scholarly journals Expression and Linkage of Genes for X-linked Hemophilias A and B in the Dog

Blood ◽  
1973 ◽  
Vol 41 (4) ◽  
pp. 577-585 ◽  
Author(s):  
K. M. Brinkhous ◽  
P. D. Davis ◽  
John B. Graham ◽  
W. Jean Dodds
Keyword(s):  
X Chromosome ◽  
Hemophilia A ◽  
Factor Ix ◽  
Neonatal Lethality ◽  
Plasma Factor ◽  
Normal Males ◽  
Linkage Of Genes ◽  
Linkage Distance ◽  
Antihemophilic Factor ◽  
Preferential Inactivation

Abstract The linkage distance on the X chromosome between the genes for hemophilia A (classic hemophilia) and B (PTC deficiency, Christmas disease) was estimated directly by breeding two strains of dogs, each segregating for a different type of hemophilia. Gene expression was determined by bioassays of plasma factor VIII (antihemophilic factor) and factor IX (PTC, Christmas factor). Double heterozygotes in repulsion for both hemophilia A and B could be readily identified by intermediate plasma levels of both procoagulants. There was no evidence of a tendency toward preferential inactivation of the paternally derived X chromosome, and the procoagulant levels showed that random inactivation had occurred at both loci. When double heterozygotes were bred against normal males or males with hemophilia A and B, the progeny that resulted indicated that the genes recombined freely. Thus, the genes are at least 50 map units apart. The phenotypes of five new hemophilic genotypes are described as a result of the various crossbreedings, including males with double hemophilia AB. When both hemophilia genes are in the coupling phase, there is evidence of increased intrauterine or neonatal lethality in males. The data from this study, along with that on gene linkage of human hemophilia A and B, provide support for the thesis of homology of the X chromosome during speciation.

scholarly journals Expression and Linkage of Genes for X-linked Hemophilias A and B in the Dog

Blood ◽  
1973 ◽  
Vol 41 (6) ◽  
pp. 948-948
Author(s):  
K. M. Brinkhous ◽  
P. D. Davis ◽  
John B. Graham ◽  
W. Jean Dodds
Keyword(s):  
X Chromosome ◽  
Hemophilia A ◽  
Recombination Frequency ◽  
X Inactivation ◽  
Hemophilia B ◽  
Adult Females ◽  
Linkage Of Genes ◽  
Linkage Distance

Abstract In the article "Expression and Linkage of Genes for X-linked Hemophilias A and B in the Dog" by Brinkhous et al. (Blood, Vol. 41, No. 4, April 1973, pp. 577-585) the following items should read as given below: Page 579, paragraph 3, Results Once doubly heterozygous adult females were available, they were bred to determine the recombination frequency among the progeny. The sires were of the three phenotypes: normal, hemophilia A, and hemophilia B. The results from 15 litters, with 78 tested progeny, are shown in Table 2. The male:female ratio was 33:45 (x2 = 2.45; p > 0.10). From these matings, four male genotypes are possible, and all were observed. The crossover ratio was 15:18 in males, suggesting a deficiency of doubly hemophilic males (aXbY) from the XY · aXXb and aXY · aXXb matings. Page 579, paragraph 5, Results The ratio of crossovers to noncrossovers for all progeny, both male and females, of the double heterozygotes is 41:37. This is so close to the maximum 50% frequency of 39:39 that the linkage distance is too great to be measured. Page 580, Table 2, line 4, Genotype of Noncrossover Females, should read aXXb. Page 584, first paragraph at top of page, the last sentence is: These data thus suggest that X-inactivation was indeed random, without respect to the paternal or maternal source of the X-chromosome.

Presence of Activated Factor VII in Factor IX Concentrates and its Persistence in the Circulation After Infusion

1979 ◽  
Author(s):  
U. Seligsohn ◽  
C.K. Kasper ◽  
B. Østerud ◽  
S.I. Rapaport
Keyword(s):  
Hemophilia A ◽  
Factor Ix ◽  
Factor Vii ◽  
Amidolytic Activity ◽  
Activated Factor Vii ◽  
Plasma Factor ◽  
Disappearance Time

Six brands of Factor IX concentrates were evaluated for their Factor VII content and for the presence of activated Factor VII through use of a coupled amidolytic assay, insensitive to activated Factor VII, and a clotting assay, sensitive to activated Factor VII. The Factor VII content of the concentrates studied (except for one concentrate purposely produced to exclude Factor VII) varied between 33 to 621 U per vial. All concentrates contained activated Factor VII, as indicated by ratios of Factor VII clotting activity to Factor VII amidolytic activity of from 1.6 to 21.5. Higher ratios were found in two brands of activated concentrates than in non-activated concentrates. In 10 patients infused with Factor IX concentrates, plasma Factor VII activity rose strikingly in the clotting assay but not in the amidolytic assay. Thus, the elevated Factor VII levels by the clotting assay after infusion of Factor IX concentrates stem from circulating activated Factor VII. A mean intravascular half-disappearance time of 144 min was found for activated Factor VII. Its persistence in the circulation makes it important to evaluate the possible role of activated Factor VII in the thrombogenicity of Factor IX concentrates and in their reported effectiveness in treating bleeding in Hemophilia A patients with inhibitors.

