Contact system activation in disseminated intravascular coagulation: activities of prekallikrein and high-molecular-weight kininogen are significant risk factors

2022 ◽  
Author(s):  
Sooyong Park ◽  
Ja-Yoon Gu ◽  
Hyun Kyung Kim
Keyword(s):  
Risk Factors ◽  
Molecular Weight ◽  
High Molecular Weight ◽  
Disseminated Intravascular Coagulation ◽  
Significant Risk ◽  
Contact System ◽  
High Molecular Weight Kininogen ◽  
Intravascular Coagulation ◽  
System Activation

High Molecular Weight Kininogen Is Cleaved by FXIa at Three Sites: Arg409-Arg410, Lys502-Thr503 and Lys325-Lys326

2000 ◽  
Vol 83 (05) ◽  
pp. 709-714 ◽  
Author(s):  
T. Mauron ◽  
B. Lämmle ◽  
W. A. Wuillemin
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Coagulation Factor ◽  
Cleavage Sites ◽  
High Molecular Weight Kininogen ◽  
Surface Binding ◽  
Amino Acid Sequence Analysis ◽  
Sds Page ◽  
System Activation

SummaryWe investigated the cleavage of high molecular weight kininogen (HK) by activated coagulation factor XI (FXIa) in vitro. Incubation of HK with FXIa resulted in the generation of cleavage products which were subjected to SDS-Page and analyzed by silverstaining, ligandblotting and immunoblotting, respectively. Upon incubation with FXIa, bands were generated at 111, 100, 88 kDa on nonreduced and at 76, 62 and 51 kDa on reduced gels. Amino acid sequence analysis of the reaction mixtures revealed three cleavage sites at Arg409-Arg410, at Lys502-Thr503 and at Lys325-Lys326. Analysis of HK-samples incubated with FXIa for 3 min, 10 min and 120 min indicated HK to be cleaved first at Arg409-Arg410, followed by cleavage at Lys502-Thr503 and then at Lys325-Lys326.In conclusion, HK is cleaved by FXIa at three sites. Cleavage of HK by FXIa results in the loss of the surface binding site of HK, which may constitute a mechanism of inactivation of HK and of control of contact system activation.

scholarly journals Treatment of invasive streptococcal infection with a peptide derived from human high-molecular weight kininogen

Blood ◽  
2009 ◽  
Vol 114 (2) ◽  
pp. 444-451 ◽  
Author(s):  
Sonja Oehmcke ◽  
Oonagh Shannon ◽  
Maren von Köckritz-Blickwede ◽  
Matthias Mörgelin ◽  
Adam Linder ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Multiorgan Failure ◽  
Medical Problem ◽  
Contact System ◽  
Lung Damage ◽  
High Molecular Weight Kininogen ◽  
Inflammatory Reactions ◽  
Disturbed Microcirculation ◽  
Sepsis And Septic Shock

Abstract Sepsis and septic shock remain an important medical problem, emphasizing the need to identify novel therapeutic opportunities. Hypovolemic hypotension, coagulation dysfunction, disturbed microcirculation, and multiorgan failure resulting from vascular leakage are often observed in these severe conditions. In the present study, we find that HKH20, a peptide derived from human high molecular weight kininogen (HK), down-regulates inflammatory reactions caused by Streptococcus pyogenes in a mouse model of sepsis. HK is a component of the pro-inflammatory and pro-coagulant contact system. Activation of the contact system in the bloodstream by S pyogenes leads to massive tissue damage in the lungs of the infected mice, which eventually results in the death of the animals. HKH20 inhibits activation of the contact system and protects mice with invasive S pyogenes infection from lung damage. In combination with clindamycin treatment, the peptide also significantly prolongs the survival of infected mice.

scholarly journals Antifungal Activities of Peptides Derived from Domain 5 of High-Molecular-Weight Kininogen

