scholarly journals A transgender person with haemophilia

2018 ◽  
Vol 5 (1) ◽  
pp. 147-151
Author(s):  
Caroline Valk
Keyword(s):  
Factor Viii ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Clotting Factor ◽  
Bilateral Mastectomy ◽  
Sex Reassignment Surgery ◽  
Haemophilia A ◽  
Cultural Changes ◽  
Transgender People ◽  
Specialist Doctor

Abstract Introduction: Transgender people face many obstacles to accessing healthcare but cultural changes are likely to increase provision of sex reassignment surgery in countries with sufficient resources. Haemophilia services traditionally focus on providing factor replacement therapy for males and should therefore understand how the care they provide can be adapted to meet the needs of transgender people. Haemophilia is an X-linked congenital bleeding disorder, caused by deficiency of coagulation factor VIII (haemophilia A) or factor IX (haemophilia B). The condition is passed on through carrier females, the majority of whom have a factor level high enough to allow for normal blood clotting. However, around 10% of carrier females are symptomatic and at risk of abnormal bleeding. Case presentation: This case report describes a person with mild haemophilia A who, on first presentation to the haemophilia service, stated he was a transgender person in transition to becoming a male. Haemophilia was diagnosed when heavy bleeding occurred following bilateral mastectomy approximately 25 years previously. He now requested phalloplasty. Management and outcome: Phalloplasty was performed at a hospital geographically separate from the haemophilia centre, requiring careful coordination between the two services. A haemophilia specialist nurse provided education and training about haemophilia and its management to the surgical nurses. Twenty-four-hour support was available from the nurse and a specialist doctor. Preparation and administration of clotting factor was the responsibility of the haemophilia nurse until the surgical team was confident in its use. Clotting factor replacement was managed using standard procedures, successfully maintaining factor VIII above a target level of 100% with a twice daily dose. Surgery went well, but wound healing was delayed, in part, due to persistent bleeding. Discussion: Close collaboration between the haemophilia and surgical teams provided effective prophylaxis of bleeding during a complex procedure that presented new challenges. Both services now have better understanding of the needs of transgender people.

Extravascular Clotting Factor Activity within Joint Tissues Protects Against Progression of Hemophilic Arthropathy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 496-496 ◽  
Author(s):  
Junjiang Sun ◽  
Narine Hakobyan ◽  
Leonard A. Valentino ◽  
Paul E. Monahan
Keyword(s):  
Factor Viii ◽  
Coagulation Factor ◽  
Joint Capsule ◽  
Factor Ix ◽  
Clotting Factor ◽  
Needle Puncture ◽  
Factor Activity ◽  
Clotting Factors ◽  
Hemophilic Arthropathy ◽  
Human Factor Viii

