From Routine to Research Laboratory: Strategies for the Diagnosis of Congenital Fibrinogen Disorders

Abstract

<jats:title>Abstract</jats:title><jats:p>Congenital fibrinogen disorders (CFDs) encompass a heterogeneous group of fibrinogen defects with a wide spectrum of biological and clinical features. An accurate diagnosis is thus essential to assure the optimal management for the patient. Diagnosis involves a multistep approach starting with routine coagulation assays and assessment of functional and antigenic fibrinogen followed by identification of the molecular anomaly. However, the diagnosis of CFD can be challenging as the sensitivity and specificity of coagulation assays depend on the fibrinogen level as well as on the fibrinogen variant. In addition, patients suffering from CFD have a heterogeneous clinical course which is often unpredictable by routine coagulation assays. To better determine the patient's clinical phenotype, global hemostasis assays and an assessment of the fibrin clot properties are performed in research laboratories. In this review, we summarize the fibrinogen work-up highlighting some common pitfalls and provide an update of the research on CFD.</jats:p>

Congenital Afibrinogenemia and Hypofibrinogenemia: Laboratory and Genetic Testing in Rare Bleeding Disorders with Life-Threatening Clinical Manifestations and Challenging Management

“…Initial laboratory diagnosis for afibrinogenemia and hypofibrinogenemia should include routine clotting times (prothrombin time (PT), activated partial thromboplastin time (aPTT), or thrombin time (TT)) and fibrinogen assays (activity and antigen) [54]. Fibrinogen activity can be determined by the Clauss or PT-derived fibrinogen assays.…”

Development and validation of a novel qualitative test for plasma fibrinogen utilizing clot waveform analysis

“…PPV was 0.875 and NPV was 0.996 for both TCFibL and Dade in combination with FactorAuto Fibrinogen reagent (FAFbg). On the other hand, the cutoff of 0.70 for Ac/Ag ratio was generally used for the screening of qualitative fibrinogen abnormalities, even though proper validation has not been performed 12 . We therefore performed ROC analysis of the validation cohort to reveal an optimal cutoff Ac/Ag ratio, yielding an optimal cutoff of 0.55 for Ac/Ag ratio.…”

“…The present study established an automated analysis that enables evaluation of the quality and quantity of plasma fibrinogen using Clauss-CWA method. In response to comments in the review article by Casini 12 , we validated automated analysis software using clinical samples and found that Clauss-CWA was useful to distinguish qualitative and quantitative abnormalities in routine testing. These results indicated that the Clauss fibrinogen assay commonly used for routine laboratory testing could perform both quantitative and qualitative analyses of plasma fibrinogen by adding CWA.…”

“…This eAg can be used as an alternative for actually measured fibrinogen antigen determined by immunological assays, and the ratio of functional fibrinogen level (Ac) to eAg (Ac/eAg ratio) can be used to identify qualitative fibrinogen defects. The clinical utility of this novel analytical method requires validation 12 .…”

A Collection of Jewels

“…5 Casini presents the multistep approach required to investigate a suspected congenital fibrinogen disorder, illustrates current tools for analyzing the fibrin-clot structure, and addresses the apparent paradox of the thrombotic tendency observed in afibrinogenemia. 6 Finally, Schröder summarizes the diagnostic approach to factor XIII deficiency, illustrating difficulties and opportunities of the available methods for assessing its function-from practical issues (the utility of an additional plasma blank) to current (flow-based) research models. 7 Furthermore, you will read about some "Current challenges": Routine analyses in specialized laboratories that are challenged by current developments.…”