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Andreas Sonesson ◽  
Emma Andersson Nordahl ◽  
Martin Malmsten ◽  
Artur Schmidtchen
Keyword(s):  
Molecular Weight ◽  
Antifungal Activity ◽  
High Molecular Weight ◽  
Clinical Manifestations ◽  
Contact System ◽  
Peptide Fragments ◽  
High Molecular Weight Kininogen ◽  
Fungal Cell ◽  
Cutaneous Infections ◽  
Modified Peptides

In both immunocompromised and immunocompetent patients, Candida and Malassezia are causing or triggering clinical manifestations such as cutaneous infections and atopic eczema. The innate immune system provides rapid responses to microbial invaders, without requiring prior stimulation, through a sophisticated system of antimicrobial peptides (AMPs). High molecular weight kininogen (HMWK) and components of the contact system have previously been reported to bind to Candida and other pathogens, leading to activation of the contact system. A cutaneous Candida infection is characterized by an accumulation of neutrophils, leading to an inflammatory response and release of enzymatically active substances. In the present study we demonstrate that antifungal peptide fragments are generated through proteolytic degradation of HMWK. The recombinant domain 5 (rD5) of HMWK, D5-derived peptides, as well as hydrophobically modified D5-derived peptides efficiently killed Candida and Malassezia. Furthermore, the antifungal activity of modified peptides was studied at physiological conditions. Binding of a D5-derived peptide, HKH20 (His479-His498), to the fungal cell membrane was visualized by fluorescence microscopy. Our data disclose a novel antifungal activity of D5-derived peptides and also show that proteolytic cleavage of HMWK results in fragments exerting antifungal activity. Of therapeutic interest is that structurally modified peptides show an enhanced antifungal activity.

Bacterial Expression of Biologically Active High Molecular Weight Kininogen Light Chain

1992 ◽  
Vol 67 (04) ◽  
pp. 428-433 ◽  
Author(s):  
Satya P Kunapuli ◽  
Raul A DeLa Cadena ◽  
Robert W Colman
Keyword(s):  
Molecular Weight ◽  
Human Plasma ◽  
High Molecular Weight ◽  
Light Chain ◽  
Specific Activity ◽  
Bacterial Expression ◽  
Contact System ◽  
Biologically Active ◽  
High Molecular Weight Kininogen ◽  
Single Chain

SummaryHuman high molecular weight kininogen (HK), a single chain plasma glycoprotein, serves as a cofactor in the contact system of blood coagulation. After cleavage by human plasma kallikrein, the nonapeptide bradykinin is released. The HK light chain (LC) contains coagulant activity, which requires both the ability to bind the contact system zymogens, prekallikrein and factor XI, and the ability to interact with negatively charged surfaces. Since bacterial expression might not be successful if carbohydrate was required for activity, we evaluated that possibility by incubating plasma HK with endoglycosydase F. Although the procedure removed detectable N-linked carbohydrate, no change in specific activity occurred. We then developed a bacterial expression system to produce recombinant HK LC. The cDNA coding for the HK LC was prepared by polymerase chain reaction (PCR), digested with restriction enzymes EcoRI and PstI, and introduced into the bacterial expression vector pKK223-3. E. coli harboring this recombinant plasmid (pSKl) expressed HK LC upon induction with isopropylthio-galactoside (IPTG). The recombinant protein (27 kDa), when transferred onto a PVDF membrane, was recognized by monospecific polyclonal anti-HK LC-antibodies. The recombinant HK LC was purified by heparin agarose affinity chromatography to homogeneity and found to have a specific activity of 28 coagulant units per mg protein, similar to the specific activity of the LC derived by proteolytic digestion of human plasma HK. We conclude: 1) The HK LC synthesized in bacteria is biologically active, and 2) the 40% carbohydrate content of the HK LC is not required for its cofactor activity.

scholarly journals Plasma thromboplastin antecedent (PTA, factor XI): a specific and sensitive radioimmunoassay