scholarly journals Oral Prophylactic Therapy in Hemophilia A and B (Factor VIII and IX Deficiencies)

1977 ◽  
Author(s):  
W.F. Stapp ◽  
H.B. Boudreaux
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Case Reports ◽  
Factor Ix ◽  
Term Therapy ◽  
Prophylactic Therapy ◽  
Plasma Fraction ◽  
Plasma Factor ◽  
Alternative Means

The purpose of this ongoing nutritional study with massive doses of choline ultimately is to try and establish an alternative means of prophylactic therapy to recently proposed use of plasma fractions, plasma factor concentrates and earlier so-called “bleeding and clotting diets”. Contrary to other prophylactic therapy studies, our premise is that if all other hemostatic and homeostatic factors are near normal through optimum nutrition, the over-all importance of Factor VIII and Factor IX deficiencies are less significant.Case reports of patients with Hemophilia A and B are presented, which indicate a comparative decrease in the plasma fraction requirements for the treatment of the bleeding episodes in these patients during long term therapy with megavitamin doses of choline (a refinement of Boudreaux’s “peanut factor”). One case (WFS) of severe Hemophilia A with less than 1% Factor VIII, under therapy for over 10 yeara has had periods of remission not requiring plasma factor infusions for almost 2 years.From our combined studies, we conclude that a long term nutritional prophylactic therapy program with emphasis on choline in Hemophilia A and B can result in a decrease in plasma needs. antibody formation and the occurrence of hepatitis.

Low Prevalence of the Factor V Leiden Mutation Among “Severe” Hemophiliacs with a “Milder” Bleeding Diathesis

1995 ◽  
Vol 74 (05) ◽  
pp. 1255-1258 ◽  
Author(s):  
Arnaldo A Arbini ◽  
Pier Mannuccio Mannucci ◽  
Kenneth A Bauer
Keyword(s):  
Hemophilia A ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor Ix ◽  
Hemophilia B ◽  
Factor V ◽  
Bleeding Diathesis ◽  
Mutation Site ◽  
Spontaneous Bleeding ◽  
Factor V Leiden Mutation

SummaryPatients with hemophilia A and B and factor levels less than 1 percent of normal bleed frequently with an average number of spontaneous bleeding episodes of 20–30 or more. However there are patients with equally low levels of factor VIII or factor IX who bleed once or twice per year or not at all. To examine whether the presence of a hereditary defect predisposing to hypercoagulability might play a role in amelio rating the hemorrhagic tendency in these so-called “mild severe” hemophiliacs, we determined the prevalence of prothrombotic defects in 17 patients with hemophilia A and four patients with hemophilia B selected from 295 and 76 individuals with these disorders, respectively, followed at a large Italian hemophilia center. We tested for the presence of the Factor V Leiden mutation by PCR-amplifying a fragment of the factor V gene which contains the mutation site and then digesting the product with the restriction enzyme Mnll. None of the patients with hemophilia A and only one patient with hemophilia B was heterozygous for Factor V Leiden. None of the 21 patients had hereditary deficiencies of antithrombin III, protein C, or protein S. Our results indicate that the milder bleeding diathesis that is occasionally seen among Italian hemophiliacs with factor levels that are less than 1 percent cannot be explained by the concomitant expression of a known prothrombotic defect.

A Survey of the Effectiveness of Prothrombin Complex Concentrates in Controlling Hemorrhage in Patients with Hemophilia and Anti-Factor VIII Antibodies

1980 ◽  
Vol 44 (01) ◽  
pp. 039-042 ◽  
Author(s):  
Philip M Blatt ◽  
Doris Ménaché ◽  
Harold R Roberts
Keyword(s):  
Factor Viii ◽  
Ad Hoc ◽  
Hemophilia A ◽  
Working Party ◽  
International Committee ◽  
Factor Ix ◽  
Prothrombin Complex Concentrates ◽  
Factor Viii Concentrates

SummaryThe treatment of patients with hemophilia A and anti-Factor VIII antibodies is difficult. Between July 1977 and June 1978, a survey was carried out by an ad hoc working party of the subcommittee on Factor IX concentrates of the International Committee on Thrombosis and Hemostasis to assess the effectiveness of Prothrombin Complex Concentrates in controlling hemorrhage in these patients. The results are presented in this paper and, although subjective, support the view that these concentrates are not as effective in patients with inhibitors as Factor VIII concentrates are in patients without inhibitors.

