Vicki Donaldson

• Fayetteville Technical Community College

Introduction As international trade disputes have shifted over the years from diplomatic exercises to more legalistic contests, the dispute settlement procedures set out in trade agreements have taken on a more important role. The dispute provisions of the GATT 1947 were a mere two paragraphs. Over the years, these provisions were supplemented with...

A highly purified protein from lysates of human umbilical vein endothelial cells (HUVECs) inhibited the activation of factor XII [Hageman factor (HF)] and removed factor XIIa from an activating surface, thus impairing HF-dependent coagulation and kinin-releasing activities. Two tryptic peptides from this protein had 100% identity with amino acids 3...

Thirty-eight previously unreported, unrelated patients with hereditary angioneurotic edema were studied, and each was found to have a single mutation in the C1 inhibitor gene. On the basis of serine protease inhibitor crystal structure, these and published mutations affect critical domains in the reactive center loop, alpha-helices A, B, C, E, and...

Patients with hereditary C4 deficiency are likely to have severe lupus erythematosus. A patient with hereditary angioneurotic edema (HANE) and systemic lupus erythematosus (SLE) had a chronic deficiency in C4 because the hereditary deficiency in C1-inhibitor allowed the C1 in her serum to become activated and then inactivate C4. An attempt was made...

Supported by Public Health Service Grants HL-15690, HD-22082, and MO1-RR08084 and by the Children's Hospital Research Foundation.

An autoantibody to C1-inhibitor produced a clinical disorder resembling that of patients with hereditary angioneurotic edema. The antibody could not interact with C1-inhibitor after exposure to synthetic peptides representing the primary structure of the reactive center region of the protein. Therefore the antibody recognized this domain of the inh...

An autoantibody to Cl-inhibitor produced a clinical disorder resembling that of patients with hereditary angioneurotic edema. The antibody could not interact with C1-inhibitor after exposure to synthetic peptides representing the primary structure of the reactive center region of the protein. Therefore the antibody recognized this domain of the inh...

Mutations in the C1 inhibitor gene that result in low functional levels of C1 inhibitor protein cause hereditary angioneurotic edema. This disease is characterized by episodic edema leading to considerable morbidity and death. Among 60 unreported kindred with the disease, four patients were discovered to have mutations clustered within a 12-bp segm...

Mutations that cause low antigenic and functional levels of C1 inhibitor protein result in type 1 hereditary angioneurotic edema. This disease is characterized by episodic edema leading to considerable morbidity and sometimes death. We present here two novel mutations in the reactive center coding region. One mutation is a deletion of an imperfect...

The 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 acti...

C1-inhibitor is a serine proteinase inhibitor that is active against C1s, C1r, kallikrein, and factor XII. Recently, it has been shown that it also has inhibitory activity against chymotrypsin. We have investigated this activity of normal human C1-inhibitor, normal rabbit C1-inhibitor, and P1 Arg to His mutant human C1-inhibitors and find that all...

Human C1- inhibitor can be rapidly purified by the affinity chromatography procedure described by Pilatte and his associates (1989), but the inhibitor so purified breaks down during storage or is in a cleaved form when initially purified. By adding an ion-exchange chromatography procedure after the affinity chromatography, a stable, single species...

Human umbilical vein endothelial cells (HUVECs) produce a property that impairs the generation of coagulant and amidolytic activity initiated when normal human plasma is exposed to glass. This inhibitory property blocks the adsorption of Hageman factor (factor XII) to glass, thereby preventing the activation of Hageman factor, but does not impair t...

When purified high molecular weight kininogen was incubated with streptokinase-activated plasmin and kallikrein, a larger amount of kinin was released than would have been predicted from the effect of either enzyme alone. To determine the mechanism of this enhancement, high molecular weight kininogen was digested sequentially with these enzymes, an...

A patient with severe acquired angioneurotic edema had essentially no C1- inhibitor activity in his serum and nearly died of cardiopulmonary arrest during an acute episode of facial, oral, and pharyngeal edema. This patient had an antibody directed against C1- inhibitor and C1- inhibitor-anti-C1- inhibitor complexes in his serum. The antibody requi...

