Mechanisms of Human Blood VII Activation in Plasma During Contact Activation, Clotting and Exposure to Cold

1979 ◽  
Author(s):  
U. Seligsohn ◽  
B. østerud ◽  
S.F. Brown ◽  
J.H. Griffin ◽  
S.I. Rapaport
Keyword(s):  
Molecular Weight ◽  
Tissue Factor ◽  
High Molecular Weight ◽  
Human Blood ◽  
Factor Vii ◽  
High Molecular Weight Kininogen ◽  
Contact Activation ◽  
Partial Activation ◽  
No Activation ◽  
Fold Activation

Factor VII(VII) is activated, giving shorter clotting times with tissue factor, when plasma is exposed to kaolin, is clotted or exposed to cold. The mechanisms involved were studied. Incubation of plasma with kaolin resulted in: No activation in XII deficiency plasma (dp), partial activation (2.5 fold) in Prekallikrein (PK) dp and High Molecular Weight Kininogen (HMWK) dp, and 4.5-9 fold activation in normal or other dp. Clotting plasma by recalcification resulted in: No activation with XII dp, HMWK dp, XI dp and IX dp, and 4-5 fold activation with VIII dp, X dp and V dp. The mechanism of cold promoted activation of VII in plasma was studied by adding purified 125-XII or 125I-IX to plasma before storage at 4° and observing the extent of their proteolysis (a measure of activation) from their radioactivity profiles on reduced Polyacrylamide gels following electrophoresis in the presence of SDS. Significantly greater 125I-IX and 125I-XII proteolysis was observed in plasma from 4 subjects whose VII activated in the cold, than in plasma from 5 subjects whose VII was not activated in the cold. Addition of anti-IX antiserum inhibited 50% of the observed cold activation of VII. Thus, with kaolin XIIa was the principal activator of VII; after clotting IXa was the principal activator and in cold activation both XIIa and IXa played roles.

scholarly journals Upregulation of tissue factor in monocytes by cleaved high molecular weight kininogen is dependent on TNF-α and IL-1β

2010 ◽  
Vol 298 (2) ◽  
pp. H652-H658 ◽  
Author(s):  
Mohammad M. Khan ◽  
Yuchuan Liu ◽  
Munir E. Khan ◽  
Megan L. Gilman ◽  
Sabina T. Khan ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Tissue Factor ◽  
High Molecular Weight ◽  
Inflammatory Diseases ◽  
Human Monocytes ◽  
High Molecular Weight Kininogen ◽  
Contact Activation ◽  
Tnf Α ◽  
Chemical Inhibitors ◽  
Inflammatory Bowel

Inflammatory bowel disease and arthritis are associated with contact activation that results in cleavage of kininogen to form high molecular weight kininogen (HKa) and bradykinin. We have previously demonstrated that HKa can stimulate inflammatory cytokine and chemokine secretion from human monocytes. We now show that HKa can upregulate tissue factor antigen and procoagulant activity on human monocytes as a function of time (1–4 h) and HKa concentration (75–900 nM). The amino acid sequence responsible to block HKa effects is G440–H455. The HKa receptor macrophage-1 (Mac-1; CD11b18) is the binding site as shown by inhibition by a monoclonal antibody to CD11b/18. Chemical inhibitors of JNK, ERK, and p38 signaling pathways block cell signaling, as does an inhibitor to the transcription factor NF-κB. A combination of monoclonal antibodies to TNF-α and IL-1β but neither alone inhibited the HKa induction of tissue factor. These results suggest that HKa mimics LPS by triggering a paracrine pathway in monocytes that depends on TNF-α and IL-1β. Antibodies to kininogen or peptidomimetics might be a useful and safe therapy in inflammatory diseases or sepsis involving cytokines.

scholarly journals Interaction of high molecular weight kininogen, factor XII, and fibrinogen in plasma at interfaces

Blood ◽  
1980 ◽  
Vol 55 (1) ◽  
pp. 156-159 ◽  
Author(s):  
L Vroman ◽  
AL Adams ◽  
GC Fischer ◽  
PC Munoz
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Marked Change ◽  
Human Platelets ◽  
Blue Staining ◽  
Factor Xii ◽  
High Molecular Weight Kininogen ◽  
Contact Activation ◽  
Coomassie Blue Staining ◽  
Coated Surfaces

