Combined high molecular weight Kininogen and factor XI deficiency

Haemophilia ◽  
2015 ◽  
Vol 22 (1) ◽  
pp. e60-e61 ◽  
Author(s):  
M. Ahmadinejad ◽  
S. Alavi ◽  
M. Ebadi ◽  
A. Rashidi ◽  
M. Tabatabaei ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
High Molecular Weight Kininogen ◽  
Factor Xi ◽  
Factor Xi Deficiency

scholarly journals The Role of High Molecular Weight Kininogen and Prothrombin as Cofactors in the Binding of Factor XI A3 Domain to the Platelet Surface

2000 ◽  
Vol 275 (33) ◽  
pp. 25139-25145 ◽  
Author(s):  
David H. Ho ◽  
Karen Badellino ◽  
Frank A. Baglia ◽  
Mao-Fu Sun ◽  
Ming-Ming Zhao ◽  
...  
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
High Molecular Weight Kininogen ◽  
Factor Xi ◽  
Platelet Surface

Surface Independent Factor XI Activation by Thrombin in the Presence of High Molecular Weight Kininogen

1994 ◽  
Vol 72 (03) ◽  
pp. 397-402 ◽  
Author(s):  
Peter A Kr von dem Borne ◽  
Stefan J Koppelman ◽  
Bonno N Bouma ◽  
Joost C M Meijers
Keyword(s):  
Molecular Weight ◽  
Blood Coagulation ◽  
High Molecular Weight ◽  
Dextran Sulfate ◽  
Factor Xa ◽  
Factor X ◽  
High Molecular Weight Kininogen ◽  
Factor Xi ◽  
Factor Xia

SummaryA deficiency of one of the proteins of the contact system of blood coagulation does not result in a bleeding disorder. For this reason activation of blood coagulation via this system is believed to be an in vitro artefact. However, patients deficient in factor XI do suffer from variable bleeding abnormalities. Recently, an alternative pathway for factor XI activation has been described. Factor XI was found to be activated by thrombin in the presence of dextran sulfate as a surface. However, high molecular weight kininogen (HK), to which factor XI is bound in plasma, and fibrinogen were shown to block this activation suggesting it to be an in vitro phenomenon. We investigated the thrombin-mediated factor XI activation using an amplified detection system consisting of factors IX, VIII and X, which was shown to be very sensitive for factor XIa activity. This assay is approximately 4 to 5 orders of magnitude more sensitive than the normal factor XIa activity assay using a chromogenic substrate. With this assay we found that factor XI activation by thrombin could take place in the absence of dextran sulfate. The initial activation rate was approximately 0.3 pM/min (using 25 nM factor XI and 10 nM thrombin). The presence of dextran sulfate enhanced this rate about 8500-fold. A very rapid and complete factor X activation was observed in the presence of dextran sulfate. Although only minute amounts of factor XIa were formed in the absence of dextran sulfate, significant activation of factor X was detected in the amplification assay within a few minutes. HK inhibited the activation of factor XI by thrombin strongly in the presence, yet only slightly in the absence of dextran sulfate (26 and 1.2 times, respectively). Despite the strong inhibition of HK on the activation of factor XI by thrombin in the presence of dextran sulfate, HK had only a minor effect on the factor Xa generation.We conclude that activation of factor XI by thrombin can take place regardless of the presence of a surface or HK. This activation might therefore be physiologically relevant. The inhibitory effect of HK on the thrombin-mediated factor XI activation is largely dextran sulfate dependent. Due to the amplification in the intrinsic system, trace amounts of factor XIa might generate physiological sufficient amounts of factor Xa for an adequate haemostatic response.

DETECTION AND QUANTITATION OF CLEAVED AND UNCLEAVED HIGH MOLECULAR WEIGHT KININOGEN IN PLASMA BY LIGAND BLOTTING WITH RADIOLABELED PLASMA PREKALLIKREIN OR FACTOR XI

1987 ◽  
Author(s):  
B Lämmle ◽  
B L Zuraw ◽  
M J Heeb ◽  
H P Schwarz ◽  
J G Curd ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Human Plasma ◽  
High Molecular Weight ◽  
Normal Human Plasma ◽  
High Molecular Weight Kininogen ◽  
Single Chain ◽  
Factor Xi ◽  
Sds Page ◽  
Normal Human

A method for the quantitative assay of native single chain and kallikrein cleaved two-chain high molecular weight kininogen (HMWK) in plasma has been developed. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole plasma is followed by electroblotting of the electropherogram to nitrocellulose membranes and detection of the inmobilized HMWK with its physiologic ligands, plasma prekallikrein or factor XI. Using 1251-prekallikrein or 125I-F.XI overlay nitrocellulose bound HMWK can be visualized by autoradiography.Using unreduced SDS-PAGE cleaved two-chain HMWK (Mr 107,000 and 95,000) is electrophoretically separated from uncleaved single chain HMWK (Mr 150,000). Counting the radioactivity of the nitrocellulose pieces corresponding to cleaved HMWK permits its quantitative measurement by comparison with standards consisting of decreasing amounts of fully dextran sulfate activated normal human plasma. Single chain HMWK is similarly assayed using reduced SDS-PAGE and unactivated normal human plasma standards.This technique is highly specific and sensitive to ˜ 50 ng of either cleaved or uncleaved HMWK. Varying concentrations of cleaved HMWK were found in plasmas from patients suffering from various systemic inflanmatory conditions. Higher levels of in vivo cleaved HMWK were observed during acute attacks of hereditary angioedema due to Cl-inhibitor deficiency.This technique may be useful for the assessment of the degree of in vitro or in vivo activation of the contact system of plasma.

