Severe fletcher factor (plasma prekallikrein) deficiency with partial deficiency of hageman factor (factor xii): Report of a case with observation on in vivo and in vitro leukocyte chemotaxis

SummaryCombinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. Factor XII (FXII, Hageman factor) is a plasma protease that initiates the contact system. The biochemistry of the contact system in vitro is well understood; however, its in vivo functions are just beginning to emerge. The current review concentrates on activators and functions of the FXII-driven contact system in vivo. Elucidating its physiologic activities offers the exciting opportunity to develop strategies for the safe interference with both thrombotic and inflammatory diseases.

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Detection of Activation of the Contact System of Coagulation In Vitro and In Vivo: Quantitation of Activated Hageman Factor-C1-Inhibitor and Kallikrein-C1-Inhibitor Complexes by Specific Radioimmunoassays

Thrombosis and Haemostasis ◽

10.1055/s-0038-1645969 ◽

1987 ◽

Vol 58 (02) ◽

pp. 778-785 ◽

Cited By ~ 37

Author(s):

J H Nuijens ◽

C C M Huijbregts ◽

M Cohen ◽

G O Navis ◽

A de Vries ◽

...

Keyword(s):

Contact System ◽

Factor Xii ◽

Plasma Samples ◽

C1 Inhibitor ◽

Hageman Factor ◽

Plasma Factor ◽

Factor Xiia ◽

Kallikrein Activity

SummaryRadioimmunoassays (RIAs) for the detection of C1-inhihitor (C1-Inh) complexed to either kallikrein or activated Hageman factor (factor XIIa) are described. Kallikrein-C1-Inh or factor XIIa-C1-Inh complexes were bound to Scpharosc to which monospecific antibodies against (pre)kallikrein or factor XII, respectively, were coupled. Bound complexes were subsequently detected by an incubation with affinity purified 125I-labeled antibodies against Ci-Inh. These RIAs were used to detect activation of the contact system of coagulation in vitro and in vivo. Addition of dextran sulfate (DXS) (20 μg/ml) to fresh plasma resulted at 37° C in the rapid generation of amidolytic kallikrein activity, which was maximal after 1 to 2 min of incubation and subsequently decreased within a few minutes. The generation of kallikrein activity coincided with the appearance of both kallikrein-C1-Inh and factor XIIa-C1-Inh complexes. However, in contrast to kallikrein activity, both types of complexes remained detectable in the incubation mixtures during the incubation period. Experiments with purified kallikrein, C1-Inh and partly purified β-factor XIIa, and activation experiments in plasmas deficient in either factor XII or prekallikrein, demonstrated the specificity of both RIAs. The minimal amount of DXS that resulted in the generation of measurable amounts of both types of complexes in plasma was 2-3 μg per ml. Similar experiments with kaolin showed that with limiting amounts of activator (1-2 mg/ ml), only kallikrein-C1-Inh complexes were detected in plasma. When larger amounts of kaolin were added to plasma, factor XIIa-C1-Inh complexes were additionally detected in plasma. In plasma samples obtained from healthy donors under conditions that prevented activation of the contact system in vitro, very low levels of both factor XIIa-C1-Inh and kallikrein-C1-Inh complexes were measured, representing approximately 0.3% activation of both factor XII and prekallikrein. In serial plasma samples from a patient with adult respiratory distress syndrome, increased levels of both types of complexes were detected. The radioimmunoassays described in this paper provide useful tools to detect activation of the contact system in vitroas well as in vivo.

