Factor VIII Complex vWF polymer
Figure 17.2 Factor VIII complex is controlled by the X chromosome and an autosomal chromosome. This complex transports factor VIII into the circulation. vWF, von Willebrand factor; AHF, antihemophilic factor.
decreased level of clotting factor. Platelet counts are normal and blood vessel function is adequate. Perhaps the most debilitating bleeds are muscle bleeds or joint bleeds, which have the potential for causing long-term disability, reduced range of motion, and intense pain. Joints become painful, swollen, and engorged with blood. Hemarthrosis occurs in the joints as pooled blood damages the surrounding tissue while a clot eventually forms. The joint become less and less mobile, limiting physical activity (Fig. 17.3). Internal hemorrhages into the muscles and deep soft tissues may compress and damage nerves. Intracranial bleeding is a leading cause of death in hemophilia A individuals, and other complications like paralysis, coma, memory loss, or stroke may precede an eventual fatality. Female carriers for the hemophilia gene rarely have symptoms, yet there are occasions when carrier females may become symptomatic. The union of a hemophilia patient and a female carrier would likely produce a symptomatic female.
Laboratory diagnosis of hemophilia patients is fairly uncomplicated. Laboratory tests which are ordered include bleeding time, PT, aPTT, and factor assays. In hemophilia, the bleeding time test is normal, the PT is normal, and aPTT is elevated, due to the reduced factor VIII. Single factor assays provide a means of assessing the percent activity of a clotting factor. These assays are performed using the aPTT test. A standard curve is created using serial dilutions of normal plasma of known factor levels and assigning a 1:10 dilution of normal plasma as 100% activity. Commercially prepared factor deficient plasma is then mixed with a 1:10 dilution of patient plasma and aPTT is performed. An aPTT that is abnormal when mixed with a specific factor-deficient plasma suggests that the patient is missing the same clotting factor as that specific factor-deficient plasma. If the patient and deficient plasma give a normal result, then obviously the patient supplied the factor missing in the factor-deficient plasma. The aPTT result is plotted on the factor-activity curve, and the level of factor activity is derived from the standard curve.
Treatment for Hemophilia A Patients
Treatment options for hemophilia patients span decades and present one of the saddest treatment histories of any patient group with an inherited disorder. Factor VIII was discovered in 1937 and was termed anti-hemophilic globulin.1 In the early days, treatment of hemophilia A patients consisted of giving whole blood units to relieve symptoms. Not until 1957 was it realized that the deficient coagulation protein was a component of the plasma portion of blood. Cryoprecipitate, a plasma derivative, was discovered in 1964. This product is produced as an insoluble precipitate that results when a unit of fresh frozen plasma is thawed in a standard blood bank refrigerator. Cryoprecipitate contains fibrinogen, factor VIII, and vWF. This product is extracted from plasma and usually pooled before it is given to the patient according to weight and level of factor VIII. This product presented a major breakthrough for the hemophilia population because it was an easily transfusable product affording the maximum level of factor to the individual. Next in the chronology of treatment products for hemophilia was clotting factor products. These freeze-dried products were developed in the early 1970s. The products were lyophilized and freeze dried and could be reconstituted and infused at home. This treatment offered the hemophilia population an independence that they had never previously experienced. Finally they were in control because they could self-infuse when necessary and provide themselves with prompt care when a bleeding episode developed. But a dark cloud loomed over the bleeding community. Approximately 80% to 90% of hemophilia A patients treated with factor concentrates became infected with the HIV virus. Factor concentrates were made from pooled plasma from a donor pool that was less than adequately screened. Additionally, manufacturing companies were less than stringent with sterilization methods and screening for HIV virus did not occur in blood banks until 1985. When each of these factors is brought to bear, the tragedy to the bleeding community is easily understood. According to the National Hemophilia Foundation,2 there are 17,000 to 18,000 hemophilia patients (hemophilia A and B) in the United States. Of those, 4200 are infected with HIV/AIDS. There are no numbers available for wives or children who could have been secondarily infected. Recombinant products became available in 1989 and represent the highest purity product because they are not human derived. Recombinant technology uses genetic engineering to insert a clone of the factor VIII gene into mammalian cells, which express the gene characteristic. Production expenses for this product are unfortunately the most costly, and these costs are passed on to potential users.
Having a child with severe hemophilia A or B presents special challenges to the parents and the family unit. The threat of hospitalizations, limited mobility, mainstreaming in schools, and the child's drive for independence present potentially stressful environments. Added to this is the cost of infusible factor, either recombinant or high purity products that could go as high as $50,000 if a patient has several bleeding episodes for which he needs to be hospitalized. Individuals with a chronic condition face many anxieties and may struggle with feelings of isolation, anger, and disappointment (Table 17.1). Fortunately, in the United States, there are hemophilia treatment centers that offer a network of needed services, and many states have local chapters of the National Hemophilia Foundation.2 Prophylaxis with factor concentrates limits bleeding episodes, and the use of magnetic resonance imaging offers the physician a more effective means of evaluating joint damage.3 Issues concerning medical insurance coverage continue to plague the hemophilia community.
