Blocking of plasma kallikrein ameliorates stroke by reducing thromboinflammation

Abstract

PK drives thrombus formation and inflammation via activation of the intrinsic coagulation cascade and the release of BK but appears to be dispensable for hemostasis. Hence, PK inhibition may offer a safe strategy to combat thromboembolic disorders including ischemic stroke.

Antithrombotic potential of the contact activation pathway

“…Reconstitution of the klkb1 −/− with purified plasma PK such that the plasma levels of BK were normalized restores their thrombotic potential to normal. These data are consistent with the findings of f12 −/− and kgn1 −/− mice and indicate that the mechanism that decreases ischemia in klkb1 −/− mice is reduced contact activation-induced thrombin generation 12,41–43 . PK deficiency is associated with reduced contact activation of plasma, but if one lets plasma sit on the bench for 3 h, the contact activation deficiency self corrects 44 .…”

“…Using the silicon rubber-coated nylon monofilament occlusion model in the MCA, klkb1 −/− mice are protected from transient brain ischemia 43 . Reconstitution of the klkb1 −/− with purified plasma PK such that the plasma levels of BK were normalized restores their thrombotic potential to normal.…”

Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke

“…The protective effects against brain infarct volume seen in Klkb1-deficient mice are consistent with previous findings showing that PPK deficiency reduces brain injury caused by permanent MCAO. 15 On the other hand, treatment with a Pkal inhibitor after permanent MCAO did not show any neuroprotective effect as demonstrated by Storini et al 37 The mechanisms that contribute to this neuroprotection by PKal blockade are not fully understood and could involve reduced inflammation and improved vascular perfusion. In addition, intravenous administration of tPA into FXII-deficient mice after stroke reduces intracerebral hemorrhage, edema, and infarct volume.…”

“…11 The role of the KKS on vascular leakage, inflammation, and thrombosis has been demonstrated in animal models of acute stroke. [12][13][14][15] Although the clinical significance of PKal and bradykinin in stroke and its cerebral complications is not yet available, these factors have been identified as clinically significant mediators of vasogenic edema associated with hereditary angioedema. 16,17 In addition, the KKS has been implicated in orolingual angioedema that is associated with tPA-mediated thrombolysis.…”

Thromboinflammation in Stroke Brain Damage

“…The involvement of this system in experimental stroke was recently demonstrated as both genetic and pharmacological inhibition of plasmakallikrein protected mice from ischemic stroke without an increase in infarct-associated hemorrhage. 45 Plasmakallikrein deficiency led to reduced intracerebral thrombosis, enhanced cerebral blood flow, maintenance of the blood-brain barrier, and reduced local inflammation. Thus, by targeting both coagulation and inflammation, plasmakallikrein inhibition may offer a safe strategy for stroke.…”