Page 2155 - Williams Hematology ( PDFDrive )

2130 Part XII: Hemostasis and Thrombosis Chapter 123: Hemophilia A and Hemophilia B 2131

of up to 3 years in the original cohort of six patients, together with Individuals requiring valve replacement should receive a biologic rather
an additional four treated individuals. The protocol consisted of a than a mechanical valve when possible.
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single intravenous injection of a self-complementary rAAV-8; at the Hemophilia patients who have atrial fibrillation should undergo
highest vector doses used, biochemical transaminitis occurred in some of cardioversion when possible. If cardioversion is not successful, some
the patients. This hepatotoxicity was mediated by a host cytotoxic physicians recommend treatment with aspirin but anticoagulants
T-lymphocyte response to viral capsid antigens expressed on trans- should be used with caution taking into consideration the severity of
fected hepatocytes. Fortunately, however, there was a consistently bene- the hemophilia and the risk of stroke.
ficial and prompt response to modest doses of oral prednisolone.
This milestone study has prompted a resurgent interest in gene REFERENCES
therapy for hemophilia, with several phase I studies now underway.
Remaining challenges include the use of purer vector preparations (with 1. Brinkhous KM: A short history of hemophilia, with some comments on the word
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applicable in a greater proportion of patients, and result in even higher Med J 1:165, 1958.
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by the inefficient expression of factor VIII, as well as the large size of the thrombin. Am J Med Sci 198:509, 1939.
coding sequence, even in the absence of the B domain. However, the use 6. Pavlovsky A: Contribution to the pathogenesis of hemophilia. Blood 2:185, 1947.
7. Aggeler PM, White SG, Glendenning MB: Plasma thromboplastin component (PTC)
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that these preclinical data translate into persistent factor VIII expression 9. Escobar M, Sallah S: Hemophilia A and hemophilia B: Focus on arthropathy and vari-
levels in patients with hemophilia A. It remains to be seen how often ables affecting bleeding and prophylaxis. J Thromb Haemost 11:1449, 2013.
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SPECIAL PROBLEMS ASSOCIATED 12. Broze GR Jr: Tissue factor pathway inhibitor and the revised theory of coagulation.
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WITH HEMOPHILIAS A AND B 13. Fay PJ: Reconstitution of human factor VIII from isolated subunits. Arch Biochem
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119
and B. Some of these are discussed in a brief publication. For example, 15. Hoffman M, Hargen A, Lewkowski A, et al: Cutaneous wound healing is impaired in
scuba diving can be dangerous in severely affected hemophiliacs and hemophilia B. Blood 108:3053, 2006.
should be avoided. Hemophilic patients requiring laser treatment for 16. Tuddenham EG: Factor VIII, in Molecular Basis of Thrombosis and Hemostasis, edited
visual problems may not require replacement therapy provided that a by KA High, HR Roberts, p 167. Marcel Dekker, New York, 1995.
surgical incision is not required during such therapy. Carriers of either 17. Factor VIII variant database. Available at: http://www.factorviii-db.org
18. Tuddenham EG, Cooper DN, Gitschier J, et al: Haemophilia A: Database of nucleotide
hemophilia A or B may have bleeding problems during delivery or sur- substitutions, deletions, insertions and rearrangements of the factor VIII gene. Nucleic
gery and will require replacement therapy. Carriers whose fetuses have Acids Res 22:4851, 1996.
hemophilia may require cesarean section if vaginal delivery is found to 19. Antonarakis SE, Rossiter JP, Young M, et al: Factor VIII gene inversions in severe hemo-
philia A: Results of an international consortium study. Blood 86:2206, 1995.
be difficult. Forceps and mechanical devices should be avoided during 20. Higuchi M, Kazazian HH Jr, Kasch L, et al: Molecular characterization of severe hemo-
delivery of infants who are hemophilic. Some patients with hemophilia philia A suggests that about half the mutations are not within the coding regions and
may also have another familial bleeding disorder, such as VWD. splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A 88:7405, 1991.
Hemophilic patients that survived the HIV epidemic are aging and 21. Gitschier J, Kogan S, Diamond C, Levinson B: Genetic basis of hemophilia A. Thromb
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are developing comorbidities similar to nonhemophilia males, includ- 22. Bagnall RD, Waseem N, Green PM, Giannelli F: Recurrent inversion breaking intron 1
ing hypertension, cardiovascular disease, renal failure, and dyslipi- of the factor VIII gene is a frequent cause of severe hemophilia A. Blood 99:168, 2002.
demias. The deficiency of either factor VIII or IX seems to provide some 23. Kazazian HH, Wong C, Youssoufian H, et al: Hemophilia A resulting from de novo
insertion of L1 sequences represents a novel mechanism for mutation in man. Nature
120
protection against thrombosis. However, myocardial infarction has 332:164, 1998.
121
been reported in hemophilic patients even without treatment. DVT 24. Mori PG, Pasino M, Vadala CR, et al: Haemophilia “A” in a 46Xi(Xq) female. Br J
Haematol 43:143, 1979.
has also been reported following replacement therapy in both hemo- 25. Lakich D, Kazazian HH, Antonarakis SE, Gitschier J: Inversions disrupting the factor
philia A and hemophilia B. Acute DVT can be treated with heparin for VIII gene are a common cause of severe hemophilia A. Nat Genet 5:236, 1993.
7 to 10 days as long as the patient receives factor replacement therapy. 26. Peake IR, Lillicrap DP, Boulyjenkov V, et al: Report of a joint WHO/WFH meeting
Thereafter, anticoagulation is not recommended. Thromboembolic epi- on control of haemophilia: Carrier detection and prenatal diagnosis. Blood Coagul
Fibrinolysis 4:313, 1993.
sodes in hemophilia B are much less common since the advent of highly 27. Ljung RC: Prenatal diagnosis of haemophilia. Haemophilia 5:84, 1999.
purified factor IX products. 28. Poon MC, Hoar DI, Low S, et al: Hemophilia A carrier detection by restriction frag-
The management of cardiovascular disease in the hemophilia pop- ment length polymorphism analysis and discriminant analysis based on ELISA of fac-
tor VIII and vWf. J Lab Clin Med 119:751, 1992.
ulation is a challenge. 122,123 The use of antiplatelet therapy seems safe in 29. Chi C, Lee CA, Shiltagh N, et al: Pregnancy in carriers of hemophilia. Haemophilia
mild and moderate individuals; for the severely deficient patient, how- 14:56, 2008.
ever, prophylaxis with factor VIII or factor IX should be used. For anti- 30. Brummel-Ziedins KE, Orfeo T, Rosendaal FR, et al: Empirical and theoretical pheno-
coagulation with heparin or vitamin K antagonists, factor trough levels typic discrimination. Phenotypic discrimination models. J Thromb Haemost 7(1):181,
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above 0.25 U/L are recommended. For the management of acute coro- 31. Nichols WC, Amano K, Cacheris PM, et al: Moderation of hemophilia A phenotype by
nary syndromes and arrhythmias requiring intervention, replacement the factor V R506Q mutation. Blood 88:1183, 1996.
with adequate factor concentrate should be done without exceeding lev- 32. Gilbert MS: Musculoskeletal complications of haemophilia: The joint. Haemophilia
6:34, 2000.
els above 80 to100 percent of normal. Radial artery access rather than 33. Jansen NA, Rosendaal G, Lafeber FP: Understanding haemophilic arthropathy: An
femoral and bare metal stents are preferred over drug-eluting stents. exploration of current issues. Br J Haematol 143:632, 2008.

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