Analysis of an Inherited Dysfibrinogenemia Pedigree Associated with a Heterozygous Mutation in the FGA Gene

Abstract Objective This article aims to analyze the phenotype and genotype of an inherited dysfibrinogenemia pedigree associated with a heterozygous mutation in the FGA gene, and to investigate the pathogenesis of this disease. Clinical Presentation The proband of interest is a 29-year-old woman. She was in her 37 weeks of gestation. Routine coagulation tests showed low fibrinogen activity (0.91 g/L; normal range: 2.0–4.0 g/L) and normal fibrinogen antigen (FIB:Ag) level (2.09 g/L; normal range: 2.0–4.0 g/L). Techniques The prothrombin time, activated partial thromboplastin time, thrombin time, and activity of plasma fibrinogen (FIB:C) were detected by the one-stage clotting method. The FIB:Ag, D-dimer, and fibrinogen degradation products were tested by the immunoturbidimetry method. To identify the novel missense mutation, fibrinogen gene sequencing and molecular modeling were performed. We used ClustalX-2.1-win and online bioinformatic software to analyze the conservation and possible effect of the amino acid substitution on fibrinogen. Results Phenotypic analysis revealed that the FIB:C of the proband was significantly reduced while the FIB:Ag was normal. Sequencing analysis detected a heterozygous C.2185G > A point mutation in the FGA gene (AαGlu710Lys). Bioinformatic and modeling analyses indicated that the mutation probably caused harmful effects on fibrinogen. Conclusion The heterozygous mutation of Glu710Lys in the FGA gene was identified that could cause the reduction of the FIB structure stability and result in the dysfibrinogenemia.

Download Full-text

Influence Of Elastase On Blood Coagulation Factors: Studies In Vitro, In Rats And In Göttinger Miniatur Pigs

10.1055/s-0038-1653045 ◽

1981 ◽

Author(s):

U Kasten ◽

U Artmann ◽

T Kaethner ◽

H Burchardi ◽

H Köstering

Keyword(s):

Blood Coagulation ◽

Coagulation Factors ◽

Bleeding Complications ◽

Thrombin Time ◽

Normal Range ◽

Blood Coagulation Factors ◽

Acute Respiratory Insufficiency ◽

Coagulation Tests ◽

Antifibrinolytic Drugs

The influence of blood coagulation factors in pat. with acute respiratory insufficiency of adults, especially of the so called “pancreatitis lungs” is still unknown. In order to find out the effect of elastase, possibly activated by trypsin in pat. with acute pancreatitis, on blood coagulation factors, we performed some studies. In vitro elastase induces in plasma and blood in correlation to the dosages Enhancement of thrombingeneration in the TGT, a shortening of PTT, Thrombin time and of r- and k-time in the TEG, a loss of fibrinogen and an increase of fibrinmono-mercomplexes. In another study, elastase (960 U/ kg b.w.) was injected intravenously in rats. 30 min. later there was found a loss of fibrinogen, number of platelets, Prothrombin and a prolongation of PTT and Thrombin time and an increase of fibrinomonomercomplexes, especially in these rats, which received beside elastase Kalikreininhibitors or antifibrinolytic drugs. After repeated injections (3 times within 30 h) we found histomorpholgically thrombi as well as bleeding complications. In another study we performed (150 min) an infusion of elastase (333 U/kg b.w./h) to 9 pigs. We determined a loss of fibrinogen of platelets, of F. II, F. VII and F. XIII, a prolongation of PTT. F. VIII and F. V remained within the normal range But there was found an enhancement of Thrombin generation in the TGT, too. Compariening the results of blood coagulation tests and of histomorphological findings, elastase induced a DIC. We have to discuss their influence on ARIA and “Pancreatic lungs”.

Download Full-text

Alteration of Coagulation in Intensively Transfused Hemophilic Patients

10.1055/s-0039-1680442 ◽

1977 ◽

Author(s):

Helen S. Hathaway ◽

Roger D. Hamstra ◽

Linda Jacobson ◽

William E. Hathaway

Keyword(s):

