To the Editor: We read with interest the paper on a family with factor X variant by Al-Hilali et al¹ but were surprised that a paper of ours on the same subject was not quoted. Also only one of our papers on factor X defect was quoted, though we have published more than fifty papers on the topic of factor X during the past twenty years. We would like to take this opportunity to propose a suitable classification of factor X defects.²

Factor X deficiency was first described in 1956 to 1957.^3-5 Since then, several variants have been described. The factor X Friuli abnormality appears to be the most important and the most extensively studied.^6-9 Recently a peculiar factor X defect with a normal partial thromboplastin time (PTT) was described as occurring on both a sporadic^10,11 and congenital basis.¹² Factor X activity level, in the extrinsic system, was 4.2% in the patient described by Nora et al,¹¹ 2 to 3% in the patient seen by Bertina et al,¹⁰ and 26 to 34% in the family studied by us.¹² This indicates that the abnormality responsible for the peculiar activation pattern with a defect only in the extrinsic system may present in different forms-severe or moderate. For two of these patients,^10,11 there is no absolute proof of the congenital nature of the defect. Unfortunately, no immunological assay is given for the patient reported by Nora et al,¹¹ and this further makes a sure classification impossible.^9,13 The patient presented by Bertina et al¹⁰ had an antigen level of 50% of normal. Factor X Padua patients show a level of 100% of normal. The family described by Al-Hilali et al¹ showed a factor X activity of 3% and normal factor X antigen level. However, there is a disturbing feature in the studies presented, namely a concomitant mild reduction in factors II, V, and VII. Apparently factor IX was not tested and no immunological assay of these three factors was available either. These data suggest the existence of a combined defect. Whether this is congenital or due to liver damage, as surmised by the authors, remains to be proved. Because the level of these factors in the family members was not studied, the possibility remains that the defect might be a combined defect (of prothrombin complex factors?). The existence of an abnormal factor X exhibiting peculiar activation patterns must be recognized. The discovery of this peculiar type of factor X deficiency (abnormality limited to the extrinsic system) has considerably complicated the differential diagnosis of factor VII and X deficiencies and abnormalities. In the past an abnormal Russell's viper venom (RVV) clotting time was used to discriminate between factor X and VII deficiency, but we demonstrated this not to be true.^6,7 Factor X Friuli in fact may be normally activated by RVV.⁶ A factor X abnormality with prolonged PTT and normal or near normal prothrombin time has also been described.^14,15 In this form the defect seems to lie only or mainly in the intrinsic system. The great heterogeneity of the factor X defect is further emphasized by the recent discovery of an additional congenital factor X variant (factor Padua 2).¹⁶ This variant displays a discrepancy between the levels of factor X obtained by clotting assay and those seen by amidolytic assay. Table 1 summarizes the factor X variants so far described. Other variants may exist, as suggested by the preliminary report of another patient¹⁷ and by other studies.¹³ Finally, it is interesting to note that bleeding manifestations varied considerably, namely from severe to none. In general it seems that those patients with defects in all three activating systems showed the most severe bleeding. The extrinsic system appears to be the least important determinant in the bleeding tendency, such that patients with only the defect are asymptomatic.^1,12