Role of High Molecular Weight Kininogen in Contact Activation

Iwaarden, Freek van; Bouma, Bonno N.

doi:10.1055/s-2007-1003472

Cited by 26 publications

(11 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With generation of factor XIIa in DIC, there is subsequent conversion of prekallikrein to kallikrein and later conversion of high molecular weight kininogen into circulating kinins [88][89][90]. This also leads to increased vascular permeability, hypotension, and shock [3].…”

Section: Consequences Of Systemic Thrombin Activitymentioning

confidence: 99%

Disseminated Intravascular Coagulation

Bick¹,

Arun²

1999

Pathophysiol Haemos Thromb

View full text Add to dashboard Cite

Disseminated intravascular coagulation (DIC) is a complex disorder, with pathophysiology being variable and highly dependent upon the triggering event(s), host response(s) and comorbid conditions. As a result of these complicated interactions, the clinical expression and laboratory findings are varied, thereby affecting the specifics of diagnosis and therapeutic approaches. The highly complex and variable pathophysiology of DIC often results in a lack of uniformity in clinical manifestations, a lack of consensus in the specific appropriate laboratory criteria of diagnosis, and a lack of specific therapeutic modalities. Indeed, recommendations for therapy are often difficult because the morbidity and survival is more dependent on the specific cause of DIC and because the generally used specific therapeutic approaches, which include for example heparin, low-molecular-weight-heparin antithrombin concentrate and protein C concentrate, have never been subjected to objective prospective randomized trials, except antithrombin concentrates. An analysis of the complex and varied pathophysiological events in DIC provide objective guidelines and criteria for the clinical diagnosis, the laboratory diagnosis, and the definition of severity. These data compounded by an understanding of complex and varied pathophysiology can be used for objective evaluation of therapeutic responses and results. DIC is an intermediary mechanism of disease usually seen in association with well-defined clinical disorders. The pathophysiology of DIC serves as an intermediary mechanism in many disease processes, which sometimes remain organ specific. This catastrophic syndrome spans all areas of medicine and presents a broad clinical spectrum that is confusing to many. Most physicians consider DIC to be a systemic hemorrhagic syndrome; however, this is only because hemorrhage is evident and often impressive. Less commonly appreciated is the profound microvascular thrombosis and sometimes, large vessel thrombosis. The hemorrhage is often simple to contend with in patients with fulminant DIC, but it is the small- and large-vessel thrombosis, with impairment in blood flow, ischemia, and associated end-organ damage that usually leads to irreversible morbidity and mortality. In conclusion, the pathophysiological mechanisms, clinical, and laboratory manifestations of DIC are complex in part due to interrelationships within the hemostasis system. Only by clearly understanding these extraordinarily complex pathophysiological interrelationships can the clinician and laboratory scientist appreciate the divergent and wide spectrum of often confusing clinical and laboratory findings in patients with DIC. Many therapeutic decisions to be made are controversial and lack validation. Nevertheless, newer antithrombotic agents, and agents which can block, blunt or modify cytokine activity and the activity of vasoactive substances appear to be of value. The complexity and variable degree of clinical expression suggests that therapy should be individualized depending o...

show abstract

Section: Consequences Of Systemic Thrombin Activitymentioning

confidence: 99%

Disseminated Intravascular Coagulation

Bick¹,

Arun²

1999

Pathophysiol Haemos Thromb

View full text Add to dashboard Cite

show abstract

“…The low-molecular-weight (L-) and high-molecular-weight (H-) kininogens are the major plasma inhibitors of cysteine proteinases [14]. In addition, both kininogens serve as precursors of kinins, and kininogen also participates in the contact phase of blood clotting [5][6][7]. The regions of the two kininogens that constitute the heavy chain after excision of the kinin segment are identical and contain three domains homologous to low-molecular-weight tissue inhibitors of cysteine proteinases, cystatins [1,8].…”

