Virginia H. Donaldson

Hereditary Angioneurotic Edema: Two Genetic Variants

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, nonfunctional protein is synthesized.

Action of Complement in Hereditary Angioneurotic Edema: The Role of C'1-Esterase *

The tendency to have severe attacks of localized alngioneurotic edema may be inherited as an autosomal dominant trait (1-7). The hereditary form of angioneurotic edema is also distinguishable by a biochemical abnormality in that affected persons lack detectable serum inhibitor of an enzyme derived from the first component of complement (C1-esterase) (8). This serum deficiency is detectable before the onset of symptoms, which may appear at any time from 1 year of age to adult life. Although serum inhibitor of C1esterase is constantly absent from sera of patients, attacks of edema are episodic and self-limited and affect only circumscribed areas of the body. The present studies were undertaken to define changes in C1-esterase and the components of complement in serum of patients during attacks of edema and during asymptomatic intervals. Affected members of a family reported earlier (9) had no inhibitor of C1-esterase in their se~rum, whereas sera from unaffected relatives contained normal amounts. Affected persons also developed C1-esterase activity in their serum, but relatives and other normal individuals did not. When patients were free of swelling, there

Defective Activation of Clotting, Fibrinolytic, and Permeability-Enhancing Systems in Human Fletcher Trait Plasma

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 impaired in plasma from an individual with Fletcher trait, despite a normal concentration of HF that is functionally and immunologically indistinguishable from that in normal plasma. This defective clotting is completely repaired by the addition of small amounts of normal plasma, HF-deficient plasma, plasma thrombo-plastin antecedent (PTA)-deficient plasma, or activated PTA but only partially repaired by the addition of activated HF. Defective fibrinolysis and permeability-enhancing activity were partially corrected by the addition of small amounts of normal plasma, HF-deficient plasma, PTA-deficient plasma, or activated HF. A preparation of partially purified plasma kallikrein largely repaired defective coagulation and fibrinolysis in Fletcher trait plasma in the presence of kaolin. In immunodif fusion studies, no precipitin line formed between Fletcher trait plasma and monospecific antikallikrein serum. Fletcher trait plasma appeared to be deficient in a plasma prekallikrein, which most probably participates in the functioning of activated HF. These studies emphasize the intimate relationships among clotting, fibrinolysis, and enhancement of vascular permeability.

Effect of C′1 esterase on vascular permeability in man: studies in normal and complement-deficient individuals and in patients with hereditary angioneurotic edema

When purified human C1 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 permeability response of individuals with a specific hereditary deficiency of C2 is evidence for the complement-dependent nature of this reaction. The apparently normal response to intradermal C1 esterase developed by individuals with an acquired specific deficiency of C3 suggests that the vasoactive substance may be derived from one of the early reacting complement components. Characteristic attacks of angioedema have been provoked by the intradermal injection of human C1 esterase in two individuals with hereditary angioneurotic edema. Patients with hereditary angioneurotic edema are unresponsive to intradermal injections of C1 esterase immediately after attacks.

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.

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 kininogen deficiency are also partially deficient in the plasma prekallikrein. It is possible that the defects are both inherited and that the inheritance of a deficiency of prekallikrein is genetically linked to the inheritance of a deficiency of kininogen. Alternatively, it is possible that the deficiency of prekallikrein may be due to its hypercatabolism which could be a consequence of a deficiency of high molecular weight kininogen that may stabilize the prekallikrein in plasma. Evidence to support this possibility is presented by the fact that prekallikrein and high molecular weight kininogen apparently exist as a complex in normal plasma, because monospecific antiserum to kininogen removed both high molecular weight kininogen and prekallikrein from plasma, and vice versa. Moreover, prekallikrein was not adsorbed from kininogen-deficient plasma by antiserum to kininogen unless high molecular weight kininogen was first added to the plasma. Low molecular weight kininogen did not participate in these reactions.

Defective Esterase and Kinin-Forming Activity in Human Fletcher Trait Plasma: A Fraction Rich in Kallikreinlike Activity

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 did not generate kinin normally in fresh normal plasma. Fractions rich in prekallikrein prepared from normal, HF-deficient, or plasma thromboplastin antecedent (PTA)-deficient plasma developed kallikrein activity by direct activation during incubation with trypsin or HF fragments formed by digesting partially purified HF with trypsin. In contrast, identical fractions of Fletcher trait plasma did not develop this activity. Although this finding suggested that Fletcher trait plasma was deficient in prekallikrein, materials eluted from Celite that had been incubated in Fletcher trait plasma contained both esterase and kinin-generating activities. Celite eluates prepared from normal and Fletcher trait plasma released kinin from partially purified kininogen equally well. This release was blocked by soybean trypsin inhibitor but not by lima-bean trypsin inhibitor. Therefore, although unfractionated Fletcher trait plasma appears to be functionally and antigenically deficient in normal prekallikrein, it may actually contain a different prekallikrein which is activated by exposure to Celite but not by exposure to activated HF or trypsin.