Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis

Abstract

Formation of fibrin is critical for limiting blood loss at a site of blood vessel injury (hemostasis), but may also contribute to vascular thrombosis. Hereditary deficiency of factor XII (FXII), the protease that triggers the intrinsic pathway of coagulation in vitro, is not associated with spontaneous or excessive injury-related bleeding, indicating FXII is not required for hemostasis. We demonstrate that deficiency or inhibition of FXII protects mice from ischemic brain injury. After transient middle cerebral artery occlusion, the volume of infarcted brain in FXII-deficient and FXII inhibitor–treated mice was substantially less than in wild-type controls, without an increase in infarct-associated hemorrhage. Targeting FXII reduced fibrin formation in ischemic vessels, and reconstitution of FXII-deficient mice with human FXII restored fibrin deposition. Mice deficient in the FXII substrate factor XI were similarly protected from vessel-occluding fibrin formation, suggesting that FXII contributes to pathologic clotting through the intrinsic pathway. These data demonstrate that some processes involved in pathologic thrombus formation are distinct from those required for normal hemostasis. As FXII appears to be instrumental in pathologic fibrin formation but dispensable for hemostasis, FXII inhibition may offer a selective and safe strategy for preventing stroke and other thromboembolic diseases.

Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation

“…Under severe conditions of tissue damage, the contribution of the contact phase proteins factors XII and XI in blood coagulation was recently demonstrated in thrombosis models, using factor XII-or factor XI-deficient mice (19,26,27), and these data were confirmed here by using an factor XIIa-inhibitor. Under physiological conditions, however, this pathway appears to be dispensable for normal haemostasis.…”

“…Under physiological conditions, however, this pathway appears to be dispensable for normal haemostasis. Whereas the mechanisms of contact phase activation under conditions of severe tissue destruction was not addressed in these studies (19,27), here we provide conclusive evidence that extracellular nucleic acids, particularly RNA, are major cofactors for amplification of blood coagulation. We consider extracellular RNA as our body's ''natural foreign surface'' to serve as procoagulant cofactor in vivo and as a potential target for the treatment of coagulationinduced thrombosis using RNase.…”

Peptide Macrocycle Inhibitor of Coagulation Factor XII with Subnanomolar Affinity and High Target Selectivity

“…Mice deficient in FXII have a much reduced risk of thrombus formation and are protected from experimental ischemic stroke and pulmonary embolism. 5,6 This observation and the limited role of FXII in hemostasis raised the prospect that inhibiting FXIIa could offer an antithrombotic therapy with low bleeding risk. The role of FXII in thrombosis has been confirmed in various experimental animal models, including rat, rabbit and baboon.…”

Targeting coagulation factor XII as a novel therapeutic option in brain trauma

“…In recent years, however, it has been shown that FXII −/− mice are resistant to experimentally induced thrombosis34, 35 and ischemic brain injury 19. As deficiency of FXII is not associated with abnormal hemorrhaging from injury sites (hemostasis) either in patients or in animals,19, 34 inhibition of activated FXII prevented arterial thrombosis and ischemic brain injury20, 36 without affecting hemostasis 20, 37. Our current study shows that FXII is a promising antithrombotic target for the acute treatment of TBI, without increasing the risk of intracranial hemorrhage.…”

“…However, the potential use of conventional anticoagulants in patients with TBI is met with controversy, due to the increased risk of intracerebral hemorrhage 13, 14, 15, 16, 17, 18. Previous studies from our laboratory have shown that both genetic deficiency and pharmacological inhibition of the coagulation factor XII (FXII), a protease that initiates the activation of the intrinsic coagulation cascade, protect mice from ischemic stroke without increasing bleeding tendencies 19, 20. Therefore, we tested whether deficiency or selective inhibition of FXII has a beneficial effect on trauma‐induced microvascular thrombus formation, lesion volume, and functional outcome in TBI.…”