Prekallikrein deficiency in a kindred with kininogen deficiency and Fitzgerald trait clotting defect. Evidence that high molecular weight kininogen and prekallikrein exist as a complex in normal human plasma.

Donaldson, Virginia H.; Kleniewski, J; Saito, Hidehiko; Sayed, J K

doi:10.1172/jci108809

Cited by 44 publications

(24 citation statements)

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“…Observations ofthe immunoelectrophoretic pattern of purified prekallikrein or plasma deficient in HMW kininogen revealed a single, discrete precipitin arc, which is in agreement with the observations of Donaldson et al (27). We were able to demonstrate, however, that the addition of purified HMW kininogen extended the precipitin arc anodally while retaining antigenic identity to the more cathodal arc, similar to the pattern observed in normal plasma.…”

Section: Discussionsupporting

confidence: 91%

“…Nevertheless, the possibility must be considered that functional or structural relationships between these two proteins might directly influence assay methods. Although the major defect in the HMW kininogen-deficient individuals (1)(2)(3)(4)(5)28) (27) confirmed the existence of the complex by adsorbing both prekallikrein and HMW kininogen from plasma with either monospecific antiserum against kallikrein or HMW kininogen. Furthermore, both proteins are important for optimal activation (7,8) and activity (9) ofthe various forms of Factor XII.…”

Section: Discussionmentioning

confidence: 89%

“…Several explanations have been offered to account for the combined deficiency of HMW kininogen and prekallikrein including genetic linkage (27). Nevertheless, the possibility must be considered that functional or structural relationships between these two proteins might directly influence assay methods.…”

Section: Discussionmentioning

confidence: 99%

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Function and Immunochemistry of Prekallikrein-High Molecular Weight Kininogen Complex in Plasma

Scott¹,

Colman²

1980

J. Clin. Invest.

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A B S T R A C T Plasma from individuals with high molecular weight (HMW) kininogen deficiency has been reported to be deficient in prekallikrein as measured by radial immunodiffusion, prekallikrein coagulant activity, and/or kaolin-activated arginine esterase activity. Addition of HMW kininogen increased the apparent prekallikrein activity in native normal plasma (as measured by esterase activity) but not in normal plasma in which inhibitors were inactivated. The apparent prekallikrein antigen concentration (as measured by radial immunodiffusion or electroimmunodiffusion) increased upon addition of HMW kininogen. Immunoelectrophoresis as well as gel filtration of normal plasma revealed the presence of free prekallikrein (17-38% of the total) in addition to the HMW kininogen-prekallikrein complex previously reported.This study emphasizes the influence of HMW kininogen on both functional and immunologic determinations of prekallikrein.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 89%

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Function and Immunochemistry of Prekallikrein-High Molecular Weight Kininogen Complex in Plasma

Scott¹,

Colman²

1980

J. Clin. Invest.

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“…In a purified system, plasma concentrations of HK partially inhibit the cofactor activity of FVa. The presence of plasma concentrations of PK, which also circulates in complex with HK (19,20), reverses this inhibition. Moreover, the cofactor role of FVa in the intrinsic pathway was demonstrated in plasma that contained normal levels of HK and PK.…”

