What is hemophilia?
Hemophilia is an inherited bleeding disorder in which one of the 13 clotting proteins, or “factors,” is missing or defective. These 13 proteins, distinguished by Roman numerals, act in sequence to form a clot that stops bleeding. People with hemophilia bleed longer but not more quickly or profusely. Small cuts or bruises usually do not cause problems, although surgeries and other injuries can cause significant bleeding. People new to interacting with persons with hemophilia need to know that they will not bleed to death from minor injuries.
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The best-known factor disorders, factor VIIl (8) and factor IX (9), are almost entirely seen in males. Factor VIII deficiency is also referred to as hemophilia A or Classic hemophilia. Factor IX deficiency is also called hemophilia B or Christmas disease for the family in which it as first identified.
About 1 in 5,000 live male births have hemophilia A. Hemophilia B occurs in about 1 in 10,000 births. One of these two affects about 400,000 persons world wide, only rarely women. About 98 persons active at West Virginia Hemophilia Treatment Centers have hemophilia A and 40 have hemophilia B.
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- Why do these disorders show up almost entirely in men?
Humans have 23 pairs of chromosomes, 22 autosomal pairs and a pair of sex chromosomes named “X” and “Y.” The genes for these disorders are carried on X-chromosomes. Females have two X-chromosomes while males have only one. A Y-chromosome replaces the other X and, in fact, makes him a male.
A woman who has a defective VIII or IX gene on one of her X’s is called a “carrier.” Because the normal gene provides a safeguard, she may not have bleeding problems. With each pregnancy, there is a 1 in 2 (or 50%) chance that she will pass the deficient gene to a child. When that happens, her daughter will become a carrier, but her son will have hemophilia. Carrier daughters have the same 50% risk of passing along the defective gene.
When a son with hemophilia fathers children, his children’s risks are different. None of his sons will have hemophilia because they receive only their father’s unaffected Y’s. However, all daughters will be carriers because they can only receive their father’s affected X.
About one third of those affected have no family history of hemophilia—the defect in the X chromosome happened spontaneously. Those rare women born with hemophilia A or B usually have mothers who are carriers and fathers who have hemophilia.
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How are the other bleeding disorders different?
Genes for other clotting proteins are located on autosomal chromosomes so men and women have an equal chance of having bleeding problems associated with defects in these proteins.
Recently, von Willebrand Disease (VWD) has been determined to be the most common of all the bleeding disorders, affecting over 2 million in the US. In most cases, VWD is mild and often goes unrecognized. About 99 West Virginians with VWD are seen at our Treatment Centers. Some of these disorders are more common in certain ethnic groups. Other factor deficiencies are quite rare with only about 1200 identified in the US. Most of them have limited or no treatment options.
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What are the symptoms of bleeding disorders?
Bleeding problems are recognized after surgery, non-routine dental work (not check-ups and cleaning), or serious injury. For those with mild hemophilia (factor level 5-50% of normal) these may be the only way people find out they have a disorder.
On the other hand, men “severely” affected (factor VIII or IX levels less than 1% of normal) stand out, usually after being circumcised. Intracranial bleeding, not necessarily linked to head injuries, can begin within the first month and pose significant risks if not treated. Mouth, nose and other soft tissue bleeds also are typical during the first year. Once children begin actively exploring their surroundings, bumps and falls may cause bleeding into joints and muscles. Most commonly elbows, knees, and ankles become painful, swollen and immobile. Bleeding also occurs spontaneously—sometimes in one’s sleep. Several days may be required to return to normal activities without bleeding starting again.
Those with moderate factor levels (2-4%) usually do not experience frequent or spontaneous bleeding. They may consider a bleed just a minor problem that will go away. Bleeds that are not fully treated then can lead to a life-threatening situation or permanent damage. A damaged joint that becomes a target of frequent bleeds can come to resemble one of a “severe” person.
