Contact with stroke

In this issue of Blood, Langhauser and colleagues report that kininogen knockout mice (KNG^−/−) are protected from stroke induced by transient mechanical occlusion of the middle artery (MCAO).¹  KNG^−/− mice develop smaller infarcts, less neurologic impairment, and exhibit lower mortality than wild-type (WT) mice studied at 24 hours and beyond. Benefit was retained in elderly mice and was conferred through reduction in microvascular thrombosis, preservation of blood-brain-barrier function, and attenuation of inflammation. These are important findings because they provide insight into the pathophysiology of stroke and identify potential novel targets for intervention.

Ischemic stroke remains the one of the most common causes of mortality and protracted morbidity. It is estimated that approximately 750 000 new patients a year in the United States are affected. Notwithstanding extensive investigation, thrombolysis by tissue-type plasminogen activator (tPA) remains the sole US Food and Drug Administration–approved intervention. However, only 3% to 6% of patients with ischemic stroke receive tPA because of delays in medical care, lesion size, and evidence of hemorrhagic transformation that make the risk of intracerebral hemorrhage prohibitive. Moreover, even patients who respond to tPA may be left with significant neurologic defects and risk for recurrent stroke. Thus, there is a clear need for new, more effective, and safer treatments.

This study by Langhauser and colleagues builds on emerging literature, which indicates that components of the contact factor pathway of coagulation, including factor XII, prekallekrein and KNG, the proteolytic product bradykinin (BK), and the BK 2 receptor, are involved in the response to vascular injury, but have less prominent roles in hemostasis. It has been posited that activation of the contact factor pathway in vivo requires higher concentrations of thrombin, found only in pathologic conditions, than does activation of the intrinsic pathway.²  On the other hand, inflammation and tissue injury expose activators of the contact factor pathway found in the extracellular matrix and others released by cell activation or injury, including polyphosphates from platelets, neutrophil serine proteases and nucleosomes, and RNA from degraded cells,^3-5  some seemingly unassociated with activation of factor XI.⁶  This suggests that specific inhibition of KNG-related activities might impede propagation of thrombosis⁷  without potentiating bleeding.

This study also highlights the concept that the pathophysiology of stroke and the sequelae of treatment in this mouse model, as in humans, extend beyond intravascular thrombosis. Neuroprotection after transient MCAO simulates human ischemic stroke treated successfully with tPA. The finding that BK restored deleterious outcomes in KNG^−/− animals and the absence of significant differences in cortical blood flow immediately after reperfusion speaks to the potential contribution of nonhemostatic pathways, including alterations in vascular contractility.^8,9  Within minutes of MCAO, cerebrovascular autoregulation, which matches blood flow to local metabolic needs, is lost, reducing blood flow to ischemic neurons and the penumbra, while diverting flow to surrounding healthy tissue. Local release of glutamate and plasminogen activators from ischemic tissue causes intense activation of N-methyl-d-aspartate and the low-density lipoprotein receptors, which exacerbates loss of adaptive cerebral vasoregulation and leads to neuronal apoptosis.^10,11  Improved outcomes are seen in models of thrombotic and mechanical occlusion when the deleterious effects of plasminogen activators on vascular contractility are blocked without affecting plasminogen activation.^10,11  Such approaches might help dissociate the deleterious effects of plasminogen activators from their salutary effects on fibrinolysis.

This study by Langauser and colleagues also points to the need to better delineate the contribution of inflammation to vascular damage and thrombosis. Generation of cytokines, up-regulation of leukocyte adhesion molecules, leukocyte infiltration and generation of metalloproteinases, reactive oxygen species, and lipid peroxidation, among diverse other factors, enhance ischemic and reperfusion injury and promote clot stability and progression. Attenuating the inflammatory response with activated protein C, cytokine antagonists and inhibitors of cell adhesion have been effective in this model, although the clinical benefits remain modest or uncertain, highlighting the complexity of human stroke.

To the extent that thrombosis is superimposed on vascular injury caused by ischemia, (peri)vascular inflammation, and changes in contractility, among many other factors, it may be possible to intervene proximal to the onset of coagulation, breaking the so far inexorable link between the benefits and risks of antithrombotic therapy. Timing here may be critical. Understanding the most proximal events and the sequence of injury will help to delineate both the targets and the windows of opportunity for preventing vascular and parenchymal damage. Thus, this important study by Langhauser and colleagues should prompt further investigation into the diverse activities of KNG and the other members of this pathway and its implications for novel approaches to mitigate thrombotic occlusion and reperfusion injury.