The fibrinolytic system is essential for adequate clot degeneration and dissolution. Plasminogen and tissue-type plasminogen activator (tPA) are two principal contributors to the fibrinolytic system. The tPA deficiency could attenuate the capacity to remove excessive clots and could contribute to venous thromboembolism. The laboratory assessment of tPA involves direct measurement of the tPA antigen or activity through enzyme-linked immunosorbent assay. Despite the ambiguous relationship between tPA gene polymorphisms and plasma levels, a comprehensive approach that integrates both laboratory diagnostics and genetic analysis may warrant understanding and effectively managing thromboembolic disorders. Further research is needed to elucidate the implications of tPA deficiency and refine diagnostic strategies that can enhance patient outcomes in the context of thrombotic diseases.