scholarly journals Immunologic studies of human coagulation factor XI and its complex with high molecular weight kininogen

Blood ◽  
1983 ◽  
Vol 62 (5) ◽  
pp. 1123-1131 ◽  
Author(s):  
BN Bouma ◽  
RA Vlooswijk ◽  
JH Griffin
Keyword(s):  
Molecular Weight ◽  
High Molecular Weight ◽  
Coagulation Factor ◽  
Ion Exchange Chromatography ◽  
Exchange Chromatography ◽  
High Molecular Weight Kininogen ◽  
Average Amount ◽  
Factor Xi ◽  
Crossed Immunoelectrophoresis ◽  
Normal Individuals

Abstract Coagulation factor XI was purified from human plasma using ion-exchange chromatography and affinity chromatography on high molecular weight kininogen-Sepharose. A monospecific precipitating antiserum was prepared and used to study factor XI antigen. Factor XI did not migrate during electrophoresis at pH 8.3. High molecular weight kininogen (HMWK), an alpha globulin, reversibly associates with factor XI. Complex formation between HMWK and factor XI was observed under conditions of crossed-immunoelectrophoresis. Using Laurell rocket immunoelectrophoresis, it was shown that the isolated alkylated light chain of kinin-free HMWK formed a complex with factor XI. In contrast to previous studies of prekallikrein, titrations of factor XI with increasing amounts of HMWK did not give a simple titration curve, suggesting that factor XI dissociates from the complex during electrophoresis. Prekallikrein and factor XI were shown to compete for the same HMWK molecules under the conditions of immunoelectrophoresis, and prekallikrein appeared to have a higher affinity for binding to HMWK than factor XI. Quantitative determinations of factor XI antigen in plasma by rocket immunoelectrophoresis were made. The average amount of factor XI measured in plasma samples from 20 normal individuals was 4.5 micrograms/ml (range 3–6). No factor XI antigen was detected in plasma from a patient deficient in factor XI. Normal factor XI antigen levels were detected in 3 different HMWK-deficient plasmas only if the plasmas were reconstituted with purified HMWK (2 U/ml). Addition of HMWK to normal plasma resulted in an increase of the factor XI antigen rocket. At HMWK levels of 2 U/ml, no further increase of the factor XI antigen rocket was observed. Therefore, accurate measurement of factor XI antigen by rocket immunoelectrophoresis is possible only if an excess of HMWK is present.

STRUCTURAL AND FUNCTIONAL CHARACTERIZATION OF DOMAINS IN THE HEAVY CHAIN REGION OF FACTOR XI (XIa) INVOLVED IN BINDING HIGH MOLECULAR WEIGHT KININOGEN AND FACTOR IX

1987 ◽  
Author(s):  
F A Baglia ◽  
D Sinha ◽  
P N Walsh
Keyword(s):  
Molecular Weight ◽  
Monoclonal Antibody ◽  
Binding Site ◽  
High Molecular Weight ◽  
Heavy Chain ◽  
Substrate Binding ◽  
The Other ◽  
High Molecular Weight Kininogen ◽  
Factor Xi ◽  
Substrate Binding Site

Previous studies from our laboratory (J. Biol. Chem. 260:10714,1985; J. Clin. Invest. 78:1631,1986) provide evidence that a monoclonal antibody (3C1) directed against the heavy chain region of factor XIa (FXIa) recognizes an epitope near a substrate binding site for FIX and a binding site for high molecular weight kininogen (HMWK). The present studies were carried out to determine whether these two sites are identical or different. Another heavy-chain-specific murine monoclonal antibody (5F7) was found to recognize an epitope distinct from that recognized by 3C1 since 3C1 did not compete with 5F7 for binding to FXI in a solid-phase radioimmunoassay. Antibody 3C1 was a competitive inhibitor of F-XIa-catalyzed F-IX activation, assayed by the release of a 3H-labeled activation peptide from FIX, whereas 5F7 had no effect on F—IX activation by FXIa. In contrast, 5F7 (which also inhibited F-XIIa-catalyzed F-XI activation in the presence of HMWK and kaolin) completely blocked FXI binding to immobilized HMWK at concentrations 1,000-fold lower than 3C1. Finally, HMWK had no effect on F-IX activation by FXIa. We therefore conclude that two separate and distinct domains are present in the heavy-chain region of FXI, one of which is a substrate binding site for FIX and the other a binding site for HMWK. A 15,000 Mr peptide containing the HMWK binding site was isolated using cyanogen bromide digests of factor XI which were bound to and eluted from a ,5F7 antibody affinity column and further purified using high performance liquid chromatography. Gas phase sequencing studies are in progress to characterize this peptide and place its sequence within the known structure of the heavy chain of FXIa. In conclusion, our antibodies have defined two domains within the heavy chain region of FXI: one defined by 5F7 is near the HMWK binding site, whereas the other, recognized by 3C1, is a substrate binding site for FIX. Finally, a peptide domain in the heavy chain of FXI that compriaes the HMWK binding site has been identified and isolated.

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