High-molecular-weight kininogen (HMWK or HK) is a circulating plasma protein which participates in the initiation of blood coagulation, and in the generation of the vasodilator bradykinin 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.
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 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 a strong inhibitor of cysteine proteinases. Responsible for this activity are domains 2 and 3 on its heavy chain.
The gene for both LMWK and HMWK is located on the 3rd chromosome (3q26).
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.
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.
- Wuepper KD, Miller DR, Lacombe MJ (Dec 1975). "Flaujeac trait. Deficiency of human plasma kininogen". The Journal of Clinical Investigation. 56 (6): 1663–72. PMC . PMID 127805. doi:10.1172/JCI108248.
- Waldmann R, Abraham JP, Rebuck JW, Caldwell J, Saito H, Ratnoff OD (Apr 1975). "Fitzgerald factor: a hitherto unrecognised coagulation factor". Lancet. 1 (7913): 949–51. PMID 48123. doi:10.1016/s0140-6736(75)92008-5.
- Stefan Offermanns, Walter Rosenthal (2008). Encyclopedia of Molecular Pharmacology. Springer. pp. 673–. ISBN 978-3-540-38916-3. Retrieved 11 December 2010.
- Higashiyama S, Ohkubo I, Ishiguro H, Kunimatsu M, Sawaki K, Sasaki M (Apr 1986). "Human high molecular weight kininogen as a thiol proteinase inhibitor: presence of the entire inhibition capacity in the native form of heavy chain". Biochemistry. 25 (7): 1669–75. PMID 3635411. doi:10.1021/bi00355a034.
- Fong D, Smith DI, Hsieh WT (Jun 1991). "The human kininogen gene (KNG) mapped to chromosome 3q26-qter by analysis of somatic cell hybrids using the polymerase chain reaction". Human Genetics. 87 (2): 189–92. PMID 2066106. doi:10.1007/BF00204179.
- Colman RW, Bagdasarian A, Talamo RC, Scott CF, Seavey M, Guimaraes JA, Pierce JV, Kaplan AP (Dec 1975). "Williams trait. Human kininogen deficiency with diminished levels of plasminogen proactivator and prekallikrein associated with abnormalities of the Hageman factor-dependent pathways". The Journal of Clinical Investigation. 56 (6): 1650–62. PMC . PMID 1202089. doi:10.1172/JCI108247.