Fibrinogen faux pas

A 2001 compilation of dysfibrinogens counted 322 affected families, of which 99 had involvement of the Aα chain, 16 of the Bβ chain, and 54 of the γ chain, with an additional 153 without a structural explanation.¹  With a molecular size of 340 000 Da and constructed of nearly 1500 amino acid residues, it is not surprising that functional defects are not uncommon and that they are clustered in the fibrinopeptides, at thrombin cleavage sites, in polymerization domains, at factor XIII cross-link sites, and near calcium or tissue plasminogen activator (tPA)–binding sites. It is likewise predictable that such mutations result in widely disparate clinical manifestations, from a simple prolonged clotting time and low plasma fibrinogen concentration to deranged hemostasis and bleeding, or hypercoagulability and abnormal fibrinolysis leading to thrombophilia. Sometimes, confusing combinations of these effects occur in one and the same patient.

In this issue of Blood, 2 new examples of hypodysfibrinogenemia are reported, each with an important and interesting insight. Hamano and colleagues (page 3045) describe Tokyo V, which has an alanine-to-threonine substitution at residue 327 of the γ chain, which in turn caused a possible insertion of an extra glycosylation site. The authors demonstrate a seemingly paradoxical combination of a loose, porous, and fragile fibrin clot formed after thrombin action, presumably secondary to poor fibrin polymerization, with a clot that is nevertheless lysis resistant, presumably secondary to a decrease in tPA-mediated events. Clinically, the patient was afflicted with both arterial (cerebral infarction at age 36 years) and venous (pulmonary embolism at age 42 years) thrombotic events. This thrombophilic picture was explained as a result of hypercoagulability due to circulating fibrin fragments liberated from fragile fibrin clots, and ineffective fibrinolysis that limited the physiologic response to thrombus. While a predisposition to venous thrombotic disease has been noted in 61 families with dysfibrinogenemia,¹  this case report will help to establish dysfibrinogenemia as perhaps the most plausible hereditary cause of combined arterial and venous thrombophilia.FIG1 

The patient described by Hamano et al also had hypofibrinogenemia, although the cause was not explained other than to speculate that there was either decreased assembly, intracellular transport defect, or hypercatabolism of the dysfibrinogen.

This brings us to the second article of interest in this issue, that by Asselta and colleagues (page 3051). In this brief report, the authors describe a compound heterozygous condition that involves a previously unreported missense mutation (Leu172Gln) as well as a known nonsense mutation (Arg17Stop), both of which are in the Bβ chains. The latter abnormality had been described over 30 years ago²  as a case of “severe congenital hypofibrinogenemia.” The unique aspect of the molecular and genetic analysis was that the hypofibrinogenemia was caused by an mRNA defect, an exonic splicing mutation, not by a protein-related mechanism. Specifically, after transfection in COS-1 cells, the Leu172Gln (5157T>A) caused a “cryptic acceptor splice site,” which resulted in a premature stop at residue 146 and synthesis of a truncated Bβ chain that lacked 70% of the C-terminal region. The mutation did not interfere with fibrinogen synthesis, intracellular processing, or secretion, thus allowing for their conclusion that future analysis of nucleotide variations must be performed at both the protein and mRNA levels.

The list of new mutations, deranged functions, instructive clinical lessons, and biologic insights that are gained by study of dysfibrinogens keeps growing. One could speculate that an enormous number of other genetic mutations involve noncritical loci of the protein, and that all of us “normals” express at least one harmless fibrinogen faux pas (literally, a “false step”; functionally, a “blunder”).