Abstract Using ellipsometry, anodized tantalum interference color, and Coomassie blue staining in conjunction with immunologic identification of proteins adsorbed at interfaces, we have previously found that fibrinogen is the main constituent deposited by plasma onto many man- made surfaces. However, the fibrinogen deposited from normal plasma onto glass and similar wettable materials is rapidly modified during contact activation until it can no longer be identified antigenically. In earlier publications, we have called this modification of the fibrinogen layer “conversion,” to indicate a process of unknown nature. Conversion of adsorbed fibrinogen by the plasma was not accompanied by marked change in film thickness, so that we presumed that this fibrinogen was not covered but replaced by other protein. Conversion is now showen to be markedly delayed in plasma lacking high molecular weight kininogen, slightly delayed in plasma lacking factor XII, and normal in plasma that lack factor XI or prekallikrein. We conclude that intact plasma will quickly replace the fibrinogen it has deposited on glass-like surfaces by high molecular weight kininogen and, to a smaller extent, by factor XII. Platelets adhere preferentially to fibrinogen-coated surfaces; human platelets adhere to hydrophobic nonactivating surfaces, since on these, adsorbed firbinogen is not exchanged by the plasma. The adsorbed fibrinogen will be replaced on glass-like surfaces during surface activation of clotting, and platelets failing to find fibrinogen will not adhere.

High Molecular Weight Kininogen Fragments Stimulate the Secretion of Interleukin 1β through the Urokinase-Type Plasminogen Activator Receptor (uPAR) and CD11b/CD18 (Mac-1) in Human Blood Mononuclear Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3800-3800
Author(s):  
Mohammad M. Khan ◽  
Harlan N. Bradford ◽  
Irma Isordia-Salas ◽  
Ricardo Espinola ◽  
Robert W. Colman
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Human Blood ◽  
Mononuclear Cells ◽  
Inflammatory Diseases ◽  
Interleukin 1Β ◽  
High Molecular Weight Kininogen ◽  
Single Chain ◽  
Blood Mononuclear Cells ◽  
Domain 3

Abstract High molecular weight kininogen (HK) is known to bind specifically and saturably to Mac-1 with a Kd = 9–18 nM for neutrophils and to uPAR with a Kd =30 nM for endothelial cells. However, the functional results of HK interaction with Mac-1 or uPAR on leukocytes is not fully understood. Kallikrein cleavage of single chain HK to a two chain form (HKa) with release of bradykinin (BK) occurs in sepsis, arthritis, and inflammatory bowel disease. We hypothesized that HKa stimulates secretion of inflammatory cytokines. Mononuclear cells were isolated from normal subjects by a Histopaque density gradient. We have expressed kininogen domain 3 (D3) and a fragment of domain 3, coded for by exon 7, E7P (aaG235-Q292), in E. Coli as glutathione S-transferase (GST) fusion proteins. HK and HKa were purified proteins. GST was recombinant. All proteins contained <0.01 EU/ml endotoxin. For all experiments, 2 X 106/ml mononuclear cells/ml were preincubated with monoclonal antibodies, murine IgG (both at 1.8 mM) or HANKS buffer containing 0.15 M NaCl, pH 7.4 for 30 minutes at 37°C. HK, HKa, GST-D3, GST-E7P, GST-D5 or GST all at 600 nM were added. Centrifugation allowed separation of the mononuclear cell suspension into cells and supernatant. The latter was used for assay of interleukin-1β (IL-1β) by ELISA. HK and all fragments tested stimulated secretion of IL-1β of 84.8 to 306.3 pg/ml when incubated with mononuclear cells for 30 minutes at 37°C. Anti-Mac-1 antibody inhibited IL-1β secretion by HK 100%, by HKa 89%, by GST-D3 78%, by GST-E7P 94% and by GST-D5 98%. Anti-uPAR antibody inhibited IL-1β release by HK 88%, by HKa 77%, by GST-D3 95%, by GST-E7P 85%, and by GST-D5 76%. Inhibition by both receptor antibodies is consistent with their known complex formation. A monoclonal antibody (mAb) to HK D5 (C11C1) and a mAb to HK D3 (2B5) both inhibited IL-1β release by HK, HKa, GST-D5 and GST-D3 indicate that both D3 and D5 are important in cytokine release. Murine IgG gave 0% inhibition in all studies. These results indicate that kininogen may contribute to the pathogenesis of inflammatory diseases by releasing IL-1β from human blood mononuclear cells.

