Family with Factor X Variant Defective Only in Factor VII Activation (X + Riyadh)

Abstract

Original ArticlesFamily with Factor X Variant Defective Only in Factor VII Activation (X + Riyadh) Akram M. Al-Hilali, MB, ChB, FRCPath Alan Lawson, and FIMLS Daryl S. FairPhD Akram M. Al-Hilali Address reprint requests and correspondence to Dr. Al-Hilali: Department of Hematology, Riyadh Armed Forces Hospital, P.O. Box 7897, Riyadh 11159, Saudi Arabia. From the Department of Hematology, Armed Forces Hospital, Riyadh Search for more papers by this author , Alan Lawson From the Department of Hematology, Armed Forces Hospital, Riyadh Search for more papers by this author , and Daryl S. Fair From the Department of Biochemistry, University of Texas Health Center, Tyler Search for more papers by this author Published Online:1 Jan 1989https://doi.org/10.5144/0256-4947.1989.48SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutAbstractThis is the first report, to our knowledge, of a familial occurrence of the abnormal variant of factor X which is defective only in its reaction with factor VII in the extrinsic coagulation pathway. All members of the family with abnormal coagulation results by prothrombin time and assay were clinically normal and had no bleeding tendency. The incidence within the family suggests an autosomal dominant mode of inheritance. We suggest naming the variant factor X+ Riyadh.IntroductionFactor X deficiency (Stuart-Prower deficiency) is a rare disease, the incidence being estimated at one case per 500,000 population.1,2 The number of cases and families reported is less than 100. Based on family studies, it has been considered an autosomal, incompletely recessive disorder.3 The level of factor X in human blood seems to be determined by an autosomal, single-locus, two-allele gene.4 The same workers4 considered the allele for low factor X the dominant one of the two.Pathways in which factor X may be activated are the intrinsic by factor IXa and the extrinsic by factor VIIa. Factor X can also be activated by the addition of Russell's viper venom to plasma.Theoretically, an abnormality could arise in the structure of the molecule that makes it impossible to react within any one of the three pathways or in a combination of pathways.Antigenically the protein concentration could be normal with abnormal biological activity or reduced in concentration.5Families having any of the possible abnormalities have been reported,6 but there has been no family report of the abnormality where only the reaction with factor VIIa was abnormal, although there was a report of a patient whose condition was not proved to be hereditary.7 Another patient was reported8 who did not have a similar abnormality in his family and whose condition was associated with spindle cell thymoma.We believe we are describing the first family with an hereditary disorder where only the reaction with factor VIIa was abnormal. The protein concentration seemed normal, and therefore it seems to be a minor structural abnormality leading to inhibition of the reaction. All members of the family with the abnormality did not have clinical bleeding diathesis. We suggest that the variant be named X+Riyadh.MATERIALS AND METHODSPlasma samples for testing were obtained in the following manner. Blood was collected into polystyrene tubes containing a one-ninth volume of 0.11 mol/L solution of trisodium citrate. The blood specimens were centrifuged immediately at 1500 g for 15 minutes. The platelet-poor plasma was separated and aliquoted into plastic tubes. Samples not to be tested within 2 hours of collection were immediately frozen at −70°C and subsequently thawed at 37°C prior to testing. Plasma samples for immunologic and immunoradiometric determinations of factor X antigen were immediately freeze-dried and dispatched to the respective test center within 72 hours of freeze-drying.Standard methods for the one-stage prothrombin time (PT), activated partial thromboplastin time (APTT), and measurement of the biological activity of factor II and factor X based on PT, APTT, and Russell's viper venom time were used.9 Manufacturer's instructions for use of reagents and reconstitution of freeze-dried materials were strictly adhered to.Radioimmunoassay was carried out by the technique previously reported.10 The quantitation of the standard was based on amino acid composition, and the patient's sample was compared to it. Samples were analyzed in an equilibrium double antibody radioimmunoassay, and parallel dose titration was used to prove identity.Reagents used were Manchester comparative reagent, British comparative thromboplastin, automated APTT reagent, reference plasma 100%, factor X deficient plasma, Russell viper venom, Bell and Alton's platelet substitute, and 0.025 mol/L calcium chloride.FAMILY REPORTPropositusThe