Protamine inhibits tissue factor-initiated extrinsic coagulation

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Abstract

The enhanced extrinsic coagulation in response to inflammation could contribute to disseminated intravascular coagulation, often manifesting cardiovascular complications. The complex mechanism remains unclear and effective management is not well established. The ability of protamine to offset bacterial endotoxin (LPS)-induced tissue factor (TF)-initiated extrinsic coagulation was demonstrated in human peripheral blood monocytes and cultured human leukaemia THP-1 monocytes, which was consistent with the inhibition of rabbit brain thromboplastin (rbTF) procoagulant activity in a cell-free in vitro model. Protamine significantly prolonged prothrombin time, further confirming the downregulation of the extrinsic pathway. However, thrombin time remained unaltered. Chromogenic assays were performed to dissect the extrinsic pathway, identifying inhibitory site(s). Protamine significantly inhibited factor VII (FVII) activation but not the dissected FX activation. The amidolytic activities of FVIIa and FXa were unaffected. The inhibited FVII activation 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 hypercoagulation.

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