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Participation of Hageman Factor Dependent Pathways in Human Disease States

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651896 ◽

1977 ◽

Vol 38 (04) ◽

pp. 0751-0775 ◽

Cited By ~ 40

Author(s):

Robert W. Colman ◽

Patrick Y. Wong

Keyword(s):

Human Disease ◽

Gouty Arthritis ◽

Factor Xii ◽

Hageman Factor ◽

Disease States ◽

Artery Disease ◽

Extracorporeal Bypass ◽

Allergic Disorders

SummaryAbnormalities of Hageman factor dependent pathways have been described in a wide variety of human disease states. Congenital deficiencies of factor XII (Hageman trait) prekallikrein (Fletcher trait) and high molecular weight kininogen (Williams, Fitzgerald and Flaujeac traits) although resulting in profound in vitro changes, do not cause in vivo difficulties. In contrast, deficiency of Cl esterase inhibitor (hereditary angioedema) results in significant morbidity and mortality. Acquired diseases may exhibit decreased synthesis of these three proteins in cirrhosis and dengue fever. In vivo activation of factor XII initiated pathways occur in septic shock, disseminated or localized intravascular coagulation, typhoid fever, polycythemia vera, hyperbetalipoproteinemia, coronary artery disease, nephrotic syndrome, transfusion reactions, hemodialysis and extracorporeal bypass. Activation of both the intrinsic system and tissue mediators contribute to the vasomotor phenomena in carcinoid syndrome and postgastrectomy dumping. Roles for factor XII, prekallikrein and kininogen have been suggested in gouty arthritis, allergic disorders and cystic fibrosis but the evidence is not yet convincing in these disorders.

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Factor XII Activation Promotes Platelet Consumption in the Presence of Bacterial-Type Long-Chain Polyphosphate In Vitro and In Vivo

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.118.311193 ◽

2018 ◽

Vol 38 (8) ◽

pp. 1748-1760 ◽

Cited By ~ 15

Author(s):

Jevgenia Zilberman-Rudenko ◽

Stéphanie E. Reitsma ◽

Cristina Puy ◽

Rachel A. Rigg ◽

Stephanie A. Smith ◽

...

Keyword(s):

Factor Xii ◽

Bacterial Type ◽

Long Chain

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Inhibition by cholera toxin of rat polymorphonuclear leukocyte chemotaxis demonstrated in vitro and in vivo.

Infection and Immunity ◽

10.1128/iai.25.1.187-190.1979 ◽

1979 ◽

Vol 25 (1) ◽

pp. 187-190 ◽

Cited By ~ 5

Author(s):

M Roch-Arveiller ◽

P Boquet ◽

D Bradshaw ◽

J P Giroud

Keyword(s):

Cholera Toxin ◽

Polymorphonuclear Leukocyte ◽

Leukocyte Chemotaxis

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Activation of human factor VII during clotting in vitro

Blood ◽

10.1182/blood.v65.1.218.218 ◽

1985 ◽

Vol 65 (1) ◽

pp. 218-226 ◽

Cited By ~ 19

Author(s):

LV Rao ◽

SP Bajaj ◽

SI Rapaport

Keyword(s):

Tissue Factor ◽

Glass Tube ◽

Factor Vii ◽

Clotting Factor ◽

Activate Factor ◽

Factor Xii ◽

Factor X ◽

Normal Plasma

Abstract We have studied factor VII activation by measuring the ratio of factor VII clotting to coupled amidolytic activity (VIIc/VIIam) and cleavage of 125I-factor VII. In purified systems, a low concentration of Xa or a higher concentration of IXa rapidly activated 125I-factor VII, yielding a VIIc/VIIam ratio of 25 and similar gel profiles of heavy and light chain peaks of VIIa. On further incubation, VIIa activity diminished and a third 125I-peak appeared. When normal blood containing added 125I- factor VII was clotted in a glass tube, the VIIc/VIIam ratio rose fivefold, and 20% of the 125I-factor VII was cleaved. Clotting normal plasma in an activated partial thromboplastin time (APTT) system yielded a VIIc/VIIam ratio of 25 and over 90% cleavage of 125I-factor VII. Clotting factor XII-deficient plasma preincubated with antibodies to factor X in an APTT system with added XIa yielded a VIIc/VIIam ratio of 19 and about 60% cleavage, which indicates that IXa, at a concentration achievable in plasma, can effectively activate factor VII. Clotting normal plasma with undiluted tissue factor yielded a VIIc/VIIam ratio of 15 to 20 and 60% cleavage of 125I-factor VII, whereas clotting plasma with diluted tissue factor activated factor VII only minimally. We conclude that both Xa and IXa can function as significant activators of factor VII in in vitro clotting mixtures but believe that only small amounts of factor VII may be activated in vivo during hemostasis.