propositus was a 40-year-old Saudi national who came to the hospital because of mild hepatitis in 1980. He did not have a bleeding diathesis. Fracture of the femur in the same year treated by nailing did not lead to undue bleeding. He also gave a history of schistosomiasis in 1977. His liver function tests were mildly abnormal on repeated occasions after 1980 with high aspartate transaminase (126 U/L in 1983, gradually dropping to 50 U/L in 1985) and slightly raised lactate dehydrogenase. He was also positive for hepatitis B surface antigen (HBsAg). Rectal biopsy showed no schistosomiasis or amyloidosis. His schistosomal antibody titer was 1/64. He was not jaundiced.In November 1981 his PT, when checked for the first time, was found to be prolonged. The APTT was normal. At that time the hematologist who commented on the results considered the diagnosis to be congenital factor VII deficiency.The patient later had other surgical procedures including removal of the nail in the femur and tooth extraction without excessive bleeding.ResultsThe PT, repeated several times during the period from 1981 to 1987, was prolonged, ranging from 63 to 80 seconds using human brain thromboplastin and from 43 to 60 seconds using Manchester comparative reagent. International normalized ratios ranged from 3 to 5.5. The Russell viper venom time and PTT were normal. Assay of factor VII ranged from 0.40 to 0.56 IU/mL. Assay of factor X coagulant activity based on the PT gave an activity of 0.03 IU/mL on many occasions, while those based on PTT and PT with Russell viper venom gave results of 0.9 to 1.0 IU/mL all the time. Assay of factor V was 0.40 IU/mL and prothrombin was 0.55 IU/mL.Factor X antigen concentration by radioimmunoassay gave a normal result of 7.90 ± 0.898 μg/mL, and slopes of inhibition indicated that the antigenic composition of the molecule was very similar, if not identical, to normal (Figure 1).Figure 1. Pure factor X antigen concentration by radioimmunoassay.Download FigureCorrection by dilution with normal plasma excluded any inhibitors for factor X, factor VII, or tissue thromboplastin.Family StudiesThe same tests were carried out on the propositus's wife, two daughters, and four sons, together with his three brothers (Figure 2). Three of his sons have exactly the same factor X abnormality using the PT-based assay. None of these abnormal individuals had any bleeding diathesis.Figure 2. Family pedigreeDownload FigureDISCUSSIONBecause of the central position of factor X in the intrinsic coagulation pathway and its reaction with factor Vila-tissue thromboplastin in the extrinsic pathway, together with its activation by Russell viper venom, factor X deficiency is expected to show pleomorphism in presentation. The first six cases studied in detail fell into five classes.5 Deficiency patterns show that activation sites (or peptide cleavage sites) for factors IXa-VIIIa complex and Vila-tissue factor (VIIa-tf) are different from that for Russell viper venom because individuals from Fruili in Italy had normal activation by Russell viper venom while they gave prolonged PTT and PT by tissue thromboplastin.11 From the well-documented family described in this article, it seems evident that at some stage, Russell viper venom and IXa-Villa complex activation of factor X diverge from that of VIIa. This seems to contrast with chemical experiments by Jesty et al12 and Fujikawa et al,13 which suggest an identical peptide cleavage site for Russell viper venom and VIIa-tf. However, although the active product resulting from peptide cleavage of the heavy chain of factor X zymogen by the two factors seemed identical in experiments by these workers, this does not necessarily mean the actual cleavage site is completely identical or that it is carried out in exactly the same steps.The recognition locus of the zymogen by the activating factors originally suggested to be common for both6 could also be different for Russell viper venom, VIIa, and IXa-VIIa complex. One of these differences has to be proposed in order to explain the differences in results of coagulation tests in the various families reported in the past and in this new variant. Most of the possible variants have been reported in the past5,11,14 in individuals or families. The commonest variant is that in which both PT and PTT are prolonged because of an abnormal molecule not reacting properly with IXa-VIIa complex and VIIa-tf. In these cases, the Russell viper venom gave a normal clotting time. It was considered classical with factor X deficiency to have prolongation of both PT and PTT. As for Russell viper venom, there were also some patients who had abnormal clotting times.4,5There are also acquired long-standing or transient deficiencies of factor X; amyloidosis is the commonest with which it is associated. In amyloidosis, the