A novel fibrinogen Bβ chain frameshift mutation in a patient with severe congenital hypofibrinogenaemia

2006 ◽  
Vol 95 (06) ◽  
pp. 931-935 ◽  
Author(s):  
Zhimin Zhai ◽  
Rongfu Zhou ◽  
Xuefeng Wang ◽  
Hongli Wang ◽  
Kaiyang Ding ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
Fibrinogen Level ◽  
Stop Codon ◽  
Genetic Defect ◽  
Severe Bleeding ◽  
Thrombin Time ◽  
Clotting Time ◽  
Congenital Afibrinogenemia ◽  
Bleeding Episodes ◽  
Low Levels

SummaryCongenital afibrinogenemia and severe hypofibrinogenemia are severe bleeding disorders characterized by either undetectable or very low levels of fibrinogen in patients’ plasma and platelets. A majority of the reported cases are caused by mutations in the fibrinogen Aα chain. In this study, we identified a genetic defect in the fibrinogen Bβ-chain (FGB) underlying severe hypofibrinogenemia. The propositus frequently displayed bleeding episodes with a prolonged blood-clotting time (thrombin time > 180 s,activated partial thromboplastin time > 300 s, prothrombin time > 120 s) and had a very low level of plasma fibrinogen (1.7–1.8 mg/dl). His parents had a consanguineous marriage, and their functional and immunological fibrinogen was approximately half of the normal level.The platelet fibrinogen level of the propositus could not be detected by western blotting, and his platelet aggregation was severely impaired. DNA screening of the whole fibrinogen gene revealed a homozygous GGGG→GGG mutation at nucleotide 7969–7972 in his FGB gene. The propositus’ parents are both heterozygous for this mutation. This mutation contributes to Gly419→Val, and the 419–434 codons are frame shifted, and a stop codon is formed at codon 435.The predicted truncated Bβ-chain is 27 amino acids shorter than the normal Bβ-chain and a central β-strand in the globular βC domain is absent,which may lead to destabilization of the entire β-domain. To the best of our knowledge, this is the first report of such a mutation which is associated with severe hypofibrinogenemia.

Disseminated Intravascular Coagulation: A Clinical/Laboratory Correlation In 48 Patients

1981 ◽  
Author(s):  
R L Bick
Keyword(s):  
Platelet Count ◽  
Disseminated Intravascular Coagulation ◽  
Clinical Laboratory ◽  
Fibrinogen Level ◽  
Degradation Products ◽  
Severe Bleeding ◽  
Thrombin Time ◽  
Intravascular Coagulation ◽  
At Iii ◽  
Pre Treatment

Disseminated intravascular coagulation (DIC) is a frequent clinical entity spanning from a moderately severe bleeding disorder to a catastrophic, fulminant, and often fatal form usually associated with hemorrhage or, less commonly,as diffuse thromboses. The clinical and laboratory features of DIC remain confusing and controversial. To critically evaluate the usefulness of coagulation tests in aiding in the diagnosis and monitoring of therapy in DIC the clinical and laboratory findings were summarized in 48 patients with DIC. All patients were subjected to a prothrombin time (PT), activated partial thromboplastin time (PTT), reptilase time (RT), thrombin time (TT), fibrin(ogen) degradation products (FDP), platelet count, protamine sulfate test (PSO4), fibrinogen determination, and biological antithrombin-III (AT-III) level at the time of diagnosis. In addition, these same laboratory modalities were used to monitor patients during and after therapy. In this series of 48 patients, 38 patients had acute DIC and 10 patients had chronic DIC. In those patients with acute DIC, 100% of patients presented with hemorrhage and 53% of patients had thrombosis; 26% of patients died of their DIC type syndrome. In those patients with chronic DIC, 100% presented with hemorrhage, 80% presented with thrombosis, and none died of their intravascular clotting process. The probability of a pre-treatment abnormality in acute DIC was: FDP > AT-III = platelet count PS04 > TT > PT > fibrinogen level > PTT > RT. The probability of pre-treatment abnormalties in chronic DIC was: FDP > PSO4 = PT > AT-III = RT platelet count fibrinogen level = TT. These studies suggest the FDP level, the AT-III level, PSO4, and fibrinogen level to be reliable for aiding in the diagnosis of acute DIC. In chronic DIC the fibrinogen level, PS04, PTT, and AT-III level appear to be the most reliable indicies.

