Fibrinogen kaiserslautern III: a new case of congenital dysfibrinogenemia with aalpha 16 arg-->cys substitution.

An abnormal fibrinogen was identified in a man with suspicious prolonged prothrombin time and a mild bleeding tendency. Coagulation studies showed marked prolonged thrombin and reptilase clotting times and a discrepancy between functional fibrinogen test and fibrinogen antigen. The rate of fibrinopeptide B release by thrombin was slightly delayed while the release of fibrinopeptide A was only half the normal amount. DNA sequencing revealed a heterozygous C to T point mutation in position 1202 of exon 2 of the Aalpha chain, resulting in the substitution of Arg-->Cys at position 16, the thrombin cleavage site. This mutation was found also in his 2 children. Both had a mild bleeding tendency too.     

Thromboembolic manifestations and congenital factor V deficiency: a family study

A case of congenital factor V deficiency is reported. Despite this defect in blood coagulation, the patient had experienced recurrent thrombophlebitis and was referred to us because of deep venous thrombosis of the lower limbs associated with pulmonary embolism. Both functional and immunological assays documented a deficiency of factor V (12 and less than 10%, respectively). The available family members were investigated and the same defect was found in 2 brothers of the propositus, who also suffered from thrombotic diseases (recurrent thrombophlebitis and myocardial infarction). The propositus has been treated with long-term oral anticoagulant therapy, no hemorrhagic complications or thrombotic recurrences being recorded in 2 years' time.     

Fibrinogen giessen I: a congenital homozygously expressed dysfibrinogenemia with A alpha 16 Arg----His substitution

Clinical reports are published for only two patients with homozygously expressed congenital dysfibrinogenemia. The patients, both of whom have a bleeding diathesis, have amino acid substitutions in the fibrinogen molecule at A alpha 16 Arg----Cys and A alpha 19 Arg----Ser, respectively. We report that a third patient with dysfibrinogenemia (fibrinogen Giessen I) is homozygous for A alpha 16 Arg----His. Although this patient has had excessive postpartum bleeding, she has had normal hemostasis throughout several minor surgical procedures and hysterectomy. Elucidation of the amino acid alterations in patients with dysfibrinogenemia may expand our understanding of structural determinants of fibrinogen that are critical to its function in vivo.     

Fibrinogen Birmingham: a heterozygous dysfibrinogenemia (A alpha 16 Arg- ---His) containing heterodimeric molecules

Fibrinogen was isolated from the plasma of a 25-year-old female with a history of mild bleeding and several recent moderate to severe hemorrhagic episodes. Coagulability with thrombin approached 100% and varied directly with the time of incubation with the enzyme. High- performance liquid chromatography analysis of thrombin-induced fibrinopeptide release demonstrated retarded fibrinopeptide A (FPA) and fibrinopeptide B (FPB) release and the presence of an abnormal A peptide (FPA) amounting to 50% of the total. The same biochemical abnormalities were found in her asymptomatic father. Amino acid analysis and carboxypeptidase digestion of FPA demonstrated the substitution of His for Arg at A alpha 16. In contrast to the thrombin- and reptilase-sensitive Arg-Gly bond in the normal A alpha chain, the abnormal A alpha chain (A alpha) sequence is resistant to reptilase attack but is slowly cleaved by thrombin. To evaluate whether Birmingham A alpha and A alpha chains had been assembled nonselectively into heterodimeric (ie, 50% A alpha, A alpha) and homodimeric (ie, 25% A alpha, A alpha; 25% A alpha, A alpha) species, the clot and the clot liquor resulting from reptilase treatment of normal or Birmingham fibrinogen were separated, and each was then further incubated with thrombin to release remaining fibrinopeptides. Assuming that fibrinogen Birmingham contained heterodimeric molecules and that these and the normal molecules were completely incorporated into a reptilase clot, the expected coagulability would be 75%. In addition, subsequent thrombin treatment of the reptilase clot would release 50% of the total FPA and 75% of the total FPB present in the original sample. On the other hand, if only homodimeric fibrinogen species (50% A alpha, A alpha; 50% A alpha, A alpha) existed, the maximum reptilase coagulability would be 50%, and after thrombin treatment, 50% of the total FPB and no FPA would be recovered from the reptilase clot. We found the propositus's fibrinogen to be 68% coagulable, and we recovered 45% of the FPA and 70% of the FPB from the reptilase clot. Essentially the same coagulability and distribution of fibrinopeptides was found in the reptilase clot from her father's fibrinogen. We therefore conclude that fibrinogen Birmingham contains heterodimeric species (A alpha, A alpha) amounting to approximately 50% of the circulating fibrinogen molecules. The existence of heterodimers is consistent with a nonselective intracellular process of constituent chain assembly of dimeric plasma fibrinogen molecules.     

