Hemophilia severe

Contraindications to heparin therapy include hypersensitivity to the drug, active bleeding, hemophilia, severe liver disease with elevated prothrombin time (PT), severe thrombocytopenia, malignant hypertension, and inability to meticulously supervise and monitor treatment. 

Antithrombin inhibits the activity of factors Ka, Xa, Xlla, and thrombin (Ila). It also inhibits thrombin-induced activation offactors V and VIII. UFH prevents the growth and propagation of a formed thrombus and allows the patient s own thrombolytic system to degrade the clot. Contrainchcations to heparin therapy include hypersensitivity to the drug, active bleeding, hemophilia, severe hver chsease with elevated prothrombin time (PT), severe thrombocytopenia, malignant hypertension, and inability to meticulously supervise and monitor treatment. 

Deficiency of the VIIFC portion of the Factor VIII complex results in classic hemophilia or hemophilia A and is inherited as a sex-linked recessive disorder. Based on the degree of deficiency of the VIIFC molecule three different forms of hemophilia A are recognized. Less than 1% VIIFC activity equals severe hemophilia A. Two to 10% of normal VIIFC activity equals moderately severe hemophilia A. Ten to 25% of normal VIIFC activity equals minimal symptomatic disease. Deficiency of the VIIFvWFAg portion of the Factor VIII complex results in von WiUebrand disease. There are at present five principal types of von WiUebrand disease and numerous subtypes or variants. For the most part, von WiUebrand disease is inherited as an autosomal dominant, and a few subtypes may be inherited as an autosomal recessive trait. 

Nineteen women underwent amniocentesis for the determination of fetal sex. Several different X-llnked abnormalities constituted the Indications for this procedure, and these Included hemophilia A, hemophilia B, Duchenne muscular dystrophy, optic albinism, X-llnked mental retardation, the Lesch-Nyhan syndrome (due to dlflclency of hypoxanthlne-guanlne phosphorlbosyltransferase, and Fabry s disease (due to deficiency of an a-galact-osldase). Fourteen of the fetuses were male. Including one which turned out to be a set of twins, and most of the male pregnancies were terminated. The sex determination being carried out for Fabry s disease Is of particular Interest, since In this case It was desired to find out whether the fetus was a female. 

Hemophilia or other hemorrhagic tendencies Severe liver disease with elevated baseline PT Severe thrombocytopenia (platelet count less than 20,000) Malignant hypertension... 

The severity of bleeding associated with hemophilia correlates with the degree of factor VIII or factor IX deficiency as measured against the normal plasma standard. Table 64-1 summarizes the age at onset and laboratory and clinical manifestations of hemophilia.3... 

O Intravenous factor replacement with recombinant or plasma-derived products to treat or prevent bleeding is the primary treatment hemophilia. Primary prophylaxis is defined as the regular administration of factor concentrates with the intention of preventing joint bleeds.4 The rationale for primary prophylaxis is that individuals with factor levels of greater than 0.02 unit/mL (2 IU/dL) rarely suffer from spontaneous bleeds and arthropathy. Therefore, to maintain a trough level above this might convert severe hemophilia to moderate disease, with the abolition of joint bleeds and the associated arthropathy.5... 

Unlike hemophilia, the bleeding tendency in vWD is less frequent and generally less severe. Consequently, chronic... 

Severe hemophilia Less than 1 lU/dL 0.01 Less than 0.01 units/mL... 

RFLPs are often a reflection of individual genetic diversity and are not related to a clinical phenotype, but occasionally they can be diagnostic of an inherited disease. This technique is relatively new yet, it has been applied to the prenatal detection of sickle cell anemia, thalassemia, phenylketonuria, a,-antitrypsin deficiency, Huntington s chorea, Duchenne muscular dystrophy, hemophilia A and B, cystic fibrosis, and several other, diseases. 

There are now thought to be several thousand different genetic diseases, about 10% of which have known biochemical lesions. As has already been seen with the thyroid diseases and diabetes, the phenotypic manifestation, hemophilia, for example, may have genetically, biochemically or clinically different causes. Some of the biochemically identified disturbances, such as those affecting glycogen or galactose, have been important in establishing metabolic pathways (see Chapter 4). 

Flowever, some associated materials might be perceived as toxic. For example, complexes of osmium find frequent use as electron mediators, because of their rich chemistry, stability, and redox activity. Osmium metal and most compounds are considered nontoxic, but the neat tetroxide of osmium is a strong oxidizer and is considered highly toxic in the U.S. and very toxic by the European Union. On the other hand, the aqueous solution, osmic acid, has been injected at 1% concentration in several European clinical trials, starting in the 1970s, for treatment of arthritis and hemophilia. - No toxic effects were observed. Thus, osmium toxicity might be a question not of in vivo chemistry, but of manufacture, where a concentrated form of the oxide might need to be handled. ... 

Contraindications HemophiliaAwithfactorVIII levels less than 5% hemophilia B severe type I, type HB, or platelet-type von Willebrand s disease... 

The investigators evaluated the safety of their nonviral somatic-cell gene therapy system, which they call transkaryotic implantation, in six patients with severe hemophilia. The procedure involved isolation of dermal fibroblasts from the patients upper arms. The fibroblasts were then transfected with a factor VIII genebearing plasmid. Cells that expressed factor VIII were cloned, propagated, and implanted into the patients abdomens. This technique can be considered as a less invasive form of ex vivo gene therapy. 

Roth,D.A.,N.E.Tawa,Jr.,J.M.O Brien,D.A. Treco, and R.F. Selden, Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. N Engl J Med, 2001.344(23) 1735-42. 

Gene therapy holds great promise for the treatment of many diseases (e.g., cancer, AIDS, cystic fibrosis, adenosine deaminase deficiency, cardiovascular diseases, Gaucher disease, a 1-antitrypsin deficiency, rheumatoid arthritis, and several others) (1,2). Advances in genomics and molecular biology have revealed that almost all diseases have a genetic component. In some cases, such as cystic fibrosis or hemophilia,... 

There have been several reports of seizures in association with hyponatremia after intravenous administration of desmopressin to cover surgery in young children with congenital bleeding disorders such as mild hemophilia A or von Willebrand s disease (58-60). Hyponatremia and convulsions have occurred in children without congenital bleeding disorders who received desmopressin for urine concentration tests or to treat nocturnal enuresis (54,61,62). 

Manno, C. S. et al. (2003). AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood 101, 2963-2972. 

Several protocols are routinely used in assessing the success of gene therapy vector treatment in the animal models of hemophilia and are described below. 

Hough, C., Kamisue, S., Cameron, C., Notley, C., Tinlin, S., Giles, A. and Lillicrap, D. (2002). Aberrant splicing and premature termination of transcription of the FVIII gene as a cause of severe canine hemophilia A Similarities with the intron 22 inversion mutation in human hemophilia. Thromb. Haemost. 87, 659-665. 

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