Plasma kallikrein is an enzyme found in blood plasma, involved in several bodily processes. As a serine protease, it breaks down proteins by cleaving specific peptide bonds. This enzyme is a component of complex systems influencing blood pressure regulation, blood clot formation and breakdown, and inflammatory responses. Its activity is tightly controlled within the body to maintain physiological balance. Research into its actions and regulation provides insights into various health conditions.
Understanding Plasma Kallikrein
Plasma kallikrein originates as an inactive precursor called prekallikrein (Fletcher factor). This precursor is a glycoprotein synthesized in the liver and circulates in the blood as a single polypeptide chain, often bound to high molecular weight kininogen (HMWK). Prekallikrein activates into plasma kallikrein primarily through activated factor XII (FXIIa), which cleaves a specific Arg-Ile bond within the prekallikrein molecule.
Once activated, plasma kallikrein consists of two chains (heavy and light) held together by a disulfide bond. The heavy chain contains four tandem “apple domains” and contributes to the enzyme’s pro-coagulant activity. The light chain contains the active site, similar to the trypsin family of serine proteases.
How Plasma Kallikrein Works in the Body
Plasma kallikrein exerts its physiological effects largely through its involvement in the Kallikrein-Kinin System (KKS). In this system, plasma kallikrein cleaves high molecular weight kininogen (HMWK) to release bradykinin. Bradykinin is a potent peptide that causes vasodilation, widening blood vessels and helping regulate blood pressure. This action contributes to a temporary decrease in blood pressure and can increase vascular permeability, allowing fluid to move from blood vessels into surrounding tissues.
Increased vascular permeability is a characteristic feature of inflammation, facilitating the movement of immune cells and other substances to the site of injury or infection. Bradykinin also interacts with specific receptors, primarily bradykinin B2 receptors, to mediate these effects, including the release of inflammatory cytokines like IL-1, IL-2, IL-6, and IL-8, and the contraction of non-vascular smooth muscle.
Beyond its role in the KKS, plasma kallikrein is also involved in the intrinsic pathway of blood coagulation, which leads to clot formation. In this pathway, plasma kallikrein can activate factor XII, setting off a cascade that ultimately leads to thrombin generation and fibrin clot formation. Recent research also suggests plasma kallikrein can directly activate Factor IX, a component of the coagulation cascade, independent of Factor XI. This pathway suggests a broader role for plasma kallikrein in initiating and amplifying coagulation.
Plasma kallikrein also plays a part in fibrinolysis, the process by which blood clots are broken down. It activates plasminogen, the inactive precursor of plasmin, into its active form. Plasmin is the primary enzyme responsible for cleaving the fibrin mesh of a blood clot, leading to its dissolution. Its contribution to fibrinolysis helps clear clots.
Plasma Kallikrein and Health Conditions
Dysregulation of plasma kallikrein activity can contribute to various health conditions. A prominent example is Hereditary Angioedema (HAE), a rare genetic disorder characterized by recurrent swelling episodes in various body parts, including the face, extremities, gastrointestinal tract, and airway. Most HAE cases involve a deficiency or dysfunction of C1-esterase inhibitor (C1-INH), a natural inhibitor of plasma kallikrein. Without sufficient C1-INH, plasma kallikrein becomes overactive, leading to excessive high molecular weight kininogen cleavage and uncontrolled bradykinin levels. This overproduction of bradykinin causes increased vascular permeability and fluid leakage into tissues, resulting in characteristic swelling attacks.
Plasma kallikrein also has implications in other systemic conditions, such as sepsis and disseminated intravascular coagulation (DIC). In sepsis, a severe systemic inflammatory response to infection, the kallikrein-kinin system can activate. This activation can contribute to widespread inflammation and coagulation abnormalities in septic patients. In DIC, characterized by widespread coagulation system activation leading to both clot formation and bleeding, plasma kallikrein’s procoagulant and profibrinolytic activities can be altered, further complicating the disease.
Regulating Plasma Kallikrein
The body maintains tight control over plasma kallikrein activity through various natural inhibitors. The most well-known is C1-esterase inhibitor (C1-INH), a protein that directly inhibits plasma kallikrein, activated factor XII (FXIIa), and factor XIa. C1-INH prevents excessive activation of the kallikrein-kinin system, limiting bradykinin production and preventing unwarranted inflammation and swelling.
Another significant plasma inhibitor of kallikrein is alpha-2-macroglobulin (α2M). This large protein can bind to and inhibit plasma kallikrein, reducing its enzymatic activity and blocking its effects on vascular permeability.
Understanding plasma kallikrein’s regulation has led to therapeutic interventions, particularly for hereditary angioedema. HAE treatments often involve C1-INH replacement therapies, which directly supplement the deficient or dysfunctional inhibitor, restoring control over plasma kallikrein activity. Additionally, specific plasma kallikrein inhibitors like ecallantide, lanadelumab, and berotralstat have been developed. These medications directly target and inhibit plasma kallikrein, reducing bradykinin production and preventing or treating HAE attacks.