Blood ◽  
1977 ◽  
Vol 50 (3) ◽  
pp. 377-385 ◽  
Author(s):  
H Saito ◽  
GH Jr Goldsmith
Keyword(s):  
Molecular Weight ◽  
Human Plasma ◽  
High Molecular Weight ◽  
Disseminated Intravascular Coagulation ◽  
Hepatic Cirrhosis ◽  
Rabbit Antiserum ◽  
Clotting Factor ◽  
High Molecular Weight Kininogen ◽  
Factor Xi ◽  
Normal Adults

Abstract A specific, sensitive, and reproducible radioimmunoassay for human plasma thromboplastin antecedent (PTA, factor XI) has been developed with purified PTA and monospecific rabbit antiserum. Precise measurements of PTA antigen were possible for concentrations as low as 0.3% of that in normal pooled plasma. Normal plasma contained approximately 6 microgram PTA/ml. A good correlation (correlation coefficient 0.68) existed between the PTA procoagulant assays and radioimmunoassays among 50 normal adults (25 males and 25 females). PTA antigen was markedly reduced in plasma of 13 patients with congenital homozygous PTA deficiency (range less than 0.003–0.128 U/ml) and 9 patients with hepatic cirrhosis (0.35+/-0.17 U/ml), but was normal in those of 9 patients under treatment with warfarin, 8 patients with disseminated intravascular coagulation and 16 patients with other congenital clotting factor abnormalities, including prekallikrein deficiency (Fletcher trait) and high molecular weight kininogen deficiency (Fitzgerald trait).

Fibrinolysis and the Contact System: A Role for Factor XI in the Down-Regulation of Fibrinolysis

1999 ◽  
Vol 82 (08) ◽  
pp. 243-250 ◽  
Author(s):  
Joost Meijers ◽  
Bonno Bouma
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Fibrinolytic System ◽  
Contact System ◽  
Factor Xii ◽  
Charged Surface ◽  
High Molecular Weight Kininogen ◽  
Factor Xi ◽  
Factor Xiia

IntroductionExposure of blood to negatively-charged surfaces, such as collagen, kaolin, or glass, results in the activation of the contact system of the intrinsic pathway of coagulation. Prekallikrein, factor XII, high molecular weight kininogen, and factor XI are the proteins involved in this contact reaction. The assembly of these components on a negatively-charged surface leads to the activation of factor XI, thereby propagating the intrinsic coagulation pathway. Simultaneously, several other reactions occur, such as the activation of factor VII and the initiation of the fibrinolytic system, kinin-forming pathway, and renin-angiotensin pathway.The first step in the contact phase is to bind factor XII to the negatively-charged surface, making it highly susceptible for proteolysis by kallikrein.1-3 Activated factor XII (α-factor XIIa) is formed in a process that may involve autoactivation.4-7 Prekallikrein is bound to high molecular weight kininogen in plasma. High molecular weight kininogen associates with a negatively-charged surface, thereby localizing prekallikrein to the surface. Limited proteolysis by α-factor XIIa converts prekallikrein to kallikrein. Kallikrein can dissociate from the surface and act on surface-bound factor XII at distant sites, thereby propagating the reciprocal cycle.7 Factor XI circulates plasma in a complex with high molcular weight kininogen. High molecular weight kininogen links factor XI to a negatively charged surface where it is activated by surface bound:α-factor XIIa. Although the in vivo, activating, negatively-charged surface is unknown, assembly and activation of the contact system on biological membranes of endothelial cells, platelets, neutrophils, and monocytes can take place, suggesting that these surfaces are the actual activating surfaces in vivo.8 The physiological significance of the contact system in blood coagulation remains unclear, however, because a deficiency of factor XII, prekallikrein, and high molecular weight kininogen does not result in a bleeding disorder. In contrast, patients deficient in factor XI, most common among Ashkenazi Jews, do suffer from variable bleeding abnormalities, especially from tissues with high local fibrinolytic activity (e.g., urinary tract, nose, oral cavity, tonsils).9,10 This suggested that there was an alternative route for the activation of factor XI, and recently, such a route was described.11,12 Thrombin was found to activate factor XI even in the absence of a negatively-charged surface,11-15 and factor XI was shown to play a role in the downregulation of fibrinolysis.16 In this article, the role of the contact system, with an emphasis on factor XI in the regulation of the fibrinolytic system, will be described.