scholarly journals Interaction of high molecular weight kininogen, factor XII, and fibrinogen in plasma at interfaces

Blood ◽  
1980 ◽  
Vol 55 (1) ◽  
pp. 156-159 ◽  
Author(s):  
L Vroman ◽  
AL Adams ◽  
GC Fischer ◽  
PC Munoz
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Marked Change ◽  
Human Platelets ◽  
Blue Staining ◽  
Factor Xii ◽  
High Molecular Weight Kininogen ◽  
Contact Activation ◽  
Coomassie Blue Staining ◽  
Coated Surfaces

Using ellipsometry, anodized tantalum interference color, and Coomassie blue staining in conjunction with immunologic identification of proteins adsorbed at interfaces, we have previously found that fibrinogen is the main constituent deposited by plasma onto many man- made surfaces. However, the fibrinogen deposited from normal plasma onto glass and similar wettable materials is rapidly modified during contact activation until it can no longer be identified antigenically. In earlier publications, we have called this modification of the fibrinogen layer “conversion,” to indicate a process of unknown nature. Conversion of adsorbed fibrinogen by the plasma was not accompanied by marked change in film thickness, so that we presumed that this fibrinogen was not covered but replaced by other protein. Conversion is now showen to be markedly delayed in plasma lacking high molecular weight kininogen, slightly delayed in plasma lacking factor XII, and normal in plasma that lack factor XI or prekallikrein. We conclude that intact plasma will quickly replace the fibrinogen it has deposited on glass-like surfaces by high molecular weight kininogen and, to a smaller extent, by factor XII. Platelets adhere preferentially to fibrinogen-coated surfaces; human platelets adhere to hydrophobic nonactivating surfaces, since on these, adsorbed firbinogen is not exchanged by the plasma. The adsorbed fibrinogen will be replaced on glass-like surfaces during surface activation of clotting, and platelets failing to find fibrinogen will not adhere.

scholarly journals Relationship of contact activation cofactor (CAC) procoagulant activity to kininogen

Blood ◽  
1977 ◽  
Vol 49 (6) ◽  
pp. 935-945 ◽  
Author(s):  
S Schiffman ◽  
P Lee ◽  
DI Feinstein ◽  
R Pecci
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Procoagulant Activity ◽  
Antigenic Determinants ◽  
High Molecular Weight Kininogen ◽  
Contact Activation ◽  
Precipitin Line ◽  
A Site ◽  
Relationship Of ◽  
The Relationship

Abstract Contact activation cofactor (CAC) facilitates the interaction of factors XI and XII. Patients lacking CAC have a coagulation defect and are deficient in high molecular weight kininogen. The coincidence of these two defects suggests that a single protein may be responsible for both physiologic functions. Immunologic and activity studies have been made on isolated CAC to clarify the relationship between CAC and kininogen. CAC forms a single precipitin line with anti-human kininogen, and antikininogen neutralizes CAC activity. CAC and high molecular weight kininogen show a reaction of identity on immunodiffusion against rabbit anti-CAC. Anti-CAC forms two precipitin lines with normal plasma which can be identified as high and low molecular weight kininogen. Monospecific immunoabsorbed anti-CAC forms a single precipitin line with plasma high molecular weight kininogen and neutralizes CAC activity. Cleavage of kinin fragment from CAC by insoluble trypsin or kalikrein does not proportionally reduce procoagulant activity. CAC neutralized by anti-CAC can release kinins on exposure to trypsin or kallikrein. The results support the conclusions that CAC procoagulant activity is a function of high molecular weight kininogen, that antigenic determinants unique to high molecular weight kininogen are shared by the CAC portion of the molecule, and that the clotting reactions may occur at a site removed from the kinin peptide.

scholarly journals Plasma Concentrations of High Molecular Weight Kininogen and Prekallikrein and Venous Thromboembolism Incidence in the General Population