abnormality is variable, usually with normal antigen of the clotting factor.6,15The transient cases occur with anticoagulant therapy,16 infection with Mycoplasma pneumoniae,17 and exposure to some fungicides.18 Usually there is inhibition of activity of all pathways.6 Factor X antigen has been abnormally low in some patients belonging to all types of factor X deficiency.6The theoretically possible deficiency of factor X activity with prolongation only of the PT was not reported before 1981. Prolonged PT alone was classically considered as indicative of factor VII deficiency as it is the only factor that functions within the extrinsic system alone.In 1981 one such patient was reported7 without family study, and that patient was said to have no history of bleeding. Findings in our family resembled that patient; however, patient's factor X was later demonstrated to be low.6 In 1985 another patient was identified,8 but this patient's family was tested and showed no similar abnormality or any other hemorrhagic disease. This patient had a bleeding disorder throughout his life; his factor X antigen has not been reported.The family we are describing is from one of the main Saudi tribes of the southwestern region of the Arabian peninsula. The propositus and his wife are distant relatives. The propositus and his three abnormal children gave no history of excessive bleeding. The propositus had mild hepatic dysfunction probably associated with recurrent hepatitis B. However, his children had no liver abnormalities. None of the six abnormal family members was on oral anticoagulants. Coagulation factors for the propositus were normal other than factor X, factor VII (0.40 IU/mL), factor V, and factor II. The moderately lowered levels of factors VII, V, and II can be explained on the basis of the patient's liver disease.The patient was first diagnosed as having factor VII deficiency before assay of factor X was carried out, but it was considered inconsistent that a level of 0.40 IU/mL of factor VII could produce excessive prolongation of the PT, and further assays were performed. It is interesting to note that the patient reported by Nora et al8 was also misdiagnosed at first as having factor VII deficiency.In the classification proposed by Fair and Edgington6 based on plasma of 33 individuals with factor X deficiency, eight main classes were identified with other possible subclasses. The only patient with a coagulation result similar to our family was that reported by Bertina et al.7 His factor X antigen was low, unlike the family under study. Within that classification this family fell under class 3b, with the exception that the antigen levels were normal.To our knowledge, this family is the first to be reported with the abnormality that seems to be functional. We suggest giving the variant the name X+Riyadh. The disease probably arose by single gene mutation in the propositus, and it has been inherited as an autosomal dominant characteristic.ARTICLE REFERENCES:1. Altman P, Katz D, eds. Human health and disease, Federation of American Societies for Experimental Biology. 1977: 121. Google Scholar2. Williams WJ, Beutler E, Erslev AJ, Rundles RW, eds. Hematology. 2nd ed. New York: McGraw Hill, 1977: 1418–9. Google Scholar3. Graham JB, Barrow EM, Hougie C. "Stuart clotting defect: II. Genetic aspects of a “new” hemorrhagic state" . J Clin Invest. 1957; 36: 497–503. Google Scholar4. Siervogel RM, Elston RC, Lester RH, Graham JB. "Major gene analysis of quantitative variation in blood clotting factor X levels" . 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Hemker HC, Veltkamp JJ, Loeliger EA. "Kinetic aspects of the interaction of blood clotting enzymes: III. Demonstration of an inhibitor of prothrombin conversion in vitamin K deficiency" . Thrombosis Diathesis Haemorrhagica. 1968; 19: 346–63. Google Scholar17. Peuscher FW, van Aken WG, van Mourik JA, et al. "Acquired transient factor X (Stuart factor) deficiency in patient with mycoplasma pneumonial infection" . Scand J Haematol. 1979; 23 (4): 257–64. Google Scholar18. Graham JB, Barrow EM, Wynne TR. Stuart clotting defect: III. An acquired case with complete recovery. In: Brinkhouse KM, deNicola P, eds. Hemophilia and other hemorrhagic states. Chapel Hill: University of North Carolina Press, 1959: 158–66. Google Scholar Previous article Next article FiguresReferencesRelatedDetailsCited byGirolami A, Simioni P and Ruzza G (2019) The Classification of Congenital Factor X Deficiency and Abnormalities, Annals of Saudi Medicine , 10:2, (218-220), Online publication date: 1-Mar-1990. Volume 9, Issue 1January 1989 Metrics History Accepted11 April 1988Published online1 January 1989 ACKNOWLEDGMENTWe thank Mrs. Yassien for her help in preparing this manuscript.InformationCopyright © 1989, Annals of Saudi MedicinePDF download