Effect of Heparin on the Activation of Factor XII and the Contact System in Plasma

1991 ◽  
Vol 66 (05) ◽  
pp. 540-547 ◽  
Author(s):  
Robin A Pixley ◽  
Anita Cassello ◽  
Raul A De La Cadena ◽  
Nathan Kaufman ◽  
Robert W Colman
Keyword(s):  
Molecular Weight ◽  
Human Plasma ◽  
High Molecular Weight ◽  
Anticoagulant Therapy ◽  
Human Factor ◽  
Dextran Sulfate ◽  
Contact System ◽  
Factor Xii ◽  
High Molecular Weight Kininogen

SummaryWe examined in purified systems and in human plasma whether heparin serves as a contact system activating compound. Purified human factor XII zymogen was not activated by heparin through an autoactivation mechanism, but was activated in the presence of purified prekallikrein. Zn2+ (12 εM) did not support autoactivation by heparin. The activation of factor XII and the contact system by heparin in plasma anticoagulated with citrate or with hirudin (not chelating ions) was examined by the cleavage of 125I-labeled factor XII and high molecular weight kininogen (HK). Heparin at 1.6 and 16 USP U/ml was not able to produce activation, in contrast to dextran sulfate (20 εg/ml) which supported activation of both factor XII and HK. This study indicates that heparinized plasma does not support activation of the contact system mediated through activation of factor XII. It is not expected that heparin anticoagulant therapy will contribute to activation of the contact system.

Factor XI and Protection of the Fibrin Clot against Lysis – a Role for the Intrinsic Pathway of Coagulation in Fibrinolysis

1998 ◽  
Vol 80 (07) ◽  
pp. 24-27 ◽  
Author(s):  
Peter von dem Borne ◽  
Joost Meijers ◽  
Bonno Bouma
Keyword(s):  
Molecular Weight ◽  
Blood Coagulation ◽  
High Molecular Weight ◽  
Fibrin Clot ◽  
Contact System ◽  
Activate Factor ◽  
Factor Xii ◽  
High Molecular Weight Kininogen ◽  
Intrinsic Pathway ◽  
Factor Xi

IntroducationBlood coagulation is an important mechanism that maintains the integrity of the vascular system to prevent blood loss after injury. The conceptions on the working mechanism of coagulation are based on the waterfall or cascade model, which was already proposed more than 30 years ago, independently by Davie and Ratnoff (1) and MacFarlane (2). Blood coagulation was viewed as a series of linked proteolytic reactions in which zymogens are converted into serine proteases, ultimately leading to the formation of thrombin, which converts soluble fibrinogen into insoluble fibrin. Coagulation was thought to proceed via two pathways, an extrinsic and an intrinsic pathway. Activation of the extrinsic pathway of coagulation occurs by the exposition of tissue factor at the site of injury (3) whereas the intrinsic system is activated after exposure of plasma to an activating surface. Although the in vivo activating surface is unknown, the contact system was believed to play a role in the initiation of the intrinsic pathway. This system consists of factor XII, prekallikrein, high molecular weight kininogen and factor XI. The physiological relevance of the contact system is unclear, since a deficiency of factor XII, prekallikrein or high molecular weight kininogen does not result in a bleeding disorder. In contrast, patients deficient in factor XI, most common among Ashkenazi Jews, do suffer from variable bleeding abnormalities especially from tissues with high local fibrinolytic activity (urinary tract, nose, oral cavity, tonsils) (4, 5). This suggested there was an alternative route for the activation of factor XI, and recently such a route was described (6, 7). Thrombin was found to activate factor XI, even in the absence of a negatively charged surface (6-11), and factor XI was shown to play a role in the protection of the fibrin clot against lysis (9). In plasma the possibility cannot be excluded that the activation of factor XI by thrombin takes place via an intermediary component. Recently, it was shown that meizothrombin was capable of activating factor XI (12).

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