ecallantide and Cerebral-Hemorrhage

Plasma prekallikrein is the liver-derived precursor of the trypsin-like serine protease plasma kallikrein (PK) and circulates in plasma bound to high molecular weight kininogen. The zymogen is converted to PK by activated factor XII. PK drives multiple proteolytic reaction cascades in the cardiovascular system such as the intrinsic pathway of coagulation, the kallikrein-kinin system, the fibrinolytic system, the renin-angiotensin system and the alternative complement pathway. Here, we review the biochemistry and cell biology of PK and focus on recent in vivo studies that have established important functions of the protease in procoagulant and proinflammatory disease states. Targeting PK offers novel strategies not previously appreciated to interfere with thrombosis and vascular inflammation in a broad variety of diseases.

Topics: Animals; Aprotinin; Blood Coagulation; Bradykinin; Cerebral Hemorrhage; Complement System Proteins; Cysteine; Diabetic Retinopathy; Disulfides; Factor XIIa; Fibrinolysis; Hemostasis; Humans; Inflammation; Kallikrein-Kinin System; Kallikreins; Kinins; Mice; Oligonucleotides, Antisense; Peptides; Plasma Kallikrein; Protein Structure, Tertiary; Proteolysis; Renin-Angiotensin System; Signal Transduction; Thrombosis; Trypsin

Plasma kallikrein (PKa) has been implicated in contributing to hemorrhage following thrombolytic therapy; however, its role in spontaneous intracerebral hemorrhage is currently not available. This report investigates the role of PKa on hemorrhage and hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were fed with a high salt-containing stroke-prone diet to increase blood pressure and induce intracerebral hemorrhage. The roles of PKa on blood pressure, hemorrhage, and survival in SHRSP were examined in rats receiving a PKa inhibitor or plasma prekallikrein antisense oligonucleotide (PK ASO) compared with rats receiving control ASO. Effects on PKa on the proteolytic cleavage of atrial natriuretic peptide (ANP) were analyzed by tandem mass spectrometry. We show that SHRSP on high-salt diet displayed increased levels of PKa activity compared with control rats. Cleaved kininogen was increased in plasma during stroke compared to SHRSP without stroke. Systemic administration of a PKa inhibitor or PK ASO to SHRSP reduced hemorrhage and blood pressure, and improved neurological function and survival compared with SHRSP receiving control ASO. Since PKa inhibition was associated with reduced blood pressure in hypertensive rats, we investigated the effects of PKa on the cleavage of ANP. Incubation of PKa with ANP resulted in the generation fragment ANP

Topics: Animals; Atrial Natriuretic Factor; Blood Pressure; Cerebral Hemorrhage; Hypertension; Plasma Kallikrein; Rats; Rats, Inbred SHR; Stroke

Hematoma expansion (HE) aggravates brain injury after intracerebral hemorrhage (ICH) and hypertension is a key contributor to HE. Plasma kallikrein (PK) is involved in hemorrhagic transformation in ischemic stroke mice. This study was conducted to explore the role of PK in HE in hypertensive ICH.. Hypertension was achieved by continuous infusion of angiotensin II (Ang II) with an osmotic pump in C57BL/6 mice. ICH was achieved by stereotactic intrastriatal injection of blood. PK-specific antibody and platelet glycoprotein VI (GPVI) agonists were administered to intervene in hematoma expansion. The hematoma volume was indicated by the erythrocyte components hemoglobin and carbonic anhydrase-1 in the ipsilateral brain hemisphere.. Ang II-induced hypertensive mice showed enhanced hematoma expansion and worsened neurologic deficits after ICH modeling. Moreover, intrastriatal injection of blood from Ang II-treated mice into normal mice increased the area of secondary hemorrhage more than blood from untreated mice. Mechanistically, elevated PK was found in Ang II-infused mice whereas, inhibition of PK and administration of the GPVI agonist convulxin decreased hematoma expansion and improved neurologic deficits after ICH.. These findings suggest that PK inhibition and GPVI agonist treatment might serve as potential methods to intervene in HE after ICH.

Topics: Angiotensin II; Animals; Blood Pressure; Cerebral Hemorrhage; Crotalid Venoms; Disease Models, Animal; Hypertension; Lectins, C-Type; Male; Mice; Plasma Kallikrein; Treatment Outcome

Thrombolytic therapy using tissue plasminogen activator (tPA) in acute stroke is associated with increased risks of cerebral hemorrhagic transformation and angioedema. Although plasma kallikrein (PKal) has been implicated in contributing to both hematoma expansion and thrombosis in stroke, its role in the complications associated with the therapeutic use of tPA in stroke is not yet available. We investigated the effects of tPA on plasma prekallikrein (PPK) activation and the role of PKal on cerebral outcomes in a murine thrombotic stroke model treated with tPA. We show that tPA increases PKal activity in vitro in both murine and human plasma, via a factor XII (FXII)-dependent mechanism. Intravenous administration of tPA increased circulating PKal activity in mice. In mice with thrombotic occlusion of the middle cerebral artery, tPA administration increased brain hemorrhage transformation, infarct volume, and edema. These adverse effects of tPA were ameliorated in PPK (Klkb1)-deficient and FXII-deficient mice and in wild-type (WT) mice pretreated with a PKal inhibitor prior to tPA. tPA-induced brain hemisphere reperfusion after photothrombolic middle cerebral artery occlusion was increased in Klkb1

Topics: Administration, Intravenous; Angioedema; Animals; Cerebral Hemorrhage; Disease Models, Animal; Factor XII; Fibrinolytic Agents; Gene Expression; Humans; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Plasma Kallikrein; Stroke; Thrombolytic Therapy; Thrombosis; Tissue Plasminogen Activator

Hyperglycemia is associated with greater hematoma expansion and poor clinical outcomes after intracerebral hemorrhage. We show that cerebral hematoma expansion triggered by intracerebral infusion of autologous blood is greater in diabetic rats and mice compared to nondiabetic controls and that this augmented expansion is ameliorated by plasma kallikrein (PK) inhibition or deficiency. Intracerebral injection of purified PK augmented hematoma expansion in both diabetic and acutely hyperglycemic rats, whereas injection of bradykinin, plasmin or tissue plasminogen activator did not elicit such a response. This response, which occurs rapidly, was prevented by co-injection of the glycoprotein VI agonist convulxin and was mimicked by glycoprotein VI inhibition or deficiency, implicating an effect of PK on inhibiting platelet aggregation. We show that PK inhibits collagen-induced platelet aggregation by binding collagen, a response enhanced by elevated glucose concentrations. The effect of hyperglycemia on hematoma expansion and PK-mediated inhibition of platelet aggregation could be mimicked by infusing mannitol. These findings suggest that hyperglycemia augments cerebral hematoma expansion by PK-mediated osmotic-sensitive inhibition of hemostasis.

Topics: Animals; Blood-Brain Barrier; Brain; Cerebral Hemorrhage; Diabetes Mellitus, Experimental; Hematoma; Hyperglycemia; Injections, Intraventricular; Mice; Mice, Inbred C57BL; Plasma Kallikrein; Plasminogen; Platelet Aggregation; Rats; Rats, Sprague-Dawley