Abstract Hemophilic arthropathy is the major morbidity of congenital factor VIII and IX deficiency. Therapies localized to hemophilic joints could provide adjunctive protection, in addition to that provided by systemic factor replacement. However, the ability of extravascular clotting factors to contribute to hemostatic protection within joint tissue is unknown. We hypothesized that replacing deficient factor VIII or IX within the injured joint capsule of mice with hemophilia A (FVIII −/ −) or hemophilia B (FIX −/ −), respectively, would decrease the progression of synovitis. We developed a bleeding model consisting of a unilateral knee joint capsule needle puncture to induce hemorrhage in hemophilic mice. Pathology of the joint at two weeks after the injury is graded 0 to 10 using a murine hemophilic synovitis grading system (Valentino, Hakobyan. Haemophilia, 2006). Hemostatically normal mice do not develop synovitis following this injury, but > 95% of FIX −/ − mice develop bleeding and synovitis with a mean grade of 3–4 or greater. Coincident with needle puncture, recombinant human coagulation factor doses ranging from 0 to 20 IU/kg body weight of factor IX or 0 to 25 IU/kg of factor VIII were instilled intraarticularly (I.A.). Comparison groups received the same injury and intravenous (I.V.) factor IX or VIII doses of 25 IU/kg to 100 IU/kg (n= 4–7 mice per study group). Joint bleeding phenotype of the two strains of mice was similar. Mice receiving only saline injection at the time of needle puncture developed mean synovitis scores of 5 ±0.5 in the FVIII −/ − mice and 6 ±0.5 in the FIX −/ − mice. Protection by human clotting factor in the mouse coagulation system was incomplete; mice receiving 100 IU/kg I.V. of factor VIII or factor IX developed synovitis scores of 2.6 ± 1.7 and 2.1 ± 0.2, respectively. In contrast, pathology grade of FVIII −/ − mice dosed with 25 IU/kg I.A. was 0.67 ± 0.3 (p = 0.05 for comparison of 25 IU/kg I.A. with 100 IU/kg IV); FIX−/ − mice receiving 20 IU/kg I.A. had synovitis scores of 0.45 ± 0.58 (p < 0.01 for comparison of 25 IU/kg I.A. with 100 IU/kg I.V.). We next ruled out the possibility that I.A. factor was entering the circulation, and via that route resulting in joint protection, either through technical error at the time of injection, or from a depot effect in the joint with late equilibration into the circulation. Additional groups of mice received factor VIII or IX intravenously at 100 IU/kg, or intraarticularly at 4 times the doses used in the hemarthrosis challenge (80 IU/kg FIX or 100 IU/kg FVIII), and factor activity assays were performed at 1, 4, 12, 24, and 48 hours. Expected circulation kinetics were seen following I.V. dosing; no increase in circulating factor VIII or IX activity were seen in the intraarticular dosing groups at any timepoint. In considering the potential immunogenicity of an intraarticular therapy approach for hemophilic joint therapy, factor VIII −/ − mice were treated with three doses of human factor VIII 100 IU/kg at five day intervals either I.V. or I.A. At two weeks after exposure, 5/5 I.V.-treated mice developed inhibitor antibodies with titers ranging 0.8–7.2 BU; 2/5 I.A.-treated mice had detectable low-titer antibodies (1.3 BU), indicating no greater immunogenicity in the I.A. model. Extravascular factor VIII and factor IX can contribute to protection against blood-induced joint deterioration; enhancing local tissue hemostasis with protein or gene therapy may prove a useful adjunct to systemic replacement.

A Factor VIII Minigene Comprising the Truncated Intron I of Factor IX Highly Improves the In Vitro Production of Factor VIII

2001 ◽  
Vol 86 (08) ◽  
pp. 596-603 ◽  
Author(s):  
Jean-Luc Plantier ◽  
Marie-Hélène Rodriguez ◽  
Nathalie Enjolras ◽  
Olivier Attali ◽  
Claude Négrier
Keyword(s):  
Factor Viii ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Haemophilia A ◽  
Intracellular Accumulation ◽  
In Vitro Production ◽  
Insertion Sites ◽  
Recombinant Fviii ◽  
Vitro Production

SummaryThe biosynthesis of coagulation factor VIII (FVIII) is hampered by successive controls that limit its production. To improve this production, a truncated intron I sequence of factor IX (TFIXI1) was inserted in FVIII cDNA in place of FVIII introns 1, 12 and 13 and also as a combination between introns 1 and 12, and introns 1 and 13. The intron 12 and 13 locations were targeted because this region was previously shown to contain a transcriptional silencer. The expression of FVIII in CHO and HepG2 cells revealed important variations in the properties of the minigenes depending on the TFIXI1 insertion sites. In FVIII intron 13 location the TFIXI1 seemed to diminish the transcriptional silencer activity, whereas it was poorly spliced in intron 12 position. Among the five constructs, FVIII I1+13 leaded to a significant improvement in FVIII secretion (13 times) that was associated with a dramatic intracellular accumulation in cells. Therefore, the FVIII I1+13 minigene could represent a particular interest to produce recombinant FVIII in vitro as well as in the aim of gene therapy of haemophilia A.

scholarly journals Dental considerations in a patient with haemophilia

2016 ◽  
Vol 3 (1) ◽  
pp. 51-54 ◽  
Author(s):  
Chandra Khyati ◽  
Mavinakote Gowda Triveni ◽  
Rini Gopal ◽  
Ab. Tarunkumar ◽  
Suresh Hanagavadi ◽  
...  
Keyword(s):  
Factor Viii ◽  
Dental Care ◽  
Coagulation Factor ◽  
Bleeding Risk ◽  
Factor Ix ◽  
Haemophilia A ◽  
Haemophilia B ◽  
Characteristic Features ◽  
Limited Health ◽  
Treatment Procedures