Quantitation of the Coagulation Inhibition in Vivo Due to Breakdown Products of Fibrin

1970 ◽  
Vol 23 (03) ◽  
pp. 477-485 ◽  
Author(s):  
P. S Mitchell ◽  
F. K Beller
Keyword(s):  
Blood Clotting ◽  
Fibrinogen Level ◽  
Degradation Products ◽  
Thrombin Time ◽  
Clotting Time ◽  
Human Fibrinogen ◽  
Quantitative Basis ◽  
Coagulation Inhibition

SummaryDegradation products of human fibrinogen were prepared by in vitro lysis of fibrin clots by urokinase activation and injected into rabbits on a quantitative basis. The dose necessary to anticoagulate the animal was equal to 2½ to 3 times the animals’ fibrinogen level. The effect on whole blood clotting time and thrombin time lasted for approximately 2 hrs. The “r” time of the TEG returned to normal after 1 hr while the “Max” value remained abnormal for more than 120 min. Degradation product E was shown to clear more rapidly than D by immunochemical techniques. The overall T ½ clearance was found to be approximately 12 hrs.

Bernard-Soulier Syndrome with Severe Bleeding: Absent Platelet Glycoprotein lb alpha Due to a Homozygous One-base Deletion

1996 ◽  
Vol 76 (05) ◽  
pp. 670-674 ◽  
Author(s):  
Chaoyang Li ◽  
Dominick N Pasquale ◽  
Gerald J Roth
Keyword(s):  
Stop Codon ◽  
Surface Membrane ◽  
Genetic Defect ◽  
Premature Stop Codon ◽  
Platelet Glycoprotein ◽  
Severe Bleeding ◽  
Giant Platelets ◽  
Platelet Disorder ◽  
Oligonucleotide Hybridization ◽  
Bernard Soulier Syndrome

SummaryBernard-Soulier syndrome is a rare congenital platelet disorder that affects a surface membrane adhesion receptor, glycoprotein (GP) Ib-V-IX. Both the genetic defects and the bleeding diatheses associated with the syndrome are heterogeneous due, in part, to the complexity of the involved receptor which consists of four different members, GPs: Ibα-Mr 143 K (contains the von Willebrand factor-binding site), Ibβ-Mr 22 K, V-Mr 83 K and IX-Mr 20 K. We studied a kindred that includes a 40 year-old man with severe Bernard-Soulier syndrome: life-threatening gastrointestinal bleeding, thrombocytopenia, giant platelets and absent ristocetin-dependent platelet aggregation. By Southern blotting, PCR amplification/sequencing, hetero-duplex analysis, and allele-specific oligonucleotide hybridization, the Ib-V-IX genes were analyzed, and the molecular genetic defect was defined as a one-base deletion in the GPIbα gene, involving an adenine of codon 19. The mutation, K19R, homozygous in the propositus and heterozygous in the available unaffected relatives, leads to a frame shift in codons 19-21 and a premature stop codon after codon 21. No functional GPIbα can be produced from the mutant allele, implying that the platelets of the affected patient lack all GPIbα. Within the spectrum of Bernard-Soulier syndrome, this patient’s disorder exemplifies a severe or “classic” extreme; an “experiment of Nature” that illustrates the effect of a complete deficiency of the ligand-binding chain (GPIbα) of the GPIb-V-IX receptor.

Intravascular Coagulation and Fibrinolysis by Stapliylocoagiilase. Comparison with Thrombin

1965 ◽  
Vol 13 (02) ◽  
pp. 457-469 ◽  
Author(s):  
J Jeljaszewicz ◽  
S Niewiarowski ◽  
A Poplawski ◽  
J Prokopowicz ◽  
K Worowski
Keyword(s):  
Intravenous Injection ◽  
Antithrombin Iii ◽  
Fibrinogen Level ◽  
Thrombin Time ◽  
Clotting Time ◽  
Short Time ◽  
Coagulation And Fibrinolysis ◽  
In Vitro Comparison

SummaryIntravascular clotting in rabbits after intravenous injection of 30 N.I.H. units of thrombin/kg and 5/mg/kg of staphylocoagulase were studied. Following determinations were made : clotting time, thrombin time, fibrinogen, factors V, VII, VIII, X, XI and XII, “true prothrombin”, two stage prothrombin, P-P test, prothrombin consumption, fibrinolysis in serum euglobulins, plasminogen, antithrombin III and VI, and coagulase reacting factor. Intravenous staphylocoagulase produced in rabbits precipitous drop of fibrinogen level in a very short time, which was not observed with the dose of thrombin used. Activity of staphylocoagulase in vivo was very much higher than of thrombin, as it could be expected on basis of the in vitro comparison. Together with defibrination caused by staphylocoagulase, fibrinogen breakdown products, identified as antithrombin VI, appear in plasma. There were no such changes observed when thrombin was used. Slight decrease of prothrombin and antithrombin III levels, together with a lack of significant changes in factors V, VII, VIII, X, XI and XII content, were observed after staphylocoagulase injection. Slight increase of CRF content in staphylo co agulase clotted plasma was noted. Fibrinolytic system was not activated during clotting process caused by staphylo-coagulase. Significance of the data obtained is discussed.

