Six novel missense mutations causing factor X deficiency and application of thrombin generation test

Several discrepancies in the description of the coagulation data presented in the article by Schiller and others1 are apparent. A patient with "definite" Factor X deficiency of a clinically severe degree should have an abnormal prothrombin time and thromboplastin generation test. The authors report these tests to be within normal limits. Also, a platelet adhesiveness of 74% is hardly "slightly reduced" by most published normal values which range from 20 to 80%. In addition, if "A.P.T.T." means "a partial thromboplastin time," then this test should also be abnormal.

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Endotoxins And Procqagulant Activities Of Ascitic Fluid

10.1055/s-0038-1652684 ◽

1981 ◽

Author(s):

H Murr ◽

P Schüssler ◽

G E Rindfleisch ◽

J Eisenburg ◽

E Hiller

Keyword(s):

Ascitic Fluid ◽

Thrombin Generation ◽

Procoagulant Activity ◽

Cirrhosis Of The Liver ◽

Coagulation System ◽

Factor X ◽

Monocytes And Macrophages ◽

Tissue Thromboplastin ◽

Generation Test ◽

Limulus Test

Procoagulant activities in ascitic fluid of patients with cirrhosis of the liver have been reported repeatedly. It has been suggested that they cause DIC after reinfusicn of ascitic fluid, however, the nature of these factors is unknown. Since endotoxins have been found in ascitic fluid and it is known that they can greatly augment the procoagulant activities of monocytes and macrophages, we assayed for the presence of endotoxin and compared the procoagulant activities in each of 15 specimens of ascitic fluid caused either by cirrhosis of the liver or by metastasizing tumors.Endotoxins were assayed by the limulus test. Procoagulant activities were determined by thrcmbelastography, thrombin generation test, the presence of soluble fibrin monomer complexes ( SFMC ) and the ability to activate prothrombin complex and factor X.Endotoxins were detected in 12 of 15 specimens of ascitic fluid caused by cirrhosis of the liver. In 11 of the endotoxin positive and in 2 of the 3 endotoxin negative samples procoagulant activity was present ( i.e. shortened reaction time, increased thrombin generation, activation of prothrombin complex ). In contrast, in only one out of the 15 samples of tumerous ascitic fluid the limulus test was positive. Nevertheless, in 9 of these 15 specimens procoagulant activity was present. In all specimens increased amounts of SFMC were found.The precise mechanism for the activation of the coagulation system following ascitic fluid reinfusion remains to be established. In addition to stimulation of macrophages by endotoxin other factors like tissue thromboplastin release from tumor cells or injured tissues may account for the procoagulant activity of ascitic fluid.

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TWO NOVEL MISSENSE MUTATIONS (THR233MET AND TRP308LEU) IN THE FACTOR X GENE AND THEIR FUNCTIONAL CONSEQUENCES IN A PATIENT WITH SEVERE FACTOR X DEFICIENCY

Journal of Thrombosis and Haemostasis ◽

10.1111/j.1538-7836.2007.tb00851.x ◽

2007 ◽

Vol 5 ◽

pp. O-M-024-O-M-024

Author(s):

Z. Bereczky ◽

T. Szabó ◽

G. Haramura ◽

I. Komáromi ◽

L. Muszbek

Keyword(s):

Missense Mutations ◽

Factor X ◽

Factor X Deficiency ◽

Functional Consequences ◽

X Gene

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Severe Congenital Factor X Deficiency in 5-Month-Old Child

Thrombosis and Haemostasis ◽

10.1055/s-0038-1654222 ◽

1970 ◽

Vol 24 (01/02) ◽

pp. 175-184 ◽

Cited By ~ 13

Author(s):

A Girolami ◽

G Molaro ◽

A Calligaris ◽

G De Luca

Keyword(s):

Normal Serum ◽

Factor Vii ◽

Brain Hemorrhage ◽

Factor X ◽

Clotting Factors ◽

Normal Limits ◽

Factor X Deficiency ◽

Normal Plasma ◽

Generation Test ◽

Congenital Factor

SummaryA case of severe congenital factor X deficiency is presented. The patient was a 5 month old child who had several episodes of melena since the first weeks of life. Other bleeding manifestations were subcutaneous hematomas and a massive brain hemorrhage. The prothrombin time was severely prolonged and was corrected by normal serum, aged normal plasma and by the plasma of patients with parahemophilia, congenital hypoprothrombinemia and factor VII deficiency. On the contrary adsorbed normal plasma and Mr. Stuart’s plasma failed to correct the abnormality.The partial thromboplastin time, prothrombin consumption and the thromboplastin generation test were abnormal too. The T.G.T. was corrected by the substitution of the patient’s serum with normal serum. The factor X level was less then 0.1% of normal. All other clotting factors were within normal limits.Both parents of the “propositus” showed slightly decreased levels of factor X in their plasmas and were considered to be heterozygotes for the defect.