Fibrinogen Milano. VI: A heterozygous dysfibrinogenemia (A alpha 16 Arg----His) with bleeding tendency

Congenital heterozygous dysfibrinogenemia was diagnosed in a young woman with bleeding tendency. 3 other asymptomatic members of her family (mother and the 2 sisters) had abnormal fibrinogen. The proposita's plasma exhibited prolonged thrombin and reptilase times. Plasma fibrinogen concentration determined by functional assay was 0.3 g/l, whereas immunologic assay revealed normal fibrinogen levels. Turbidity curves, representing the rate of thrombin-induced fibrin formation, were markedly delayed both in the presence and absence of Ca2+. Isoelectric focusing and SDS electrophoresis of reduced fibrinogen showed normal charge and size of the subunit chains. Release of fibrinopeptide B by thrombin was normal, whereas HPLC elution diagrams of fibrinopeptide A showed an abnormal peak A* with a slightly shorter retention time than the normal fibrinopeptide A. The amino acid analysis showed that the arginine in peak A* is replaced by histidine (A alpha 16 Arg----His).     

Fibrinogen Poissy II (gammaN361K): a novel dysfibrinogenemia associated with defective polymerization and peptide B release.

A fibrinogen variant was identified in a pregnant patient with disseminated intravascular coagulation and abruptio placentae. This dysfibrinogen was also found in four asymptomatic members of the patient's family. Coagulation studies showed prolongation of both the thrombin and reptilase times, and discrepancy was noted between the levels of plasma fibrinogen as determined by a kinetic versus an immunological determination or light-scattering assay. Studies on purified fibrinogen revealed an impaired release of fibrinopeptide B by thrombin related to a delayed thrombin-induced fibrin polymerization. DNA sequencing revealed a heterozygous T <-- A point mutation in position 9373 of the gamma-chain gene (exon 9), which substituted a K for an N at position 361.     

Familial pancreatic cancer: a family study.

The etiology of pancreatic cancer remains elusive. Recent attention has been given to host factors, as evidenced by the recognition of familial aggregations of this disease and its association with several hereditary cancer-prone disorders. We have investigated a remarkable family wherein pancreatic cancer has been documented through three generations, including progeny from two of the progenitor's three marriages. The protocol involved a search for documentation of cancer of all anatomic sites. We did not find any pattern of extrapancreatic cancer occurrences, and age at onset of pancreatic cancer corresponded to population expectations. The recognition of patients at high risk for pancreatic cancer should lead to research into potential environmental factors interacting with host susceptibility for elucidation of etiology and for earlier diagnosis.     

Molecular basis of congenital afibrinogenaemia in a Dutch family.

Congenital afibrinogenaemia is a rare autosomal recessive disorder characterized by complete absence or trace amounts of fibrinogen. Here we report the identification of the molecular defect underlying afibrinogenaemia in a Dutch patient. DNA sequence analysis of the fibrinogen Aalpha, Bbeta and gamma-genes revealed a homozygous deletion of two adenines between nucleotides 3120 and 3122 in exon 4 of the gene coding for the Aalpha-chain. This deletion results in a frameshift with a predicted premature end of translation at codon 140. This is the first report of a patient homozygous for this rare mutation associated with afibrinogenaemia.     

Severe factor XI deficiency in a Lebanese family: identification of a novel missense mutation (Trp501Cys) in the catalytic domain.

In this study, a Lebanese woman with severe factor XI deficiency as well as several unaffected family members were analysed. The F11 gene was screened by polymerase chain reaction amplification of all 15 exons, including intron-exon junctions followed by single-strand conformational analysis. Variant single-strand conformational analysis profiles were obtained for exon 13; sequencing of these products allowed the identification of a novel missense mutation (Trp501Cys) situated in the catalytic domain, in homozygosity in the proband.