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A mechanism for hereditary angioedema with normal C1 inhibitor: an inhibitory regulatory role for the factor XII heavy chain

Blood ◽

10.1182/blood-2018-06-860270 ◽

2019 ◽

Vol 133 (10) ◽

pp. 1152-1163 ◽

Cited By ~ 22

Author(s):

Ivan Ivanov ◽

Anton Matafonov ◽

Mao-fu Sun ◽

Bassem M. Mohammed ◽

Qiufang Cheng ◽

...

Keyword(s):

Heavy Chain ◽

Hereditary Angioedema ◽

Catalytic Efficiency ◽

Regulatory Function ◽

Factor Xii ◽

C1 Inhibitor ◽

Contact Activation ◽

Inhibitory Function

Abstract The plasma proteins factor XII (FXII) and prekallikrein (PK) undergo reciprocal activation to the proteases FXIIa and kallikrein by a process that is enhanced by surfaces (contact activation) and regulated by the serpin C1 inhibitor. Kallikrein cleaves high-molecular-weight kininogen (HK), releasing the vasoactive peptide bradykinin. Patients with hereditary angioedema (HAE) experience episodes of soft tissue swelling as a consequence of unregulated kallikrein activity or increased prekallikrein activation. Although most HAE cases are caused by reduced plasma C1-inhibitor activity, HAE has been linked to lysine/arginine substitutions for Thr309 in FXII (FXII-Lys/Arg309). Here, we show that FXII-Lys/Arg309 is susceptible to cleavage after residue 309 by coagulation proteases (thrombin and FXIa), resulting in generation of a truncated form of FXII (δFXII). The catalytic efficiency of δFXII activation by kallikrein is 15-fold greater than for full-length FXII. The enhanced rate of reciprocal activation of PK and δFXII in human plasma and in mice appears to overwhelm the normal inhibitory function of C1 inhibitor, leading to increased HK cleavage. In mice given human FXII-Lys/Arg309, induction of thrombin generation by infusion of tissue factor results in enhanced HK cleavage as a consequence of δFXII formation. The effects of δFXII in vitro and in vivo are reproduced when wild-type FXII is bound by an antibody to the FXII heavy chain (HC; 15H8). The results contribute to our understanding of the predisposition of patients carrying FXII-Lys/Arg309 to angioedema after trauma, and reveal a regulatory function for the FXII HC that normally limits PK activation in plasma.

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Effect of short-term protein deprivation on hemopoietic functions of healthy volunteers

Blood ◽

10.1182/blood.v55.4.625.625 ◽

1980 ◽

Vol 55 (4) ◽

pp. 625-628 ◽

Cited By ~ 18

Author(s):

R Catchatourian ◽

G Eckerling ◽

W Fried

Keyword(s):

Body Weight ◽

G Protein ◽

Protein Deprivation ◽

Low Protein ◽

Leukocyte Function ◽

Leukocyte Chemotaxis ◽

Complete Blood Counts ◽

Excretion Rates

Abstract To ascertain the effects of protein deprivation on hemopoietic parameters in otherwise healthy subjects, three volunteers were placed on diets containing 0.15 g protein/kg body weight for 8 days followed in 2 mo by another 8-day study period during which they ingested their usual diets containing more than 0.9 g protein/kg body weight. Complete blood counts, serum protein determinations, and tests of in vitro and in vivo leukocyte chemotaxis were performed prior to and at the conclusion of each study period. Subjects were phlebotomized of 500 ml on day 7 of each study period. Twenty-four-hour urinary erythropoietin excretion rates were assayed just prior to and again postphlebotomy. Reticulocyte counts were performed at intervals up to 1 wk postphlebotomy. Some of these determinations were replicated during a subsequent study. The hemoglobin and hematocrits decrased slightly but significantly after 8 days on low protein diets. Erythropoietin excretion rates and reticulocyte responses to phlebotomy were also less marked while subjects were on protein depleted diets. Leukocyte chemotaxis, measured both in vitro and in vivo, was also markedly reduced while subjects were on protein-depleted diets. We conclude that 8 days of moderately severe protein deprivation significantly impairs erythropoiesis and leukocyte function in otherwise healthy individuals.