Coagulation Studies in Acute Hepatic Necrosis

1971 ◽  
Vol 26 (02) ◽  
pp. 341-352
Author(s):  
H. J Böhmig ◽  
G. M Abouna ◽  
J. A Diez-Pardo
Keyword(s):  
Factor Viii ◽  
Human Liver ◽  
Fibrinogen Level ◽  
Liver Perfusion ◽  
Hepatic Necrosis ◽  
Factor Ix ◽  
Factor V ◽  
Thrombin Time ◽  
Clotting Factors ◽  
Low Levels

SummaryIn 2 patients with post-hepatitic acute hepatic necrosis, a complex coagulation defect characterized by low levels of prothrombin, factor V, and factor IX, hypofibrinogenemia, thrombocytopenia, and pathologic thrombin time was present. Levels of factor VIII were abnormally elevated. Exchange blood transfusions led to striking but shortlasting improvement in coagulation and were found to be an efficient means in control of bleeding. Extracorporal perfusion of the livers of pigs, and of a human liver raised the levels of the liver-synthesized clotting factors prothrombin, factor V, and factor IX in the patient’s blood. Increase of fibrinogen level occurred solely after 36 h perfusion of a human liver. Adverse effects of extracorporeal liver perfusion were decrease of platelets, fibrinogen, and factor VIII.

The Measurement of Heparin

1973 ◽  
Vol 30 (03) ◽  
pp. 471-479 ◽  
Author(s):  
K. W. E Denson ◽  
John Bonnar
Keyword(s):  
Degradation Products ◽  
Factor Xa ◽  
Assay Method ◽  
Thrombin Time ◽  
Fibrinogen Degradation Products ◽  
Low Levels

SummaryA method for the measurement of heparin utilising the potentiating effect of heparin on the action of anti-factor Xa is described. The effect on the assay of platelet contamination of plasma, the presence of fibrinogen degradation products and low levels of anti-factor Xa have been studied. The assay method has been compared with the calcium thrombin time method and a group of obstetrical patients have been studied using both methods.

The Genetic Defect of Type I von Willebrand Disease “Vicenza” Is Linked to the von Willebrand Factor Gene

1993 ◽  
Vol 69 (02) ◽  
pp. 173-176 ◽  
Author(s):  
Anna M Randi ◽  
Elisabetta Sacchi ◽  
Gian Carlo Castaman ◽  
Francesco Rodeghiero ◽  
Pier Mannuccio Mannucci
Keyword(s):  
Von Willebrand Factor ◽  
Autosomal Dominant ◽  
Genetic Defect ◽  
Von Willebrand Disease ◽  
Type I ◽  
Bleeding Tendency ◽  
Factor Gene ◽  
Low Levels ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryType I von Willebrand disease (vWD) Vicenza is a rare variant with autosomal dominant transmission, characterized by the presence of supranormal von Willebrand factor (vWF) multimers in plasma, similar to those normally found in endothelial cells and megakaryocytes. The patients have very low levels of plasma vWF contrasting with a mild bleeding tendency. The pathophysiology of this subtype is still unknown. The presence of supranormal multimers in the patients’ plasma could be due to a mutation in the vWF molecule which affects post-translational processing, or to a defect in the cells’ processing machinery, independent of the vWF molecule. In order to determne if type I vWD Vicenza is linked to the vWF gene, we studied six polymorphic systems identified within the vWF gene in two apparently unrelated families with type I vWD Vicenza. The results of this study indicate a linkage between vWF gene and the type I vWD Vicenza trait. This strongly suggests that type I vWD Vicenza is due to a mutation in one of the vWF alleles, which results in an abnormal vWF molecule that is processed to a lesser extent than normal vWF.

Coagulation Disorders in Thrombocythaemia, a Study of Seven Cases

1962 ◽  
Vol 07 (01) ◽  
pp. 114-128 ◽  
Author(s):  
Stefan Niewiarowski ◽  
Halina Zywicka ◽  
Zbigniew Latałło
Keyword(s):  
Liver Parenchyma ◽  
Platelet Factor 4 ◽  
Coagulation System ◽  
Severe Bleeding ◽  
Clotting Factors ◽  
Platelet Factor ◽  
Antiheparin Activity ◽  
Thromboplastic Activity ◽  
Bleeding Episodes ◽  
Routine Coagulation