Abstract Haemophilia is a rare blood clotting disorder, characteristic features of which include extemporaneous and post-traumatic subcutaneous bleeding and mucosal haemorrhages. Genetic deficiency of coagulation factor VIII results in haemophilia A, while deficiency of factor IX leads to haemophilia B. The most common treatment for haemophilia A is administration of recombinant or plasma-derived factor VIII concentrate, to raise the levels of the deficient factor VIII. Tranexamic acid is also used as an anti-fibrinolytic agent that inhibits plasminogen activators present in oral secretion and stabilises the clot. Administration of factor IX is required in haemophilia B. Treatment leads to increased longevity and quality of life for patients. Dental conditions and treatments are more complicated and uncertain in patients with haemophilia due to bleeding risk, thus restorative dental care is of paramount importance for those with haemophilia. The fear of bleeding during treatment procedures is the primary cause of lack of proper dental care for people with haemophilia in countries with limited health care resources. This case report highlights the significance of clinical examination and investigation, and the importance of proper interaction between a haematologist and the periodontist for correct multidisciplinary and uneventful management of periodontal health of a patient with haemophilia.

Detection of the Carrier State in Hereditary Coagulation Disorders II

1968 ◽  
Vol 19 (03/04) ◽  
pp. 403-422 ◽  
Author(s):  
J. J Veltkamp ◽  
E. F Drion ◽  
E. A Loeliger
Keyword(s):  
Standard Deviation ◽  
Factor Viii ◽  
Normal Population ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Ix ◽  
Factor Xii ◽  
Haemophilia A ◽  
Coagulation Defects ◽  
The Individual

Summary and ConclusionsSpecific determination of the coagulation factors makes it possible to demonstrate that heterozygotes of hereditary coagulation defects on the average display about 50% of the normal activity of the relevant coagulation factor. For the autosomally inherited defects, the published values of the coefficient of variation of the carrier population and the normal population show little disparity. It appears that discrimination of carriers of the factor II, V, VII, X, or XI deficiencies can be carried out with reasonable success. An exception, however, is the discrimination of carriers of haemophilia A and B. The large overlapping of the normal and the carrier distributions has been attributed to technical inadequacies in the assessment of factor VIII and IX activity and also to the possibly disturbing effect of the random inactivation of one of the two X-chromosomes (Lyon hypothesis). The statistical approaches described in the literature for the calculation of chance of carriership in individual cases are not accepted.Throughout the present investigation a one-stage method for the measurement of coagulation factor activity was used; this method was based on established principles, and adapted for use in Schnitger’s coagulometer. The experimental error (which with the two-stage method amounted to 25%) is 5.7% for factor VIII, 8.1 % for factor IX, and 7.3% for factor XII, expressed as the coefficient of variation of the result. This drastic improvement of the accuracy of the method was accomplished chiefly by automatic registration. The procedure is also more rapid and less tiring to perform than the two-stage method.The average factor VIII activity found in 30 proven carriers of haemophilia A was antilog 1.71 % (51 %) of normal. The standard deviation for this population was 0.21, as calculated from logarithms of the factor VIII activities, and the values were symmetrically distributed. For the normal population, which consisted of 60 persons, the standard deviation was 0.12. The biological variation of the factor VIII activity within the individual was 0.084 for carriers and 0.061 for normals; these values do not differ significantly.For the carriers of haemophilia B the average factor IX activity was antilog 1.7% (50%) and the standard deviation 0.13. The average activity in the normal population of 65 persons was antilog 2.007% (100.4%) and the standard deviation 0.105. There was a significant increase in factor IX activity with increasing age, at least for females. The variation within the individual was 0.066 for carriers and 0.0577 for normals.The wide variation within the populations of carriers of haemophilia A and B as compared to the normal population as well as to the populations of heterozygotes of autosomally inherited coagulation defects could be interpreted as support for the hypothesis of Lyon. This phenomenon could be caused, however, by different normal iso-alleles and the influence of other genetic or environmental factors.On the basis of our observations, it is possible to make the discrimination of carriers and normals on a 95% confidence level in the population of potential carriers of haemophilia A in 34% and of haemophilia B in 60% of the cases. The chance of carriership can be calculated for individual cases, with Bayes’ theorem, from the known chance of carriership on genetic grounds and the observed factor VIII or IX activity.The bimodal distribution of the results obtained in 50 obligatory heterozygotes for Hageman trait reflect the occurrence of two normal iso-alleles for the Hageman locus, one with 23% and the other 60% factor XII activity. The whole group still shows a mean activity of about 50% as compared to the normal population.Laboratory methods for measuring blood coagulation factors, adequate for the detection of heterozygotes of most autosomally inherited coagulation defects, have been shown to make only a modest contribution to the improvement of genetic counselling in haemophilia A and B. More fundamental approaches to the problem of discrimination of haemophilia carriers are required, because further standardization of the laboratory procedures cannot substantially improve the results obtained in this study. Theoretically, this problem will be easily solved when new common X-linked markers, closely linked to the haemophilia loci, are discovered.

