IntroductionHemophilia 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 hemophiliahave 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 historyHemophilia 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 laterdeveloped 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 ofthe 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 isalso 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, thedisorder will be present. Whether or not a child will have hemophilia or be a carrier forthe disorder depends on the status of the mother and of the father. The figure belowshows how this type of disorder is inherited. Males have an X chromosome and an Y chromosome.
The X chromosome comes fromthe mother and the Y chromosome comes from the father. If the mother has adefective gene, the son’s chance of having hemophilia is 50%, depending on which Xchromosome is inherited. A son cannot inherit the disorder from his father, even if thefather has hemophilia. Females have two X chromosomes. One X chromosome comes from the mother andone 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 theiroffspring. The daughter also has a 50% chance of becoming a carrier if the mother is acarrier, depending on which X chromosome is inherited. In most cases, one of the daughter’s two X chromosomes is normal. Most femaleswith a gene for hemophilia do not have symptoms of the disorder because a normalgene 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 willhave low factor levels. When factor levels are low, the female can show symptoms ofhemophilia such as excessive menstrual bleeding and excessive bleeding afterchildbirth, surgery and dental work.
Hemophilia occurs in about 1 of every 7,500 males. Of these, about 90% of cases areFactor 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 clotwhen it should, patients experience frequent and excessive bleeding.
The degree towhich bleeding occurs depends in part on the severity of the disorder. Patients canhave severe, moderate or mild hemophilia. A hallmark of severe hemophilia is spontaneous bleeding. In these cases, bleedingoccurs 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 andspine. Spontaneous bleeds are most common in the knees, ankles, elbows andshoulders. Repeated bleeding into the joints is called hemarthrosis. Hemarthrosis usually begins after the child begins to walk. As the bleeding begins, theperson may experience a warmth or tingling in the joint.
As bleeding progresses, thereis usually a feeling of stiffness, fullness, and pain. The joint swells and may be warmand 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 afterinjections 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 withone exception.
Spontaneous bleeding is rare in moderate hemophilia. When bleedingoccurs, 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 thedisorder. Many patients with mild hemophilia may not realize they have the disorderuntil bleeding occurs due to a major event such as an accident or surgery.
The difference between symptoms for Factor VIII Deficiency (Hemophilia A) and FactorIX Deficiency (Hemophilia B) is the degree of severity. Symptoms are often milder forFactor IX Deficiency, due in part to the severity of the disorder. Severe Factor IXDeficiency is less common. Many patients with Factor IX deficiency do not havesymptoms until stressed by surgery or trauma. The goal of treatment for hemophilia is to prevent and/or reduce the frequency ofsymptoms.
Increasing factor levels to at least 5% of normal can cause symptoms ofsevere hemophilia to improve to the level of moderate or even mild hemophilia. This canbe achieved with regular preventive infusions of factor. More recent advances in hemophiliaThe most significant advances in hemophilia treatment have been made in the last four decades. BaxterHealthcare Corporation introduced the first commercially available plasma-derived factor concentrate inthe mid-1960s.
This was a major advancement over earlier formulations, which contained much lowerconcentrations of antihemophilic factor. In the early 1970s, home treatment of hemophilia becamewidely 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 factorVIII 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 theamount present is too low for normal clotting to occur. Factor VIII is missing or too lowin about 90% of hemophilia cases. Factor IX is deficient in about 9% of cases.
FactorXI, 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 walloccurs. Platelets begin collecting at the damaged site. As more platelets collect, aplug 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 andbleeding 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 acascade or stepwise fashion with the product in one step acting as the trigger for thenext step. These pathways are diagramed below.
The first pathway (extrinsic system) is triggered when damage causes a substancecalled tissue thromboplastin to be released from the tissue. The second pathway(intrinsic system) is triggered when the blood comes into contact with the blood vesselwall. 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 casesof hemophilia, the defective gene is passed from parent to child. In cases where thereis no family history of the disorder, hemophilia occurs due to a change or mutation ofthe gene. In such cases, the mutation may only be discovered after the birth of a sonwith hemophilia.
How is Hemophilia Diagnosed?The diagnosis of hemophilia is made through a series of tests on a sample of thepatient’s blood. The pattern of positive and negative results from different tests willdiagnose the presence of hemophilia as well as the type. The tests listed below areused to diagnose hemophilia. Platelet count: This test counts the number of blood platelets. This test is normal forpatients with hemophilia. Activated partial thromboplastin time (APTT): This test diagnoses problems withFactor VIII and Factor IX.
Almost 100% of patients with severe and moderate FactorVIII deficiency can be diagnosed with an APTT. Diagnosis of mild cases variesdepending on the type of materials used in testing the blood sample. Most carrierscannot be diagnosed with an APTT. The test measures the length of time that it takesfor a blood clot to form.
The activated partial thromboplastin time is longer than normalfor 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 factorassay 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 resultfor Factor IX deficiency. Adding normal plasma to the patient’s serum will correct theabnormal APTT test result for Factor VIII deficiency. How Blood ClotsTo 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 FactorAnitemophilic 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 tahn 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 RateClotting 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 untill 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.Words/ Pages : 2,242 / 24