VWD bleeding patterns are different. Bleeds more often involve the mucous membranes, especially of the nose, mouth, gastro-intestinal and genitor-urinary tracts. Heavy bruising is another sign. Additionally, in women heavy menstrual flow and prolonged bleeding after delivery signal the possibility of VWD.
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What should women with bleeding disorders know?
Bleeding of the vaginal tract is of prime concern to women with bleeding disorders who must deal with it on a monthly basis. Interestingly, girls who grow up in a family where women with bleeding disorders are common do not realize their period’s length or flow is heavier than normal.
The first clear symptom often is a heavy flow at the first period. Of women treated at ERs for heavy periods, 20 % will have VWD. Some may experience bleeding between their cycles or throughout the month. Unfortunately, the cause is frequently diagnosed as a gynecological, not a bleeding, problem. Many hysterectomies performed to treat severe bleeding are unnecessary when bleeding disorders are the underlying cause and treatment options exist.
A study of over 16,824,00 births in the US from 2000 through 2003 showed that women with bleeding disorders had 10 times the normal risk for bleeding before or during pregnancy (ante-partum).This ante-partum bleeding increased the risk for premature delivery or stillborn death. However, bleeding disorders were not linked to increased risk for preterm labor or fetal deaths. Affected women’s risk for post–partum bleeding was five times the normal risk. Risk for maternal death also increased, working out to about 1 in 1000, but that rate is considered very low.
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How is hemophilia treated?
Bleeding is stopped by injecting a dose of the missing factor into the affected person’s vein. This approach is called “on demand” or “replacement therapy,” although replacement is not permanent. For example, about half of the factor VIII given will be used up in 8-12 hours requiring more doses to stop a severe bleed. Family members or the person himself can be taught to administer factor. Dosing is based on body weight (kg.) and the desired factor level to be reached.
Hemophilia doctors now recommend infusing factor 2 to 3 times a week on a regular schedule (“prophylactic therapy”) for those with severe hemophilia A and B. This treatment can start very early in life and effectively prevent joint bleeds and permanent damage. One drawback to this approach is the higher cost of factor because more is used. On the other hand, ankle, knee and hip surgeries required to correct joint damage are not cheap.
Different types and severities characterize VWD. These variations determine therapy used. A synthetic product, DDAVP, or certain factor VIII blood products are used to treat prolonged or severe bleeding.
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How safe are factor concentrates?
Introduced in mid-1960, factors packaged in freeze-dried, concentrated form were the first effective way to treat Factor VIII, IX and severe VWD. Previous treatment, which relied on whole blood or fresh frozen plasma, was inadequate. There would be too much fluid for the body to absorb if the necessary dose was given.
To make factor concentrates, manufacturers pooled blood donations of thousands of people. Concentrates delivered a great deal of foreign protein in each treatment and some recipients had life threatening allergic responses. Worse, these early concentrates contained viruses causing hepatitis B, C and, later, HIV to users. In the US, HIV infected nearly 90% of those with severe hemophilia.
Improved donor screening procedures and new tests for infectious agents have made the US blood supply safer than ever. A certification for facilities that collect plasma requires the screening of potential donors for drug use and other high-risk behaviors. Only community donors who pass two physical and two laboratory screenings are considered “qualified” donors.
Manufacturers of factor concentrates have different certification requirements. Only donations from qualified donors can be accepted. Such donations must be held for 60 days and discarded if its donor tests positive for a blood-borne virus. New techniques that detect viruses before the donor has symptoms or develops antibodies must be applied to identify donations that passed initials tests. All plasma collected for processing must meet certain viral marker standards. Measures to decrease viral load and destroy or deactivate infectious agents that may have escaped plasma screening also have been incorporated in the manufacturing process.
The most recent developments in eliminating viral contamination has been the genetic engineering of factor concentrates that have little to no human plasma or animal proteins in the finished product. These products are referred to as “recombinant” concentrates and are available for factors VIII, IX, and VII (7). At present, there is no recombinant product for treating VWD although research is under way to develop one.
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