Activated high molecular weight Hageman factor (75 Kd) and Hageman factor carboxy-terminal fragments both formed complexes with purified C1(-)-inhibitor, but the Hageman factor fragments appeared to have a higher affinity for the C1(-)-inhibitor than activated Hageman factor. Therefore, the clot-promoting activity of activated Hageman factor might...

Activated high molecular weight Hageman factor (75 Kd) and Hageman factor carboxy-terminal fragments both formed complexes with purified C1(-)-inhibitor, but the Hageman factor fragments appeared to have a higher affinity for the C1(-)-inhibitor than activated Hageman factor. Therefore, the clot-promoting activity of activated Hageman factor might...

C1 inhibitor plays an important role in the regulation of vascular permeability through its ability to inactivate enzymes which release polypeptide kinins. Dysfunctional C1 inhibitor molecules are present in the plasma of affected members of the Da and Ri hereditary angioneurotic edema kindreds. We constructed genomic libraries from Da and Ri patie...

Synthetic peptides that correspond to the COOH-terminal portion of C2b enhance vascular permeability in human and guinea pig skin. In human studies, 1 nmol of the most active peptide of 25-amino acid residues produced substantial local edema. A pentapeptide and a heptapeptide corresponding to the COOH-terminal sequence of C2b each induced contracti...

Purified human granulocyte elastase cleaved purified human high molecular weight (HMW) kininogen into multiple low molecular weight fragments, and destroyed the clot-promoting activity of the HMW kininogen. Elastase digestion did not release kinin or destroy the bradykinin portion of the HMW kininogen molecule; kallikrein could release kinin from t...

A murine hybridoma monoclonal line-secreted antibody (C3G5) against the light chain of human high molecular weight kininogen (HMWK), which consisted of gamma-1 kappa isotype, was largely composed of 190 kd molecules, and gave an optimal reaction when used in an equimolar concentration with HMWK. It did not influence the initial digestion of HMWK or...

Type II HANE is characterized by a deficiency of Cl-inhibitor (Cl-INH) activity in serum which is associated with a dysfunctional inhibitor protein having a normal or increased quantity o|_the antigenic properties of normal serum Cl-inhibitor. Dysfunctional Cl-INH proteins were purified from members_of eight different kindred with Type II HANE and...

After limited digestion of purified human HMW-kininogen by plasmin, the kininogen molecule consists of two disulfide-linked chains in which the bradykinin sequence resides in the "light chain" portion. Kinin was released from this molecule by plasma kallikrein at a two- to three-fold more rapid rate than from uncleaved HMW-kininogen. Similarly, whe...

Purified Hageman factor activated with a mixture of brain sulfatides and bovine serum albumin (BSA) developed clot-promoting activity which was inhibited by purified normal human Cl-inhibitor, but during extended incubation there was an apparent loss of inhibition in these mixtures. When a preparation of Hageman factor fragments (HFf), which had a...

Purified preparations of normal C1(-)-inhibitor (C1(-)-INH) formed high mol wt complexes with plasma kallikrein that were stable during sodium dodecyl sulfate (SDS)-gel electrophoresis, but most of the dysfunctional C1(-)-INH proteins isolated from plasma of patients with type II hereditary angioneurotic edema (HANE) did not. Two of eight dysfuncti...

Both kallikrein and plasmin readily released 112,000 and 102,000 molecular weight derivatives from purified human high molecular weight (HMW)-kininogen. In each instance, these early digestion products were composed of disulfide-linked chains of 64,000 and 58,000 molecular weights. Under the experimental conditions used, kallikrein failed to releas...

Purified preparations of normal C1(-)-inhibitor (C1(-)-INH) formed high mol wt complexes with plasma kallikrein that were stable during sodium dodecyl sulfate (SDS)-gel electrophoresis, but most of the dysfunctional C1(-)-INH proteins isolated from plasma of patients with type II hereditary angioneurotic edema (HANE) did not. Two of eight dysfuncti...