Section: Introductionmentioning

confidence: 99%

Interaction of cysteine proteinases with recombinant kininogen domain 2, expressed in Escherichia coli

et al. 1995

View full text Add to dashboard Cite

The caipain-binding domain 2 of the kininogens, the major plasma inhibitors of cysteine proteinases, was expressed in Escherichia coli. Expression of soluble protein was optimal at 15°C and was augmented by growing the bacteria in sorbitol and betaine. The recombinant domain showed high affinity (Ki 0.3-1 nM) for cathepsin L and papain, and a somewhat lower affinity (Ki~ 15 riM) for caipain. The binding to cathepsin H was substantially weaker, and no inhibition of actinidin and cathepsin B was detected. The affinity for catbepsin L was comparable to that reported for the domain isolated from plasma L-kininogen, whereas the affinities for papain and calpain were about tenfold lower. The latter difference may be due to the recombinant domain being nonglycosylated.

show abstract

“…In human plasma, respectively, 0.9 and 2.7 µ m of high‐ and low‐molecular weight kininogens (HMWK and LMWK) are present, and both are effective inhibitors of cysteine proteinases such as cathepsin L and H (8). The HMWK circulates as a complex with plasma prekallikrein, which upon contact activation gives kallikrein, whose proteolysis of HMWK generates BK (9). Tissue kallikreins differ from plasma kallikrein in molecular weight, isoelectric pH, substrate specificity (LMWK and HMWK) and the formation of Lys 0 ‐BK (4, 10).…”

mentioning

confidence: 99%

“…This folded cyclo (1,9) [Lys 1 ]-BK peptide was highly hypotensive, but elicited little (2.5%) vascular permeability and no myotropic effect (32). More importantly, the lack of a COOH-terminus hindered kininase inactivation, and extended the depressor duration from minutes for BK to hours for cyclo (1,9)…”

mentioning

confidence: 99%

Cyclic and linear bradykinin analogues: implications for B₂ antagonist design

Hsieh

Stewart

1999

The Journal of Peptide Research

View full text Add to dashboard Cite

Bradykinin (BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) antagonists are potentially useful for treating inflammation, pain and severe trauma. To identify what chemical features might promote effective antagonism, we replaced Arg1 and Pro7 with structurally constrained and proteolytic-resistant residues, such as Bip (biphenylalanine), Dip (diphenylalanine) or 2Ind (indane amino acid). To determine which BK folding might lead to favourable interactions with receptors, the effects of cyclo(3,8) vs. cyclo(5,8) analogues were compared. The resulting BK analogues were examined for their agonistic and antagonistic activities in guinea pig ileum, rat uterus and depressor assays. The results suggest that co-planarity of the residue-7 side chain with its backbone NH is important for potent agonism as well as antagonism, and a D-directed side chain is crucial for antagonism. For residue-1 an L-orientation is important, and Dip1 may mimic a folded Arg1 side chain to elicit agonistic activities, with Bip1 mimicking an extended Arg1 side chain to elicit inhibitory activities. However, ileal and uterine receptors appear to prefer differently folded BK. For ileum, a BK conformation in which residues-3 and -8 are proximal to each other, but apart from residue-5, led to improved pA2.

show abstract

Role of High Molecular Weight Kininogen in Contact Activation

Cited by 26 publications

References 41 publications

Disseminated Intravascular Coagulation

Disseminated Intravascular Coagulation

Interaction of cysteine proteinases with recombinant kininogen domain 2, expressed in Escherichia coli

Cyclic and linear bradykinin analogues: implications for B₂ antagonist design

Contact Info

Product

Resources

About

Role of High Molecular Weight Kininogen in Contact Activation

Cited by 26 publications

References 41 publications

Disseminated Intravascular Coagulation

Disseminated Intravascular Coagulation

Interaction of cysteine proteinases with recombinant kininogen domain 2, expressed in Escherichia coli

Cyclic and linear bradykinin analogues: implications for B2 antagonist design

Contact Info

Product

Resources

About

Cyclic and linear bradykinin analogues: implications for B₂ antagonist design