Section: Discussionmentioning

confidence: 99%

Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma

Maas

Meijers

Marquart

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The mechanism by which the intrinsic pathway of coagulation contributes to physiological hemostasis is enigmatic. Thrombin activates factor XI, a key zymogen in this pathway, which leads to increased thrombin generation. As thrombin-dependent activation of factor XI in vitro is relatively inefficient, we hypothesized that a physiological cofactor supports this reaction in a plasma environment. We therefore investigated whether the cofactors of coagulation, activated factor V, activated factor VIII, high-molecular weight kininogen, or protein S, influenced activation of factor XI by thrombin. Only activated factor V stimulated activation of factor XI by thrombin in a purified system. Binding studies demonstrated that factor XI specifically interacts with both factor V and factor Va through multiple binding sites. We further investigated this cofactor function of activated factor V in plasma. Depletion of factor V, or the addition of activated protein C, decreased the activation of the intrinsic pathway by thrombin in plasma. However, activated protein C did not exert this effect in the plasma of a homozygous carrier of the prothrombotic factor V Leiden mutation. In conclusion, we propose a role for (activated) factor V as a cofactor in the activation of factor XI by thrombin. These findings offer insights into the coagulation system in both health and disease.coagulation | coagulation factor V | coagulation factor XI | feedback activation T he mechanism behind the activation of the intrinsic pathway of coagulation in vivo has been subject to discussion since the introduction of the model of coagulation (1, 2). The importance of the intrinsic pathway for physiological hemostasis is apparent from the bleeding phenotypes that are seen in factor VIII (FVIII) deficiency, factor IX (FIX) deficiency and, to a lesser extent, in factor XI (FXI) deficiency. In vitro, activation of the intrinsic pathway can be initiated by factor XII (FXII) on negatively charged surfaces, which results in clotting. However, the role of FXII-dependent coagulation in physiological hemostasis is controversial. FXII deficiency, for instance, protects against thrombosis in murine models (3), which conflicts with the protective role of high FXII antigen levels in epidemiological studies on thrombosis in humans (4), as well as with the absence of bleeding symptoms in FXII-deficient individuals. Additionally, FXII hyperactivity leads to angioedema, rather than to thrombosis (5), which corresponds with evidence that activation of the kallikrein-kinin system by FXII can take place independent of coagulation (6).As FXI deficiency, unlike FXII deficiency, is associated with mild bleeding phenomena, a FXI activator other than FXII is likely. Thrombin, the final and central enzyme of the coagulation cascade, can directly activate FXI, which leads to downstream formation of more thrombin (7,8). This feedback activation mechanism offered an alternative explanation for the existence of the intrinsic pathway: The amplification of minute amounts of thrombin, ...

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“…However, when any two of these plasmas were combined before incubation, activity was generated in all instances except the combination of prekallikrein-deficient plasma with HK-and LKdeficient plasma. Presumably, this mixture remains deficient in prekallikrein because the plasma from patients with inherited deficiency of HK and LK (Fitzgerald trait) is also prekallikreindeficient [21][22][23][24]. The addition of excess Cls to normal plasma and to C2-deficient plasma resulted in kinin generation during subsequent incubation.…”

Section: Resultsmentioning

confidence: 99%

Hereditary angioneurotic oedema: characterization of plasma kinin and vascular permeability-enhancing activities

Shoemaker

Schurman

Donaldson

et al. 1994

Clinical and Experimental Immunology

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SUMMARYThe mediator(s) responsible for localized enhanced vascular permeability that characterizes an exacerbation of hereditary angioneurotic oedema (HAE) is thought to be a product of either contact or complement system activation. In contrast to normal individuals, plasma from these patients generates both kinin and vascular permeability-enhancing activity following incubation at 37°C. Depletion of C1 inhibitor in both normal and C2-deficient plasma, but not in contact factor-deficient plasmas, resulted in generation ofthese activities. The kinin activity from incubated HAE plasma was susceptible to kininase inactivation and was blocked by a Bk2 receptor antagonist. Furthermore, this activity was isolated from HAE plasma; amino acid sequence analysis proved it to be bradykinin. Similarly, the vasopermeability-enhancing activity from ethanol-fractionated or boiled HAE plasma, collected during either attack or remission, co-eluted with bradykinin on reverse-phase high performance liquid chromatography (HPLC). These studies conclusively demonstrate that bradykinin is the major kinin and mediator ofenhanced vascular permeability generated during incubation of HAE plasma. The role of other bioactive products, such as the C2 kinin, at local sites of oedema formation remains to be further defined.

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Prekallikrein deficiency in a kindred with kininogen deficiency and Fitzgerald trait clotting defect. Evidence that high molecular weight kininogen and prekallikrein exist as a complex in normal human plasma.

Cited by 44 publications

References 24 publications

Function and Immunochemistry of Prekallikrein-High Molecular Weight Kininogen Complex in Plasma

Function and Immunochemistry of Prekallikrein-High Molecular Weight Kininogen Complex in Plasma

Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma

Hereditary angioneurotic oedema: characterization of plasma kinin and vascular permeability-enhancing activities

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