Medical Literature - 1986

Alpha-1-antitrypsin-Pittsburgh. A potent inhibitor of human plasma factor XIa, kallikrein, and factor XIIf

Scott CF, Carrell RW, Glaser CB, Kueppers F, Lewis JH, Colman RW 2/1986 The Journal of Clinical Investigation

Alpha-1-antitrypsin-Pittsburgh is a human variant that resulted from a point mutation in the plasma protease inhibitor, alpha 1-antitrypsin (358 Met—-Arg). This defect in the alpha 1-antitrypsin molecule causes it to have greatly diminished anti-elastase activity but markedly increased antithrombin activity. In this report, we demonstrate that this variant protein also has greatly increased inhibitory activity towards the arginine-specific enzymes of the contact system of plasma proteolysis (Factor XIa, kallikrein, and Factor XIIf), in contrast to normal alpha 1-antitrypsin, which has modest to no inhibitory activity towards these enzymes. We determined the second-order-inactivation rate constant (k”) of purified, human Factor XIa by purified alpha 1-antitrypsin-Pittsburgh and found it to be 5.1 X 10(5) M-1 s-1 (23 degrees C), which is a 7,700-fold increase over the k” for Factor XIa by its major inhibitor, normal purified alpha 1-antitrypsin (i.e., 6.6 X 10(1) M-1 s-1). Human plasma kallikrein, which is poorly inhibited by alpha 1-antitrypsin (k” = 4.2 M-1 s-1), exhibited a k” for alpha 1-antitrypsin-Pittsburgh of 8.9 X 10(4) M-1 s-1 (a 21,000-fold increase), making it a more efficient inhibitor than either of the naturally occurring major inhibitors of kallikrein (C-1-inhibitor and alpha 2-macroglobulin). Factor XIIf, which is not inhibited by normal alpha 1-antitrypsin, displayed a k” for alpha 1-antitrypsin-Pittsburgh of 2.5 X 10(4) M-1 s-1. This enhanced inhibitory activity is similar to the effect of alpha 1-antitrypsin-Pittsburgh that has been reported for thrombin. In addition to its potential as an anticoagulant, this recently cloned protein may prove to be clinically valuable in the management of septic shock, hereditary angioedema, or other syndromes involving activation of the surface-mediated plasma proteolytic system.


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Danazol-induced cystitis: an undescribed source of hematuria in patients with hereditary angioneurotic edema

Andriole GL, Brickman C, Lack EE, Sesterhenn IA, Javadpour N, Linehan WM, et al. 1/1986 The Journal of Urology


From 1975 through 1983, 69 patients with hereditary angioneurotic edema were treated with danazol, a semisynthetic anabolic steroid. Hematuria developed in 13 of these patients (19 per cent). Careful evaluation of the genitourinary tract showed the presence of a distinct form of hemorrhagic cystitis in 10 patients. Clinically, 9 patients presented with microscopic and 1 with intermittent gross hematuria. Irritative bladder symptoms were reported by 2 patients. Neither the dose nor duration of danazol therapy correlated with the severity of the cystoscopic or pathological findings. Cystoscopically, a rather nonspecific pattern of erythema, submucosal telangiectasia and neovascularity was observed. Histopathologically, bladder biopsy typically showed numerous dilated submucosal vessels with hemorrhage, mucosal ulceration and occasional inflammatory cells. These changes regressed in all but 1 patient when danazol therapy was discontinued. Further studies are needed to elucidate the role of danazol itself or of the danazol-hereditary angioneurotic edema interaction in the pathogenesis of these abnormalities.

Not available online.

Immunoreactive precipitation of C1 inhibitor protein from plasma of normal subjects and of patients with hereditary angioedema after isoelectric focusing

Bergamaschini L, Valle C, Franzinelli M, Cicardi M, Agostoni A. 10/1986 Journal of Clinical Chemistry & Clinical Biochemistry


C1-inhibitor is an acid glycoprotein, isoelectric point 3.5-3.6. Plasma of some patients with a variant form of hereditary angioedema contains high levels of functionless C1-inhibitor-albumin complex with an isoelectric point at 4.5-4.6. Therapy with Danazol, which increases C1-inhibitor levels, does not modify the isoelectric focusing pattern of such protein in patients with hereditary angioedema.

