Pseudohomozygous dysfibrinogenemia

Abstract

Hypodysfibrinogenemia (HD) is a heterogeneous disorder in which plasma fibrinogen antigen and function are both reduced but discordant. This report addresses the key clinical question of whether genetic analysis enables clinically useful subclassification of patients with HD. We report a new case and identify a further eight previously documented cases that have the laboratory features of HD but biallelic inheritance of quantitative and qualitative fibrinogen gene variants. The cases displayed both bleeding and thrombosis and sometimes had undetectable fibrinogen activity. In all cases, the predicted effect of the coinherited variants is reduced levels of circulating fibrinogen that is all dysfunctional. We propose the term pseudohomozygous dysfibrinogenemia for this subtype of recessively inherited HD that is distinct from the more commonly recognized monoallelic HD caused by a single fibrinogen gene variant.

Keywords: afibrinogenemia; bleeding; fibrinogen deficiency; hypodysfibrinogenemia.

FIGURE 1

Characteristics of the study pedigree. A, The family relationships of the index case (9; arrowed) with gray and black symbols indicating the laboratory features of dysfibrinogenemia and hypodysfibrinogenemia, respectively. Below each symbol are indicated the Clauss fibrinogen activity (g/L) and the FGA genotype (+= normal sequence; H= p.Arg178* and D= p.Arg35Ser). B, Results of coagulation and fibrinogen tests. Plasma samples anticoagulated with 0.105 M trisodium citrate were analyzed using a Sysmex CA7000 coagulometer and Dade‐Behring reagents according to manufacturer’s instructions unless otherwise stated. C, Viscoelastometric analysis of plasma samples from case 9 and a healthy control performed using a ROTEM delta thromboelastometer (Tem International GmbH, Munich, Germany) with EXTEM and FIBTEM reagents. D, Light transmission aggregation of platelet‐rich plasma from a healthy control and case 9 after stimulation with the stated reagents (thrombin receptor activating peptide, HART Biologicals, Hartlepool, UK; collagen, Takeda Pharmaceutical Company, Tokyo, Japan) using a PAP8 aggregometer (Alpha Laboratories, Hampshire, UK). APTT, activated partial thromboplastin time (Actin FS); FIB‐ACT, Clauss fibrinogen activity (thrombin reagent; 33 μ/mL bovine thrombin); FGN‐ANT, FIB‐ATG fibrinogen antigen (Liaphen immunoturbidometric assay, Hyphen Biomed, Neuville‐sur‐Oise, France); NR, not recorded; PT, prothrombin time (Innovin); RT, reptilase time (4.8 BU batroxobin); TT, thrombin clotting time (Thromboclotin reagent; 1.25 U/mL bovine thrombin)