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Hemophilia
Hemophilia
Hemophilia is a rare genetic blood clotting disorder that primarily affects males. People living with hemophilia do not have enough of, or are missing, one of the blood clotting proteins naturally found in blood. Two of the most common forms of hemophilia are A and B. In persons with hemophilia A (also called classic hemophilia), clotting factor VIII is not present in sufficient amounts or is absent. In persons with hemophilia B (also called Christmas disease), clotting factor IX is not present in sufficient amounts or is absent. People with hemophilia do not bleed more profusely or bleed faster than normal; they bleed for a longer period of time.



Virtually all people who have hemophilia A or B are born with it. The majority of people with hemophilia

have a family history (it is a hereditary disorder).



In as many as 30% of cases, there is no family history of hemophilia. In these cases, the mother may not be aware that she carries the gene for hemophilia, or a gene mutation may have occurred spontaneously.



A long history



Hemophilia was identified as early as biblical times. Doctors in medieval times were familiar with it as well. In 1803, a Philadelphia doctor published the first description of hemophilia in the United States.

But it was not until 30 years later that hemophilia became widely recognized. Hemophilia later

developed a reputation as the "royal disease" because it passed from Queen Victoria of England to her descendants throughout the royal houses of Europe.



Who Gets Hemophilia?



Hemophilia occurs when the gene to produce clotting factor does not work correctly.

Without the proper amount of clotting factor, bleeding occurs easily.

Hemophilia is an inherited disorder in about two thirds of the cases. About one third of

the cases of hemophilia occur due to spontaneous changes in the gene or mutations.

The presence of a mutated gene may not be noted until a woman with no family

history of hemophilia has a son with the disorder.



The gene for hemophilia is carried on the X chromosome. The gene for hemophilia is

also recessive. This is why hemophilia is referred to as an X-linked recessive disorder.

If there is not a normal gene present to offset the defective, recessive gene, the

disorder will be present. Whether or not a child will have hemophilia or be a carrier for

the disorder depends on the status of the mother and of the father. The figure below

shows how this type of disorder is inherited.



Males have an X chromosome and an Y chromosome. The X chromosome comes from

the mother and the Y chromosome comes from the father. If the mother has a

defective gene, the son's chance of having hemophilia is 50%, depending on which X

chromosome is inherited. A son cannot inherit the disorder from his father, even if the

father has hemophilia.



Females have two X chromosomes. One X chromosome comes from the mother and

one comes from the father. All daughters of men with hemophilia will be carriers.

Carriers rarely have the disorder but are able to pass the defective gene to their

offspring. The daughter also has a 50% chance of becoming a carrier if the mother is a

carrier, depending on which X chromosome is inherited.



In most cases, one of the daughter's two X chromosomes is normal. Most females

with a gene for hemophilia do not have symptoms of the disorder because a normal

gene offsets any problems caused by the one that is defective. In some cases,

however, the normal gene cannot offset the problem completely and the female will

have low factor levels. When factor levels are low, the female can show symptoms of

hemophilia such as excessive menstrual bleeding and excessive bleeding after

childbirth, surgery and dental work.



Hemophilia occurs in about 1 of every 7,500 males. Of these, about 90% of cases are

Factor VIII Deficiency (Hemophilia A) and 9% are Factor IX Deficiency (Hemophilia B).

About 1% of hemophilia cases is due to deficiencies of Factor XI, X, VII or V.



What are the Symptoms of Hemophilia?



Hemophilia is a disorder of the blood clotting system. Because blood does not clot

when it should, patients experience frequent and excessive bleeding. The degree to

which bleeding occurs depends in part on the severity of the disorder. Patients can

have severe, moderate or mild hemophilia.



A hallmark of severe hemophilia is spontaneous bleeding. In these cases, bleeding

occurs without any recognizable trauma. Bleeding can occur in any part of the body.

However, spontaneous bleeds are unusual in the joints of the fingers, wrists, feet and

spine. Spontaneous bleeds are most common in the knees, ankles, elbows and

shoulders. Repeated bleeding into the joints is called hemarthrosis.