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Recombinant alpha 1-antitrypsin Pittsburgh (Met 358—-Arg) is a potent inhibitor of plasma kallikrein and activated factor XII fragment.

Schapira M, Ramus MA, Jallat S, Carvallo D, Courtney M. 2/1986 Journal of Clinical Investigations


In normal plasma, the serine protease inhibitor alpha 1-antitrypsin (alpha 1-AT) plays little or no role in the control of plasma kallikrein or activated Factor XII fragment (Factor XIIf), this function being performed by Cl-inhibitor. Recently, an alpha 1-AT variant was described with a Met—-Arg mutation at the reactive center P1 residue (position 358) which altered the specificity of inhibition from the Met- or Val-specific protease neutrophil elastase to thrombin, an Arg-specific protease. We have now examined the inhibition of plasma kallikrein and Factor XIIf, both Arg-specific enzymes, with recombinant alpha 1-AT(Met358—-Arg) produced by an Escherichia coli strain carrying a mutated human alpha 1-AT gene. The engineered protein was a very efficient inhibitor of both enzymes. It was more effective than Cl-inhibitor by a factor of 4.1 for kallikrein and 11.5 for Factor XIIf. These results suggest that recombinant alpha 1-AT(Met358—-Arg) has therapeutic potential for disease states where activation of the plasma kinin-forming system is observed, for example in hereditary angioedema or septic shock.

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The metabolism of C1 inhibitor and C1q in patients with acquired C1-inhibitor deficiency

Melamed J, Alper CA, Cicardi M, Rosen FS. 2/1986 Journal of Allergy & Clinical Immunology


The metabolism of 125I-labeled C1 inhibitor (C1INH) and C1q was studied in five patients with B cell lymphoproliferative disorders, C1INH deficiency, and angioedema. C1INH catabolism was markedly accelerated in these patients. The fractional catabolic rate (FCR) was 0.053 of the plasma pool per hour compared to that of normal subjects (0.025) or patients with hereditary angioneurotic edema (HANE) (0.035). The catabolism of two dysfunctional proteins Wel and Ta was studied. Protein Wel was catabolized at an accelerated rate (0.041) compared to that in patients with HANE (0.029) or in normal subjects (0.020). In contrast, the FCR of protein Ta was 0.012, which is similar to that in normal patients and in patients with HANE. The extravascular to plasma ratio (E/P) of the normal C1INH in patients was 1.55 compared to 0.60 in normal patients. This is consistent with the rapid extravascular sequestration of the C1INH. The synthesis rate of the C1INH was 0.29 mg/kg/hr in patients that is similar to that in control subjects. The metabolism of C1q was studied in two normal control subjects and three patients. The FCR of C1q was 0.051 in patients compared to 0.023 in control subjects. The E/P was increased in patients (2.8) compared to E/P in control subjects (0.6). The acquisition of C1INH deficiency results from increased consumption of C1INH in vivo.

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The value of rocket immunoelectrophoresis for C4 activation in the evaluation of patients with angioedema or C1-inhibitor deficiency

Zuraw BL, Sugimoto S, Curd JG 12/1986 Journal of Allergy & Clinical Immunology

The correct diagnosis and characterization of C1-inhibitor deficiency depends on both clinical observations and laboratory evaluation of complement in plasma. Rocket immunoelectrophoresis for C4d is a sensitive assay for C4 activation in plasma. We have evaluated the value of this assay in identifying patients with C1-inhibitor deficiency. C4 activation was assessed in the plasmas of 15 patients with hereditary angioedema, five patients with variant form of hereditary angioedema, and four patients with acquired C1-inhibitor deficiency. Control groups consisted of 27 patients with chronic idiopathic urticaria and/or angioedema and seven normal volunteers. C4 activation was detected in all 52 plasma samples collected from the 24 patients with C1-inhibitor deficiency. The degree of C4 activation increased during attacks of angioedema and decreased (but remained elevated) during treatment with attenuated androgens. The concentrations of C4, C2, and C1 inhibitor were also measured; however, none of these measurements identified all of the patients with C1-inhibitor deficiency. Thus, we conclude that the measurement of C4 activation is one of the best tests available to evaluate a patient for C1-inhibitor deficiency, and a normal result will exclude the diagnosis of C1-inhibitor deficiency.


Available online at:

Funding for Canadian Hereditary Angioedema Network has been generously provided by unrestricted grants from:


CSL Behring


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