SummaryThree novel polymorphisms were found in the repeated region of the large exon 13 of factor V gene, one giving rise to a codon dimorphism (Serl240) and two causing aminoacid substitutions (Hisl299Arg, Leul257Ile). An increasing frequency of the Argl299 (R2 allele) correlated with a decreasing mean plasma factor V activity in the groups of subjects under study, which included 26 unrelated subjects with partial factor V deficiency. Family studies supported the co-inheritance both of low factor V activity and of R2 allele. The reduction of factor V activity associated with the R2 allele was not clinically symptomatic even in the homozygous condition and was characterized by a parallel reduction of antigen in plasma, in which abnormal molecules were not detected. Data suggest that the R2 allele represents a marker in linkage with an unknown defect rather than a functional polymorphism.These studies provide the first evidence of a genetic component in determining factor V levels in plasma and of a genetic linkage between the factor V gene and factor V deficiency. They also define specific haplotypes which are associated with factor V deficiency or with APC resistance (Arg506Gln) and are valuable fools for the study of factor V defects.

Prophylaxis replacement therapy has been assessed for a period of 12 months in 10 patients with severe haemophilia B showing a high incidence of spontaneous bleeding episodes. Two different schedules of administration of a freeze‐dried factor IX concentrate were randomly evaluated: according to scheme A, 7.5 U/kg were administrated biweekly, whereas scheme B was based on the weekly infusion of 15 U/kg. On prophylaxis the frequency of bleeding episodes was significantly reduced (P < 0.005) when compared with that observed in the one‐year period preceding the trial. Biweekly infusions were superior to weekly infusion (P < 0.01), and the benefit appeared to be related to the higher number of days in which measurable levels of factor IX were attained in plasma. Range of motion, which was reduced at the start of the trial in 26 joints, was found to have improved in 23. Favourable changes of the joint radiological picture were observed in 6 cases. Hepatitis and factor IX inhibitors did not develop during the trial period. Side effects were rare and mild.

SummarySixteen patients with mild and moderate hemophilia were given Desmopressin (DDAVP) subcutaneously in the absence of any actual bleeding. The response to the drug – in terms of factor VIII coagulant activity rise – became apparent 15 min after the injection, reaching the maximal response after one hour (x̄ 3.2 times the baseline levels; SD 1.21). This response was not different from that elicited using the intravenous route in 18 hemophiliacs of comparable severity after the same time interval. No local or general side-effects were recorded after the subcutaneous administration of DDAVP. We therefore conclude that the subcutaneous route adds further evidence to the reliability of this alternative treatment in mild factor VIII deficiencies, thus making home treatment with this vasopressin analogue possible.

equilibrium between the h/A3 genes is "back lit" by a strong selective force originating approximately 400 generations ago.The "reconstructed' location of the h-allele remarkably corresponds to the calculation that in 400 generations a biological fitness 1% greater than average would produce a change in frequency of the gene for adult lactase persistence from 0.05 (in lactase intolerant populations) to 0.60 in tolerant populations [ 121. Prior to the domestication of animals and the invention of dairying, lactose was not available to adults in significant quantities. Therefore, adult man, like other adult mammals, was naturally lactase deficient. Dairying cultures tended to select for adult lactose tolerance. The milk is a poor source of iron and may actually inhibit absorption of the metal. A separate, and easily disproved, argument for selection would be a proposition that the frequency of the h-allele should be high in populations depending on milk and cereals in their diet. The higher the proportion of lactose tolerance in the population, the higher the frequency of the h-allele in it. So far unsuspected, the evolutionary rivalry between the h-allele and the gene for lactase persistence is likely. It would suggest that these genes coevolved and probably originated some 400 generations ago. In conclusion, the h-allele evolved as an evolutionary rehabilitation of iron carency in farming and pastoralist populations. Its location is approximately 401 kb centromeric from the HLA A genes. REFERENCES 1 . Edwards CQ, Griffen LM, Dadone MM, Skolnick MH, Kushner JP: Mapping the locus for hereditary hemochromatosis: Localization between HLA-B and HLA-A. Am J Hum Genet 38:805-811, 1986. 2. Cox TM: Prevalence of the hemochromatosis gene. N Engl J Med 302695496, 1980. 3. JankoviC GM, coloviC MD, PetroviC MD, SuvajdiiC N, BogdanoviC G , Rado-vanEeviC R, TomaSeviC R, Trpinac D P Selective advantage for females with h-allele? Eur J Haematol43:265-266, 1989. 4. JankoviC GM, PetroviC MD, colovii. MD, MiloSeviC R, JanoSevii. S, Trpinac D P Increased transplacental and breast milk iron delivery in hereditary hemochromatosis. Am J Hematol 38:153-155, 1991.

In 30 subjects on stabilized oral anticoagulant treatment, factor VII activity (VII:C) and factor VII antigen (VIl·Ag) were evaluated. The average VII:C and VIl·Ag levels were 8.7 and 30.7, respectively. All plasma samples were treated with 1 M barium chloride: all the activity and a corresponding average amount of antigen were adsorbed by the salt. The cold-promoted activation of factor VII was found in 5/30 subjects. Corresponding amounts of VII:C and VII: Ag were also removed from the plasma of these subjects after cold activation following the addition of barium chloride. It clearly results from these studies that a portion of VIl·Ag cannot be adsorbed by barium chloride because of a reduction (or a lack) of the γ-carboxyglutamic groups. This portion of VIl·Ag can therefore be identified as Pivka VII.