The development of factor VIII inhibitors occurs in 15% to 20% of all hemophilia A individuals.4 These inhibitors are autoantibodies against factor VIII that are time and temperature dependent and capable of neutralizing the coagulant portion of factor VIII. Treatment for patients who develop inhibitors is difficult and treatment protocols follow various paths. When the inhibitor is low titer or the individual is a low responder, physicians may infuse an appropriate level of factor VIII in an attempt to neutralize the inhibitor.4 If this is not effective, patients must be treated with a factor sub-
Table 17.1 O Quality of Life Issues for Hemophilia A and B Patients
• Reduced mobility
• Physical restrictions
• Future insurability stitute, usually porcine factor VIII or alternative therapies such as anti-inhibitor coagulant complex.5 Gene therapy, as a treatment alternative, continues to provide hope for those suffering from hemophilia. The idea here is to insert a copy of the factor VIII or factor IX gene into a virus vector that will then lodge in the body and start producing normal amounts of circulating factor. Complications from rejection of the virus vector in humans have proved to be a delicate issue, yet there is optimism that gene therapy for hemophilia patients could eventually succeed.
Individuals with hemophilia B lack factor IX clotting factor. All of the conditions concerning inheritance, clinical symptoms, laboratory diagnosis, and complications are the same for severe hemophilia B individuals as for severe hemophilia A individuals. Hemophilia B accounts for only 10% of those with hemophilia. Patients with hemophilia B will have a prolonged aPTT and will have decreased factor assay activity. Treatment of hemophilia B consists of factor IX concentrates or prothrombin complex that is a mixture of factors II, VII, IX, and X.
Congenital Factor Deficiencies With Bleeding Manifestations
Patients having deficiencies of factors II, V, VII, and X are rare and are usually the result of consanguinity. Most of these disorders are autosomal recessive, affecting both males and females. Types of bleeding that may be observed are skin and mucous membrane bleeding. Joint and knee bleeding is unusual except for factor VII deficient patients. These patients may show joint hemorrhages and epistaxis. In a recent survey of the 225 hemophilia treatment centers in the United States, 7% of patients were identified with having a rare bleeding disorder.6 Of these, factor VII was the most common. Abnormal preoperative screenings led to the diagnosis of most of these patients. When bleeding occurred in one half of these patients, no therapy was necessary.6 Those individuals inheriting these deficiencies het-erozygously tend to have few bleeding manifestations, since they will have one half of factor activity. Treatment of patients with inherited deficiencies of factors II, VII, and X consists of prothrombin complex concentrates. Factor VII clears rapidly from the plasma, and therefore booster doses are usually necessary to maintain clotting. Two new gene mutations, recently discovered, are especially pertinent to this discussion.
A prothrombin, factor II deficiency may occur as a result of a dysfunctional protein or as a result of diminished production of factor II. A structural defect in the protein is termed dysproteinemia and individuals with this particular deficiency may bleed. Additionally, a specific mutation in the prothrombin gene has been recognized since 1996. Located on chromosome 11, a single substitution of guanine to adenine at position 20210 of the prothrombin gene produces prothrombin G20210A. This mutation increases the prothrombin level and predisposes an individual to venous thrombo-sis.7 Individuals should be screened for this mutation if any of the following are part of their patient history: a history of venous thrombosis at any age, venous thrombosis in unusual sites, a history of venous thrombosis during pregnancy, and a first episode of thrombosis before age 50.8
Another mutation recently discovered (1993) is factor V Leiden. This mutation is produced by substituting arginine with glutamine at position 506 of the factor V gene. The new gene product is factor V Leiden. In the normal coagulation scheme, once protein C is activated, it works to inactivate factors V and VIII, to inhibit the clotting mechanism. The mutated gene, factor V Leiden, impedes the degradation of factor V by protein C, causing activated protein C resistance. This condition accounts for increased clot formation with the subsequent development of deep vein thrombosis or other hypercoagulability conditions (see Chapter 19).