Hemarthrosis usually begins after the child begins to walk. As the bleeding begins, the

person may experience a warmth or tingling in the joint. As bleeding progresses, there

is usually a feeling of stiffness, fullness, and pain. The joint swells and may be warm

and tender. Bleeding into the joint limits the ability to move the joint. If not treated,

hemarthrosis can cause chronic joint problems.



Severe hemophilia can cause bleeding from circumcision. Bruising often occurs after

injections in infants. As the child becomes more active, excessive bruising occurs.

Excessive bleeding also occurs when teeth are pulled or other trauma occurs.



Symptoms of moderate hemophilia are the same as those for severe hemophilia with

one exception. Spontaneous bleeding is rare in moderate hemophilia. When bleeding

occurs, the person is usually able to identify some trauma that caused the event.



Patients with mild hemophilia have excessive bleeding with severe trauma or surgery.

However, these patients may not experience any other problems or symptoms of the

disorder. Many patients with mild hemophilia may not realize they have the disorder

until bleeding occurs due to a major event such as an accident or surgery.



The difference between symptoms for Factor VIII Deficiency (Hemophilia A) and Factor

IX Deficiency (Hemophilia B) is the degree of severity. Symptoms are often milder for

Factor IX Deficiency, due in part to the severity of the disorder. Severe Factor IX

Deficiency is less common. Many patients with Factor IX deficiency do not have

symptoms until stressed by surgery or trauma.



The goal of treatment for hemophilia is to prevent and/or reduce the frequency of

symptoms. Increasing factor levels to at least 5% of normal can cause symptoms of

severe hemophilia to improve to the level of moderate or even mild hemophilia. This can

be achieved with regular preventive infusions of factor.



More recent advances in hemophilia



The most significant advances in hemophilia treatment have been made in the last four decades. Baxter

Healthcare Corporation introduced the first commercially available plasma-derived factor concentrate in

the mid-1960s. This was a major advancement over earlier formulations, which contained much lower

concentrations of antihemophilic factor. In the early 1970s, home treatment of hemophilia became

widely available, offering people with hemophilia greater independence and reduced hospital stays. Today, recombinant DNA technology and the discovery of the genes that control production of factor

VIII have led to the development of recombinant factor concentrates that do not rely on plasma at all.



What is the Cause of Hemophilia?



Hemophilia occurs when one of the factors needed for blood to clot is missing or the

amount present is too low for normal clotting to occur. Factor VIII is missing or too low

in about 90% of hemophilia cases. Factor IX is deficient in about 9% of cases. Factor

XI, X, VII or V is missing or too low in the remaining 1% of hemophilia cases.



The process of blood clotting starts the moment damage to the blood vessel wall

occurs. Platelets begin collecting at the damaged site. As more platelets collect, a

plug forms in the hole to stop bleeding. Although the platelet plug can hold for a while,

without a "glue" to permanently hold the platelets together, the plug breaks apart and

bleeding begins again. The "glue" that holds the plug together is called fibrin.



Fibrin is the end product of two blood clotting pathways. Each pathway proceeds in a

cascade or stepwise fashion with the product in one step acting as the trigger for the

next step. These pathways are diagramed below.



The first pathway (extrinsic system) is triggered when damage causes a substance

called tissue thromboplastin to be released from the tissue. The second pathway

(intrinsic system) is triggered when the blood comes into contact with the blood vessel

wall. The steps that lead to the formation of fibrin requires factors VIII and IX.



The body produces the different clotting factors based on the instructions from a gene.

In hemophilia, the gene that causes factor to be produced is defective. In most cases

of hemophilia, the defective gene is passed from parent to child. In cases where there

is no family history of the disorder, hemophilia occurs due to a change or mutation of

the gene. In such cases, the mutation may only be discovered after the birth of a son

with hemophilia.



How is Hemophilia Diagnosed?



The diagnosis of hemophilia is made through a series of tests on a sample of the

patient's blood. The pattern of positive and negative results from different tests will

diagnose the presence of hemophilia as well as the type. The tests listed below are

used to diagnose hemophilia.



Platelet count: This test counts the number of blood platelets. This test is normal for

patients with hemophilia.



