Patients with factor X congenital deficiency (FX CD) present with symptoms similar to other coagulation factor disorders. Depending on severity, patients often have epistaxis, haemarthrosis and hematomas. Because FX plays a central role in both the intrinsic and extrinsic clotting pathways, patients with severe FX CD (FX activity <10% of normal activity) tend to have serious symptoms, often presenting during infancy. Umbilical stump, central nervous system (CNS) or gastrointestinal bleeding may occur early in life.1,2
Prolonged activated partial thromboplastin time (aPTT) and prothrombin times (PT) can exclude factor deficiencies strictly related to only the intrinsic or extrinsic pathway such as FVII, FVIII, FIX, FXI or FXII deficiencies. However, specific variants of FX CD are known to affect only the intrinsic or extrinsic clotting pathway, and patients with these forms may only have prolongation of either aPTT or PT. Correction of aPTT and PT by mixing samples 1:1 with normal plasma can exclude FX inhibitory antibodies or another anticoagulant.1-3
The Russell viper venom test (RVVT) is prolonged in patients with FX CD, as RVV is a direct activator or FX. However, specific variants of FX CD (such as FX CD Friuli) show normal RVVT times. FX CD diagnosis is confirmed and characterised by a FX activity assay and by measuring the amount of FX antigen in the plasma.1,2
Algorithm for the laboratory diagnosis of FX CD.
Initial laboratory screening
As FX acts at the convergence of both the intrinsic and extrinsic clotting cascades, most patients with FX CD have prolonged activated partial thromboplastin time (aPTT) and prothrombin time (PT) beyond normal reference ranges, but some patients may have only aPTT or PT prolongation. However, as patients with acquired FX, FV, combined FV and FVIII, prothrombin or fibrinogen deficiency also exhibit prolonged aPTT and PT, the initial laboratory investigation is not diagnostic.1,2
Corrected mixing tests performed with normal human plasma should exclude inhibitory coagulation factor antibodies and other anticoagulants. aPTT and PT of samples from patients with FX CD and no inhibitor should correct upon mixing.1
Russell viper venom test
Russell viper venom (RVV) directly activates FV and FX. Thus, patients with FX CD should have prolonged RVVT times. However, specific variants of FX CD, such as the Friuli variant, have normal RVVT times. If a variant of FX CD is suspected, individual factor activity should be measured regardless of the RVVT result.1,3
Factor activity assays
A FX activity assay can confirm the FX CD diagnosis, with severe FX CD defined as patients with activity levels <10% of normal activity. Further tests, such as genotyping and a FX antigen (FX:Ag) assay can help to classify the type of FX CD.
FX:Ag assays measure the quantitative amount of FX present. Sandwich enzyme-linked immunosorbent assays (ELISA) capture the FX antigen, thereby measuring the biological amount present. Patients with an equal decrease in FX activity and FX:Ag are considered to have type I FX CD while patients with a decrease in FX activity and normal FX:Ag are considered to have type II FX CD.1,2
1. Girolami A, Cosi E, Sambado L, Girolami B, Randi ML. Complex history of the discovery and characterization of congenital factor X deficiency. Semin Thromb Hemost 2015;41:359-65.
2. Menegatti M, Peyvandi F. Factor X deficiency. Semin Thromb Hemost 2009;35:407-15.
3. Girolami A, Scarparo P, Scandellari R, Allemand E. Congenital factor X deficiencies with a defect only or predominantly in the extrinsic or in the intrinsic system: a critical evaluation. Am J Hematol 2008;83:668-71.