SummaryThe blood coagulation system has been studied in 7 patients with thrombocythaemia. 4 of these patients had thrombocythaemia after splenectomy, 2 of them had thrombocythaemia associated with myeloid leukemia, and 1 thrombocythaemia associated with polycythaemia. Severe bleeding episodes were noted in 5 cases, 2 patients had only mild bleeding symptoms.Each patient was examined several times. The period of observations varied from 2 months to 3 years. Platelet count varied from 350 000 to 3 800 000 per mm3.Bleeding time and tourniquet test were normal in all cases. Routine coagulation and fibrinolysis studies did not reveale characteristic abnormalities in plasma clotting factors. A decrease of prothrombin complex components was observed in 4 cases. This disturbance was due to the coexisting injury of liver parenchyma or myeloid changes but not to an increase of platelets or to the abnormalities in the platelet system.An increase of antiheparin activity was found in the plasma of 4 patients. This activity is probably due to the escape of platelet factor 4 from destroyed or qualitatively changed platelets into plasma.Platelet clotting factors were investigated in isolated platelet suspensions, A significant decrease of platelet factor 1 was observed in all patients and a decrease of platelet factor 4 in 5 patients. In 2 cases platelet factor 4 increased. Platelet thromboplastic activity showed a great variety of disturbances in conformity with other workers observations.Recent views on the pathogenesis of bleedings in thrombocythaemia are discussed. On the basis of their own investigations the authors suggest that the significant disturbances of platelet function may contribute to the development of bleeding, and that the increase of antiheparin activity in plasma may produce hypercoagulability and favorize the formation of thrombi.

scholarly journals An FGA Frameshift Variant Associated with Afibrinogenemia in Dachshunds

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1065
Author(s):  
Reinhard Mischke ◽  
Julia Metzger ◽  
Ottmar Distl
Keyword(s):  
Protein Sequence ◽  
Sanger Sequencing ◽  
Selective Breeding ◽  
Genome Wide Association Study ◽  
Frameshift Mutation ◽  
Homozygosity Mapping ◽  
Genomic Region ◽  
Severe Bleeding ◽  
Genome Wide ◽  
A Genome

Congenital fibrinogen disorders are very rare in dogs. Cases of afibrinogenemia have been reported in Bernese Mountain, Bichon Frise, Cocker Spaniel, Collie, Lhasa Apso, Viszla, and St. Bernard dogs. In the present study, we examined four miniature wire-haired Dachshunds with afibrinogenemia and ascertained their pedigree. Homozygosity mapping and a genome-wide association study identified a candidate genomic region at 50,188,932–64,187,680 bp on CFA15 harboring FGB (fibrinogen beta chain), FGA (fibrinogen alpha chain), and FGG (fibrinogen gamma-B chain). Sanger sequencing of all three fibrinogen genes in two cases and validation of the FGA-associated mutation (FGA:g.6296delT, NC_006597.3:g.52240694delA, rs1152388481) in pedigree members showed a perfect co-segregation with afibrinogenemia-affected phenotypes, obligate carriers, and healthy animals. In addition, the rs1152388481 variant was validated in 393 Dachshunds and samples from 33 other dog breeds. The rs1152388481 variant is predicted to modify the protein sequence of both FGA transcripts (FGA201:p.Ile486Met and FGA-202:p.Ile555Met) leading to proteins truncated by 306 amino acids. The present data provide evidence for a novel FGA truncating frameshift mutation that is very likely to explain the cases of severe bleeding due to afibrinogenemia in a Dachshund family. This mutation has already been spread in Dachshunds through carriers before cases were ascertained. Genetic testing allows selective breeding to prevent afibrinogenemia-affected puppies in the future.

Antihemostatic Effect of Hsien-Ho-T'sao (Agrimonia pilosa)

1984 ◽  
Vol 12 (01n04) ◽  
pp. 116-123 ◽  
Author(s):  
Jih-Pyang Wang ◽  
Mei-Feng Hsu ◽  
Che-Ming Teng
Keyword(s):  
Prothrombin Time ◽  
Blood Coagulation ◽  
Partial Thromboplastin Time ◽  
Bleeding Time ◽  
Fibrinogen Level ◽  
Platelet Rich Plasma ◽  
Water Extract ◽  
Activated Partial Thromboplastin Time ◽  
Thrombin Time

Bleeding time in rats was markedly prolonged after the adminstration of the water extract of Hsien-Ho-T'sao. This antihemostatic effect was more marked in the group of i.p. injection of the drug than in the group of p.o. administration for 2 to 7 consecutive days. Blood coagulation studies showed that plasma prothrombin time, activated partial thromboplastin time and stypven time were prolonged, while thrombin time adnd fibrinogen level were not changed. The thromboelastographic recording showed that reation time was prolonged and maximal elasticity of clot was decreased. In addition, ADP- and collagen- induced aggregations of platelet-rich plasma was suppressed. In conclusion, the prolongation of the bleeding time might be due to both anticoagulant and antiplatelet action of the drug.

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