The primary structure of human C1 inhibitor was determined by peptide and DNA sequencing. The single-chain polypeptide moiety of the intact inhibitor is 478 residues (52,869 Da), accounting for only 51% of the apparent molecular mass of the circulating protein (104,000 Da). The positions of six glucosamine-based and five galactosamine-based oligosa...

Purification of Hageman factor (HF, factor XII) from human plasma is a tedious procedure and the product is not always in the precursor form. Hojima has described a protein derived from corn kernels that inhibits the enzymatic properties of HF. This inhibitor binds to the precursor form of HF. Rapid purification of HF was achieved by using as the m...

Low density lipoprotein (LDL) from human plasma was digested with the specific endoprotease, kallikrein. Apolipoprotein B-100, the protein moiety of LDL, was cleaved by kallikrein into two fragments (K1 and K2) which we have compared to the naturally occurring fragments, B-74 and B-26. We have found that K1 and K2 precisely match B-74 and B-26 with...

Purification of Hageman factor (HF, factor XII) from human plasma is a tedious procedure and the product is not always in the precursor form. Hojima has described a protein derived from corn kernels that inhibits the enzymatic properties of HF. This inhibitor binds to the precursor form of HF. Rapid purification of HF was achieved by using as the m...

Human plasma low density lipoporteins (LDL) are the major carriers of cholesterol and cholesteryl esters in the circulation. Their increased levels correlate positively with increased risk of coronary artery disease. LDL contain a single major apolipoprotein of apparent molecualr weight (Mr) = 550,000, designated apolipoprotein B-100 (apoB-100), an...

C1(-)-inhibitor (C1(-)-INH) proteins from normal persons and members of eight different kindred with dysfunctional C1(-)-INH proteins associated with hereditary angioneurotic edema (HANE) were compared with respect to their inhibitory activity against purified preparations of C1s-, plasma kallikrein, activated forms of Hageman factor, and plasmin....

Human plasma low density lipoproteins (LDL) contain one major apoprotein of apparent Mr = 550,000 designated apolipoprotein B-100 (apo-B-100) and in some LDL preparations, minor components termed apo-B-74 (Mr = 410,000) and apo-B-26 (Mr = 145,000). The structural and metabolic relationships among these LDL apoproteins remain obscure. In the present...

A commentary is given on recent findings that activation of the plasma kallikrein system may induce attacks of hereditary angioneurotic edema.

A rapid and sensitive assay for plasma kallikrein has been developed using the radiolabeled tripeptide substrate N-benzoyl-L-prolyl-L-phenylalanyl-L-arginyl-(14C)-anilide. This assay can measure kallikrein in plasma at concentrations ranging from 25–1000 ng/ml. The assay does not require inactivation of kallikrein inhibitors.

When normal human plasma was adsorbed at 4°C with monospecific antibody globulins to human C1̄-INH inhibitor (anti-C1̄-INH), C1̄-INH was removed from the plasma in proportion to the amount of antibody globulins used. Clotting activity attributable to Fletcher factor (prekallikrein), high molecular weight kininogen (HMW-K), and irregularly, plasma t...

When purified human HMW-kininogen was digested by plasmin, its specific antigenic properties were initially enhanced and then gradually destroyed, but its clot-promoting activity (Fitzgerald factor activity) was only slightly decreased. When endogenous serum plasminogen was activated by streptokinase, similar alterations in specific HMW-kininogen a...

Hageman factor (factor XII) is a procoagulant upon which the surface-mediated generation of fibrinolytic activity and kinin formation depends. We found that the clotpromoting activity and antigenic properties of Hageman factor were present in lower levels in the plasma of a small group of Oriental subjects than in that of American whites, whereas t...

The use of OCAs has been associated with multiple hemostatic abnormalities and an increased risk of thromboembolic disease. These changes have been attributed to increased synthesis of various clotting factors and decreased titers of antithrombin III. Paradoxically, enhanced in vitro fibrinolytic activity is also found in plasmas of women using OCA...

A preparation of human a-thrombin previously reported to release kinin from human high molecular weight kininogen (1) was contaminated with small amounts of plasminogen and plasmin which were probably responsible for the kinin release. Inhibitors of plasmin which did not inhibit thrombin clotting activity blocked kinin release, and the removal of p...