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A hitherto undescribed plasma factor acting at the contact phase of blood coagulation (Flaujeac factor): case report and coagulation studies

Blood ◽

10.1182/blood.v46.5.761.761 ◽

1975 ◽

Vol 46 (5) ◽

pp. 761-768 ◽

Cited By ~ 22

Author(s):

MJ Lacombe ◽

B Varet ◽

JP Levy

Keyword(s):

Blood Coagulation ◽

Coagulation Factor ◽

Old French ◽

Bleeding Tendency ◽

Contact Phase ◽

Hageman Factor ◽

Coagulation Defect ◽

Plasma Factor ◽

Fletcher Factor

Abstract This paper reports an asymptomatic coagulation defect responsible for an abnormality at the contact phase of blood coagulation in vitro, distinct from Hageman factor and Fletcher factor deficiencies. Coagulation studies in a 50-yr-old French woman without bleeding tendency revealed the following results: whole-blood clotting time in glass tubes and activated partial thromboplastin time with kaolin and ellagic acid were greatly prolonged; one-stage prothrombin was normal; no circulating anticoagulant was detected, and the infusion of normal plasma corrected the coagulation defect with an estimated half-life of 6.5 days; the levels of factor VIII, IX, XI, and XII were normal; mutual correction was obtained with a Fletcher factor-deficient plasma; the level of whole complement was normal. Studies of the contact phase of blood coagulation and contact-induced fibrinolysis showed the same abnormalities as in Hageman factor- and Fletcher-deficient plasmas. These results indicate that the patient's plasma is deficient in a previously undescribed coagulation factor, which participates in the initial stage of the blood coagulation process in vitro. Family studies revealed consanguinity in the propositus' parents. The assay of this newly described factor in the propositus' children revealed a partial defect, compatible with a heterozygous state, in three of the four tested children. This indicates a recessive inheritance of this new blood coagulation defect.

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In vivo roles of factor XII

Blood ◽

10.1182/blood-2012-07-292094 ◽

2012 ◽

Vol 120 (22) ◽

pp. 4296-4303 ◽

Cited By ~ 188

Author(s):

Thomas Renné ◽

Alvin H. Schmaier ◽

Katrin F. Nickel ◽

Margareta Blombäck ◽

Coen Maas

Keyword(s):

Thrombus Formation ◽

Coagulation Factor ◽

Special Focus ◽

Factor Xii ◽

Excessive Bleeding ◽

Charged Surfaces ◽

Factor Xiia ◽

Knockout Model

Abstract Coagulation factor XII (FXII, Hageman factor, EC = 3.4.21.38) is the zymogen of the serine protease, factor XIIa (FXIIa). FXII is converted to FXIIa through autoactivation induced by “contact” to charged surfaces. FXIIa is of crucial importance for fibrin formation in vitro, but deficiency in the protease is not associated with excessive bleeding. For decades, FXII was considered to have no function for coagulation in vivo. Our laboratory developed the first murine knockout model of FXII. Consistent with their human counterparts, FXII−/− mice have a normal hemostatic capacity. However, thrombus formation in FXII−/− mice is largely defective, and the animals are protected from experimental cerebral ischemia and pulmonary embolism. This murine model has created new interest in FXII because it raises the possibility for safe anticoagulation, which targets thrombosis without influence on hemostasis. We recently have identified platelet polyphosphate (an inorganic polymer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema during hypersensitivity reactions. Independent of its protease activity, FXII exerts mitogenic activity with implications for angiogenesis. The goal of this review is to summarize the in vivo functions of FXII, with special focus to its functions in thrombosis and vascular biology.

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