What is hemophilia?

Causes and Symptoms

Thecirculatory system must be self-healing; otherwise, continued blood loss from even the smallest injury would be life-threatening. Normally, all except the most catastrophic bleeding is rapidly stopped in a process known as hemostasis. Hemostasis takes place through several sequential steps or processes. First, an injury stimulates platelets (unpigmented blood cells) to adhere to the damaged blood vessels and then to one another, forming a plug that can stop minor bleeding. This association is mediated by what is called the von Willebrand factor, a protein that binds to the platelets. As the platelets aggregate, they release several substances that stimulate vasoconstriction, or a reduction in size of the blood vessels. This reduces the blood flow at the injury site. Finally, the aggregating platelets and damaged tissue initiate blood clotting, or coagulation. Once bleeding has stopped, the firmly adhering clot slowly contracts, drawing the edge of the wounds together so that tough scar tissue can form a permanent repair on the site.

Formation of a blood clot involves the participation of nearly twenty different substances, most of which are proteins synthesized by plasma. All but two of these substances, or factors, are designated by a roman numeral and a common name. A blood clot will be defective if one of the clotting factors is absent or deficient in the blood, and clotting time will be longer. The clotting factors, with some of their alternative names, are factor I (fibrinogen), factor II (prothrombin), factor III (tissue factor or thromboplastin), factor IV (calcium), factor V (proaccelerin), factor VII (proconvertin), factor VIII (antihemophilic factor), factor IX (Christmas factor), factor X (Stuart factor), factor XI (plasma thromboplastin antecedent), factor XII (Hageman factor), and factor XIII (fibrin stabilizing factor).

Several of the clotting factors have been discovered by the diagnosis of their deficiencies in various clotting disorders. The inherited coagulation disorders are uncommon conditions with an overall incidence of probably no more than 10 to 20 per 100,000 of the population. Hemophilia A, the most common or classic type of coagulation disorder, is caused by factor VIII deficiency. Hemophilia B (or Christmas disease) is the result of factor IX deficiency. It is quite common for severe hemophilia to manifest itself during the first year of life. Hazardous bleeding occurs in areas such as the central nervous system, the retropharyngeal area, and the retroperitoneal area. Bleeding in these areas requires admission to the hospital for observation and therapy. Joint lesions are very common in hemophilia because of acute spontaneous hemorrhage in the area, especially in weight-bearing joints such as ankles and knees. Urinary bleeding is often present at some time. The appearance of pseudotumors, caused by swelling involving muscle and bone produced by recurrent bleeding, is also common.

Hemophilia is transmitted entirely by unaffected women (carriers) to their sons in a sex-linked inheritance deficiency. Congenital deficiencies of the other coagulation factors are well recognized, even though bleeding episodes in these cases are uncommon. Deficiency of more than one factor is also possible, although documentation of such cases is rare, perhaps because only patients with milder variations of the disease survive.

Von Willebrand’s disease, unlike the hemophilias that mainly involve bleeding in joints and muscles, involves mainly bleeding of mucocutaneous tissues or skin. It affects both men and women. This disease shares clinical characteristics with hemophilia A, or classic hemophilia, including decreased levels of clotting factor VIII. This similarity made the differentiation between the two diseases very difficult for a long time. It has been established that there are two different factors involved in von Willebrand’s disease, each with a different function. The von Willebrand factor is involved in the adhesion of platelets to the injured blood vessel wall and to one another and, together with factor VIII, circulates in plasma as a complex held by electrostatic and hydrophobic forces. The von Willebrand factor is a very large molecule, consisting of a series of possible multimeric structures. The bigger and heavier the multimer, the better it works against bleeding. Von Willebrand’s disease is one of the least understood clotting disorders. Three types have been identified, with at least twenty-seven variations. With type I, all the multimers needed for successful clotting are present in the blood, but in lesser amounts than in healthy individuals. In type II, the larger multimers, which are more active in hemostasis, are lacking, and type III patients exhibit a severe lack of all multimers.

Treatment and Therapy

The normal body is continually producing clotting factors in order to keep up with natural loss. Sometimes the production is stepped up to cover a real or anticipated increase in the need for these factors, such as in childbirth. Hemophiliacs, lacking some of these clotting factors, may lose large amounts of blood from even the smallest injury and sometimes hemorrhage without any apparent cause. The symptoms of their diseases may be alleviated by the intravenous administration of the deficient clotting factor. How this is done depends on the specific factor deficiency and the magnitude of the bleeding episode, the age and size of the patient, convenience, acceptability, cost of product, and method and place of delivery of care.