HMW-KGN bears antigenic determinants shared by LMW-KGN, but also has antigenic properties unique to HMW-KGN. An antiserum which reacted only with HMW-KGN was prepared by exhaustive adsorption of antiserum to both HMW-KGN and LMW-KGN with a preparation of LMW-KGN. Using such an antiserum, HMW-KGN can be quantified by a hemagglutination inhibition as...

Plasma from an individual with a hereditary deficiency of kininogens is deficient in kininogen antigens; heterozygous relatives are partially deficient in plasma kininogen antigens. In addition, plasma from the proband is partially deficient in functional and antigenic properties of a plasma prekallikrein, and the relatives heterozygous for kininog...

Inherited deficiencies of components of complement have been reported in association with connective tissue disorders, including lupus erythematosus. In hereditary angioneurotic edema serum the fourth (C4) and sometimes the second (C2) components of complement are readily depleted largely because of the activation of C1 that occurs in this heredita...

Plasma from an asymptomatic person with defects in blood coagulation, release of kinin, and evolution of fibrinolytic activity upon contact with a foreign surface was deficient in kininogen. The coagulation defect was identified as "Fitzgerald trait." A preparation of high molecular weight kininogen repaired the defects in clotting, kinin release a...

Intradermally injected preparations of purified Cls̄ and polypeptide from plasma of persons with hereditary angioneurotic edema (HANE) induced venular lesions with ultrastructural changes of the endothelium similar to changes induced by histamine (1). Treatment of test animals with an antihistaminic did not block increased vascular permeability abo...

A 28 year old black man who had never had a bleeding syndrome was found to have a long plasma activated partial thromboplastin time which could not be attributed to deficiencies of Hageman factor, Fletcher factor (a prekallikrein), PTA, Factor VIII, or factor IX. The prothrombin time was normal. In addition to delayed clotting, the release of kinin...

The clot-promoting action of glass or similar agents upon plasma is generally thought to be related to an action upon Hageman factor (HF, Factor XII). HF-deficient or Fletcher-trait plasma inhibited the clot-promoting action of glass. The inhibitory properties were not demonstrable if small amounts of normal plasma, purified HF, or plasma kallikrei...

When normal plasma is exposed to foreign surfaces, Hageman factor (HF, factor XII) is activated; under appropriate circumstances, it then initiates reactions leading to coagulation, fibrinolysis, increased vascular permeability, esterolytic activity, and kinin formation. However, coagulation, fibrinolysis, and increased vascular permeability were i...

Fletcher trait plasma failed to generate kinin and developed only a small amount of arginine esterase activity at an abnormally slow rate following surface activation. Neither defect was due to a deficiency of Hageman factor (HF, factor XII) or kininogen or to an excessively rapid inactivation of evolving kinin. Pyrex pretreated with Fletcher trait...

The plasma of patients with hereditary angioneurotic edema (HANE) is deficient in inhibitory activity against an esterase derived from the first component of complement (Cl). The inhibitor of Cl (Cl inactivator) also inhibits activated plasma thromboplastin antecedent (activated PTA, factor XIa). A second plasma inhibitor of activated PTA is known...

Episodic swellings of hereditary angioneurotic edema (HANE) are apparently secondary to deficient function of serum inhibitor of C1 esterase, inherited as an autosomal dominant trait in this syndrome. As another consequence of deficient inhibitor function, the behavior of the first component of complement, C1, is poorly regulated and its activation...

UPON activation, the Hageman factor in plasma initiates blood coagulation as well as events that lead to the release of biologically active polypeptides, called kinins. Kinins produce signs of inflammation by inducing vasodilatation, increased vascular permeability and pain.1 2 3 4 5 6 The case to be described raises an important exception to the p...

Normal human serum contains 18 +/-5 mg/100 ml of C1 esterase inhibitor (alpha-2 neuraminoglycoprotein) as estimated by immunochemical means. Of 118 patients with hereditary angioneurotic edema, the sera of 80, from 42 kindred, contained a mean concentration of 3.15 mg/100 ml or 17.5% of normal. The mean serum concentration in 35 patients in 7 other...

