Targeted deletion of murine coagulation factor XII gene-a model for contact phase activation in vivo

2004 ◽  
Vol 92 (09) ◽  
pp. 503-508 ◽  
Author(s):  
Hans-Ulrich Pauer ◽  
Thomas Renné ◽  
Bernhard Hemmerlein ◽  
Tobias Legler ◽  
Saskia Fritzlar ◽  
...  
Keyword(s):  
Fetal Loss ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Mendelian Inheritance ◽  
Biological Role ◽  
Factor Xii ◽  
Wild Type ◽  
Contact Phase ◽  
Health And Disease

SummaryTo analyze the biological role of factor XII (FXII, Hageman Factor) in vivo, we generated mice deficient for FXII using a gene targeting approach on two distinct genetic backgrounds, i.e. mixed C57Bl/6J X 129X1/SvJ and inbred 129X1/SvJ. Homozygous FXII knockout (FXII-/-) mice showed no FXII plasma activity and had a markedly prolonged activated partial thromboplastin time (aPTT). In contrast, coagulation factors XI, VIII, IX, X,VII,V, II and fibrinogen did not differ between FXII-/- mice and their wild-type littermates. Heterozygous matings segregated according to the Mendelian inheritance indicating that FXII deficiency does not increase fetal loss. Furthermore, matings of FXII-/- males and FXII-/females resulted in normal litter sizes demonstrating that total FXII deficiency in FXII-/females does not affect pregnancy outcome. Also, gross and histological anatomy of FXII-/mice was indistinguishable from that of their wild-type littermates on both genetic backgrounds. Thus it appears that deficiency of murine FXII does not cause thrombophilia or impaired fibrinolysis in vivo. These results indicate that FXII deficiency does not affect hemostasis in vivo and we anticipate that the FXII-/mice will be helpful to elucidate the biological role(s) of FXII in health and disease.

Coagulation Factors Are Activators Of Human Plasma “Prorenin”

1981 ◽  
Author(s):  
D H Osmond ◽  
S R Tatemichi ◽  
E A Wilczynski ◽  
A D Purdon
Keyword(s):  
Human Plasma ◽  
Coagulation Factor ◽  
Plasma Renin ◽  
Coagulation Factors ◽  
Coagulation System ◽  
Activation Process ◽  
Special Importance ◽  
Factor Xii ◽  
Renin Content

We have demonstrated that human plasma “prorenin”, an inactive precursor of the blood pressure regulating enzyme renin, can be activated by cold, e.g. -4 to +4°C for 1-30 days (Can. J. Physiol. Pharmacol. 51:705, 1973). Several workers have reported cold activation of the coagulation system. Suspecting a link between these two cold- activated enzyme systems, we established that in factor XII deficient plasma, the rate of cold activation of prorenin is halved (Lancet i, 1313, 1978). Trypsinization of plasma can mimic within 1 minute the effect of prolonged cold (Circ. Res. Suppl . 1, 41:171, 1977), and can overcome specific coagulation factor deficiencies in varying degrees. FXII, VII, V, and especially FX deficient plasmas, all have subnormal basal active renin levels, implying an impaired state of prorenin conversion in vivo. FXII deficientplasma activates least by cold, suggesting special importance of FXII for operation of cold activation. All the plasmas activate better with 0.5 mg trypsin/ml plasma than with cold, except FX, suggesting that it especially mediates tryptic activation. Increasing the trypsin concentration corrects for factor deficiencies in varying degrees, implying some non-specificity and interchangeability of factor requirements for prorenin activation. Our data point to a hierarchy of factor importance, and to a “cascade7#x201D; of prorenin activation, by which plasma renin content can be rapidly increased. Thus, plasma renin activity is a function of renal release of renin, plus renin formation from renal (and possibly extrarenal) prorenin by an activation process involving the coagulation system.

scholarly journals Cold-induced contact surface activation of the prothrombin time in whole blood

Blood ◽  
1982 ◽  
Vol 59 (1) ◽  
pp. 38-42 ◽  
Author(s):  
RN Palmer ◽  
HR Gralnick
Keyword(s):  
Prothrombin Time ◽  
Whole Blood ◽  
Room Temperature ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Factor Xii ◽  
Contact Phase ◽  
Fletcher Factor ◽  
Esterase Inhibitor