There are many sources for clotting factors. Fresh frozen plasma contains all the clotting factors, but since the concentration of the factors in plasma is relatively low, a large volume is required for treatment. Therefore, it can be used only when small amounts of clotting factor must be delivered. Its use is the only therapy for deficiencies of factors V, XI, and XII. Plasma is commonly harvested from single donor units to minimize the risk of infection by the
hepatitis virus or
Human immunodeficiency virus (HIV), thus eliminating the risk involved in using pooled concentrates from many donors. Cryoprecipitates are the proteins that precipitate in fresh frozen plasma thawed at 4 degrees Celsius. The precipitate is rich in factors VIII and XIII and in fibrinogen, and carries less chance of infection with hepatitis. Its standardization is difficult, however, and is not required by the Food and Drug Administration. As a result, dosage calculation can be a problem. In addition, there is no method for the control of viral contamination. Therefore, cryoprecipitates are not commonly used unless harvested from a special known and tested donor pool. Clotting factor concentrates present many advantages. They are made from pooled plasma obtained from plasmapheresis or a program of total donor unit fractionation and are widely available. Factors VIII and IX can also be produced from plasma using monoclonal methods. Porcine factor VIII presents an alternative to patients with a naturally occurring antibody to human factor VIII.

Other substances can replace missing clotting factors as well. The synthetic hormone desmopressin acetate (also known by the letters DDAVP) has been used to stimulate the release of factor VIII and von Willebrand factor from the endothelial cells lining blood vessels. It is commonly used for patients with mild hemophilia and von Willebrand’s disease. DDAVP has no effect on the concentration of the other factors, and aside from the common side effect of water retention, it is a safe drug. Antifibrinolytic drugs prevent the natural breakdown of blood clots that have already been formed. Although such drugs are not useful for the primary care of hemophiliacs, they are useful for use after dental extractions and in the treatment of other open wounds, after a clot has formed.

Between 10 and 15 percent of the patients affected with severe hemophilia develop factor VIII inhibitors (antibodies), which prevents their treatment with the usual methods. Newer therapeutic approaches have provided additional options for the management and control of bleeding episodes. The use of prothrombin complex concentrates or porcine factor VIII concentrates is indicated for low responders (those with a low amount of antibodies present in their system). An option for high responders is to try to eradicate the inhibitor present in their systems. One way to do this is with a regimen of immunosuppressive drugs. These are very limited in value, however, and cannot be used with HIV-positive hemophiliacs. The drugs used in this approach include substances such as cyclophosphamide, vincristine, azathioprine, and corticosteroids. Another approach utilizes intravenous doses of gamma globulin to suppress, but not eradicate, the inhibitors. Yet another strategy is an immune tolerance regimen, in which factor VIII is administered daily in small amounts. This method causes the inhibitors to decrease and, in some cases, disappear. The regimen can also involve the prophylactic use of factor VIII (or factor VIII in combination with immunosuppressive drugs).

The introduction of plasma clotting factor concentrates has changed the treatment of patients with clotting factor deficiencies. It has brought about a remarkable change in the longevity of these patients and their quality of life. The availability of cryoprecipitates and concentrates of factors II, VII, VIII, IX, X, and XIII has made outpatient treatment for bleeding episodes routine and home infusion or self-infusion a possibility for many patients. Hospitalization for inpatient treatment is rare, and early outpatient therapy of bleeding episodes has decreased the severity of joint deformities.

Nevertheless, other problems are apparent in hemophiliac patients. Viral contamination of the factor concentrates has allowed the development of chronic illnesses, infection with HIV, immunologic diseases, liver and renal diseases, joint disorders, and cardiovascular diseases. While the use of heat for virus inactivation, beginning in 1983, resulted in a reduction in HIV infections, the majority of patients exposed to the virus had already been infected. The strategies to prevent contraction of hepatitis from these concentrates include vaccination against the contaminating viruses and the elimination of viruses from the factor replacement product. The non-A, non-B hepatitis virus is difficult to remove, however, and the use of monoclonal factors seems to be the only solution to this problem. In general, difficulties associated with treatment have been largely eliminated through the production of the required clotting factors using recombinant DNA techniques, a process performed independent of human blood.

Treatment of von Willebrand’s disease also includes pressure dressing, suturing, and oral contraceptives. A pasteurized antihemophiliac concentrate that contains substantial amounts of von Willebrand factor is used in severe cases.

