What are high molecular weight kininogen and prekallikrein?

High Molecular Weight Kininogen and Prekallikrein: Key Components of the Contact System

High molecular weight kininogen (HK) and prekallikrein (PK) are essential proteins in the kallikrein-kinin system that play crucial roles in bradykinin production, coagulation, and inflammation.

What is High Molecular Weight Kininogen (HK)?

• HK is a multifunctional plasma glycoprotein that occupies a critical position linking inflammation and coagulation pathways 1
• It consists of a 65-kDa N-terminal heavy chain (HK-HC) connected to a 45-kDa C-terminal light chain (HK-LC) by a disulfide bridge 1
• HK is encoded by the KNG1 gene located on chromosome 3, which produces both high molecular weight kininogen and low molecular weight kininogen through alternative splicing 2
• HK functions as a cofactor in the contact activation system of the intrinsic coagulation pathway 3
• When cleaved by plasma kallikrein, HK releases bradykinin, a potent vasodilator peptide responsible for increased vascular permeability and angioedema symptoms 4
• Mutations in the KNG1 gene (such as c.1136T > A; p.Met379Lys) have been identified in patients with hereditary angioedema with normal C1 inhibitor (HAE-nC1INH) 2

What is Prekallikrein (PK)?

• Prekallikrein is a serine protease zymogen (inactive precursor) that circulates in plasma 5
• When activated to plasma kallikrein, it cleaves HK to release bradykinin 4
• PK has a molecular weight of approximately 115,000 Da when isolated, but circulates in plasma primarily as a complex with HK at a molecular weight of 285,000 Da 5
• PK plays a key role in the contact activation system of the intrinsic coagulation pathway 3
• Plasma kallikrein (activated PK) is a critical enzyme that converts HK to bradykinin, contributing to angioedema pathophysiology 4

The HK-PK Complex in Plasma

• PK and HK circulate in plasma as a noncovalently linked complex 5
• This complex formation involves strong binding between PK and HK with an association constant of 3.4 x 10^7 M^-1 6
• The light chain of HK contains the binding site for PK 6
• About 62-83% of plasma PK exists in complex with HK, while 17-38% circulates as free PK 7
• The complex formation enhances the functional and immunologic detection of PK in plasma 7

Role in Pathophysiology

• In hereditary angioedema (HAE), unregulated activity of plasma kallikrein results in excessive bradykinin generation 4
• Bradykinin is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain 4
• Mutations in the KNG1 gene near the cleavage site for kinin production can alter normal cleavage patterns and contribute to angioedema 2
• The kallikrein-kinin system interacts with the complement and intrinsic coagulation pathways 4
• In HAE with C1 inhibitor deficiency, normal regulation of plasma kallikrein activity is impaired, leading to excessive bradykinin production 2

Clinical Significance

• HK and PK are therapeutic targets for treating bradykinin-mediated angioedema 4
• Ecallantide (Kalbitor) is a potent, selective inhibitor of plasma kallikrein that blocks the conversion of HK to bradykinin, thereby treating HAE symptoms 4
• Fresh frozen plasma contains HK and PK, which may potentially worsen angioedema attacks in some cases due to providing additional contact system substrates 2
• Standard angioedema treatments like epinephrine, corticosteroids, and antihistamines are not effective for HAE because they don't affect bradykinin generation or antagonize its effects 2
• Prospective population studies have not found significant associations between plasma HK or PK concentrations and incident coronary heart disease, ischemic stroke, or heart failure 3

Diagnostic Considerations

• Measurement of HK cleavage products can serve as a biomarker for bradykinin release during acute angioedema episodes 2
• Both semi-quantitative (immunoblot) and quantitative (immunoassay) methods have been developed to assess HK cleavage 2
• The presence of a circulating FXII doublet detectable in western blot assays is specific for FXII-Lys/Arg309 variant carriers 2
• Increased spontaneous amidase activity has been proposed as a diagnostic tool for bradykinin-mediated angioedema 2