Decreased Thrombin Generation Potential in Lymphoma Patients is associated with Increased D‐dimer, CRP, vWF and TNF‐α. Interrelationship between Thrombogenesis and Inflammation

Abstract

IntroductionInflammation and other vascular factors contribute to the pathogenesis of thrombotic complications in lymphoma patients. Biomarkers of hemostatic activation, vascular dysfunction and inflammation are upregulated in lymphoma. It has been reported that thrombin generation and inflammatory biomarkers are increased in cancer while the thrombin generation potential is decreased. This study compares the thrombin generation potential and its relevance to the generation of various biomarkers of hemostatic activation process and inflammatory responses.Materials and MethodCitrated blood samples from 90 patients with confirmed diagnosis of non‐Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) and Chronic lymphocytic leukemia/Small lymphocytic lymphoma (CLL/SLL) were collected from University of Belgrade Clinic, Belgrade, Serbia. 50 samples of normal human plasma (NHP) was obtained from George King Biomedical (Overland park, KS). Thrombin generation studies were carried out using a commercially available a kinetic system. Thrombin generation parameters such as peak thrombin (PT), lag time (LT) and area under the curve (AUC) were compiled. Plasma levels of D‐Dimer, CRP, vWF and TNF‐α were measured by using commercially available Sandwich ELISA assays. Results were compiled in terms of mean ± SD. Correlation analysis were carried out by using Prism, Graphpad.ResultsOn a cumulative basis, lymphoma patients showed an increase in lag time (2.9 ± 1.17) in comparison to the NHP (2.7± 0.61). The peak thrombin levels was decreased (119.0 ± 46.2) in the lymphoma patients in comparison to NHP (159.7 ± 31.1). The AUC was decreased (670.2 ± 290.01) in the lymphoma patients in comparison to NHP (700.9 ± 198.0). When the lymphoma patients were sub grouped, peak thrombin levels were similar in HL (129.9), NHL (114.7) and CLL (127.4) and were decreased compared to NHP (159.7). However the AUC was increased in the HL (769), decreased in NHL (642.4) and was comparable for CLL (715.4) compared to NHP (700.9). Lymphoma patients also exhibited elevated levels of D‐Dimer (878 ± 1205 ng/ml) in comparison to NHP (280 ng/ml), CRP (15.2 ± 26.6 ug/ml) in comparison to NHP (0.9 ug/ml), vWF (271.8 ± 189.7 %) in comparison to NHP (122%) and TNF‐α (16.4 ± 20.64 pg/ml) in comparison to NHP (4.2 pg/ml). In the HL group D‐Dimer and CRP correlated well with AUC and PT, in this group vWF also showed a good correlation with PT. In the NHL group, CRP correlated well with LT.ConclusionLymphoma patients represent a heterogenous group in which both the hypercoagulable state and inflammatory responses simultaneously occur as evident by increase in D‐Dimer and inflammatory biomarkers. The decrease in thrombin generation potential in these patients may be due to the consumption of prothrombin and other coagulation factors. Wide variations in circulating levels of various biomarkers and thrombin generation parameters between various lymphoma groups are noted. Profiling of thrombin generation and inflammatory biomarkers may be helpful in thrombotic risk stratification of lymphoma patients and their anti‐thrombotic management.