Abstract Studies of the prothrombin time (PT) have revealed that contact with borosilicate or commercial siliconized borosilicate markedly shortens the PT. This shortening is related to the activation of the contact phase of blood coagulation. This shortening of the PT occurs in both normal whole blood and plasma when stored in borosilicate or siliconized borosilicate tubes at 4 degree C and to a lesser degree at room temperature. Studies indicated the importance of several coagulation factors in decreasing the PT. The PT did not change in blood deficient in factor XII or in plasma deficient in Fletcher factor or high molecular weight kininogen, while blood deficient in CI esterase inhibitor (CI INH) had the most profound shortening. Shortening of the PT correlated directly with increased levels of factor VII. When purified CI INH was added to normal blood, it markedly reduced the activation of factor VII and the shortening of the PT in a dose-related manner. These studies indicate the pivotal roles of the contact phase of coagulation in initiating activation of the PT and of CI INH in inhibiting the activation of the coagulation factor(s) responsible for the cold-promoted activation of factor VII.

scholarly journals Cold-induced contact surface activation of the prothrombin time in whole blood

Blood ◽  
1982 ◽  
Vol 59 (1) ◽  
pp. 38-42
Author(s):  
RN Palmer ◽  
HR Gralnick
Keyword(s):  
Prothrombin Time ◽  
Whole Blood ◽  
Room Temperature ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Factor Xii ◽  
Contact Phase ◽  
Fletcher Factor ◽  
Esterase Inhibitor

Studies of the prothrombin time (PT) have revealed that contact with borosilicate or commercial siliconized borosilicate markedly shortens the PT. This shortening is related to the activation of the contact phase of blood coagulation. This shortening of the PT occurs in both normal whole blood and plasma when stored in borosilicate or siliconized borosilicate tubes at 4 degree C and to a lesser degree at room temperature. Studies indicated the importance of several coagulation factors in decreasing the PT. The PT did not change in blood deficient in factor XII or in plasma deficient in Fletcher factor or high molecular weight kininogen, while blood deficient in CI esterase inhibitor (CI INH) had the most profound shortening. Shortening of the PT correlated directly with increased levels of factor VII. When purified CI INH was added to normal blood, it markedly reduced the activation of factor VII and the shortening of the PT in a dose-related manner. These studies indicate the pivotal roles of the contact phase of coagulation in initiating activation of the PT and of CI INH in inhibiting the activation of the coagulation factor(s) responsible for the cold-promoted activation of factor VII.

scholarly journals Characterization and visualization of murine coagulation factor VIII-producing cells in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Morisada Hayakawa ◽  
Asuka Sakata ◽  
Hiroko Hayakawa ◽  
Hikari Matsumoto ◽  
Takafumi Hiramoto ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Factor Viii ◽  
Fluorescent Protein ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Genetically Engineered ◽  
Coagulation Factor Viii ◽  
Liver Sinusoidal Endothelial Cells ◽  
Genetically Engineered Mice

AbstractCoagulation factors are produced from hepatocytes, whereas production of coagulation factor VIII (FVIII) from primary tissues and cell species is still controversial. Here, we tried to characterize primary FVIII-producing organ and cell species using genetically engineered mice, in which enhanced green fluorescent protein (EGFP) was expressed instead of the F8 gene. EGFP-positive FVIII-producing cells existed only in thin sinusoidal layer of the liver and characterized as CD31high, CD146high, and lymphatic vascular endothelial hyaluronan receptor 1 (Lyve1)+. EGFP-positive cells can be clearly distinguished from lymphatic endothelial cells in the expression profile of the podoplanin− and C-type lectin-like receptor-2 (CLEC-2)+. In embryogenesis, EGFP-positive cells began to emerge at E14.5 and subsequently increased according to liver maturation. Furthermore, plasma FVIII could be abolished by crossing F8 conditional deficient mice with Lyve1-Cre mice. In conclusion, in mice, FVIII is only produced from endothelial cells exhibiting CD31high, CD146high, Lyve1+, CLEC-2+, and podoplanin− in liver sinusoidal endothelial cells.

Fibrinolyse- und Thrombophilieparameter unter systemischer Prostaglandin E1-Therapie bei peripherer arterieller Verschlusskrankheit

VASA ◽  
2003 ◽  
Vol 32 (3) ◽  
pp. 145-148 ◽  
Author(s):  
Kuss ◽  
Heidrich ◽  
Koettgen
Keyword(s):  
Coagulation Factor ◽  
Plasminogen Activator Inhibitor ◽  
Bleeding Risk ◽  
Arterial Disease ◽  
Prostaglandin E ◽  
Factor Xii ◽  
Significant Difference ◽  
Peripheral Arterial ◽  
Fibrinolytic Capacity

