High-molecular-weight kininogen

High-molecular-weight kininogen (HMWK or HK) is a circulating plasma protein which participates in the initiation of blood

Other names

In the past, HMWK has been called HMWK-kallikrein factor, Flaujeac factor (1975),^[1] Fitzgerald factor (1975),^[2] and Williams-Fitzgerald-Flaujeac factor, - the eponyms being for people first reported to have HMWK deficiency. Its current accepted name is to contrast it with low-molecular-weight kininogen (LMWK) which has a similar function to HMWK in the tissue (as opposed to serum) kinin-kallikrein system.

Structure and function

HMWK is an alpha-globulin with six functional domains. It circulates as a single-chain 626 amino acid polypeptide . The heavy chain contains domains 1, 2, and 3; the light chain, domains 5 and 6. Domain 4 links the heavy and light chains in addition to a

HMWK is one of four proteins which interact to initiate the contact activation pathway (also called the intrinsic pathway) of coagulation: the other three are Factor XII, Factor XI and prekallikrein. HMWK is not enzymatically active, and functions only as a cofactor for the activation of kallikrein and factor XII. It is also necessary for the activation of factor XI by factor XIIa.

HMWK is also a precursor of

HMWK is a strong inhibitor of cysteine proteinases. Responsible for this activity are domains 2 and 3 on its heavy chain.[5]

Cleavage of HMWK by activated factor XI abrogates HMWK's ability to act as a cofactor, establishing negative feedback.^[3][6]

Genetics

The gene for both LMWK and HMWK is located on the 3rd chromosome (3q26).^[7] Alternative splicing of the KNG1 gene transcript gives rise to processed mRNA that differs by what is included from the last two exons of the pre-mRNA.^[8][9] Consequently, HMWK protein differs from LMWK only in having a larger light chain: the heavy chain and bradykinin portions are identical.^[9]

Measurement

Measurement of HMWK is usually done with mixing studies, in which plasma deficient in HMWK is mixed with the patient's sample and a partial thromboplastin time (PTT) is determined. Results are expressed in % of normal - a value under 60% indicates a deficiency.^{[citation needed]}

Clinical features

The existence of HMWK was hypothesised in 1975 when several patients were described with a deficiency of a class of plasma protein and a prolonged bleeding time and PTT.^[10] There is no increased risk of bleeding or any other symptoms, so the deficiency is a trait, not a disease.

References