The antigenic properties of human serum inhibitor of C1 esterase were identified in serum from a number of primates, but were absent from serum of all lower species tested. Among primates the antigenic determinants in human and chimpanzee serum were identical with one another. In serum of the black ape, and rhesus monkey, antigenic determinants wer...

Fletcher trait plasma failed to generate kinin and developed only a small amount of arginine esterase activity at an abnormally slow rate following surface activation. Neither defect was due to a deficiency of Hageman factor (HF, factor XII) or kininogen or to an excessively rapid inactivation of evolving kinin. Pyrex pretreated with Fletcher trait...

Plasma from persons with hereditary angioneurotic edema readily developed the capacity to increase vascular permeability and to induce the isolated rat uterus to contract. Both activities resided in a small, heat-stable molecule that was apparently a polypeptide. Crude preparations of the polypeptide were inactivated during incubation with trypsin....

Plasma from persons with hereditary angioneurotic edema develops permeability factor and kinin activity, both of which seem to be due to the action of a relatively small polypeptide molecule. Histamine plays no role in these activities, clearly distinguishing the permeability factor and kinin properties in this plasma from the anaphylatoxins which...

The generation of C'1 esterase activity in siliconed plasma obtained from individuals with hereditary angioneurotic edema in remission tends to occur spontaneously, but can be hastened during its incubation with preparations of activated Hageman factor. This effect of activated Hageman factor could not be shown during its incubation with normal sil...

When purified human C'1 esterase is injected intradermally in man, increased vascular permeability results. This effect is not blocked by soybean trypsin inhibitor and is not abolished by pretreatment with the antihistamine, pyribenzamine, or by compound 48/80. Thus, the effect is not due to the release of endogenous histamine. The decreased permea...

The generation of C'1 esterase activity in siliconed plasma obtained from individuals with hereditary angioneurotic edema in remission tends to occur spontaneously, but can be hastened during its incubation with preparations of activated Hageman factor. This effect of activated Hageman factor could not be shown during its incubation with normal sil...

The decapeptide, lysyl brady-kinin (Kallidin I) was more effective in increasing vascular permeability in the skin of guinea pigs than was the nonapeptide, bradykinin, or Kallidin II. Bradykinin has been reported to be more active in some other assays measuring pharmacological effects than lysyl bradykinin. All other analogues of bradykinin tested...

Inasmuch as hereditary angioneurotic edema has generally been overlooked in the pediatric literature, it is hoped that this report may alert pediatricians to the possibiity of the existence of the disease in children of families with appropriate histories. It is likely that the symptomatology will not be severe in childhood; nonetheless, swellings...

Highly purified preparations of Hageman factor, a potent clotpromoting agent in normal mammalian plasma, had a sedimentation coefficient of approximately 5S before activation. After activation, the Hageman factor behaved as a much less soluble or larger molecule during ultracentrifugation and gel filtration. No significant change in sedimentation b...

Serums of patients with hereditary angioneurotic edema lack inhibitory activity against the esterase derived from the first component of complement. In one group of patients this lack appears to result from failure to synthesize the esterase inhibitor of the first component of complement, whereas in another group of patients an abnormal, nonfunctio...

Affected persons in three families with hereditary angioneurotic edema completely lack naturally occurring serum inhibitor of C′1esterase. This inhibitor is also absent from some younger relatives who have not yet had typical attacks of swelling. Its absence is characteristic of the hereditary form of angioneurotic edema, for those with nonheredita...

The proteolytic activity in chloroform-treated plasma euglobulins has been attributed to plasmin. Plasmin can digest both casein and fibrin. Epsilon aminocaproic acid, which inhibits the activation of plasminogen, the precursor of plasmin, by streptokinase, urokinase, and tissue activators enhanced the development of casein hydrolytic activity in a...

Spontaneous fibrinolytic activity, as tested in vitro, is more rapid when the plasma is obtained from a person undergoing stress. The mechanisms responsible for this rapid lysis and its physiologic meaning are obscure. The rapid lysis of blood drawn after exercise or childbirth is not accompanied by a fall in the concentration of fibrinogen in the...