Congenital Factor Deficiencies Where Bleeding Is Mild or Absent
In this group of factor deficiencies are those concerned with contact activation and clot stabilization. Factors XI, XII, Fletcher, and Fitzgerald are each synthesized by the liver and are involved early in the coagulation cascade, in vitro. They become responsive when they contact surfaces such as glass in test tubes or ellagic acid in testing reagents. Factor XII deficiency is an autosomal recessive trait where there is a prolonged PTT in laboratory testing. Individuals with this deficiency do not bleed, however, and are more prone to pathologic clot formation. Factor XI deficiency or hemophilia C is an autosomal recessive trait with a high predominance in the Ashkenazi Jewish and Basque population in Southern France. The heterozygous frequency of this gene in this population group is 1:8.9 Bleeding is unlikely, unless trauma or surgery occurs. There is little correlation between the level of factor XI activity and the severity of bleeding episodes. Fletcher factor or prekallikrein deficiency manifests itself as an autosomal dominant and recessive trait. Again patients experience thrombotic events such as myocardial infarction or pulmonary embolism. An interesting feature of this deficiency, in vitro, is that the initially prolonged aPTT will shorten upon prolonged incubation with kaolin reagents. Fitzgerald factor deficiency, also called high-molecular-weight kininogen deficiency, is a rare autosomal recessive trait. Deep vein thrombosis and pulmonary embolism are features of this disorder.10
Factor XIII is unique in that it is a transglutaminase rather than a protease as are most of the other coagulation factors. The role of this factor in coagulation is to provide stabilization to the fibrin clot through cross-linkage of fibrin polymers. Proper levels of factor XIII are essential for proper wound healing, hemostasis, and the maintenance of pregnancy. This factor is not tested for in the traditional coagulation tests such as PT, aPTT, thrombin time, or bleeding time. Therefore, in a patient with factor XIII disorder, the traditional coagulation screening test will be normal. Screening for factor XIII deficiency is accomplished through the 5 mol/L urea test, a primitive test which measures the stability or firmness of the clot after 24 hours in a 5 mol/L urea solution. If factor XIII is decreased, then the clot that is formed is stringy and loose, rather than the firm clot of stable hemostasis. Additionally, quantitative assays for factor XIII are available. Congenital deficiencies of factor XIII are rare autosomal recessive disorders. Deficiencies have been linked to poor wound healing, keloid formation, spontaneous abortion, and recurrent hematomas. Approximately, one half of patients have a family bleeding history, and large keloid scar formation appears to be a consistent finding in these patients.11 Treatment of inherited disorders is through fresh frozen plasma or cryoprecipitate, a source of factor XIII. Acquired deficiencies of this factor may be associated with Crohn's disease, leukemias, DIC, and ulcerative colitis.
Liver disease, renal disease, and autoimmune processes may lead to deficiencies in clotting factors that can cause bleeding. Because almost all of the procoagulants and inhibitors are synthesized by the liver, conditions such as alcoholic cirrhosis, biliary cancer, congenital liver defects, obstructive liver disease, and hepatitis can each negatively affect clotting factor production and clotting factor function. Factors that have a short halflife such as factor VII and the vitamin K-dependent factors (II, VII, IX, and X) are particularly vulnerable. Liver disease brings a myriad of potential problems to coagulation capability. In addition to poor production and function of clotting factors, there is weak clearance of activated clotting factors and the accumulation of plas-minogen activators. If plasmin is activated to a high degree, excessive clot lysis will be stimulated and DIC and hemorrhaging may result. Unexpectedly elevated prothrombin times in a previously well patient may signal the advent of liver disease and the patient should be carefully monitored. Patients with liver disease who are bleeding are treated with fresh frozen plasma, a source of all clotting factors and natural inhibitors. As little as 15 mL of plasma can increase the clotting factor activity by 15% to 25%.12
Renal disease, especially nephrotic syndrome, usually leads to poor renal filtration and the presence of low-molecular-weight coagulation proteins in the urine of about 25% of patients with these disorders. Impaired platelet function is a feature of renal disease, and patients with renal disorders are cautioned against taking aspirin or other platelet inhibitors.
Vitamin K is a fat-soluble vitamin necessary for the activation of factors II, VII, IX, and X. This vitamin is taken in through the diet in the form of green leafy vegetables, fish, and liver. It is also synthesized in small amounts by the intestinal bacteria Bacteroides fragilis and some strains of Escherichia coli. Newborns are usually vitamin K deficient because of the sterile environment of the small intestine, and therefore their levels of factors II, VII, IX, and X are low. Premature infants have levels of vitamin K-dependent factors as low as 20% to 30%.13 As of the 1960s, all newborns are given vitamin K to avoid hemorrhagic disease of the newborn.
The vitamin K-dependent factors are low-molecular-weight proteins, with gamma-carboxyl residues at their terminal ends. To become activated and fully participate in the coagulation scheme, they must take on a second carboxyl group through the action of the enzyme gamma glutamyl carboxylase (Fig. 17.4). This reaction requires vitamin K. Once this reaction is accomplished, these factors can then bind to calcium and then to phospholipids for full participation in coagulation pathways.
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