Tissue factor around dermal vessels has bound factor VII in the absence of injury

Abstract

Summary. Background: ÔIdlingÕ or ongoing low-level activity of the tissue factor (TF) pathway is a postulated mechanism by which the coagulation process can become active without a lag period at sites of injury. Objective: To determine whether TF around cutaneous vessels has bound factor VIIa in the absence of injury, and thus could participate in the idling process. Methods: Immunostaining of mouse skin with antibodies against a 15-residue peptide from the sequence of mouse TF, and against the whole extracellular portion of TF. Results: The whole TF antibody recognized TF in squamous epithelium and around vessels in the dermis. By contrast, the monospecific antibody only recognized TF in the squamous epithelium, but not around vessels. We also found that biotinylated, active siteinhibited FVIIa (FVIIai) bound to tissue sections in the same areas in which TF was recognized by the monospecific antibody (squamous epithelium), but did not bind around vessels. Molecular modeling revealed that FVIIa and FX binding to TF masked a significant part of the surface of the target peptide. Conclusions: In the aggregate, these data are most consistent with the interpretation that TF in perivascular sites has bound FVIIa, even in the absence of any injury. The presence of endogenously bound FVIIa prevents the subsequent binding of the monospecific antibody or exogenous FVIIai to perivascular TF.

The endothelial protein C receptor enhances hemostasis of FVIIa administration in hemophilic mice in vivo

“…Notably, in a study of rhFVIIa secondary prophylaxis in hemophilic patients with inhibitors, patients receiving daily rhFVIIa infusions for 3 months, followed by a 3-month postprophylaxis period, showed clinical benefits even in the postprophylaxis period. 46 Previous mouse studies suggested that rhFVIIa is transported via an EPCR-dependent mechanism to the extravascular space, 18 where it can persist for extended periods of time in complex with TF, 47 potentially preventing minor bleeds before they escalate. Such mechanism may explain the prolonged clinical benefits of rhFVIIa prophylaxis.…”

Long-term expression of murine activated factor VII is safe, but elevated levels cause premature mortality

“…Additionally, hFVIIa activity of 34% has been reported in human lymph fluid that bathes the extravascular space (20). More pertinent to this study, the presence of mFVIIa has previously been demonstrated in the perivascular space outside dermal vessels even in the absence of tissue damage (21).…”

The Nature of the Stable Blood Clot Procoagulant Activities

“…In one view of normal hemostasis, Tf is sequestered outside of blood vessels (12)(13)(14)(15), requiring disruption of blood vessel integrity to exert its effects, and within circulating blood cells, requiring specific signaling events to promote its intravascular expression (16,17). If a sufficient Tf challenge is presented, a full coagulant response follows; if the Tf challenge is insufficient, the procoagulant response is arrested, primarily by the activity of the stoichiometric inhibitor Tf pathway inhibitor (TFPI) (18).…”