A Novel Antithrombotic Mechanism Mediated by the Receptors of the Kallikrein/Kinin and Renin–Angiotensin Systems

Figures

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  Figure 1. The contact activation and kallikrein/kinin systems (KKS) have two mechanisms, whereby they influence thrombosis risk in the intravascular compartment. First, through contact autoactivation of factor XII (XII) to factor XIIa (XIIa), plasma prekallikrein (PK) is activated to plasma kallikrein (Kal) that then reciprocally activates XII and amplifies each other’s activation. Formed XIIa activates factor XI to factor XIa (XIa) that leads to thrombin formation. This pathway occurs in sepsis, adult respiratory distress syndrome, and on mechanical surfaces of devices used in the medical practice. The second pathway for thrombosis risk reduction is through the interaction of the plasma KKS with the renin–angiotensin system (RAS). Formed Kal cleaves bradykinin (BK) from high-molecular weight kininogen (HK), and it binds to the constitutive bradykinin B2 receptor (B2R). It stimulates cells to produce prostacyclin and NO. BK is metabolized by angiotensin-converting enzyme (ACE) that also converts angiotensin I to angiotensin II (AngII). If the angiotensin receptor 2 (AT2R) has more copies than the angiotensin receptor I (not shown), it binds to stimulate prostacyclin and NO. Also, AngII is…

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  Figure 2. Model for vessel wall tissue factor regulation in prekallikrein deficiency. In the absence of plasma prekallikrein (PK), there is reduced bradykinin (BK) and the bradykinin B2 receptor (B2R). This result is also associated with reduced angiotensin-converting enzyme activity (ACE) and the angiotensin receptor 2 (AT2R) with elevation of the G-protein-coupled receptor Mas with normal angiotensin-(1–7) [Ang-(1–7), its natural ligand]. Increased Mas receptor alone is associated with a 1.5- to 2-fold elevation of prostacyclin (PGI2) with increased vessel wall Sirt1 and KLF4 and reduced vessel wall tissue factor (TF). There is no platelet function defect in prekallikrein-deficient platelets. The delayed thrombosis in PK-deficient mice is due to reduced vessel wall TF alone.

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  Figure 3. Mechanisms for thrombosis delay in the bradykinin B2 receptor-deleted mice. In the absence of the bradykinin B2 receptor (B2R), there is increased plasma bradykinin (BK), its ACE breakdown product, BK-(1–5) (RPPGF). There is also increased ACE, angiotensin II (AngII), and angiotensin-(1–7) [Ang-(1–7)]. Elevated AngII and Ang-(1–7) bind to increased angiotensin receptor 2 (AT2R) and Mas to increase prostacyclin (PGI2) levels twofold to threefold above normal. This elevation in plasma PGI2 results in increased vessel wall Sirt1 and KLF4 with reduced TF and a selective platelet function defect. The selective platelet function defect is reduced GPVI activation with normal thrombin- and ADP-induced platelet activation and reduced spreading on collagen and adhesive glycoproteins through β1 integrin binding. The delayed thrombosis in B2R-deficient mice is reduced vessel wall tissue factor a selective platelet function defect of GPVI activation and spreading.

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  Figure 4. The prostacyclin axis-induced thrombosis protection. PK and B2R deficiency produces thrombosis protection through the prostacyclin axis. In the absence of PK or the B2R, there is increased prostacyclin production due to overexpression of the AT2R and/or Mas receptors to compensate for reduced or absent B2R. Prostacyclin induces a graded increase in thrombosis protection. First, at levels up to twofold increased, it effects the vessel wall reducing TF production. Second, at levels up to twofold to threefold increased, it downregulates vessel wall TF and induces a selective platelet function defect of reduced GPVI activation and spreading on collagen- and integrin-binding adhesive glycoproteins. Finally, at levels greater that threefold, prostacyclin produces the overall platelet anesthesia generally recognized with it.