Demonstration of heterodimeric fibrinogen molecules partially conjugated with albumin in a novel dysfibrinogen: fibrinogen Mannheim V.
A 30-year-old female experienced three miscarriages in early pregnancy. Extensive laboratory screening showed a low plasma fibrinogen level of approximately l g/l detected by PT-derived fibrinogen assay. The fibrinogen level in the immunological assay was 3 g/l. The functional Clauss assay yielded an intermediate result of 1.78 g/l. During her fourth and fifth pregnancy, the patient received fibrinogen concentrates (Haemocomplettan, CLS Behring, Marburg, Germany), starting with 4 grams of human fibrinogen, followed by 2 grams every second day until the 15(th) week of pregnancy. The further course of these pregnancies was uneventful. SDS-PAGE and immunoblotting showed doublet bands in the positions of the high-molecular weight (HMW)- and low-molecular-weight (LMW)-fibrinogen, a single LMW' fibrinogen band, plus additional bands with higher molecular weight than HMW-fibrinogen, which were also reactive with anti-human serum albumin (HSA) antiserum. These bands correspond to variant fibrinogen conjugated with albumin. Reduced SDS-PAGE and immunoblotting using polyclonal anti-fibrinopeptide A antiserum disclosed one additional Aalpha-chain band with lower molecular weight. Amplification and sequencing of exon 5 of the alpha gene indicated heterozygosity for a novel single nucleotide deletion at codon Aalpha494 (C1537delA). His494 is replaced by Pro and this is followed by 23 (LMKLPSSTLPQLEKHSQ VSSHLC) new amino acids before premature truncation after Cys517, yielding a free C-terminal cysteine, which may link with albumin. This new fibrinogen mutation, leads to a balanced array of homo- and heterodimeric fibrinogen molecules, some of which are conjugated to albumin.
Dempfle
Carl-Erik
CE
Department of Medicine, University Hospital of Mannheim, Mannheim, Germany. carl-erik.dempfle@med.ma.uni-heidelberg.de
George
Peter M
PM
Borggrefe
Martin
M
Neumaier
Michael
M
Brennan
Stephen O
SO
D000026:Abortion, Habitual / Q000097:blood* / Q000235:genetics*; D000328:Adult; D000595:Amino Acid Sequence; D019281:Dimerization; D005260:Female; D015241:Fibrinogens, Abnormal / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014644:Genetic Variation; D006801:Humans; D008969:Molecular Sequence Data; D008970:Molecular Weight; D017354:Point Mutation; D011247:Pregnancy; D012709:Serum Albumin / Q000378:metabolism*
D015241:Fibrinogens, Abnormal; D012709:Serum Albumin; C543436:fibrinogen Mannheim V