Protamine inhibits tissue factor-initiated extrinsic coagulation

The enhanced extrinsic coagulation in response to inflammation could contri bute to disseminated intravascular coagulation, often manifesting cardiovas cular complications. The complex mechanism remains unclear and effective ma nagement is not well established. The ability of protamine to offset bacter ial endotoxin (LPS)-induced tissue factor (TF)-initiated extrinsic coagulat ion was demonstrated in human peripheral blood monocytes and cultured human leukaemia THP-1 monocytes, which was consistent with the inhibition of rab bit brain thromboplastin (rbTF) procoagulant activity in a cell-free in vit ro model. Protamine significantly prolonged prothrombin time, further confi rming the downregulation of the extrinsic pathway. However, thrombin time r emained unaltered. Chromogenic assays were performed to dissect the extrins ic pathway, identifying inhibitory site(s). Protamine significantly inhibit ed factor VII (FVII) activation but not the dissected FX activation. The am idolytic activities of FVIIa and FXa were unaffected. The inhibited FVII ac tivation in the presence of protamine was confirmed by the diminished FVIIa formation on Western blot analyses. Protamine preferentially inhibited TF- catalysed FVII activation, downregulating the extrinsic cascade. Protamine could be of anticoagulant significance in the management of the extrinsic h ypercoagulation.