Transfusion of Packed RBC units (PRBC) in multi-transfused patients often results in a progressive rise in transfusion requirements. To evaluate the procoagulant potential of PRBC in multi-transfused patients. We conducted this prospective cohort study (2020–2022) on multi-transfused patients (n = 31) having a lifetime transfusion of ≧ 4 units PRBCs. Biochemical parameters pre-, post-transfusion (≤ 24 hours) samples included, highly sensitive C reactive protein (HsCRP) for inflammation, LDH for hemolysis, tissue plasminogen activator (tPA), Antithrombin 3 (ATIII) levels as coagulopathy, anti-hemostatic marker and blood microparticle (MPs) (flowcytometry) as Annexin 5+ (AV+) events for TF. We performed Wilcoxon signed rank test (P≤ 0.05), pre-, posttransfusion (P≤ 0.05) and association pre- and posttransfusion by Spearman’s rho correlation coefficient (CC), Linear regression (r2). Median (95% CI; P≤ 0.05) biochemical parameters pre-, posttransfusion, tPA (P = 0.012) and ATIII (P = 0.011) respectively. A pre-, posttransfusion comparison of HsCRP (P = 0.45); LDH (P = 0.87) and MPs (number of events) (P = 0.54) pre-, posttransfusion were not significantly different. We observed a significant CC pre-posttransfusion HsCRP (0.61, P < 0.01); ATIII (0.480, P = 0.006); tPA (0.807, P < 0.01); MPs (0.625, P < 0.004) and r2 tPA (posttransfusion) (dependent variable) tPA (pre-transfusion), ATIII (pre-transfusion) (predictor variables) r2 = 0.85 (P < 0.01); ATIII (posttransfusion) (dependent variable) and ATIII (pre-transfusion); LDH (pre-transfusion) (predictor variable) r2 = 0.45 (P = 0.026). A significant differences tPA, ATIII (pre-posttransfusion) and an association ‘pre-posttransfusion’ may be attributed to PRBC transfusions. tPA levels with corresponding changes in ATIII indicate coagulopathic response, following PRBC transfusions.