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

coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a thrombus, blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of co ...

, and in the generation of the vasodilator

bradykinin Bradykinin (BK) (from Greek ''brady-'' 'slow' + ''-kinin'', ''kīn(eîn)'' 'to move') is a peptide that promotes inflammation. It causes arterioles to dilate (enlarge) via the release of prostacyclin, nitric oxide, and endothelium-derived hyperpo ...

via the kallikrein-kinin system. HMWK is inactive until it either adheres to binding proteins beneath an endothelium disrupted by injury, thereby initiating coagulation; or it binds to intact endothelial cells or platelets for functions other than coagulation.

Other names

In the past, HMWK has been called HMWK-kallikrein factor, Flaujeac factor (1975), Fitzgerald factor (1975), 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

disulfide bond In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inor ...

between positions close to the N- and C-termini. The domains contain the following functional sites: *Domain 1 - calcium binding *Domain 2 - cysteine protease inhibition *Domain 3 - cysteine protease inhibition; platelet and endothelial cell binding *Domain 4 - bradykinin generation *Domain 5 - heparin and cell binding; antiangiogenic properties; binding to negatively charged surfaces *Domain 6 - prekallikrein and factor XI binding (amino acids 420 to 510)(histidine rich) HMWK is one of four proteins which interact to initiate the contact activation pathway (also called the intrinsic pathway) of

: the other three are

Factor XII Coagulation factor XII, also known as Hageman factor, is a plasma protein involved in coagulation. It is the zymogen form of factor XIIa (), an enzyme of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by ' ...

Factor XI Factor XI, or plasma thromboplastin antecedent, is the zymogen form of factor XIa, one of the enzymes involved in coagulation. Like many other coagulation factors, it is a serine protease. In humans, factor XI is encoded by ''F11'' gene. Fu ...

and

prekallikrein Prekallikrein (PK), also known as Fletcher factor, is an 85,000 Mr serine protease that complexes with high-molecular-weight kininogen. PK is the precursor of plasma kallikrein, which is a serine protease that activates kinins. PK is cleaved to ...

. HMWK is not enzymatically active, and functions only as a cofactor for the activation of

kallikrein Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein (encoded by ''KLKB1 gene'') has no known paralogue, while tissue kallikrein-related peptidases (''KLKs'') encode a f ...

and factor XII. It is also necessary for the activation of factor XI by factor XIIa. HMWK is also a precursor of

; this

vasodilator Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wal ...

is released through positive feedback by

. Cleavage by kallikein results in the liberation of two peptides, one of which is bradykinin, from HMWK's fourth domain. Cleavage by kallikrein also helps HMWK to optimally function as a coactivator. The cleavage results in a change in the conformation of HMWK that may increase the accessibility of its surface binding domain, which could explain cleaved HMWK's increased affinity for negatively charged surfaces. The resulting severed light and heavy chains remain connected by the aforementioned disulfide bond near the original N- and C-termini. HMWK is a strong inhibitor of cysteine proteinases. Responsible for this activity are domains 2 and 3 on its heavy chain. Cleavage of HMWK by activated factor XI abrogates HMWK's ability to act as a cofactor, establishing negative feedback.

Genetics

The gene for both LMWK and HMWK is located on the 3rd chromosome (3q26).

Alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

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. Consequently, HMWK protein differs from LMWK only in having a larger light chain: the heavy chain and bradykinin portions are identical.

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 The partial thromboplastin time (PTT), also known as the activated partial thromboplastin time (aPTT or APTT), is a blood test that characterizes coagulation of the blood. A historical name for this measure is the Kaolin-cephalin clotting time ...

(PTT) is determined. Results are expressed in % of normal - a value under 60% indicates a deficiency.

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. There is no increased risk of bleeding or any other symptoms, so the deficiency is a trait, not a disease.

References

{{Autacoids Coagulation system Kinin–kallikrein system Cofactors