Factor Viii ◽

Degradation Products ◽

Bleeding Tendency ◽

Transfusion Therapy ◽

Coagulation Tests ◽

Factor Viii Concentrates ◽

The One ◽

Altered Proteins ◽

Dose Factor

Bleeding may occasionally occur in adequately transfused hemophilic patients. To investigate this phenomenon, 11 patients with classical hemophilia had serial coagulation studies performed during intensive transfusion therapy with factor VIII concentrates given for surgical procedures. The studies included kaolin partial thromboplastin times (KPTT), fibrinogen, monomer, and fibrin split products (FSP) levels, and assays for factor VIII by the one-stage PTT method (PTT-VIII), thromboplastin generation time method (TGT-VIII), and immunologic method (VIII Ag). After an initial correcting dose, factor VIII concentrates were administered once to twice daily in a dose to keep the minimal level above 20 percent. Alterations of coagulation assays were most pronounced 7–10 days postoperatively. These included (1) KPTT values at least 20 seconds longer than expected for the percent factor VIII;(2) TGT-VIII levels consistently higher than PTT-VIII levels (mean difference was 20 percent);(3) VIII Ag values from 216–660 percent of normal. Fibrin monomer and FSP tests were frequently positive and fibrinogen levels ranged from 300–700 mgm percent. Four patients exhibited spontaneous wound bleeding on postoperative days 7, 7, 9, and 12 in spite of adequate factor VIII levels. These studies and the results of in vitro experiments with factor VIII concentrates suggest that altered proteins or degradation products of fibrinogen or factor VIII may produce spurious values for coagulation tests and may be associated with an increased bleeding tendency and/or abnormal wound healing.

Download Full-text

Two Novel Mutations Cause Hereditary Antithrombin Deficiency in a Chinese Family

Acta Haematologica ◽

10.1159/000502109 ◽

2019 ◽

Vol 143 (3) ◽

pp. 260-265

Author(s):

Haiyue Zhang ◽

Siqi Liu ◽

Shasha Luo ◽

Yanhui Jin ◽

Lihong Yang ◽

...

Keyword(s):

Frameshift Mutation ◽

Gene Sequencing ◽

Chinese Family ◽

Compound Heterozygous ◽

Sequencing Analysis ◽

The Novel ◽

Normal Range ◽

Novel Mutations ◽

Antithrombin Deficiency ◽

At Deficiency

Objective: To study the molecular basis of hereditary antithrombin (AT) deficiency in a Chinese family. It will help us understand the pathogenesis of this type of disease. Method: AT activity (AT:A) and the AT antigen (AT:Ag) level were tested by chromogenic substrate and immunoturbidimetry, respectively. To identify the novel mutations, SERPINC1 gene sequencing was carried out. The possible impact of the mutations was analyzed by model and bioinformatic analyses. Results: AT:A and the AT:Ag level of the proband were 43% and 113 mg/L (normal range: 98–119% and 250–360 mg/L), respectively. Sequencing analysis revealed compound heterozygous mutations, including a frameshift mutation (c.318_319insT) resulting in Asn75stop and a missense mutation (c.922G>T) resulting in Gly276Cys. The bioinformatic and model analyses indicated that these mutations may disrupt the function and structure of the AT protein. Conclusion: We detected 2 novel heterozygous mutations (c.318_319insT and c.922G>T) in the proband, and these were associated with decreased AT:A.

Download Full-text

Genetic and clinical phenotypic analysis of familial stapes sclerosis caused by a NOG mutation

10.21203/rs.3.rs-42135/v3 ◽

2020 ◽

Author(s):

Rong Yu ◽

Hongqun Jiang ◽

Wugen Luo

Keyword(s):

Clinical Phenotype ◽

Skeletal Development ◽

Family Members ◽

Sequencing Analysis ◽

The Novel ◽

Phenotypic Analysis ◽

Her Family ◽

Morphogenetic Protein ◽

Second Generation Sequencing ◽

Normal Controls

Abstract Background: The noggin protein encoded by the NOG gene can interfere with the binding of bone morphogenetic protein to its receptor, thus affecting bone and joint development. The symptoms include abnormal skeletal development and conductive deafness.Methods: In a retrospective study, clinical data of the proband and her family members, including 8 people and 50 healthy normal controls, were collected. Second-generation sequencing was performed on peripheral blood samples from them.Results: The sequencing analysis indicated that in the proband, the NOG gene had a c.532T>C, p.C178R (cytosine deletion, NM_005450.6:c.532T>C), leading to an amino acid change. The proband's father, grandmother, second sister, and third sister also had this mutation, whereas family members with normal phenotypes did not have the mutation.Conclusion: Analysis of this family showed that the novel presentation of the c.532T>C mutation in the NOG gene resulted in syndrome-type autosomal dominant inheritance reflected in a mild clinical phenotype, which is of great importance for further studies of the clinical phenotype and pathogenesis of stapes sclerosis.