Hematomas
, or hemorrhages under the skin and within muscles, can frequently be controlled by application of elastic bandage pressure and ice. The ones that cannot be controlled easily within a few hours may cause muscle contraction and require factor replacement therapy. Exercise is recommended for joints after bleeding, as it helps protect joints by increasing muscle bulk and power and can also help relieve stress. Devices to protect joints, such as elastic bandages and splints, are commonly used. In extreme cases, orthopedic surgical procedures are readily available.

Analgesics, or painkillers, play an important part in the alleviation of chronic pain. Because patients cannot use products with aspirin and/or antihistamines, which inhibit platelet aggregation and prolong bleeding time, substances such as acetaminophen, codeine, and morphine are used. Chronic joint inflammation is reduced by the use of anti-inflammatory agents such as ibuprofen and drugs used with rheumatoid arthritis patients.

The need for so many specialties and disciplines in the management of hemophilia has led to the development of multidisciplinary hemophilia centers. Genetic education (information on how the disease is transmitted), genetic counseling (the discussion of an individual’s genetic risks and reproductive options), and genetic testing have provided great help to patients and affected families. Early and prenatal diagnosis and carrier detection have provided options for family planning.

Perspective and Prospects

Descriptions of hemophilia are among the oldest known accounts of genetic disease. References to a bleeding condition highly suggestive of hemophilia go back to the fifth century, in the Babylonian Talmud. The first significant report in medical literature appeared in 1803 when John C. Otto, a Philadelphia physician, described several bleeder families with only males affected and with transmission through the mothers. The literature of the nineteenth century contains many descriptions of the disease, particularly the clinical characteristics of the hemorrhages and family histories. The disease was originally called haemorrhaphilia, or “tendency toward hemorrhages,” but the name was later contracted through usage to hemophilia (“tendency toward blood”), the accepted name since around 1828.

Transfusion therapy was proposed as early as 1832, and the first successful transfusion for the treatment of a hemophiliac patient was reported in 1840 by Samuel Armstrong Lane. The use of blood from cows and pigs in the transfusions was explored but abandoned because of the numerous side effects. It was not until the beginning of the twentieth century that serious studies on clotting in hemophilia were started. Attention was directed to the use of normal human serum for treatment of bleeding episodes. Some of the patients responded well, while others did not. This result is probably attributable to the fact that some had hemophilia A—these patients did not respond because factor VIII, in which they are deficient, is not present in serum—while some others had hemophilia B, for which the therapy worked. In 1923, harvested blood plasma was used in transfusion, and it was shown to work as well as whole blood. With blood banking becoming a reality in the 1930s, transfusions were performed more frequently as a treatment for hemophilia.

The history of the fractionation of plasma began around 1911 with a Dr. Addis, who prepared a very crude fraction by acidification of plasma. In 1937, Drs. Patek and Taylor produced a crude fraction which, on injection, lowered the blood-clotting time in hemophiliacs. In the period from 1945 to 1960, a number of plasma fractions with antihemophiliac activity were developed. The use of fresh frozen plasma increased as a result of advances in the purification of the fractions. Some milestones can be identified in the production of the plasma fractions: the development of quantitative assays for antihemophiliac factors, the discovery of cryoprecipitation, and the development of glycine and polyethylene precipitation.

In 1952, four significant and independent publications indicated that there is a plasma-clotting activity separate from that concerned with classic hemophilia—in other words, that there are two types of hemophilia. One (hemophilia A) is characterized by a deficiency in factor VIII, while the other (hemophilia B) is characterized by deficiency in factor IX. Carriers of hemophilia A can have a mean factor VIII level that is 50 percent lower than that of normal females, while carriers of hemophilia B show levels of factor IX that are 60 percent below normal. The two diseases have the same pattern of inheritance, are similar in clinical appearance, and can be distinguished only by laboratory tests.

Hemophilias are caused by a disordered and complex biological mechanism that continues to be explored. Recombinant DNA techniques have now revealed the molecular defect in factor VIII or factor IX deficiencies in some families, demonstrating that a variety of gene defects can produce the classic phenotype of hemophilia. These techniques have also provided new tools for carrier detection and prenatal diagnosis.

Current treatment of hemophilia has converted the hemophiliac from an in-hospital patient to an individual with more independent status. Crucial in this development has been the creation of comprehensive care centers and of the National Hemophilia Foundation, which provide comprehensive treatment for the hemophilia patient. Home treatment with replacement therapy has become common. With the advancement of recombinant DNA technology, the future looks brighter for the sufferers of this disease.

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