Background: The study was designed to evaluate if there is any evidence of a hyperfibrinolytic bleeding-risk under systemic treatment with prostaglandin E1 (PGE1) of patients with peripheral arterial disease (PAD). Patients and methods: The in vivo effect of PGE1 on the fibrinolytic and hemostatic process was tested on 15 patients before and after treatment with Alprostadil for 21 days using D-dimers (DD), fibrinogen, prothrombin time (PT), partial thromboplastin time (PTT), antithrombin (AT), ProC-Global®, plasminogen, plasminogen activator inhibitor activity (PAI), alpha2-antiplasmin, coagulation factor XII, basal and activated fibrinolytic capacity (fib. cap.). Results: There was no significant difference in DD, fibrinogen, PT, PTT, AT, ProC-Global®, plasminogen, PAI, alpha2-antiplasmin, coagulation factor XII, basal and activated fibrinolytic capacity observed after the treatment. Conclusion: Summarizing this study there is no hyperfibrinolytic bleeding-risk after the systemic therapy with Alprostadil to be expected.

scholarly journals Coagulation Factor XII protects neurons from apoptosis by triggering a crosstalk between HGFR/c-Met and EGFR/ErbB1 signaling pathways

2020 ◽  
Author(s):  
Eugénie Garnier ◽  
Damien Levard ◽  
Carine Ali ◽  
Yannick Hommet ◽  
Tiziana Crepaldi ◽  
...  
Keyword(s):  
Growth Factor ◽  
Egf Receptor ◽  
Neuronal Cell ◽  
Coagulation Factor ◽  
Receptor Activation ◽  
Target Cells ◽  
Cultured Neurons ◽  
Factor Xii ◽  
Protective Effects

Abstract Background Factor XII (FXII) is a serine protease that participates in the intrinsic coagulation pathway. Several studies have shown that plasmatic FXII exert a deleterious role in cerebral ischemia and traumatic brain injury by promoting thrombo-inflammation. Nevertheless, the direct impact of FXII on neuronal cell fate remains unknown.Methods We investigated whether FXII influenced neuronal death induced in vivo by stereotaxic injection of N-methyl-D-Aspartate (NMDA) and in vitro by serum deprivation of cultured neurons.Results We found that FXII reduced brain lesions induced in vivo and protected cultured neurons from apoptosis through a growth factor-like effect. This mechanism was triggered by direct interaction with epidermal growth factor (EGF) receptor, activation of this receptor and engagement of anti-apoptotic intracellular pathways. Interestingly, the “proteolytically” active and two-chain form of FXII, αFXIIa, exerted additional protective effects by converting the pro-form of hepatocyte growth factor (HGF) into its mature form, which in turn activated HGF receptor (HGFR/c-Met) pathway. Lastly, the use of non-proteolytic FXII (αFXIIa-PPACK) unveiled an alternative EGFR and HGFR co-activation pathway, through co-receptor transphosphorylation. Conclusion This study describes novel mechanisms of action of FXII and discloses neurons as target cells for the protective effects of single and double-chain forms of FXII.

scholarly journals In vivo effects of human granulocyte neutral proteases on blood coagulation in green monkeys (cercopithecus aetiops)

1977 ◽  
Author(s):  
R. Egbring ◽  
M. Gramse ◽  
N. Heimburger ◽  
K. Havemann
Keyword(s):  
Proteolytic Enzymes ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Fibrinogen Concentration ◽  
Α2 Macroglobulin ◽  
In Vivo Effects ◽  
Neutral Proteases ◽  
Green Monkeys

Two neutral proteases (elastase-1ike = ELP, and chymotrypsin-like = CLP) derived from human PMN in highly purified form inactivate in vitro humanisolated coagulation factors (Thromb. Res. 6, 315, 1975). These effects can be observed also in human plasma, despite its high antiprotease capacity. (Blood February 1977).ELP and CLP (both free of endotoxin) were infused into green monkeys either separate or in combination to investigate a possible role of these proteolytic enzymes also in vivo. Activity of coagulation factors I - XIII and antiprotease potential has been followed for a 24 hour period in short intervals.A loss of activity of coagulation factor II, V, VIII, IX, X and XIII could be demonstrated. Fibrinogen concentration decreased and fibrinogen split products could be detected. In two-dimensional immunelectrophoresis α1-antitrypsin-ELP and α2-macroglobulin-ELP-complexes were demonstrable for about 6 hours after protease infusion. Bleeding complication occurred after injection of both enzymes.The results indicate a direct proteolysis of coagulation factors by PMN neutral proteases in vivo.We suggest that similar conditions are present in patients with acute leukemia or septicemia.