Download Full-text

Genetic and clinical phenotypic analysis of familial stapes sclerosis caused by a NOG mutation

10.21203/rs.3.rs-42135/v4 ◽

2020 ◽

Author(s):

Rong Yu ◽

Hong-Qun Jiang ◽

Hui-Huang Liao ◽

Wu-Gen Luo

Keyword(s):

Clinical Phenotype ◽

Skeletal Development ◽

Family Members ◽

Sequencing Analysis ◽

The Novel ◽

Phenotypic Analysis ◽

Her Family ◽

Morphogenetic Protein ◽

Second Generation Sequencing ◽

Normal Controls

Abstract Background: The noggin protein encoded by the NOG gene can interfere with the binding of bone morphogenetic protein to its receptor, thus affecting bone and joint development. The symptoms include abnormal skeletal development and conductive deafness.Methods: In a retrospective study, clinical data of the proband and her family members, including 8 people and 50 healthy normal controls, were collected. Second-generation sequencing was performed on peripheral blood samples from them.Results: The sequencing analysis indicated that in the proband, the NOG gene had a c.532T>C, p.C178R (cytosine deletion, NM_005450.6:c.532T>C), leading to an amino acid change. The proband's father, grandmother, second sister, and third sister also had this mutation, whereas family members with normal phenotypes did not have the mutation.Conclusion: Analysis of this family showed that the novel presentation of the c.532T>C, p.C178R mutation in the NOG gene resulted in syndrome-type autosomal dominant inheritance reflected in a mild clinical phenotype, which is of great importance for further studies of the clinical phenotype and pathogenesis of stapes sclerosis.

Download Full-text

Genetic and clinical phenotypic analysis of familial stapes sclerosis caused by an NOG mutation

BMC Medical Genomics ◽

10.1186/s12920-020-00843-5 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Rong Yu ◽

Hongqun Jiang ◽

Huihuang Liao ◽

Wugen Luo

Keyword(s):

Clinical Phenotype ◽

Skeletal Development ◽

Family Members ◽

Sequencing Analysis ◽

The Novel ◽

Phenotypic Analysis ◽

Her Family ◽

Morphogenetic Protein ◽

Second Generation Sequencing ◽

Normal Controls

Abstract Background The noggin protein encoded by the NOG gene can interfere with the binding of bone morphogenetic protein to its receptor, thus affecting bone and joint development. The symptoms include abnormal skeletal development and conductive deafness. Methods In a retrospective study, clinical data of the proband and her family members, including 8 people and 50 healthy normal controls, were collected. Second-generation sequencing was performed on peripheral blood samples from them. Results The sequencing analysis indicated that in the proband, the NOG gene had a c.532T > C, p.C178R (cytosine deletion, NM_005450.6:c.532T > C), leading to an amino acid change. The proband's father, grandmother, second sister, and third sister also had this mutation, whereas family members with normal phenotypes did not have the mutation. Conclusion Analysis of this family showed that the novel presentation of the c.532T > C, p.C178R mutation in the NOG gene resulted in syndrome-type autosomal dominant inheritance reflected in a mild clinical phenotype, which is of great importance for further studies of the clinical phenotype and pathogenesis of stapes sclerosis.

Download Full-text

A New Type of Congenital Dysfibrinogenemia (Fibrinogen Tokyo) with Defective Stabilization of Fibrin Polymers

10.1055/s-0039-1689117 ◽

1975 ◽

Cited By ~ 2

Author(s):

T. Samori ◽

M. Yatabe ◽

M. Ukita ◽

M. Fujimaki ◽

K. Fukutake

Keyword(s):

Factor Xiii ◽

Fibrinogen Level ◽

Degradation Products ◽

Immunological Methods ◽

Thrombin Time ◽

Normal Range ◽

Plasma Factor ◽

New Type ◽

Abnormal Pattern ◽

Assay Methods

A new type of congenital dysfibrinogenemia characterized by abnormal stabilization of fibrin polymers under the normal concentration of plasma factor XIII and normal thrombin time has been discovered in Tokyo.The molecular abnormality of this abnormal fibrinogen are shown by an anodal immunoelectrophoretic mobility and an abnormal pattern of D fragment in fibrinogen degradation products by plasmin digest on Immunoelectrophoresis and crossimmunoelectrophoresis.However, the plasma fibrinogen level of this case measures always in the normal range, when immunological methods or thrombin dependent methods are used, and the decreased level of plasma factor XIII is indicated by the use of assay methods based on clotlysis.

Download Full-text

Mechanisms Of Coagulopathy After Envenomation By The Eastern Diamondback Rattlesnake

10.1055/s-0038-1652103 ◽

1981 ◽

Author(s):

C S Kitchens ◽

L H S Van Mierop

Keyword(s):