Epitope specificity of anti-factor VIII antibodies from inhibitor positive acquired and congenital haemophilia A patients using synthetic peptides spanning A and C domains

2009 ◽  
Vol 101 (05) ◽  
pp. 834-839 ◽  
Author(s):  
Soheila Gharagozlou ◽  
Ramazan Sharifian ◽  
Jalal Khoshnoodi ◽  
Katayoon Karimi ◽  
Monica Milani ◽  
...  
Keyword(s):  
Factor Viii ◽  
Binding Sites ◽  
Synthetic Peptides ◽  
Coagulation Factor ◽  
Phosphatidyl Serine ◽  
Factor Ix ◽  
Peptide Sequence ◽  
Haemophilia A ◽  
Antigen Specificity ◽  
Acquired Haemophilia

SummaryDevelopment of antibodies (Ab) that either block the function of coagulation factor VIII (FVIII) (inhibitors) or clear it from circulation, seriously complicate the treatment of haemophilia A patients with FVIII products. Autoantibodies which develop in subjects without congenital FVIII defects, cause acquired haemophilia, a rare but life-threatening coagulopathy. Identification of the FVIII epitopes to which inhibitor Abs bind will help understanding the mechanisms of inhibitor activity, and perhaps development of new therapies. Here, we examined the FVIII peptide sequence regions recognised by anti-FVIII Ab in the plasma of six congenital and one acquired haemophilia patients with high inhibitor titers (24.4–2000 BU/ml). We used indirect ELISA and overlapping synthetic peptides, 20 residues long, spanning the sequence of the A and C FVIII domains. None of the plasma samples reacted with A1, A3 or C1 domain peptides. Six plasmas reacted with A2 and/or C2 peptides. Peptides spanning residues A2–521–690 and C2–2251–2332 were recognised most frequently and strongly. They include residues that contribute to the binding sites for activated factor IX and phosphatidyl serine/ von Willebrand factor. These results suggest that anti-FVIII Abs share a pattern of antigen specificity in our panel of patients, and that exposed regions of the FVIII molecule that form functionally important binding sites elicit an intense Ab response.

Management of Haemophilia in Sweden

1976 ◽  
Vol 35 (03) ◽  
pp. 510-521 ◽  
Author(s):  
Inga Marie Nilsson
Keyword(s):  
Factor Viii ◽  
Total Population ◽  
Age Groups ◽  
Factor Ix ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Haemophilia B ◽  
Human Fraction ◽  
Mild Haemophilia

SummaryThe incidence of living haemophiliacs in Sweden (total population 8.1 millions) is about 1:15,000 males and about 1:30,000 of the entire population. The number of haemophiliacs born in Sweden in 5-year periods between 1931-1975 (June) has remained almost unchanged. The total number of haemophilia families in Sweden is 284 (77% haemophilia A, 23% haemophilia B) with altogether 557 (436 with A and 121 with B) living haemophiliacs. Of the haemophilia A patients 40 % have severe, 18 % moderate, and 42 % mild, haemophilia. The distribution of the haemophilia B patients is about the same. Inhibitors have been demonstrated in 8% of the patients with severe haemophilia A and in 10% of those with severe haemophilia B.There are 2 main Haemophilia Centres (Stockholm, Malmo) to which haemophiliacs from the whole of Sweden are admitted for diagnosis, follow-up and treatment for severe bleedings, joint defects and surgery. Minor bleedings are treated at local hospitals in cooperation with the Haemophilia Centres. The concentrates available for treatment in haemophilia A are human fraction 1-0 (AHF-Kabi), cryoprecipitate, Antihaemophilic Factor (Hyland 4) and Kryobulin (Immuno, Wien). AHF-Kabi is the most commonly used preparation. The concentrates available for treatment in haemophilia B are Preconativ (Kabi) and Prothromplex (Immuno). Sufficient amounts of concentrates are available. In Sweden 3.2 million units of factor VIII and 1.0 million units of factor IX are given per year. Treatment is free of charge.Only 5 patients receive domiciliary treatment, but since 1958 we in Sweden have practised prophylactic treatment of boys (4–18 years old) with severe haemophilia A. At about 5-10 days interval they receive AHF in amounts sufficient to raise the AHF level to 40–50%. This regimen has reduced severe haemophilia to moderate. The joint score is identical with that found in moderate haemophilia in the same age groups. For treatment of patients with haemophilia A and haemophilia B complicated by inhibitors we have used a large dose of antigen (factor VIII or factor IX) combined with cyclophosphamide. In most cases this treatment produced satisfactory haemostasis for 5 to 30 days and prevented the secondary antibody rise.