Activated partial thromboplastin time (APTT): This test diagnoses problems with

Factor VIII and Factor IX. Almost 100% of patients with severe and moderate Factor

VIII deficiency can be diagnosed with an APTT. Diagnosis of mild cases varies

depending on the type of materials used in testing the blood sample. Most carriers

cannot be diagnosed with an APTT. The test measures the length of time that it takes

for a blood clot to form. The activated partial thromboplastin time is longer than normal

for patients with Factor VIII Deficiency (Hemophilia A) and Factor IX Deficiency

(Hemophilia B).



Factor assay: This is the most exact test to diagnose the type of hemophilia. A factor

assay can distinguish between a Factor VIII deficiency and a Factor IX deficiency.

Adding normal serum to the patient's serum will correct the abnormal APTT test result

for Factor IX deficiency. Adding normal plasma to the patient's serum will correct the

abnormal APTT test result for Factor VIII deficiency.



How Blood Clots



To understand inhibitors, it helps to know how blood normally clots. When blood starts to flow out of a damaged blood vessel, the process is called coagulation. Coagulation is the body's way of sealing a leak. The seal, or clot, consists of red and white blood cells and platelets, which cling to threadlike material called fibrin. Tweleve clotting factors must work in sequence to produce wnough fibrin to make a strong clot.



The coagulation process can be compared to a domino effect(figure 1) . Each clotting factor in the blood must activate the next one in the series in order to form a clot. When there is an insufficient amount of any one of these cloting factors, the process stops permatuerly, interrupting the production of fibrin. In most people with Hemophilia, replacement clotting factor can compensate for the deficient clotting factor, enabling the clotting process to continue. For people with inhibitors, replacement factor may be inactivated befor it ahs a chance to work.





Antihemophilic Factor



Anitemophilic factor (human) Method M monoclonal purified monarc-M is a sterile, nonpyogenic, dried preparation of anti hemophilic factor( factorVIII, factorVIII:C AHF) in concentrated form with a specific activity rang of 2 to 15 AHF international units/mg of total protein. When reconstituted with the appropriate volume of diluent, it contains approximatly 12.5 mg/ml Albumin(human), 1.5 mg/ml polythylene glyo; (3350), 0.055 M histidine and 0.03 M glycine as stabilizing agents. In the absencs of the addes Albumin(human), the specific activity is approximately 2,000 AHF internationsl Units/mg of proteain. It also contains, per AHF international Units, not more than
0.1 ng mouse protein, 18 ng organic solvent (tri-n-butyl phosphate) and 50 ng detergent (octoxynol 9)



Monarc-M is perpared by the method M process from pooled human plasma by immunoaffinity chromatography utilizing a murine monoclonal antibody to factor VIII:C, flollowed by an ion exchane chromatographc step for further purification. Monarc-M also includesan organic solvent (tri-n-butyl phosphate) and detergent (octoxynol 9) virus inactivation step designed to reduce the risck of transmiting of hepatitis and other viral disases. However, no procedure has been shown to be totally effictive in removing the viral infectivity fron coagulation factor products.



Monarc-M can ONLY be administered intravenosly and takes approxmiatly 12-14 hours befor the factor begins to work and the cloting factor in the blood is brought up. After 24-28 hours after that the factor is wiped out of the blood, befor this time the Factor is leaving the blood it is at this time that ALL of the factor is gone, and the person rezooms there blood cloting factor in there blood.



Factor Survivla Rate



Clotting factor normally circulaes at constant levels in the blood and only works when an injury occurs. Whne clotting factor replacmnet is given with factor concentrate, fresh frozen Plasma or cryoperecipitate, the factor only survives for a short time. It's different for every Hemophiliac. Your hemotologist can find out by doing a test called a factor Survivlal or Recovery. For factor VIII, Half of the dose given will be used up in 4 Hours, in another 8, it will again be reduced by half and so on until
it is all used up. Factor IX, given as plasma or factor IX concentrate, usually last a littal longer.



Factor survival studies are not usually needed for everyday treatment, but befor major surgery we ofen ike patients to be tested. Blood samples are draw befor and after the administration of the clotting factor. this helps us decide on the dose of factore necessary for control of bleeding following surgery.

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