scholarly journals Factor XII in PMM2-CDG patients: role of N-glycosylation in the secretion and function of the first element of the contact pathway

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Raquel López-Gálvez ◽  
María Eugenia de la Morena-Barrio ◽  
Alberto López-Lera ◽  
Monika Pathak ◽  
Antonia Miñano ◽  
...  
Keyword(s):  
Factor Xii ◽  
Clinical Effects ◽  
Wild Type ◽  
Vascular Events ◽  
Contact Phase ◽  
Glycosylation Sites ◽  
Expression Model ◽  
Contact Pathway ◽  
And Function

Abstract Background Congenital disorders of glycosylation (CDG) are rare diseases with impaired glycosylation and multiorgan disfunction, including hemostatic and inflammatory disorders. Factor XII (FXII), the first element of the contact phase, has an emerging role in hemostasia and inflammation. FXII deficiency protects against thrombosis and the p.Thr309Lys variant is involved in hereditary angioedema through the hyperreactivity caused by the associated defective O-glycosylation. We studied FXII in CDG aiming to supply further information of the glycosylation of this molecule, and its functional and clinical effects. Plasma FXII from 46 PMM2-CDG patients was evaluated by coagulometric and by Western Blot in basal conditions, treated with N-glycosydase F or activated by silica or dextran sulfate. A recombinant FXII expression model was used to validate the secretion and glycosylation of wild-type and variants targeting the two described FXII N-glycosylation sites (p.Asn230Lys; p.Asn414Lys) as well as the p.Thr309Lys variant. Results PMM2-CDG patients had normal FXII levels (117%) but high proportions of a form lacking N-glycosylation at Asn414. Recombinant FXII p.Asn230Lys, and p.Asn230Lys&p.Asn414Lys had impaired secretion and increased intracellular retention compared to wild-type, p.Thr309Lys and p.Asn414Lys variants. The hypoglycosylated form of PMM2-CDG activated similarly than FXII fully glycosylated. Accordingly, no PMM2-CDG had angioedema. FXII levels did not associate to vascular events, but hypoglycosylated FXII, like hypoglycosylated transferrin, antithrombin and FXI levels did it. Conclusions N-glycosylation at Asn230 is essential for FXII secretion. PMM2-CDG have high levels of FXII lacking N-glycosylation at Asn414, but this glycoform displays similar activation than fully glycosylated, explaining the absence of angioedema in CDG.

scholarly journals In vivo roles of factor XII

Blood ◽  
2012 ◽  
Vol 120 (22) ◽  
pp. 4296-4303 ◽  
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.

Implications of Heparinoid-Induced Inactivation of Coagulation Cascade Factors and In Vivo Proenzyme Concentration.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1621-1621
Author(s):  
Sanjay Patel ◽  
Leslie R. Berry ◽  
Mark W.C. Hatton ◽  
Anthony Chan
Keyword(s):  
Plasma Concentration ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Coagulation Cascade ◽  
Factor Xii ◽  
Initiation Factors ◽  
Inhibition Studies ◽  
The Impact ◽  
Covalent Complex

Abstract Heparin is a commonly used anticoagulant in the treatment of thrombosis. We have compared heparinoid-stimulated inhibition rates with the in vivo plasma concentration of antithrombin (AT)-inhibitable coagulation factors. Second order rate constants (k2) for inhibition of activated factors by either AT + unfractionated heparin (AT+UFH) mixtures or a novel covalent complex of AT and heparin (ATH) (Chan et al, J Biol Chem, 272:22111, 1997) were determined by discontinuous assay. A plot of k2 values (mean ± SEM; n ≥5) versus the respective human plasma concentration of coagulation factors revealed a linear correlation (with R2 values of 0.93 for AT+UFH and 0.90 for ATH, excluding factor XII), in which neutralization efficiency was proportional to in vivo factor level (see Figure). Anticoagulant actions of AT+UFH and ATH were more oriented towards treatment than prophylaxis since inhibition of cascade end point enzymes (thrombin and factor Xa) was more rapid than factors involved in coagulation initiation (factors VIIa and XIa). However, ATH exhibited more enhanced inhibition rates against factors VIIa, IXa and XIa than against factor Xa and thrombin, suggestive of an improved prophylactic profile compared to AT+UFH. Intriguingly, factor XII did not follow this trend, further challenging its role in the coagulation cascade. The impact of these assertions requires confirmation by in vivo inhibition studies. Figure Figure

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