A Variant of Factor X That Is Defective Only In Extrinsic Coagulation

Abstract

Screening - prior to liver biopsy - of the blood of a 48- year-old patient with a negative anamnesis for bleeding complications, revealed a strongly prolonged prothrombin time (PT), while the APTT was normal. The PT prolongation was not the consequence of an antithromboplastin, vitamin K deficiency, oral anticoagulation or factor VII deficiency (FVII 0.5 U/ml). A more detailed analysis demonstrated the presence of an abnormal factor X molecule with the following properties: coagulation assays: 0.016 U/ml (thromboplastin), 0.43 U/ml (RVV/cephalin), 0.44 U/ml (kaolin/cephalin); spectrophoto- metric assay (RVV-X/S2337), 0.47 U/ml; immunological assay (Laurell), 0.50 U/ml. The low reactivity towards the extrinsic activator depends on the thromboplastin used: human brain, 0.016 U/ml; bovin brain, 0.11 U/ml.The FX-variant has a normal electrophoretic mobility (crossed immunoelectrophoresis) and can be absorbed from plasma by Al(OH)3 The variant has been purified from the patients plasma using affinity chromatography on anti-factor X Sepharose, followed by DEAE-Sephadex gradient elution.The isolated variant shows the same low reactivity towards extrinsic activation. Comparison with isolated normal FX showed that it has the same molecular weight (NR 70,000; R 51,000 and 19,000). The heavy chain stains positive with the Schiff’s reagent. Variant FX can be activated by RVV-X under formation of αXa (51,000), which in the presence of phospholipid is degraded to αβXa (48,000) and αγX (35,000).Analysis of the kinetics of activation of normal and abnormal FX by FIXa, FIXa plus FVIII, or RVV-X revealed no essential differences. Only the activation by FVII-thrombo- plastin showed to be abnormal.The complete absence of bleeding complications in this particular patient, might indicate that in vivo the extrinsic activation of factor X is only of minor importance.