The Effect of Adrenaline Infusions on Blood Coagulation in Normal and Haemophilia B Dogs

1966 ◽  
Vol 15 (03/04) ◽  
pp. 349-364 ◽  
Author(s):  
A.H Özge ◽  
H.C Rowsell ◽  
H.G Downie ◽  
J.F Mustard
Keyword(s):  
Body Weight ◽  
Factor Viii ◽  
Factor Ix ◽  
Clotting Factor ◽  
Blood Ph ◽  
Order Of Magnitude ◽  
Dose Dependent ◽  
Generation Test ◽  
Plasma Activity

SummaryThe addition of trace amounts of adrenaline to whole blood in plasma in vitro increased factor VIII, factor IX and whole plasma activity in the thromboplastin generation test. This was dose dependent.Adrenaline infusions less than 22 (μg/kg body weight in normal dogs accelerated clotting, increased factor IX, factor VIII and whole plasma activity in the thromboplastin generation test and caused a fall in blood pH. In a factor IX deficient dog, there was no increase in factor IX activity. After adrenaline infusions, however, the other changes occurred and were of the same order of magnitude as in the normal. Adrenaline in doses greater than 22 μg/kg body weight did not produce as great an effect on clotting in normal or factor IX deficient dogs. The platelet count in the peripheral blood was increased following the infusion of all doses of adrenaline. These observations suggest that the accelerating effect of adrenaline on clotting is not mediated through increase in activity of a specific clotting factor.

scholarly journals Gene Therapy in Hemophilia: Recent Advances

2021 ◽  
Vol 22 (14) ◽  
pp. 7647
Author(s):  
E. Carlos Rodríguez-Merchán ◽  
Juan Andres De Pablo-Moreno ◽  
Antonio Liras
Keyword(s):  
Gene Therapy ◽  
Adverse Events ◽  
Factor Viii ◽  
Coagulation Factor ◽  
Cost Savings ◽  
Factor Ix ◽  
Clotting Factors ◽  
Advanced Therapies ◽  
Potential Benefits

Hemophilia is a monogenic mutational disease affecting coagulation factor VIII or factor IX genes. The palliative treatment of choice is based on the use of safe and effective recombinant clotting factors. Advanced therapies will be curative, ensuring stable and durable concentrations of the defective circulating factor. Results have so far been encouraging in terms of levels and times of expression using mainly adeno-associated vectors. However, these therapies are associated with immunogenicity and hepatotoxicity. Optimizing the vector serotypes and the transgene (variants) will boost clotting efficacy, thus increasing the viability of these protocols. It is essential that both physicians and patients be informed about the potential benefits and risks of the new therapies, and a register of gene therapy patients be kept with information of the efficacy and long-term adverse events associated with the treatments administered. In the context of hemophilia, gene therapy may result in (particularly indirect) cost savings and in a more equitable allocation of treatments. In the case of hemophilia A, further research is needed into how to effectively package the large factor VIII gene into the vector; and in the case of hemophilia B, the priority should be to optimize both the vector serotype, reducing its immunogenicity and hepatotoxicity, and the transgene, boosting its clotting efficacy so as to minimize the amount of vector administered and decrease the incidence of adverse events without compromising the efficacy of the protein expressed.

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