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Severe factor X deficiency in three unrelated Palestinian patients is caused by homozygosity for the mutation c302delG-correlation with thrombin generation and thromboelastometry

Blood Coagulation & Fibrinolysis ◽

10.1097/mbc.0b013e32834ad785 ◽

2011 ◽

Vol 22 (8) ◽

pp. 673-679 ◽

Cited By ~ 2

Author(s):

Tami Livnat ◽

Boris Shenkman ◽

Gili Kenet ◽

Ilia Tamarin ◽

Samuel Gillis ◽

...

Keyword(s):

Thrombin Generation ◽

Factor X ◽

Factor X Deficiency

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Immunological Studies on the Blood Coagulation Factor X and Its Warfarin-induced Precursor

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649144 ◽

1974 ◽

Vol 31 (01) ◽

pp. 040-051 ◽

Cited By ~ 5

Author(s):

Gustav Gaudernack ◽

Åse Gladhaug Berre ◽

Bjarne Østerud ◽

Hans Prydz

Keyword(s):

Coagulation Factor ◽

Factor X ◽

Intrinsic Pathway ◽

Coagulation Activity ◽

Factor X Deficiency ◽

Warfarin Treatment ◽

The Cross ◽

Monospecific Antisera ◽

Purified Antigen ◽

Congenital Factor

SummaryMonospecific antisera against the human coagulation factor X have been raised in rabbits by injections of purified antigen. Such antiserum was used to study the cross-reacting material without factor X activity which is present in the blood of warfarin-treated patients and animals as well as to study the changes in factor X during coagulation. One patient with congenital factor X deficiency was also studied.A complete identity was found between factor X in Macaca mulatta and human blood. During warfarin treatment antigenically cross-reacting material appeared in plasma. This was not adsorbed on BaSO4, and inhibited the coagulation activity of normal factor X.Both this material, normal factor X and the cross-reacting material in plasma from a patient congenitally deficient in factor X gave rise to split products during coagulation by the intrinsic pathway, i. e. all of them served as substrates for the intrinsic activator of factor X.

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Experimental Studies on a Recombinant Hirudin, CGP 39393

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648151 ◽

1991 ◽

Vol 65 (04) ◽

pp. 355-359 ◽

Cited By ~ 12

Author(s):

E Gray ◽

J Watton ◽

S Cesmeli ◽

T W Barrowcliffe ◽

D P Thomas

Keyword(s):

Thrombin Generation ◽

Bleeding Time ◽

Thrombus Formation ◽

Experimental Studies ◽

Venous Stasis ◽

Antithrombotic Agent ◽

Recombinant Hirudin ◽

Excessive Bleeding ◽

Generation Test

SummaryThe in vitro anticoagulant activities of recombinant desulphatohirudin (r-hirudin) were studied in the activated partial thromboplastin time (APTT) and the thrombin generation test : systems. In the APTT at concentrations below 5 μg/ml, r-hirudin showed a dose-response curye. At concentrations above 5 μg/ml, the plasma became unclottable, but in the thrombin generation test , at least 10 μg/ml of r-hirudin was required for full inhibition of thrombin generation. The antithrombotic effect was assessed using a rabbit venous stasis model; 150 μg/ml r-hirudin completely prevented thrombus formation at 10 and 20 min stasis. At antithrombotic dose, the mean bleeding time ratio measured in a rabbit ear template model, was not prolonged over control values. At higher doses, the bleeding time ratios were higher than those observed for the same dosage of heparin. These data indicate that while r-hirudin is an effective antithrombotic agent, antithrombotic doses have to be carefully titrated to avoid excessive bleeding.

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The Ability of Thrombin Inhibitors to Reduce the Thrombin Activity Generated in Plasma on Extrinsic and Intrinsic Activation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655996 ◽

1997 ◽

Vol 77 (03) ◽

pp. 498-503 ◽

Cited By ~ 26

Author(s):

D Prasa ◽

L Svendsen ◽

J Stürzebecher

Keyword(s):

Active Site ◽

Thrombin Generation ◽

Anion Binding ◽

Thrombin Inhibitors ◽

Coagulation System ◽

Thrombin Activity ◽

Continuous Registration ◽

High Concentrations ◽

20 Nm ◽

Generation Test

SummaryIn a thrombin generation test with continuous registration of thrombin activity in plasma we studied the ability of a variety of thrombin inhibitors of different type and mechanism of action to influence the activity of thrombin after activation of the coagulation system. Depending on the inhibitor, the peak of thrombin activity is delayed and/or reduced.By blocking the active site of generated thrombin inhibitors cause a concentration dependent reduction of the thrombin peak and inhibit feed-back reactions of thrombin resulting in a delay of thrombin generation. Highly potent synthetic active-site directed inhibitors (Ki ≤ 20 nM) reduce the thrombin activity formed in plasma after extrinsic or intrinsic activation with the same efficiency (IC50 0.1 - 0.6 μM) as hirudin. The delay and reduction of thrombin generation by inhibitors of the anion-binding exosite 1 of thrombin is only attributed to an inhibition of feed-back reactions of thrombin. For a 50% reduction of thrombin activity in plasma by this type of inhibitors relatively high concentrations were determined.

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