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Background: D-dimer is a fibrin degradation product (FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. Aim: To evaluate the association of D-dimer level with prognosis, disease progression and survival of patients in cases of solid malignancies. Setting and Design: Analytical cross sectional study conducted from February 2021 to February 2023. Materials and Methods: Data regarding 100 solid malignancy cases including their preintervention D-dimer levels and its value at follow up, grading, TNM [Tumor size (T), node (N), and metastases (M)] staging of tumor, disease progression and patient status were recorded. Statistical Analysis: Kaplan–Meier curve and Log Rank. Results: Amplified D-dimer level was noted in 85% cancer cases. 76.3% of oral cancer, 82% of breast cancer, 100% cases of digestive tract and ovarian cancer were presented with high D-dimer level. D-dimer in T1 + T2 stage was statistically lower than the D-dimer level of T3 + T4 stage. (χ2 = 5.40, P = 0.002). Comparison of Lymph node in N0 versus N1 + N2 stage (χ2 = 5.82, P = 0.0001) as well as no metastases stage (Mo) versus M1 stages (χ2 = 3.02, P = 0.003) of solid malignancies had significant difference in D-dimer level. D-dimer increased significantly and linearly with recurrence and advancement of solid malignancy. Dead patient had higher D-dimer than alive patients (t = 3.75, P = 0.0001). Increased D-dimer was associated with elevated mortality (P = 0.023, odd ratio = 3.73, survival coefficient = 1.31 with standard error = 0.578). Conclusion: D-dimer is a promising prognostic biomarker which can predict poor clinical outcomes in cancer patients, cancer recurrence, progression, metastases, poor survival.