2019 ◽  
Vol 119 (05) ◽  
pp. 834-843 ◽  
Author(s):  
Aaron Folsom ◽  
Weihong Tang ◽  
Saonli Basu ◽  
Jeffrey Misialek ◽  
David Couper ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Venous Thromboembolism ◽  
General Population ◽  
High Molecular Weight ◽  
Plasma Levels ◽  
Plasma Concentrations ◽  
The United States ◽  
Enzyme Linked Immunosorbent Assay ◽  
High Molecular Weight Kininogen ◽  
Contact Activation

AbstractThe kallikrein/kinin system, an intravascular biochemical pathway that includes several proteins involved in the contact activation system of coagulation, renin–angiotensin activation and inflammation, may or may not play a role in venous thromboembolism (VTE) occurrence. Within a large prospective population-based study in the United States, we conducted a nested case–cohort study to test the hypothesis that higher plasma levels of high molecular weight kininogen (HK) or prekallikrein are associated with greater VTE incidence. We related baseline enzyme-linked immunosorbent assay measures of HK and prekallikrein in 1993 to 1995 to incidence VTE of the lower extremity (n = 612) through 2015 (mean follow-up = 18 years). We found no evidence that plasma HK or prekallikrein was associated positively with incident VTE. HK, in fact, was associated inversely and significantly with VTE in most proportional hazards regression models. For example, the hazard ratio of VTE per standard deviation higher HK concentration was 0.88 (95% confidence interval = 0.81, 0.97), after adjustment for several VTE risk factors. Our findings suggest that plasma levels of these factors do not determine the risk of VTE in the general population.

KINETIC EFFECTS OF HIGH MOLECULAR WEIGHT KININOGEN AND ZINC ON CONTACT ACTIVATION

1987 ◽  
Author(s):  
J D Shore ◽  
D E Day ◽  
S T Olson
Keyword(s):  
Molecular Weight ◽  
Ionic Strength ◽  
High Molecular Weight ◽  
Proper Function ◽  
Factor Xii ◽  
High Molecular Weight Kininogen ◽  
Contact Activation ◽  
Kinetic Effects ◽  
Activation Rates ◽  
Kinetics Of

Previous work in our laboratory showed that Zn2+ enhanced the rate of kallikrein generation by dextran sulfate (DxSO4) in dialyzed normal plasma, but not in Fitzgerald or Hageman prismas. This could be partially explained by a marked effect of Zn2+ on factor XII autoactivation, and our present work involves zinc effects on other reactions of contact activation. At physiological ionic strength (0.15 μ), the kcat/Km for Xlla activation of prekallikrein (PK) was 0.62 μM™1 s™1 which was increased to 4.35 μM™1 s™1 by the presence of 25μg/ml DxSO4. High molecular weight kininogen (HMK) at 40 nM further increased this to 10.8 μM™1 s™1 , and 5 ¼M Zn2+ had no effect. To determine whether these cofactors promote a surface-dependent activation of PK by XIIa under conditions which weaken the protein-surface interactions, the kinetics were examined at 0.3μ. At this ionic strength, kcat/Km was 0.18 μM™1 s™1 and was unchanged by 25μg/ml DxSO4. This was increased to .805 μM™1 s™1 by 150 nM HMK and further increased 10-fold to 8.35 μM™1 s™1 by 10 μM™1 Zn2+ . Qualitative results were obtained at 0.3 μ for the other reciprocal reaction, XII activation by kallikrein (K). To observe XII activation within 2 hours, both 10 μM Zn2+ and 25 μM HMK were essential, indicating that these cofactors have a very large enhancing effect on the kinetics of this reaction. Chromatography of HMWK on DxSO4-agarose ^ljiowed elution of the protein at 0.42 M NaCl in the absence of Zn2+ ,but at 0.88M in its presence, providing evidence that Zn+ markedly increases the affinity of HMK for DxSO4. Our results are consistent with the increased activation rates observed in the presence of Zn2+ and HMK due to enhanced binding affinity of the reacting proteins to surfaces. This is likely to be essential for proper function of the contact system in blood, where many other proteins compete for surface. Supported by USPHS grant HL-25670

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