Ticks provide insight into human coagulation

If you want to identify novel anticoagulant mechanisms, you should ask the experts: hemovores. In this issue of Blood, De Paula and colleagues delineate the unique mechanism by which the tick salivary anticoagulant Ixolaris inhibits the initiation of clotting, by blocking the tissue factor (TF)/factor VIIa (FVIIa) complex from activating factor X (FX) to FXa (see figure).¹ Ixolaris is a Kunitz-type protease inhibitor, with similarity to human tissue factor pathway inhibitor (TFPI). TFPI inhibits TF/FVIIa through a 2-step mechanism.² First, TF/ FVIIa activates some FXa. Next, the first Kunitz domain (K1) and the second Kunitz domain (K2) of TFPI simultaneously bind the FVIIa and FXa active sites, respectively, forming the inhibitory TF/FVIIa/FXa/TFPI quaternary complex. In this way, TFPI allows some FXa generation before TF/FVIIa inhibition can be achieved. The tick Ixodes scapularis, the common deer tick that is a vector for Lyme disease, utilizes a variation of this mechanism to more completely prevent coagulation in its prey. Its salivary protein Ixolaris forms a similar inhibitory quaternary complex, but, unlike TFPI, does not require FX activation.³ Rather, Ixolaris binds either FX or FXa with similar affinity.