Robert Flaumenhaft, MD, PhD

2010-03-01

Dr. Flaumenhaft indicated no relevant conflicts of interest.

Decrem Y, Rath G, Blasioli V, et al. Ir-CPI, a coagulation contact phase inhibitor from the tick Ixodes ricinus, inhibits thrombus formation without impairing hemostasis. J Exp Med. 2009;206:2381-95.

The most common adverse effect of currently marketed anti-thrombotic agents is bleeding. This observation is obvious if one assumes that thrombosis and hemostasis are inexorably linked, involving the same coagulation factors and activation pathways. But, what if this assumption is not quite right? Could reagents be identified that interfere with pathological thrombosis but not physiological hemostasis? Evidence from mice deficient in factor XII or factor XI first suggested that this possibility may be a reality. These mice demonstrated impaired thrombus formation following vascular injury but did not suffer a bleeding diathesis.^1,2 Similarly, a modified peptide inhibitor of factor XII reduced infarct size in a model of ischemic brain injury, but it did not affect hemostasis.³

An even more potent contact-phase inhibitor found in the saliva of the tick Ixodes ricinus has now been characterized by Decrem et al. The mRNA for this protein, termed Ixodes ricinus contact-phase inhibitor (Ir-CPI), was identified in the salivary glands of fed, but not unfed, ticks and showed sequence similarity to tissue factor pathway inhibitor (TFPI).⁴ Recombinant Ir-CPI bound to human contactphase factors (FXIIa, FXIa, and kallikrein) and inhibited their activity. Coagulation studies showed that Ir-CPI prolonged the aPTT sevenfold, but it had no effect on PT, thrombin time, or platelet function. When infused into mice, Ir-CPI conferred a survival advantage in a model of collagen- and epinephrine-induced pulmonary embolism. Infusion of Ir-CPI also resulted in decreased thrombus size in an IVC ligation model, in which thrombus formation was initiated using FeCl₃. Ir-CPI inhibited rose bengal-induced thrombus formation in dorsal skin flap arterioles. In contrast, Ir-CPI failed to affect bleeding time in a standard tail-transection hemostasis model. These observations indicate that Ir-CPI inhibits both venous and arterial thrombus formation without significantly affecting hemostasis.

The Holy Grail of antithrombotic therapy is to prevent pathological thrombosis without increasing the risk of bleeding. Previous studies using mice deficient in factor XI or XII demonstrated that loss of these factors was protective against thrombosis but did not result in excessive bleeding. Such observations initiated the concept that inhibition of contact-phase proteases could lead to safer antithrombotics. The discovery that a tick protein acts as a contact-phase inhibitor and prevents thrombus formation without affecting bleeding time further supports this notion. The promise of this approach for antithrombotic therapy is somewhat tempered by the fact that current animal models of hemostasis are limited and that studies evaluating the incidence of thrombosis in factor XI- and factor XII-deficient patients do not unequivocally demonstrate a protective effect. Human trials will be required to determine whether contact-phase inhibitors replicate the intriguing observations in animal models demonstrating efficient inhibition of thrombosis without increased bleeding.

1. Renné T, Pozgajová M, Grüner S, et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med. 2005;202:271-81.
2. Wang X, Smith PL, Hsu MY, et al. Effects of factor XI deficiency on ferric chloride-induced vena cava thrombosis in mice. J Thromb Haemost. 2006;4:1982-88.
3. Kleinschnitz C, Stoll G, Bendszus M, et al. Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis. J Exp Med. 2006;203:513-18.
4. Leboulle G, Rochez C, Louahed J, et al. Isolation of Ixodes ricinus salivary gland mRNA encoding factors induced during blood feeding. Am J Trop Med Hyg. 2002;66:225-33.

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