In this study, the blood compatibility of the tip-to-tip coated and flow-optimized extracorporeal circuits were investigated using poly(2-methoxyethylacrylate) PMEA-coated oxygenators and tubing sets. Total protein, human serum albumin, fibrinogen, erythrocyte, leukocyte and platelets loss quantities were analyzed on blood samples withdrawn five different times during cardiopulmonary bypass (CPB) such as: baseline (T1), during CP13 (T2), end of CPB (T3), after protamine injection (T4) and intensive care (T5), no fibrinogen loss was observed for the tip-to-tip coated system. After an operation, protein desorption assays from fiber surfaces of the tip-to-tip coated and flow-optimized extracorporeal circuits showed very little desorption. Less protein desorption was found between sonicated fibers and fiber sample solutions at <0.2 mg/dL and 0.58 mg/dL, respectively. For tip-to-tip coated and flow-optimized extracorporeal system, no platelet aggregation and no erythrocyte, leukocyte losses were observed. Optimized flow path and eliminated straight turns due to integration of exchangers minimized turbulent flows. Larger surface areas of the fibers optimized blood flow speed and improved gentle flow conditions and lowered shear stress. Clinically, no excessive postoperative bleeding was observed by the patients with the tip-to-tip coated system after 24 hours (hemorrhage was 387 mL). The average unit of red blood cell and fresh frozen plasma transfusions were 0.98 and 2.10 units, respectively. Differences in adsorbed HSA on the hollow fiber surfaces were examined by STM which indicated that less protein existed on the sample solution of the non-sonicated fiber surfaces.