Chromosome studies on normal males in 16 families with the marker X chromosome

2008 ◽  
Vol 26 (2) ◽  
pp. 166-167 ◽  
Author(s):  
P. A. Venter ◽  
D. J. Coetzee ◽  
J. Wilmot ◽  
D. Behari ◽  
S. A. Battson ◽  
...  
Keyword(s):  
X Chromosome ◽  
Normal Males

Detrimental effects of two active X chromosomes on early mouse development

Development ◽  
1990 ◽  
Vol 109 (1) ◽  
pp. 189-201 ◽  
Author(s):  
N. Takagi ◽  
K. Abe
Keyword(s):  
X Chromosome ◽  
Distal Segment ◽  
Translocation Chromosome ◽  
Mouse Development ◽  
X Chromosomes ◽  
Developmental Abnormalities ◽  
Inactivation Center ◽  
Normal Males ◽  
Early Mouse ◽  
Embryonic Ectoderm

Matings between female mice carrying Searle's translocation, T(X;16)16H, and normal males give rise to chromosomally unbalanced zygotes with two complete sets of autosomes, one normal X chromosome and one X16 translocation chromosome (XnX16 embryos). Since X chromosome inactivation does not occur in these embryos, probably due to the lack of the inactivation center on X16, XnX16 embryos are functionally disomic for the proximal 63% of the X chromosome and trisomic for the distal segment of chromosome 16. Developmental abnormalities found in XnX16 embryos include: (1) growth retardation detected as early as stage 9, (2) continual loss of embryonic ectoderm cells either by death or by expulsion into the proamniotic cavity, (3) underdevelopment of the ectoplacental cone throughout the course of development, (4) very limited, if any, mesoderm formation, (5) failure in early organogenesis including the embryo, amnion, chorion and yolk sac. Death occurred at 10 days p.c. Since the combination of XO and trisomy 16 does not severely affect early mouse development, it is likely that regulatory mechanisms essential for early embryogenesis do not function correctly in XnX16 embryos due to activity of the extra X chromosome segment of X16.

scholarly journals Plasma factor IX levels in patients given hexoestrol or stilboestrol to suppress lactation

BMJ ◽  
1969 ◽  
Vol 4 (5675) ◽  
pp. 82-84 ◽  
Author(s):  
C. A. Hakim ◽  
M. G. Elder ◽  
D. F. Hawkins
Keyword(s):  
Factor Ix ◽  
Plasma Factor

scholarly journals Pharmacokinetic Parameter Driven Outcomes Model Predicts a Reduction in Bleeding Events Associated with BAY 81-8973 Versus Antihemophilic Factor (Recombinant) Plasma/Albumin- Free Method in a Chinese Healthcare Setting

2022 ◽  
Author(s):  
Rong Chen ◽  
Dmitry Gultyaev ◽  
Johanna Lister ◽  
Rong Han ◽  
Nan Hu ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Cost Savings ◽  
Standard Of Care ◽  
Healthcare Setting ◽  
Bleeding Events ◽  
Plasma Albumin ◽  
Lifetime Horizon ◽  
Life Years ◽  
Antihemophilic Factor

Abstract Background: Long-term prophylactic therapy is considered the standard of care for hemophilia A patients. This study models the long-term clinical and cost outcomes of two factor VIII (FVIII) products using a pharmacokinetic (PK) simulation model in a Chinese population. Methods: Head-to-head PK profile data of BAY 81-8973 (KOVALTRY®) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM, ADVATE®) were applied to a two-state (alive and dead) Markov model to simulate blood FVIII concentrations at a steady state in prophylactically-treated patients with hemophilia A. Worsening of the Pettersson score was simulated and decline was associated with the probability of having orthopaedic surgery. The only difference between the compounds was FVIII concentration at a given time; each subject was treated with 25 IU/kg every 3 days. The model used a lifetime horizon, with cycle lengths of 1 year. Results: Cumulative bleeding events, joint bleeding events, and major bleeding events were reduced by 19.3%, 9.3% and 19.3%, respectively for BAY 81-8973 compared to rAHF-PFM. Hospitalizations and hospitalization days were also reduced by 19.3% for BAY 81-8973 compared to rAHF-PFM. BAY 81-8973 resulted in both cost savings and a gain in quality adjusted life years (QALYs) compared to rAHF-PFM. Conclusion: Based on modeled head-to-head comparisons, differences in PK-properties between BAY 81-8973 and rAHF-PFM result in a reduced number of bleeding events, leading to reduced costs and increased quality of life for BAY 81-8973. These results should be used to inform clinical practice in China when caring for patients with severe hemophilia A.

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