were found to correlate with acquired APC resistance in cancer patients, which could explain the plasmatic mechanism of thisphenomenon [6]. In addition to its anticoagulant activity in malignancy, APC induces direct cellular effects that could promote cancer cell migration, invasion, and angiogenesis, and inhibit cancer cell apoptosis [7–9]. Another important component of the protein C pathway is the endothelial protein C receptor (EPCR), which binds protein C and enhances the rate of its activation [10]. A soluble form of EPCR (sEPCR) can be detected in plasma, probably resulting from shedding of membrane EPCR. sEPCR binds protein C and APC with similar affinity, and inhibits APC anticoagulant activity by blocking its interaction with negatively charged phospholipids [11]. High levels of sEPCR were found to be associated with the EPCR A6936G polymorphism, and appeared to constitute a moderate risk factor for VTE, with an OR of 1.8 [12]. The aims of this prospective study were to determine a possible prognostic value of hypercoagulable parameters, especially those of the anticoagulant protein C pathway, for the survival of patients with non-small cell lung carcinoma (NSCLC), and to compare them with known predictors, such as gender, weight loss, disease stage, performance status, histological subtype, leukocytosis, anemia, and lactate dehydrogenase (LDH) levels [13]. The study was approved by the Rambam Institutional Review Board (approval number 2092), and by the Israel Ministry of Health (approval number 920051312), and is registered on the NIH ClinicalTrials.gov website (ClinicalTrials.gov ID: NCT00192829). One hundred and two patients with newly diagnosed NSCLC who were referred to the Rambam Oncology Institute were eligible to participate in the study, according to the following criteria: (i) histologically or cytologically confirmed diagnosis of NSCLC; (ii) presence of active malignancy; (iii) no prior malignancy apart from treated basal cell or squamous cell carcinoma of the skin; (iv) no prior chemotherapy or radiotherapy; (v) no major surgery during the last month before investigation; (vi) no anticoagulant therapy during the last month before investigation; (vii) no evidence of active infectious disease; (viii) normal serum bilirubin; (ix) serum transaminases 2.0 times the upper limit of normal; (x) serum creatinine level of 1.5 mg dL ; and (xi) availability of signed informed consent. The patients’ ages ranged between 43 and 90 years (median: 66 years); 77 patients were male. The majority (61%) had stage IIIB or IV disease. First-line therapy included a carboplatin-based combination in most of these patients (78%). Before the start of therapy, blood samples were collected into 3.2% sodium citrate tubes. Fibrinogen and Correspondence: Galit Sarig, Hematology Laboratory, Rambam Health Care Campus, P.O. Box 9602, Haifa 31096, Israel. Tel.: +972 4 8542217; fax: +972 4 8543636. E-mail: g_sarig@rambam.health.gov.il