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New research on the anticoagulation properties of tick saliva has answered a long-posed question about early activation of coagulation processes.
After decades of searching, scientists were still unsure what roles factor V and Xa played during the initiation of coagulation, according to Tim Schuijt, PhD, from the Center for Experimental and Molecular Medicine at the University of Amsterdam in the Netherlands, and colleagues.
But the analysis of a protein in tick saliva (P23, renamed TIX-5) showed that it postpones activation of the coagulation system by specifically inhibiting the factor Xa-mediated activation of factor V. And it works in a dose-dependent manner, they reported in the study published online in Circulation: Journal of the American Heart Association.
The results of the study could bring new understanding to how clots are formed, why certain anti-clotting drugs help, and how new drugs could be developed, Schuijt and colleagues said.
It had been thought that factor V was activated only by thrombin or meizothrombin.
"This study has not only identified a novel anticoagulant protein in ticks, but, importantly, the identification of TIX-5's biological target reveals the physiological importance of a pathway not previously described during mammalian coagulation in vivo," wrote Alisa S. Wolberg, PhD, and Maria M. Aleman, PhD, of the University of North Carolina at Chapel Hill, in an accompanying editorial.
The investigators showed that recombinant TIX-5 (tick inhibitor of factor Xa toward factor V) prolongs the lag time to thrombin generation in human and rabbit plasma, as well as in human whole blood.
They also demonstrated that adult ticks fed on rabbits immunized with recombinant TIX-5 weighed significantly less than controls, "indicating that inhibiting TIX-5 prevents the natural anticoagulation mechanism needed for optimal feeding," Wolberg and Aleman noted.
"This simple, but elegant, assay shows for the first time, the relevance of this pathway during coagulation in vivo," the editorialists added.
One of the most widely used anti-clotting medications is warfarin, which has been the sole oral anticoagulant agent on the market for the last 50 years.
Warfarin works by depleting levels of vitamin K, which in turn inhibits a process called carboxylation. Without carboxylation, clotting factors II, VII, IX and X, as well as the regulatory factors protein C, protein S, and protein Z, remain biologically inactive.
The newer class of anticoagulants that has emerged in the last several years has taken advantage of blocking specific processes in the coagulation cascade.
At the end of the coagulation cascade, thrombin jump starts several coagulation-related reactions, including the conversion of soluble fibrinogen to fibrin, which is the backbone of solid clots.
Schuijt and colleagues also found that the presence of fibrinogen was important for factor Xa to activate factor V for the generation of thrombin.
"This underscores the notion that fibrinogen, also referred to as antithrombin I, binds and inhibits thrombin, thereby shifting the role of factor Xa to a crucial factor V activator in plasma," they wrote.
However, TIX-5 was shown to inhibit thrombin generation in the complete absence of fibrinogen, "which indicates that the action of TIX-5 is not dependent but is more efficient in the presence of fibrinogen," researchers wrote.
The investigators used the saliva of the ixodes ticks, which are also known as blacklegged ticks, or deer ticks. They surmised that TIX-5 probably belongs to a larger protein family in ticks.
From the American Heart Association:
- AHA Emerging Science Series: Outcomes of Discontinuing Rivaroxaban Compared with Warfarin in Patients with Nonvalvular Atrial Fibrillation: Analysis from the ROCKET AF Trial
- New Guidelines for the Early Management of Patients with Acute Ischemic Stroke
The study was partially supported by National Institutes of Health. Schuijt had grant support from the Onze Lieve Vrouwe Gasthuis research fund.
The researchers and editorialists reported they had no conflicts of interest.
CirculationSource Reference: Schuijt TJ, et al "Factor Xa activation of factor V is of paramount importance in initiating the coagulation system: Lessons from a tick salivary protein" Circulation 2013; DOI 10.1161/CIRCULATIONAHA.113.003191
CirculationSource Reference: Aleman MM, et al "Tick spit shines a light on the initiation of coagulation" Circulation 2013; DOI: 10.1161/ CIRCULATIONAHA.113.003800.