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 blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...

, and in the generation of the vasodilator

bradykinin Bradykinin (BK) (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 hyperpolarizing factor and ...

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. 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. 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 the ''F12'' gene. Struct ...

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

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 pr ...

. 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 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. The process is the opposite of vasoconstriction, ...

is released through positive feedback by

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

Genetics

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

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 Bleeding time is a medical test done on someone to assess their platelets function. It involves making a patient bleed, then timing how long it takes for them to stop bleeding using a stopwatch or other suitable devices. The term template bleedin ...

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