Platelet Count ◽

Degradation Products ◽

Thrombin Time ◽

Agkistrodon Piscivorus ◽

Fibrin Degradation Products ◽

Coagulation Tests ◽

At Iii ◽

Diamondback Rattlesnake ◽

Sistrurus Miliarius ◽

Secondary Activation

All 34 patients seen at this hospital during the 19781980 period who were envenomated by poisonous snakes were studied in a prospective manner with respect to their hemostatic system. Blood was drawn on the patient’s arrival to the emergency room and every 6 h thereafter. Blood was analysed for platelet count; routine coagulation tests; levels of factors II, VIII, IX, XII; clottable fibrinogen; fibrinogen antigen; fibrin degradation products (FDP); plasminogen (PI); antithrombin III (AT III); α2 plasmin inhibitor (API); and plasminogen activator (PA). Twelve of the 34 patients underwent a coagulopathy as described below. These patients included all 10 patients envenomated by the Eastern diamondback rattlesnake (Crotalus adamanteus) and 2 of 17 patients bitten by the pygmy rattlesnake (Sistrurus miliarius). Values of all the above coagulation tests in 15 pygmy rattlesnake and 7 moccasin (Agkistrodon piscivorus) victims were indistinguishable from normal. Patients undergoing coagulopathy rapidly developed noncoagulable blood as defined by a thrombin time (TT) >120 s; blood remained incoagulable for an average of 18 h. The nadir clottable fibrinogen (0 mg/dl), fibrinogen antigen (99 mg/dl), Pl (20% of normal), API (17% of normal), and maximal levels of FDP (1:4096) and PA (20 times normal) were all significantly (p < 0.001) altered when compared with normal values. The platelet count and AT III levels were only midly decreased. Factors II, VIII, IX, and XII were normal. Because venom from the Eastern diamondback rattlesnake does not directly activate Pl, we conclude that the coagulopathy following envenomation by that reptile appears to be due to partial proteolysis of the fibrinogen with secondary activation of Pl by PA released from the endothelium. The resulting defibrination is distinguishable from disseminated intravascular coagulation.

Download Full-text

Genetic and clinical phenotypic analysis of familial stapes sclerosis caused by a NOG mutation

10.21203/rs.3.rs-42135/v2 ◽

2020 ◽

Author(s):

Rong Yu ◽

HONGQUN JIANG ◽

WU GEN LUO

Keyword(s):

Clinical Phenotype ◽

Skeletal Development ◽

Family Members ◽

Sequencing Analysis ◽

The Novel ◽

Phenotypic Analysis ◽

Her Family ◽

Morphogenetic Protein ◽

Second Generation Sequencing ◽

Normal Controls

Abstract Background: The noggin protein encoded by the NOG gene can interfere with the binding of bone morphogenetic protein to its receptor, thus affecting bone and joint development. The symptoms include abnormal skeletal development and conductive deafness. Methods: In a retrospective study, clinical data of the proband and her family members, including 8 people and 50 healthy normal controls, were collected. Second-generation sequencing was performed on peripheral blood samples from them. Results: The sequencing analysis indicated that in the proband, the NOG gene had a c.532T>C mutation (cytosine deletion, NM_005450.6:c.532T>C), leading to an amino acid change. The proband's father, grandmother, second sister, and third sister also had this mutation, whereas family members with normal phenotypes did not have the mutation. Conclusion: Analysis of this family showed that the novel presentation of the c.532T>C mutation in the NOG gene resulted in syndrome-type autosomal dominant inheritance reflected in a mild clinical phenotype, which is of great importance for further studies of the clinical phenotype and pathogenesis of stapes sclerosis.

Download Full-text

Coagulation Abnormalities in Dogs with Neoplastic Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650076 ◽

1980 ◽

Vol 44 (01) ◽

pp. 035-038 ◽

Cited By ~ 38

Author(s):

Bruce R Madewell ◽

Bernard F Feldman ◽

Sharron O’Neill

Keyword(s):

Clinical Evidence ◽

Degradation Products ◽

Blood Film ◽

Neoplastic Disease ◽

Thrombin Time ◽

Laboratory Methods ◽

Fibrin Degradation Products ◽

Lysis Time ◽

Coagulation Tests ◽

Euglobulin Lysis Time

SummaryConventional laboratory methods were used to screen untreated tumor-bearing dogs for hemostatic abnormalities. Excluded from study were dogs with clinical evidence of bleeding. The primary site for neoplastic disease in 100 dogs studied included hemolymphatic system, skin, bone, thyroid gland, oropharynx, mammary gland, and nasal cavity.Eighty-three percent of the dogs had one or more abnormal coagulation tests. Thrombocytopenia occurred in 36 dogs and 3 had thrombocytosis. Twenty-five dogs had hypofibrinogenemia, and 25 had hyperfibrinogenemia. There were 32 dogs with prolongation of the activated partial thromboplastin time, 10 dogs with shortened prothrombin time, and 6 dogs with prolongation of the thrombin time. Sixteen dogs had positive protamine sulfate (paracoagulation) reaction, and 8% had increased plasma fibrin degradation products. The euglobulin lysis time was accelerated in 24% of the dogs, and 15% had schistocytes on blood film.These data indicate that the majority of dogs with advanced neoplasms are likely to have abnormal coagulation tests.

Download Full-text