Plasma kallikrein (PK) is a powerful serine protease enzyme circulating in the blood. PK is synthesized primarily in the liver and circulates as an inactive precursor, prekallikrein, which is converted to its active state when needed. Its function is to cleave specific proteins, activating various cascades within the plasma. PK plays a significant role in regulating vascular function, including the control of inflammation, permeability, and the initiation of blood clotting. This dual activity links the body’s inflammatory response with its coagulation system.
PK’s Central Function: The Kallikrein-Kinin System
Plasma kallikrein’s most well-known function is its central role within the kallikrein-kinin system (KKS), a cascade that produces a potent inflammatory mediator. Active PK cleaves high molecular weight kininogen (HMWK), releasing bradykinin. This small peptide acts locally to regulate tissue responses.
Bradykinin is a powerful agent that affects the circulatory system. It causes vasodilation, relaxing blood vessel walls and increasing blood flow to the affected area. The peptide also significantly increases vascular permeability by widening the gaps between endothelial cells. This allows fluid and immune cells to leak into the surrounding tissue, resulting in localized swelling (edema).
The effects of bradykinin are associated with the classic signs of inflammation, including pain, redness, and heat. The KKS is designed to trigger an immediate, localized response to injury or infection, helping deliver immune components to the site of damage. Plasma kallikrein is a regulator of this acute inflammatory process. Uncontrolled PK activity leads to bradykinin overproduction, which can trigger severe, pathological swelling if regulation is lost.
Initiating Coagulation: PK’s Role in the Contact System
Plasma kallikrein also initiates the contact system, historically known as the intrinsic pathway of blood coagulation. This system activates when blood encounters negatively charged surfaces, such as damaged blood vessel linings. Prekallikrein circulates complexed with HMWK, and this complex binds to these surfaces.
Once bound, prekallikrein is converted into active PK by activated Factor XII (FXIIa). The newly formed PK then cleaves more Factor XII, accelerating its activation in a positive feedback loop. This mutual activation rapidly generates pro-coagulant factors at an injury site.
While the contact system was once considered the primary initiator of physiological blood clotting, its function is now understood to be more complex. Deficiency in PK does not typically cause bleeding disorders, suggesting other pathways are more important for normal hemostasis. PK’s role in the contact system is instead linked to pathological clot formation (thrombosis) under certain conditions. Activation of FXII by PK ultimately leads to Factor XI activation, which feeds into the fibrin-forming coagulation cascade.
Plasma Kallikrein and Disease States
Dysregulation of plasma kallikrein activity is implicated in several serious medical conditions, primarily through the uncontrolled release of bradykinin. The most recognized condition is hereditary angioedema (HAE), characterized by recurrent, severe swelling episodes.
In HAE, a genetic deficiency or dysfunction in the C1 inhibitor protein allows PK to become overactive. This results in excessive bradykinin production, causing life-threatening tissue swelling. Attacks can affect the face, limbs, gastrointestinal tract, and the throat, potentially leading to airway obstruction.
PK is also linked to vascular diseases, especially those involving the blood vessels of the eye. In diabetic retinopathy and diabetic macular edema (DME), the PK-kinin system is abnormally abundant. It contributes to the breakdown of the blood-retinal barrier, causing fluid leakage into the retina, swelling, and impaired vision.
Furthermore, PK’s role in activating the contact system suggests a connection to thrombosis risk. Activation of the contact system is associated with pathological clot formation in inflammatory or cardiovascular states.
Targeting Plasma Kallikrein in Medicine
Plasma kallikrein has emerged as a promising therapeutic target due to its central role in inflammatory and vascular leakage diseases. The primary rationale for intervention is to block the runaway bradykinin production that causes pathological swelling. Inhibiting PK stops the cascade at its source, rather than targeting the downstream effects of bradykinin.
Several classes of PK inhibitors have been developed and approved for treating HAE:
- Monoclonal antibodies, such as lanadelumab, which bind directly to prekallikrein to prevent activation.
- Small-molecule inhibitors, such as berotralstat, which are taken orally to prevent HAE attacks.
- Ecallantide, a protein-based inhibitor, which is used for the acute treatment of attacks by directly inhibiting the active enzyme.
Beyond HAE, targeting PK is actively investigated for other vascular diseases. Inhibitors are being studied in clinical trials as a potential treatment for diabetic macular edema (DME), aiming to reduce the vascular leakage that impairs vision. This strategy offers a focused approach for managing conditions where the body’s regulatory systems have become detrimental.