Factor VIII deficiency hemophilia

Salmon et al., 1970), pseudocholinesterase deficiency (Hodgkin et al., 1965), myophosphorylase deficiency (Robbins, 1960), acatalasia (Nishi-mura et al., 1961 Takahara et al., 1962), a variant of factor VIII deficiency (hemophilia) (Feinstein et al., 1969), and several others (Boyer et al., 1973). Because of the absence of any identifiable protein in these conditions, it has been cautioned that enzyme or nonenzyme replacement be carefully weighed, since the patient may treat such replacement as foreign protein (Boyer et al., 1973). 

Inherited deficiencies of the clotting system that result in bleeding are found in humans. The most common is deficiency of factor VIII, causing hemophilia A, an X chromosome-hnked disease that has played a major role in the history of the royal families of Europe. Hemophilia B is due to a deficiency of factor IX its clinical Feamres are almost identical to those of hemophilia A, but the conditions can be separated on the basis of specific assays that distinguish between the two factors. 

Hemophilia A and B are coagulation disorders that result from defects in the genes encoding for plasma coagulation proteins. Hemophilia A (classic hemophilia) is caused by the deficiency of factor VIII, and hemophilia B (Christmas disease) is caused by the deficiency of factor IX. The incidences of hemophilia A and B are estimated at 1 in 5000 and 1 in 30,000 male births, respectively. Both types of hemophilia are evenly distributed across all ethnic and racial groups.1... 

Table 4 contains products available for Factor VII, Factor VIII C (hemophilia A), Factor IX, and von Willebrand protein deficiency. Table 5 lists miscellaneous hemostatics and their proposed mechanisms of action. 

Replacement of deficient gene products or even of organs is also utilized in the treatment of genetic disorders for example, replacement of coagulation factor VIII in hemophilia A, of or-antitrypsin in persons deficient in this factor or of pancreatic islet cells in some forms of diabetes mellitus. 

Lipshutz, G. S., Sarkar, R., Flebbe-Rehwaldt, L., Kazazian, H. and Gaensler, K. M. (1999). Short-term correction of factor VIII deficiency in a murine model of hemophilia A after delivery of adenovirus murine factor VIII in utero. Proc. Natl. Acad. Sci. USA 96, 13324-13329. 

There are two types of hemophilias that have been identified, hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency). The incidence of hemophilia A is I in every 5000 live male births and for hemophilia B the incidence is I in every 30,000 live male births. Both types of hemophilia are... 

Antonarakis SE, Kazazian HH, Tuddenham EG. Molecular etiology of factor VIII deficiency in hemophilia A. Hum Mutat 1995 5(l) l-22. 

Giles AR,Tinlin S, Hoogendoorn H, Fournel MA, Ng P, Pancham N. In vivo characterization of recombinant factor VIII in a canine model of hemophilia a (factor VIII deficiency). Blood 1988 72 335-9. 

A revealing assay. Suppose that you have just examined ayoung hoy with a bleeding disorder highly suggestive of classic hemophilia (factor VIII deficiency). Because of the late hour, the laboratory that carries out specialized coagulation assays is closed. However, you happen to have a sample of blood from a classic hemophiliac whom you admitted to the hospital an hour earlier. What is the simplest and most rapid test that you can perform to determine whether your present patient also is deficient in factor VIII activity ... 

Before the screening of blood and plasma and before virus inactivation procedures were applied to coagulation factor products (for example factor VIII and factor IX), many hemophiliacs who were treated with substitution therapy were exposed to infection with HIV. In the USA about 70% of tested persons with hemophiha A (factor VIII deficiency) and 35% with hemophilia B (factor IX deficiency) were HIV-seropositive (177). 

The answer is e. (Murray, pp 812-828. Scriver, pp 3-45. Sack, pp 121—144. Wilson, pp 23—98.) Hemophilia A is caused by deficiency of factor VIII and hemophilia B by deficiency of factor IX. Both factors are involved in the intrinsic blood coagulation pathway that results in activation of factor X. Alternatively, factor X can be activated by tissue factors through the extrinsic blood coagulation pathway Activated factors X and V produce thromin from prothrombin, which in turn cleaves fibrinogen to produce fi-... 

The dose of desmopressin for von WiUebrand disease is identical to that used in the treatment of mild factor VIII deficiency, 0.3 mcg/kg diluted in 30 to 50 mL of normal saline and given intravenously over 15 to 30 minutes. In general, patients with von WiUebrand disease have a better response to desmopressin than those with hemophilia, with an average three- to fivefold rise in von WiUebrand factor and factor VIII levels. These levels remain elevated for about 6 to 8 hours. The response to desmopressin in a given patient is usuaUy consistent, and a trial of desmopressin should establish if the medication is likely to be effective for the individual. Desmopressin is preferable to the use of plasma-derived products for patients who have an adequate response because desmopressin does not carry a risk of viral transmission. An added benefit is that desmopressin is substantiaUy less costly than the plasma-derived products. (For a discussion of the side effects of desmopressin, see the section on the treatment of hemophUia A.)... 

Clinically, disorders of Factor VIII are the most common inherited abnormalities of hemostasis. Classical hemophilia A, Factor VIII deficiency, occurs in approximately 1 out of 20,000 live births in the United States. 

Factor IX complex, a blood derivative with hemostatic properties, is used in factor IX deficiency (hemophilia B or Christmas disease) in patients with factor VIII inhibition, in factor VII deficiency, and in overdosage with anticoagulant (see also Tables 17 and 18 and Figure 92). 

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. 

The pathophysiology of hemophilia is based on the factor VIII or IX deficiency resulting in inadequate thrombin generation and an impaired intrinsic-pathway coagulation cascade (see... 

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... 

Clinical pharmacology Activated factor IX in combination with activated factor VIII activates factor X. This results ultimately in the conversion of prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, and a clot can be formed. Factor IX is the specific clotting factor deficient in patients with hemophilia B and in patients with acquired factor IX deficiencies. The administration of Coagulation Factor IX (Recombinant) increases plasma levels of factor IX and can temporarily correct the coagulation defect in these patients. 

Indications Treatment of classical hemophilia (hemophilia A) in which there is a demonstrated deficiency of activity of the plasma clotting factor, factor VIII... 

VIII Hemophilia A 30-50% 100% for major bleeding or trauma 12 hours Recombinant factor VIII products Plasma-derived high purity concentrates Cryoprecipitate1 Some patients with mild deficiency will respond to DDAVP... 

Congenital deficiency of Factor IX results in hemophilia B, also known as Christmas disease, and is inherited in a sex-linked recessive manner. Instructive is the fact that some female carriers are symptomatic. Combined deficiencies of Factors VIII C and IX have been described. 

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